Product Overview
[Drug Name]
Generic Name: Entecavir Capsules
Trade Name: Gan Bei Qing
English Name: Entecavir Capsules
Chinese Pinyin: EnTiKaWeiJiaoNang (GanBeiQing)
[Ingredients]
The main ingredient of this product is entecavir. Chemical Name: 2-Amino-9-[(1S,3R,4S)-4-hydroxy-3-hydroxymethyl-2-methylenecyclopentyl]-1,9-dihydro-6H-purin-6-one monohydrate. Molecular Formula: C₁₂H₁₅N₅O₃·H₂O. Molecular Weight: 295.3
[Properties]
This product is a capsule containing a white or off-white fine powder.
[Indications]
This product is indicated for the treatment of chronic hepatitis B in adults with active viral replication, persistently elevated serum alanine aminotransferase (ALT), or active liver histological lesions.
[Dosage and Administration]
This product should be taken under the guidance of an experienced physician. Recommended Dose: Adults and adolescents 16 years and older should take 0.5 mg orally once daily. Patients who develop viremia or lamivudine-resistant mutations during lamivudine treatment should take 1 mg once daily. This drug 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 those receiving hemodialysis or continuous ambulatory peritoneal dialysis (CAPD)) should have their dose adjusted. Hepatic Insufficiency: No dose adjustment is required for patients with hepatic insufficiency. Treatment Duration: The optimal duration of treatment with this drug and its relationship to long-term treatment outcomes, such as cirrhosis and liver cancer, are currently unknown.
[Adverse Reactions]
1. In international studies, the most common adverse events with this drug were headache, fatigue, dizziness, and nausea. 2. 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 abnormal laboratory test values.
[Contraindications]
Entecavir is contraindicated in patients with allergies to entecavir or any of the ingredients in the formulation.
[Precautions]
For patients with renal insufficiency and creatinine clearance, please read the package insert carefully and use as directed by your healthcare provider.
[Special Use in Special Populations]
Precautions for Pediatric Use:
Safety and efficacy data for this drug in children under 16 years of age have not been established.
Precautions for Pregnancy and Lactation:
The effects of entecavir on pregnant women have not been adequately studied. This drug should only be used after a thorough balance of potential risks and benefits has been made with the fetus. 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 is unknown. Therefore, breastfeeding is not recommended for mothers taking this drug.
Precautions for Elderly Patients:
Due to insufficient 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 also failed to identify differences between elderly and younger patients. Entecavir is primarily excreted by the kidneys, and patients with renal impairment may be at increased risk for toxic reactions. Because elderly patients often have decreased renal function, careful dosing and monitoring of renal function are recommended.
[Drug Interactions] Entecavir metabolism has been 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, 2B6, and 2E1. At concentrations approximately 340 times the human concentration, entecavir does not induce the following human CYP450 enzymes: 1A2, 2C9, 2C19, 3A4, 3A5, and 2B6. Concomitant administration of drugs that inhibit or induce CYP450 metabolism has no effect on the pharmacokinetics of entecavir. Furthermore, concomitant administration of entecavir has no effect on the pharmacokinetics of known CYP substrates.
[Pharmacological Action]
Microbiological Mechanism of Action: This product is a guanine nucleoside analog that inhibits hepatitis B virus (HBV) polymerase. It is 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] Sealed.
[Strength] 0.5 mg
[Packaging] 0.5 mg x 7 s/plate
[Expiry Life] 36 months
[Approval Number] National Medicine Standard H20130031
[Manufacturer] Company Name: Sichuan Hiseko Pharmaceutical Co., Ltd.
