The term 'hepatitis' simply means inflammation of the liver. Hepatitis may be caused by a virus or a toxin such as alcohol. Other viruses that can cause injury to liver cells include the hepatitis A and hepatitis C viruses. These viruses are not related to each other or to hepatitis B virus and differ in their structure, the ways they are spread among individuals, the severity of symptoms they can cause, the way they are treated, and the outcome of the infection.
What is the scope of the problem?
Hepatitis B is an infection of the liver caused by the hepatitis B virus (HBV). It is estimated that 350 million individuals worldwide are infected with the virus, which causes 620,000 deaths worldwide each year. According to the Centers for Disease Control (CDC), approximately 46,000 new cases of hepatitis B occurred in the United States in 2006.
In the United States, rates of new infection were highest ...
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Severe acute exacerbations of hepatitis B have been reported in patients who have discontinued anti-hepatitis B therapy, including entecavir [see ADVERSE REACTIONS]. 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.
BARACLUDE (entecavir) 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 (entecavir) is used to treat chronic hepatitis B virus infection in patients with HIV infection that is not being treated [see CLINICAL PHARMACOLOGY]. Therefore, therapy with BARACLUDE (entecavir) is not recommended for HIV/HBV co-infected patients who are not also receiving HAART. Before initiating BARACLUDE (entecavir) therapy, HIV antibody testing should be offered to all patients. BARACLUDE (entecavir) has not been studied as a treatment for HIV infection and is not recommended for this use.
Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues, including BARACLUDE (entecavir) , alone or in combination with antiretrovirals. A majority of these cases have been in women. Obesity and prolonged nucleoside exposure may be risk factors. Particular caution should be exercised when administering nucleoside analogues to any patient with known risk factors for liver disease; however, cases have also been reported in patients with no known risk factors.
Lactic acidosis with BARACLUDE (entecavir) use has been reported, often in association with hepatic decompensation, other serious medical conditions, or drug exposures. Patients with decompensated liver disease may be at higher risk for lactic acidosis. Treatment with BARACLUDE (entecavir) should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations).
See FDA-approved Patient Labeling.
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 (entecavir) therapy. They should be informed that if they have HIV infection and are not receiving effective HIV treatment, BARACLUDE (entecavir) may increase the chance of HIV resistance to HIV medication.
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 greater than 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 or greater than those achieved in humans. No testicular changes were evident in monkeys.
There are no adequate and well-controlled studies of BARACLUDE (entecavir) in pregnant women. When pregnant rats and rabbits received entecavir at 28 and 212 times the human exposure at the highest human dose, there were no signs of embryofetal toxicity. 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.
Developmental toxicity studies were performed in rats and rabbits. There were no signs of embryofetal or maternal toxicity when pregnant animals received oral entecavir at approximately 28 (rat) and 212 (rabbit) times the human exposure achieved at the highest recommended human dose of 1 mg/day. In rats, maternal toxicity, embryofetal 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, embryofetal toxicity (resorptions), reduced ossification (hyoid), and an increased incidence of 13th rib were observed at exposures 883 times those in humans. In a peri-postnatal study, no adverse effects on offspring occurred when rats received oral entecavir at exposures greater than 94 times those in humans.
There are no studies in pregnant women and no data on the effect of BARACLUDE (entecavir) on transmission of HBV from mother to infant. Therefore, appropriate interventions should be used to prevent neonatal acquisition of HBV.
It is not known whether BARACLUDE is excreted into human milk; however, entecavir is excreted into the milk of rats. Because many drugs are excreted into human milk and because of the potential for serious adverse reactions in nursing infants from BARACLUDE (entecavir) , a decision should be made to discontinue nursing or to discontinue BARACLUDE (entecavir) taking into consideration the importance of continued hepatitis B therapy to the mother and the known benefits of breastfeeding.
Safety and effectiveness of entecavir in pediatric patients below the age of 16 years have not been established.
Clinical studies of BARACLUDE (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 [see DOSAGE AND ADMINISTRATION].
Clinical studies of BARACLUDE (entecavir) 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.
Dosage adjustment of BARACLUDE (entecavir) is recommended for patients with creatinine clearance less than 50 mL/min, including patients on hemodialysis or CAPD [see DOSAGE AND ADMINISTRATION and CLINICAL PHARMACOLOGY].
Liver transplant recipients: The safety and efficacy of BARACLUDE (entecavir) in liver transplant recipients are unknown. If BARACLUDE (entecavir) 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 DOSAGE AND ADMINISTRATION and CLINICAL PHARMACOLOGY].
Last reviewed on RxList: 2/17/2011
This monograph has been modified to include the generic and brand name in many instances.
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