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英文药名：SOVALDI(sofosbuvir)tablets
中文药名：索非布韦片
生产厂家：Gilead
药品介绍
2014年1月19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。
温馨提示：SOVALDI(Sofosbuvir Tablets）中文药名：索非布韦片目前已在美国、德国、英国、加拿大等国上市销售，购买时请以在线咨询为准！
包装规格：400毫克*28片/瓶[本品美国包装]
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use SOVALDI safely and effectively. See full prescribing information for SOVALDI.
SOVALDI ® (sofosbuvir) tablets, for oral use
Initial U.S. Approval: 2013
RECENT MAJOR CHANGES
Warnings and Precautions (5.1) 11/2014
INDICATIONS AND USAGE
SOVALDI is a hepatitis C virus (HCV) nucleotide analog NS5B polymerase inhibitor indicated for the treatment of chronic hepatitis C (CHC) infection as a component of a combination antiviral treatment regimen. (1)
SOVALDI efficacy has been established in subjects with HCV genotype 1, 2, 3 or 4 infection, including those with hepatocellular carcinoma meeting Milan criteria (awaiting liver transplantation) and those with HCV/HIV-1 co-infection. (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 CHC. Recommended combination therapy: (2.1)
| HCV Mono-infected and HCV/HIV-1 Co-infected |
Treatment |
Duration |
| Genotype 1 or 4 |
SOVALDI + peg-interferon alfa + ribavirin |
12 weeks |
| Genotype 2 |
SOVALDI + ribavirin |
12 weeks |
| Genotype 3 |
SOVALDI + ribavirin |
24 weeks |
SOVALDI in combination with ribavirin for 24 weeks can be considered for CHC patients with genotype 1 infection who are interferon ineligible. (2.1)
Should be used in combination with ribavirin for treatment of CHC in patients with hepatocellular carcinoma awaiting liver transplantation for up to 48 weeks or until liver transplantation, whichever occurs first. (2.1)
A dose 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)
Because ribavirin may cause birth defects and fetal death, SOVALDI in combination with peginterferon alfa/ribavirin or ribavirin is contraindicated in pregnant women and in men whose female partners are pregnant. (4)
WARNINGS AND PRECAUTIONS
Pregnancy: Ribavirin may cause birth defects and fetal death and animal studies have shown interferons have abortifacient effects; avoid pregnancy in female patients and female partners of male patients. Patients must have a negative pregnancy test prior to initiating therapy, use at least 2 effective methods of contraception and have monthly pregnancy tests. (5.1)
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
Drugs that are potent intestinal P-gp inducers (e.g., rifampin, St. John's wort) may alter the concentrations of sofosbuvir. Consult the full prescribing information prior to use for potential drug-drug interactions. (5.2, 7, 12.3)
USE IN SPECIFIC POPULATIONS
Patients with HCV/HIV-1 co-infection: Safety and efficacy have been studied. (8.8, 14.4)
Patients with hepatocellular carcinoma awaiting liver transplantation: Safety and efficacy have been studied. (8.9)
See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling.
Revised: 11/2014
FULL PRESCRIBING INFORMATION: CONTENTS*
1 INDICATIONS AND USAGE
SOVALDI is a hepatitis C virus (HCV) nucleotide analog NS5B polymerase inhibitor indicated for the treatment of chronic hepatitis C (CHC) infection as a component of a combination antiviral treatment regimen.
SOVALDI efficacy has been established in subjects with HCV genotype 1, 2, 3 or 4 infection, including those with hepatocellular carcinoma meeting Milan criteria (awaiting liver transplantation) and those with HCV/HIV-1 co-infection [See Dosage and Administration (2), Use in Specific Populations (8) and Clinical Studies (14)].
The following points should be considered when initiating treatment with SOVALDI:
Monotherapy of SOVALDI is not recommended for treatment of CHC.
Treatment regimen and duration are dependent on both viral genotype and patient population [See Dosage and Administration (2)].
Treatment response varies based on baseline host and viral factors [See Use in Specific Populations (8) and Clinical Studies (14)].
2 DOSAGE AND ADMINISTRATION
2.1 Recommended Dose in AdultsThe recommended dose of SOVALDI is one 400 mg tablet, taken orally, once daily with or without food [See Clinical Pharmacology (12.3)].
SOVALDI should be used in combination with ribavirin or in combination with pegylated interferon and ribavirin for the treatment of CHC in adults. The recommended regimen and treatment duration for SOVALDI combination therapy is provided in Table 1.
Table 1 Recommended Regimens and Treatment Duration for SOVALDI Combination Therapy in HCV Mono-infected and HCV/HIV-1 Co-infected Patients
| Treatment |
Duration |
|
|
| Patients with genotype 1 or 4 CHC |
SOVALDI + peginterferon alfa* + ribavirin† |
12 weeks |
| Patients with genotype 2 CHC |
SOVALDI + ribavirin† |
12 weeks |
| Patients with genotype 3 CHC |
SOVALDI + ribavirin† |
24 weeks | SOVALDI in combination with ribavirin for 24 weeks can be considered as a therapeutic option for CHC patients with genotype 1 infection who are ineligible to receive an interferon-based regimen [See Use in Specific Populations (8.8) and 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
SOVALDI in combination with ribavirin is recommended 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 (8.9)].
2.2 Dose ModificationDose reduction of SOVALDI is not recommended.
Genotype 1 and 4:
If a patient has a serious adverse reaction potentially related to peginterferon alfa and/or ribavirin, the peginterferon alfa and/or ribavirin dose should be reduced or discontinued. 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 dose.
Genotype 2 and 3:
If a patient has a serious adverse reaction potentially related to ribavirin, the ribavirin dose should be modified or discontinued, if appropriate, until the adverse reaction abates or decreases in severity. Table 2 provides guidelines for dose modifications and discontinuation based on the patient's hemoglobin concentration and cardiac status.
Table 2 Ribavirin Dose Modification Guideline for Coadministration with SOVALDI
| Laboratory Values |
Reduce Ribavirin Dose to 600 mg/day* If: |
Discontinue Ribavirin If:† |
|
|
| Hemoglobin in patients with no cardiac disease |
<10 g/dL |
<8.5 g/dL |
| Hemoglobin in patients with history of stable cardiac disease |
≥2 g/dL decrease in hemoglobin during any 4 week treatment period |
<12 g/dL despite 4 weeks at reduced dose | 2.3 Discontinuation of DosingIf 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 DiseaseNo dose recommendation can be given for patients with severe renal impairment (estimated Glomerular Filtration Rate (eGFR) <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(What is this?)
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.
SOVALDI combination treatment with ribavirin or peginterferon alfa/ribavirin is contraindicated in women who are pregnant or may become pregnant and men whose female partners are pregnant because of the risks for birth defects and fetal death associated with ribavirin [See Warnings and Precautions (5.1) and Use in Specific Populations (8.1)].
5 WARNINGS AND PRECAUTIONS
5.1 Pregnancy: Use with Ribavirin or Peginterferon Alfa/RibavirinRibavirin may cause birth defects and/or death of the exposed fetus and animal studies have shown that interferons have abortifacient effects [See Contraindications (4)]. Extreme care must be taken to avoid pregnancy in female patients and in female partners of male patients. Ribavirin therapy should not be started unless a report of a negative pregnancy test has been obtained immediately prior to initiation of therapy.
When SOVALDI is used in combination with ribavirin or peginterferon alfa/ribavirin, women of childbearing potential and their male partners must use two forms of effective contraception during treatment and for at least 6 months after treatment has concluded. Routine monthly pregnancy tests must be performed during this time. [See Contraindications (4) and Use in Specific Populations (8.1)]. Refer also to the prescribing information for ribavirin.
5.2 Use with Potent P-gp InducersDrugs that are potent 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. Rifampin and St. John's wort should not be used with SOVALDI [See Drug Interactions (7.2)].
6 ADVERSE REACTIONS
6.1 Adverse Reactions from Clinical Trials ExperienceSOVALDI should be administered with ribavirin or peginterferon alfa/ribavirin. Refer to the prescribing information of peginterferon alfa and ribavirin for a description of adverse reactions associated with their use.
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.
The safety assessment of SOVALDI is 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.
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, <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.
Treatment-emergent adverse events observed in ≥15% of subjects in clinical trials are provided in Table 3. A side-by-side tabulation is to simplify presentation; direct comparison across trials should not be made due to differing trial designs.
The most common adverse events (≥ 20%) for SOVALDI + ribavirin combination therapy were fatigue and headache. The most common adverse events (≥ 20%) for SOVALDI + peginterferon alfa + ribavirin combination therapy were fatigue, headache, nausea, insomnia and anemia.
Table 3 Treatment-Emergent Adverse Events (All Grades) Reported in ≥ 15% of Subjects in Any Treatment Arm
| Interferon-free Regimens |
Interferon-containing Regimens |
|
PBO
12 weeks |
SOVALDI + RBV
12 weeks |
SOVALDI + RBV
24 weeks |
Peg-IFN alfa + RBV†
24 weeks |
SOVALDI + Peg-IFN alfa + RBV
12 weeks |
|
N=71 |
N=650 |
N=250 |
N=243 |
N=327 |
|
|
| Fatigue |
24% |
38% |
30% |
55% |
59% |
| Headache |
20% |
24% |
30% |
44% |
36% |
| Nausea |
18% |
22% |
13% |
29% |
34% |
| Insomnia |
4% |
15% |
16% |
29% |
25% |
| Pruritus |
8% |
11% |
27% |
17% |
17% |
| Anemia |
0% |
10% |
6% |
12% |
21% |
| Asthenia |
3% |
6% |
21% |
3% |
5% |
| Rash |
8% |
8% |
9% |
18% |
18% |
| Decreased Appetite |
10% |
6% |
6% |
18% |
18% |
| Chills |
1% |
2% |
2% |
18% |
17% |
| Influenza Like Illness |
3% |
3% |
6% |
18% |
16% |
| Pyrexia |
0% |
4% |
4% |
14% |
18% |
| Diarrhea |
6% |
9% |
12% |
17% |
12% |
| Neutropenia |
0% |
<1% |
<1% |
12% |
17% |
| Myalgia |
0% |
6% |
9% |
16% |
14% |
| Irritability |
1% |
10% |
10% |
16% |
13% | With the exception of anemia and neutropenia, the majority of events presented in Table 3 occurred at severity of grade 1 in SOVALDI-containing regimens.
Less Common Adverse Reactions Reported in Clinical Trials (<1%): The following ADRs occurred in <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 4. A side-by-side tabulation is to simplify presentation; direct comparison across trials should not be made due to differing trial designs.
Table 4 Percentage of Subjects Reporting Selected Hematological Parameters
| Interferon-free Regimens |
Interferon-containing Regimens |
| Hematological Parameters |
PBO
12 weeks |
SOVALDI + RBV
12 weeks |
SOVALDI+ RBV
24 weeks |
Peg-IFN + RBV†
24 weeks |
SOVALDI + Peg-IFN + RBV*
12 weeks |
|
N=71 |
N=647 |
N=250 |
N=242 |
N=327 |
|
|
| Hemoglobin (g/dL) |
|
|
|
|
|
| < 10 |
0 |
8% |
6% |
14% |
23% |
| < 8.5 |
0 |
1% |
<1% |
2% |
2% |
| Neutrophils (×109/L) |
|
|
|
|
|
| ≥0.5 – < 0.75 |
1% |
<1% |
0 |
12% |
15% |
| < 0.5 |
0 |
<1% |
0 |
2% |
5% |
| Platelets (×109/L) |
|
|
|
|
|
| ≥25 – < 50 |
3% |
<1% |
1% |
7% |
<1% |
| < 25 |
0 |
0 |
0 |
0 |
0 | 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 <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 <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.
7 DRUG INTERACTIONS
7.1 Potential for Drug InteractionsAfter oral administration of SOVALDI, sofosbuvir is rapidly converted to the predominant circulating metabolite GS-331007 that accounts for greater than 90% of drug related material systemic exposure, while the parent sofosbuvir accounts for approximately 4% of drug related material [See Clinical Pharmacology (12.3)]. In clinical pharmacology studies, both sofosbuvir and GS-331007 were monitored for purposes of pharmacokinetic analyses.
Sofosbuvir is a substrate of drug transporter P-gp and breast cancer resistance protein (BCRP) while GS-331007 is not. Drugs that are potent 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 should not be used with SOVALDI [See Warnings and Precautions (5.2)]. Coadministration of SOVALDI with drugs that inhibit P-gp and/or BCRP may increase sofosbuvir plasma concentration without increasing GS-331007 plasma concentration; accordingly, SOVALDI may be coadministered with P-gp and/or BCRP inhibitors. Sofosbuvir and GS-331007 are not inhibitors of P-gp and BCRP and thus are not expected to increase exposures of drugs that are substrates of these transporters.
The intracellular metabolic activation pathway of sofosbuvir is mediated by generally low affinity and high capacity hydrolase and nucleotide phosphorylation pathways that are unlikely to be affected by concomitant drugs [See Clinical Pharmacology (12.3)].
7.2 Potentially Significant Drug InteractionsDrug interaction information for SOVALDI with potential concomitant drugs is summarized in Table 5. The drug interactions described are based on potential drug interactions that may occur with SOVALDI. The table is not all-inclusive [See Warnings and Precautions (5.2) and Clinical Pharmacology (12.3)].
Table 5 Potentially Significant Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Studies or Predicted Interaction*
| Concomitant Drug Class: Drug Name |
Effect on Concentration† |
Clinical Comment |
|
|
Anticonvulsants:
carbamazepine
phenytoin
phenobarbital
oxcarbazepine |
↓ sofosbuvir
↓ GS-331007 |
Coadministration of SOVALDI with carbamazepine, phenytoin, phenobarbital or oxcarbazepine is expected to decrease the concentration of sofosbuvir, leading to reduced therapeutic effect of SOVALDI. Coadministration is not recommended. |
Antimycobacterials:
rifabutin
rifampin
rifapentine |
↓ sofosbuvir
↓ GS-331007 |
Coadministration of SOVALDI with rifabutin or rifapentine is expected to decrease the concentration of sofosbuvir, leading to reduced therapeutic effect of SOVALDI. Coadministration is not recommended.
SOVALDI should not be used with rifampin, a potent intestinal P-gp inducer [See Warnings and Precautions (5.2)]. |
Herbal Supplements:
St. John's wort
(Hypericum perforatum) |
↓ sofosbuvir
↓ GS-331007 |
SOVALDI should not be used with St. John's wort, a potent intestinal P-gp inducer [See Warnings and Precautions (5.2)]. |
HIV Protease Inhibitors:
tipranavir/ritonavir |
↓ sofosbuvir
↓ GS-331007 |
Coadministration of SOVALDI with tipranavir/ritonavir is expected to decrease the concentration of sofosbuvir, leading to reduced therapeutic effect of SOVALDI. Coadministration is not recommended. | 7.3 Drugs without Clinically Significant Interactions with SOVALDIIn addition to the drugs included in Table 5, 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 X: Use with Ribavirin or Peginterferon Alfa/Ribavirin
Extreme caution must be taken to avoid pregnancy in female patients and female partners of male patients while taking this combination. Women of childbearing potential and their male partners should not receive ribavirin unless they are using two forms of effective contraception during treatment with ribavirin and for 6 months after treatment has concluded [See Warnings and Precautions (5.1)].
In case of exposure during pregnancy, a Ribavirin Pregnancy Registry has been established to monitor maternal-fetal outcomes of pregnancies in female patients and female partners of male patients exposed to ribavirin during treatment and for 6 months following cessation of treatment. Healthcare providers and patients are encouraged to report such cases by calling Ribavirin Pregnancy Registry at 1-800-593-2214. For patients who are HCV/HIV-1 co-infected and taking concomitant antiretrovirals, an Antiretroviral Pregnancy Registry is also available at 1-800-258-4263.
Animal Data
Significant teratogenic and/or embryocidal effects have been demonstrated in all animal species exposed to ribavirin; and therefore ribavirin is contraindicated in women who are pregnant and in the male partners of women who are pregnant [See Contraindications (4), Warnings and Precautions (5.1) and ribavirin Package Insert]. Interferons have abortifacient effects in animals and should be assumed to have abortifacient potential in humans [See peginterferon alfa Package Insert].
Pregnancy Category B: SOVALDI
There are no adequate and well-controlled studies with SOVALDI in pregnant women.
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 MothersIt 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. Because of the potential for adverse reactions from the drug in nursing infants, a decision must be made whether to discontinue nursing or discontinue treatment with ribavirin-containing regimens, taking into account the importance of the therapy to the mother. See also the prescribing information for ribavirin.
8.4 Pediatric UseSafety and effectiveness of SOVALDI in children less than 18 years of age have not been established.
8.5 Geriatric UseSOVALDI 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 dose adjustment of SOVALDI is warranted in geriatric patients [See Clinical Pharmacology (12.3)].
8.6 Renal ImpairmentNo dose 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 <30 mL/min/1.73m2) or end stage renal disease (ESRD) requiring hemodialysis. No dose 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 <50 mL/min.
8.7 Hepatic ImpairmentNo dose 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 HCV/HIV-1 Co-infectionThe safety and efficacy of SOVALDI was assessed in 223 HCV/HIV-1 co-infected subjects [See Clinical Studies (14.4)]. See Dosage and Administration (2.1) for dosing recommendations in HCV/HIV-1 co-infected patients. 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 [See Adverse Reactions (6.1)].
8.9 Patients with Hepatocellular Carcinoma Awaiting Liver TransplantationSOVALDI 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 < 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 ≤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 < 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.
8.10 Post-Liver Transplant PatientsThe safety and efficacy of SOVALDI have not been established in post-liver transplant patients.
8.11 CHC Patients with Genotype 5 or 6 HCV InfectionAvailable data on subjects with genotype 5 or 6 HCV infection are insufficient for dosing recommendations.
10 OVERDOSAGE
The highest documented dose of sofosbuvir was a single supratherapeutic dose of sofosbuvir 1200 mg administered to 59 healthy subjects. In that trial, there were no untoward effects observed at this dose 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 doses 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 is the brand name for sofosbuvir, 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:
Sofosbuvir is a white to off-white crystalline solid with a solubility of ≥ 2 mg/mL across the pH range of 2–7.7 at 37 °C and is slightly soluble in water.
SOVALDI tablets are for oral administration. Each tablet contains 400 mg of sofosbuvir. The tablets include the following inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, magnesium stearate, mannitol, and microcrystalline cellulose. The tablets are film-coated with a coating material containing the following inactive ingredients: polyethylene glycol, polyvinyl alcohol, talc, titanium dioxide, and yellow iron oxide.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of ActionSofosbuvir is a direct-acting antiviral agent against the hepatitis C virus [See Microbiology (12.4)].
12.2 Pharmacodynamics
Effect on Electrocardiogram
The effect of sofosbuvir 400 and 1200 mg on QTc interval was evaluated in a randomized, single-dose, placebo-, and active-controlled (moxifloxacin 400 mg) four period crossover thorough QT trial in 59 healthy subjects. At a dose three times the maximum recommended dose, SOVALDI does not prolong QTc to any clinically relevant extent.
12.3 Pharmacokinetics
Absorption
The pharmacokinetic properties of sofosbuvir and the predominant circulating metabolite GS-331007 have been evaluated in healthy adult subjects and in subjects with chronic hepatitis C. Following oral administration of SOVALDI, sofosbuvir was absorbed with a peak plasma concentration observed at ~0.5–2 hour post-dose, regardless of dose level. Peak plasma concentration of GS-331007 was observed between 2 to 4 hours post-dose. Based on population pharmacokinetic analysis in subjects with genotype 1 to 6 HCV infection who were coadministered ribavirin (with or without pegylated interferon), geometric mean steady state AUC0-24 was 969 ng∙hr/mL for sofosbuvir (N=838), and 6790 ng∙hr/mL for GS-331007 (N=1695), respectively. Relative to healthy subjects administered sofosbuvir alone (N = 272), the sofosbuvir AUC0–24 was 60% higher; and GS-331007 AUC0–24 was 39% lower, respectively, in HCV-infected subjects. Sofosbuvir and GS-331007 AUCs are near dose proportional over the dose range of 200 mg to 1200 mg.
Effect of Food
Relative to fasting conditions, the administration of a single dose of SOVALDI with a standardized high fat meal did not substantially affect the sofosbuvir Cmax or AUC0–inf. The exposure of GS-331007 was not altered in the presence of a high-fat meal. Therefore, SOVALDI can be administered without regard to food.
Distribution
Sofosbuvir is approximately 61–65% bound to human plasma proteins and the binding is independent of drug concentration over the range of 1 µg/mL to 20 µg/mL. Protein binding of GS-331007 was minimal in human plasma. After a single 400 mg dose of [14C]-sofosbuvir in healthy subjects, the blood to plasma ratio of 14C-radioactivity was approximately 0.7.
Metabolism
Sofosbuvir is extensively metabolized in the liver to form the pharmacologically active nucleoside analog triphosphate GS-461203. The metabolic activation pathway involves sequential hydrolysis of the carboxyl ester moiety catalyzed by human cathepsin A (CatA) or carboxylesterase 1 (CES1) and phosphoramidate cleavage by histidine triad nucleotide-binding protein 1 (HINT1) followed by phosphorylation by the pyrimidine nucleotide biosynthesis pathway. Dephosphorylation results in the formation of nucleoside metabolite GS-331007 that cannot be efficiently rephosphorylated and lacks anti-HCV activity in vitro.
After a single 400 mg oral dose of [14C]-sofosbuvir, sofosbuvir and GS-331007 accounted for approximately 4% and >90% of drug related material (sum of molecular weight-adjusted AUC of sofosbuvir and its metabolites) systemic exposure, respectively.
Elimination
Following a single 400 mg oral dose of [14C]-sofosbuvir, mean total recovery of the dose was greater than 92%, consisting of approximately 80%, 14%, and 2.5% recovered in urine, feces, and expired air, respectively. The majority of the sofosbuvir dose recovered in urine was GS-331007 (78%) while 3.5% was recovered as sofosbuvir. These data indicate that renal clearance is the major elimination pathway for GS-331007. The median terminal half-lives of sofosbuvir and GS-331007 were 0.4 and 27 hours, respectively.
Specific Populations
Race
Population pharmacokinetics analysis in HCV-infected subjects indicated that race had no clinically relevant effect on the exposure of sofosbuvir and GS-331007.
Gender
No clinically relevant pharmacokinetic differences have been observed between men and women for sofosbuvir and GS-331007.
Pediatric Patients
The pharmacokinetics of sofosbuvir in pediatric patients have not been established [See Use in Specific Populations (8.4)].
Geriatric Patients
Population pharmacokinetic analysis in HCV-infected subjects showed that within the age range (19 to 75 years) analyzed, age did not have a clinically relevant effect on the exposure to sofosbuvir and GS-331007 [See Use in Specific Populations (8.5)].
Patients with Renal Impairment
The pharmacokinetics of sofosbuvir were studied in HCV negative subjects with mild (eGFR ≥ 50 and < 80 mL/min/1.73m2), moderate (eGFR ≥30 and <50 mL/min/1.73m2), severe renal impairment (eGFR <30 mL/min/1.73m2) and subjects with end stage renal disease (ESRD) requiring hemodialysis following a single 400 mg dose of sofosbuvir. Relative to subjects with normal renal function (eGFR >80 mL/min/1.73m2), the sofosbuvir AUC0–inf was 61%, 107% and 171% higher in mild, moderate and severe renal impairment, while the GS-331007 AUC0–inf was 55%, 88% and 451% higher, respectively. In subjects with ESRD, relative to subjects with normal renal function, sofosbuvir and GS-331007 AUC0–inf was 28% and 1280% higher when sofosbuvir was dosed 1 hour before hemodialysis compared with 60% and 2070% higher when sofosbuvir was dosed 1 hour after hemodialysis, respectively. A 4 hour hemodialysis session removed approximately 18% of administered dose. No dose adjustment 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 or ESRD. No dose recommendation can be given for patients with severe renal impairment or ESRD [See Dosage and Administration (2.4) and Use in Specific Populations (8.6)].
Patients with Hepatic Impairment
The pharmacokinetics of sofosbuvir were studied following 7-day dosing of 400 mg sofosbuvir in HCV-infected subjects with moderate and severe hepatic impairment (Child-Pugh Class B and C). Relative to subjects with normal hepatic function, the sofosbuvir AUC0–24 were 126% and 143% higher in moderate and severe hepatic impairment, while the GS-331007 AUC0–24 were 18% and 9% higher, respectively. Population pharmacokinetics analysis in HCV-infected subjects indicated that cirrhosis had no clinically relevant effect on the exposure of sofosbuvir and GS-331007. No dose adjustment of SOVALDI is recommended for patients with mild, moderate and severe hepatic impairment [See Use in Specific Populations (8.7)].
Assessment of Drug Interactions
The effects of coadministered drugs on the exposure of sofosbuvir and GS-331007 are shown in Table 6. The effects of sofosbuvir on the exposure of coadministered drugs are shown in Table 7 [See Drug Interactions (7.3)].
Table 6 Drug Interactions: Changes in Pharmacokinetic Parameters for Sofosbuvir and the Predominant Circulating Metabolite GS-331007 in the Presence of the Coadministered Drug*
| Co-administered Drug |
Dose of Coadministered Drug (mg) |
Sofosbuvir Dose (mg) |
N |
Mean Ratio (90% CI) of Sofosbuvir and GS-331007 PK With/Without Coadministered Drug
No Effect=1.00 |
|
Cmax |
AUC |
Cmin |
| NA = not available/not applicable |
|
|
| Cyclosporine |
600 single dose |
400 single dose |
19 |
sofosbuvir |
2.54
(1.87, 3.45) |
4.53
(3.26, 6.30) |
NA |
| GS-331007 |
0.60
(0.53, 0.69) |
1.04
(0.90, 1.20) |
NA |
Darunavir
(boosted with ritonavir) |
800/100 once daily |
400 single dose |
18 |
sofosbuvir |
1.45
(1.10, 1.92) |
1.34
(1.12, 1.59) |
NA |
| GS-331007 |
0.97
(0.90, 1.05) |
1.24
(1.18, 1.30) |
NA |
| Efavirenz† |
600 once daily |
400 single dose
|
16 |
sofosbuvir |
0.81
(0.60, 1.10) |
0.94
(0.76, 1.16) |
NA |
| Emtricitabine† |
200 once daily |
| Tenofovir disoproxil fumarate† |
300 once daily |
GS-331007 |
0.77
(0.70, 0.84) |
0.84
(0.76, 0.92) |
NA |
| Methadone |
30 to 130 once daily |
400 once daily |
14 |
sofosbuvir |
0.95‡
(0.68, 1.33) |
1.30‡
(1.00, 1.69) |
NA |
| GS-331007 |
0.73‡
(0.65, 0.83) |
1.04‡
(0.89, 1.22) |
NA |
| Rilpivirine |
25 once daily |
400 single dose |
17 |
sofosbuvir |
1.21
(0.90, 1.62) |
1.09
(0.94, 1.27) |
NA |
| GS-331007 |
1.06
(0.99, 1.14) |
1.01
(0.97, 1.04) |
NA |
| Tacrolimus |
5 single dose |
400 single dose |
16 |
sofosbuvir |
0.97
(0.65, 1.43) |
1.13
(0.81, 1.57) |
NA |
| GS-331007 |
0.97
(0.83, 1.14) |
1.00
(0.87, 1.13) | No effect on the pharmacokinetic parameters of sofosbuvir and GS-331007 was observed with raltegravir.
Table 7 Drug Interactions: Changes in Pharmacokinetic Parameters for Coadministered Drug in the Presence of Sofosbuvir*
| Coadministered Drug |
Dose of Coadministered
Drug (mg) |
Sofosbuvir Dose (mg) |
N |
Mean Ratio (90% CI) of Coadministered Drug PK With/Without Sofosbuvir
No Effect=1.00 |
| Cmax |
AUC |
Cmin |
| NA = not available/not applicable |
|
|
| Norelgestromin |
norgestimate 0.18/0.215/0.25/ ethinyl estradiol 0.025 once daily |
400 once daily |
15 |
1.07
(0.94, 1.22) |
1.06
(0.92, 1.21) |
1.07
(0.89, 1.28) |
| Norgestrel |
1.18
(0.99, 1.41) |
1.19
(0.98, 1.45) |
1.23
(1.00, 1.51) |
| Ethinyl estradiol |
1.15
(0.97, 1.36) |
1.09
(0.94, 1.26) |
0.99
(0.80, 1.23) |
| Raltegravir |
400 twice daily |
400 single dose |
19 |
0.57
(0.44, 0.75) |
0.73
(0.59, 0.91) |
0.95
(0.81, 1.12) |
| Tacrolimus |
5 single dose |
400 single dose |
16 |
0.73
(0.59, 0.90) |
1.09
(0.84, 1.40) |
NA |
| Tenofovir disoproxil fumarate† |
300 once daily |
400 single dose |
16
|
1.25
(1.08, 1.45) |
0.98
(0.91, 1.05) |
0.99
(0.91, 1.07) | 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 µM. GS-461203 is not 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 µM. The median EC50 value of sofosbuvir against chimeric replicons encoding NS5B sequences from clinical isolates was 0.062 µM for genotype 1a (range 0.029–0.128 µM; N=67), 0.102 µM for genotype 1b (range 0.045–0.170 µM; N=29), 0.029 µM for genotype 2 (range 0.014–0.081 µM; N=15) and 0.081 µM for genotype 3a (range 0.024–0.181 µM; N=106). In infectious virus assays, the EC50 values of sofosbuvir against genotype 1a and 2a were 0.03 and 0.02 µM, 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 cut off 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: Ribavirin was shown to be genotoxic in several in vitro and in vivo assays. Ribavirin was not oncogenic in a 6-month p53+/- transgenic mouse study or a 2-year carcinogenicity study in rats. See the prescribing information for ribavirin.
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: In fertility studies in male animals, ribavirin induced reversible testicular toxicity, while peginterferon alfa may impair fertility in females. Refer to prescribing information for ribavirin and peginterferon alfa for additional information.
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.
13.2 Animal Toxicology and/or PharmacologyHeart degeneration and inflammation were observed in rats following GS-9851 (a stereoisomeric mixture containing approximately 50% sofosbuvir) doses of 2000 mg/kg/day for up to 5 days. At this dose, AUC exposure to the predominant metabolite GS-331007 is approximately 29-fold higher than human exposure at the recommended clinical dose. No heart degeneration or inflammation was observed in rats following sofosbuvir doses of up to 500 mg/kg/day for 6 months at a GS-331007 AUC exposure approximately 9-fold higher than human exposure at the recommended clinical dose. In dogs and mice, heart degeneration and inflammation were not observed following sofosbuvir doses of up to 500 and 1000 mg/kg/day for 9 and 3 months, respectively, the highest doses tested. At these doses, GS-331007 AUC exposures are approximately 27- and 41-fold higher, respectively, than human exposure at the recommended clinical dose.
14 CLINICAL STUDIES
14.1 Description of Clinical TrialsThe 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 (CHC) and one Phase 3 trial in 223 HCV/HIV-1 co-infected subjects with genotype 1, 2 or 3 CHC. Among the five trials in HCV mono-infected subjects, one was conducted in treatment-naïve subjects with genotype 1, 4, 5 or 6 CHC in combination with peginterferon alfa 2a and ribavirin and the other four were conducted in subjects with genotype 2 or 3 CHC in combination with ribavirin, including one in treatment-naïve subjects, one in interferon intolerant, ineligible or unwilling subjects, one in subjects previously treated with an interferon-based regimen, and one in all subjects irrespective of prior treatment history or ability to take interferon. The trial in HCV/HIV-1 co-infected subjects was conducted in combination with ribavirin in treatment-naïve subjects with genotype 1 CHC and all subjects with genotype 2 or 3 CHC irrespective of prior treatment history or ability to take interferon. Subjects in these trials had compensated liver disease including cirrhosis. SOVALDI was administered at a dose of 400 mg once daily. The ribavirin (RBV) dose was weight-based at 1000–1200 mg daily administered in two divided doses when used in combination with SOVALDI, and the peginterferon alfa 2a dose, where applicable, was 180 micrograms per week. Treatment duration was fixed in each trial and was not guided by subjects' HCV RNA levels (no response guided algorithm). Plasma HCV RNA values were measured during the clinical trials using the COBAS TaqMan HCV test (version 2.0), for use with the High Pure System. The assay had a lower limit of quantification (LLOQ) of 25 IU per mL. Sustained virologic response (SVR) was the primary endpoint which was defined as HCV RNA less than LLOQ at 12 weeks after the end of treatment.
14.2 Clinical Trials in Subjects with Genotype 1 or 4 CHC
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 response rates for the treatment group of SOVALDI + peginterferon alfa + ribavirin.
Table 8 Response Rates in Study NEUTRINO
| SOVALDI + Peg-IFN alfa + RBV 12 weeks |
|
N=327 |
|
|
| Overall SVR |
90% (295/327) |
| Genotype 1† |
89% (261/292) |
| Genotype 1a |
92% (206/225) |
| Genotype 1b |
82% (54/66) |
| Genotype 4 |
96% (27/28) |
| Outcome for subjects without SVR |
| On-treatment virologic failure |
0/327 |
| Relapse‡ |
9% (28/326) |
| Other§ |
1% (4/327) | Response rates for selected subgroups are presented in Table 9.
Table 9 SVR Rates for Selected Subgroups in NEUTRINO
| SOVALDI + Peg-IFN alfa + RBV 12 weeks |
| Cirrhosis |
| No |
92% (252/273) |
| Yes |
80% (43/54) |
| Race |
| Black |
87% (47/54) |
| Non-black |
91% (248/273) |
| Multiple Baseline Factors |
| Genotype 1, Metavir F3/F4 fibrosis, IL28B non-C/C, HCV RNA >800,000 IU/mL |
71% (37/52) | SVR rates were 98% (93/95) in subjects with baseline IL28B C/C allele and 87% (202/232) in subjects with baseline IL28B non-C/C alleles.
It is estimated that the response rate in patients who previously failed pegylated interferon and ribavirin therapy will approximate the observed response rate in NEUTRINO subjects with multiple baseline factors traditionally associated with a lower response to interferon-based treatment (Table 9). The SVR rate in the NEUTRINO trial in genotype 1 subjects with IL28B non-C/C alleles, HCV RNA >800,000 IU/mL and Metavir F3/F4 fibrosis was 71% (37/52).
14.3 Clinical Trials in Subjects with Genotype 2 or 3 CHC
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 doses 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 (<6 log10IU/mL vs. ≥6 log10IU/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 10 presents the response rates for the treatment groups of SOVALDI + ribavirin and peginterferon alfa + ribavirin.
Table 10 Response Rates in Study FISSION
| SOVALDI + RBV 12 weeks |
Peg-IFN alfa + RBV 24 weeks |
|
N=256 |
N=243 |
|
|
| Overall SVR |
67% (171/256) |
67% (162/243) |
| Treatment difference† |
0.3% (95% CI: -7.5% to 8.0%) |
| Genotype 2 |
95% (69/73) |
78% (52/67) |
| Genotype 3 |
56% (102/183) |
63% (110/176) |
| Outcome for subjects without SVR |
| On-treatment virologic failure |
<1% (1/256) |
7% (18/243) |
| Relapse‡ |
30% (76/252) |
21% (46/217) |
| Genotype 2 |
5% (4/73) |
15% (9/62) |
| Genotype 3 |
40% (72/179) |
24% (37/155) |
| Other§ |
3% (8/256) |
7% (17/243) | Response rates for subjects with cirrhosis at baseline are presented in Table 11 by genotype.
Table 11 SVR Rates by Cirrhosis and Genotype in Study FISSION
| Genotype 2 |
Genotype 3 |
|
SOVALDI + RBV
12 weeks |
Peg-IFN alfa + RBV
24 weeks |
SOVALDI + RBV
12 weeks |
Peg-IFN alfa + RBV
24 weeks |
|
N=73 |
N=67 |
N=183 |
N=176 |
| Cirrhosis |
| No |
97% (59/61) |
81% (44/54) |
61% (89/145) |
71% (99/139) |
| Yes |
83% (10/12) |
62% (8/13) |
34% (13/38) |
30% (11/37) | Interferon Intolerant, Ineligible or Unwilling Adults — POSITRON (Study 107)
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 12 presents the response rates for the treatment groups of SOVALDI + ribavirin and placebo.
Table 12 Response Rates in Study POSITRON
| SOVALDI + RBV 12 weeks |
Placebo 12 weeks |
|
N=207 |
N=71 |
|
|
| Overall SVR |
78% (161/207) |
0/71 |
| Genotype 2 |
93% (101/109) |
0/34 |
| Genotype 3 |
61% (60/98) |
0/37 |
| Outcome for subjects without SVR |
| On-treatment virologic failure |
0/207 |
97% (69/71) |
| Relapse |
20% (42/205) |
0/0 |
| Genotype 2 |
5% (5/107) |
0/0 |
| Genotype 3 |
38% (37/98) |
0/0 |
| Other† |
2% (4/207) |
3% (2/71) | Table 13 presents the subgroup analysis by genotype for cirrhosis and interferon classification.
Table 13 SVR Rates for Selected Subgroups by Genotype in POSITRON
| SOVALDI + RBV 12 weeks |
|
Genotype 2 |
Genotype 3 |
|
N=109 |
N=98 |
| Cirrhosis |
| No |
92% (85/92) |
68% (57/84) |
| Yes |
94% (16/17) |
21% (3/14) |
| Interferon Classification |
| Ineligible |
88% (36/41) |
70% (33/47) |
| Intolerant |
100% (9/9) |
50% (4/8) |
| Unwilling |
95% (56/59) |
53% (23/43) | Previously Treated Adults — FUSION (Study 108)
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 6log10 IU per mL; 34% had cirrhosis; 63% had HCV genotype 3; 75% were prior relapsers. Table 14 presents the response rates for the treatment groups of SOVALDI + ribavirin for 12 weeks and 16 weeks.
Table 14 Response Rates in Study FUSION
SOVALDI + RBV
12 weeks |
SOVALDI + RBV
16 weeks |
|
N= 103 |
N=98 |
|
|
| Overall SVR |
50% (51/103) |
71% (70/98) |
| Genotype 2 |
82% (32/39) |
89% (31/35) |
| Genotype 3 |
30% (19/64) |
62% (39/63) |
| Outcome for subjects without SVR |
| On-treatment virologic failure |
0/103 |
0/98 |
| Relapse† |
48% (49/103) |
29% (28/98) |
| Genotype 2 |
18% (7/39) |
11% (4/35) |
| Genotype 3 |
66% (42/64) |
38% (24/63) |
| Other‡ |
3% (3/103) |
0/98 | Table 15 presents the subgroup analysis by genotype for cirrhosis and response to prior HCV treatment.
Table 15 SVR Rates for Selected Subgroups by Genotype in Study FUSION
| Genotype 2 |
Genotype 3 |
|
SOVALDI + RBV
12 weeks |
SOVALDI + RBV
16 weeks |
SOVALDI + RBV
12 weeks |
SOVALDI + RBV
16 weeks |
|
N=39 |
N=35 |
N=64 |
N=63 |
| Cirrhosis |
| No |
90% (26/29) |
92% (24/26) |
37% (14/38) |
63% (25/40) |
| Yes |
60% (6/10) |
78% (7/9) |
19% (5/26) |
61% (14/23) |
| Response to prior HCV treatment |
| Relapser/breakthrough |
86% (25/29) |
89% (24/27) |
31% (15/49) |
65% (30/46) |
| Nonresponder |
70% (7/10) |
88% (7/8) |
27% (4/15) |
53% (9/17) | Treatment-Naïve and Previously Treated Adults — VALENCE (Study 133)
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 response rates for the treatment groups of SOVALDI + ribavirin for 12 weeks and 24 weeks.
Table 16 Response Rates in Study VALENCE*
Genotype 2
SOVALDI + RBV
12 weeks |
Genotype 3
SOVALDI + RBV
24 weeks |
|
N=73 |
N=250 |
|
|
| Overall SVR |
93% (68/73) |
84% (210/250) |
| Outcome for subjects without SVR |
| On-treatment virologic failure |
0% (0/73) |
<1% (1/250) |
| Relapse† |
7% (5/73) |
14% (34/249) |
| Treatment-naïve |
3% (1/32) |
5% (5/105) |
| Treatment-experienced |
10% (4/41) |
20% (29/144) |
| Other‡ |
0% (0/73) |
2% (5/250) | Table 17 presents the subgroup analysis by genotype for cirrhosis and prior HCV treatment experience.
Table 17 SVR Rates for Selected Subgroup by Genotype in Study VALENCE
Genotype 2
SOVALDI + RBV
12 weeks |
Genotype 3
SOVALDI + RBV
24 weeks |
|
N=73 |
N=250 |
| Treatment-naïve |
97% (31/32) |
93% (98/105) |
| Non-cirrhotic |
97% (29/30) |
93% (86/92) |
| Cirrhotic |
100% (2/2) |
92% (12/13) |
| Treatment-experienced |
90% (37/41) |
77% (112/145) |
| Non-cirrhotic |
91% (30/33) |
85% (85/100) |
| Cirrhotic |
88% (7/8) |
60% (27/45) | 14.4 Clinical Trials in Subjects Co-infected with HCV and HIV-1 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 <75 kg or 1200 mg for subjects weighing ≥75kg) 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 >500 cells/mm3 or had virologically suppressed HIV-1 with a CD4+ cell count >200 cells/mm3. Efficacy data 12 weeks post treatment are available for 210 subjects (see Table 18).
Table 18 Response Rates in Study PHOTON-1*
| HCV genotype 1 |
HCV genotype 2 |
HCV genotype 3 |
|
SOVALDI + RBV
24 weeks
TN (N=114) |
SOVALDI + RBV
12 weeks
TN (N=26) |
SOVALDI + RBV
24 weeks
TE (N=13) |
| TN = Treatment-naïve; TE = Treatment-experienced |
|
|
| Overall |
76% (87/114) |
88% (23/26) |
92% (12/13) |
| Outcome for subjects without SVR12 |
| On-treatment virologic failure |
1% (1/114) |
4% (1/26) |
0/13 |
| Relapse† |
22% (25/113) |
0/25 |
8% (1/13) |
| Other‡ |
1% (1/114) |
8% (2/26) |
0/13 | In subjects with HCV genotype 1 infection, the SVR 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. SVR 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 CHC 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, polyester coil and is closed 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
FDA批准Sovaldi用于治疗慢性丙型肝炎病毒感染
12月6日，美国食品药品管理局（FDA）批准Sovaldi(Sofosbuvir)用于治疗慢性丙型肝炎病毒(HCV)感染。Sovaldi是首款用于治疗某些类型HCV感染而无需同时使用干扰素的安全、有效药物。“今天的批准标志着慢性丙型肝炎患者的治疗上有了一个重要的转变，”FDA药物评价与研究中心抗菌产品办公室主任、医学博士Edward Cox说。Sovaldi是FDA在过去两周内批准用于治疗慢性HCV感染的第二款药物。11月22日，FDA批准了Olysio (Simeprevir)。
丙型肝炎是一种病毒性疾病，它可以引起肝脏炎症，导致肝功能减弱或肝衰竭。大多数HCV感染患者直到肝损伤变得比较明显时才出现症状，这一过程可能需要几年的时间。一些慢性HCV感染患多年以后会出现瘢痕及肝硬化，可导致出血、黄疸(眼睛或皮肤变黄)、肝腹水、感染或肝癌等并发症。据美国疾病控制与预防中心的信息，大约有320万美国人感染有丙肝病毒。
Sovaldi是一种核苷酸类似物抑制剂，它能够阻断丙型肝炎病毒复制所需要的一种特异性蛋白质。Sovaldi用作慢性HCV感染一种抗病毒联合治疗方案。HCV感染有几种不同类型。依据患者HCV感染的类型，治疗方案可包括Sovaldi和利巴韦林，或者Sovaldi、利巴韦林和聚乙二醇干扰素α。利巴韦林和聚乙二醇干扰素α也是用于治疗HCV感染的两款药物。
Sovaldi的有效性通过6项有1947名受试者参与的临床试验得到了评价，受试者为之前未接受过治疗（初始治疗）或对之前治疗无效（有治疗史）的HCV感染患者，包括HCV与HIV合并感染患者。临床试验的目的是检测完成了至少12周的治疗后受试者血液中是否还能检测到HCV病毒（持续病毒学应答），如果检测不到病毒就表明受试者的HCV感染已经治愈。
所有临床试验的结果显示，一种包含Sovaldi的治疗方案对多种类型的丙型肝炎病毒有效。此外，Sovaldi还对对不能耐受或采用以干扰素为基础治疗方案的受试者以及等待肝移植的肝癌受试者有效，能为这些患者人群中提供未满足的医疗需求。
临床研究中，以Sovaldi和利巴韦林治疗受试者报道最常见的副作用是疲劳和头痛。以Sovaldi、利巴韦林和聚乙二醇干扰素α治疗受试者最常见的副作用是疲劳、头痛、恶心、失眠和贫血。
Sovaldi是第三个以FDA授予的突破性治疗药物资格获批的药物。如果初步的临床研究证据证明一款药物相比现有治疗可以为严重或危及生命疾病患者提供一种实质性改善，那么该药物的申办者可以为这款药物向FDA申请突破性治疗药物资格。Sovaldi的审批在FDA优先审评计划下完成，该计划可以为那些治疗严重病症的药物提供一个加快的审评程序，如果该药物获得批准，申办者还需要提供药物安全性或有效性显著性改进的资料。Sovaldi由位于加利福尼亚州福斯特市的吉利德上市销售。Olysio由位于新泽西州力登的杨森制药上市销售。 |
