Baraclude

Side Effects
Interactions

SIDE EFFECTS

The following adverse reactions are discussed in other sections of the labeling:

Clinical Trial Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Compensated Liver Disease

Assessment of adverse reactions is based on four studies (AI463014, AI463022, AI463026, and AI463027) in which 1720 subjects with chronic hepatitis B virus infection and compensated liver disease received double-blind treatment with BARACLUDE 0.5 mg/day (n=679),

BARACLUDE 1 mg/day (n=183), or lamivudine (n=858) for up to 2 years. Median duration of therapy was 69 weeks for BARACLUDE-treated subjects and 63 weeks for lamivudine-treated subjects in Studies AI463022 and AI463027 and 73 weeks for BARACLUDE-treated subjects and 51 weeks for lamivudine-treated subjects in Studies AI463026 and AI463014. The safety profiles of BARACLUDE and lamivudine were comparable in these studies.

The most common adverse reactions of any severity ( ≥ 3%) with at least a possible relation to study drug for BARACLUDE-treated subjects were headache, fatigue, dizziness, and nausea. The most common adverse reactions among lamivudine-treated subjects were headache, fatigue, and dizziness. One percent of BARACLUDE-treated subjects in these four studies compared with 4% of lamivudine-treated subjects discontinued for adverse events or abnormal laboratory test results.

Clinical adverse reactions of moderate-severe intensity and considered at least possibly related to treatment occurring during therapy in four clinical studies in which BARACLUDE was compared with lamivudine are presented in Table 2.

Table 2: Clinical Adverse Reactionsa of Moderate-Severe Intensity (Grades 2–4) Reported in Four Entecavir Clinical Trials Through 2 Years

Body System/ Adverse Reaction Nucleoside-Naiveb Lamivudine-Refractoryc
BARACLUDE 0.5 mg
n=679
Lamivudine 100 mg
n=668
BARACLUDE 1 mg
n=183
Lamivudine 100 mg
n=190
Any Grade 2-4 adverse reactiona 15% 18% 22% 23%
Gastrointestinal
  Diarrhea < 1% 0 1% 0
  Dyspepsia < 1% < 1% 1% 0
  Nausea < 1% < 1% < 1% 2%
  Vomiting < 1% < 1% < 1% 0
General
  Fatigue 1% 1% 3% 3%
Nervous System
  Headache 2% 2% 4% 1%
  Dizziness < 1% < 1% 0 1%
  Somnolence < 1% < 1% 0 0
  Psychiatric Insomnia < 1% < 1% 0 < 1%
a Includes events of possible, probable, certain, or unknown relationship to treatment regimen.
b Studies AI463022 and AI463027.
c Includes Study AI463026 and the BARACLUDE 1 mg and lamivudine treatment arms of Study AI463014, a Phase 2 multinational, randomized, double-blind study of three doses of BARACLUDE (0.1, 0.5, and 1 mg) once daily versus continued lamivudine 100 mg once daily for up to 52 weeks in subjects who experienced recurrent viremia on lamivudine therapy.

Laboratory Abnormalities

Frequencies of selected treatment-emergent laboratory abnormalities reported during therapy in four clinical trials of BARACLUDE compared with lamivudine are listed in Table 3.

Table 3: Selected Treatment-Emergenta Laboratory Abnormalities Reported in Four Entecavir Clinical Trials Through 2 Years

Test Nucleoside--Naiveb Lamivudine-Refractoryc
BARACLUDE 0.5 mg
n=679
Lamivudine 100 mg
n=668
BARACLUDE 1 mg
n=183
Lamivudine 100 mg
n=190
Any Grade 3-4 laboratory abnormalityd 35% 36% 37% 45%
ALT > 10 x ULN and > 2 x baseline 2% 4% 2% 11%
ALT > 5.0 x ULN 11% 16% 12% 24%
Albumin < 2.5 g/dL < 1% < 1% 0 2%
Total bilirubin > 2.5 x ULN 2% 2% 3% 2%
Lipase ≥ 2.1 x ULN 7% 6% 7% 7%
Creatinine > 3.0 x ULN 0 0 0 0
Confirmed creatinine increase ≥ 0.5 mg/dL 1% 1% 2% 1%
Hyperglycemia, fasting > 250 mg/dL 2% 1% 3% 1%
Glycosuriae 4% 3% 4% 6%
Hematuriaf 9% 10% 9% 6%
3 Platelets < 50,000/mm < 1% < 1% < 1% < 1%
a On-treatment value worsened from baseline to Grade 3 or Grade 4 for all parameters except albumin (any on-treatment value < 2.5 g/dL), confirmed creatinine increase ≥ 0.5 mg/dL, and ALT > 10 x ULN and > 2 x baseline.
b Studies AI463022 and AI463027.
c Includes Study AI463026 and the BARACLUDE 1 mg and lamivudine treatment arms of Study AI463014, a Phase 2 multinational, randomized, double-blind study of three doses of BARACLUDE (0.1, 0.5, and 1 mg) once daily versus continued lamivudine 100 mg once daily for up to 52 weeks in subjects who experienced recurrent viremia on lamivudine therapy.
d Includes hematology, routine chemistries, renal and liver function tests, pancreatic enzymes, and urinalysis.
e Grade 3 = 3+, large, ≥ 500 mg/dL; Grade 4 = 4+, marked, severe.
f Grade 3 = 3+, large; Grade 4 = ≥ 4+, marked, severe, many.
ULN=upper limit of normal.

Among BARACLUDE-treated subjects in these studies, on-treatment ALT elevations greater than 10 times the upper limit of normal (ULN) and greater than 2 times baseline generally resolved with continued treatment. A majority of these exacerbations were associated with a ≥ 2 log10/mL reduction in viral load that preceded or coincided with the ALT elevation. Periodic monitoring of hepatic function is recommended during treatment.

Exacerbations of Hepatitis after Discontinuation of Treatment

An exacerbation of hepatitis or ALT flare was defined as ALT greater than 10 times ULN and greater than 2 times the subject's reference level (minimum of the baseline or last measurement at end of dosing). For all subjects who discontinued treatment (regardless of reason), Table 4 presents the proportion of subjects in each study who experienced post-treatment ALT flares. In these studies, a subset of subjects was allowed to discontinue treatment at or after 52 weeks if they achieved a protocol-defined response to therapy. If BARACLUDE is discontinued without regard to treatment response, the rate of post-treatment flares could be higher. [See also WARNINGS AND PRECAUTIONS]

Table 4: Exacerbations of Hepatitis During Off-Treatment Follow-up, Subjects in Studies AI463022, AI463027, and AI463026

  Subjects with ALT Elevations > 10 x ULN and > 2 x Referencea
BARACLUDE Lamivudine
Nucleoside-naive
  HBeAg-positive 4/174 (2%) 13/147 (9%)
  HBeAg-negative 24/302 (8%) 30/270 (11%)
Lamivudine-refractory 6/52 (12%) 0/16
a Reference is the minimum of the baseline or last measurement at end of dosing. Median time to off-treatment exacerbation was 23 weeks for BARACLUDE-treated subjects and 10 weeks for lamivudine-treated subjects.

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]. 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 (15%), pyrexia (14%), hepatic encephalopathy (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.

HIV/HBV Co-Infected

The safety profile of BARACLUDE 1 mg (n=51) in HIV/HBV co-infected subjects enrolled in Study AI463038 was similar to that of placebo (n=17) through 24 weeks of blinded treatment and similar to that seen in non-HIV infected subjects [see WARNINGS AND PRECAUTIONS].

Liver Transplant Recipients

Among 65 subjects receiving BARACLUDE in an open-label, post-liver transplant trial [see Use In Specific Populations], the frequency and nature of adverse events were consistent with those expected in patients who have received a liver transplant and the known safety profile of BARACLUDE.

Postmarketing Experience

The following adverse reactions have been reported during postmarketing use of BARACLUDE. Because these reactions were reported voluntarily from a population of unknown size, it is not possible to reliably estimate their frequency or establish a causal relationship to BARACLUDE exposure.

Immune system disorders: Anaphylactoid reaction.

Metabolism and nutrition disorders: Lactic acidosis.

Hepatobiliary disorders: Increased transaminases.

Skin and subcutaneous tissue disorders: Alopecia, rash.

Read the Baraclude (entecavir) Side Effects Center for a complete guide to possible side effects

DRUG INTERACTIONS

Since entecavir is primarily eliminated by the kidneys [see CLINICAL PHARMACOLOGY], coadministration of BARACLUDE with drugs that reduce renal function or compete for active tubular secretion may increase serum concentrations of either entecavir or the coadministered drug. Coadministration of entecavir with lamivudine, adefovir dipivoxil, or tenofovir disoproxil fumarate did not result in significant drug interactions. The effects of coadministration of BARACLUDE with other drugs that are renally eliminated or are known to affect renal function have not been evaluated, and patients should be monitored closely for adverse events when BARACLUDE is coadministered with such drugs.

Read the Baraclude Drug Interactions Center for a complete guide to possible interactions

Last reviewed on RxList: 1/6/2014
This monograph has been modified to include the generic and brand name in many instances.

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