FDA Hepatitis Update - changes to VIREAD (tenofovir DF) labeling for Hepatitis B

FDA recently approved changes to VIREAD (tenofovir DF) product labeling regarding the 96-week safety and efficacy data from Study GS-US-174-0121 in adult subjects with lamivudine-resistant chronic hepatitis B virus (HBV) infection. Additionally the Drug Interactions and Clinical Pharmacology sections of the labeling were updated with information on the coadministration of Viread® with didanosine. The revisions are summarized below.
In section 1, INDICATIONS AND USAGE, the following revisions were made.
1.2         Chronic Hepatitis B
The following point was updated regarding what clinicians should consider when initiating therapy with VIREAD for the treatment of HBV infection:

•           The indication in adults is based on safety and efficacy data from treatment of subjects who were nucleoside-treatment-naïve and subjects who were treatment-experienced with documented resistance to lamivudine. Subjects were adults with HBeAg-positive and HBeAg-negative chronic hepatitis B with compensated liver disease [See Clinical Studies (14.2)].

In section 6 ADVERSE REACTIONS under sub-section 6.1 Adverse Reactions from Clinical Trials Experience, the following text was added.
The adverse reactions observed in subjects with chronic hepatitis B and lamivudine resistance who received treatment with VIREAD were consistent with those observed in other hepatitis B clinical trials in adults
In section 7 DRUG INTERACTIONS the following was revised.
7.1         Didanosine
In patients weighing greater than 60 kg, the didanosine dose should be reduced to 250 mg once daily when it is coadministered with VIREAD.  In patients weighing less than 60 kg, the didanosine dose should be reduced to 200 mg once daily when it is coadministered with VIREAD.  When coadministered, VIREAD and didanosine EC may be taken under fasted conditions or with a light meal (less than 400 kcal, 20% fat).  For additional information on coadministration of VIREAD and didanosine, please refer to the full prescribing information for didanosine.
In section 12, CLINICAL PHARMACOLOGY under sub-section 12.3 Pharmacokinetics, the following text was added
Coadministration of VIREAD with didanosine results in changes in the pharmacokinetics of didanosine that may be of clinical significance. Concomitant dosing of VIREAD with didanosine significantly increases the Cmax and AUC of didanosine. When didanosine 250 mg enteric-coated capsules were administered with VIREAD, systemic exposures of didanosine were similar to those seen with the 400 mg enteric-coated capsules alone under fasted conditions (Table 14). The mechanism of this interaction is unknown.
In section 14, CLINICAL STUDIES under sub-section 14.2 Clinical Efficacy in Adults with Chronic Hepatitis B, the following changes were made. Additional changes to section 12.4 Microbiology were also made.
Patients with Lamivudine-Resistant Chronic Hepatitis B
Study 121 was a randomized, double-blind, active-controlled trial evaluating the safety and efficacy of VIREAD compared to an unapproved antiviral regimen in subjects with chronic hepatitis B, persistent viremia (HBV DNA ≥ 1,000 IU/mL), and genotypic evidence of lamivudine resistance (rtM204I/V +/- rtL180M).  One hundred forty-one adult subjects were randomized to the VIREAD treatment arm.  The mean age of subjects randomized to VIREAD was 47 years (range 18-73), 74% were male, 59% were Caucasian, and 37% were Asian.  At baseline, 54% of subjects were HBeAg-negative, 46% were HBeAg-positive, and 56% had abnormal ALT.  Subjects had a mean HBV DNA of 6.4 log10 copies/mL and mean serum ALT of 71 U/L at baseline.
After 96 weeks of treatment, 126 of 141 subjects (89%) randomized to VIREAD had HBV DNA < 400 copies/mL, and 49 of 79 subjects (62%) with abnormal ALT at baseline had ALT normalization.  Among the HBeAg-positive subjects randomized to VIREAD, 10 of 65 subjects (15%) experienced HBeAg loss, and 7 of 65 subjects (11%) experienced anti-HBe seroconversion through Week 96.  The proportion of subjects with HBV DNA concentrations below 400 copies/mL at Week 96 was similar between the VIREAD monotherapy and the comparator arms.
Across the combined chronic hepatitis B treatment trials, the number of subjects with adefovir-resistance associated substitutions at baseline was too small to establish efficacy in this subgroup.
Richard Klein
Office of Health and Constituent Affairs
Food and Drug Administration
Kimberly Struble
Division of Antiviral Drug Products
Food and Drug Administration
Steve Morin
Office of Health and Constituent Affairs
Food and Drug Administration