Entecavir

RECENT MAJOR CHANGES Indications and Usage (1) 3/2014 Dosage and Administration Recommended Dosage in Pediatric Patients (2.3) 3/2014 Renal Impairment (2.4) 3/2014 Indications and Usage (1) 3/2014 Dosage and Administration Renal Impairment (2.4) 3/2014

1 INDICATIONS AND USAGE Entecavir tablets are 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 tablets: 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 tablets are 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)

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 ) • Nucleoside-inhibitor-treatment-naïve and lamivudine-experienced pediatric patients at least 2 years of age and weighing at least 10 kg: dosing is based on weight. ( 2.3 ) • 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 tablets should be administered on an empty stomach. ( 2.1 ) 2.1 Timing of Administration Entecavir tablets 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 tablets 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 tablets 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 tablets for chronic hepatitis B virus infection in adults with decompensated liver disease is 1 mg once daily. 2.3 Recommended Dosage in Pediatric Patients Table 1 describes the recommended dose of entecavir tablets for pediatric patients 2 years of age or older and weighing at least 10 kg. The oral solution should be used for patients with body weight up to 30 kg. Table 1: Dosing Schedule for Pediatric Patients Recommended Once-Daily Dose of Oral Solution (mL) Body Weight (kg) Treatment-Naïve Lamivudine-Experienced Patients a Patients b 10 to 11 3 6 greater than 11 to 14 4 8 greater than 14 to 17 5 10 greater than 17 to 20 6 12 greater than 20 to 23 7 14 greater than 23 to 26 8 16 greater than 26 to 30 9 18 greater than 30 10 20 a Children with body weight greater than 30 kg should receive 10 mL (0.5 mg) of oral solution or one 0.5 mg tablet once daily. b Children with body weight greater than 30 kg should receive 20 mL (1 mg) of oral solution or one 1 mg tablet once daily. 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 0.25 mg once daily a 0.5 mg once daily OR OR 0.5 mg every 48 hours 1 mg every 48 hours 10 to less than 30 0.15 mg once daily a 0.3 mg once daily a OR OR 0.5 mg every 72 hours 1 mg every 72 hours Less than 10 Hemodialysis b or CAPD 0.05 mg once daily a 0.1 mg once daily a OR OR 0.5 mg every 7 days 1 mg every 7 days a For doses less than 0.5 mg, Entecavir Oral Solution is recommended. b If administered on a hemodialysis day, administer entecavir tablets after the hemodialysis session. Although there are insufficient data to recommend a specific dose adjustment of entecavir in pediatric patients with renal impairment, a reduction in the dose or an increase in the dosing interval similar to adjustments for adults should be considered. 2.5 Hepatic Impairment No dosage adjustment is necessary for patients with h …

3 DOSAGE FORMS AND STRENGTHS Tablets: 0.5 mg and 1 mg ( 3 , 16 ) Entecavir 0.5 mg film-coated tablets, USP are White to off-white, triangular shaped biconvex, film coated tablet debossed with 'CL' on one side and '426' on the other side. Entecavir 1 mg film-coated tablets, USP are Pink coloured, triangular shaped biconvex, film coated tablet debossed with 'CL' on one side and '425' on the other side.

4 CONTRAINDICATIONS None. • None. (4)

6 ADVERSE REACTIONS In adults, the most common adverse reactions (≥3%, all severity grades) are headache, fatigue, dizziness, and nausea. The adverse reactions observed in pediatric were consistent with those observed in adults. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact NorthStar Rx LLC at 1-800-206-7821 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 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 ) ]. 6.1 Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Clinical Trial Experience in Adults Compensated Liver Disease Assessment of adverse reactions is based on four studies (AI463014, AI463022, AI463026, and AI463027) in which 1720 subjects with chronic hepatitis B virus infection and compensated liver disease received 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 Mode rate Severe Intensity (Grades 2-4) Reported in Entecavir Clinical Trials Through 2 Years Nucleoside- Inhibitor-Naïve b Lamivudine-Refractory c 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. Body System/ Adverse Reaction Entecavir 0.5mg n= 679 Lamivudine 100mg n= 668 Entecavir 1mg n= 183 Lamivudine 100mg n= 190 Any Grade 2-4 adverse reaction a 15% 18% 22% 23% Gastrointestinal Diarrhea 10 x ULN and >2 x baseline 2% 4% 2% 11% ALT>5 x ULN 11% 16% 12% 24% Albumin 2.5 x ULN 2% 2% 3% 2% Lipase≥2.1 x ULN 7% 6% 7% 7% Creatinine >3 x ULN 0 0 0 0 Confirmed creatinine increase ≥0.5mg/dL 1% 1% 2% 1% Hyperglycemia, fasting >250mg/dL 2% 1% 3% 1% Glycosuria e 4% 3% 4% 6% Hematuria f 9% 10% 9% 6% Platelets10 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 G …

7 DRUG INTERACTIONS Since entecavir is primarily eliminated by the kidneys [see Clinical Pharmacology (12.3) ] , co-administration of entecavir with drugs that reduce renal function or compete for active tubular secretion may increase serum concentrations of either entecavir or the co-administered drug. Co-administration of entecavir with lamivudine, adefovir dipivoxil, or tenofovir disoproxil fumarate did not result in significant drug interactions. The effects of co-administration 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 co-administered with such drugs. To report SUSPECTED ADVERSE REACTIONS contact AvKARE at 1-855-361-3993; email drugsafety@avkare.com; or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

8 USE IN SPECIFIC POPULATIONS Liver transplant recipients: Limited data on safety and efficacy are available. (8.8) See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling. 8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to entecavir during pregnancy. Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) at 1-800-258-4263. Risk Summary Prospective pregnancy data from the APR are not sufficient to adequately assess the risk of birth defects, miscarriage or adverse maternal or fetal outcomes. Entecavir use during pregnancy has been evaluated in a limited number of individuals reported to the APR and the number of exposures to entecavir is insufficient to make a risk assessment compared to a reference population. The estimated background rate for major birth defects is 2.7% in the U.S. reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP). The rate of miscarriage is not reported in the APR. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of miscarriage in clinically recognized pregnancies is 15 to 20%. In animal reproduction studies, no adverse developmental effects were observed with entecavir at clinically relevant exposures. No developmental toxicities were observed at systemic exposures (AUC) approximately 25 (rats) and 200 (rabbits) times the exposure at the maximum recommended human dose (MRHD) of 1 mg/day ( see Data ). Data 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 Lactation Risk Summary It is not known whether entecavir is present in human breast milk, affects human milk production, or has effects on the breastfed infant. When administered to lactating rats, entecavir was present in milk (see Data). The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for entecavir and any potential adverse effects on the breastfed infant from entecavir or from the underlying maternal condition. Data Entecavir was excreted into the milk of lactating rats following a single oral dose of 10 mg per kg on lactation day 7. Entecavir in milk was approximately 25% that in maternal plasma (based on AUC). 8.4 Pediatric Use Entecavir was evaluated in two clinical trials of pediatric subjects 2 years of age and older with HBeAg-positive chronic HBV infection and compensated liver disease. The exposure of entecavir in nucleoside-inhibitor-treatment-naïve and lamivudine-experienced pediatric subjects 2 years of age and older with HBeAg-positive chronic HBV infection and compensated liver disease receiving 0.015 mg/kg (up to 0.5 mg once daily) or 0.03 mg/kg (up to 1 mg once daily), respectively, was evaluated in Study AI463028. Safety and efficacy of the selected dose in treatment-naïve pediatric subjects were confirmed in Study AI463189, a randomi …

12.1 Mechanism of Action Entecavir is an antiviral drug against the hepatitis B virus [see Microbiology (12.4) ] .

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 film-coated tablets 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: lactose monohydrate, microcrystalline cellulose, crospovidone, povidone, and magnesium stearate. The tablet coating contains titanium dioxide, hypromellose, polyethylene glycol 400, polysorbate 80 (0.5 mg tablet only), and iron oxide red (1 mg tablet only). FDA approved dissolution test specifications differ from USP. Chemical Structure

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.

16 HOW SUPPLIED/STORAGE AND HANDLING Entecavir tablets USP, 0.5 mg are white to off-white, round-shaped, biconvex with beveled edge, film-coated tablets, debossed with "920" on one side and plain on the other side and are supplied as follows: NDC 68382-920-06 in bottle of 30 tablets NDC 68382-920-16 in bottle of 90 tablets NDC 68382-920-01 in bottle of 100 tablets NDC 68382-920-77 in unit-dose blister cartons of 100 (10 x 10) unit-dose tablets Entecavir tablets USP, 1 mg are light-pink to pink, round-shaped, biconvex with beveled edge, film-coated tablets, debossed with "921" on one side and plain on the other side and are supplied as follows: NDC 68382-921-06 in bottle of 30 tablets NDC 68382-921-16 in bottle of 90 tablets NDC 68382-921-01 in bottle of 100 tablets NDC 68382-921-77 in unit-dose blister cartons of 100 (10 x 10) unit-dose tablets Storage Entecavir tablets should be stored in a tightly closed container at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature]. Protect from light.