WARNINGS AND PRECAUTIONS
Severe Acute Exacerbations of Hepatitis B
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.
Patients Co-infected with HIV or HBV
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 Clinical Pharmacology ]. Therefore, therapy with BARACLUDE is not recommended for HIV/HBV co-infected patients who are not also receiving 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.
Lactic Acidosis and Severe Hepatomegaly with Steatosis
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.
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. Treatment with BARACLUDE 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).
USE IN SPECIFIC POPULATIONS
Pregnancy Category C.
There are no adequate and well-controlled studies of BARACLUDE 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 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.
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.
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, a decision should be made to discontinue nursing or to discontinue BARACLUDE 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 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 ].
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.
Dosage adjustment of BARACLUDE 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 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 Dosage and Administration and Clinical Pharmacology ].