Adefovir Dipivoxil Tablets

Chronic toxicity: In animal experiments, tubular nephropathy characterized by histological changes and/or increased urea nitrogen and serum creatinine is the main dose-limiting toxic reaction of adefovir dipivoxil. The exposure of nephrotoxicity observed in animal experiments is at least 3-10 times the exposure at the recommended human therapeutic dose (10 mg/day). Genotoxicity: In in vitro mouse lymphocytoma cell experiments (with or without metabolic activation), adefovir has a mutagenic effect. Adefovir can induce chromosomal aberrations in in vitro experiments of human peripheral blood lymphocytes without metabolic activation. In the in vivo mouse micronucleus experiment, adefovir has no chromosomal clastogen effect; in the Ames bacterial reverse mutation experiment using Salmonella typhimurium and Escherichia coli strains (with or without metabolic activation), adefovir has no mutagenicity. Reproductive toxicity: No effect on rat fertility was observed at an exposure of approximately 19 times the exposure at the human therapeutic dose. Oral administration of adefovir dipivoxil to rats and rabbits (exposures were approximately 23 times and 40 times the human therapeutic dose of 10 mg/day, respectively) did not result in embryotoxicity or teratogenicity. Adefovir was administered intravenously to pregnant rats, and at doses that could produce significant maternal toxicity (equivalent to 38 times the exposure at the recommended therapeutic dose for humans), the incidence of embryotoxicity and fetal malformations (systemic edema, sunken eyelids, umbilical hernia, and tail kinking) increased. No adverse effects were observed at intravenous doses equivalent to 12 times the human exposure. Carcinogenicity: In long-term carcinogenicity studies in mice and rats, mice and rats were orally administered adefovir dipivoxil at doses equivalent to 10 times and 4 times the exposure of the human therapeutic dose (10 mg/day), respectively, and no carcinogenic effects were observed. Pharmacological action: Mechanism of action Adefovir is an acyclic phosphorylated nucleoside analog of adenosine monophosphate. It is phosphorylated to an active metabolite, adefovir diphosphate, under the action of cellular kinases. Adefovir diphosphate inhibits HBV DNA polymerase (reverse transcriptase) in the following two ways: one is to compete with the natural substrate deoxyadenosine triphosphate, and the other is to cause DNA chain extension termination after integration into viral DNA. The inhibition constant (Ki) of adefovir diphosphate on HBV DNA polymerase is 0.1mu;M. However, the inhibitory effect on human DNA polymerase alpha; and gamma; is weaker, with Ki values of 1.18mu;M and 0.97mu;M, respectively. Antiviral activity: The concentration of adefovir that inhibits 50% viral DNA replication in vitro (IC50) determined by human hepatoma cell lines transfected with HBV is 0.2~2.5mu;M. Adefovir combined with lamivudine exhibits additional anti-HBV activity in vitro. Drug resistance: Long-term (96-144 weeks) drug resistance genotype analysis was performed on patients who still had detectable serum HBV DNA after receiving adefovir treatment, and it was determined that rtN236T and rtA181V mutations were associated with adefovir resistance. In vitro studies found that the rtN236T mutation caused HBV to be 4-14 times less sensitive to adefovir, and the serum HBVDNA levels of the six patients with this mutation rebounded. The rtA181V mutation caused its in vitro sensitivity to adefovir to be reduced by 2.5-3 times. Among the three patients with this mutation, the serum HBVDNA levels of two patients rebounded. The incidence of mutations associated with adefovir resistance was 0% (0/629) in 0-48 weeks, 2% (6/293) in 49-96 weeks, and 1.8% (3/163) in 97-144 weeks, with a cumulative probability of 3.9% in 3 years. Cross-resistance: Recombinant HBV variants containing lamivudine resistance-related mutations (rtL_180M, rtM204l, rtM204V, rtL180MrtM204V, rtV173L) on the HBV DNA polymerase gene are sensitive to adefovir in vitro. In patients with lamivudine-resistant null HBV, adefovir also showed anti-HBV effects, with a median decrease of 4.3log10 copies/ml in serum HBV DNA. HBV variants containing DNA polymerase mutations (rtT128N and rtR153Q or rtW153Q, which are associated with hepatitis B immunoglobulin resistance) are sensitive to adefovir in vitro. The HBV strain expressing the rtN236T variant associated with adefovir resistance is 2-3 times less sensitive to lamivudine in vitro, but is still sensitive to lamivudine in vivo. The HBV strain expressing the adefovir resistance-associated rtA181V variant was 3-fold less sensitive to lamivudine in vitro.

The main ingredient is adefovir dipivoxil.

This product is a white to off-white tablet. One side is engraved with "GSKKNU" and the other side is blank.

This product is suitable for the treatment of adult patients with chronic hepatitis B with active replication of hepatitis B virus and compensated liver function with persistent elevation of serum amino acid transferase.

Patients must be treated with this product under the guidance of a physician with experience in treating chronic hepatitis B. For adults (18-65 years old) with normal renal function, the recommended dose of this product is 10 mg once a day. It can be taken orally before or after meals. This indication is mainly based on the results of a 48-week clinical trial. The optimal course of treatment has not yet been determined. Do not exceed the recommended dose. The relationship between treatment efficacy and long-term clinical prognosis (such as hepatocellular carcinoma or decompensated cirrhosis) has not yet been determined. Patients should regularly monitor hepatitis B biochemical indicators, virological indicators and serum markers, at least once every 6 months. The following situations may consider discontinuation of the drug According to the experience of lamivudine treatment, HBeAg-positive patients who have HBeAg seroconversion after using this product should continue treatment for 6 months. Testing confirms that the efficacy has been consolidated and treatment may be considered. For HBeAg-negative patients, long-term treatment is recommended. At least HBsAg seroconversion occurs or the drug is discontinued when the efficacy is lost. The pros and cons must be weighed when discontinuing the drug. Experienced doctors should monitor patients closely. It is not recommended to stop the drug in patients with decompensated liver disease or decompensated cirrhosis during treatment. Adefovir is excreted by the kidneys in patients with renal impairment, so patients with renal insufficiency need to adjust the dosing interval. Patients with creatinine clearance of ≥50mL/min need to adjust the dosing interval. The detailed adjustment plan for the dosing interval for patients with creatinine clearance of 50mL/min is shown in Table 1. The number of doses should not exceed the recommended number in the table (see [Precautions] - Renal function). Although patients with renal impairment were included in the pharmacokinetic study, the safety and effectiveness of these guidance on dosing interval adjustment have not been clinically evaluated. Therefore, the clinical efficacy of these patients should be closely monitored. Studies have not been conducted in patients with creatinine clearance less than 10mL/min. Therefore, there is no reference medication regimen. Table 1: Recommended dosing regimen for patients with renal impairment Creatinine clearance (ml/min) 20-49 10-19 Patients on hemodialysis* Recommended dose and dosing interval 10 mg once every 48 hours 10 mg once every 72 hours After dialysis, 10 mg once every 7 days * The recommended dosing regimen is based on the results of a study of high-flow dialysis three times a week. Patients with impaired liver function No dosage adjustment is required for patients with impaired liver function (see [Pharmacokinetics] Patients with impaired liver function)

Domestic clinical research study ADF30001 is a randomized, double-blind, placebo-controlled, 52-week study conducted in 480 Chinese HBeAg-positive compensated chronic hepatitis B patients to evaluate the efficacy and safety of adefovir dipivoxil 10 mg in Chinese patients. The following are the adverse events that were reported in at least one case in the study population during the 52-week study and were assessed by the investigator to be drug-related: fatigue, gastrointestinal reactions (abdominal discomfort, upper abdominal pain, diarrhea, nausea, stomach discomfort), nasopharyngitis, dizziness, rash, hair loss, liver pain, spontaneous abortion, insomnia, laboratory abnormalities (elevated ALT, CPK and ALP, neutropenia and leukopenia). The overall incidence of any single adverse event was 2%. The most common

This product is contraindicated in patients with known hypersensitivity to adefovir, adefovir dipivoxil, or any excipients in adefovir dipivoxil tablets.

Precautions for children: The efficacy and safety of Hevili in patients under 18 years of age have not been determined (see [Precautions] - Others). Adefovir dipivoxil should not be used in children and adolescents. Precautions for pregnancy and lactation: Pregnancy: There is insufficient data on the use of adefovir dipivoxil in pregnant women. Animal studies of intravenous adefovir have shown reproductive toxicity (see [Pharmacology and Toxicology] - Clinical Safety Data). Pregnant women should avoid using adefovir dipivoxil as much as possible. If it is necessary to use it, the pros and cons should be weighed. The use of adefovir dipivoxil during pregnancy can only be considered when the potential benefits definitely outweigh the risks to the fetus. There is currently no data on the effect of adefovir dipivoxil on mother-to-child transmission of HBV. Therefore, infants should be immunized according to standard recommendations to prevent neonatal HBV infection. Because the potential risk to the developing human embryo is not clear, it is recommended that women of childbearing age treated with adefovir dipivoxil take effective contraceptive measures. Lactation: It is not yet known whether adefovir is secreted into human breast milk. Therefore, mothers who are taking adefovir dipivoxil should be warned not to breastfeed their babies. Precautions for the elderly: The efficacy and safety of Hevily in elderly patients over 65 years old have not been clearly established (see [Precautions] - Others).

Adefovir dipivoxil is rapidly converted to adefovir in the body. At concentrations significantly higher than those observed in vivo (4000 times), adefovir has no inhibitory effect on any of the following common human CYP450 enzymes: CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4. Adefovir dipivoxil is not a substrate for these enzymes. However, it is not clear whether adefovir can induce CYP450 enzymes. Based on the results of in vitro experiments and the renal elimination pathway of adefovir, the possibility of adefovir interacting with other drugs mediated by CYP450 as an inhibitor or substrate is very small. Adefovir is excreted through the kidneys by glomerular filtration and active tubular secretion (see [Pharmacokinetics] - Elimination). The combined use of 10 mg of adefovir dipivoxil with other drugs secreted by the renal tubules or drugs that change the renal tubular secretion function can increase the serum concentration of adefovir dipivoxil or the combined drug (see [Precautions] - Renal Function). Caution should be exercised when 10 mg of adefovir dipivoxil is used in combination with drugs that are actively secreted by the renal tubules, because the two drugs compete for the same elimination pathway, which may cause an increase in the serum concentration of adefovir or the co-administered drug. Adefovir dipivoxil does not change the pharmacokinetics of lamivudine, trimethoprim/sulfamethoxazole, acetaminophen, and ibuprofen. When adefovir dipivoxil is used simultaneously with lamivudine, trimethoprim/sulfamethoxazole, and acetaminophen, the pharmacokinetics of adefovir dipivoxil are not changed. When adefovir dipivoxil is used simultaneously with ibuprofen (800 g, 3 times a day), adefovir dipivoxil Cmax (33%), AUC (23%), and urinary recovery increase, which appears to be due to increased oral bioavailability rather than decreased renal clearance.

Seal tightly and store in a dry place below 25℃.

10mg/tablet

Tentatively 24 months.