Product Overview
Warning: 1. Exacerbation of hepatitis after stopping treatment When patients with chronic hepatitis B stop anti-hepatitis B treatment, including entecavir, there are reports of severe acute exacerbation of hepatitis B. The liver function of those patients who stop anti-hepatitis B treatment should be closely monitored from clinical and laboratory examinations and followed up for at least several months. If necessary, the anti-hepatitis B virus treatment can be resumed. 2. Nucleoside drugs used alone or in combination with other antiretroviral drugs, there have been reports of moderate and severe lactic acid-induced fatty liver enlargement, including death cases. 3. Co-infection with HIV Entecavir has not been evaluated in patients with HBV co-infection with HIV and who have not received effective HIV treatment. Limited clinical experience suggests that if entecavir is used in patients with chronic hepatitis B combined with HIV infection and without anti-HIV treatment, resistance to HIV nucleoside anti-reverse transcriptase inhibitors may appear. (See [Pharmacology and Toxicology] Microbiology, Antiviral Activity, Anti-HIV Virus Activity). Therefore, it is not recommended to use entecavir in patients with HBV co-infected with HIV who have not received high-efficiency antiretroviral therapy (HAART). Before starting entecavir treatment, all patients should be tested for HIV antibodies. Entecavir has not been studied for the treatment of HIV infection, so this use is not recommended.
Generic name: Entecavir Dispersible Tablets
Chinese Pinyin: Entikawei Fensanpian
Product name: Runzhong
Ingredients: The main ingredient of this product is: Entecavir.
Properties: This product is white or off-white flakes.
Indications: This product is suitable for the treatment of chronic hepatitis B in adults with active viral replication, continuous increase in serum transaminase ALT, or active liver histology.
Specification: 0.5mg*7 tablets/box
Usage and dosage: Patients should take this product under the guidance of an experienced doctor. Recommended dose: Adults and adolescents aged 16 and above take this product once a day, 0.5 mg each time. For patients with viremia or lamivudine resistance mutation during lamivudine treatment, 1 mg (0.5 mg two tablets) once a day. This product should be taken on an empty stomach (at least 2 hours before or after a meal). Renal insufficiency: In patients with renal insufficiency, the oral clearance of entecavir decreases with the decrease in creatinine clearance (see Pharmacokinetics, Special Populations). Patients whose creatinine clearance rate is less than 50ml/min (including patients undergoing hemodialysis or CAPD treatment) should adjust the medication dose. See Table 1. Table 1: Entecavir recommended interval adjustment for creatinine clearance in patients with renal insufficiency (ml/min) Normal dose (0.5mg) Lamivudine treatment failure (1.0mg) ≥50 once a day, 0.5 mg once a day, 1mg each time 30 to <50 once every 48 hours, 0.5mg each time once every 48 hours, 1mg each time 10 to <30 once every 72 hours, each time 0.5mg once every 72 hours, 1mg each time <10 or hemodialysis or CAPD Once every 5-7 days, 0.5 mg each time, once every 5-7 days, 1 mg each time Hepatic insufficiency: Patients with liver insufficiency do not need to adjust the medication dose. Treatment period: The best treatment time of this product and the relationship with long-term treatment results, such as liver cirrhosis, liver tumor, etc., are not yet clear.
Adverse reactions: The evaluation of adverse reactions is based on 4 global clinical trials: A1463014, A1463022, A1463026, A1463027 and 3 clinical trials conducted in China (A1463012, A1463023, A1463056). In these 7 studies, a total of 2596 patients with chronic hepatitis B were enrolled. In a controlled study with lamivudine, the adverse events and laboratory abnormalities of entecavir and lamivudine were similar. In studies conducted abroad, the most common adverse events of this product are: headache, fatigue, dizziness, and nausea. Common adverse events in patients treated with lamivudine include headache, fatigue, and dizziness. In these 4 studies, 1% of entecavir-treated patients and 4% of lamivudine-treated patients were launched due to adverse events and abnormal laboratory test indicators. Foreign clinical adverse events: Table 2 (see detailed instructions) compares the differences between entecavir and lamivudine in 4 clinical studies. Among them, moderate to severe adverse events and clinical adverse events that occurred during the treatment process that are at least likely to be related to the treatment were selected as indicators for comparison. Abnormal laboratory test indicators in foreign countries: Table 3 (see detailed instructions) lists the frequency of abnormal laboratory tests after treatment with entecavir and lamivudine in four clinical trials. In these studies, when the ALT increased to 10 times the upper limit of normal value and 2 times the baseline value in patients taking Entecavir during treatment, they usually continue to take the drug for a period of time, and ALT can return to normal; before or at the same time, it is accompanied by virus Decrease in load capacity by 2 log values. Therefore, liver function needs to be tested regularly during the medication period. Exacerbation of hepatitis after stopping treatment (see [Warning]) Acute exacerbation of hepatitis or recurrence of ALT is defined as: ALT greater than 10 times the upper limit of normal and greater than 2 times the patient's reference level (baseline value or the last measured value at the time of withdrawal Minimum). Among all patients who stopped treatment (regardless of the reason), the number of patients with ALT re-combustion was recorded in Table 4 (see detailed instructions). In these studies, a subgroup of patients may be allowed to discontinue the drug if the treatment response specified in the protocol is reached at week 52 or later. If the treatment response is not achieved and entecavir is discontinued, the probability of ALT re-ignition may be higher after discontinuation. In the double-blind study of A1463038, it was observed that patients with HBV co-infected with HIV received entecavir 1mg (N=51) or placebo (N=17) for 24 weeks. The safety of the two groups was similar and was observed in patients without co-infected HIV The safety is similar (see [Warning] 3: Co-infection with HIV) In clinical trials conducted in China, the most common adverse events are: ALT elevation, fatigue, dizziness, nausea, abdominal pain, abdominal discomfort, epigastric pain, liver Area discomfort, myalgia, insomnia and rubella. These adverse events were mostly mild to moderate. In a controlled trial with lamivudine, the incidence of adverse events of this product was equivalent to that of lamivudine.
Contraindications: People who are allergic to entecavir or any ingredient in the preparation should not be used.
Note: Patients with renal insufficiency: creatinine clearance rate <50ml/min, including patients with hemodialysis or CAPD, it is recommended to adjust the dosage of entecavir (see [Usage and Dosage]). Liver transplant recipients: The safety and effectiveness of entecavir in the treatment of liver transplant recipients are unclear. If it is believed that liver transplant recipients need to receive entecavir treatment, they have been or are receiving immunosuppression that may affect renal function, such as cyclosporine or tacrolimus treatment, should be closely monitored before and during the administration of entecavir Kidney function. (See [Pharmacokinetics]) Instructions for patients: Patients should take Entecavir under the guidance of a doctor and inform the doctor of any new symptoms and concomitant medications. Patients should be informed that if the drug is discontinued, liver disease sometimes worsens, so the treatment should be changed under the guidance of a doctor. Patients need to be tested for HIV antibodies before starting entecavir treatment. Patients should be informed that if they are infected with HIV and have not received effective HIV drug treatment, entecavir may increase the chance of resistance to HIV drug treatment (see [Warning] 3. Co-infection with HIV). Entecavir treatment does not reduce the risk of HBV transmission through sexual contact or contaminated blood sources. Therefore, appropriate protective measures need to be taken.
Drug interactions: Microbiological mechanism of action: This product is a guanine nucleoside analog, which has an inhibitory effect on hepatitis B virus (HBV) polymerase. It can be phosphorylated into active triphosphate, the half-life of triphosphate in the cell is 15 hours. By competing with deoxyguanosine triphosphate, the natural substrate of HBV polymerase, entecavir triphosphate can inhibit all three activities of viral polymerase (reverse transcriptase): (1) HBV polymerase initiation; (2) pre-genomic mRNA The formation of the negative strand of reverse transcription; (3) The synthesis of the positive strand of HBV DNA. Entecavir triphosphate has weak inhibitory effects on cell α, β, δ DNA polymerase and mitochondrial γ DNA polymerase, with Ki values ranging from 18 to more than 160 μM. Antiviral activity: In human HepG2 cells transfected with wild-type hepatitis B virus, the concentration required for entecavir to inhibit 50% of viral DNA synthesis (EC50) is less than 0.004μM. The median EC50 of entecavir against lamivudine-resistant virus strains (rtL 180M, rtM204V) is 0.026μM (range 0.01 to 0.059μM). Co-administration of entecavir and 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. HBV combination therapy was tested in cell culture, and it was found that in a wide range of concentrations, abacavir, didanosine, lamivudine, stavudine, tenofovir or zidovudine had anti-HBV activity against entecavir There is no antagonistic effect. In the HIV antiviral activity experiment, when the concentration of entecavir was 4 times greater than the peak concentration in the body, entecavir had no antagonistic effect on the anti-HIV activity of the six NRTIs in cell culture. Anti-HIV virus activity: A comprehensive analysis of the inhibitory activity of Entecavir against a group of laboratory-isolated strains and clinically isolated human immunodeficiency virus strains (HIV-1). The EC50 value range obtained under different cells and experimental conditions is 0.026 To >10 μM; lower EC50 values are observed when virus levels decrease. In cell culture, entecavir can select the M184I site replacement of HIV reverse transcriptase at the micromolar concentration level, and the inhibitory effect is confirmed at the high concentration level of entecavir. HIV variants containing M184V site substitutions lose sensitivity to entecavir. Drug resistance: Cell culture: Lamivudine-resistant strains (LVDr) with rtM204I/V and rtL180M sites in the reverse transcriptase region are less sensitive to entecavir than HBV wild strains. Combined with additional entecavir-resistant amino acid rtT184, rtS202 and/or rtM250 site changes, cell culture was also found to reduce the sensitivity to entecavir. The clinical isolates combined with additional (reT184A, C, F, G, I, L, M or S; rtS202C, G or I; and/or rtM250I, L or V) site replacement compared with wild strains are more effective against entecavir The sensitivity is further reduced by 16 to 741 times. The virus strains with rtT184, rtS202 and rtM250 entecavir-resistant site substitutions alone had only a moderate effect on the sensitivity of entecavir, and no reduction in sensitivity was observed in more than 1,000 patients without lamivudine-resistant site substitutions. In cell culture, it is found that drug resistance is mediated by changing HBV reverse transcriptase to reduce competitive binding, and the replication ability of drug-resistant HBV strains is weakened. Clinical research: In clinical research, patients who initially received entecavir 0.5mg (nucleoside initial treatment) or 1mg (lamivudine ineffective) treatment, and were treated with HBV DNA PCR test values for 24 weeks or later were resistant Drug monitoring. Nucleoside drug-naive patients: In the study of nucleoside drug-naive patients, entecavir was treated for 144 weeks and found to have evidence of rtT184, rt202 and/or rtM250 entecavir-resistant site replacement gene detection evidence <1% (see table 5 (see detailed instructions)). It was found that the replacement of these sites only caused entecavir resistance based on the appearance of lamivudine resistance sites (rtM204V and rtL180M). Patients with failure of lamivudine treatment: Among the baseline virus isolates of patients who failed to treat lamivudine with entecavir and undergoing drug resistance monitoring, 10 out of 187 cases with replacement of entecavir resistance sites were found, accounting for 5%. It shows that the previous lamivudine treatment can select these resistance sites and exist in a low-level state before entecavir treatment. During the 144 weeks of the study, 3 out of 10 patients experienced a virological rebound (increased by ≥1 log10 from the lowest point). The occurrence of entecavir resistance in the 144-week lamivudine failure study of the entire study is summarized in Table 6 (see detailed instructions). Cross-resistance: Cross-resistance has been found in nucleoside anti-HBV drugs. In cell experiments, it was found that the inhibitory effect of Entecavir on the HBV DNA synthesis of hepatitis B virus containing lamivudine and telbivudine resistance mutations (rtM204I/V±rtL180M) was 8 to 30 times weaker than that of the wild strain. The substitution mutation of RtM204I/V±rtL180M, rtL80I/V or rtV173L locus is related to the resistance of lamivudine and telbivudine, and also leads to reduced phenotypic sensitivity to entecavir. Genotoxicity: In the experiment of human lymphocyte culture, it was found that Entecavir is an inducer of chromosome breakage. In the Ames experiment (using typhoid bacteria, E. coli, with or without metabolic activators), gene mutation experiments, and Syrian hamster embryo cell transfection experiments, it was found that Entecavir was not a mutation inducer. In the oral administration of micronucleus test and DNA repair test in rats, entecavir was also negative. Reproductive toxicity: In the reproductive toxicity study, entecavir was administered for 4 consecutive weeks at a dose of up to 30 mg/kg. When the dose exceeded the maximum recommended dose of 1.0 mg/day in humans, no fertility was found in male and female rats. affected. In the toxicology study of Entecavir, when the dose reached 35 times or more than the human dose, rodents and dogs were found to have degeneration of the vas deferens. In monkey experiments, no testicular changes were found. In the reproductive toxicity study of rats and rabbits, the oral doses of this product reached 200 and 16mg/kg/day, which is equivalent to 28 times the highest human dose of 1.0mg/day ( For rats) and 212 times (for rabbits), no embryonic and maternal toxicity was found. In rat experiments, when the dosage of cassava was 3100 times the human dose, the toxic effect of entecavir on embryonic first-feet mice (reabsorption), weight loss, abnormal tail and spine morphology, and reduced ossification level (spine , Phalanges and phalanges), and additional lumbar vertebrae and ribs were observed. In rabbit experiments, the level of ossification decreased (hyoid bone) and the incidence of the 13th rib increased. In the study of oral entecavir in rats before and after birth, it was found that the dosage of the drug was greater than 94 times the human 1.0 mg/day dose without affecting the offspring. Entecavir can be secreted from rat milk. Carcinogenicity: In the long-term carcinogenicity study of oral entecavir in mice and rats, the drug exposure was approximately 42 times (rats) and 35 times (mouse) the highest recommended dose (1.0 mg/day) in humans, respectively. In the above studies, the carcinogenicity of entecavir showed positive results. In mouse experiments, the incidence of lung adenomas in male and female mice increased when the dose was 3 to 40 times the human dose. When the dose reaches 40 times the human dose, the incidence of lung tumors in male and female mice
