Entecavir
Tablet, Film Coated · Oral
Uses
Entecavir is indicated for the treatment of chronic hepatitis B virus infection in adults and pediatric patients 2 years of age and older with evidence of active viral replication and either evidence of persistent elevations in serum aminotransferases (ALT or AST) or histologically active disease Entecavir is a hepatitis B virus nucleoside analogue reverse transcriptase inhibitor indicated for the treatment of chronic hepatitis B virus infection in adults and children at least 2 years of age with evidence of active viral replication and either evidence of persistent elevations in serum aminotransferases (ALT or AST) or histologically active disease. (1)
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 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 Table 1 describes the recommended dose of entecavir 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 Patients a Lamivudine-Experienced 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) a For doses less than 0.5 mg, entecavir Oral Solution is recommended. b If administered on a hemodialysis day, administer entecavir after the hemodialysis session. 50 or greater 0.5 mg once daily 1 mg once daily 30 to less than 50 0.25 mg once daily a OR 0.5 mg every 48 hours 0.5 mg once daily OR 1 mg every 48 hours 10 to less than 30 0.15 mg once daily a OR 0.5 mg every 72 hours 0.3 mg once daily a OR 1 mg every 72 hours Less than 10 Hemodialysis b or CAPD 0.05 mg once daily a OR 0.5 mg every 7 days 0.1 mg once daily a OR 1 mg every 7 days 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 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.
Dosage forms and strengths
Entecavir Tablets, USP, 0.5 mg, are supplied as a white to off-white, round film coated tablets, debossed with “Y13” on one side. Entecavir Tablets, USP, 1 mg, are supplied as a white to off-white, round film coated tablets, debossed with “Y14” on one side. Tablets: 0.5 mg and 1 mg (3 , 16)
Contraindications
None. None. (4)
Warnings and precautions
Severe acute exacerbations of hepatitis B virus infection after discontinuation: Monitor hepatic function closely for at least several months. (5.1 , 6.1) Co-infection with HIV: Entecavir is not recommended unless the patient is also receiving HAART. (5.2) Lactic acidosis and severe hepatomegaly with steatosis: If suspected, treatment should be suspended. (5.3) 5.1 Severe Acute Exacerbations of Hepatitis B Severe acute exacerbations of hepatitis B have been reported in patients who have discontinued anti-hepatitis B therapy, including entecavir [see Adverse Reactions (6.1) ] . 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. 5.2 Patients Co-infected with HIV and HBV Entecavir has not been evaluated in HIV/HBV co-infected patients who were not simultaneously receiving effective HIV treatment. Limited clinical experience suggests there is a potential for the development of resistance to HIV nucleoside reverse transcriptase inhibitors if entecavir is used to treat chronic hepatitis B virus infection in patients with HIV infection that is not being treated [see Microbiology (12.4) ] . Therefore, therapy with entecavir is not recommended for HIV/HBV co-infected patients who are not also receiving HAART. Before initiating entecavir therapy, HIV antibody testing should be offered to all patients. Entecavir has not been studied as a treatment for HIV infection and is not recommended for this use. 5.3 Lactic Acidosis and Severe Hepatomegaly with Steatosis Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogue inhibitors, including entecavir, alone or in combination with antiretrovirals. A majority of these cases have been in women. Obesity and prolonged nucleoside inhibitor exposure may be risk factors. Particular caution should be exercised when administering nucleoside analogue inhibitors to any patient with known risk factors for liver disease; however, cases have also been reported in patients with no known risk factors. Lactic acidosis with entecavir use has been reported, often in association with hepatic decompensation, other serious medical conditions, or drug exposures. Patients with decompensated liver disease may be at higher risk for lactic acidosis. Treatment with entecavir should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations). 5.1 Severe Acute Exacerbations of Hepatitis B Severe acute exacerbations of hepatitis B have been reported in patients who have discontinued anti-hepatitis B therapy, including entecavir [see Adverse Reactions (6.1) ] . 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. 5.2 Patients Co-infected with HIV and HBV Entecavir has not been evaluated in HIV/HBV co-infected patients who were not simultaneously receiving effective HIV treatment. Limited clinical experience suggests there is a potential for the development of resistance to HIV nucleoside reverse transcriptase inhibitors if entecavir is used to treat chronic hepatitis B virus infection in patients with HIV infection that is not being treated [see Microbiology (12.4) ] . Therefore, therapy with entecavir is not recommended for HIV/HBV co-infected patients who are not also receiving HAART. Before initiating entecavir therapy, HIV antibody testing should be offered to all patients. Entecavir has not been studied as a treatment for HIV infection and is not recommended for this use. 5.3 Lactic Acidosis and Severe Hepatomegaly with Steatosis Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogue inhibitors, including entecavir, alone or in combination with antiretrovirals. A majority of these cases have been in women. Obesity and prolonged nucleoside inhibitor exposure may be risk factors. Particular caution should be exercised when administering nucleoside analogue inhibitors to any patient with known risk factors for liver disease; however, cases have also been reported in patients with no known risk factors. Lactic acidosis with entecavir use has been reported, often in association with hepatic decompensation, other serious medical conditions, or drug exposures. Patients with decompensated liver disease may be at higher risk for lactic acidosis. Treatment with entecavir should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations).
Side effects
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) ] . In adults, the most common adverse reactions (≥ 3%, all severity grades) are headache, fatigue, dizziness, and nausea. The adverse reactions observed in pediatric patients were consistent with those observed in adults. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Yaopharma at 1-609-285-5783 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 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 Moderate-Severe Intensity (Grades 2–4) Reported in Four Entecavir Clinical Trials Through 2 Years Nucleoside-Inhibitor-Naïve b Lamivudine-Refractory c Body System/ Adverse Reaction Entecavir 0.5 mg n=679 Lamivudine 100 mg n = 668 Entecavir 1 mg n = 183 Lamivudine 100 mg n = 190 a Includes events of possible, probable, certain, or unknown relationship to treatment regimen. b Studies AI463022 and AI463027. c Includes Study AI463026 and the entecavir 1 mg and lamivudine treatment arms of Study AI463014, a Phase 2 multinational, randomized, double-blind study of three doses of entecavir (0.1, 0.5, and 1 mg) once daily versus continued lamivudine 100 mg once daily for up to 52 weeks in subjects who experienced recurrent viremia on lamivudine therapy. Any Grade 2–4 adverse reaction a 15% 18% 22% 23% Gastrointestinal Diarrhea <1% 0 1% 0 Dyspepsia <1% <1% 1% 0 Nausea <1% <1% <1% 2% Vomiting <1% <1% <1% 0 General Fatigue 1% 1% 3% 3% Nervous System Headache 2% 2% 4% 1% Dizziness <1% <1% 0 1% Somnolence <1% <1% 0 0 Psychiatric Insomnia <1% <1% 0 <1% Laboratory Abnormalities Frequencies of selected treatment-emergent laboratory abnormalities reported during therapy in four clinical trials of entecavir compared with lamivudine are listed in Table 4. Table 4: Selected Treatment-Emergent a Laboratory Abnormalities Reported in Four Entecavir Clinical Trials Through 2 Years Nucleoside-Inhibitor-Naïve b Lamivudine-Refractory c Test Entecavir 0.5 mg n=679 Lamivudine 100 mg n = 668 Entecavir 1 mg n = 183 Lamivudine 100 mg n = 190 a On-treatment value worsened from baseline to Grade 3 or Grade 4 for all parameters except albumin (any on-treatment value <2.5 g/dL), confirmed creatinine increase ≥0.5 mg/dL, and ALT >10 × ULN and >2 × baseline. b Studies AI463022 and AI463027. c Includes Study AI463026 and the entecavir 1 mg and lamivudine treatment arms of Study AI463014, a Phase 2 multinational, randomized, double-blind study of three doses of entecavir (0.1, 0.5, and 1 mg) once daily versus continued lamivudine 100 mg once daily for up to 52 weeks in subjects who experienced recurrent viremia on lamivudine therapy. d Includes hematology, routine chemistries, renal and liver function tests, pancreatic enzymes, and urinalysis. e Grade 3 = 3+, large, ≥500 mg/dL; Grade 4 = 4+, marked, severe. f Grade 3 = 3+, large; Grade 4 = ≥4+, marked, severe, many. ULN=upper limit of normal. Any Grade 3–4 laboratory abnormality d 35% 36% 37% 45% ALT >10 × ULN and >2 × baseline 2% 4% 2% 11% ALT >5 × 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 × 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 e 4% 3% 4% 6% Hematuria f 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).
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.
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 randomized, placebo-controlled treatment trial [see Indications and Usage (1) , Dosage and Administration (2.3) , Adverse Reactions (6.1) , Clinical Pharmacology (12.3) , and Clinical Studies (14.2) ] . There are limited data available on the use of entecavir in lamivudine-experienced pediatric patients; entecavir should be used in these patients only if the potential benefit justifies the potential risk to the child. Since some pediatric patients may require long-term or even lifetime management of chronic active hepatitis B, consideration should be given to the impact of entecavir on future treatment options [see Microbiology (12.4) ] . 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. 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 log 10 IU/mL, and the mean baseline ALT was 162 U/L.
Pregnancy
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.
Pediatric use
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 randomized, placebo-controlled treatment trial [see Indications and Usage (1) , Dosage and Administration (2.3) , Adverse Reactions (6.1) , Clinical Pharmacology (12.3) , and Clinical Studies (14.2) ] . There are limited data available on the use of entecavir in lamivudine-experienced pediatric patients; entecavir should be used in these patients only if the potential benefit justifies the potential risk to the child. Since some pediatric patients may require long-term or even lifetime management of chronic active hepatitis B, consideration should be given to the impact of entecavir on future treatment options [see Microbiology (12.4) ] . 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.
Geriatric use
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) ] .
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.
Description
Entecavir is the tradename for entecavir, 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: crospovidone, hypromellose, lactose monohydrate, microcrystalline cellulose, magnesium stearate, polyethylene glycol, polyvinyl alcohol, talc, titanium dioxide and water. Entecavir Chemical Structure
Mechanism of action
12.1 Mechanism of Action Entecavir is an antiviral drug against the hepatitis B virus [see Microbiology (12.4) ] .
How supplied
Entecavir Tablets are available in the following strengths and configurations of plastic bottles with child-resistant closures: Product Strength and Dosage Form Description Quantity NDC Number Entecavir Tablets, USP 0.5 mg White to off-white, round tablet, debossed with “Y13” on one side. 30 tablets 90 tablets 50771-013-01 50771-013-02 Entecavir Tablets, USP 1 mg White to off-white, round tablet, debossed with “Y14” on one side. 30 tablets 50771-014-01 Storage Entecavir Tablets should be stored in a tightly closed container at 25°C (77°F); excursions permitted between 15°C and 30°C (59°F and 86°F) [see USP Controlled Room Temperature]. Store entecavir tablets in a tightly closed container to protect from light.
Storage
Storage Entecavir Tablets should be stored in a tightly closed container at 25°C (77°F); excursions permitted between 15°C and 30°C (59°F and 86°F) [see USP Controlled Room Temperature]. Store entecavir tablets in a tightly closed container to protect from light. Storage Entecavir Tablets should be stored in a tightly closed container at 25°C (77°F); excursions permitted between 15°C and 30°C (59°F and 86°F) [see USP Controlled Room Temperature]. Store entecavir tablets in a tightly closed container to protect from light.
Label text from the FDA structured product label by Yaopharma Co., Ltd. (revised Jul 7, 2026). Long sections are shortened; the complete label is on DailyMed.
Active ingredients
- Entecavir in 20 products
- Entecavir Anhydrous in 8 products
Entecavir NDC products (28)
| NDC | Strength & form | Labeler | Type |
|---|---|---|---|
| 60687-216 | Entecavir .5 mg/1 Tablet | American Health Packaging | ANDA |
| 65162-446 | Entecavir .5 mg/1 Tablet, Film Coated | Amneal Pharmaceuticals LLC | ANDA |
| 65162-449 | Entecavir 1 mg/1 Tablet, Film Coated | Amneal Pharmaceuticals LLC | ANDA |
| 65862-842 | Entecavir 1 mg/1 Tablet | Aurobindo Pharma Limited | ANDA |
| 65862-841 | Entecavir .5 mg/1 Tablet | Aurobindo Pharma Limited | ANDA |
| 42291-261 | Entecavir .5 mg/1 Tablet, Film Coated | AvKARE | ANDA |
| 31722-833 | Entecavir Anhydrous .5 mg/1 Tablet | Camber Pharmaceuticals, Inc. | ANDA |
| 31722-834 | Entecavir Anhydrous 1 mg/1 Tablet | Camber Pharmaceuticals, Inc. | ANDA |
| 42494-457 | Entecavir Anhydrous .5 mg/1 Tablet | Cameron Pharmaceuticals | ANDA |
| 42494-458 | Entecavir Anhydrous 1 mg/1 Tablet | Cameron Pharmaceuticals | ANDA |
| 61442-311 | Entecavir .5 mg/1 Tablet | Carlsbad Technology, Inc. | ANDA |
| 69097-425 | Entecavir 1 mg/1 Tablet, Film Coated | Cipla USA Inc. | ANDA |
| 69097-426 | Entecavir .5 mg/1 Tablet, Film Coated | Cipla USA Inc. | ANDA |
| 42806-668 | Entecavir Anhydrous 1 mg/1 Tablet, Film Coated | Epic Pharma, LLC | ANDA |
| 42806-667 | Entecavir Anhydrous .5 mg/1 Tablet, Film Coated | Epic Pharma, LLC | ANDA |
| 42806-659 | Entecavir 1 mg/1 Tablet | EPIC PHARMA, LLC | ANDA |
| 42806-658 | Entecavir .5 mg/1 Tablet | EPIC PHARMA, LLC | ANDA |
| 51407-589 | Entecavir .5 mg/1 Tablet | Golden State Medical Supply, Inc. | ANDA |
| 16714-718 | Entecavir 1 mg/1 Tablet, Film Coated | NorthStar RxLLC | ANDA |
| 16714-717 | Entecavir .5 mg/1 Tablet, Film Coated | NorthStar RxLLC | ANDA |
| 43547-437 | Entecavir Anhydrous 1 mg/1 Tablet, Film Coated | Solco Healthcare LLC | ANDA |
| 43547-436 | Entecavir Anhydrous .5 mg/1 Tablet, Film Coated | Solco Healthcare LLC | ANDA |
| 50771-014 | Entecavir 1 mg/1 Tablet, Film Coated | Yaopharma Co., Ltd. | ANDA |
| 50771-013 | Entecavir .5 mg/1 Tablet, Film Coated | Yaopharma Co., Ltd. | ANDA |
| 70771-1019 | Entecavir .5 mg/1 Tablet, Film Coated | Zydus Lifesciences Limited | ANDA |
| 70771-1020 | Entecavir 1 mg/1 Tablet, Film Coated | Zydus Lifesciences Limited | ANDA |
| 68382-921 | Entecavir 1 mg/1 Tablet, Film Coated | Zydus Pharmaceuticals USA Inc. | ANDA |
| 68382-920 | Entecavir .5 mg/1 Tablet, Film Coated | Zydus Pharmaceuticals USA Inc. | ANDA |
Entecavir recalls
- D-0001-2026 Oct 8, 2025 · Class II · Ongoing
Failed impurity/degradation specifications:Out of Specification result for an individual organic impurity - D-0002-2026 Oct 8, 2025 · Class II · Ongoing
Failed impurity/degradation specifications:Out of Specification result for an individual organic impurity - D-0656-2025 Sep 24, 2025 · Class II · Ongoing
Failed Impurity/Degradation Specifications - D-0657-2025 Sep 24, 2025 · Class II · Ongoing
Failed Impurity/Degradation Specifications - D-1095-2017 Aug 23, 2017 · Class II · Terminated
Failed Impurities/Degradation Specification: single unknown impurity OOS 0.33% (Limit:NMT 0.20%W/W) at the three month stability point.
Frequently asked questions
What is Entecavir used for?
Entecavir is indicated for the treatment of chronic hepatitis B virus infection in adults and pediatric patients 2 years of age and older with evidence of active viral replication and either evidence of persistent elevations in serum aminotransferases (ALT or AST) or histologically active disease Entecavir is a hepatitis B virus nucleoside analogue reverse transcriptase inhibitor indicated for…
What are the side effects of Entecavir?
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) ] . In adults, the most common adverse reactions (≥ 3%, all severity grades) are headache,… See the full label for the complete list.
Who makes Entecavir?
Entecavir is listed by 16 labelers in the FDA NDC directory, including American Health Packaging, Amneal Pharmaceuticals LLC, Aurobindo Pharma Limited, AvKARE.
Has Entecavir been recalled?
The FDA enforcement database lists 5 recalls for Entecavir, most recently D-0001-2026 (class ii): Failed impurity/degradation specifications:Out of Specification result for an individual organic impurity