ERTIVIX

Entecavir, USP is a guanosine nucleoside analogue with selective activity against HBV.

The chemical name for entecavir, USP 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, USP 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, USP film-coated tablets are available for oral administration in strengths of 0.5 mg and 1 mg of entecavir, USP.

Entecavir, USP 0.5 mg and 1 mg film-coated tablets contain the following inactive ingredients: Crospovidone, lactose monohydrate, magnesium stearate, microcrystalline cellulose and povidone.

The tablet coating contains hypromellose, iron oxide red (in 1 mg tablet only), polyethylene glycol and titanium dioxide.

Intencaviar is used in the following cases: chronic hepatitis B virus, in adults and children aged 2 years and over, with evidence of an effective tissue disease or through continuous increases in liver enzymes.

Carefully used, under medical supervision, in the following cases: pregnancy or breastfeeding; kidney diseases; liver diseases; or, in the case of liver transplantation.

Entecavir is an antiviral drug against the hepatitis B virus. 12.3 Pharmacokinetics The single.

• and multiple-dose pharmacokinetics of entecavir were evaluated in healthy subjects and subjects with chronic hepatitis B virus infection.

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 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 to 1.5 hours fed vs. 0.75 hours fasted), a decrease in C max of 44% to 46% and a decrease in AUC of 18% to 20% .

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%.

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.

Interactions, below.

After reaching peak concentration, entecavir plasma concentrations decreased in a bi-exponential manner with a terminal elimination half-life of approximately to 149 hours.

The observed drug accumulation index is approximately 2-fold with once-daily dosing, suggesting an effective accumulation half-life of approximately 24 hours.

Entecavir is predominantly eliminated by the kidney with urinary recovery of unchanged drug at steady-state ranging from 62% to 73% of the administered dose.

Renal clearance is independent of dose and ranges from to 471 mL/min suggesting that entecavir undergoes both glomerular filtration and net tubular secretion.

There are no significant gender differences in entecavir pharmacokinetics.

There are no significant racial differences in entecavir pharmacokinetics.

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.

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.

The steady-state pharmacokinetics of entecavir were evaluated in nucleoside-inhibitor-naïve and lamivudine-experienced HBeAg-positive pediatric subjects 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 a n=24 Lamivudine-Experienced b n=19 C max (ng/mL) (CV%) 6.31 14.48 AUC (0–24) (ng•h/mL) (CV%) 18.33 38.58 C min (ng/mL) (CV%) 0.28 0.47 a Subjects received once-daily doses of 0.015 mg/kg up to a maximum of 0.5 mg. b Subjects received once-daily doses of 0.030 mg/kg up to a maximum of 1 mg. 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).

Table 8.

Table 8: Pharmacokinetic Parameters in Subjects with Selected Degrees of Renal Function Renal Function Group Baseline Creatinine Clearance (mL/min) Unimpaired Mild Moderate Severe Severe Severe >80 >50 to ≤80 30 to 50 <30 Managed with Hemodialysis a Managed with CAPD n=6 n=6 n=6 n=6 n=6 n=4 C max (ng/mL) 8.1 10.4 10.5 15.3 15.4 16.6 (CV%) AUC (0-T) (ng•h/mL) 27.9 51.5 69.5 145.7 233.9 221.8 (CV) CLR (mL/min) 383.2 197.9 135.6 40.3 NA NA (SD) CLT/F (mL/min) 588.1 309.2 226.3 100.6 50.6 35.7 (SD) a Dosed immediately following hemodialysis.

CLR = renal clearance; CLT/F = apparent oral clearance.

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.

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.

The metabolism of entecavir was evaluated in in vitro and in vivo studies.

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 co-administration 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 co-administration of entecavir.

The steady-state pharmacokinetics of entecavir and co-administered drug were not altered in interaction studies of entecavir with lamivudine, adefovir dipivoxil, and tenofovir disoproxil fumarate. 12.4 Microbiology Mechanism of Action Entecavir, a deoxyguanosine nucleoside analogue with activity against HBV reverse transcriptase (rt), is efficiently phosphorylated to the active triphosphate form, which has an intracellular half-life of 15 hours.

By competing with the natural substrate deoxyguanosine triphosphate, entecavir triphosphate functionally inhibits all three activities of the HBV reverse transcriptase: base priming, reverse transcription of the negative strand from the pregenomic messenger RNA, and synthesis of the positive strand of HBV DNA.

Entecavir triphosphate is a weak inhibitor of cellular DNA polymerases α, β, and δ and mitochondrial DNA polymerase γ with K i values ranging from to >160 μM. Antiviral Activity Entecavir inhibited HBV DNA synthesis (50% reduction, EC 50 ) at a concentration of 0.004 μM in human HepG2 cells transfected with wild-type HBV.

The median

EC 50 value for entecavir against lamivudine-resistant HBV (rtL180M, rtM204V) was 0.026 μM (range 0.010 to 0.059 μM).

The co-administration of

HIV nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) with entecavir is unlikely to reduce the antiviral efficacy of entecavir against HBV or of any of these agents against HIV.

In HBV combination assays in cell culture, abacavir, didanosine, lamivudine, stavudine, tenofovir, or zidovudine were not antagonistic to the anti-HBV activity of entecavir over a wide range of concentrations.

In HIV antiviral assays, entecavir was not antagonistic to the cell culture anti-HIV activity of these six NRTIs or emtricitabine at concentrations greater than 100 times the C max of entecavir using the 1 mg dose.

A comprehensive analysis of the inhibitory activity of entecavir against a panel of laboratory and clinical HIV type 1 (HIV-1) isolates using a variety of cells and assay conditions yielded EC 50 values ranging from 0.026 to >10 μM; the lower EC 50 values were observed when decreased levels of virus were used in the assay.

In cell culture, entecavir selected for an M184I substitution in HIV reverse transcriptase at micromolar concentrations, confirming inhibitory pressure at high entecavir concentrations.

HIV variants containing the

M184V substitution showed loss of susceptibility to entecavir.

In cell-based assays, 8.

• to 30-fold reductions in entecavir phenotypic susceptibility were observed for lamivudine-resistant strains.

Further reductions (>70-fold) in entecavir phenotypic susceptibility required the presence of amino acid substitutions rtM204I/V with or without rtL180M along with additional substitutions at residues rtT184, rtS202, or rtM250, or a combination of these substitutions with or without an rtI169 substitution in the HBV reverse transcriptase.

Lamivudine-resistant strains harboring rtL180M plus rtM204V in combination with the amino acid substitution rtA181C conferred 16.

• to 122-fold reductions in entecavir phenotypic susceptibility.

Nucleoside-inhibitor-naïve subjects: Genotypic evaluations were performed on evaluable samples (>300 copies/mL serum HBV DNA) from 562 subjects who were treated with entecavir for up to 96 weeks in nucleoside-inhibitor-naïve studies (AI463022, AI463027, and rollover study AI463901).

By Week 96, evidence of emerging amino acid substitution rtS202G with rtL180M and rtM204V substitutions was detected in the HBV of 2 subjects (2/562=<1%), and of them experienced virologic rebound (≥1 log 10 increase above nadir).

In addition, emerging amino acid substitutions at rtM204I/V and rtL80I, rtV173L, or rtL180M, which conferred decreased phenotypic susceptibility to entecavir in the absence of rtT184, rtS202, or rtM250 changes, were detected in the HBV of 3 subjects (3/562=<1%) who experienced virologic rebound.

For subjects who continued treatment beyond 48 weeks, 75% (202/269) had HBV DNA <30.

Paracloud therapy (P) is a pill used to reduce hepatitis B symptoms, as it contains an effective metaphylaxis (Entecavir), an antiviral from the Nucleozid isotope group, which prevents the virus from multiplying through certain enzymes, which impedes cell growth and reproduction.

Why does

Baracloud use an antigen?

The following adverse reactions are discussed in other sections of the labeling: Exacerbations of hepatitis after discontinuation of treatment.

Lactic acidosis and severe hepatomegaly with steatosis.

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.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 1,720 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 to 4) Reported in Four Entecavir Clinical Trials Through 2 Years Nucleoside-Inhibitor-Naïve b Lamivudine-Refractory c Entecavir Lamivudine Entecavir Lamivudine Body System/ Adverse Reaction 0.5 mg 100 mg 1 mg 100 mg n=679 n=668 n=183 n=190 Any Grade to 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% 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.

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 Entecavir Lamivudine Entecavir Lamivudine 0.5 mg 100 mg 1 mg 100 mg Test n=679 n=668 n=183 n=190 Any Grade to 4 laboratory abnormality d 35% 36% 37% 45% ALT >10 x ULN and >2 x baseline 2% 4% 2% 11% ALT >5 x ULN 11% 16% 12% 24% Albumin <2.5 g/dL <1% <1% 0 2% Total bilirubin >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 ≥0.5 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% a On-treatment value worsened from baseline to Grade 3 or Grade for all parameters except albumin (any on-treatment value <2.5 g/dL), confirmed creatinine increase ≥0.5 mg/dL, and ALT >10 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 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.

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.

Table 5: Exacerbations of Hepatitis During Off-Treatment Follow-up, Subjects in Studies AI463022, AI463027, and AI463026 Subjects with ALT Elevations >10 x ULN and >2 x Reference a 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 a 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.

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.

Among the 102 subjects receiving entecavir, the most common treatment-emergent adverse events of any severity, regardless of causality, occurring through Week 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 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 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 x baseline and >10 x 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.

Among 65 subjects receiving entecavir in an open-label, post-liver transplant trial, 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 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 HBeAg-positive 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 long-­term 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 c Number of Subjects with Events Entecavir N=6,216 Non-ETV N=6,162 Hazard Ratio [Entecavir:Non-ETV] (CI a ) Primary Endpoints Overall malignant neoplasm 331 337 0.93 Liver-related HBV disease progression 350 375 0.89 Death.

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.

Nucleoside-inhibitor-treatment-naïve with compensated liver disease (greater than or equal to 16 years old): 0.5 mg once daily.

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.

Lamivudine-refractory or known lamivudine or telbivudine resistance substitutions (greater than or equal to 16 years old): 1 mg once daily.

Decompensated liver disease (adults): 1 mg once daily.

Renal impairment

Dosage adjustment is recommended if creatinine clearance is less than 50 mL/min. Entecavir tablets should be administered on an empty stomach. 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.

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 Patients a Lamivudine-Experienced Patients b to 11 3 6 greater than to 14 4 8 greater than to 17 5 10 greater than to 20 6 12 greater than to 23 7 14 greater than to 26 8 16 greater than 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.

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 Tablets 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 to less than 50 0.5 mg every 48 hours 0.5 mg once daily OR 1 mg every 48 hours to less than 30 0.5 mg every 72 hours 1 mg every 72 hours Less than 10 Hemodialysis or CAPD 0.5 mg every 7 days 1 mg every 7 days 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 tablets 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 tablets 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.

Entecavir tablets, USP 0.5 mg, are supplied as white to off-white, oval, film-coated, biconvex bevel edged, unscored tablet, debossed with “AN” on one side and “446” on the other side.

They are available as follows

Bottles of 30: NDC 65162-446-03 Bottles of 90: NDC 65162-446-09 Entecavir tablets, USP 1 mg, are supplied as pink, oval, film-coated, biconvex bevel edged, unscored tablet, debossed with “AN” on one side and “449” on the other side.

Bottles of 30: NDC 65162-449-03 Storage Entecavir tablets, USP should be stored in a tightly closed container at 20° to 25°C (68° to 77°F); excursions permitted between 15° to 30°C (59° to 86°F) .

Protect from light.

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.

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 post implantation 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 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.

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.

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.

The efficacy and safety of entecavir have not been established in patients less than 2 years of age.

Use of entecavir in this has not been evaluated because treatment of HBV in this is rarely required.

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.