Entecavir Anhydrous

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 )

Entecavir Tablets, USP, 0.5 mg, are white round-shaped, film-coated tablets, debossed with "C1" on one side. Entecavir Tablets, USP, 1 mg, are pink round-shaped, film-coated tablet, debossed with "C2" on one side. Tablets: 0.5 mg and 1 mg ( 3 , 16 )

None. None. ( 4 )

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).

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 Conba USA Inc. at 1-609-924-0905 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 Includes events of possible, probable, certain, or unknown relationship to treatment regimen. of Moderate-Severe Intensity (Grades 2–4) 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 2–4 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 ULN=upper limit of normal. Any Grade 3–4 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 × 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 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. 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 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. […]

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.

Liver transplant recipients: Limited data on safety and efficacy are available. ( 8.8 )

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 15–20%. 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 Entecavir was administered orally to pregnant rats (at 2, 20, and 200 mg per kg per day) and rabbits (at 1, 4, and 16 mg per kg per day) during organogenesis (on gestation Days 6 through 15 [rat] and 6 through 18 [rabbit]). In rats, embryofetal toxicity including post-implantation loss, resorptions, tail and vertebral malformations, skeletal variations including reduced ossification (vertebrate, sternebrae, and phalanges) and extra lumbar vertebrae and ribs, and lower fetal body weights were observed at systemic exposures (AUC) 3,100 times those in humans at the MRHD. Maternal toxicity was also observed at this dose level. In rabbits, embryofetal toxicity including postimplantation loss, resorptions and skeletal variations, including reduced ossification (hyoid) and increased incidence of 13 th rib, were observed at systemic exposures (AUC) 883 times those in humans at the MRHD. There were no signs of embryofetal toxicity when pregnant animals received oral entecavir at 28 (rat) and 212 (rabbit) times the human exposure (AUC) at the MRHD. In a pre/postnatal development study, entecavir was administered orally to pregnant rats at 0.3, 3, and 30 mg per kg per day from gestation day 6 to lactation/post-partum day 20. No adverse effects on the offspring occurred at up to the highest dose evaluated, resulting in exposures (AUC) greater than 94 times those in humans at the MRHD.

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. 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 (2.4) 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). […]

Entecavir is an antiviral drug against hepatitis B virus [see Microbiology (12.4) ] .