Entecavir Anhydrous

1 INDICATIONS AND USAGE 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 )

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 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 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. Lamivudine-Experienced Patients Children with body weight greater than 30 kg should receive 20 mL (1 mg) of oral solution or one 1 mg tablet once daily. 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 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 (1mg) 50 or greater 0.5 mg once daily 1 mg once daily 30 to less than 50 0.25 mg once daily For doses less than 0.5 mg, Baraclude Oral Solution is recommended. 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 OR 0.5 mg every 72 hours 0.3 mg once daily OR 1 mg every 72 hours Less than 10 Hemodialysis If administered on a hemodialysis day, administer entecavir after the hemodialysis session. or CAPD 0.05 mg once daily OR 0.5 mg every 7 days 0.1 mg once daily 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.

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) ] . 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. 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. Clinical Trial Experience in Pediatric Subjects The safety of entecavir in pediatric subjects 2 to less than 18 years of age is based on two clinical trials in subjects with chronic HBV infection (one Phase 2 pharmacokinetic trial [AI463028] and one Phase 3 trial [AI463189]). These trials provided experience in 168 HBeAgpositive subjects treated with entecavir for a median duration of 72 weeks. The adverse reactions observed in pediatric subjects who received treatment with entecavir were consistent with those observed in clinical trials of entecavir in adults. Adverse drug reactions reported in greater than 1% of pediatric subjects included abdominal pain, rash events, poor palatability ("product taste abnormal"), nausea, diarrhea, and vomiting. 6.2 Postmarketing Experience Data from Long-Term Observational Study Study AI463080 was a randomized, global, observational, open-label Phase 4 study to assess longterm risks and benefits of entecavir (0.5 mg/day or 1 mg/day) treatment as compared to other standard-of-care HBV nucleos(t)ide analogues in subjects with chronic HBV infection. A total of 12,378 patients were treated with entecavir (n=6,216) or other HBV nucleos(t)ide treatment [non-entecavir (ETV)] (n=6,162). Patients were evaluated at baseline and subsequently every 6 months for up to 10 years. The principal clinical outcome events assessed during the study were overall malignant neoplasms, liver-related HBV disease progression, HCC, non-HCC malignant neoplasms, and death. The study showed that entecavir was not significantly associated with an increased risk of malignant neoplasms compared to other standard-of-care HBV nucleos(t)ides, as assessed by either the composite endpoint of overall malignant neoplasms or the individual endpoint of non-HCC malignant neoplasms. The most commonly reported malignancy in both the entecavir and non-ETV groups was HCC followed by gastrointestinal malignancies. The data also showed that long-term entecavir use was not associated with a lower occurrence of HBV disease progression or a lower rate of death overall compared to other HBV nucleos(t)ides. The principal clinical outcome event assessments are shown in Table 6. Table 6: Principal Analyses of Time to Adjudicated Events–Randomized Treated Subjects Endpoint Overall malignant neoplasm is a composite event of HCC or non-HCC malignant neoplasm. Liver-related HBV disease progression is a composite event of liver-related death, HCC, or non-HCC HBV disease progression. Number of Subjects with Events Entecavir N=6,216 Non-ETV N=6,162 Hazard Ratio [Entecavir: Non-ETV] (CI 95.03% CI for overall malignant neoplasm, death, and liver-related HBV disease progression; 95% CI for nonHCC malignant neoplasm and HCC. ) Analyses were stratified by geographic region and prior HBV nucleos(t)ide experience. CI = confidence interval; N = total number of subjects. Primary Endpoints Overall malignant neoplasm 331 337 0.93 (0.800, 1.084) Liver-related HBV disease progression 350 375 0.89 (0.769, 1.030) Death 238 264 0.85 (0.713, 1.012) Secondary Endpoints Non-HCC malignant neoplasm 95 81 1.10 (0.817, 1.478) HCC 240 One subject had a pre-treatment HCC event and was excluded from the analysis. 263 0.87 (0.727, 1.032) Limitations of the study included population changes over the long-term follow-up period and more frequent post-randomization treatment changes in the non-ETV group. In addition, the study was underpowered to demonstrate a difference in the non-HCC malignancy rate because of the lower than expected background rate. Adverse Reactions from Postmarketing Spontaneous Reports 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.

12.3 Pharmacokinetics The single- and multiple-dose pharmacokinetics of entecavir were 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 solution. 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 (1.0–1.5 hours fed vs. 0.75 hours fasted), a decrease in C max of 44%–46%, and a decrease in AUC of 18%– 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 128–149 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: The steady-state pharmacokinetics of entecavir were evaluated in nucleoside-inhibitor-naïve and lamivudine-experienced HBeAg-positive pediatric subjects 2 to less than 18 years of age with compensated liver disease. Results are shown in Table 7. Entecavir exposure among nucleoside- inhibitor-naïve subjects was similar to the exposure achieved in adults receiving once-daily doses of 0.5 mg. Entecavir exposure among lamivudine-experienced subjects was similar to the exposure achieved in adults receiving once-daily doses of 1 mg. Table 7: Pharmacokinetic Parameters in Pediatric Subjects Nucleoside-Inhibitor-Naïve Subjects received once-daily doses of 0.015 mg/kg up to a maximum of 0.5 mg. n=24 Lamivudine-Experienced Subjects received once-daily doses of 0.030 mg/kg up to a maximum of 1 mg. n=19 C max (ng/mL) (CV%) 6.31 (30) 14.48 (31) AUC (0–24) (ng∙h/mL) (CV%) 18.33 (27) 38.58 (26) C min (ng/mL) (CV%) 0.28 (22) 0.47 (23) 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 8 [see Dosage and Administration (2.4) ] . Table 8: Pharmacokinetic Parameters in Subjects with Selected Degrees of Renal Function Renal Function Group Baseline Creatinine Clearance (mL/min) Severe Managed with Hemodialysis Dosed immediately following hemodialysis. Severe Managed with CAPD Unimpaired >80 Mild >50–≤80 Moderate 30–50 Severe <30 n=6 n=6 n=6 n=6 n=6 n=4 CLR = renal clearance; CLT/F = apparent oral clearance. 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 are 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 are 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) ] .