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Viread labeling updates

The following revisions were made with respect to the pediatric information:

Section 2 Dosage and Administration was revised, stating the recommended dose for the treatment of chronic hepatitis B in pediatric patients 12 years of age and older (35 kg or more) is 300 mg once daily taken orally without regard to food.  In addition this section states the safety and efficacy in pediatric patients with chronic hepatitis B weighing less than 35 kg and in patients younger than 12 years of age have not been established.
 

Section 5.6 Decreases in Bone Mineral Density was updated with the following text:

In a clinical trial (Study 115) conducted in pediatric subjects 12 to less than 18 years of age with chronic hepatitis B infection, both the VIREAD and placebo treatment arms experienced an overall increase in mean lumbar spine BMD (bone mineral density) over 72 weeks, as expected for an adolescent population.  The BMD gains from baseline to Week 72 in lumbar spine and total body BMD in VIREAD-treated subjects (+5% and +3%, respectively) were less than the BMD gains observed in placebo-treated subjects (+8% and +5%, respectively).  Three subjects in the VIREAD group and two subjects in the placebo group had significant (greater than 4%) lumbar spine BMD loss at Week 72.  At baseline, mean BMD Z-scores in subjects randomized to VIREAD were −0.43 for lumbar spine and −0.20 for total body, and mean BMD Z-scores in subjects randomized to placebo were −0.28 for lumbar spine and −0.26 for total body.  In subjects receiving VIREAD for 72 weeks, the mean change in BMD Z-score was −0.05 for lumbar spine and −0.15 for total body compared to +0.07 and +0.06, respectively, in subjects receiving placebo.  As observed in pediatric studies of HIV-infected patients, skeletal growth (height) appeared to be unaffected.

Section 6.1 Adverse Reactions from Clinical Trials Experience was updated as follows:

Clinical Trials in Pediatric Subjects 12 Years of Age and Older with Chronic Hepatitis B

Assessment of adverse reactions is based on one randomized study (Study GS‑US‑174‑0115) in 106 pediatric subjects (12 to less than 18 years of age) infected with chronic hepatitis B receiving treatment with VIREAD (N = 52) or placebo (N = 54) for 72 weeks. The adverse reactions observed in pediatric subjects who received treatment with VIREAD were consistent with those observed in clinical trials of VIREAD in adults.

The mean rate of bone mineral density gain was less in VIREAD-treated subjects compared to placebo.

The following text was added to Section 8.4 Pediatric Use:

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 VIREAD 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 VIREAD, 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 VIREAD group and 0% (0/54) of subjects in the placebo group had HBV DNA <400 copies/mL. Among subjects with abnormal ALT at baseline, 74% (26/35) of subjects receiving VIREAD had normalized ALT at Week 72 compared to 31% (13/42) in the placebo group. One VIREAD-treated subject experienced sustained HBsAg-loss and seroconversion to anti-HBs during the first 72 weeks of study participation.

Safety and effectiveness of VIREAD in pediatric patients younger than 12 years of age or less than 35 kg with chronic hepatitis B have not been established.

Section 12.3 Pharmacokinetics was updated to include the following information in pediatric subjects:

Tenofovir exposures in 52 HBV-infected pediatric subjects (12 to less than 18 years of age) receiving oral once-daily doses of VIREAD 300 mg tablet were comparable to exposures achieved in HIV-1-infected adults and adolescents receiving once-daily doses of 300 mg.

The following information was added regarding with 240 week data in

Section 12.4, Microbiology Table 17 Amino Acid Substitutions in Viremic Subjects across HBV Trials of VIREAD was updated.
 

Section 14.2, Clinical Efficacy in Adults with Chronic Hepatitis B, the following changes were made:

In Studies 0102 (HBeAg-negative) and 0103 (HBeAg-positive), subjects who completed double-blind treatment (389 and 196 subjects who were originally randomized to VIREAD and HEPSERA, respectively) were eligible to roll over to open-label VIREAD with no interruption in treatment.

In Study 0102, 304 of 375 subjects (81%) continued in the study through Week 240. Among subjects randomized to VIREAD followed by open-label treatment with VIREAD, 82% had HBV DNA < 400 copies/mL, and 69% had ALT normalization at Week 240. Among subjects randomized to HEPSERA followed by open-label treatment with VIREAD, 88% had HBV DNA < 400 copies/mL and 76% had ALT normalization through Week 240. No subject in either treatment group experienced HBsAg loss/seroconversion through Week 240.

In Study 0103, 185 of 266 subjects (69%) continued in the study through Week 240. Among subjects randomized to VIREAD, 63% had HBV DNA < 400 copies/mL, 44% had ALT normalization, and 34% had HBeAg loss (26% seroconversion to anti-HBe antibody) through Week 240. Among subjects randomized to HEPSERA followed by up to 192 weeks of open-label treatment with VIREAD, 64% had HBV DNA < 400 copies/mL, 54% had ALT normalization, and 34% had HBeAg loss (29% seroconversion to anti-HBe antibody) through Week 240. At Week 240, HBsAg loss was 9% in both treatment groups, and seroconversion to anti-HBs was 7% for the subjects initially randomized to VIREAD and 9% for subjects initially randomized to HEPSERA.

Of the originally randomized and treated 641 subjects in the two studies, liver biopsy data from 328 subjects who received continuing open-label treatment with VIREAD monotherapy were available for analysis at baseline, Week 48 and Week 240. There were no apparent differences between the subset of subjects who had liver biopsy data at Week 240 and those subjects remaining on open-label VIREAD without biopsy data that would be expected to affect histological outcomes at Week 240. Among the 328 subjects evaluated, the observed histological response rates were 80% and 88% at Week 48 and Week 240, respectively. In the subjects without cirrhosis at baseline (Ishak fibrosis score 0-4), 92% (216/235) and 95% (223/235) had either improvement or no change in Ishak fibrosis score at Week 48 and Week 240, respectively. In subjects with cirrhosis at baseline (Ishak fibrosis score 5-6), 97% (90/93) and 99% (92/93) had either improvement or no change in Ishak fibrosis score at Week 48 and Week 240, respectively. Twenty-nine percent (27/93) and 72% (67/93) of subjects with cirrhosis at baseline experienced regression of cirrhosis by Week 48 and Week 240, respectively, with a reduction in Ishak fibrosis score of at least 2 points. No definitive conclusions can be established about the remaining study population who were not part of this subset analysis.

Across the combined HBV treatment trials, the number of subjects with lamivudine-or adefovir-resistance associated substitutions at baseline was too small to establish efficacy in this subgroup.

The complete revised label may be viewed at Drugs@FDA

Richard Klein
Office of Special Health Issues
Food and Drug Administration

Kimberly Struble
Division of Antiviral Drug Products
Food and Drug Administration