BARACLUDE SIDE EFFECTS
- Generic Name: entecavir
- Brand Name: Baraclude
- Drug Class: Hepatitis B Hepatitis C Agents
SIDE EFFECTS
The following adverse reactions are discussed in other sections of the labeling:
- Exacerbations of hepatitis after discontinuation of treatment
- Lactic acidosis and severe hepatomegaly with steatosis.
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.
Clinical Trial Experience In Adults
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 doubleblind 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 BARACLUDEtreated 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 3.
Table 1: Clinical Adverse Reactionsa of Moderate-Severe Intensity (Grades 2-4) Reported in Four Entecavir Clinical Trials Through 2 Years
| Body System/ Adverse Reaction | Nucleoside-Inhibitor- 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% |
| aIncludes events of possible, probable, certain, or unknown relationship to treatment regimen. bStudies AI463022 and AI463027. cIncludes 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. |
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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 4.
Table 2: Selected Treatment-Emergent Laboratory Abnormalities Reported in Four Entecavir Clinical Trials Through 2 Years
| Test | Nucleoside-Inhibitor-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 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 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% |
| Platelets <50,000/mm³ | <1% | <1% | <1% | <1% |
| aOn-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. bStudies AI463022 and AI463027. cIncludes 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. dIncludes hematology, routine chemistries, renal and liver function tests, pancreatic enzymes, and urinalysis. eGrade 3 = 3+, large, ≥500 mg/dL; Grade 4 = 4+, marked, severe. fGrade 3 = 3+, large; Grade 4 = ≥4+, marked, severe, many. ULN=upper limit of normal. |
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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 5 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.
Table 3: 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-inhibitor-naive | ||
| HBeAg-positive- | – | – |
| HBeAg-negative | 24/302 (8%) | 30/270 (11%) |
| Lamivudine-refractory | 6/52 (12%) | 0/16 |
| aReference 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. 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 3 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.
Liver Transplant Recipients
Among 65 subjects receiving BARACLUDE in an open-label, post-liver transplant trial, 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.
Clinical Trial Experience In Pediatric Subjects
The safety of BARACLUDE in pediatric subjects 2 to less than 18 years of age is based on two clinical trials in subjects with chronic HBV infection (one Phase 2 pharmacokinetic trial [AI463028] and one Phase 3 trial [AI463189]). These trials provided experience in 168 HBeAg-positive subjects treated with BARACLUDE for a median duration of 72 weeks. The adverse reactions observed in pediatric subjects who received treatment with BARACLUDE were consistent with those observed in clinical trials of BARACLUDE in adults. Adverse drug reactions reported in greater than 1% of pediatric subjects included abdominal pain, rash events, poor palatability (“product taste abnormal”), nausea, diarrhea, and vomiting.
Postmarketing Experience
Data from Long-Term Observational Study
Study AI463080 was a randomized, global, observational, open-label Phase 4 study to assess long-term risks and benefits of BARACLUDE (0.5 mg/day or 1 mg/day) treatment as compared to other standard-of-care HBV nucleos(t)ide analogues in subjects with chronic HBV infection.
A total of 12,378 patients were treated with BARACLUDE (n=6,216) or other HBV nucleos(t)ide treatment [non-entecavir (ETV)] (n=6,162). Patients were evaluated at baseline and subsequently every 6 months for up to 10 years. The principal clinical outcome events assessed during the study were overall malignant neoplasms, liver-related HBV disease progression, HCC, non-HCC malignant neoplasms, and death. The study showed that BARACLUDE was not significantly associated with an increased risk of malignant neoplasms compared to other standard-of-care HBV nucleos(t)ides, as assessed by either the composite endpoint of overall malignant neoplasms or the individual endpoint of non-HCC malignant neoplasms. The most commonly reported malignancy in both the BARACLUDE and non-ETV groups was HCC followed by gastrointestinal malignancies. The data also showed that long-term BARACLUDE use was not associated with a lower occurrence of HBV disease progression or a lower rate of death overall compared to other HBV nucleos(t)ides. The principal clinical outcome event assessments are shown in Table 6.
Table 4: Principal Analyses of Time to Adjudicated Events – Randomized Treated Subjects
| Endpointc | Number of Subjects with Events | ||
| BARACLUDE N=6,216 |
Non-ETV N=6,162 |
Hazard Ratio TBARACLIJDE: Non-ET VI (CIa) | |
| Primarv Endpoints | |||
| Overall malignant neoplasm | 331 | 337 | 0.93 (0.800, 1.084) |
| Liver-related HBV disease progression | 350 | 375 | 0.89 (0.769, 1.030) |
| Death | 238 | 264 | 0.85 (0.713, 1.012) |
| Secondarv Endpoints | |||
| Non-HCC malignant neoplasm | 95 | 81 | 1.10 (0.817, 1.478) |
| HCC | 240b | 263 | 0.87 (0.727, 1.032) |
| Analyses were stratified by geographic region and prior HBV nucleos(t)ide experience. a95.03% CI for overall malignant neoplasm, death, and liver-related HBV disease progression; 95% CI for non-HCC malignant neoplasm and HCC. bOne subject had a pre-treatment HCC event and was excluded from the analysis. cOverall malignant neoplasm is a composite event of HCC or non-HCC malignant neoplasm. Liver-related HBV disease progression is a composite event of liver-related death, HCC, or non-HCC HBV disease progression. CI = confidence interval; N = total number of subjects. |
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Limitations of the study included population changes over the long-term follow-up period and more frequent post-randomization treatment changes in the non-ETV group. In addition, the study was underpowered to demonstrate a difference in the non-HCC malignancy rate because of the lower than expected background rate.
Adverse Reactions From Postmarketing Spontaneous Reports
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.
SRC: NLM .