Exacerbations of Hepatitis after Discontinuation of Treatment

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 (see ADVERSE REACTIONS: Exacerbations of Hepatitis after Discontinuation of Treatment).

Co-infection with HIV

BARACLUDE 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 BARACLUDE is used to treat chronic hepatitis B virus infection in patients with HIV infection that is not being treated (see Microbiology: Antiviral Activity, Antiviral Activity against HIV). Therefore, 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.

General

Renal Impairment

Dosage adjustment of BARACLUDE is recommended for patients with a creatinine clearance < 50 mL/min, including patients on hemodialysis or CAPD (see DOSAGE AND ADMINISTRATION: Renal Impairment).

Liver Transplant Recipients

The safety and efficacy of BARACLUDE in liver transplant recipients are unknown. If BARACLUDE treatment is determined to be necessary for a liver transplant recipient who has received or is receiving an immunosuppressant that may affect renal function, such as cyclosporine or tacrolimus, renal function must be carefully monitored both before and during treatment with BARACLUDE (see CLINICAL PHARMACOLOGY: Special Populations and DOSAGE AND ADMINISTRATION: Renal Impairment).

Information for Patients

A patient package insert (PPI) for BARACLUDE is available for patient information.

Patients should remain under the care of a physician while taking BARACLUDE. They should discuss any new symptoms or concurrent medications with their physician.

Patients should be advised to take BARACLUDE on an empty stomach (at least 2 hours after a meal and 2 hours before the next meal).

Patients should be informed that deterioration of liver disease may occur in some cases if treatment is discontinued, and that they should discuss any change in regimen with their physician.

Patients should be offered HIV antibody testing before starting BARACLUDE therapy.They should be informed that if they have HIV infection and are not receiving effective HIV treatment, BARACLUDE may increase the chance of HIV resistance to HIV medication (see WARNINGS: Co-infection with HIV).

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 (see Labor and Delivery).

Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term oral carcinogenicity studies of entecavir in mice and rats were carried out at exposures up to approximately 42 times (mice) and 35 times (rats) those observed in humans at the highest recommended dose of 1 mg/day.In mouse and rat studies, entecavir was positive for carcinogenic findings.

In mice, lung adenomas were increased in males and females at exposures 3 and 40 times those in humans. Lung carcinomas in both male and female mice were increased at exposures 40 times those in humans. Combined lung adenomas and carcinomas were increased in male mice at exposures 3 times and in female mice at exposures 40 times those in humans.Tumor development was preceded by pneumocyte proliferation in the lung, which was not observed in rats, dogs, or monkeys administered entecavir, supporting the conclusion that lung tumors in mice may be a species-specific event. Hepatocellular carcinomas were increased in males and combined liver adenomas and carcinomas were also increased at exposures 42 times those in humans. Vascular tumors in female mice (hemangiomas of ovaries and uterus and hemangiosarcomas of spleen) were increased at exposures 40 times those in humans. In rats, hepatocellular adenomas were increased in females at exposures 24 times those in humans; combined adenomas and carcinomas were also increased in females at exposures 24 times those in humans. Brain gliomas were induced in both males and females at exposures 35 and 24 times those in humans. Skin fibromas were induced in females at exposures 4 times those in humans.

It is not known how predictive the results of rodent carcinogenicity studies may be for humans.

Entecavir was clastogenic to human lymphocyte cultures. Entecavir was not mutagenic in the Ames bacterial reverse mutation assay using S. typhimurium and E. coli strains in the presence or absence of metabolic activation, a mammalian-cell gene mutation assay, and a transformation assay with Syrian hamster embryo cells.Entecavir was also negative in an oral micronucleus study and an oral DNA repair study in rats. In reproductive toxicology studies, in which animals were administered entecavir at up to 30 mg/kg for up to 4 weeks, no evidence of impaired fertility was seen in male or female rats at systemic exposures > 90 times those achieved in humans at the highest recommended dose of 1 mg/day. In rodent and dog toxicology studies, seminiferous tubular degeneration was observed at exposures ≥ 35 times those achieved in humans. No testicular changes were evident in monkeys.

Pregnancy

Pregnancy Category C

Reproduction studies have been performed in rats and rabbits at orally administered doses up to 200 and 16 mg/kg/day and showed no embryotoxicity or maternal toxicity at 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 3100 times those in humans. In rabbits, embryo-fetal toxicity (resorptions), reduced ossification (hyoid), and an increased incidence of 13th rib were observed at exposures 883 times those in humans. In a per-post natal study, no adverse effects on offspring were seen with entecavir administered orally to rats at exposures > 94 times those in humans. There are no adequate and well-controlled studies in pregnant women.Because animal reproduction studies are not always predictive of human response, BARACLUDE (entecavir) should be used during pregnancy only if clearly needed and after careful consideration of the risks and benefits.

Pregnancy Registry: To monitor fetal outcomes of pregnant women exposed to entecavir, a pregnancy registry has been established. Healthcare providers are encouraged to register patients by calling 1-800-258-4263.

Labor and Delivery

There are no studies in pregnant women and no data 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.

Nursing Mothers

Entecavir is excreted in the milk of rats. It is not known whether this drug is excreted in human milk. Mothers should be instructed not to breast-feed if they are taking BARACLUDE.

Pediatric Use

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

Geriatric Use

Clinical studies of BARACLUDE 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: Renal Impairment).

Use in Racial/Ethnic Groups

Clinical studies of BARACLUDE did not include sufficient numbers of subjects from some racial/ ethnic minorities (black/African American,Hispanic) to determine whether they respond differently to treatment with the drug.There are no significant racial differences in entecavir pharmacokinetics.

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