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新型丙型肝炎药物-索非布韦(商品名：Sovaldi,通用名：Sofosbuvir, 之前名为GS-7977,PSI-7977, 400mg片剂）获美国FDA及欧洲等国家批准上市
SOVALDI is a hepatitis C virus (HCV) nucleotide analog NS5B polymerase inhibitor indicated for the treatment of genotype 1, 2, 3 or 4 chronic hepatitis C virus (HCV) infection as a component of a combination antiviral treatment regimen. (1) DOSAGE AND ADMINISTRATION One 400 mg tablet taken once daily with or without food. (2.1) Should be used in combination with ribavirin or in combination with pegylated interferon and ribavirin for the treatment of HCV. Recommended combination therapy: (2.1)
SOVALDI in combination with ribavirin for 24 weeks can be considered for patients with genotype 1 infection who are interferon ineligible. (2.1) Should be used in combination with ribavirin for treatment of HCV in patients with hepatocellular carcinoma awaiting liver transplantation for up to 48 weeks or until liver transplantation, whichever occurs first. (2.1) A dosage recommendation cannot be made for patients with severe renal impairment or end stage renal disease. (2.4, 8.6) DOSAGE FORMS AND STRENGTHS Tablets: 400 mg. (3) CONTRAINDICATIONS When used in combination with peginterferon alfa/ribavirin or ribavirin alone, all contraindications to peginterferon alfa and/or ribavirin also apply to SOVALDI combination therapy. (4) WARNINGS AND PRECAUTIONS Bradycardia with amiodarone coadministration: Serious symptomatic bradycardia may occur in patients taking amiodarone and SOVALDI in combination with another direct acting antiviral (DAA), particularly in patients also receiving beta blockers, or those with underlying cardiac comorbidities and/or advanced liver disease. Coadministration of amiodarone with SOVALDI in combination with another DAA is not recommended. In patients without alternative, viable treatment options, cardiac monitoring is recommended. (5.1, 6.2,7.1) Use with other drugs containing sofosbuvir is not recommended (5.4) ADVERSE REACTIONS The most common adverse events (incidence greater than or equal to 20%, all grades) observed with SOVALDI in combination with ribavirin were fatigue and headache. The most common adverse events observed with SOVALDI in combination with peginterferon alfa and ribavirin were fatigue, headache, nausea, insomnia and anemia. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Gilead Sciences, Inc. at 1-800-GILEAD-5 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. DRUG INTERACTIONS Coadministration of amiodarone with SOVALDI in combination with another DAA may result in serious symptomatic bradycardia. (5.1, 6.2, 7.1) Drugs that are intestinal P-gp inducers (e.g., rifampin, St. John's wort) may alter the concentrations of sofosbuvir. (5.2, 7, 12.3) Consult the full prescribing information prior to use for potential drug-drug interactions. (5.1, 5.2, 7, 12.3) USE IN SPECIFIC POPULATIONS Patients with HCV/HIV-1 co-infection: Safety and efficacy have been studied. (14.4) Patients with hepatocellular carcinoma awaiting liver transplantation: Safety and efficacy have been studied. (8.8) See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling. Revised: 8/2015 FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE SOVALDI is indicated for the treatment of genotype 1, 2, 3 or 4 chronic hepatitis C virus (HCV) infection as a component of a combination antiviral treatment regimen [see Clinical Studies (14)]. 2 DOSAGE AND ADMINISTRATION 2.1 Recommended Dosage The recommended dosage of SOVALDI is one 400 mg tablet, taken orally, once daily with or without food [see Clinical Pharmacology (12.3)]. Administer SOVALDI in combination with ribavirin or in combination with pegylated interferon and ribavirin for the treatment of HCV. The recommended treatment regimen and duration for SOVALDI combination therapy is provided in Table 1. For patients with HCV/HIV-1 co-infection, follow the dosage recommendations in Table 1. Refer to Drug Interactions (7) for dosage recommendations for concomitant HIV-1 antiviral drugs. Table 1 Recommended Treatment Regimens and Duration
Dosage of ribavirin is weight-based (<75 kg = 1000 mg and ≥75 kg = 1200 mg). The daily dosage of ribavirin is administered orally in two divided doses with food. Patients with renal impairment (CrCl ≤50 mL/min) require ribavirin dosage reduction; refer to ribavirin prescribing information. Patients with Genotype 1 HCV Who are Ineligible to Receive an Interferon-Based Regimen SOVALDI in combination with ribavirin for 24 weeks can be considered as a therapeutic option for patients with genotype 1 infection who are ineligible to receive an interferon-based regimen [see Clinical Studies (14.4)]. Treatment decision should be guided by an assessment of the potential benefits and risks for the individual patient. Patients with Hepatocellular Carcinoma Awaiting Liver Transplantation Administer SOVALDI in combination with ribavirin for up to 48 weeks or until the time of liver transplantation, whichever occurs first, to prevent post-transplant HCV reinfection [see Use in Specific Populations (8.8)]. 2.2 Dosage Modification Dosage reduction of SOVALDI is not recommended. If a patient has a serious adverse reaction potentially related to peginterferon alfa and/or ribavirin, the peginterferon alfa and/or ribavirin dosage should be reduced or discontinued, if appropriate, until the adverse reaction abates or decreases in severity. Refer to the peginterferon alfa and ribavirin prescribing information for additional information about how to reduce and/or discontinue the peginterferon alfa and/or ribavirin dosage. 2.3 Discontinuation of Dosing If the other agents used in combination with SOVALDI are permanently discontinued, SOVALDI should also be discontinued. 2.4 Severe Renal Impairment and End Stage Renal Disease No dosage recommendation can be given for patients with severe renal impairment (estimated Glomerular Filtration Rate [eGFR] less than 30 mL/min/1.73m2) or with end stage renal disease (ESRD) due to higher exposures (up to 20-fold) of the predominant sofosbuvir metabolite [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)]. 3 DOSAGE FORMS AND STRENGTHS SOVALDI is available as a yellow-colored, capsule-shaped, film-coated tablet debossed with "GSI" on one side and "7977" on the other side. Each tablet contains 400 mg sofosbuvir. 4 CONTRAINDICATIONS When SOVALDI is used in combination with ribavirin or peginterferon alfa/ribavirin, the contraindications applicable to those agents are applicable to combination therapies. Refer to the prescribing information of peginterferon alfa and ribavirin for a list of their contraindications. 5 WARNINGS AND PRECAUTIONS 5.1 Serious Symptomatic Bradycardia When Coadministered with Amiodarone and Another HCV Direct Acting Antiviral Postmarketing cases of symptomatic bradycardia and cases requiring pacemaker intervention have been reported when amiodarone is coadministered with SOVALDI in combination with an investigational agent (NS5A inhibitor) or simeprevir. A fatal cardiac arrest was reported in a patient receiving a sofosbuvir-containing regimen (HARVONI (ledipasvir/sofosbuvir)). Bradycardia has generally occurred within hours to days, but cases have been observed up to 2 weeks after initiating HCV treatment. Patients also taking beta blockers, or those with underlying cardiac comorbidities and/or advanced liver disease may be at increased risk for symptomatic bradycardia with coadministration of amiodarone. Bradycardia generally resolved after discontinuation of HCV treatment. The mechanism for this effect is unknown. Coadministration of amiodarone with SOVALDI in combination with another direct acting antiviral (DAA) is not recommended. For patients taking amiodarone who have no other alternative, viable treatment options and who will be coadministered SOVALDI and another DAA: Counsel patients about the risk of serious symptomatic bradycardia Cardiac monitoring in an in-patient setting for the first 48 hours of coadministration is recommended, after which outpatient or self-monitoring of the heart rate should occur on a daily basis through at least the first 2 weeks of treatment. Patients who are taking SOVALDI in combination with another DAA who need to start amiodarone therapy due to no other alternative, viable treatment options should undergo similar cardiac monitoring as outlined above. Due to amiodarone's long half-life, patients discontinuing amiodarone just prior to starting SOVALDI in combination with a DAA should also undergo similar cardiac monitoring as outlined above. Patients who develop signs or symptoms of bradycardia should seek medical evaluation immediately. Symptoms may include near-fainting or fainting, dizziness or lightheadedness, malaise, weakness, excessive tiredness, shortness of breath, chest pains, confusion or memory problems [see Adverse Reactions (6.2), Drug Interactions (7.1)]. 5.2 Risk of Reduced Therapeutic Effect Due to Use with P-gp Inducers Drugs that are P-gp inducers in the intestine (e.g., rifampin, St. John's wort) may significantly decrease sofosbuvir plasma concentrations and may lead to a reduced therapeutic effect of SOVALDI. The use of rifampin and St. John's wort with SOVALDI is not recommended [see Drug Interactions (7.1)]. 5.3 Risks Associated with Combination Treatment Because SOVALDI is used in combination with other antiviral drugs for treatment of HCV infection, consult the prescribing information for these drugs used in combination with SOVALDI. Warnings and Precautions related to these drugs also apply to their use in SOVALDI combination treatment. 5.4 Related Products Not Recommended The use of SOVALDI with other products containing sofosbuvir is not recommended. 6 ADVERSE REACTIONS The following serious adverse reactions are described below and elsewhere in the labeling: Serious Symptomatic Bradycardia When Coadministered with Amiodarone and Another HCV Direct Acting Antiviral [see Warnings and Precautions (5.1)]. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. When SOVALDI is administered with ribavirin or peginterferon alfa/ribavirin, refer to the respective prescribing information for a description of adverse reactions associated with their use. The safety assessment of SOVALDI was based on pooled Phase 3 clinical trial data (both controlled and uncontrolled) including: 650 subjects who received SOVALDI + ribavirin (RBV) combination therapy for 12 weeks, 98 subjects who received SOVALDI + ribavirin combination therapy for 16 weeks, 250 subjects who received SOVALDI + ribavirin combination therapy for 24 weeks, 327 subjects who received SOVALDI + peginterferon (Peg-IFN) alfa + ribavirin combination therapy for 12 weeks, 243 subjects who received peginterferon alfa + ribavirin for 24 weeks, and 71 subjects who received placebo (PBO) for 12 weeks [see Clinical Studies (14)]. The proportion of subjects who permanently discontinued treatment due to adverse events was 4% for subjects receiving placebo, 1% for subjects receiving SOVALDI + ribavirin for 12 weeks, less than 1% for subjects receiving SOVALDI + ribavirin for 24 weeks, 11% for subjects receiving peginterferon alfa + ribavirin for 24 weeks and 2% for subjects receiving SOVALDI + peginterferon alfa + ribavirin for 12 weeks. Adverse events observed in at least 15% of subjects in the Phase 3 clinical trials outlined above are provided in Table 2. A side-by-side tabulation is displayed to simplify presentation; direct comparison across trials should not be made due to differing trial designs. The most common adverse events (at least 20%) for SOVALDI + ribavirin combination therapy were fatigue and headache. The most common adverse events (at least 20%) for SOVALDI + peginterferon alfa + ribavirin combination therapy were fatigue, headache, nausea, insomnia and anemia. Table 2 Adverse Events (All Grades and without Regard to Causality) Reported in ≥15% of Subjects with HCV in Any Treatment Arm
Subjects received 800 mg ribavirin per day regardless of weight With the exception of anemia and neutropenia, the majority of events presented in Table 2 occurred at severity of grade 1 in SOVALDI-containing regimens. Less Common Adverse Reactions Reported in Clinical Trials (less than 1%): The following adverse reactions occurred in less than 1% of subjects receiving SOVALDI in a combination regimen in any one trial. These events have been included because of their seriousness or assessment of potential causal relationship. Hematologic Effects: pancytopenia (particularly in subjects receiving concomitant pegylated interferon). Psychiatric Disorders: severe depression (particularly in subjects with pre-existing history of psychiatric illness), including suicidal ideation and suicide. Laboratory Abnormalities: Changes in selected hematological parameters are described in Table 3. A side-by-side tabulation is displayed to simplify presentation; direct comparison across trials should not be made due to differing trial designs. Table 3 Percentage of Subjects Reporting Selected Hematological Parameters
Subjects received 800 mg ribavirin per day regardless of weight. Bilirubin Elevations Total bilirubin elevation of more than 2.5×ULN was observed in none of the subjects in the SOVALDI + peginterferon alfa + ribavirin 12 weeks group and in 1%, 3% and 3% of subjects in the peginterferon alfa + ribavirin 24 weeks, SOVALDI + ribavirin 12 weeks and SOVALDI + ribavirin 24 weeks groups, respectively. Bilirubin levels peaked during the first 1 to 2 weeks of treatment and subsequently decreased and returned to baseline levels by post-treatment Week 4. These bilirubin elevations were not associated with transaminase elevations. Creatine Kinase Elevations Creatine kinase was assessed in the FISSION and NEUTRINO trials. Isolated, asymptomatic creatine kinase elevation of greater than or equal to 10×ULN was observed in less than 1%, 1% and 2% of subjects in the peginterferon alfa + ribavirin 24 weeks, SOVALDI + peginterferon alfa + ribavirin 12 weeks and SOVALDI + ribavirin 12 weeks groups, respectively. Lipase Elevations Isolated, asymptomatic lipase elevation of greater than 3×ULN was observed in less than 1%, 2%, 2%, and 2% of subjects in the SOVALDI + peginterferon alfa + ribavirin 12 weeks, SOVALDI + ribavirin 12 weeks, SOVALDI + ribavirin 24 weeks and peginterferon alfa + ribavirin 24 weeks groups, respectively. Patients with HCV/HIV-1 Co-infection SOVALDI used in combination with ribavirin was assessed in 223 HCV/HIV-1 co-infected subjects [see Clinical Studies (14.4)]. The safety profile in HCV/HIV-1 co-infected subjects was similar to that observed in HCV mono-infected subjects. Elevated total bilirubin (grade 3 or 4) was observed in 30/32 (94%) subjects receiving atazanavir as part of the antiretroviral regimen. None of the subjects had concomitant transaminase increases. Among subjects not taking atazanavir, grade 3 or 4 elevated total bilirubin was observed in 2 (1.5%) subjects, similar to the rate observed with HCV mono-infected subjects receiving SOVALDI + ribavirin in Phase 3 trials. 6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of SOVALDI. Because postmarketing reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Cardiac Disorders Serious symptomatic bradycardia has been reported in patients taking amiodarone who initiate treatment with SOVALDI in combination with another HCV direct acting antiviral [see Warnings and Precautions (5.1), Drug Interactions (7.1)]. 7 DRUG INTERACTIONS 7.1 Potentially Significant Drug Interactions Sofosbuvir is a substrate of drug transporter P-gp and breast cancer resistance protein (BCRP) while the predominant circulating metabolite GS-331007 is not. Drugs that are P-gp inducers in the intestine (e.g., rifampin or St. John's wort) may decrease sofosbuvir plasma concentration, leading to reduced therapeutic effect of SOVALDI, and thus concomitant use with SOVALDI is not recommended [see Warnings and Precautions (5.2)]. Information on potential drug interactions with SOVALDI is summarized in Table 4. The table is not all-inclusive [see Warnings and Precautions (5.1, 5.2) and Clinical Pharmacology (12.3)]. Table 4 Potentially Significant Drug Interactions: Alteration in Dosage or Regimen May Be Recommended Based on Drug Interaction Studies or Predicted Interaction*
↓ = decrease 7.2 Drugs without Clinically Significant Interactions with SOVALDI In addition to the drugs included in Table 4, the interaction between SOVALDI and the following drugs was evaluated in clinical trials and no dose adjustment is needed for either drug [See Clinical Pharmacology (12.3)]: cyclosporine, darunavir/ritonavir, efavirenz, emtricitabine, methadone, oral contraceptives, raltegravir, rilpivirine, tacrolimus, or tenofovir disoproxil fumarate. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category B: There are no adequate and well-controlled studies with SOVALDI in pregnant women. Because animal reproduction studies are not always predictive of human response, SOVALDI should be used during pregnancy only if the potential for benefit justifies the potential risk to the fetus. If SOVALDI is administered with ribavirin or peginterferon and ribavirin, the combination regimen is contraindicated in pregnant women and in men whose female partners are pregnant. Refer to the ribavirin and/or peginterferon prescribing information for more information on use in males and females of child-bearing potential. Animal Data No effects on fetal development have been observed in rats and rabbits at the highest doses tested. In the rat and rabbit, AUC exposure to the predominant circulating metabolite GS-331007 increased over the course of gestation from approximately 5- to 10-fold and 12- to 28-fold the exposure in humans at the recommended clinical dose, respectively. 8.3 Nursing Mothers It is not known whether SOVALDI and its metabolites are present in human breast milk. The predominant circulating metabolite GS-331007 was the primary component observed in the milk of lactating rats, without effect on nursing pups. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for SOVALDI and any potential adverse effects on the breastfed child from the drug or from the underlying maternal condition. If SOVALDI is administered in a regimen containing ribavirin, the information for ribavirin with regard to nursing mothers also applies to this combination regimen. Refer to the ribavirin prescribing information for more information on use in nursing mothers. 8.4 Pediatric Use Safety and effectiveness of SOVALDI in children less than 18 years of age have not been established. 8.5 Geriatric Use SOVALDI was administered to 90 subjects aged 65 and over. The response rates observed for subjects over 65 years of age were similar to that of younger subjects across treatment groups. No dosage adjustment of SOVALDI is warranted in geriatric patients [see Clinical Pharmacology (12.3)]. 8.6 Renal Impairment No dosage adjustment of SOVALDI is required for patients with mild or moderate renal impairment. The safety and efficacy of SOVALDI have not been established in patients with severe renal impairment (eGFR less than 30 mL/min/1.73m2) or ESRD requiring hemodialysis. No dosage recommendation can be given for patients with severe renal impairment or ESRD [see Dosage and Administration (2.4) and Clinical Pharmacology (12.3)]. Refer also to ribavirin and peginterferon alfa prescribing information for patients with CrCl less than 50 mL/min. 8.7 Hepatic Impairment No dosage adjustment of SOVALDI is required for patients with mild, moderate or severe hepatic impairment (Child-Pugh Class A, B or C) [see Clinical Pharmacology (12.3)]. Safety and efficacy of SOVALDI have not been established in patients with decompensated cirrhosis. See peginterferon alfa prescribing information for contraindication in hepatic decompensation. 8.8 Patients with Hepatocellular Carcinoma Awaiting Liver Transplantation SOVALDI was studied in HCV-infected subjects with hepatocellular carcinoma prior to undergoing liver transplantation in an open-label clinical trial evaluating the safety and efficacy of SOVALDI and ribavirin administered pre-transplant to prevent post-transplant HCV reinfection. The primary endpoint of the trial was post-transplant virologic response (pTVR) defined as HCV RNA less than lower limit of quantification (LLOQ) at 12 weeks post-transplant. HCV-infected subjects, regardless of genotype, with hepatocellular carcinoma (HCC) meeting the MILAN criteria (defined as the presence of a tumor 5 cm or less in diameter in patients with single hepatocellular carcinomas and no more than three tumor nodules, each 3 cm or less in diameter in patients with multiple tumors and no extrahepatic manifestations of the cancer or evidence of vascular invasion of tumor) received 400 mg SOVALDI and weight-based 1000–1200 mg ribavirin daily for 24–48 weeks or until the time of liver transplantation, whichever occurred first. An interim analysis was conducted on 61 subjects who received SOVALDI and ribavirin; 45 subjects had HCV genotype 1; 44 subjects had a baseline CPT score less than 7 and all subjects had a baseline unadjusted MELD score up to 14. Of these 61 subjects, 41 subjects underwent liver transplantation following up to 48 weeks of treatment with SOVALDI and ribavirin; 37 had HCV RNA less than LLOQ at the time of transplantation. Of the 37 subjects, the post-transplant virologic response (pTVR) rate is 64% (23/36) in the 36 evaluable subjects who have reached the 12 week post-transplant time point. The safety profile of SOVALDI and ribavirin in HCV-infected subjects prior to liver transplantation was comparable to that observed in subjects treated with SOVALDI and ribavirin in Phase 3 clinical trials. 8.9 Post-Liver Transplant Patients The safety and efficacy of SOVALDI have not been established in post-liver transplant patients. 8.10 Patients with Genotype 5 or 6 HCV Infection Available data on subjects with genotype 5 or 6 HCV infection are insufficient for dosing recommendations. 10 OVERDOSAGE The highest documented dosage of sofosbuvir was a single dose of sofosbuvir 1200 mg (three times the recommended dosage) administered to 59 healthy subjects. In that trial, there were no untoward effects observed at this dosage level, and adverse events were similar in frequency and severity to those reported in the placebo and sofosbuvir 400 mg treatment groups. The effects of higher dosages are not known. No specific antidote is available for overdose with SOVALDI. If overdose occurs, the patient must be monitored for evidence of toxicity. Treatment of overdose with SOVALDI consists of general supportive measures including monitoring of vital signs as well as observation of the clinical status of the patient. A 4-hour hemodialysis session removed 18% of the administered dose. 11 DESCRIPTION SOVALDI (sofosbuvir) is a nucleotide analog inhibitor of HCV NS5B polymerase. The IUPAC name for sofosbuvir is (S)-Isopropyl 2-((S)-(((2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)-(phenoxy)phosphorylamino)propanoate. It has a molecular formula of C22H29FN3O9P and a molecular weight of 529.45. It has the following structural formula:
* All interaction studies conducted in healthy volunteers Administered as efavirenz/emtricitabine/tenofovir disoproxil fumarate fixed dose tablet Comparison based on historic control No effect on the pharmacokinetic parameters of sofosbuvir and GS-331007 was observed with raltegravir. Table 6 Drug Interactions: Changes in Pharmacokinetic Parameters for Coadministered Drug in the Presence of Sofosbuvir*
All interaction studies conducted in healthy volunteers Administered as efavirenz/emtricitabine/tenofovir disoproxil fumarate fixed dose tablet No effect on the pharmacokinetic parameters of the following coadministered drugs was observed with sofosbuvir: cyclosporine, darunavir/ritonavir, efavirenz, emtricitabine, methadone, or rilpivirine. 12.4 Microbiology Mechanism of Action Sofosbuvir is an inhibitor of the HCV NS5B RNA-dependent RNA polymerase, which is essential for viral replication. Sofosbuvir is a nucleotide prodrug that undergoes intracellular metabolism to form the pharmacologically active uridine analog triphosphate (GS-461203), which can be incorporated into HCV RNA by the NS5B polymerase and acts as a chain terminator. In a biochemical assay, GS-461203 inhibited the polymerase activity of the recombinant NS5B from HCV genotype 1b, 2a, 3a and 4a with IC50 values ranging from 0.7 to 2.6 micromolar. GS-461203 is neither an inhibitor of human DNA and RNA polymerases nor an inhibitor of mitochondrial RNA polymerase. Antiviral Activity In HCV replicon assays, the EC50 values of sofosbuvir against full-length replicons from genotype 1a, 1b, 2a, 3a and 4a, and chimeric 1b replicons encoding NS5B from genotype 2b, 5a or 6a ranged from 0.014 to 0.11 micromolar. The median EC50 value of sofosbuvir against chimeric replicons encoding NS5B sequences from clinical isolates was 0.062 micromolar for genotype 1a (range 0.029–0.128 micromolar; N=67), 0.102 micromolar for genotype 1b (range 0.045–0.170 micromolar; N=29), 0.029 micromolar for genotype 2 (range 0.014–0.081 micromolar; N=15) and 0.081 micromolar for genotype 3a (range 0.024–0.181 micromolar; N=106). In infectious virus assays, the EC50 values of sofosbuvir against genotype 1a and 2a were 0.03 and 0.02 micromolar, respectively. The presence of 40% human serum had no effect on the anti-HCV activity of sofosbuvir. Evaluation of sofosbuvir in combination with interferon alpha or ribavirin showed no antagonistic effect in reducing HCV RNA levels in replicon cells. Resistance In Cell Culture HCV replicons with reduced susceptibility to sofosbuvir have been selected in cell culture for multiple genotypes including 1b, 2a, 2b, 3a, 4a, 5a and 6a. Reduced susceptibility to sofosbuvir was associated with the primary NS5B substitution S282T in all replicon genotypes examined. An M289L substitution developed along with the S282T substitution in genotype 2a, 5 and 6 replicons. Site-directed mutagenesis of the S282T substitution in replicons of 8 genotypes conferred 2- to 18-fold reduced susceptibility to sofosbuvir and reduced the replication viral capacity by 89% to 99% compared to the corresponding wild-type. In biochemical assays, recombinant NS5B polymerase from genotypes 1b, 2a, 3a and 4a expressing the S282T substitution showed reduced susceptibility to GS-461203 compared to respective wild-types. In Clinical Trials In a pooled analysis of 982 subjects who received SOVALDI in Phase 3 trials, 224 subjects had post-baseline NS5B genotypic data from next generation nucleotide sequencing (assay cutoff of 1%). Treatment-emergent substitutions L159F (n=6) and V321A (n=5) were detected in post-baseline samples from GT3a-infected subjects across the Phase 3 trials. No detectable shift in the phenotypic susceptibility to sofosbuvir of subject isolates with L159F or V321A substitutions was seen. The sofosbuvir-associated resistance substitution S282T was not detected at baseline or in the failure isolates from Phase 3 trials. However, an S282T substitution was detected in one genotype 2b subject who relapsed at Week 4 post-treatment after 12 weeks of sofosbuvir monotherapy in the Phase 2 trial P7977-0523 [ELECTRON]. The isolate from this subject displayed a mean 13.5-fold reduced susceptibility to sofosbuvir. For this subject, the S282T substitution was no longer detectable at Week 12 post-treatment by next generation sequencing with an assay cutoff of 1%. In the trial done in subjects with hepatocellular carcinoma awaiting liver transplantation where subjects received up to 48 weeks of sofosbuvir and ribavirin, the L159F substitution emerged in multiple subjects with GT1a or GT2b HCV who experienced virologic failure (breakthrough and relapse). Furthermore, the presence of substitutions L159F and/or C316N at baseline was associated with sofosbuvir breakthrough and relapse post-transplant in multiple subjects infected with GT1b HCV. In addition, S282R and L320F substitutions were detected on-treatment by next generation sequencing in a subject infected with GT1a HCV with a partial treatment response. The clinical significance of these substitutions is not known. Cross Resistance HCV replicons expressing the sofosbuvir-associated resistance substitution S282T were susceptible to NS5A inhibitors and ribavirin. HCV replicons expressing the ribavirin-associated substitutions T390I and F415Y were susceptible to sofosbuvir. Sofosbuvir was active against HCV replicons with NS3/4A protease inhibitor, NS5B non-nucleoside inhibitor and NS5A inhibitor resistant variants. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis and Mutagenesis Use with Ribavirin and/or Peginterferon alfa: Refer to prescribing information for ribavirin and/or peginterferon alfa for information on carcinogenesis and mutagenesis. Sofosbuvir was not genotoxic in a battery of in vitro or in vivo assays, including bacterial mutagenicity, chromosome aberration using human peripheral blood lymphocytes and in vivo mouse micronucleus assays. Two-year carcinogenicity studies in mice and rats were conducted with sofosbuvir. Mice were administered doses of up to 200 mg/kg/day in males and 600 mg/kg/day in females, while rats were administered doses of up to 750 mg/kg/day in males and females. No increase in the incidence of drug-related neoplasms were observed at the highest doses tested in mice and rats, resulting in AUC exposure to the predominant circulating metabolite GS-331007 of approximately 7- and 30-fold (in mice) and 13- and 17-fold (in rats), in males and females respectively, the exposure in humans at the recommended clinical dose. Impairment of Fertility Use with Ribavirin and/or Peginterferon alfa: Refer to prescribing information for ribavirin and/or peginterferon for information on impairment of fertility. Sofosbuvir had no effects on embryo-fetal viability or on fertility when evaluated in rats. At the highest dose tested, AUC exposure to the predominant circulating metabolite GS-331007 was approximately 8-fold the exposure in humans at the recommended clinical dose. 14 CLINICAL STUDIES 14.1 Description of Clinical Trials The safety and efficacy of SOVALDI was evaluated in five Phase 3 trials in a total of 1724 HCV mono-infected subjects with genotypes 1 to 6 chronic hepatitis C virus and one Phase 3 trial in 223 HCV/HIV-1 co-infected subjects with genotype 1, 2 or 3 HCV, as summarized in Table 7. Table 7 Trials Conducted with SOVALDI with Peginterferon Alfa and/or Ribavirin in Subjects with Chronic HCV Genotype 1, 2, 3, or 4 Infection
14.2 Clinical Trials in Subjects with Genotype 1 or 4 HCV Treatment-Naïve Adults ─ NEUTRINO (Study 110) NEUTRINO was an open-label, single-arm trial that evaluated 12 weeks of treatment with SOVALDI in combination with peginterferon alfa 2a and ribavirin in treatment-naïve subjects with genotype 1, 4, 5 or 6 HCV infection compared to pre-specified historical control. Treated subjects (N=327) had a median age of 54 years (range: 19 to 70); 64% of the subjects were male; 79% were White, 17% were Black; 14% were Hispanic or Latino; mean body mass index was 29 kg/m2 (range: 18 to 56 kg/m2); 78% had baseline HCV RNA greater than 6 log10 IU per mL; 17% had cirrhosis; 89% had HCV genotype 1; 9% had HCV genotype 4 and 2% had HCV genotype 5 or 6. Table 8 presents the SVR12 for the treatment group of SOVALDI + peginterferon alfa + ribavirin in subjects with genotype 1 or 4 HCV. Available data on subjects with genotype 5 or 6 HCV treated with SOVALDI + peginterferon alfa + ribavirin for 12 weeks were insufficient for dosing recommendations; therefore these results are not presented in Table 8 [see Use in Specific Populations (8.10)]. Table 8 Study NEUTRINO: SVR12 for Treatment-Naïve Subjects with Genotype 1 or 4 HCV
The denominator for relapse is the number of subjects with HCV RNA <LLOQ at their last on-treatment assessment. Other includes subjects who did not achieve SVR and did not meet virologic failure criteria (e.g., lost to follow-up). SVR12 for selected subgroups are presented in Table 9. Table 9 SVR12 Rates for Selected Subgroups in NEUTRINO in Subjects with Genotype 1 or 4 HCV
It is estimated that the SVR12 in patients who previously failed pegylated interferon and ribavirin therapy will approximate the observed SVR12 in NEUTRINO subjects with multiple baseline factors traditionally associated with a lower response to interferon-based treatment (Table 9). The SVR12 rate in the NEUTRINO trial in genotype 1 subjects with IL28B non-C/C alleles, HCV RNA greater than 800,000 IU/mL and Metavir F3/F4 fibrosis was 71% (37/52). 14.3 Clinical Trials in Subjects with Genotype 2 or 3 HCV Treatment-Naïve Adults ─ FISSION (Study 1231) FISSION was a randomized, open-label, active-controlled trial that evaluated 12 weeks of treatment with SOVALDI and ribavirin compared to 24 weeks of treatment with peginterferon alfa 2a and ribavirin in treatment-naïve subjects with genotype 2 and 3 HCV. The ribavirin dosage used in the SOVALDI + ribavirin and peginterferon alfa 2a + ribavirin arms were weight-based 1000–1200 mg per day and 800 mg per day regardless of weight, respectively. Subjects were randomized in a 1:1 ratio and stratified by cirrhosis (presence vs. absence), HCV genotype (2 vs. 3) and baseline HCV RNA level (less than 6 log10 IU/mL vs. at least 6 log10 IU/mL). Subjects with genotype 2 or 3 HCV were enrolled in an approximately 1:3 ratio. Treated subjects (N=499) had a median age of 50 years (range: 19 to 77); 66% of the subjects were male; 87% were White, 3% were Black; 14% were Hispanic or Latino; mean body mass index was 28 kg/m2 (range: 17 to 52 kg/m2); 57% had baseline HCV RNA levels greater than 6 log10 IU per mL; 20% had cirrhosis; 72% had HCV genotype 3. Table 11 presents the SVR12 for the treatment groups of SOVALDI + ribavirin and peginterferon alfa + ribavirin in subjects with genotype 2 HCV. SVR12 for genotype 3 subjects treated with SOVALDI + ribavirin for 12 weeks was suboptimal; therefore these results are not presented in Table 10. Table 10 Study FISSION: SVR12 in Treatment-Naïve Subjects with Genotype 2 HCV
The denominator for relapse is the number of subjects with HCV RNA <LLOQ at their last on-treatment assessment. Other includes subjects who did not achieve SVR and did not meet virologic failure criteria (e.g., lost to follow-up). SVR12 for genotype 2 HCV infected subjects with cirrhosis at baseline are presented in Table 11. Table 11 SVR12 Rates by Cirrhosis in Study FISSION in Subjects with Genotype 2 HCV
POSITRON was a randomized, double-blinded, placebo-controlled trial that evaluated 12 weeks of treatment with SOVALDI and ribavirin (N=207) compared to placebo (N=71) in subjects who are interferon intolerant, ineligible or unwilling. Subjects were randomized in 3:1 ratio and stratified by cirrhosis (presence vs. absence). Treated subjects (N=278) had a median age of 54 years (range: 21 to 75); 54% of the subjects were male; 91% were White, 5% were Black; 11% were Hispanic or Latino; mean body mass index was 28 kg/m2 (range: 18 to 53 kg/m2); 70% had baseline HCV RNA levels greater than 6 log10 IU per mL; 16% had cirrhosis; 49% had HCV genotype 3. The proportions of subjects who were interferon intolerant, ineligible, or unwilling were 9%, 44%, and 47%, respectively. Most subjects had no prior HCV treatment (81%). Table 13 presents the SVR12 for the treatment groups of SOVALDI + ribavirin and placebo in subjects with genotype 2 HCV. SVR12 for genotype 3 subjects treated with SOVALDI + ribavirin for 12 weeks was suboptimal; therefore these results are not presented in Table 12. Table 12 Study POSITRON: SVR12 in Interferon Intolerant, Ineligible or Unwilling Subjects with Genotype 2 HCV
Other includes subjects who did not achieve SVR and did not meet virologic failure criteria (e.g., lost to follow-up). Table 13 presents the subgroup analysis for cirrhosis and interferon classification in subjects with genotype 2 HCV. Table 13 SVR12 Rates for Selected Subgroups in POSITRON in Subjects with Genotype 2 HCV
FUSION was a randomized, double-blinded trial that evaluated 12 or 16 weeks of treatment with SOVALDI and ribavirin in subjects who did not achieve SVR with prior interferon-based treatment (relapsers and nonresponders). Subjects were randomized in a 1:1 ratio and stratified by cirrhosis (presence vs. absence) and HCV genotype (2 vs. 3). Treated subjects (N=201) had a median age of 56 years (range: 24 to 70); 70% of the subjects were male; 87% were White; 3% were Black; 9% were Hispanic or Latino; mean body mass index was 29 kg/m2 (range: 19 to 44 kg/m2); 73% had baseline HCV RNA levels greater than 6 log10 IU per mL; 34% had cirrhosis; 63% had HCV genotype 3; 75% were prior relapsers. Table 15 presents the SVR12 for the treatment groups of SOVALDI + ribavirin for 12 weeks in subjects with genotype 2 HCV. Treatment of 16 weeks in subjects with genotype 2 HCV was not shown to increase the SVR12 observed with 12 weeks of treatment. SVR12 for genotype 3 subjects treated with SOVALDI + ribavirin for 12 or 16 weeks was suboptimal; therefore these results are not presented in Table 14. Table 14 Study FUSION: SVR12 in Previous Interferon Relapsers and Nonresponders with Genotype 2 HCV
The denominator for relapse is the number of subjects with HCV RNA <LLOQ at their last on-treatment assessment. Other includes subjects who did not achieve SVR and did not meet virologic failure criteria (e.g., lost to follow-up). Table 15 presents the subgroup analysis for cirrhosis and response to prior HCV treatment in subjects with genotype 2 HCV. Table 15 SVR12 Rates for Selected Subgroups in Study FUSION in Subjects with Genotype 2 HCV
The VALENCE trial evaluated SOVALDI in combination with weight-based ribavirin for the treatment of genotype 2 or 3 HCV infection in treatment-naïve subjects or subjects who did not achieve SVR with prior interferon-based treatment, including subjects with compensated cirrhosis. The original trial design was a 4 to 1 randomization to SOVALDI + ribavirin for 12 weeks or placebo. Based on emerging data, this trial was unblinded and all genotype 2 HCV-infected subjects continued the original planned treatment and received SOVALDI + ribavirin for 12 weeks, and duration of treatment with SOVALDI + ribavirin in genotype 3 HCV-infected subjects was extended to 24 weeks. Eleven genotype 3 subjects had already completed SOVALDI + ribavirin for 12 weeks at the time of the amendment. Treated subjects (N=419) had a median age of 51 years (range: 19 to 74); 60% of the subjects were male; mean body mass index was 26 kg/m2 (range: 17 to 44 kg/m2); the mean baseline HCV RNA level was 6.4 log10 IU per mL; 78% had HCV genotype 3; 58% of the subjects were treatment-experienced and 65% of those subjects experienced relapse/breakthrough to prior HCV treatment. Table 16 presents the SVR12 for the treatment groups of SOVALDI + ribavirin for 12 weeks and 24 weeks. Table 16 Study VALENCE*: SVR12 in Subjects with Genotype 2 or 3 HCV Who were Treatment-Naïve or Who Did Not Achieve SVR12 with Prior Interferon-Based Treatment
The denominator for relapse is the number of subjects with HCV RNA <LLOQ at their last on-treatment assessment. Other includes subjects who did not achieve SVR12 and did not meet virologic failure criteria (e.g., lost to follow-up). Table 17 presents the subgroup analysis by genotype for cirrhosis and prior HCV treatment experience. Table 17 SVR12 Rates for Selected Subgroups by Genotype in Study VALENCE in Subjects with Genotype 2 or 3 HCV
SOVALDI was studied in an open-label clinical trial (Study PHOTON-1) evaluating the safety and efficacy of 12 or 24 weeks of treatment with SOVALDI and ribavirin in subjects with genotype 1, 2 or 3 chronic hepatitis C co-infected with HIV-1. Genotype 2 and 3 subjects were either HCV treatment-naïve or experienced, whereas genotype 1 subjects were all treatment-naïve. Subjects received 400 mg SOVALDI and weight-based ribavirin (1000 mg for subjects weighing less than 75 kg or 1200 mg for subjects weighing at least 75 kg) daily for 12 or 24 weeks based on genotype and prior treatment history. Subjects were either not on antiretroviral therapy with a CD4+ cell count greater than 500 cells/mm3 or had virologically suppressed HIV-1 with a CD4+ cell count greater than 200 cells/mm3. Efficacy data 12 weeks post treatment are available for 210 subjects (see Table 18). Table 18 Study PHOTON-1*: SVR12 in Treatment-Naïve or Treatment-Experienced Subjects with Genotype 1, 2, or 3 HCV
The denominator for relapse is the number of subjects with HCV RNA <LLOQ at their last on-treatment assessment. Other includes subjects who did not achieve SVR12 and did not meet virologic failure criteria (e.g., lost to follow-up). In subjects with HCV genotype 1 infection, the SVR12 rate was 82% (74/90) in subjects with genotype 1a infection and 54% (13/24) in subjects with genotype 1b infection, with relapse accounting for the majority of treatment failures. SVR12 rates in subjects with HCV genotype 1 infection were 80% (24/30) in subjects with baseline IL28B C/C allele and 75% (62/83) in subjects with baseline IL28B non-C/C alleles. In the 223 HCV subjects with HIV-1 co-infection, the percentage of CD4+ cells did not change during treatment. Median CD4+ cell count decreases of 85 cells/mm3 and 84 cells/mm3 were observed at the end of treatment with SOVALDI + ribavirin for 12 or 24 weeks, respectively. HIV-1 rebound during SOVALDI + ribavirin treatment occurred in 2 subjects (0.9%) on antiretroviral therapy. 16 HOW SUPPLIED/STORAGE AND HANDLING SOVALDI tablets are yellow, capsule-shaped, film-coated tablets containing 400 mg sofosbuvir debossed with "GSI" on one side and "7977" on the other side. Each bottle contains 28 tablets (NDC 61958-1501-1), a silica gel desiccant and polyester coil with a child-resistant closure. Store at room temperature below 30 °C (86 °F). Dispense only in original container Do not use if seal over bottle opening is broken or missing 17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information). Serious Symptomatic Bradycardia When Coadministered with Amiodarone and Another HCV Direct Acting Antiviral Advise patients to seek medical evaluation immediately for symptoms of bradycardia such as near-fainting or fainting, dizziness or lightheadedness, malaise, weakness, excessive tiredness, shortness of breath, chest pain, confusion or memory problems [see Warnings and Precautions (5.1), Adverse Reactions (6.2), and Drug Interactions (7.1)]. Pregnancy Advise patients to avoid pregnancy during combination treatment with SOVALDI and ribavirin or SOVALDI and peginterferon and ribavirin. Inform patients to notify their health care provider immediately in the event of a pregnancy [see Use in Specific Populations (8.1)]. Drug Interactions Advise patients that SOVALDI may interact with some drugs; therefore, patients should be advised to report the use of any prescription, non-prescription medication or herbal products to their healthcare provider [see Warnings and Precautions (5.2) and Drug Interactions (7.1)]. Hepatitis C Virus Transmission Inform patients that the effect of treatment of hepatitis C infection on transmission is not known, and that appropriate precautions to prevent transmission of the hepatitis C virus during treatment or in the event of treatment failure should be taken. Important Information on Co-Administration with Ribavirin or Peginterferon and Ribavirin Advise patients that the recommended regimen for patients with genotype 1 or 4 HCV infection is SOVALDI administered in combination with peginterferon alfa and ribavirin and the recommended regimen for patients with genotype 2 or 3 HCV infection is SOVALDI administered in combination with ribavirin. If peginterferon and/or ribavirin are permanently discontinued, SOVALDI should also be discontinued. http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=80beab2c-396e-4a37-a4dc-40fdb62859cf 索非布韦片Sovaldi(Sofosbuvir Tablets)获欧盟批 2014年1月17日，丙肝新药Sovaldi（sofosbuvir，400mg片剂）获欧盟批准，作为抗病毒治疗方案的一部分，用于慢性丙型肝炎（HCV）成人感染者的治疗。Sovaldi为每日一次的口服核苷类似物聚合酶抑制剂，此次批准，为该药在整个欧盟的上市铺平了道路。 此前，Sovaldi已于2013年11月获得了欧洲药品管理局（EMA）人用医药产品委员会（CHMP）建议批准的积极意见。CHMP通过加速审批程序对Sovaldi上市许可申请（MAA）进行了评估，该药MAA由6个III期研究（NEUTRINO, FISSION, POSITRON, FUSION, VALENCE, PHOTON-1）的数据支持。 在美国，Sovaldi已于2013年12月获FDA批准，该药是首个获批可用于C型肝炎全口服治疗方案的药物，在用于特定基因型慢性丙型肝炎治疗时，可消除对传统注射药物干扰素（IFN）的需求。 具体而言，FDA已批准sofosbuvir联合利巴韦林（ribavirin）用于基因型2和基因型3慢性丙型肝炎（hepatitis C）成人患者的治疗。同时，FDA还批准sofosbuvir联合聚乙二醇干扰素（PEG-IFN）和利巴韦林，用于基因型1和基因型4慢性丙型肝炎初治（treat-naive）成人患者的治疗。 在欧洲和世界各地，慢性丙型肝炎（HCV）是导致肝癌和肝移植的主要原因。当前的HCV护理标准涉及长达48周的含聚乙二醇干扰素（peg-IFN）/利巴韦林（RBV）方案。这些方案并不总是有效，而且具有显著的副作用，并与其他药物具有用药禁忌。在欧洲，许多患者被认为不适合当前的治疗方案。 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
