Vemlidy(tenofovir alafenamide,TAF)是近十年来首个获FDA批准每日一次治疗慢性乙肝新药
Renal Laboratory Tests In a pooled analysis of Studies 108 and 110 in adult subjects with chronic hepatitis B and a median baseline eGFR of 106 and 105 mL per minute (for the VEMLIDY and tenofovir disoproxil fumarate [TDF] groups, respectively), mean serum creatinine increased by less than 0.1 mg/dL and median serum phosphorus decreased by 0.1 mg/ dL in both treatment groups. Median change from baseline in eGFR was -1.2 mL per minute in the VEMLIDY group and -5.4 mL per minute in those receiving TDF. The long-term clinical significance of these renal laboratory changes on adverse reaction frequencies between VEMLIDY and TDF is not known. Decrease in Bone Mineral Density In a pooled analysis of Studies 108 and 110, the mean percentage change in bone mineral density (BMD) from baseline to Week 48 as assessed by dual-energy X-ray absorptiometry (DXA) was -0.6% with VEMLIDY compared to -2.4% with TDF at the lumbar spine and -0.2% compared to -1.9% at the total hip. BMD declines of 5% or greater at the lumbar spine were experienced by 6% of VEMLIDY subjects and 20% of TDF subjects. BMD declines of 7% or greater at the femoral neck were experienced by 3% of VEMLIDY subjects and 6% of TDF subjects. The long-term clinical significance of these BMD changes is not known. Laboratory Abnormalities The frequency of laboratory abnormalities (Grades 3–4) occurring in at least 2% of subjects receiving VEMLIDY in Studies 108 and 110 are presented in Table 2. Table 2 Laboratory Abnormalities (Grades 3–4) Reported in ≥2% of Subjects with Chronic HBV Infection and Compensated Liver Disease in Studies 108 and 110 (Week 48 analysis)
Amylase and Lipase Elevations and Pancreatitis In Studies 108 and 110, seven subjects treated with VEMLIDY with elevated amylase levels had associated symptoms, such as nausea, low back pain, abdominal tenderness, biliary pancreatitis and pancreatitis. Of these seven, two subjects discontinued VEMLIDY due to elevated amylase and/or lipase; one subject experienced recurrence of adverse events when VEMLIDY was restarted. No subject treated with tenofovir disoproxil fumarate had associated symptoms or discontinued treatment. Serum Lipids Changes from baseline in total cholesterol, HDL-cholesterol, LDL-cholesterol, triglycerides, and total cholesterol to HDL ratio among subjects treated with VEMLIDY and tenofovir disoproxil fumarate are presented in Table 3. Table 3 Lipid Abnormalities: Mean Change from Baseline in Lipid Parameters in Patients with Chronic HBV Infection and Compensated Liver Disease in Studies 108 and 110 (Week 48 Analysis)
7 DRUG INTERACTIONS 7.1 Potential for Other Drugs to Affect VEMLIDY VEMLIDY is a substrate of P-glycoprotein (P-gp) and BCRP. Drugs that strongly affect P-gp and BCRP activity may lead to changes in tenofovir alafenamide absorption (see Table 4). Drugs that induce P-gp activity are expected to decrease the absorption of tenofovir alafenamide, resulting in decreased plasma concentrations of tenofovir alafenamide, which may lead to loss of therapeutic effect of VEMLIDY. Coadministration of VEMLIDY with other drugs that inhibit P-gp and BCRP may increase the absorption and plasma concentration of tenofovir alafenamide. 7.2 Drugs Affecting Renal Function Because tenofovir is primarily excreted by the kidneys by a combination of glomerular filtration and active tubular secretion, coadministration of VEMLIDY with drugs that reduce renal function or compete for active tubular secretion may increase concentrations of tenofovir and other renally eliminated drugs and this may increase the risk of adverse reactions. Some examples of drugs that are eliminated by active tubular secretion include, but are not limited to, acyclovir, cidofovir, ganciclovir, valacyclovir, valganciclovir, aminoglycosides (e.g., gentamicin), and high-dose or multiple NSAIDs [see Warnings and Precautions (5.4)]. 7.3 Established and Other Potentially Significant Interactions Table 4 provides a listing of established or potentially clinically significant drug interactions. The drug interactions described are based on studies conducted with tenofovir alafenamide or are predicted drug interactions that may occur with VEMLIDY. [For magnitude of interaction, see Clinical Pharmacology (12.3)]. Information regarding potential drug-drug interactions with HIV antiretrovirals is not provided (see the prescribing information for emtricitabine/tenofovir alafenamide for interactions with HIV antiretrovirals). The table includes potentially significant interactions but is not all inclusive. Table 4 Established and Other Potentially Significant Drug Interactions*
↓ = decrease. Indicates that a drug interaction study was conducted. P-gp inducer 7.4 Drugs without Clinically Significant Interactions with VEMLIDY Based on drug interaction studies conducted with VEMLIDY, no clinically significant drug interactions have been observed with: ethinyl estradiol, itraconazole, ketoconazole, ledipasvir/sofosbuvir, midazolam, norgestimate, sertraline, sofosbuvir, and sofosbuvir/velpatasvir. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to VEMLIDY during pregnancy. Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) at 1-800-258-4263. Risk Summary There are no human data on the use of VEMLIDY in pregnant women to inform a drug-associated risks of adverse fetal developmental outcome. In animal studies, no adverse developmental effects were observed when tenofovir alafenamide was administered during the period of organogenesis at exposure equal to or 51 times (rats and rabbits, respectively) the tenofovir alafenamide exposure at the recommended daily dose of VEMLIDY [see Data]. No adverse effects were observed in the offspring when TDF (tenofovir disoproxil fumarate) was administered through lactation at tenofovir exposures of approximately 12 times the exposure at the recommended daily dosage of VEMLIDY. The background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2–4% and 15–20%, respectively. Data Animal Data Embryonic fetal development studies performed in rats and rabbits revealed no evidence of impaired fertility or harm to the fetus. The embryo-fetal NOAELs (no observed adverse effect level) in rats and rabbits occurred at tenofovir alafenamide exposures similar to and 51 times higher than, respectively, the exposure in humans at the recommended daily dose. Tenofovir alafenamide is rapidly converted to tenofovir; the observed tenofovir exposure in rats and rabbits were 54 (rats) and 85 (rabbits) times higher than human tenofovir exposures at the recommended daily dose. Tenofovir alafenamide was administered orally to pregnant rats (25, 100, or 250 mg/kg/day) and rabbits (10, 30, or 100 mg/kg/day) through organogenesis (on gestation days 6 through 17, and 7 through 20, respectively). No adverse embryo-fetal effects were observed in rats and rabbits at tenofovir alafenamide exposures approximately similar to (rats) and 51 (rabbits) times higher than the exposure in humans at the recommended daily dose of VEMLIDY. Tenofovir alafenamide is rapidly converted to tenofovir; the observed tenofovir exposures in rats and rabbits were 54 (rats) and 85 (rabbits) times higher than human tenofovir exposures at the recommended daily dose. Since tenofovir alafenamide is rapidly converted to tenofovir and a lower tenofovir exposure in rats and mice was observed after tenofovir alafenamide administration compared to TDF, another prodrug for tenofovir administration, a pre/postnatal development study in rats was conducted only with TDF. Doses up to 600 mg/kg/day were administered through lactation; no adverse effects were observed in the offspring on gestation day 7 [and lactation day 20] at tenofovir exposures of approximately 12 [18] times higher than the exposures in humans at the recommended daily dose of VEMLIDY. 8.2 Lactation Risk Summary It is not known whether VEMLIDY and its metabolites are present in human breast milk, affect human milk production, or have effects on the breastfed infant. Tenofovir has been shown to be present in the milk of lactating rats and rhesus monkeys after administration of TDF [see Data]. It is not known if tenofovir alafenamide can be present in animal milk. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for VEMLIDY and any potential adverse effects on the breastfed infant from VEMLIDY or from the underlying maternal condition. Data Animal Data Studies in rats and monkeys have demonstrated that tenofovir is secreted in milk. Tenofovir was excreted into the milk of lactating rats following oral administration of TDF (up to 600 mg/kg/day) at up to approximately 24% of the median plasma concentration in the highest dosed animals at lactation day 11 [see Data (8.1)]. Tenofovir was excreted into the milk of lactating monkeys following a single subcutaneous (30 mg/kg) dose of tenofovir at concentrations up to approximately 4% of plasma concentration, resulting in exposure (AUC) of approximately 20% of plasma exposure. 8.4 Pediatric Use Safety and effectiveness of VEMLIDY in pediatric patients less than 18 years of age have not been established. 8.5 Geriatric Use Clinical trials of VEMLIDY did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. 8.6 Renal Impairment No dosage adjustment of VEMLIDY is required in patients with mild, moderate, or severe renal impairment. VEMLIDY is not recommended in patients with end stage renal disease (estimated creatinine clearance below 15 mL per minute) [see Clinical Pharmacology (12.3)]. 8.7 Hepatic Impairment No dosage adjustment of VEMLIDY is required in patients with mild hepatic impairment (Child-Pugh A). The safety and efficacy of VEMLIDY in patients with decompensated cirrhosis (Child-Pugh B or C) have not been established; therefore VEMLIDY is not recommended in patients with decompensated (Child-Pugh B or C) hepatic impairment [see Dosage and Administration (2.4) and Clinical Pharmacology (12.3)]. 10 OVERDOSAGE If overdose occurs, monitor patient for evidence of toxicity. Treatment of overdosage with VEMLIDY consists of general supportive measures including monitoring of vital signs as well as observation of the clinical status of the patient. Tenofovir is efficiently removed by hemodialysis with an extraction coefficient of approximately 54%. 11 DESCRIPTION VEMLIDY is a tablet containing tenofovir alafenamide for oral administration. Tenofovir alafenamide, a hepatitis B virus (HBV) nucleoside analog reverse transcriptase inhibitor, is converted in vivo to tenofovir, an acyclic nucleoside phosphonate (nucleotide) analog of adenosine 5'-monophosphate. Each tablet contains 25 mg of tenofovir alafenamide (equivalent to 28 mg of tenofovir alafenamide fumarate). The tablets include the following inactive ingredients: croscarmellose sodium, lactose monohydrate, magnesium stearate, and microcrystalline cellulose. The tablets are film coated with a coating material containing: iron oxide yellow, polyethylene glycol, polyvinyl alcohol, talc, and titanium dioxide. The chemical name of tenofovir alafenamide fumarate drug substance is L-alanine, N-[(S)-[[(1R)-2-(6-amino-9H-purin-9-yl)-1-methylethoxy]methyl]phenoxyphosphinyl]-, 1-methylethyl ester, (2E)-2-butenedioate (2:1). It has an empirical formula of C21H29O5N6P∙½(C4H4O4) and a formula weight of 534.50. It has the following structural formula:
Values refer to geometric mean ratio in AUC last [fed/fasted] and (90% confidence interval). High fat meal = ~800 kcal, 50% fat. In vivo, TAF is hydrolyzed within cells to form tenofovir (major metabolite), which is phosphorylated to the active metabolite, tenofovir diphosphate. In vitro studies have shown that TAF is metabolized to tenofovir by CES1 in hepatocytes, and by cathepsin A in PBMCs and macrophages. t 1/2 values refer to median terminal plasma half-life. Dosing in mass balance study: TAF 25 mg (single dose administration of [ 14C] TAF). Table 6 Multiple Dose PK Parameters of Tenofovir Alafenamide and its Metabolite Tenofovir Following Oral Administration in Adults with Chronic Hepatitis B
From Intensive PK analyses in Study 108 and Study 110; N = 8. Specific Populations Geriatric Patients, Race, and Gender No clinically relevant differences in tenofovir alafenamide or tenofovir pharmacokinetics due to race or gender have been identified. Limited data in subjects aged 65 and over suggest a lack of clinically relevant differences in tenofovir alafenamide or tenofovir pharmacokinetics [see Use in Specific Populations (8.5)]. Patients with Renal Impairment Relative to subjects with normal renal function (estimated creatinine clearance ≥90 mL/min), the tenofovir alafenamide and tenofovir systemic exposures in subjects with severe renal impairment were 1.9-fold and 5.7-fold higher, respectively. The pharmacokinetics of tenofovir alafenamide have not been evaluated in patients with creatinine clearance less than 15 mL per minute. Patients with Hepatic Impairment Relative to subjects with normal hepatic function, tenofovir alafenamide and tenofovir systemic exposures were 7.5% and 11% lower in subjects with mild hepatic impairment, respectively. HIV and/or Hepatitis C Virus Coinfection The pharmacokinetics of tenofovir alafenamide have not been fully evaluated in subjects coinfected with HIV and/or hepatitis C virus. Drug Interaction Studies [see Drug Interactions (7)] The effects of coadministered drugs on the exposure of tenofovir alafenamide are shown in Table 7. The effects of tenofovir alafenamide on the exposure of coadministered drugs are shown in Table 8 [For information regarding clinical recommendations, see Drug Interactions (7)]. Information regarding potential drug-drug interactions with HIV antiretrovirals is not provided (see the prescribing information for emtricitabine/tenofovir alafenamide for interactions with HIV antiretrovirals). Table 7 Drug Interactions: Changes in Pharmacokinetic Parameters for Tenofovir Alafenamide in the Presence of the Coadministered Drug*
All no effect boundaries are 70%–143%. Study conducted with emtricitabine/tenofovir alafenamide. A representative inhibitor of P-glycoprotein. Study conducted with emtricitabine/rilpivirine/tenofovir alafenamide. Study conducted with elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide. Table 8 Drug Interactions: Changes in Pharmacokinetic Parameters for Coadministered Drug in the Presence of Tenofovir Alafenamide*
Study conducted with emtricitabine/rilpivirine/tenofovir alafenamide. The predominant circulating nucleoside metabolite of sofosbuvir. A sensitive CYP3A4 substrate. Study conducted with emtricitabine/tenofovir alafenamide. Study conducted with elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide. 12.4 Microbiology Mechanism of Action Tenofovir alafenamide is a phosphonamidate prodrug of tenofovir (2'-deoxyadenosine monophosphate analog). Tenofovir alafenamide as a lipophilic cell-permeant compound enters primary hepatocytes by passive diffusion and by the hepatic uptake transporters OATP1B1 and OATP1B3. Tenofovir alafenamide is then converted to tenofovir through hydrolysis primarily by carboxylesterase 1 (CES1) in primary hepatocytes. Intracellular tenofovir is subsequently phosphorylated by cellular kinases to the pharmacologically active metabolite tenofovir diphosphate. Tenofovir diphosphate inhibits HBV replication through incorporation into viral DNA by the HBV reverse transcriptase, which results in DNA chain-termination. Tenofovir diphosphate is a weak inhibitor of mammalian DNA polymerases that include mitochondrial DNA polymerase γ and there is no evidence of toxicity to mitochondria in cell culture. Antiviral Activity in Cell Culture The antiviral activity of tenofovir alafenamide was assessed in a transient transfection assay using HepG2 cells against a panel of HBV clinical isolates representing genotypes A-H. The EC50 (50% effective concentration) values for tenofovir alafenamide ranged from 34.7 to 134.4 nM, with an overall mean EC50 value of 86.6 nM. The CC50 (50% cytotoxicity concentration) values in HepG2 cells were greater than 44,400 nM. In cell culture combination antiviral activity studies of tenofovir with the HBV nucleoside reverse transcriptase inhibitors entecavir, lamivudine, and telbivudine, no antagonistic activity was observed. Resistance in Clinical Trials In a pooled analysis of treatment-naïve and treatment-experienced subjects receiving VEMLIDY in Studies 108 and 110, genotypic resistance analysis was performed on paired baseline and on-treatment HBV isolates for subjects who either experienced virologic breakthrough (2 consecutive visits with HBV DNA greater than or equal to 69 IU/mL [400 copies/mL] after having been less than 69 IU/mL, or 1.0-log10 or greater increase in HBV DNA from nadir) through Week 48, or had HBV DNA greater than or equal to 69 IU/mL at early discontinuation at or after Week 24. Treatment-emergent amino acid substitutions in the HBV reverse transcriptase domain, all occurring at polymorphic positions, were observed in some HBV isolates evaluated (5/20); however, no specific substitutions occurred at a sufficient frequency to be associated with resistance to VEMLIDY. Cross-Resistance The antiviral activity of tenofovir alafenamide was evaluated against a panel of isolates containing substitutions associated with HBV nucleoside reverse transcriptase inhibitor resistance in a transient transfection assay using HepG2 cells. HBV isolates expressing the lamivudine resistance-associated substitutions rtM204V/I (±rtL180M±rtV173L) and expressing the entecavir resistance-associated substitutions rtT184G, rtS202G, or rtM250V in the presence of rtL180M and rtM204V showed less than 2-fold reduced susceptibility (within the inter-assay variability) to tenofovir alafenamide. HBV isolates expressing the rtA181T, rtA181V, or rtN236T single substitutions associated with resistance to adefovir also had less than 2-fold changes in EC50 values; however, the HBV isolate expressing the rtA181V plus rtN236T double substitutions exhibited reduced susceptibility (3.7-fold) to tenofovir alafenamide. The clinical relevance of these substitutions is not known. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Since tenofovir alafenamide is rapidly converted to tenofovir and a lower tenofovir exposure in rats and mice was observed after tenofovir alafenamide administration compared to tenofovir disoproxil fumarate administration, carcinogenicity studies were conducted only with tenofovir disoproxil fumarate. Long-term oral carcinogenicity studies of tenofovir disoproxil fumarate in mice and rats were carried out at exposures up to approximately 10 times (mice) and 4 times (rats) those observed in humans at the 300 mg therapeutic dose of tenofovir disoproxil fumarate for chronic hepatitis B. The tenofovir exposure in these studies was approximately 151 times (mice) and 50 times (rat) those observed in humans after administration of VEMLIDY treatment. At the high dose in female mice, liver adenomas were increased at tenofovir exposures approximately 151 times those observed after VEMLIDY administration in humans. In rats, the study was negative for carcinogenic findings. Tenofovir alafenamide was not genotoxic in the reverse mutation bacterial test (Ames test), mouse lymphoma or rat micronucleus assays. There were no effects on fertility, mating performance or early embryonic development when tenofovir alafenamide was administered to male rats at a dose equivalent to 155 times the human dose based on body surface area comparisons for 28 days prior to mating and to female rats for 14 days prior to mating through Day 7 of gestation. 13.2 Animal Toxicology and/or Pharmacology Minimal to slight infiltration of mononuclear cells in the posterior uvea was observed in dogs with similar severity after three- and nine-month administration of tenofovir alafenamide; reversibility was seen after a three month recovery period. At the NOAEL for eye toxicity, the systemic exposure in dogs was 5 (tenofovir alafenamide) and 14 (tenofovir) times the exposure seen in humans at the recommended daily VEMLIDY dosage. 14 CLINICAL STUDIES 14.1 Clinical Trials in Adults with Chronic Hepatitis B Virus Infection and Compensated Liver Disease The efficacy and safety of VEMLIDY in the treatment of adults with chronic hepatitis B virus infection with compensated liver disease are based on 48-week data from two randomized, double-blind, active-controlled studies, Study 108 (N=425) and Study 110 (N=873). In both studies, besides study treatment, patients were not allowed to receive other nucleosides, nucleotides, or interferon. In Study 108, HBeAg-negative treatment-naïve and treatment-experienced subjects with compensated liver disease (no evidence of ascites, hepatic encephalopathy, variceal bleeding, INR <1.5× ULN, total bilirubin <2.5× ULN, and albumin >3.0 mg/dL) were randomized in a 2:1 ratio to receive VEMLIDY 25 mg (N=285) once daily or tenofovir disoproxil fumarate 300 mg (N=140) once daily for 48 weeks. The mean age was 46 years, 61% were male, 72% were Asian, 25% were White, 2% were Black, and 1% were other races. 24%, 38%, and 31% had HBV genotype B, C, and D, respectively. 21% were treatment experienced [previous treatment with oral antivirals, including entecavir (N=41), lamivudine (N=42), tenofovir disoproxil fumarate (N=21), or other (N=18)]. At baseline, mean plasma HBV DNA was 5.8 log10 IU/mL, mean serum ALT was 94 U/L, and 9% of subjects had a history of cirrhosis. In Study 110, HBeAg-positive treatment-naïve and treatment-experienced subjects with compensated liver disease were randomized in a 2:1 ratio to receive VEMLIDY 25 mg (N=581) once daily or tenofovir disoproxil fumarate 300 mg (N=292) once daily for 48 weeks. The mean age was 38 years, 64% were male, 82% were Asian, 17% were White, and 1% were Black or other races. 17%, 52%, and 23% had HBV genotype B, C, and D, respectively. 26% were treatment experienced [previous treatment with oral antivirals, including adefovir (N=42), entecavir (N=117), lamivudine (N=84), telbivudine (N=25), tenofovir disoproxil fumarate (N=70), or other (n=17)]. At baseline, mean plasma HBV DNA was 7.6 log10 IU/mL, mean serum ALT was 120 U/L, and 7% of subjects had a history of cirrhosis. In both studies, randomization was stratified on prior treatment history (nucleoside naïve or experienced) and baseline HBV DNA (<7, ≥7 to <8, and ≥8 log10 IU/mL in Study 108; and <8 and ≥8 log10 IU/mL in Study 110). The efficacy endpoint in both trials was the proportion of subjects with plasma HBV DNA levels below 29 IU/mL at Week 48. Additional efficacy endpoints include the proportion of subjects with ALT normalization, HBsAg loss and seroconversion, and HBeAg loss and seroconversion in Study 110. Treatment outcomes of Studies 108 and 110 at Week 48 are presented in Table 9 and Table 10. Table 9 Studies 108 and 110: HBV DNA Virologic Outcome at Week 48* in Patients with Chronic HBV Infection and Compensated Liver Disease
Adjusted by baseline plasma HBV DNA categories and oral antiviral treatment status strata. Treatment-naïve subjects received <12 weeks of oral antiviral treatment with any nucleoside or nucleotide analog including TDF or VEMLIDY. Includes subjects who discontinued due to lack of efficacy, adverse event or death, for reasons other than an AE, death or lack or loss of efficacy, e.g., withdrew consent, loss to follow-up, etc., or missing data during Week 48 window but still on study drug. In Study 108, the proportion of subjects with cirrhosis who achieved HBV DNA <29 IU/mL at Week 48 was 92% (22/24) in the VEMLIDY group and 93% (13/14) in the TDF group. The corresponding proportions in Study 110 were 63% (26/41) and 67% (16/24) in the VEMLIDY and TDF groups, respectively. Table 10 Additional Efficacy Parameters at Week 48* N/A = not applicable
The population used for analysis of ALT normalization included only subjects with ALT above upper limit of normal (ULN) of the central laboratory range (>43 U/L for males aged 18 to <69 years and >35 U/L for males ≥69 years; >34 U/L for females 18 to <69 years and >32 U/L for females ≥69 years) at baseline. The population used for analysis of ALT normalization included only subjects with ALT above ULN of the American Association of the Study of Liver Diseases (AASLD) criteria (>30 U/L males and >19 U/L females) at baseline. The population used for serology analysis included only subjects with antigen (HBeAg) positive and anti-body (HBeAb) negative or missing at baseline. 16 HOW SUPPLIED/STORAGE AND HANDLING VEMLIDY tablets containing 25 mg of tenofovir alafenamide are yellow, round, film-coated, debossed with "GSI" on one side and "25" on the other side. Each bottle contains 30 tablets (NDC 61958-2301-1), a silica gel desiccant, polyester coil, and is closed with a child-resistant closure. Store below 30 °C (86 °F). Keep container tightly closed. Dispense only in original container. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=72e6b33c-0351-4070-9172-eeaa186c01d2 |
Vemlidy Tablets(tenofovir alafenamide,TAF)简介:
Vemlidy(tenofovir alafenamide,TAF)是近十年来首个获FDA批准每日一次治疗慢性乙肝新药近日,美国FDA批准其新药产品Vemlidy(tenofovir alafenamide,TAF)25mg,每日一次治疗伴有代偿性肝病的慢性乙 ... 责任编辑:p53
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