Dosing

The recommended dosage of entecavir is a single 0.5 mg tablet once-daily for chronic hepatitis B patients beginning treatment for the first time (nucleoside-naïve patients), and a single 1 mg tablet once-daily for patients experiencing resistance to lamivudine.

Entecavir comes in tablet and oral suspension forms and is taken by mouth without food. The tablets are film-coated, triangular-shaped and contain 0.5 or 1.0 mg entecavir. The oral solution contains 0.05 mg/ml entecavir in a 260 ml bottle.

Entecavir should be taken 2 hours after a meal and 2 hours before the next meal. 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.

Pharmacology

Pregnancy

Entecavir is in FDA Pregnancy Category C. There are no adequate and well-controlled studies in pregnant women. Reproduction studies have been performed in rats and rabbits at orally administered doses of 200 and 16 mg/kg/day and showed no embryo-toxicity or maternal toxicity in rat and rabbit at doses producing systemic exposures approximately 28 and 212 times those achieved at the highest recommended dose of 1 mg/day in humans.

In rats, maternal toxicity, embryo-fetal 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 3,100 times those in humans.

Because animal reproduction studies are not always predictive of human response, entecavir should be used during pregnancy only if clearly needed and after careful consideration of the risks and benefits. To monitor fetal outcomes of pregnant women exposed to entecavir, an Antiretroviral Pregnancy Registry has been established. Healthcare providers are encouraged to register patients online at http://www.APRegistry.com or by calling 1-800-258-4263.

Food and Drug Interactions

Food Interactions

Oral administration of entecavir 0.5 mg with a standard high-fat meal (945 kcal, 54.6 g fat) or a light meal (379 kcal, 8.2 g fat) resulted in delayed absorption (1.0 to 1.5 hour fed vs. 0.75 hours fasted), a decrease in Cmax of 44% to 46%, and a decrease in AUC of 18% to 20%. For this reason, and for best results, it is recommended to take entecavir 2 hours after a meal and 2 hours before the next meal.

The pharmacokinetics of entecavir following a single 1 mg dose were studied in patients without chronic hepatitis B infection with selected degrees of renal impairment. Dosage adjustment is recommended for patients with a creatinine clearance of less than 50 ml/min, including patients on hemodialysis or continuous ambulatory peritoneal dialysis (CAPD). Entecavir should be administered after hemodialysis. CAPD removed approximately 0.3% of the dose over 7 days.

Drug Interactions

Coadministration of the HIV nucleoside/tide analogues with entecavir does not appear to reduce the antiviral efficacy of entecavir against HBV or of any of these agents against HBV. In HBV combination assays in vitro, (Ziagen), (Videx), (Epivir-HBV), (Zerit), (Viread), and (Retrovir) 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 in vitro anti-HIV activity of these NRTIs at greater than 4 times the Cmax of entecavir.

Cross resistance has been observed among HBV nucleoside analogues. In cell-based assays entecavir had 8- to 30-fold less inhibition of replication of HBV that contained lamivudine resistance mutations rtL180M and rtM204V/I than of wild-type vius.

Important Safety Information

Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues alone or in combination with antiretrovirals.

• Severe acute exacerbations of hepatitis B have been reported in patients who have discontinued anti-hepatitis B therapy, including BARACLUDE. 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 BARACLUDE is used to treat chronic hepatitis B virus infection in patients with HIV infection that is not being treated. Therapy with BARACLUDE is not recommended for HIV/HBV co-infected patients who are not also receiving highly active antiretroviral therapy (HAART). Before initiating BARACLUDE therapy, HIV antibody testing should be offered to all patients.

• BARACLUDE has not been studied as a treatment for HIV infection and is not recommended for this use.

• Dosage adjustment of BARACLUDE is recommended for patients with a creatinine clearance <50 mL/min, patients with age-related decreases in renal function, and those on hemodialysis or continuous ambulatory peritoneal dialysis (CAPD).

• Since entecavir is primarily eliminated by the kidneys, coadministration of BARACLUDE with drugs that reduce renal function or compete for active tubular secretion may increase serum concentrations of either entecavir or the coadministered drug.

• The safety and efficacy of BARACLUDE in liver transplant recipients are unknown. Renal function must be carefully monitored both before and during treatment with BARACLUDE in a liver transplant recipient who has received or is receiving an immunosuppressant that may affect renal function, such as cyclosporine or tacrolimus.

• Patients should be advised that treatment with BARACLUDE has not been shown to reduce the risk of transmission of HBV to others through sexual contact or blood contamination.

• There are no adequate and well-controlled studies of BARACLUDE administered to pregnant women. BARACLUDE should be used during pregnancy only if clearly needed and after careful consideration of the risks and benefits. There are no studies on the effect of BARACLUDE on transmission of HBV from mother to infant. Therefore, appropriate interventions should be used to prevent neonatal acquisition of HBV. Women should be instructed not to breast-feed if they are taking BARACLUDE.

• Safety and effectiveness of BARACLUDE in pediatric patients below the age of 16 years have not been established.

The most common adverse events of moderate to severe intensity among patients treated with BARACLUDE in clinical trials included: headache (4%), fatigue (3%), diarrhea (1%), and dyspepsia (1%).

The recommended dose of BARACLUDE is 0.5 mg once daily in nucleoside-naïve adults, and 1 mg once daily in lamivudine-refractory adults. BARACLUDE should be administered on an empty stomach (at least 2 hours after a meal and at least 2 hours before the next meal). The optimal duration of treatment with BARACLUDE for patients with chronic hepatitis B infection and the relationship between treatment and long-term outcomes such as cirrhosis and hepatocellular carcinoma are unknown.