Entecavir Tablets

1. Microbiological mechanism of action: This product is a guanine nucleoside analog that has an inhibitory effect on hepatitis B virus (HBV) polymerase. It can be converted into an active triphosphate through phosphorylation, and the half-life of the triphosphate in the cell is 15 hours. By competing with the natural substrate of HBV polymerase, deoxyguanosine triphosphate, entecavir triphosphate can inhibit all three activities of viral polymerase (reverse transcriptase): (1) HBV polymerase initiation; (2) formation of pregenomic mRNA reverse transcription negative strand; (3) synthesis of HBV DNA positive strand. The inhibition constant (Ki) of entecavir triphosphate on HBV DNA polymerase is 0.0012mu;M. Entecavir triphosphate has a weak inhibitory effect on cellular alpha;, beta;, delta; DNA polymerase and mitochondrial gamma; DNA polymerase, with Ki values of 18 to 160mu;M. 2. Antiviral activity In human HepG2 cells transfected with wild-type hepatitis B virus, the concentration required for entecavir to inhibit 50% viral DNA synthesis (EC50) is 0.004mu;M. The median EC50 of entecavir against lamivudine-resistant virus strains (rtL180M, rtM204V) is 0.026mu;M (range 0.01 to 0.059mu;M), while entecavir has no clinically relevant activity against type Ⅰ human immunodeficiency virus (HIV) grown in cell culture (EC5010mu;M). Daily or weekly use of this product can reduce the level of hepatitis virus DNA in North American woodchucks and ducks (4 to 8 log10). Long-term studies on five North American woodchucks showed that weekly oral administration of 0.5 mg/kg of entecavir (equivalent to a human dose of 1.0 mg) could keep viral DNA in three of the woodchucks at undetectable levels (viral DNA level 200 copies/mL, PCR method) for up to 3 years. No changes in HBV polymerase associated with entecavir resistance were found in any animal treated with the drug for up to 3 years. 3. In vitro studies of drug resistance: In cell experiments, it was found that the phenotypic sensitivity of lamivudine-resistant virus strains to entecavir was reduced by 8 to 30 times. If the hepatitis B virus polymerase already has amino acid substitutions that are resistant to lamivudine (rtL180M and/or rtM204V/I), in addition to substitution mutations at rtT184, rtS202 or rtM250, or on the basis of the occurrence of the above two mutations at the same time, whether or not the substitution mutation of rtI169 occurs, the phenotypic sensitivity to entecavir will be reduced even more (70 times). 4. Clinical study: Patients who were first treated with nucleoside drugs: 81% of patients who were first treated with nucleoside drugs had a viral load of 300 copies/mL after taking entecavir 0.5 mg/day orally for 48 weeks.

Entecavir

This product is a film-coated tablet, which appears white after removing the coating.

This product is suitable for the treatment of chronic hepatitis B in adults with active viral replication, persistently elevated serum alanine aminotransferase (ALT) or active lesions shown in liver histology.

Patients should take Boludin under the guidance of an experienced physician. 1. Recommended dose: Adults and youths over 16 years old should take Boludin orally, once a day, 0.5 mg each time. Patients with viremia or lamivudine-resistant mutations during lamivudine treatment should take 1.0 mg (two 0.5 mg tablets) once a day. Boludin should be taken on an empty stomach (at least 2 hours before or after a meal). 2. Renal insufficiency In patients with renal insufficiency, the oral clearance of entecavir decreases with decreasing creatinine clearance (see Pharmacokinetics: Special Populations). Patients with creatinine clearance <50 ml/min (including patients receiving hemodialysis or CAPD) should adjust the dosage. Recommended dose of entecavir for patients with renal insufficiency Creatinine clearance (mL/min) Usual dose (0.5 mg) Lamivudine treatment failure (1.0 mg) ≥50 Once a day, 0.5 mg each time Once a day, 1.0 mg each time 30 to <50 Once a day, 0.25 mg Once a day, 0.5 mg each time 10 to <30 Once a day, 0.15 mg Once a day, 0.3 mg each time Hemodialysis or CAPD Once a day, 0.15 mg once a day, 0.3 mg each time 3. Medication after hemodialysis Hepatic insufficiency No dosage adjustment is required for patients with hepatic insufficiency.

The evaluation of adverse reactions is based on 4 global clinical trials: AI463014, AI463022, AI463026, AI463027 and 3 clinical trials conducted in China (AI463012, AI463023, AI463056). A total of 2596 patients with chronic hepatitis B were enrolled in these 7 studies. In studies compared with lamivudine, the adverse reactions and laboratory abnormalities of entecavir and lamivudine were similar. In studies conducted abroad, the most common adverse reactions of this product are: headache, fatigue, dizziness, and nausea. Common adverse reactions in patients treated with lamivudine are: headache, fatigue, and dizziness. In these 4 studies, 1% of patients treated with entecavir and 4% of patients treated with lamivudine withdrew from the study due to adverse reactions and abnormal laboratory test indicators.

It is contraindicated for patients who are allergic to entecavir or any ingredient in the preparation.

Precautions for children: The safety and efficacy data of this product for children under 16 years old have not been established. Precautions for pregnancy and lactation: The effects of entecavir on pregnant women have not been fully studied. This product can only be used when the potential risks and benefits of the fetus have been fully weighed. There is currently no information suggesting that this product can affect the mother-to-child transmission of HBV, so appropriate intervention measures should be taken to prevent neonatal HBV infection. Entecavir can be secreted from rat milk. However, it is still unclear whether it is secreted in human milk, so it is not recommended for mothers taking this product to breastfeed. Precautions for the elderly: Since there are not enough elderly patients aged 65 and above to participate in clinical studies of this product, it is not clear how elderly patients and younger patients respond to this product. Other clinical trial reports have not found differences between elderly and young patients. Entecavir is mainly excreted by the kidneys, and the risk of toxic reactions may be higher in patients with renal impairment. Because most elderly patients have decreased renal function, attention should be paid to the selection of drug doses and renal function should be monitored.

1. The metabolism of entecavir was evaluated in vivo and in vitro. Entecavir is not a substrate, inhibitor or inducer of the cytochrome P450 (CYP450) enzyme system. At concentrations of about 10,000 times the concentration in humans, entecavir does not inhibit any of the major human CYP450 enzymes: 1A2, 2C9, 2C19, 2D6, 3A4, 2B6 and 2E1. At concentrations of about 340 times the concentration in humans, entecavir does not induce human CYP450 enzymes: 1A2, 2C9, 2C19, 3A4, 3A5 and 2B6. Concomitant administration of drugs that are metabolized by inhibiting or inducing the CYP450 system has no effect on the pharmacokinetics of entecavir. In addition, concomitant administration of entecavir has no effect on the pharmacokinetics of known CYP substrates. 2. When studying the interaction between entecavir and lamivudine, adefovir and tenofovir, it was found that the steady-state pharmacokinetics of entecavir and its interacting drugs were not changed. 3. Since entecavir is mainly cleared by the kidneys, taking entecavir while taking drugs that reduce renal function or compete for active glomerular secretion may increase the blood concentration of these two drugs. Taking entecavir with lamivudine, adefovir, and tenofovir at the same time will not cause obvious drug interactions. The interaction between taking entecavir and other drugs that are cleared by the kidneys or are known to affect renal function has not been studied. Patients should be closely monitored for the occurrence of adverse reactions when taking entecavir and such drugs at the same time.

Sealed and stored in a dry place.

1.0mg

36 months

SINO-AMERICAN Shanghai Squibb Pharmaceuticals Ltd.

• Founded in:

  1982-10-14

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  No. 1315, Jianchuan Road, Minhang District, Shanghai

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