Revisions were made to the VIREAD (tenofovir disoproxil fumarate) label to include use in chronic hepatitis B pediatric patients ages 2 to < 12 years of age based on Week 48 safety, efficacy and pharmacokinetic data from trial GS-US-174-0144. A summary of the key changes are provided below:
1 INDICATIONS AND USAGE
1.2 Chronic Hepatitis B
VIREAD is indicated for the treatment of chronic hepatitis B virus (HBV) in adults and pediatric patients 2 years of age and older weighing at least 10 kg.
2 DOSAGE AND ADMINISTRATION
The recommended dosage sections were revised to separate tablet dosage from the oral powder formulation dosage for ease of use by the provider, as well as to also highlight that the dose of VIREAD is the same for both HIV and HBV indications. Please refer to the label for current dosing instructions.
6 ADVERSE REACTIONS
In Trial 144 (2 years to less than 12 years of age), mean percentage BMD gains from baseline to Week 48 in lumbar spine and total body BMD in VIREAD-treated subjects were less than the mean percentage BMD gains observed in placebo-treated subjects. At Week 48, the cumulative percentage of subjects with greater than or equal to 4% decreases in spine or whole body BMD was numerically higher for subjects in the TDF group compared with the placebo group (please refer to the label for the detailed study results). As observed in pediatric studies of HIV-infected subjects, normal skeletal growth (height) was not affected for the duration of the clinical trial.
The effects of VIREAD-associated changes in BMD and biochemical markers on long-term bone health and future fracture risk in pediatric patients 2 years and older are unknown. The long-term effect of lower spine and total body BMD on skeletal growth in pediatric patients 2 years and older, and in particular, the effects of long-duration exposure in younger children is unknown.
8 USE IN SPECIFIC POPULATIONS
8.4 Pediatric Use
Pediatric Patients 2 Years of Age and Older with Chronic Hepatitis B
The safety and effectiveness of VIREAD in pediatric patients 2 years to less than 18 years of age is supported by data from two randomized trials (Trial 115 and Trial 144) in which VIREAD was administered to HBV-infected treatment-experienced subjects.
In Trial 144, 89 HBeAg positive (96%) and negative (4%) subjects 2 years to less than 12 years of age were treated with VIREAD 8 mg/kg up to maximum dose of 300 mg or placebo once daily for 48 weeks. At Week 48, 77% of subjects in the VIREAD group and 7% of subjects in the placebo group had HBV DNA <400 copies/mL (69 IU/mL).
The effects of VIREAD-associated changes in BMD and biochemical markers on long-term bone health and future fracture risk in chronic HBV-infected pediatric patients 2 years and older are unknown. The long-term effect of lower spine and total body BMD on skeletal growth in pediatric patients 2 years and older, and in particular, the effects of long-duration exposure in younger children is unknown.
Safety and effectiveness of VIREAD in chronic HBV-infected pediatric patients younger than 2 years of age and weighing less than 10 kg have not been established.
12 CLINICAL PHARMACOLOGY
Tenofovir exposures in HBV-infected pediatric subjects 2 years to less than 12 years of age receiving VIREAD 8 mg/kg of body weight (tablet or powder) up to a maximum dose of 300 mg were comparable to exposures achieved in HIV-1 infected adult subjects receiving identical doses.
14 CLINICAL STUDIES
14.5 Clinical Trial Results in Pediatric Subjects with Chronic Hepatitis B
In Trial 144, 89 HBeAg positive (96%) and negative (4%) subjects 2 years to less than 12 years of age with chronic HBV infection were treated with VIREAD 8 mg/kg up to a maximum dose of 300 mg (N=60) or placebo (N=29) once daily for 48 weeks. At trial entry, the mean HBV DNA was 8.1 log10 IU/mL and mean ALT was 123 U/L. There was an overall higher proportion in the VIREAD group with HBV DNA <400 copies/mL (69 IU/mL) and ALT normalization rate at Week 48 compared to the placebo group (see results below). There was no difference between treatment groups in those who achieved HBeAg loss or HBeAg seroconversion.
Outcomes of Randomized Treatment (Trial 144) in Children 2 Years to <12 Years of Age At Week 48
- HBV DNA <400 copies/mL (69 IU/ml)
- VIREAD – 46/60 (77%)
- Placebo – 2/29 (7%)
- ALT Normalization
- VIREAD – 38/58 (66%)
- Placebo – 4/27 (15%)
- HBeAg loss
- VIREAD – 17/56 (30%)
- Placebo) – 8/29 (28%)
- HBeAg seroconversion
- VIREAD – 14/56 (25%)
- Placebo – 7/29 (24%)
In Trials 115 and 144, sequencing data from paired baseline and on treatment HBV isolates from subjects who received VIREAD were available for 14 of 15 subjects who had plasma HBV DNA ≥400 copies/mL No amino acid substitutions associated with resistance to VIREAD were identified in these isolates by Week 72 (Trial 115) or Week 48 (Trial 144).