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adverse reactions
6 ADVERSE REACTIONS The following adverse reactions are discussed in other sections of the labeling: Exacerbations of hepatitis after discontinuation of treatment [see Boxed Warning , Warnings and Precautions (5.1) ]. Lactic acidosis and severe hepatomegaly with steatosis [see Boxed Warning , Warnings and Precautions (5.3) ]. Most common adverse reactions (≥3%, all severity grades) are headache, fatigue, dizziness and nausea. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trial Experience in Adults 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 Entecavir 0.5 mg/day (n=679), Entecavir 1 mg/day (n=183), or lamivudine (n=858) for up to 2 years. Median duration of therapy was 69 weeks for Entecavir-treated subjects and 63 weeks for lamivudine-treated subjects in Studies AI463022 and AI463027 and 73 weeks for Entecavir-treated subjects and 51 weeks for lamivudine-treated subjects in Studies AI463026 and AI463014. The safety profiles of Entecavir 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 Entecavir-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 Entecavir-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 Entecavir was compared with lamivudine are presented in Table 3. Table 3: Clinical Adverse Reactions a of Moderate-Severe Intens ity (Grades 2 to 4) Reported in Four Entecavir Clinical Trials Through 2 Years Nucleos ide-Inhibitor-Naïve b Lamivudine-Refractory c Body System / Adverse Reaction Entecavir 0.5 mg N=679 Lamivudine 100 mg N=668 Entecavir 1 mg N=183 Lamivudine 100 mg N=190 Any Grade 2 to 4 adverse reaction a 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 Entecavir 1 mg and lamivudine treatment arms of Study AI463014, a Phase 2 multinational, randomized, double-blind study of three doses of Entecavir (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 Entecavir compared with lamivudine are listed in Table 4. Table 4: Selected Treatment-Emergent a Laboratory Abnormalities Reported in Four Entecavir Clinical Trials Through 2 Years Nucleoside-Inhibitor-Naïve b Lamivudine-Refractory c Test Entecavir 0.5 mg N=679 Lamivudine 100 mg N=668 Entecavir 1 mg N=183 Lamivudine 100 mg N=190 Any Grade 3 to 4 laboratory abnormality d ALT >10 x ULN and >2 x baseline ALT >5 x ULN Albumin <2.5 g/dL Total bilirubin >2.5 x ULN Lipase > 2.1 x ULN Creatinine >3 x ULN Confirmed creatinine increase > 0.5 mg/dL Hyperglycemia, fasting >250 mg/dL Glycosuria e Hematuria f Platelets <50,000/mm³ 35% 2% 11% <1% 2% 7% 0 1% 2% 4% 9% <1% 36% 4% 16% <1% 2% 6% 0 1% 1% 3% 10% <1% 37% 2% 12% 0 3% 7% 0 2% 3% 4% 9% <1% 45% 11% 24% 2% 2% 7% 0 1% 1% 6% 6% <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 Entecavir 1 mg and lamivudine treatment arms of Study AI463014, a Phase 2 multinational, randomized, double-blind study of three doses of Entecavir (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 Entecavir-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 log /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 entecavir is discontinued without regard to treatment response, the rate of post-treatment flares could be higher [see also Warnings and Precautions (5.1) ]. Table 5: 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 Reference a Entecavir Lamivudine Nucleoside-inhibitor-naïve HBeAg-positive HBeAg-negative Lamivudine-refractory 4/174 (2%) 24/320 (8%) 6/52 (12%) 13/147 (9%) 30/270 (11%) 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 Entecavir-treated subjects and 10 weeks for lamivudine-treated subjects. Decompensated Liver Disease Study AI463048 was a randomized, open-label study of Entecavir 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 Entecavir, the most common treatmentemergent 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 Entecavir and 18/89 (20%) subjects treated with adefovir dipivoxil died during the first 48 weeks of therapy. The majority of deaths (11 in the Entecavir 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 Entecavir 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 entecavir 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 Entecavir 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 (5.2) ]. 6.2 Clinical Trial Experience in Pediatric Subjects Pediatric use information is approved for Bristol-Myers Squibb Company’s Baraclude (Entecavir) tablets. However, due to Bristol-Myers Squibb Company’s marketing exclusivity rights, this drug product is not labeled with that information. 6.3 Postmarketing Experience The following adverse reactions have been reported during postmarketing use of Entecavir. 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 Entecavir exposure. Immune system disorders: Anaphylactoid reaction. Metabolism and nutrition disorders: Lactic acidosis. Hepatobiliary disorders: Increased transaminases. Skin and subcutaneous tissue disorders: Alopecia, rash.