Each Tablet Contains: Entecavir monohydrate 0.53mg (eq. to Entecavir 0.5mg).
ENTIGIN is indicated for the treatment of chronic hepatitis B virus infection in adults with evidence of active viral replication.
Entecavir should be administered on an empty stomach (at least 2 hours after a meal and 2 hours before the next meal).
Recommended Dosage: The recommended dose of entecavir for chronic hepatitis B virus infection in nucleoside-treatment-naive adults and adolescents 16 years of age and older is 0.5mg once daily.
The recommended dose of entecavir in adults and adolescents (≥16 years of age) with a history of hepatitis B viremia while receiving lamivudine or known lamivudine resistance mutations is 1mg once daily.
Renal Impairment: In subjects with renal impairment, the apparent oral clearance of entecavir decreased as creatinine clearance decreased. Dosage adjustment is recommended for patients with creatinine clearance <50ml/min, including patients on hemodialysis or continuous ambulatory peritoneal dialysis (CAPD), as shown in Table 1. (See Table 1.)
Click on icon to see table/diagram/image
Hepatic Impairment: No dosage adjustment is necessary for patients with hepatic impairment.
Duration of Therapy: The optimal duration of treatment with entecavir for patients with chronic hepatitis B infection and the relationship between treatment and long-term outcomes (such as cirrhosis and hepatocellular carcinoma) are unknown.
There is no experience of entecavir overdosage reported in patients. Healthy subjects who received single entecavir doses up to 40mg or multiple doses up to 20mg/day for up to 14 days had no increase in or unexpected adverse events. If overdose occurs, the patient must be monitored for evidence of toxicity, and standard supportive treatment applied as necessary. Following a single 1mg dose of entecavir, a 4-hour hemodialysis session removed approximately 13% of the entecavir dose.
ENTIGIN is contraindicated in patients with previously demonstrated hypersensitivity to entecavir or any component of the product.
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 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 entecavir is used to treat chronic hepatitis B virus infection in patients with HIV infection that is not being treated. Therapy with entecavir is not recommended for HIV/HBV co-infected patients who are not also receiving highly active antiretroviral therapy (HAART).
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.
Co-infection with HIV: 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 entecavir is used to treat chronic hepatitis B virus infection in patients with HIV infection that is not being treated. Therefore, therapy with entecavir is not recommended for HIV/HBV co-infected patients who are not also receiving highly active antiretroviral therapy (HAART). Before initiating entecavir therapy, HIV antibody testing should be offered to all patients. 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: 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.
Use in Racial/Ethnic Groups: Clinical studies of 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.
Use in Children: Safety and effectiveness of entecavir in pediatric patients below the age of 16 years have not been established.
Use in Elderly: Clinical studies of 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.
Pregnancy: Pregnancy Category C.
Reproduction studies have been performed in rats and rabbits at orally administered doses up to 200 and 16mg/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 1mg/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 peri-postnatal 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, entecavir should be used during pregnancy only if clearly needed and after careful consideration of the risks and benefits.
Labor and Delivery: There are no studies in pregnant women and no data on the effect of entecavir 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 entecavir.
Assessment of adverse reactions is based on four studies (AI463014, AI463022, AI463026, AI463027) in which 1720 subjects with chronic hepatitis B infection received double-blind treatment with entecavir 0.5mg/day (n=679), entecavir 1mg/day (n=183), or lamivudine (n=858) for up to 2 years. Median duration of therapy was 69 weeks for entecavir-treated subjects and 63 weeks for lamivudine-treated subjects in Studies AI463022 and AI463027 and 73 weeks for entecavir-treated subjects and 51 weeks for lamivudine-treated subjects in Studies AI463026 and AI463014. The safety profiles of entecavir and lamivudine were comparable in these studies. The most common adverse events of any severity with at least a possible relation to study drug for entecavir-treated subjects were headache, fatigue, dizziness, and nausea. The most common adverse events among lamivudine-treated subjects were headache, fatigue, and dizziness. 1% of entecavir-treated in these four studies compared with 4% of lamivudine-treated subjects discontinued for adverse events or abnormal laboratory test results.
Clinical Adverse Events:
Selected clinical adverse events of moderate-severe intensity and considered at least possibly related to treatment occurring during therapy in four clinical studies in which entecavir was compared with lamivudine are presented in Table 2. (See Table 2.)
Click on icon to see table/diagram/image
Exacerbations of Hepatitis after Discontinuation of Treatment:
An exacerbation of hepatitis or ALT flare was defined as ALT>10 x ULN and >2 x the subject's reference level (minimum of the baseline or last measurement at end of dosing). For all subjects who discontinued treatment (regardless of reason), Table 3 presents the proportion of subjects in each study who experienced post-treatment ALT flares. In these studies, a subset of subjects was allowed to discontinue treatment at or after 52 weeks if they achieved a protocol-defined response to therapy. If entecavir is discontinued without regard to treatment response, the rate of post-treatment flares could be higher. (See Table 3.)
Click on icon to see table/diagram/image
Since Entecavir is primarily eliminated by the kidneys, coadministration of Entecavir with drugs that reduce renal function or compete for active tubular secretion may increase serum concentrations of either Entecavir or the coadministered drug. Coadministration of Entecavir with lamivudine, adefovir dipivoxil, or tenofovir disoproxil fumarate did not result in significant drug interactions. The effects of coadministration of Entecavir with other drugs that are renally eliminated or are known to affect renal function have not been evaluated, and patients should be monitored closely for adverse events when Entecavir is coadministered with such drugs.
J05AF10 - entecavir ; Belongs to the class of nucleoside and nucleotide reverse transcriptase inhibitors. Used in the systemic treatment of viral infections.