Entecavir

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 Accord Healthcare Inc, at 1-866-941-7875 or 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 Includes events of possible, probable, certain, or unknown relationship to treatment regimen. of Moderate-Severe Intensity (Grades 2 to 4) Reported in Four Entecavir Clinical Trials Through 2 Years Nucleoside-Inhibitor-Naïve Studies AI463022 and AI463027. Lamivudine-Refractory 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. 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 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% 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 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 × ULN and >2 × baseline. Laboratory Abnormalities Reported in Four Entecavir Clinical Trials Through 2 Years Nucleoside-Inhibitor-Naïve Studies AI463022 and AI463027. Lamivudine-Refractory 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. 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 Includes hematology, routine chemistries, renal and liver function tests, pancreatic enzymes, and urinalysis. 35% 36% 37% 45% ALT >10 × ULN and >2 × baseline 2% 4% 2% 11% ALT >5.0 × ULN 11% 16% 12% 24% Albumin <2.5 g/dL <1% <1% 0 2% Total bilirubin >2.5 × ULN 2% 2% 3% 2% Lipase ≥2.1 × ULN 7% 6% 7% 7% Creatinine >3.0 × 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% Glycosuria Grade 3 = 3+, large, ≥ 500 mg/dL; Grade 4 = 4+, marked, severe. 4% 3% 4% 6% Hematuria Grade 3 = 3+, large; Grade 4 = ≥ 4+, marked, severe, many. ULN=upper limit of normal. 9% 10% 9% 6% Platelets <50,000/mm 3 <1% <1% <1% <1% 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 10 /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 × ULN and >2 × Reference 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. Entecavir Lamivudine Nucleoside-inhibitor-naïve HBeAg-positive 4/174 (2%) 13/147 (9%) HBeAg-negative 24/302 (8%) 30/270 (11%) Lamivudine-refractory 6/52 (12%) 0/16 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 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 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 × baseline and >10 × 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) ]. Liver Transplant Recipients Among 65 subjects receiving entecavir in an open-label, post-liver transplant trial [see Use in Specific Populations (8.8) ], 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 entecavir. 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.

4 CONTRAINDICATIONS None. None. (4)

11 DESCRIPTION Entecavir is a guanosine nucleoside analogue with selective activity against HBV. The chemical name for entecavir is 2-amino-1,9-dihydro-9-[( 1S,3R,4S )-4-hydroxy-3-(hydroxymethyl)-2-methylenecyclopentyl]-6 H -purin-6-one, monohydrate. Its molecular formula is C 12 H 15 N 5 O ∙3 ∙H 2 O, which corresponds to a molecular weight of 295.3. Entecavir has the following structural formula: Entecavir is a white to off-white powder. It is slightly soluble in water (2.4 mg/mL), and the pH of the saturated solution in water is 7.9 at 25° C ± 0.5° C. Entecavir tablets USP are available for oral administration in strengths of 0.5 mg and 1 mg of entecavir. Entecavir 0.5 mg and 1 mg film-coated tablets contain the following inactive ingredients: colloidal silicon dioxide, microcrystalline cellulose, sodium starch glycolate and magnesium stearate. The tablet coating contains hypromellose, titanium dioxide, polyethylene glycol, and FD&C Red #40 (1 mg tablet only). USP dissolution test is pending. Entecavir Chemical Structure

2 DOSAGE AND ADMINISTRATION Nucleoside-inhibitor-treatment-naïve with compensated liver disease (greater than or equal to 16 years old): 0.5 mg once daily. (2.2) Lamivudine-refractory or known lamivudine or telbivudine resistance substitutions (greater than or equal to 16 years old): 1 mg once daily. (2.2) Decompensated liver disease (adults): 1 mg once daily. (2.2) Renal impairment: Dosage adjustment is recommended if creatinine clearance is less than 50 mL/min. (2.4) Entecavir should be administered on an empty stomach. (2.1) 2.1 Timing of Administration Entecavir should be administered on an empty stomach (at least 2 hours after a meal and 2 hours before the next meal). 2.2 Recommended Dosage in Adults Compensated Liver Disease The recommended dose of entecavir for chronic hepatitis B virus infection in nucleoside-inhibitor-treatment-naïve adults and adolescents 16 years of age and older is 0.5 mg once daily. The recommended dose of entecavir in adults and adolescents (at least 16 years of age) with a history of hepatitis B viremia while receiving lamivudine or known lamivudine or telbivudine resistance substitutions rtM204I/V with or without rtL180M, rtL80I/V, or rtV173L is 1 mg once daily. Decompensated Liver Disease The recommended dose of entecavir for chronic hepatitis B virus infection in adults with decompensated liver disease is 1 mg once daily. 2.3 Recommended Dosage in Pediatric Patients 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. 2.4 Renal Impairment In adult subjects with renal impairment, the apparent oral clearance of entecavir decreased as creatinine clearance decreased [see Clinical Pharmacology (12.3) ]. Dosage adjustment is recommended for patients with creatinine clearance less than 50 mL/min, including patients on hemodialysis or continuous ambulatory peritoneal dialysis (CAPD), as shown in Table 2 . The once-daily dosing regimens are preferred. Table 2: Recommended Dosage of Entecavir in Adult Patients with Renal Impairment Creatinine Clearance (mL/min) Usual Dose (0.5 mg) Lamivudine-Refractory or Decompensated Liver Disease (1 mg) 50 or greater 0.5 mg once daily 1 mg once daily 30 to less than 50 0.5 mg every 48 hours 0.5 mg once daily OR 1 mg every 48 hours 10 to less than 30 0.5 mg every 72 hours 1 mg every 72 hours Less than 10 Hemodialysis If administered on a hemodialysis day, administer entecavir after the hemodialysis session. or CAPD 0.5 mg every 7 days 1 mg every 7 days 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. 2.5 Hepatic Impairment No dosage adjustment is necessary for patients with hepatic impairment. 2.6 Duration of Therapy The optimal duration of treatment with entecavir for patients with chronic hepatitis B virus infection and the relationship between treatment and long-term outcomes such as cirrhosis and hepatocellular carcinoma are unknown.

1 INDICATIONS AND USAGE Entecavir is indicated for the treatment of chronic hepatitis B virus infection in adults with evidence of active viral replication and either evidence of persistent elevations in serum aminotransferases (ALT or AST) or histologically active disease. The following points should be considered when initiating therapy with entecavir: • In adult patients, this indication is based on clinical trial data in nucleoside-inhibitor-treatment-naïve and lamivudine-resistant subjects with HBeAg-positive and HBeAg-negative HBV infection and compensated liver disease and a more limited number of subjects with decompensated liver disease. [see Clinical Studies (14.1) ]. 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. Entecavir is a Hepatitis B virus nucleoside analogue reverse transcriptase inhibitor indicated for the treatment of chronic hepatitis B virus infection in adults with evidence of active viral replication and either evidence of persistent elevations in serum aminotransferases (ALT or AST) or histologically active disease. (1)

10 OVERDOSAGE There is limited experience of entecavir overdosage reported in patients. Healthy subjects who received single entecavir doses up to 40 mg or multiple doses up to 20 mg/day for up to 14 days had no increase in or unexpected adverse events. If overdose occurs, the patient must be monitored for evidence of toxicity, and standard supportive treatment applied as necessary. Following a single 1 mg dose of entecavir, a 4-hour hemodialysis session removed approximately 13% of the entecavir dose.

7 DRUG INTERACTIONS Since entecavir is primarily eliminated by the kidneys [see Clinical Pharmacology (12.3) ], coadministration of entecavir 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 entecavir 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 entecavir is coadministered with such drugs.

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Entecavir is an antiviral drug [see Microbiology (12.4) ]. 12.3 Pharmacokinetics The single- and multiple-dose pharmacokinetics of entecavir was evaluated in healthy subjects and subjects with chronic hepatitis B virus infection. Absorption Following oral administration in healthy subjects, entecavir peak plasma concentrations occurred between 0.5 and 1.5 hours. Following multiple daily doses ranging from 0.1 to 1 mg, C max and area under the concentration-time curve (AUC) at steady state increased in proportion to dose. Steady state was achieved after 6 to 10 days of once-daily administration with approximately 2-fold accumulation. For a 0.5 mg oral dose, C max at steady state was 4.2 ng/mL and trough plasma concentration (C trough ) was 0.3 ng/mL. For a 1 mg oral dose, C max was 8.2 ng/mL and C trough was 0.5 ng/mL. In healthy subjects, the bioavailability of the tablet was 100% relative to the oral solutions. The oral solution and tablet may be used interchangeably. Effects of food on oral absorption: Oral administration of 0.5 mg of entecavir with a standard high-fat meal (945 kcal, 54.6 g fat) or a light meal (379 kcal, 8.2 g fat) resulted in a delay in absorption (1.0 to 1.5 hours fed vs. 0.75 hours fasted), a decrease in C max of 44% to 46%, and a decrease in AUC of 18% to 20% [see Dosage and Administration (2) ]. Distribution Based on the pharmacokinetic profile of entecavir after oral dosing, the estimated apparent volume of distribution is in excess of total body water, suggesting that entecavir is extensively distributed into tissues. Binding of entecavir to human serum proteins in vitro was approximately 13%. Metabolism and Elimination Following administration of 14 C-entecavir in humans and rats, no oxidative or acetylated metabolites were observed. Minor amounts of phase II metabolites (glucuronide and sulfate conjugates) were observed. Entecavir is not a substrate, inhibitor, or inducer of the cytochrome P450 (CYP450) enzyme system [see Drug Interactions, below]. After reaching peak concentration, entecavir plasma concentrations decreased in a bi-exponential manner with a terminal elimination half-life of approximately 128 to 149 hours. The observed drug accumulation index is approximately 2-fold with once-daily dosing, suggesting an effective accumulation half-life of approximately 24 hours. Entecavir is predominantly eliminated by the kidney with urinary recovery of unchanged drug at steady state ranging from 62% to 73% of the administered dose. Renal clearance is independent of dose and ranges from 360 to 471 mL/min suggesting that entecavir undergoes both glomerular filtration and net tubular secretion [see Drug Interactions (7) ]. Special Populations Gender: There are no significant gender differences in entecavir pharmacokinetics. Race: There are no significant racial differences in entecavir pharmacokinetics. Elderly: The effect of age on the pharmacokinetics of entecavir was evaluated following administration of a single 1 mg oral dose in healthy young and elderly volunteers. Entecavir AUC was 29.3% greater in elderly subjects compared to young subjects. The disparity in exposure between elderly and young subjects was most likely attributable to differences in renal function. Dosage adjustment of entecavir should be based on the renal function of the patient, rather than age [see Dosage and Administration (2.4) ]. Pediatrics: 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. Renal impairment: The pharmacokinetics of entecavir following a single 1 mg dose were studied in subjects (without chronic hepatitis B virus infection) with selected degrees of renal impairment, including subjects whose renal impairment was managed by hemodialysis or continuous ambulatory peritoneal dialysis (CAPD). Results are shown in Table 7 [see Dosage and Administration (2.4) ]. Table 7: Pharmacokinetic Parameters in Subjects with Selected Degrees of Renal Function Renal Function Group Baseline Creatinine Clearance (mL/min) Unimpaired >80 n=6 Mild >50 to ≤80 n=6 Moderate 30 to 50 n=6 Severe <30 n=6 Severe Managed with Hemodialysis Dosed immediately following hemodialysis. CLR = renal clearance; CLT/F = apparent oral clearance. n=6 Severe Managed with CAPD n=4 C max (ng/mL) (CV%) 8.1 (30.7) 10.4 (37.2) 10.5 (22.7) 15.3 (33.8) 15.4 (56.4) 16.6 (29.7) AUC (0–T) (ng•h/mL) (CV) 27.9 (25.6) 51.5 (22.8) 69.5 (22.7) 145.7 (31.5) 233.9 (28.4) 221.8 (11.6) CLR (mL/min) (SD) 383.2 (101.8) 197.9 (78.1) 135.6 (31.6) 40.3 (10.1) NA NA CLT/F (mL/min) (SD) 588.1 (153.7) 309.2 (62.6) 226.3 (60.1) 100.6 (29.1) 50.6 (16.5) 35.7 (19.6) Following a single 1 mg dose of entecavir administered 2 hours before the hemodialysis session, hemodialysis removed approximately 13% of the entecavir dose over 4 hours. CAPD removed approximately 0.3% of the dose over 7 days [see Dosage and Administration (2.4) ]. Hepatic impairment: The pharmacokinetics of entecavir following a single 1 mg dose were studied in adult subjects (without chronic hepatitis B virus infection) with moderate or severe hepatic impairment (Child-Turcotte-Pugh Class B or C). The pharmacokinetics of entecavir were similar between hepatically impaired and healthy control subjects; therefore, no dosage adjustment of entecavir is recommended for patients with hepatic impairment. The pharmacokinetics of entecavir have not been studied in pediatric subjects with hepatic impairment. Post-liver transplant: Limited data are available on the safety and efficacy of entecavir in liver transplant recipients. In a small pilot study of entecavir use in HBV-infected liver transplant recipients on a stable dose of cyclosporine A (n=5) or tacrolimus (n=4), entecavir exposure was approximately 2-fold the exposure in healthy subjects with normal renal function. Altered renal function contributed to the increase in entecavir exposure in these subjects. The potential for pharmacokinetic interactions between entecavir and cyclosporine A or tacrolimus was not formally evaluated [see Use in Specific Populations (8.8) ]. Drug Interactions The metabolism of entecavir was evaluated in in vitro and in vivo studies. Entecavir is not a substrate, inhibitor, or inducer of the cytochrome P450 (CYP450) enzyme system. At concentrations up to approximately 10,000-fold higher than those obtained in humans, entecavir inhibited none of the major human CYP450 enzymes 1A2, 2C9, 2C19, 2D6, 3A4, 2B6, and 2E1. At concentrations up to approximately 340-fold higher than those observed in humans, entecavir did not induce the human CYP450 enzymes 1A2, 2C9, 2C19, 3A4, 3A5, and 2B6. The pharmacokinetics of entecavir is unlikely to be affected by coadministration with agents that are either metabolized by, inhibit, or induce the CYP450 system. Likewise, the pharmacokinetics of known CYP substrates is unlikely to be affected by coadministration of entecavir. The steady-state pharmacokinetics of entecavir and coadministered drug were not altered in interaction studies of entecavir with lamivudine, adefovir dipivoxil, and tenofovir disoproxil fumarate [see Drug Interactions (7) ]. 12.4 Microbiology Mechanism of Action Entecavir, a guanosine nucleoside analogue with activity against HBV reverse transcriptase (rt), is efficiently phosphorylated to the active triphosphate form, which has an intracellular half-life of 15 hours. By competing with the natural substrate deoxyguanosine triphosphate, entecavir triphosphate functionally inhibits all three activities of the HBV reverse transcriptase: (1) base priming, (2) reverse transcription of the negative strand from the pregenomic messenger RNA, and (3) synthesis of the positive strand of HBV DNA. Entecavir triphosphate is a weak inhibitor of cellular DNA polymerases α, β, and δ and mitochondrial DNA polymerase γ with K i values ranging from 18 to >160 μM. Antiviral Activity Entecavir inhibited HBV DNA synthesis (50% reduction, EC 50 ) at a concentration of 0.004 μM in human HepG2 cells transfected with wild-type HBV. The median EC 50 value for entecavir against lamivudine-resistant HBV (rtL180M, rtM204V) was 0.026 μM (range 0.010 to 0.059 μM). The coadministration of HIV nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) with entecavir is unlikely to reduce the antiviral efficacy of entecavir against HBV or of any of these agents against HIV. In HBV combination assays in cell culture, abacavir, didanosine, lamivudine, stavudine, tenofovir, or zidovudine were not antagonistic to the anti-HBV activity of entecavir over a wide range of concentrations. In HIV antiviral assays, entecavir was not antagonistic to the cell culture anti-HIV activity of these six NRTIs or emtricitabine at concentrations greater than 100 times the C max of entecavir using the 1 mg dose. Antiviral Activity against HIV A comprehensive analysis of the inhibitory activity of entecavir against a panel of laboratory and clinical HIV type 1 (HIV-1) isolates using a variety of cells and assay conditions yielded EC 50 values ranging from 0.026 to >10 μM; the lower EC 50 values were observed when decreased levels of virus were used in the assay. In cell culture, entecavir selected for an M184I substitution in HIV reverse transcriptase at micromolar concentrations, confirming inhibitory pressure at high entecavir concentrations. HIV variants containing the M184V substitution showed loss of susceptibility to entecavir. Resistance In Cell Culture In cell-based assays, 8- to 30-fold reductions in entecavir phenotypic susceptibility were observed for lamivudine-resistant strains. Further reductions (>70-fold) in entecavir phenotypic susceptibility required the presence of amino acid substitutions rtM204I/V with or without rtL180M along with additional substitutions at residues rtT184, rtS202, or rtM250, or a combination of these substitutions with or without an rtI169 substitution in the HBV reverse transcriptase. Clinical Studies Nucleoside-inhibitor-naïve subjects: Genotypic evaluations were performed on evaluable samples (>300 copies/mL serum HBV DNA) from 562 subjects who were treated with entecavir for up to 96 weeks in nucleoside-inhibitor-naïve studies (AI463022, AI463027, and rollover study AI463901). By Week 96, evidence of emerging amino acid substitution rtS202G with rtM204V and rtL180M substitutions was detected in the HBV of 2 subjects (2/562=<1%), and 1 of them experienced virologic rebound (≥1 log 10 increase above nadir). In addition, emerging amino acid substitutions at rtM204I/V and rtL180M, rtL80I, or rtV173L, which conferred decreased phenotypic susceptibility to entecavir in the absence of rtT184, rtS202, or rtM250 changes, were detected in the HBV of 3 subjects (3/562=<1%) who experienced virologic rebound. For subjects who continued treatment beyond 48 weeks, 75% (202/269) had HBV DNA <300 copies/mL at end of dosing (up to 96 weeks). HBeAg-positive (n=243) and -negative (n=39) treatment-naïve subjects who failed to achieve the study-defined complete response by 96 weeks were offered continued entecavir treatment in a rollover study. Complete response for HBeAg-positive was <0.7 MEq/mL (approximately 7 × 10 5 copies/mL) serum HBV DNA and HBeAg loss and, for HBeAg-negative was <0.7 MEq/mL HBV DNA and ALT normalization. Subjects received 1 mg entecavir once daily for up to an additional 144 weeks. Of these 282 subjects, 141 HBeAg-positive and 8 HBeAg-negative subjects entered the long-term follow-up rollover study and were evaluated for entecavir resistance. Of the 149 subjects entering the rollover study, 88% (131/149), 92% (137/149), and 92% (137/149) attained serum HBV DNA <300 copies/mL by Weeks 144, 192, and 240 (including end of dosing), respectively. No novel entecavir resistance-associated substitutions were identified in a comparison of the genotypes of evaluable isolates with their respective baseline isolates. The cumulative probability of developing rtT184, rtS202, or rtM250 entecavir resistance-associated substitutions (in the presence of rtM204V and rtL180M substitutions) at Weeks 48, 96, 144, 192, and 240 was 0.2%, 0.5%, 1.2%, 1.2%, and 1.2%, respectively. Lamivudine-refractory subjects: Genotypic evaluations were performed on evaluable samples from 190 subjects treated with entecavir for up to 96 weeks in studies of lamivudine-refractory HBV (AI463026, AI463014, AI463015, and rollover study AI463901). By Week 96, resistance-associated amino acid substitutions at rtS202, rtT184, or rtM250, with or without rtI169 changes, in the presence of amino acid substitutions rtM204I/V with or without rtL180M, rtL80V, or rtV173L/M emerged in the HBV from 22 subjects (22/190=12%), 16 of whom experienced virologic rebound (≥1 log 10 increase above nadir) and 4 of whom were never suppressed <300 copies/mL. The HBV from 4 of these subjects had entecavir resistance substitutions at baseline and acquired further changes on entecavir treatment. In addition to the 22 subjects, 3 subjects experienced virologic rebound with the emergence of rtM204I/V and rtL180M, rtL80V, or rtV173L/M. For isolates from subjects who experienced virologic rebound with the emergence of resistance substitutions (n=19), the median fold-change in entecavir EC 50 values from reference was 19-fold at baseline and 106-fold at the time of virologic rebound. For subjects who continued treatment beyond 48 weeks, 40% (31/77) had HBV DNA <300 copies/mL at end of dosing (up to 96 weeks). Lamivudine-refractory subjects (n=157) who failed to achieve the study-defined complete response by Week 96 were offered continued entecavir treatment. Subjects received 1 mg entecavir once daily for up to an additional 144 weeks. Of these subjects, 80 subjects entered the long-term follow-up study and were evaluated for entecavir resistance. By Weeks 144, 192, and 240 (including end of dosing), 34% (27/80), 35% (28/80), and 36% (29/80), respectively, attained HBV DNA <300 copies/mL. The cumulative probability of developing rtT184, rtS202, or rtM250 entecavir resistance-associated substitutions (in the presence of rtM204I/V with or without rtL180M substitutions) at Weeks 48, 96, 144, 192, and 240 was 6.2%, 15%, 36.3%, 46.6%, and 51.5%, respectively. The HBV of 6 subjects developed rtA181C/G/S/T amino acid substitutions while receiving entecavir, and of these, 4 developed entecavir resistance-associated substitutions at rtT184, rtS202, or rtM250 and 1 had an rtT184S substitution at baseline. Of 7 subjects whose HBV had an rtA181 substitution at baseline, 2 also had substitutions at rtT184, rtS202, or rtM250 at baseline and another 2 developed them while on treatment with entecavir. Cross-resistance Cross-resistance has been observed among HBV nucleoside analogue inhibitors. In cell-based assays, entecavir had 8- to 30-fold less inhibition of HBV DNA synthesis for HBV containing lamivudine and telbivudine resistance substitutions rtM204I/V with or without rtL180M than for wild-type HBV. Substitutions rtM204I/V with or without rtL180M, rtL80I/V, or rtV173L, which are associated with lamivudine and telbivudine resistance, also confer decreased phenotypic susceptibility to entecavir. The efficacy of entecavir against HBV harboring adefovir resistance-associated substitutions has not been established in clinical trials. HBV isolates from lamivudine-refractory subjects failing entecavir therapy were susceptible in cell culture to adefovir but remained resistant to lamivudine. Recombinant HBV genomes encoding adefovir resistance-associated substitutions at either rtN236T or rtA181V had 0.3- and 1.1-fold shifts in susceptibility to entecavir in cell culture, respectively.

12.1 Mechanism of Action Entecavir is an antiviral drug [see Microbiology (12.4) ].

12.3 Pharmacokinetics The single- and multiple-dose pharmacokinetics of entecavir was evaluated in healthy subjects and subjects with chronic hepatitis B virus infection. Absorption Following oral administration in healthy subjects, entecavir peak plasma concentrations occurred between 0.5 and 1.5 hours. Following multiple daily doses ranging from 0.1 to 1 mg, C max and area under the concentration-time curve (AUC) at steady state increased in proportion to dose. Steady state was achieved after 6 to 10 days of once-daily administration with approximately 2-fold accumulation. For a 0.5 mg oral dose, C max at steady state was 4.2 ng/mL and trough plasma concentration (C trough ) was 0.3 ng/mL. For a 1 mg oral dose, C max was 8.2 ng/mL and C trough was 0.5 ng/mL. In healthy subjects, the bioavailability of the tablet was 100% relative to the oral solutions. The oral solution and tablet may be used interchangeably. Effects of food on oral absorption: Oral administration of 0.5 mg of entecavir with a standard high-fat meal (945 kcal, 54.6 g fat) or a light meal (379 kcal, 8.2 g fat) resulted in a delay in absorption (1.0 to 1.5 hours fed vs. 0.75 hours fasted), a decrease in C max of 44% to 46%, and a decrease in AUC of 18% to 20% [see Dosage and Administration (2) ]. Distribution Based on the pharmacokinetic profile of entecavir after oral dosing, the estimated apparent volume of distribution is in excess of total body water, suggesting that entecavir is extensively distributed into tissues. Binding of entecavir to human serum proteins in vitro was approximately 13%. Metabolism and Elimination Following administration of 14 C-entecavir in humans and rats, no oxidative or acetylated metabolites were observed. Minor amounts of phase II metabolites (glucuronide and sulfate conjugates) were observed. Entecavir is not a substrate, inhibitor, or inducer of the cytochrome P450 (CYP450) enzyme system [see Drug Interactions, below]. After reaching peak concentration, entecavir plasma concentrations decreased in a bi-exponential manner with a terminal elimination half-life of approximately 128 to 149 hours. The observed drug accumulation index is approximately 2-fold with once-daily dosing, suggesting an effective accumulation half-life of approximately 24 hours. Entecavir is predominantly eliminated by the kidney with urinary recovery of unchanged drug at steady state ranging from 62% to 73% of the administered dose. Renal clearance is independent of dose and ranges from 360 to 471 mL/min suggesting that entecavir undergoes both glomerular filtration and net tubular secretion [see Drug Interactions (7) ]. Special Populations Gender: There are no significant gender differences in entecavir pharmacokinetics. Race: There are no significant racial differences in entecavir pharmacokinetics. Elderly: The effect of age on the pharmacokinetics of entecavir was evaluated following administration of a single 1 mg oral dose in healthy young and elderly volunteers. Entecavir AUC was 29.3% greater in elderly subjects compared to young subjects. The disparity in exposure between elderly and young subjects was most likely attributable to differences in renal function. Dosage adjustment of entecavir should be based on the renal function of the patient, rather than age [see Dosage and Administration (2.4) ]. Pediatrics: 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. Renal impairment: The pharmacokinetics of entecavir following a single 1 mg dose were studied in subjects (without chronic hepatitis B virus infection) with selected degrees of renal impairment, including subjects whose renal impairment was managed by hemodialysis or continuous ambulatory peritoneal dialysis (CAPD). Results are shown in Table 7 [see Dosage and Administration (2.4) ]. Table 7: Pharmacokinetic Parameters in Subjects with Selected Degrees of Renal Function Renal Function Group Baseline Creatinine Clearance (mL/min) Unimpaired >80 n=6 Mild >50 to ≤80 n=6 Moderate 30 to 50 n=6 Severe <30 n=6 Severe Managed with Hemodialysis Dosed immediately following hemodialysis. CLR = renal clearance; CLT/F = apparent oral clearance. n=6 Severe Managed with CAPD n=4 C max (ng/mL) (CV%) 8.1 (30.7) 10.4 (37.2) 10.5 (22.7) 15.3 (33.8) 15.4 (56.4) 16.6 (29.7) AUC (0–T) (ng•h/mL) (CV) 27.9 (25.6) 51.5 (22.8) 69.5 (22.7) 145.7 (31.5) 233.9 (28.4) 221.8 (11.6) CLR (mL/min) (SD) 383.2 (101.8) 197.9 (78.1) 135.6 (31.6) 40.3 (10.1) NA NA CLT/F (mL/min) (SD) 588.1 (153.7) 309.2 (62.6) 226.3 (60.1) 100.6 (29.1) 50.6 (16.5) 35.7 (19.6) Following a single 1 mg dose of entecavir administered 2 hours before the hemodialysis session, hemodialysis removed approximately 13% of the entecavir dose over 4 hours. CAPD removed approximately 0.3% of the dose over 7 days [see Dosage and Administration (2.4) ]. Hepatic impairment: The pharmacokinetics of entecavir following a single 1 mg dose were studied in adult subjects (without chronic hepatitis B virus infection) with moderate or severe hepatic impairment (Child-Turcotte-Pugh Class B or C). The pharmacokinetics of entecavir were similar between hepatically impaired and healthy control subjects; therefore, no dosage adjustment of entecavir is recommended for patients with hepatic impairment. The pharmacokinetics of entecavir have not been studied in pediatric subjects with hepatic impairment. Post-liver transplant: Limited data are available on the safety and efficacy of entecavir in liver transplant recipients. In a small pilot study of entecavir use in HBV-infected liver transplant recipients on a stable dose of cyclosporine A (n=5) or tacrolimus (n=4), entecavir exposure was approximately 2-fold the exposure in healthy subjects with normal renal function. Altered renal function contributed to the increase in entecavir exposure in these subjects. The potential for pharmacokinetic interactions between entecavir and cyclosporine A or tacrolimus was not formally evaluated [see Use in Specific Populations (8.8) ]. Drug Interactions The metabolism of entecavir was evaluated in in vitro and in vivo studies. Entecavir is not a substrate, inhibitor, or inducer of the cytochrome P450 (CYP450) enzyme system. At concentrations up to approximately 10,000-fold higher than those obtained in humans, entecavir inhibited none of the major human CYP450 enzymes 1A2, 2C9, 2C19, 2D6, 3A4, 2B6, and 2E1. At concentrations up to approximately 340-fold higher than those observed in humans, entecavir did not induce the human CYP450 enzymes 1A2, 2C9, 2C19, 3A4, 3A5, and 2B6. The pharmacokinetics of entecavir is unlikely to be affected by coadministration with agents that are either metabolized by, inhibit, or induce the CYP450 system. Likewise, the pharmacokinetics of known CYP substrates is unlikely to be affected by coadministration of entecavir. The steady-state pharmacokinetics of entecavir and coadministered drug were not altered in interaction studies of entecavir with lamivudine, adefovir dipivoxil, and tenofovir disoproxil fumarate [see Drug Interactions (7) ].

20210209

10

3 DOSAGE FORMS AND STRENGTHS Entecavir tablets USP 0.5 mg are white to off-white, round, film-coated tablets and debossed with '0.5' on one side and plain on the reverse. Entecavir tablets USP 1 mg are pink, round, film-coated tablets and debossed with '1' on one side and plain on the reverse Tablets: 0.5 mg and 1 mg (3 , 16)

Entecavir Entecavir CELLULOSE, MICROCRYSTALLINE HYPROMELLOSES TITANIUM DIOXIDE SODIUM STARCH GLYCOLATE TYPE A POTATO MAGNESIUM STEARATE SILICON DIOXIDE ENTECAVIR ENTECAVIR ANHYDROUS white-to-off-white 0;5 Entecavir Entecavir CELLULOSE, MICROCRYSTALLINE HYPROMELLOSES TITANIUM DIOXIDE SODIUM STARCH GLYCOLATE TYPE A POTATO MAGNESIUM STEARATE FD&C RED NO. 40 SILICON DIOXIDE ENTECAVIR ENTECAVIR ANHYDROUS 1

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Long-term oral carcinogenicity studies of entecavir in mice and rats were carried out at exposures up to approximately 42 times (mice) and 35 times (rats) those observed in humans at the highest recommended dose of 1 mg/day. In mouse and rat studies, entecavir was positive for carcinogenic findings. In mice, lung adenomas were increased in males and females at exposures 3 and 40 times those in humans. Lung carcinomas in both male and female mice were increased at exposures 40 times those in humans. Combined lung adenomas and carcinomas were increased in male mice at exposures 3 times and in female mice at exposures 40 times those in humans. Tumor development was preceded by pneumocyte proliferation in the lung, which was not observed in rats, dogs, or monkeys administered entecavir, supporting the conclusion that lung tumors in mice may be a species-specific event. Hepatocellular carcinomas were increased in males and combined liver adenomas and carcinomas were also increased at exposures 42 times those in humans. Vascular tumors in female mice (hemangiomas of ovaries and uterus and hemangiosarcomas of spleen) were increased at exposures 40 times those in humans. In rats, hepatocellular adenomas were increased in females at exposures 24 times those in humans; combined adenomas and carcinomas were also increased in females at exposures 24 times those in humans. Brain gliomas were induced in both males and females at exposures 35 and 24 times those in humans. Skin fibromas were induced in females at exposures 4 times those in humans. It is not known how predictive the results of rodent carcinogenicity studies may be for humans. Mutagenesis Entecavir was clastogenic to human lymphocyte cultures. Entecavir was not mutagenic in the Ames bacterial reverse mutation assay using S. typhimurium and E. coli strains in the presence or absence of metabolic activation, a mammalian-cell gene mutation assay, and a transformation assay with Syrian hamster embryo cells. Entecavir was also negative in an oral micronucleus study and an oral DNA repair study in rats. Impairment of Fertility In reproductive toxicology studies, in which animals were administered entecavir at up to 30 mg/kg for up to 4 weeks, no evidence of impaired fertility was seen in male or female rats at systemic exposures greater than 90 times those achieved in humans at the highest recommended dose of 1 mg/day. In rodent and dog toxicology studies, seminiferous tubular degeneration was observed at exposures 35 times or greater than those achieved in humans. No testicular changes were evident in monkeys.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Long-term oral carcinogenicity studies of entecavir in mice and rats were carried out at exposures up to approximately 42 times (mice) and 35 times (rats) those observed in humans at the highest recommended dose of 1 mg/day. In mouse and rat studies, entecavir was positive for carcinogenic findings. In mice, lung adenomas were increased in males and females at exposures 3 and 40 times those in humans. Lung carcinomas in both male and female mice were increased at exposures 40 times those in humans. Combined lung adenomas and carcinomas were increased in male mice at exposures 3 times and in female mice at exposures 40 times those in humans. Tumor development was preceded by pneumocyte proliferation in the lung, which was not observed in rats, dogs, or monkeys administered entecavir, supporting the conclusion that lung tumors in mice may be a species-specific event. Hepatocellular carcinomas were increased in males and combined liver adenomas and carcinomas were also increased at exposures 42 times those in humans. Vascular tumors in female mice (hemangiomas of ovaries and uterus and hemangiosarcomas of spleen) were increased at exposures 40 times those in humans. In rats, hepatocellular adenomas were increased in females at exposures 24 times those in humans; combined adenomas and carcinomas were also increased in females at exposures 24 times those in humans. Brain gliomas were induced in both males and females at exposures 35 and 24 times those in humans. Skin fibromas were induced in females at exposures 4 times those in humans. It is not known how predictive the results of rodent carcinogenicity studies may be for humans. Mutagenesis Entecavir was clastogenic to human lymphocyte cultures. Entecavir was not mutagenic in the Ames bacterial reverse mutation assay using S. typhimurium and E. coli strains in the presence or absence of metabolic activation, a mammalian-cell gene mutation assay, and a transformation assay with Syrian hamster embryo cells. Entecavir was also negative in an oral micronucleus study and an oral DNA repair study in rats. Impairment of Fertility In reproductive toxicology studies, in which animals were administered entecavir at up to 30 mg/kg for up to 4 weeks, no evidence of impaired fertility was seen in male or female rats at systemic exposures greater than 90 times those achieved in humans at the highest recommended dose of 1 mg/day. In rodent and dog toxicology studies, seminiferous tubular degeneration was observed at exposures 35 times or greater than those achieved in humans. No testicular changes were evident in monkeys.

ANDA205824

Entecavir

Entecavir

16729-389

HUMAN PRESCRIPTION DRUG

ORAL

12.4 Microbiology Mechanism of Action Entecavir, a guanosine nucleoside analogue with activity against HBV reverse transcriptase (rt), is efficiently phosphorylated to the active triphosphate form, which has an intracellular half-life of 15 hours. By competing with the natural substrate deoxyguanosine triphosphate, entecavir triphosphate functionally inhibits all three activities of the HBV reverse transcriptase: (1) base priming, (2) reverse transcription of the negative strand from the pregenomic messenger RNA, and (3) synthesis of the positive strand of HBV DNA. Entecavir triphosphate is a weak inhibitor of cellular DNA polymerases α, β, and δ and mitochondrial DNA polymerase γ with K i values ranging from 18 to >160 μM. Antiviral Activity Entecavir inhibited HBV DNA synthesis (50% reduction, EC 50 ) at a concentration of 0.004 μM in human HepG2 cells transfected with wild-type HBV. The median EC 50 value for entecavir against lamivudine-resistant HBV (rtL180M, rtM204V) was 0.026 μM (range 0.010 to 0.059 μM). The coadministration of HIV nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) with entecavir is unlikely to reduce the antiviral efficacy of entecavir against HBV or of any of these agents against HIV. In HBV combination assays in cell culture, abacavir, didanosine, lamivudine, stavudine, tenofovir, or zidovudine were not antagonistic to the anti-HBV activity of entecavir over a wide range of concentrations. In HIV antiviral assays, entecavir was not antagonistic to the cell culture anti-HIV activity of these six NRTIs or emtricitabine at concentrations greater than 100 times the C max of entecavir using the 1 mg dose. Antiviral Activity against HIV A comprehensive analysis of the inhibitory activity of entecavir against a panel of laboratory and clinical HIV type 1 (HIV-1) isolates using a variety of cells and assay conditions yielded EC 50 values ranging from 0.026 to >10 μM; the lower EC 50 values were observed when decreased levels of virus were used in the assay. In cell culture, entecavir selected for an M184I substitution in HIV reverse transcriptase at micromolar concentrations, confirming inhibitory pressure at high entecavir concentrations. HIV variants containing the M184V substitution showed loss of susceptibility to entecavir. Resistance In Cell Culture In cell-based assays, 8- to 30-fold reductions in entecavir phenotypic susceptibility were observed for lamivudine-resistant strains. Further reductions (>70-fold) in entecavir phenotypic susceptibility required the presence of amino acid substitutions rtM204I/V with or without rtL180M along with additional substitutions at residues rtT184, rtS202, or rtM250, or a combination of these substitutions with or without an rtI169 substitution in the HBV reverse transcriptase. Clinical Studies Nucleoside-inhibitor-naïve subjects: Genotypic evaluations were performed on evaluable samples (>300 copies/mL serum HBV DNA) from 562 subjects who were treated with entecavir for up to 96 weeks in nucleoside-inhibitor-naïve studies (AI463022, AI463027, and rollover study AI463901). By Week 96, evidence of emerging amino acid substitution rtS202G with rtM204V and rtL180M substitutions was detected in the HBV of 2 subjects (2/562=<1%), and 1 of them experienced virologic rebound (≥1 log 10 increase above nadir). In addition, emerging amino acid substitutions at rtM204I/V and rtL180M, rtL80I, or rtV173L, which conferred decreased phenotypic susceptibility to entecavir in the absence of rtT184, rtS202, or rtM250 changes, were detected in the HBV of 3 subjects (3/562=<1%) who experienced virologic rebound. For subjects who continued treatment beyond 48 weeks, 75% (202/269) had HBV DNA <300 copies/mL at end of dosing (up to 96 weeks). HBeAg-positive (n=243) and -negative (n=39) treatment-naïve subjects who failed to achieve the study-defined complete response by 96 weeks were offered continued entecavir treatment in a rollover study. Complete response for HBeAg-positive was <0.7 MEq/mL (approximately 7 × 10 5 copies/mL) serum HBV DNA and HBeAg loss and, for HBeAg-negative was <0.7 MEq/mL HBV DNA and ALT normalization. Subjects received 1 mg entecavir once daily for up to an additional 144 weeks. Of these 282 subjects, 141 HBeAg-positive and 8 HBeAg-negative subjects entered the long-term follow-up rollover study and were evaluated for entecavir resistance. Of the 149 subjects entering the rollover study, 88% (131/149), 92% (137/149), and 92% (137/149) attained serum HBV DNA <300 copies/mL by Weeks 144, 192, and 240 (including end of dosing), respectively. No novel entecavir resistance-associated substitutions were identified in a comparison of the genotypes of evaluable isolates with their respective baseline isolates. The cumulative probability of developing rtT184, rtS202, or rtM250 entecavir resistance-associated substitutions (in the presence of rtM204V and rtL180M substitutions) at Weeks 48, 96, 144, 192, and 240 was 0.2%, 0.5%, 1.2%, 1.2%, and 1.2%, respectively. Lamivudine-refractory subjects: Genotypic evaluations were performed on evaluable samples from 190 subjects treated with entecavir for up to 96 weeks in studies of lamivudine-refractory HBV (AI463026, AI463014, AI463015, and rollover study AI463901). By Week 96, resistance-associated amino acid substitutions at rtS202, rtT184, or rtM250, with or without rtI169 changes, in the presence of amino acid substitutions rtM204I/V with or without rtL180M, rtL80V, or rtV173L/M emerged in the HBV from 22 subjects (22/190=12%), 16 of whom experienced virologic rebound (≥1 log 10 increase above nadir) and 4 of whom were never suppressed <300 copies/mL. The HBV from 4 of these subjects had entecavir resistance substitutions at baseline and acquired further changes on entecavir treatment. In addition to the 22 subjects, 3 subjects experienced virologic rebound with the emergence of rtM204I/V and rtL180M, rtL80V, or rtV173L/M. For isolates from subjects who experienced virologic rebound with the emergence of resistance substitutions (n=19), the median fold-change in entecavir EC 50 values from reference was 19-fold at baseline and 106-fold at the time of virologic rebound. For subjects who continued treatment beyond 48 weeks, 40% (31/77) had HBV DNA <300 copies/mL at end of dosing (up to 96 weeks). Lamivudine-refractory subjects (n=157) who failed to achieve the study-defined complete response by Week 96 were offered continued entecavir treatment. Subjects received 1 mg entecavir once daily for up to an additional 144 weeks. Of these subjects, 80 subjects entered the long-term follow-up study and were evaluated for entecavir resistance. By Weeks 144, 192, and 240 (including end of dosing), 34% (27/80), 35% (28/80), and 36% (29/80), respectively, attained HBV DNA <300 copies/mL. The cumulative probability of developing rtT184, rtS202, or rtM250 entecavir resistance-associated substitutions (in the presence of rtM204I/V with or without rtL180M substitutions) at Weeks 48, 96, 144, 192, and 240 was 6.2%, 15%, 36.3%, 46.6%, and 51.5%, respectively. The HBV of 6 subjects developed rtA181C/G/S/T amino acid substitutions while receiving entecavir, and of these, 4 developed entecavir resistance-associated substitutions at rtT184, rtS202, or rtM250 and 1 had an rtT184S substitution at baseline. Of 7 subjects whose HBV had an rtA181 substitution at baseline, 2 also had substitutions at rtT184, rtS202, or rtM250 at baseline and another 2 developed them while on treatment with entecavir. Cross-resistance Cross-resistance has been observed among HBV nucleoside analogue inhibitors. In cell-based assays, entecavir had 8- to 30-fold less inhibition of HBV DNA synthesis for HBV containing lamivudine and telbivudine resistance substitutions rtM204I/V with or without rtL180M than for wild-type HBV. Substitutions rtM204I/V with or without rtL180M, rtL80I/V, or rtV173L, which are associated with lamivudine and telbivudine resistance, also confer decreased phenotypic susceptibility to entecavir. The efficacy of entecavir against HBV harboring adefovir resistance-associated substitutions has not been established in clinical trials. HBV isolates from lamivudine-refractory subjects failing entecavir therapy were susceptible in cell culture to adefovir but remained resistant to lamivudine. Recombinant HBV genomes encoding adefovir resistance-associated substitutions at either rtN236T or rtA181V had 0.3- and 1.1-fold shifts in susceptibility to entecavir in cell culture, respectively.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL - 0.5 mg - 30 tablets NDC 16729- 388 -10 Entecavir Tablets, USP 0.5 mg Rx only 30 Tablets Entecavir 0.5-mg Tablet Bottle Label

Manufactured By: EirGen Pharma Ltd Waterford, Ireland Distributed By: Accord Healthcare Inc.,1009 Slater Road, Suite 210-B, Durham, NC 27703, USA. This Patient Information Leaflet has been approved by the U.S. Food and Drug Administration. Revised: January 2017

17 PATIENT COUNSELING INFORMATION See FDA-approved patient labeling (Patient Information). Information about Treatment Physicians should inform their patients of the following important points when initiating entecavir treatment: Patients should remain under the care of a physician while taking entecavir. They should discuss any new symptoms or concurrent medications with their physician. Patients should be advised that treatment with entecavir has not been shown to reduce the risk of transmission of HBV to others through sexual contact or blood contamination. Patients should be advised to take entecavir on an empty stomach (at least 2 hours after a meal and 2 hours before the next meal). Patients should be advised to take a missed dose as soon as remembered unless it is almost time for the next dose. Patients should not take two doses at the same time. Patients should be advised that treatment with entecavir will not cure HBV. Patients should be informed that entecavir may lower the amount of HBV in the body, may lower the ability of HBV to multiply and infect new liver cells, and may improve the condition of the liver. Patients should be informed that it is not known whether entecavir will reduce their chances of getting liver cancer or cirrhosis. Post-treatment Exacerbation of Hepatitis Patients should be informed that deterioration of liver disease may occur in some cases if treatment is discontinued, and that they should discuss any change in regimen with their physician. HIV/HBV Co-infection Patients should be offered HIV antibody testing before starting entecavir therapy. They should be informed that if they have HIV infection and are not receiving effective HIV treatment, entecavir may increase the chance of HIV resistance to HIV medication.

14 CLINICAL STUDIES 14.1 Outcomes in Adults The safety and efficacy of entecavir in adults were evaluated in three Phase 3 active-controlled trials. These studies included 1633 subjects 16 years of age or older with chronic hepatitis B virus infection (serum HBsAg-positive for at least 6 months) accompanied by evidence of viral replication (detectable serum HBV DNA, as measured by the bDNA hybridization or PCR assay). Subjects had persistently elevated ALT levels at least 1.3 times ULN and chronic inflammation on liver biopsy compatible with a diagnosis of chronic viral hepatitis. The safety and efficacy of entecavir were also evaluated in a study of 191 HBV-infected subjects with decompensated liver disease and in a study of 68 subjects co-infected with HBV and HIV. Nucleoside-inhibitor-naïve Subjects with Compensated Liver Disease HBeAg-positive: Study AI463022 was a multinational, randomized, double-blind study of entecavir 0.5 mg once daily versus lamivudine 100 mg once daily for a minimum of 52 weeks in 709 (of 715 randomized) nucleoside-inhibitor-naïve subjects with chronic hepatitis B virus infection, compensated liver disease, and detectable HBeAg. The mean age of subjects was 35 years, 75% were male, 57% were Asian, 40% were Caucasian, and 13% had previously received interferon-α. At baseline, subjects had a mean Knodell Necroinflammatory Score of 7.8, mean serum HBV DNA as measured by Roche COBAS Amplicor PCR assay was 9.66 log 10 copies/mL, and mean serum ALT level was 143 U/L. Paired, adequate liver biopsy samples were available for 89% of subjects. HBeAg-negative (anti-HBe-positive/HBV DNA-positive): Study AI463027 was a multinational, randomized, double-blind study of entecavir 0.5 mg once daily versus lamivudine 100 mg once daily for a minimum of 52 weeks in 638 (of 648 randomized) nucleoside-inhibitor-naïve subjects with HBeAg-negative (HBeAb-positive) chronic hepatitis B virus infection and compensated liver disease. The mean age of subjects was 44 years, 76% were male, 39% were Asian, 58% were Caucasian, and 13% had previously received interferon-α. At baseline, subjects had a mean Knodell Necroinflammatory Score of 7.8, mean serum HBV DNA as measured by Roche COBAS Amplicor PCR assay was 7.58 log 10 copies/mL, and mean serum ALT level was 142 U/L. Paired, adequate liver biopsy samples were available for 88% of subjects. In Studies AI463022 and AI463027, entecavir was superior to lamivudine on the primary efficacy endpoint of Histologic Improvement, defined as a 2-point or greater reduction in Knodell Necroinflammatory Score with no worsening in Knodell Fibrosis Score at Week 48, and on the secondary efficacy measures of reduction in viral load and ALT normalization. Histologic Improvement and change in Ishak Fibrosis Score are shown in Table 8 . Selected virologic, biochemical, and serologic outcome measures are shown in Table 9 . Table 8: Histologic Improvement and Change in Ishak Fibrosis Score at Week 48, Nucleoside-Inhibitor-Naïve Subjects in Studies AI463022 and AI463027 Study AI463022 (HBeAg-Positive) Study AI463027 (HBeAg-Negative) Entecavir 0.5 mg n=314 Subjects with evaluable baseline histology (baseline Knodell Necroinflammatory Score ≥2). Lamivudine 100 mg n=314 Entecavir 0.5 mg n=296 Lamivudine 100 mg n=287 Histologic Improvement (Knodell Scores) Improvement ≥2-point decrease in Knodell Necroinflammatory Score from baseline with no worsening of the Knodell Fibrosis Score. 72% 62% 70% 61% No improvement 21% 24% 19% 26% Ishak Fibrosis Score Improvement For Ishak Fibrosis Score, improvement = ≥1-point decrease from baseline and worsening = ≥1-point increase from baseline. 39% 35% 36% 38% No change 46% 40% 41% 34% Worsening 8% 10% 12% 15% Missing Week 48 biopsy 7% 14% 10% 13% Table 9: Selected Virologic, Biochemical, and Serologic Endpoints at Week 48, Nucleoside-Inhibitor-Naïve Subjects in Studies AI463022 and AI463027 Study AI463022 (HBeAg-Positive) Study AI463027 (HBeAg-Negative) Entecavir 0.5 mg n=354 Lamivudine 100 mg n=355 Entecavir 0.5 mg n=325 Lamivudine 100 mg n=313 HBV DNA Roche COBAS Amplicor PCR assay [lower limit of quantification (LLOQ) = 300 copies/mL]. Proportion undetectable (<300 copies/mL) 67% 36% 90% 72% Mean change from baseline (log 10 copies/mL) −6.86 −5.39 −5.04 −4.53 ALT normalization (≤1 × ULN) 68% 60% 78% 71% HBeAg seroconversion 21% 18% NA NA Histologic Improvement was independent of baseline levels of HBV DNA or ALT. Lamivudine-refractory Subjects with Compensated Liver Disease Study AI463026 was a multinational, randomized, double-blind study of entecavir in 286 (of 293 randomized) subjects with lamivudine-refractory chronic hepatitis B virus infection and compensated liver disease. Subjects receiving lamivudine at study entry either switched to entecavir 1 mg once daily (with neither a washout nor an overlap period) or continued on lamivudine 100 mg for a minimum of 52 weeks. The mean age of subjects was 39 years, 76% were male, 37% were Asian, 62% were Caucasian, and 52% had previously received interferon-α. The mean duration of prior lamivudine therapy was 2.7 years, and 85% had lamivudine resistance substitutions at baseline by an investigational line probe assay. At baseline, subjects had a mean Knodell Necroinflammatory Score of 6.5, mean serum HBV DNA as measured by Roche COBAS Amplicor PCR assay was 9.36 log 10 copies/mL, and mean serum ALT level was 128 U/L. Paired, adequate liver biopsy samples were available for 87% of subjects. Entecavir was superior to lamivudine on a primary endpoint of Histologic Improvement (using the Knodell Score at Week 48). These results and change in Ishak Fibrosis Score are shown in Table 10 . Table 11 shows selected virologic, biochemical, and serologic endpoints. Table 10: Histologic Improvement and Change in Ishak Fibrosis Score at Week 48, Lamivudine-Refractory Subjects in Study AI463026 Entecavir 1 mg n=124 Subjects with evaluable baseline histology (baseline Knodell Necroinflammatory Score ≥2). Lamivudine 100 mg n=116 Histologic Improvement (Knodell Scores) Improvement ≥2-point decrease in Knodell Necroinflammatory Score from baseline with no worsening of the Knodell Fibrosis Score. 55% 28% No improvement 34% 57% Ishak Fibrosis Score Improvement For Ishak Fibrosis Score, improvement = ≥1-point decrease from baseline and worsening = ≥1-point increase from baseline. 34% 16% No change 44% 42% Worsening 11% 26% Missing Week 48 biopsy 11% 16% Table 11: Selected Virologic, Biochemical, and Serologic Endpoints at Week 48, Lamivudine-Refractory Subjects in Study AI463026 Entecavir 1 mg n=141 Lamivudine 100 mg n=145 HBV DNA Roche COBAS Amplicor PCR assay (LLOQ = 300 copies/mL). Proportion undetectable (<300 copies/mL) 19% 1% Mean change from baseline (log 10 copies/mL) −5.11 −0.48 ALT normalization (≤1 × ULN) 61% 15% HBeAg seroconversion 8% 3% Histologic Improvement was independent of baseline levels of HBV DNA or ALT. Subjects with Decompensated Liver Disease Study AI463048 was a randomized, open-label study of entecavir 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 entecavir and 91 subjects to treatment with adefovir dipivoxil. Two subjects randomized to treatment with adefovir dipivoxil actually received treatment with entecavir 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 log 10 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 12 . Table 12: Selected Endpoints at Week 48, Subjects with Decompensated Liver Disease, Study AI463048 ULN=upper limit of normal. Entecavir 1 mg n=100 Endpoints were analyzed using intention-to-treat (ITT) method, treated subjects as randomized. Adefovir Dipivoxil 10 mg n=91 HBV DNA Roche COBAS Amplicor PCR assay (LLOQ = 300 copies/mL). Proportion undetectable (<300 copies/mL) 57% 20% Stable or improved CTP score Defined as decrease or no change from baseline in CTP score. 61% 67% HBsAg loss 5% 0 Normalization of ALT (≤1 × ULN) Denominator is subjects with abnormal values at baseline. 49/78 (63%) 33/71 (46%) Subjects Co-infected with HIV and HBV Study AI463038 was a randomized, double-blind, placebo-controlled study of entecavir versus placebo in 68 subjects co-infected with HIV and HBV who experienced recurrence of HBV viremia while receiving a lamivudine-containing highly active antiretroviral (HAART) regimen. Subjects continued their lamivudine-containing HAART regimen (lamivudine dose 300 mg/day) and were assigned to add either entecavir 1 mg once daily (51 subjects) or placebo (17 subjects) for 24 weeks followed by an open-label phase for an additional 24 weeks where all subjects received entecavir. At baseline, subjects had a mean serum HBV DNA level by PCR of 9.13 log 10 copies/mL. Ninety-nine percent of subjects were HBeAg-positive at baseline, with a mean baseline ALT level of 71.5 U/L. Median HIV RNA level remained stable at approximately 2 log 10 copies/mL through 24 weeks of blinded therapy. Virologic and biochemical endpoints at Week 24 are shown in Table 13 . There are no data in patients with HIV/HBV co-infection who have not received prior lamivudine therapy. Entecavir has not been evaluated in HIV/HBV co-infected patients who were not simultaneously receiving effective HIV treatment [see Warnings and Precautions (5.2) ]. Table 13: Virologic and Biochemical Endpoints at Week 24, Study AI463038 Entecavir 1 mg All subjects also received a lamivudine-containing HAART regimen. n=51 Placebo n=17 HBV DNA Roche COBAS Amplicor PCR assay (LLOQ = 300 copies/mL). Proportion undetectable (<300 copies/mL) 6% 0 Mean change from baseline (log 10 copies/mL) −3.65 +0.11 ALT normalization (≤1 × ULN) 34% ‡ 8% Percentage of subjects with abnormal ALT (>1 × ULN) at baseline who achieved ALT normalization (n=35 for entecavir and n=12 for placebo). For subjects originally assigned to entecavir, at the end of the open-label phase (Week 48), 8% of subjects had HBV DNA <300 copies/mL by PCR, the mean change from baseline HBV DNA by PCR was −4.20 log 10 copies/mL, and 37% of subjects with abnormal ALT at baseline had ALT normalization (≤1 × ULN). Beyond 48 Weeks The optimal duration of therapy with entecavir is unknown. According to protocol-mandated criteria in the Phase 3 clinical trials, subjects discontinued entecavir or lamivudine treatment after 52 weeks according to a definition of response based on HBV virologic suppression (<0.7 MEq/mL by bDNA assay) and loss of HBeAg (in HBeAg-positive subjects) or ALT <1.25 × ULN (in HBeAg-negative subjects) at Week 48. Subjects who achieved virologic suppression but did not have serologic response (HBeAg-positive) or did not achieve ALT <1.25 × ULN (HBeAg-negative) continued blinded dosing through 96 weeks or until the response criteria were met. These protocol-specified subject management guidelines are not intended as guidance for clinical practice. Nucleoside-inhibitor-naïve subjects: Among nucleoside-inhibitor-naïve, HBeAg-positive subjects (Study AI463022), 243 (69%) entecavir-treated subjects and 164 (46%) lamivudine-treated subjects continued blinded treatment for up to 96 weeks. Of those continuing blinded treatment in Year 2, 180 (74%) entecavir subjects and 60 (37%) lamivudine subjects achieved HBV DNA <300 copies/mL by PCR at the end of dosing (up to 96 weeks). 193 (79%) entecavir subjects achieved ALT ≤1 × ULN compared to 112 (68%) lamivudine subjects, and HBeAg seroconversion occurred in 26 (11%) entecavir subjects and 20 (12%) lamivudine subjects. Among nucleoside-inhibitor-naïve, HBeAg-positive subjects, 74 (21%) entecavir subjects and 67 (19%) lamivudine subjects met the definition of response at Week 48, discontinued study drugs, and were followed off treatment for 24 weeks. Among entecavir responders, 26 (35%) subjects had HBV DNA <300 copies/mL, 55 (74%) subjects had ALT ≤1 × ULN, and 56 (76%) subjects sustained HBeAg seroconversion at the end of follow-up. Among lamivudine responders, 20 (30%) subjects had HBV DNA <300 copies/mL, 41 (61%) subjects had ALT ≤1 × ULN, and 47 (70%) subjects sustained HBeAg seroconversion at the end of follow-up. Among nucleoside-inhibitor-naïve, HBeAg-negative subjects (Study AI463027), 26 (8%) entecavir-treated subjects and 28 (9%) lamivudine-treated subjects continued blinded treatment for up to 96 weeks. In this small cohort continuing treatment in Year 2, 22 entecavir and 16 lamivudine subjects had HBV DNA <300 copies/mL by PCR, and 7 and 6 subjects, respectively, had ALT ≤1 × ULN at the end of dosing (up to 96 weeks). Among nucleoside-inhibitor-naïve, HBeAg-negative subjects, 275 (85%) entecavir subjects and 245 (78%) lamivudine subjects met the definition of response at Week 48, discontinued study drugs, and were followed off treatment for 24 weeks. In this cohort, very few subjects in each treatment arm had HBV DNA <300 copies/mL by PCR at the end of follow-up. At the end of follow-up, 126 (46%) entecavir subjects and 84 (34%) lamivudine subjects had ALT ≤1 × ULN. Lamivudine-refractory subjects: Among lamivudine-refractory subjects (Study AI463026), 77 (55%) entecavir-treated subjects and 3 (2%) lamivudine subjects continued blinded treatment for up to 96 weeks. In this cohort of entecavir subjects, 31 (40%) subjects achieved HBV DNA <300 copies/mL, 62 (81%) subjects had ALT ≤1 × ULN, and 8 (10%) subjects demonstrated HBeAg seroconversion at the end of dosing. 14.2 Outcomes 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.

8.5 Geriatric Use Clinical studies of entecavir did not include sufficient numbers of subjects aged 65 years and over to determine whether they respond differently from younger subjects. Entecavir is substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function [see Dosage and Administration (2.4) ].

8.2 Labor and Delivery There are no studies in pregnant women and no data on the effect of entecavir on transmission of HBV from mother to infant. Therefore, appropriate interventions should be used to prevent neonatal acquisition of HBV.

8.3 Nursing Mothers It is not known whether entecavir is excreted into human milk; however, entecavir is excreted into the milk of rats. Because many drugs are excreted into human milk and because of the potential for serious adverse reactions in nursing infants from entecavir, a decision should be made to discontinue nursing or to discontinue entecavir taking into consideration the importance of continued hepatitis B therapy to the mother and the known benefits of breastfeeding.

8.4 Pediatric Use The efficacy and safety of entecavir have not been established in patients less than 2 years of age. Use of entecavir in this age group has not been evaluated because treatment of HBV in this age group is rarely required. 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.

8.1 Pregnancy Pregnancy Category C There are no adequate and well-controlled studies of entecavir in pregnant women. Because animal reproduction studies are not always predictive of human response, entecavir should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Antiretroviral Pregnancy Registry: To monitor fetal outcomes of pregnant women exposed to entecavir, an Antiretroviral Pregnancy Registry has been established. Healthcare providers are encouraged to register patients by calling 1-800-258-4263. Animal Data Animal reproduction studies with entecavir in rats and rabbits revealed no evidence of teratogenicity. Developmental toxicity studies were performed in rats and rabbits. There were no signs of embryofetal or maternal toxicity when pregnant animals received oral entecavir at approximately 28 (rat) and 212 (rabbit) times the human exposure achieved at the highest recommended human dose of 1 mg/day. In rats, maternal toxicity, embryofetal toxicity (resorptions), lower fetal body weights, tail and vertebral malformations, reduced ossification (vertebrae, sternebrae, and phalanges), and extra lumbar vertebrae and ribs were observed at exposures 3100 times those in humans. In rabbits, embryofetal toxicity (resorptions), reduced ossification (hyoid), and an increased incidence of 13th rib were observed at exposures 883 times those in humans. In a peri-postnatal study, no adverse effects on offspring occurred when rats received oral entecavir at exposures greater than 94 times those in humans.

Pregnancy Category C There are no adequate and well-controlled studies of entecavir in pregnant women. Because animal reproduction studies are not always predictive of human response, entecavir should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Antiretroviral Pregnancy Registry: To monitor fetal outcomes of pregnant women exposed to entecavir, an Antiretroviral Pregnancy Registry has been established. Healthcare providers are encouraged to register patients by calling 1-800-258-4263. Animal Data Animal reproduction studies with entecavir in rats and rabbits revealed no evidence of teratogenicity. Developmental toxicity studies were performed in rats and rabbits. There were no signs of embryofetal or maternal toxicity when pregnant animals received oral entecavir at approximately 28 (rat) and 212 (rabbit) times the human exposure achieved at the highest recommended human dose of 1 mg/day. In rats, maternal toxicity, embryofetal toxicity (resorptions), lower fetal body weights, tail and vertebral malformations, reduced ossification (vertebrae, sternebrae, and phalanges), and extra lumbar vertebrae and ribs were observed at exposures 3100 times those in humans. In rabbits, embryofetal toxicity (resorptions), reduced ossification (hyoid), and an increased incidence of 13th rib were observed at exposures 883 times those in humans. In a peri-postnatal study, no adverse effects on offspring occurred when rats received oral entecavir at exposures greater than 94 times those in humans.

8 USE IN SPECIFIC POPULATIONS Nursing mothers: Discontinue nursing or entecavir taking into consideration the importance of entecavir to the mother. (8.3) Liver transplant recipients: Limited data on safety and efficacy are available. (8.8) 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. 8.1 Pregnancy Pregnancy Category C There are no adequate and well-controlled studies of entecavir in pregnant women. Because animal reproduction studies are not always predictive of human response, entecavir should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Antiretroviral Pregnancy Registry: To monitor fetal outcomes of pregnant women exposed to entecavir, an Antiretroviral Pregnancy Registry has been established. Healthcare providers are encouraged to register patients by calling 1-800-258-4263. Animal Data Animal reproduction studies with entecavir in rats and rabbits revealed no evidence of teratogenicity. Developmental toxicity studies were performed in rats and rabbits. There were no signs of embryofetal or maternal toxicity when pregnant animals received oral entecavir at approximately 28 (rat) and 212 (rabbit) times the human exposure achieved at the highest recommended human dose of 1 mg/day. In rats, maternal toxicity, embryofetal toxicity (resorptions), lower fetal body weights, tail and vertebral malformations, reduced ossification (vertebrae, sternebrae, and phalanges), and extra lumbar vertebrae and ribs were observed at exposures 3100 times those in humans. In rabbits, embryofetal toxicity (resorptions), reduced ossification (hyoid), and an increased incidence of 13th rib were observed at exposures 883 times those in humans. In a peri-postnatal study, no adverse effects on offspring occurred when rats received oral entecavir at exposures greater than 94 times those in humans. 8.2 Labor and Delivery There are no studies in pregnant women and no data on the effect of entecavir on transmission of HBV from mother to infant. Therefore, appropriate interventions should be used to prevent neonatal acquisition of HBV. 8.3 Nursing Mothers It is not known whether entecavir is excreted into human milk; however, entecavir is excreted into the milk of rats. Because many drugs are excreted into human milk and because of the potential for serious adverse reactions in nursing infants from entecavir, a decision should be made to discontinue nursing or to discontinue entecavir taking into consideration the importance of continued hepatitis B therapy to the mother and the known benefits of breastfeeding. 8.4 Pediatric Use The efficacy and safety of entecavir have not been established in patients less than 2 years of age. Use of entecavir in this age group has not been evaluated because treatment of HBV in this age group is rarely required. 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. 8.5 Geriatric Use Clinical studies of entecavir did not include sufficient numbers of subjects aged 65 years and over to determine whether they respond differently from younger subjects. Entecavir is substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function [see Dosage and Administration (2.4) ]. 8.6 Racial/Ethnic Groups There are no significant racial differences in entecavir pharmacokinetics.The safety and efficacy of entecavir 0.5 mg once daily were assessed in a single-arm, open-label trial of HBeAg-positive or -negative, nucleoside-inhibitor-naïve, Black/African American (n=40) and Hispanic (n=6) subjects with chronic HBV infection. In this trial, 76% of subjects were male, the mean age was 42 years, 57% were HBeAg-positive, the mean baseline HBV DNA was 7.0 log10 IU/mL, and the mean baseline ALT was 162 U/L. At Week 48 of treatment, 32 of 46 (70%) subjects had HBV DNA <50 IU/mL (approximately 300 copies/mL), 31 of 46 (67%) subjects had ALT normalization (≤1 × ULN), and 12 of 26 (46%) HBeAg-positive subjects had HBe seroconversion. Safety data were similar to those observed in the larger controlled clinical trials. Because of low enrollment, safety and efficacy have not been established in the US Hispanic population. 8.7 Renal Impairment Dosage adjustment of entecavir is recommended for patients with creatinine clearance less than 50 mL/min, including patients on hemodialysis or CAPD [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3) ]. 8.8 Liver Transplant Recipients The safety and efficacy of entecavir were assessed in a single-arm, open-label trial in 65 subjects who received a liver transplant for complications of chronic HBV infection. Eligible subjects who had HBV DNA less than 172 IU/mL (approximately 1000 copies/mL) at the time of transplant were treated with entecavir 1 mg once daily in addition to usual post-transplantation management, including hepatitis B immune globulin. The trial population was 82% male, 39% Caucasian, and 37% Asian, with a mean age of 49 years; 89% of subjects had HBeAg-negative disease at the time of transplant. Four of the 65 subjects received 4 weeks or less of entecavir (2 deaths, 1 retransplantation, and 1 protocol violation) and were not considered evaluable. Of the 61 subjects who received more than 4 weeks of entecavir, 60 received hepatitis B immune globulin post-transplant. Fifty-three subjects (82% of all 65 subjects treated) completed the trial and had HBV DNA measurements at or after 72 weeks treatment post-transplant. All 53 subjects had HBV DNA <50 IU/mL (approximately 300 copies/mL). Eight evaluable subjects did not have HBV DNA data available at 72 weeks, including 3 subjects who died prior to study completion. No subjects had HBV DNA values ≥50 IU/mL while receiving entecavir (plus hepatitis B immune globulin). All 61 evaluable subjects lost HBsAg post-transplant; 2 of these subjects experienced recurrence of measurable HBsAg without recurrence of HBV viremia. This trial was not designed to determine whether addition of entecavir to hepatitis B immune globulin decreased the proportion of subjects with measurable HBV DNA post-transplant compared to hepatitis B immune globulin alone. If entecavir treatment is determined to be necessary for a liver transplant recipient who has received or is receiving an immunosuppressant that may affect renal function, such as cyclosporine or tacrolimus, renal function must be carefully monitored both before and during treatment with entecavir [see Dosage and Administration (2.4) and Clinical Pharmacology (12.3) ].

16 HOW SUPPLIED/STORAGE AND HANDLING Entecavir tablets USP are available in the following strengths and configurations of bottles with child-resistant closures: Product Strength and Dosage Form Description Quantity NDC Number 0.5 mg film-coated tablet Round, white to off-white, coated tablets, debossed with '0.5' on one side and plain on the reverse 30 tablets 16729-388-10 250 tablets 16729-388-84 1 mg film-coated tablet Round, pink, coated tablets, debossed with '1' on one side and plain on the reverse 30 tablets 16729-389-10 250 tablets 16729-389-84 Storage Entecavir tablets USP should be stored in a tightly closed container at 25° C (77° F); excursions permitted between 15° C to 30° C (59° F to 86° F) [see USP Controlled Room Temperature]. Protect from light.

WARNING: SEVERE ACUTE EXACERBATIONS OF HEPATITIS B, PATIENTS CO-INFECTED WITH HIV AND HBV, and LACTIC ACIDOSIS AND HEPATOMEGALY Severe acute exacerbations of hepatitis B have been reported in patients who have discontinued anti-hepatitis B therapy, including entecavir. Hepatic function should be monitored closely with both clinical and laboratory follow-up for at least several months in patients who discontinue anti-hepatitis B therapy. If appropriate, initiation of anti-hepatitis B therapy may be warranted [see Warnings and Precautions (5.1) ]. Limited clinical experience suggests there is a potential for the development of resistance to HIV (human immunodeficiency virus) nucleoside reverse transcriptase inhibitors if entecavir is used to treat chronic hepatitis B virus (HBV) infection in patients with HIV infection that is not being treated. Therapy with entecavir is not recommended for HIV/HBV co-infected patients who are not also receiving highly active antiretroviral therapy (HAART) [see Warnings and Precautions (5.2) ]. Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogue inhibitors alone or in combination with antiretrovirals [see Warnings and Precautions (5.3) ]. WARNING: SEVERE ACUTE EXACERBATIONS OF HEPATITIS B, PATIENTS CO-INFECTED WITH HIV AND HBV, and LACTIC ACIDOSIS AND HEPATOMEGALY See full prescribing information for complete boxed warning. Severe acute exacerbations of hepatitis B have been reported in patients who have discontinued anti-hepatitis B therapy, including entecavir. Hepatic function should be monitored closely for at least several months after discontinuation. Initiation of anti-hepatitis B therapy may be warranted. (5.1) Entecavir is not recommended for patients co-infected with human immunodeficiency virus (HIV) and hepatitis B virus (HBV) who are not also receiving highly active antiretroviral therapy (HAART), because of the potential for the development of resistance to HIV nucleoside reverse transcriptase inhibitors. (5.2) Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogue inhibitors. (5.3)