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FDA approved changes to the labeling for BARACLUDE (entecavir) to provide a dosing regimen for adult patients with chronic hepatitis B (HBV) and decompensated liver disease, based on efficacy data through Week 48 and cumulative safety data from one trial. The following is a summary of the label changes:
Section 1 INDICATIONS AND USAGE was updated to include the following bullet point in this subsection:
The following points should be considered when initiating therapy with BARACLUDE:
Virologic, biochemical, serologic, and safety data are available from a controlled study in adult subjects with chronic HBV infection and decompensated liver disease [see Adverse Reactions (6.1) and Clinical Studies (14.1)].
Section 2 DOSAGE AND ADMINISTRATION includes dosing for decompensated liver disease as follows:
2.1 Recommend Dosage
Decompensated Liver Disease
The recommended dose of BARACLUDE for chronic hepatitis B virus infection in adults with decompensated liver disease is 1 mg once daily.
Section 2.2 Renal Impairment table 1 was updated to provide the recommended dosage of BARACLUDE in patients with renal impairment
Section 6 ADVERSE REACTIONS was updated as follows:
Decompensated Liver Disease
Study AI463048 was a randomized, open-label study of BARACLUDE 1 mg once daily versus adefovir dipivoxil 10 mg once daily given for up to 48 weeks in adult subjects with chronic HBV infection and evidence of hepatic decompensation, defined as a Child-Turcotte-Pugh (CTP) score of 7 or higher [see Clinical Studies (14.1)]. Among the 102 subjects receiving BARACLUDE, the most common treatment-emergent adverse events of any severity, regardless of causality, occurring through Week 48 were
peripheral edema (16%), ascites [accumulation of fluid in the abdomen] (15%), pyrexia [fever] (14%), hepatic encephalopathy [brain malfunction] (10%), and upper respiratory infection (10%). Clinical adverse reactions not listed in Table 2 that were observed through Week 48 include blood bicarbonate decreased (2%) and renal failure (<1%).
Eighteen of 102 (18%) subjects treated with BARACLUDE and 18/89 (20%) subjects treated with adefovir dipivoxil died during the first 48 weeks of therapy. The majority of deaths (11 in the BARACLUDE group and 16 in the adefovir dipivoxil group) were due to liver-related causes such as hepatic failure, hepatic encephalopathy, hepatorenal syndrome, and upper gastrointestinal hemorrhage. The rate of hepatocellular carcinoma (HCC) through Week 48 was 6% (6/102) for subjects treated with
BARACLUDE and 8% (7/89) for subjects treated with adefovir dipivoxil. Five percent of subjects in either treatment arm discontinued therapy due to an adverse event through Week 48.
No subject in either treatment arm experienced an on-treatment hepatic flare (ALT > 2 X baseline and > 10 X ULN) through Week 48. Eleven of 102 (11%) subjects treated with BARACLUDE and 11/89 (13%) subjects treated with adefovir dipivoxil had a confirmed increase in serum creatinine of 0.5 mg/dL through Week 48.
Section 14 CLINICAL STUDIES was updated to include data from study AI463048 in subjects with decompensated liver disease as follows:
Subjects with Decompensated Liver Disease
Study AI463048 was a randomized, open-label study of BARACLUDE 1 mg once daily versus adefovir dipivoxil 10 mg once daily in 191 (of 195 randomized) adult subjects with HBeAg-positive or ‑negative chronic HBV infection and evidence of hepatic decompensation, defined as a Child-Turcotte-Pugh (CTP) score of 7 or higher. Subjects were either HBV-treatment-naïve or previously treated, predominantly with lamivudine or interferon-α.
In Study AI463048, 100 subjects were randomized to treatment with BARACLUDE and 91 subjects to treatment with adefovir dipivoxil. Two subjects randomized to treatment with adefovir dipivoxil actually received treatment with BARACLUDE for the duration of the study. The mean age of subjects was 52 years, 74% were male, 54% were Asian, 33% were Caucasian, and 5% were Black/African American. At baseline, subjects had a mean serum HBV DNA by PCR of 7.83 log10 copies/mL and mean ALT level of
100 U/L; 54% of subjects were HBeAg-positive; 35% had genotypic evidence of lamivudine resistance. The baseline mean CTP score was 8.6. Results for selected study endpoints at Week 48 are shown in Table 10 of the package insert. In summary at Week 48 the proportion of patients with undetectable HBV DAN (< 300 copies/mL) was 57% for BARACLUDE 1 mg compared to 20% for adefovir dipivoxil 10 mg. Proportion of BARACLUDE patients with stable or improvied CTP score, HBsAG loss or normalization of
ALT (< 1 x ULN) was 61%, 5% and 63%, respectively compared to 67%, 0% and 46% for patients receiving adefovir dipivoxil, respectively.
The complete revised labeling will be available soon on the FDA website 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
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