| Generic Name |
Entecavir Tablets |
| Strength |
0.5mg |
| Packing |
30 Tablets/bottle |
| Origin |
China |
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Product name:
Entecavir Tablets
Character:
This product is a film coating, after removing the coating will appear white.
Indications:
This product is indicated for the treatment of chronic hepatitis B in adults with active viral replication, persistent elevated serum alanine aminotransferase (ALT) or active liver histology.
Also suitable for treatment from 2 years to < An 18-year-old child with chronic HBV compensatory liver disease who was initially treated with nucleoside had evidence of active viral replication and persistently elevated serum ALT levels or histological evidence of moderate to severe inflammation and/or fibrosis. For the specific use method, see [Usage and Dosage]
Adverse reactions:
The evaluation of adverse reactions was based on four global clinical trials: AI463014, AI463022, AI463026, AI463027, and three clinical trials conducted in China (AI463012, AI463023, AI463056). In these seven studies, a total of 2596 patients with chronic hepatitis B were enrolled. In studies with lamivudine, Entecavir and lamivudine had similar adverse reactions and laboratory abnormalities.
In studies conducted abroad, the most common adverse reactions of this product are: headache, fatigue, dizziness, nausea. Common adverse reactions in patients treated with lamivudine were headache, fatigue and vertigo. In these four studies, 1% of entecavir treated patients and 4% of lamivudine treated patients dropped out of the study due to adverse effects and abnormal laboratory measures.
Pharmacology and toxicology:
Pharmacological action
Microbial mechanism of action
This product is a guanine nucleoside analogue and has an inhibitory effect on hepatitis B virus (HBV) polymerase. It can be phosphorylated into an active triphosphate, which has a half-life of 15 hours in the cell. By competing with deoxyguanosine triphosphate, a natural substrate of HBV polymerase, Entecavir triphosphate inhibits all three activities of viral polymerase (reverse transcriptase) : (1) initiation of HBV polymerase; (2) Formation of reverse transcriptional negative chains of pregenomic mRNA; (3) Synthesis of positive strand of HBV DNA. The inhibitory constant (Ki) of Entecavir triphosphate on HBV DNA polymerase was 0.0012μM. Entecavir triphosphate had weak inhibitory effects on α, β, δDNA polymerase and mitochondrial γDNA polymerase, with Ki values ranging from 18 to 160μM.
Antiviral activity
In human HepG2 cells transfected with wild-type HBV, the concentration required for Entecavir to inhibit 50% viral DNA synthesis (EC50) was 0.004μM. The median EC50 value of Entecavir against lamivudine-resistant virus strains (rtL180M, rtM204V) was 0.026μM (range 0.01 to 0.059μM), while Entecavir had no clinically relevant activity against human immunodeficiency virus type 1 (HIV) grown in cell culture (EC50) 10μM).
Daily or weekly use of this product reduces hepatitis virus DNA levels (4 to 8 log10) in North American groundhogs and ducks. A long-term study of five North American marmots showed that oral administration of 0.5mg/kg of entecavir per week (equivalent to a human dose of 1.0mg) kept viral DNA at undetectable levels (viral DNA levels [200 copies /mL, PCR method) in three of them for up to 3 years. In any animal treated with the drug for up to 3 years, no changes in HBV polymerase associated with entecavir resistance were found.
In vitro study of drug resistance
In cell tests, lamivudine-resistant virus strains were found to be 8 to 30 times less susceptible to entecavir phenotypes. If the hepatitis B virus polymerase is inherently lamivudine-resistant to amino acid substitution (rtL180M and/or rtM204V/I), coupled with a substitution mutation at rtT184, rtS202, or rtM250, or in combination with or without a substitution mutation at rtI169, Both cause an even greater (] 70-fold reduction in phenotype sensitivity to entecavir.
Clinical research
For patients initially treated with nucleoside drugs: 81% of nucleoside primary patients achieved viral load of [300 copies /mL] after 48 weeks of oral entecavir 0.5mg/ day. Genotype analysis of patients initially treated with HBeAg-positive (AI463022 study, n=219) or HBeAg-negative (AI463027 study, n=211) after 48 weeks of treatment showed that HBV DNA polymerase genes did not develop genotype variation associated with phenotypic resistance. In the AI463022 study, two patients developed a virological rebound (1 log10 increase in HBV DNA from the lowest point), but no genotypic or phenotypic evidence was found to be associated with entecavir resistance.
Patients with lamivudine failure: 22% of lamivudine failure patients achieved viral load of [300 copies /mL] after 48 weeks of oral entecavir 1.0mg/ day. Genotypic analysis of patients with detectable levels of serum HBV DNA showed that 7%(13/189) of patients with preexisting lamivudine resistance variants (rtL180M and/or rtM204V/ I) developed rtI169, rtT184, RTI169, RTT184, RTI169, and RTT184 within 48 weeks. Replacement variants at rtS202 and/or rtM250 were associated with Entecavir resistance. Of the 13 patients with mutations, 3 developed a virological rebound (HBV DNA rise from lowest point ≥1 log10) within 48 weeks, and most patients developed a virological rebound after 48 weeks.
Cross resistance
Cross-resistance has been found in nucleoside analogitics against HBV, and Entecavir was found in cell tests to be 8 to 30 times less inhibitory against lamivudine-resistant (rtL180M and/or rtM204V/I) strains than wild strains. Entecavir is also fully sensitive to recombinant viruses with adefovir resistance variants (HBV DNA polymerase rtN236T or rtA181V variants). In vitro tests showed that virus strains isolated from patients in whom both lamivudine and Entecavir had failed were sensitive to adefovir, but remained resistant to lamivudine.
Toxicology studies genotoxicity
In human lymphocyte culture experiments, Entecavir was found to be an inducer of chromosome breakage. Entecavir was not found to be a mutational inducer in Ames experiments (using typhi, E. coli, with or without metabolic activators), gene mutation experiments, and transfection experiments in Syrian hamster embryos. Entecavir was also negative in oral administration of micronucleus and DNA repair tests in rats.
Reproductive toxicity
In the reproductive toxicity study, when Entecavir was administered for 4 weeks at a dose of up to 30mg/kg, no fertility was found to be affected in male and female rats when administered at a dose 90 times higher than the maximum recommended human dose of 1.0mg/ day. In toxicological studies of Entecavir, degeneration of the vas deferens was found in rodents and dogs at doses 35 times or more higher than the human dose. In the monkey experiments, no testicular changes were found.
In studies of reproductive toxicity in rats and rabbits, no fetal and maternal toxicity was found at oral doses of 200 and 16mg/kg/ day, which is equivalent to 28 times (for rats) and 212 times (for rabbits) the maximum human dose of 1.0mg/ day. In rat experiments, when the mother rats were given doses equivalent to 3100 times the human dose, toxic effects of entecavir were observed in embryo-fetal mice (reabsorption), weight loss, abnormal morphology of the tail and spine and reduced levels of ossification (spine, phalanx and phalanx), and additional lumbar vertebrae and ribs were observed. In domestic rabbit experiments, when the dose was 883 times the human dose of 1.0mg/ day in female rabbits, toxic effects (absorption), reduced ossification level (hyoid), and increased incidence of the 13th rib were observed in embryo-fetal rabbits. In a study of oral entecavir in rats before and after birth, it was found that doses greater than 94 times the human dose of 1.0mg/ day had no effect on offspring.
Entecavir can be secreted from rat milk.
carcinogenicity
In long-term carcinogenicity studies of oral entecavir in mice and rats, exposure to the drug was approximately 42 times (rats) and 35 times (mice) the maximum recommended dose (1.0mg/ day) for humans, respectively. In the above study, Entecavir showed positive results for carcinogenicity.
In mouse trials, the incidence of lung adenomas increased in male or female mice when the dose was 3 to 40 times that of the human dose. When the dose reached 40 times the human dose, the incidence of lung tumors increased in male or female mice. When the dose was 3 times the human dose, the incidence of lung adenomas and tumors increased in male mice. When the dose reached 40 times the human dose, the incidence of lung adenomas and tumors increased in female mice. The mice developed lung cell hyperplasia followed by lung tumor, but no lung cell hyperplasia was found in rats, dogs, and monkeys given this product, suggesting that lung tumor in mice may be species-specific. When the dose reached 42 times the human dose, the incidence of hepatocellular tumors and mixed tumors (tumors and adenomas) increased in male mice. When the dose was 40 times that of the human dose, the incidence of vascular tumors (including hemangiomas of the ovaries, uterus, and angiosarcoma of the spleen) increased in female mice. In the rat trials, when the dose was up to 24 times the human dose, the incidence of hepatocellular adenomas in female rats increased, as did the incidence of mixed tumors (tumors and adenomas). At doses up to 35 and 24 times the human dose, brain gliomas were found in male and female rats, respectively. When the dose was 4 times the human dose, skin fibroma was found in female rats.
It is unclear whether the results of carcinogenicity tests in rodents can predict carcinogenic effects of this product in humans.
Storage:
Seal and store in a dry place at 15-30ºC.
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