Product Overview
[Drug Name]
Generic Name: Entecavir Capsules
Trade Name: Heding
English Name: Entecavir Capsules
[Ingredients]
The main ingredient of this product is entecavir.
[Appearance]
This product consists of white or off-white granules or powder.
[Indications]
This product is indicated for the treatment of chronic hepatitis B in adults with active viral replication, persistently elevated serum ALT, or active liver histological lesions.
[Dosage and Administration]
Patients should take Entecavir under the guidance of an experienced physician. Recommended Dose: Adults and adolescents aged 16 years and above should take 0.5 mg of Entecavir orally once daily. Patients who develop viremia or lamivudine-resistant mutations during lamivudine treatment should take 1 mg orally once daily. Entecavir should be taken on an empty stomach (at least 2 hours before or after a meal). Renal Impairment: In patients with renal impairment, the apparent oral clearance of entecavir decreases with decreasing creatinine clearance. Patients with creatinine clearance < 50 ml/min (including those receiving hemodialysis or continuous ambulatory peritoneal dialysis (CAPD)) should have their dose adjusted. Hepatic Impairment: No dose adjustment is required for patients with hepatic impairment. Treatment Duration: The optimal duration of entecavir treatment and its relationship to long-term treatment outcomes, such as cirrhosis and liver cancer, are currently unknown.
[Adverse Reactions]
The evaluation of adverse reactions was based on four global clinical trials: AI463014, AI463022, AI463026, and AI463027, as well as three clinical trials conducted in China (AI463012, AI463023, and AI463056). A total of 2,596 patients with chronic hepatitis B were enrolled in these seven studies. In studies comparing entecavir with lamivudine, adverse events and laboratory abnormalities were similar. In studies conducted internationally, the most common adverse events for entecavir were headache, fatigue, dizziness, and nausea. Common adverse events in patients treated with lamivudine were headache, fatigue, and dizziness. In these four studies, 1% of entecavir-treated patients and 4% of lamivudine-treated patients withdrew from the study due to adverse events and laboratory abnormalities.
[Contraindications]
1. Entecavir is contraindicated in patients with allergies to entecavir or any of its ingredients.
2. Due to a lack of sufficient enrollment of patients aged 65 and older in clinical studies of this drug, it is unclear whether elderly patients respond differently to entecavir than younger patients. Other clinical trial reports have also failed to identify differences between elderly and younger patients. Entecavir is primarily excreted by the kidneys, and the risk of toxic reactions may be higher in patients with renal impairment. Because elderly patients often have decreased renal function, careful consideration should be given to dosage selection and renal function monitoring should be performed.
3. The effects of entecavir on pregnant women are insufficiently studied. This product should only be used after a thorough balance of potential risks and benefits to the fetus.
4. Currently, there is no data suggesting that this product can affect mother-to-child transmission of HBV. Therefore, appropriate interventions should be implemented to prevent neonatal HBV infection.
5. Entecavir is secreted in rat milk. However, whether it is secreted in human milk remains unclear, so breastfeeding is not recommended for mothers taking this product.
[Precautions]
1. Patients with renal insufficiency: For patients with creatinine clearance ≤ 50 mL/min, including those on hemodialysis or CAPD, an adjustment of the entecavir dose is recommended.
2. Liver transplant recipients: The safety and efficacy of entecavir in liver transplant recipients is unknown. If a liver transplant recipient is deemed to require entecavir treatment and has been or is currently receiving immunosuppressive medications that may affect renal function, such as cyclosporine or tacrolimus, renal function should be closely monitored before and during entecavir administration.
[Use in Special Populations]
Precautions for children:
Safety and efficacy data for this product in children under 16 years of age have not been established.
Precautions During Pregnancy and Breastfeeding:
The effects of entecavir on pregnant women are inadequately studied. This drug should only be used after a thorough balance of potential risks and benefits to the fetus has been made. Currently, there are no data suggesting that this drug affects mother-to-child transmission of HBV. Therefore, appropriate interventions should be implemented to prevent neonatal HBV infection. Entecavir is secreted in rat milk. However, whether it is secreted in human milk remains unclear. Therefore, breastfeeding is not recommended for mothers taking this drug.
Precautions for Elderly Patients:
Due to the lack of sufficient clinical studies involving patients aged 65 years and older, it is unclear whether elderly patients respond differently to this drug compared to younger patients. Other clinical trial reports have not found differences between elderly and younger patients. Entecavir is primarily excreted by the kidneys, and the risk of toxic reactions may be higher in patients with renal impairment. Because elderly patients often have decreased renal function, careful dosing and renal function monitoring are important.
[Drug Interactions]
Entecavir's metabolism 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 did not inhibit any of the major human CYP450 enzymes: 1A2, 2C9, 2C19, 2D6, 3A4, 2B6, and 2E1. At concentrations approximately 340 times the human concentration, entecavir did not induce the following human CYP450 enzymes: 1A2, 2C9, 2C19, 3A4, 3A5, and 2B6. Concomitant administration of drugs that are metabolized by CYP450 inhibitors or inducers did not affect the pharmacokinetics of entecavir. Furthermore, concomitant administration of entecavir did not affect the pharmacokinetics of known CYP substrates. Studies of the interaction between entecavir and lamivudine, adefovir, and tenofovir revealed no changes in the steady-state pharmacokinetics of either entecavir or the interacting drugs. Because entecavir is primarily eliminated through the kidneys, concurrent use of entecavir with drugs that reduce renal function or compete for active glomerular secretion may increase the plasma concentrations of these drugs. Concomitant administration of entecavir with lamivudine, adefovir, and tenofovir does not result in significant drug interactions. Concomitant interactions between entecavir and other drugs that are eliminated through the kidneys or are known to affect renal function have not been studied. Patients should be closely monitored for adverse reactions when taking entecavir with these drugs.
[Pharmacological Actions]
Pharmacological Actions: Microbiological Mechanism of Action: This product is a guanine nucleoside analog that inhibits hepatitis B virus (HBV) polymerase. It can be phosphorylated to its active triphosphate, which has an intracellular half-life of 15 hours. By competing with deoxyguanosine triphosphate, the natural substrate of HBV polymerase, entecavir triphosphate inhibits all three activities of the viral polymerase (reverse transcriptase): (1) initiation of HBV polymerase; (2) formation of the reverse transcriptase negative strand of pregenomic mRNA; and (3) synthesis of the positive strand of HBV DNA. The inhibition constant (Ki) of entecavir triphosphate against HBV DNA polymerase is 0.0012M. Entecavir triphosphate has weaker inhibitory effects on cellular α, β, and δ DNA polymerases and mitochondrial γ DNA polymerase, with Ki values ranging from 18 to greater than 160uM. Antiviral activity In human HepG2 cells transfected with wild-type hepatitis B virus, the concentration required for 50% inhibition of viral DNA synthesis (EC50) of entecavir is 0.004uM. The median EC50 of entecavir against lamivudine-resistant viral strains (rtL180M, rtM204V) was 0.026 μM (range, 0.01-0.059 μM). Coadministration 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 NRTIs. In cell culture studies examining HBV combination therapy, abacavir, didanosine, lamivudine, stavudine, tenofovir, or zidovudine did not antagonize the anti-HBV activity of entecavir over a wide range of concentrations. In HIV antiviral activity studies, entecavir did not antagonize the anti-HIV activity of six NRTIs in cell culture at concentrations four times greater than their peak in vivo concentration. A comprehensive analysis of entecavir's antiviral activity against a panel of laboratory and clinical isolates of human immunodeficiency virus type 1 (HIV-1) revealed an EC50 range of 0.026 to 10 μM across various cell types and experimental conditions; lower EC50 values were observed when viral levels decreased. In cell culture, entecavir selects for the M184I substitution in the HIV reverse transcriptase at micromolar concentrations, and inhibition was demonstrated at high entecavir concentrations. HIV variants harboring the M184V substitution lose sensitivity to entecavir. Lamivudine-resistant (LVDr) strains harboring the rtM204I/V and rtL180M substitutions in the reverse transcriptase region exhibited an 8-fold decrease in susceptibility to entecavir compared to wild-type HBV strains in resistant cell culture. Combining additional entecavir-resistance amino acid substitutions at rtT184, rtS202, and/or rtM250 also reduced entecavir susceptibility in cell culture. Clinical isolates harboring additional substitutions (rtT184A, C, F, G, I, L, M, or S; rtS202C, G, or I; and/or rtM250I, L, or V) further reduced entecavir susceptibility by 16- to 741-fold compared to field-derived strains. Entecavir-resistance substitutions at rtT184, rtS202, and rtM250 alone had only a modest effect on entecavir susceptibility, and no reduction in susceptibility was observed in over 1,000 patients without lamivudine-resistance substitutions. Resistance in cell culture was shown to be mediated by alterations in HBV reverse transcriptase that reduce competitive binding, resulting in reduced replication of resistant HBV strains. Clinical studies: Patients initially treated with entecavir 0.5 mg (nucleoside-naive) or 1 mg (lamivudine failure) who had on-treatment HBV DNA PCR values at or after week 24 of treatment were monitored for resistance. In nucleoside-naive patients, genetic testing evidence of substitutions at the rtT184, rtS202, and/or rtM250 entecavir resistance loci was found in 1% of patients treated with entecavir for up to 144 weeks (see table below). Substitutions at these loci were found to confer entecavir resistance only in the presence of lamivudine-resistant loci (rtM204V and rtL180M). The number of patients who developed genotypic entecavir resistance during the 144-week study in nucleoside-naive patients (including patients with on-treatment PCR-detected HBV DNA values at or after Week 24 of the entire 58-week study (1 year), between Weeks 58 and 102 of the entire study (2 years), or between Weeks 102 and 156 of the entire study) was: 663 at Year 1, 278 at Year 2, and 149 at Year 3a. The number of patients who developed genotypic entecavir resistance (in patients with concurrent lamivudine-resistance site substitutions) was: 1 patient (1%) at Year 1, 1 patient (1%) at Year 2, and 1 patient (1%) at Year 3a. The cumulative incidence of genotypic entecavir resistance (in patients with concurrent lamivudine-resistance site substitutions) was: 0.2% at Year 1, 0.5% at Year 2, and 1.2% at Year 3a. 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 (in patients with concurrent lamivudine resistance site substitutions): 1 patient (1%) at 1 year, 0 patients at 2 years, and 1 patient (1%) at 3 yearsa. The 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 with lamivudine failure: 10 of 187 baseline viral isolates (5%) from patients who failed entecavir therapy and underwent resistance surveillance were found to have entecavir resistance site substitutions, suggesting that prior lamivudine therapy selected for these resistance sites and that they were present at low levels before entecavir treatment. Throughout the 144-week study, 3 of the 10 patients experienced virological rebound (an increase of ≥1 log10 from the nadir).
Storage: Store in a dark, airtight container in a dry place below 25°C.
Specification: 0.5 mg
Packaging: 0.5 mg x 14 capsules
Expiry Date: 24 months
Approval Number: National Medicine Standard H20100065
Manufacturer: Hainan Zhonghe Pharmaceutical Co., Ltd.
