Entecavir STELLA

Entecavir.

Each film-coated tablet contains Entecavir 0.5 mg (As entecavir monohydrate 0.532 mg).
Excipients/Inactive Ingredients: Calcium carbonate, pregelatinized starch, soy polysaccharide, carmellose sodium, citric acid anhydrous, sodium stearyl fumarate, opadry white 13B58802.

Pharmacotherapeutic group: Nucleoside and nucleotide reverse transcriptase inhibitors. ATC Code: J05AF10.
Pharmacology: Pharmacodynamics: Entecavir, a guanosine nucleoside analogue with activity against HBV polymerase, is efficiently phosphorylated to the active triphosphate form, which has an intracellular half-life of 15 hours. By competing with the natural substrate deoxyguanosine triphosphate, entecavir triphosphate functionally inhibits all three activities of the HBV polymerase (reverse transcriptase): Base priming; Reverse transcription of the negative strand from the pregenomic messenger RNA; Synthesis of the positive strand of HBV DNA.
Entecavir triphosphate has an inhibition constant (Ki) for HBV DNA polymerase of 0.0012 μM. It is a weak inhibitor of cellular DNA polymerases (alpha), (beta), and (delta) and mitochondrial DNA polymerase (gamma) with Ki values ranging from 18 to >160 μM.
Pharmacokinetics: Absorption: Following oral administration in healthy subjects, entecavir peak plasma concentrations occurred between 0.5 and 1.5 hours.
Effects of food on oral absorption: Oral administration of 0.5 mg of entecavir with a standard high-fat meal or a light meal resulted in a delay in absorption (1.0-1.5 hours fed vs. 0.75 hours fasted), a decrease in C_max of 44-46%, and a decrease in AUC of 18-20%.
Distribution: Based on the pharmacokinetic profile of entecavir after oral dosing, the estimated apparent volume of distribution is in excess of total body water, suggesting that entecavir is extensively distributed into tissues.
Binding of entecavir to human serum proteins in vitro was approximately 13%.
Metabolism and elimination: Following administration of ¹⁴C-entecavir in humans, no oxidative or acetylated metabolites were observed. Minor amounts of phase II metabolites (glucuronide and sulfate conjugates) were observed. Entecavir is not a substrate, inhibitor, or inducer of the cytochrome P450 (CYP450) enzyme system.
After reaching peak concentration, entecavir plasma concentrations decreased in a bi-exponential manner with a terminal elimination half-life of approximately 128-149 hours. The observed drug accumulation index is approximately 2-fold with once-daily dosing, suggesting an effective accumulation half-life of approximately 24 hours.
Entecavir is predominantly eliminated by the kidney with urinary recovery of unchanged drug at steady state ranging from 62% to 73% of the administered dose. Renal clearance is independent of dose and ranges from 360 to 471 ml/min suggesting that entecavir undergoes both glomerular filtration and net tubular secretion.

Treatment of chronic hepatitis B in adults with compensated liver disease with evidence of active viral replication, persistently elevated liver enzyme values, and histologically active disease, including those resistant to lamivudine.

Entecavir STELLA 0.5 mg should be administered on an empty stomach (at least 2 hours after a meal and 2 hours before the next meal).
The recommended dose of entecavir for chronic hepatitis B virus infection in nucleoside-treatment-naive adults and adolescents 16 years of age and older: 0.5 mg 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: 1 mg once daily.
Patients with renal impairment: See table.


Click on icon to see table/diagram/image


Hepatic impairment: No dosage adjustment is necessary for patients with hepatic impairment.

There is no 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.

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.
Dosage adjustment of entecavir is recommended for patients with a creatinine clearance <50 ml/min, including patients on hemodialysis or CAPD.
The safety and efficacy of entecavir in liver transplant recipients are unknown. If 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 entecavir.
Effects on ability to drive and use machines: No studies on the effects on the ability to drive and use machines have been performed. Dizziness, fatigue and somnolence are common side effects which may impair ability to drive and use machines.

Pregnancy: 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.
Lactation: 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.

The most common adverse effects of entecavir have been headache, fatigue, dizziness, and nausea. Other adverse effects include diarrhoea, dyspepsia, insomnia, somnolence, and vomiting. Raised liver enzyme concentrations may occur and exacerbation of hepatitis has been reported after stopping treatment with entecavir. Lactic acidosis, usually associated with severe hepatomegaly and steatosis, has been associated with treatment with nucleoside analogues alone or with antiretrovirals.

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.

Incompatibilities: In the absence of incompatibility studies, this medicinal product must not be mixed with other medicinal products. 

Store in a well-closed container, in a dry place. Do not store above 30°C.
Shelf-Life: 24 months from the date of manufacturing.

Antivirals

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