Do not use Entavir 1 mg Tablet for any conditions other than those specified by the doctor. Do not share the medicine with anyone else. Report to the doctor all your medical conditions and current medicines before taking this medication. Report any undesired effects or lack of improvement to the doctor on priority.

Black Box Warning

Severe Acute Exacerbations of Hepatitis B, Patients Co-Infected with HIV and HBV, and Lactic Acidosis and Hepatomegaly Severe acute exacerbations of hepatitis B have been reported in patients who have discontinued anti-hepatitis B therapy, including entecavir. 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 . Limited clinical experience suggests there is a potential for the development of resistance to HIV (human immunodeficiency virus) nucleoside reverse transcriptase inhibitors if ENTAVIR is used to treat chronic hepatitis B virus (HBV) infection in patients with HIV infection that is not being treated. Therapy with ENTAVIR is not recommended for HIV/HBV co-infected patients who are not also receiving highly active antiretroviral therapy (HAART) . Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs alone or in combination with antiretrovirals .

Composition

ENTAVIR 0.5 mg

Each film-coated tablet contains:

Entecavir …………….………………………………. 0.5 mg

ENTAVIR 1.0 mg

Each film-coated tablet contains:

Entecavir …………….………………………………. 1.0 mg

Dosage Form

Oral, film-coated tablet

Pharmacology

Pharmacodynamics

Mechanism of Action

Entecavir is an antiviral drug. Entecavir, a guanosine 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: (1) base priming, (2) reverse transcription of the negative strand from the pregenomic messenger RNA, and (3) 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 gamma  with Ki values ranging from 18 to >160 μM.

Pharmacokinetics
The single- and multiple-dose pharmacokinetics of entecavir were evaluated in healthy subjects and subjects with chronic HBV 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 1.0 mg, Cmax 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, Cmax at steady state was 4.2 ng/mL and trough plasma concentration (Ctrough) was 0.3 ng/mL. For a 1 mg oral dose, Cmax was 8.2 ng/mL and Ctrough was 0.5 ng/mL.

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 versus 0.75 hours fasted), a decrease in Cmax of 44–46%, and a decrease in AUC of 18–20% .

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

Following administration of 14C-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 .

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.

Elimination

Entecavir is predominantly eliminated by the kidneys, with urinary recovery of the 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 .

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 ENTAVIR Tablets should be based on the renal function of the patient, rather than age .

Pediatrics:

Pharmacokinetic studies have not been conducted in children.

Renal impairment:

The pharmacokinetics of entecavir following a single 1 mg dose were studied in subjects (without chronic HBV 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 1 .