Entecavir Capsules

Pharmacological action 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 the negative strand of pregenomic mRNA reverse transcription; (3) synthesis of the positive strand of HBVDNA. The inhibition constant (Ki) of entecavir triphosphate on HBVDNA polymerase is 0.0012M. Entecavir triphosphate has a weak inhibitory effect on cellular α, β, δDNA polymerase and mitochondrial γDNA polymerase, with Ki values ranging from 18 to greater than 160uM. Antiviral activity In human HepG2 cells transfected with wild-type HBV, the concentration required for entecavir to inhibit 50% viral DNA synthesis (EC50) was 0.004uM. The median EC50 of entecavir against lamivudine-resistant strains (rtL180M, rtM204V) was 0.026uM (range 0.01-0.059uM). Co-administration of entecavir with HIV nucleoside reverse transcriptase inhibitors (NRTIs) is unlikely to reduce the anti-HBV efficacy of entecavir or the anti-HIV efficacy of any of the latter drugs. Combination therapy for HBV was tested in cell culture and found that abacavir, didanosine, lamivudine, stavudine, tenofovir or zidovudine had no antagonistic effect on the anti-HBV activity of entecavir over a wide range of concentrations. In the HIV antiviral activity experiment, when the concentration of entecavir was 4 times greater than the peak concentration in vivo, entecavir had no antagonistic effect on the anti-HIV activity of 6 NRTIs in cell culture. Anti-HIV viral activity A comprehensive analysis of the inhibitory activity of entecavir against a group of laboratory isolated strains and clinically isolated human immunodeficiency virus type 1 (HIV-1) strains, the EC50 values obtained under different cell and experimental conditions ranged from 0.026 to 10uM; lower EC50 values were observed when the virus level decreased. In cell culture, entecavir can select the M184I site substitution of HIV reverse transcriptase at micromolar concentration levels, and the inhibitory effect was confirmed at high concentration levels of entecavir. HIV variants containing the M184V site substitution lose sensitivity to entecavir. The sensitivity of lamivudine-resistant strains (LVDr) with rtM204I/V and rtL180M site substitutions in the reverse transcriptase region to entecavir was reduced by 8 times compared with wild-type HBV strains in drug-resistant cell culture. The sensitivity to entecavir was also reduced in cell culture in the presence of additional entecavir-resistant amino acid changes at rtT184, rtS202 and/or rtM250 sites. Clinical isolates with additional (rtT184A, C, F, G, I, L, M or S; rtS202C, G or I; and/or rtM250I, L or V) site substitutions were further reduced by 16-741 times to entecavir compared with wild-type strains. Virus strains with rtT184, rtS202, and rtM250 entecavir resistance site substitutions alone have only a modest effect on entecavir sensitivity, and no reduced sensitivity was observed in more than 1,000 patients without lamivudine resistance site substitutions. In cell culture, resistance was found to be mediated by changes in HBV reverse transcriptase that reduced competitive binding, and the replication ability of resistant HBV strains was weakened. Clinical studies In clinical studies, patients who initially received entecavir 0.5 mg (nucleoside-naive) or 1 mg (lamivudine failure) and had HBV DNA PCR test values during treatment at or after 24 weeks of treatment were monitored for resistance. Nucleoside-naive patients: In a study of nucleoside-naive patients, the proportion of patients with genetic evidence of rtT184, rts202, and/or rtM250 entecavir resistance site substitutions was 1% (see table below). Substitutions at these sites were found to generate entecavir resistance only on the basis of the emergence of lamivudine resistance sites (rtM204V and rtL180M). The number of patients with genotypic entecavir resistance and resistance testing during the 144-week study in nucleoside-naive patients [including patients with on-treatment PCR-detected HBV DNA values at or after Week 24 for the entire 58 weeks of the study (1 year), between Weeks 58 and 102 for the entire study (2 years), or between Weeks 102 and 156 for the entire study]: 663 at Year 1, 278 at Year 2, and 149 at Year 3a. Number of patients with genotypic resistance to entecavir (patients also had lamivudine-resistance site substitutions): 1 case at 1 year (1%), 1 case at 2 years (1%), and 1 case at 3 yearsa (1%) Cumulative incidence of genotypic resistance to entecavir (patients also had lamivudine-resistance site substitutions): 0.2% at 1 year, 0.5% at 2 years, and 1.2% at 3 yearsa. Number of patients with virologic rebound (≥1 log10 increase in HBV DNA from nadir by PCR, confirmed by serial testing or at the end of the time window) due to entecavir resistance (patients also had lamivudine resistance site substitutions): 1 patient (1%) at 1 year, 0 patients at 2 years, and 1 patient (1%) at 3 yearsa.aThe 3-year results reflect 147 of 149 patients who received entecavir 1.0 mg in the entecavir continuation study and 130 patients who received entecavir and lamivudine combination therapy for a median of 20 weeks (followed by long-term entecavir therapy).Patients who failed lamivudine therapy: Among baseline viral isolates from patients who failed entecavir therapy and underwent resistance surveillance, 10 of 187 patients (5%) had entecavir resistance site substitutions, suggesting that prior lamivudine therapy could select for these resistance sites and that they were present at low levels prior to entecavir therapy. During the entire 144 weeks of the study, 3 of the 10 patients experienced virological rebound (increase of ≥1log10 from the nadir).

The main ingredient of this product is entecavir

The content of this product is white or off-white granules or powder.

This product is suitable for the treatment of chronic hepatitis B in adults with active viral replication, persistent elevation of serum transaminase ALT, or active lesions shown in liver histology.

Patients should take Engandin under the guidance of an experienced physician. Recommended dose: Adults and adolescents aged 16 years and above should take Engandin orally, 0.5 mg once a day. Patients who develop viremia or lamivudine-resistant mutations during lamivudine treatment should take 1 mg once a day. Engandin should be taken on an empty stomach (at least 2 hours before or after a meal). Renal insufficiency: In patients with renal insufficiency, the apparent oral clearance of entecavir decreases with decreasing creatinine clearance. Patients with creatinine clearance <50 ml/min [including patients receiving hemodialysis or continuous ambulatory peritoneal dialysis (CAPD)] should adjust their dosage. Hepatic insufficiency: No dosage adjustment is required for patients with hepatic insufficiency. Treatment period: The optimal treatment duration of Engandin and its relationship with long-term treatment outcomes, such as cirrhosis and liver cancer, are not yet clear.

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 events and abnormal laboratory tests of entecavir and lamivudine were similar. In studies conducted abroad, the most common adverse events of this product were: headache, fatigue, dizziness, and nausea. Common adverse events in patients treated with lamivudine were: 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 events and abnormal laboratory test indicators.

1. It is contraindicated for those who are allergic to entecavir or any ingredient in the preparation; 2. Since there are not enough elderly patients aged 65 and above to participate in the clinical study of this product, it is not clear how the elderly patients react to this product differently from the younger patients. Other clinical trial reports have not found any difference between the elderly and the younger 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 choice of drug dosage and renal function should be monitored; 3. 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; 4. There is currently no data suggesting that this product can affect the mother-to-child transmission of HBV, so appropriate intervention measures should be taken to prevent newborns from being infected with HBV; 5. 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 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 to 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.

The metabolism of entecavir was evaluated in vitro and in vivo. Entecavir is not a substrate, inhibitor, or inducer of the cytochrome P450 (CYP450) enzyme system. At concentrations approximately 10,000 times the human concentration, entecavir does not inhibit any of the major human CYP450 enzymes: 1A2, 2C9, 2C19, 2D6, 3A4, 286, and 2E1. At concentrations approximately 340 times the human concentration, 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. When studying the interaction of entecavir with lamivudine, adefovir and tenofovir, it was found that the steady-state pharmacokinetics of entecavir and its interacting drugs were not changed. Since entecavir is mainly cleared by the kidneys, taking entecavir at the same time as 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.

Keep in a dark place, sealed and stored in a dry place below 25℃.

0.5mg

24 months

Hainan Zhonghe Pharmaceutical Co., Ltd.

• Founded in:

  1995-04-17

• Address:

  No.168 Nanhai Avenue, Haikou City, Haikou Free Trade Zone

• Tax NO.:

  91460000293675844T

• Registered Funds:

  360 million yuan

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