Hepavance

Entecavir.

HEPAVANCE Film-Coated Tablet 0.5 mg contains Entecavir 0.53 mg (0.5 mg as Entecavir anhydrous) and Lactose Hydrate (Animal origin: Cow, Part of Use: Milk).

HEPAVANCE (entecavir) is indicated for the treatment of chronic hepatitis B virus infection in adults with evidence of active viral replication and either evidence of persistent elevations in serum aminotransferases (ALT or AST) or histologically active disease.

HEPAVANCE should be administered on an empty stomach (at least 2 hours after a meal and 2 hours before the next meal).
For chronic hepatitis B virus infection in nucleoside inhibitor-treatment-naïve adults and adolescents 16 years of age and older is 0.5 mg once daily. The recommended dose in adults and adolescents (at least 16 years of age) with a history of hepatitis B viremia while receiving lamivudine or known lamivudine or telbivudine resistance substitutions rtM204I/V with or without rtL180M, rtL80I/V, or rtV173L is 1 mg once daily.
For adult subjects with renal impairment, the apparent oral clearance of entecavir decreased as creatinine clearance decreased. Dosage adjustment is recommended for patients with creatinine clearance less than 50 mL/min, including patients on hemodialysis or continuous ambulatory peritoneal dialysis (CAPD), as shown in Table 1. The once-daily dosing regimens are preferred. (See Table 1.)

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Although there are insufficient data to recommend a specific dose adjustment of HEPAVANCE in pediatric patients with renal impairment, a reduction in the dose or an increase in the dosing interval similar to adjustments for adults should be considered.
No dosage adjustment is necessary for patients with hepatic impairment.
The optimal duration of treatment with HEPAVANCE for patients with chronic hepatitis B virus infection and the relationship between treatment and long-term outcomes such as cirrhosis and hepatocellular carcinoma are unknown.

There is limited experience of entecavir overdosage reported in patients. Healthy subjects who received single entecavir doses up to 40 mg or multiple doses up to 20 mg/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 1 mg dose of entecavir, a 4-hour hemodialysis session removed approximately 13% of the entecavir dose.

None.

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 HEPAVANCE is used to treat chronic hepatitis B virus (HBV) infection in patients with HIV infection that is not being treated. Therapy with HEPAVANCE is not recommended for HIV/HBV co-infected patients who are not also receiving highly active antiretroviral therapy (HAART).
Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogue inhibitors alone or in combination with antiretrovirals.

General Precautions: Patients should remain under the care of a physician while taking HEPAVANCE. They should discuss any new symptoms or concurrent medications with their physician.
Patients should be advised that treatment with HEPAVANCE has not been shown to reduce the risk of transmission of HBV to others through sexual contact or blood contamination.
Patients should be advised to take HEPAVANCE on an empty stomach (at least 2 hours after a meal and 2 hours before the next meal).
Patients should be advised to take a missed dose as soon as remembered unless it is almost time for the next dose. Patients should not take two doses at the same time.
Patients should be advised that treatment with HEPAVANCE will not cure HBV.
Patients should be informed that HEPAVANCE may lower the amount of HBV in the body, may lower the ability of HBV to multiply and infect new liver cells, and may improve the condition of the liver.
Patients should be informed that it is not known whether HEPAVANCE will reduce their chances of getting liver cancer or cirrhosis.
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. 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 and HBV: HEPAVANCE 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 HEPAVANCE is used to treat chronic hepatitis B virus infection in patients with HIV infection that is not being treated. Therefore, therapy with HEPAVANCE is not recommended for HIV/HBV co-infected patients who are not also receiving HAART. Before initiating HEPAVANCE therapy, HIV antibody testing should be offered to all patients. HEPAVANCE 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 analogue inhibitors, including HEPAVANCE, alone or in combination with antiretrovirals. A majority of these cases have been in women. Obesity and prolonged nucleoside inhibitor exposure may be risk factors. Particular caution should be exercised when administering nucleoside analogue inhibitors 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 HEPAVANCE 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 HEPAVANCE 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).
Racial/Ethnic Groups: There are no significant racial differences in entecavir pharmacokinetics.
Renal Impairment: Dosage adjustment of HEPAVANCE is recommended for patients with creatinine clearance less than 50 mL/min, including patients on hemodialysis or CAPD.
Liver Transplant Recipients: If HEPAVANCE 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 HEPAVANCE.
Use in Children: There are limited data available on the use of HEPAVANCE in lamivudine-experienced pediatric patients; HEPAVANCE should be used in these patients only if the potential benefit justifies the potential risk to the child. Since some pediatric patients may require long-term or even lifetime management of chronic active hepatitis B, consideration should be given to the impact of HEPAVANCE on future treatment options. The efficacy and safety of HEPAVANCE have not been established in patients less than 2 years of age. Use of HEPAVANCE in this age group has not been evaluated because treatment of HBV in this age group is rarely required.
Use in Elderly: Clinical studies of HEPAVANCE 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 Category C: There are no adequate and well-controlled studies of HEPAVANCE in pregnant women. Because animal reproduction studies are not always predictive of human response, HEPAVANCE should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Labor and Delivery: There are no studies in pregnant women and no data on the effect of HEPAVANCE on transmission of HBV from mother to infant. Therefore, appropriate interventions should be used to prevent neonatal acquisition of HBV.
Nursing Mothers: It is not known whether HEPAVANCE 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 HEPAVANCE, a decision should be made to discontinue nursing or to discontinue HEPAVANCE taking into consideration the importance of continued hepatitis B therapy to the mother and the known benefits of breastfeeding.

Clinical Trial Experience in Adults: Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
Compensated Liver Disease: Assessment of adverse reactions is based on four studies (AI463014, AI463022, AI463026, and AI463027) in which 1720 subjects with chronic hepatitis B virus infection and compensated liver disease received double-blind treatment with entecavir 0.5 mg/day (n=679), entecavir 1 mg/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 reactions of any severity (≥3%) with at least a possible relation to study drug for entecavir-treated subjects were headache, fatigue, dizziness, and nausea. The most common adverse reactions among lamivudine-treated subjects were headache, fatigue, and dizziness. One percent of entecavir-treated subjects in these four studies compared with 4% of lamivudine-treated subjects discontinued for adverse events or abnormal laboratory test results.
Clinical adverse reactions 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.)

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Laboratory Abnormalities: Frequencies of selected treatment-emergent laboratory abnormalities reported during therapy in four clinical trials of entecavir compared with lamivudine are listed in Table 3. (See Table 3.)

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Among entecavir-treated subjects in these studies, on-treatment ALT elevations greater than 10 times the upper limit of normal (ULN) and greater than 2 times baseline generally resolved with continued treatment. A majority of these exacerbations were associated with a ≥2 log₁₀/mL reduction in viral load that preceded or coincided with the ALT elevation. Periodic monitoring of hepatic function is recommended during treatment.
Exacerbations of Hepatitis after Discontinuation of Treatment: An exacerbation of hepatitis or ALT flare was defined as ALT greater than 10 times ULN and greater than 2 times 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 4 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 4.)

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Postmarketing Experience: The following adverse reactions have been reported during postmarketing use of HEPAVANCE. Because these reactions were reported voluntarily from a population of unknown size, it is not possible to reliably estimate their frequency or establish a causal relationship to HEPAVANCE exposure.
Immune system disorders: Anaphylactoid reaction.
Metabolism and nutrition disorders: Lactic acidosis.
Hepatobiliary disorders: Increased transaminases.
Skin and subcutaneous tissue disorders: Alopecia, rash.

Since entecavir is primarily eliminated by the kidneys, coadministration of HEPAVANCE 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 HEPAVANCE 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 HEPAVANCE is coadministered with such drugs.

Store in a tightly closed container and store below 25°C.

Antivirals

J05AF10 - entecavir ; Belongs to the class of nucleoside and nucleotide reverse transcriptase inhibitors. Used in the systemic treatment of viral infections.

P₁S₁S₃

Tab 0.5 mg (off-white, triangular-shaped, engraved as "Ls2" on one side) x 30's, 120's.