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。
适应证和用途
SOVALDI是一种丙型肝炎病毒(HCV)核苷酸类似物NS5B聚合酶抑制剂适用为慢性丙型肝炎(CHC)感染的治疗作为组合抗病毒治疗方案的一个组分。
（1）SOVALDI疗效已在有HCV基因型1，2，3或4感染受试者中被确定，包括有肝细胞癌符合米兰[Milan]标准(等待肝移植)和有HCV/HIV-1共-感染受试者。
剂量和给药方法
（1）一片400 mg片每天1次有或无食物服用。
（2）应与利巴韦林[ribavirin]联用或与聚乙二醇化干扰素[pegylated干扰素]和利巴韦林联用为CHC的治疗。建议联合治疗：
（3）SOVALDI与利巴韦林联用共24周干扰素不合格可被考虑为被基因型1感染CHC患者。
（4）在有肝细胞癌等待肝移植直至48周或直至肝移植患者应被与联用利巴韦林为CHC的治疗，以先发生为准。
（5）对有严重肾受损或肾病终末期患者不能建议剂量。
剂型和规格
片：400mg。
禁忌证
（1）当与聚乙二醇干扰素α/利巴韦林或单独利巴韦林联用时，对聚乙二醇干扰素α和/或利巴韦林的所有禁忌证也都应用于SOVALDI联合治疗。
（2）因为利巴韦林可能引起出生缺陷和胎儿死亡，在妊娠妇女和男性其女性伴侣妊娠时禁忌SOVALDI与聚乙二醇干扰素α/利巴韦林或利巴韦林联用。
警告和注意事项
妊娠：利巴韦林可能致出生缺陷和胎儿死亡和动物研究已证明干扰素有流产效应；女性患者和男性患者的女性伴侣避免妊娠。治疗开始前患者必须有一个阴性妊娠测试，使用至少2种有效非激素避孕方法和每月妊娠测试。
不良反应
SOVALDI与利巴韦林联用观察到最常见不良事件(发生率大于或等于20%，所有级别)是疲乏和头痛。SOVALDI与聚乙二醇干扰素α和利巴韦林联用观察到最常见不良事件是疲乏，头痛，恶心，失眠和贫血。
药物相互作用
药物是强肠道P-gp诱导剂(如，利福平[rifampin]，圣约翰草[St. John’s wort])可能改变sofosbuvir的浓度。对潜在药物-药物相互作用使用前咨询完整咨询资料)
特殊人群中使用
（1）有HCV/HIV-1共-感染患者: 曾研究安全性和疗效。
（2）有肝细胞癌等待肝移植患者: 曾研究安全性和疗效。
Sovaldi: a new treatment option for chronic hepatitis C
Sovaldi (sofosbuvir) is a novel oral treatment for chronic hepatitis C licensed for use in combination with ribavirin, with or without peginterferon alfa.
PHARMACOLOGY
Sofosbuvir is an oral nucleotide prodrug which inhibits the HCV-specific NS5B RNA polymerase, thereby acting as a chain terminator and preventing viral replication.1
CLINICAL STUDIES
The safety and efficacy of sofosbuvir (400mg once daily) together with ribavirin (1g [<75kg] or 1.2g [≥75kg] daily in divided doses) with or without peginterferon alfa-2a (180 microgram by subcutaneous injection once weekly) were assessed in clinical studies involving 1,568 patients with chronic hepatitis. In all studies, the sustained virologic response was assessed at 12 weeks after the end of treatment.1
Patients without treatment options
Genotype 2 or 3
Two phase III studies were conducted to assess the efficacy of sofosbuvir plus ribavirin in patients with hepatitis C virus (HCV) genotype 2 or 3 infection for whom peginterferon was unsuitable (POSITRON, n=278) or who had not responded to prior interferon treatment (FUSION, n=201).2
In the POSITRON study, the rate of sustained virologic response following 12 weeks of treatment was 78% (95% CI 72−83) in the sofosbuvir-ribavirin group compared with 0% in the placebo group (p<0.001).2
In the FUSION study, the rate of sustained virologic response was 50% (95% CI 40–60) after 12 weeks of treatment and 73% (95% CI 63–81) after 16 weeks of treatment (difference, -23 percentage points [95% CI -35 to -11; p<0.001).2
In both studies, responses occurred more frequently among patients with HCV genotype 2 infection than among those with genotype 3 infection and among genotype 3 patients without cirrhosis than among those with cirrhosis.2
Treatment-naive patients
Genotype 1, 4, 5 or 6
In the phase III open-label NEUTRINO study, 327 patients with previously untreated hepatitis C genotype 1, 4, 5 or 6 infection received sofosbuvir, ribavirin and peginterferon alfa-2a for 12 weeks.3
In total, 90% of patients achieved a sustained virologic response (95% CI 87−93). Response rates did not differ greatly according to HCV genotype.3
Genotype 2 or 3
In another phase III open-label study (FISSION, n=499) patients with HCV genotype 2 or 3 infection were randomised to receive sofosbuvir plus ribavirin for 12 weeks or peginterferon alfa-2a plus ribavirin (800mg daily in two divided doses) for 24 weeks.3
The rate of sustained virologic response was 67% in both groups, demonstrating non-inferiority of the sofosbuvir-ribavirin regimen to the peginterferon-ribavirin regimen. In both groups, response rates were higher among patients with genotype 2 infection than in those with genotype 3 infection (97% vs 56% in the sofosbuvir group and 78% vs 63% in the peginterferon group).3
HIV/HCV co-infection
The efficacy of a sofosbuvir-ribavirin regimen in patients with HIV/HCV co-infection already receiving antiretroviral therapy was assessed in the open-label PHOTON-1 study. Treatment duration was 24 weeks in genotype 1 patients (n=114) and 12 weeks in genotype 2 (n=26) and 3 (n=42) patients; all patients were treatment-naive.4
A sustained virologic response was observed in 76%, 88% and 67% of genotype 1, 2 and 3 patients, respectively.4
Treatment-naive and previously treated patients
Genotype 2 or 3
The placebo-controlled VALENCE study investigated the efficacy of a sofosbuvir-ribavirin regimen administered for 12 weeks in patients with HCV genotype 2 infection (n=73) and for 12 or 24 weeks in patients with HCV genotype 3 infection (n=11 and n=250, respectively). Both treatment-naive and treatment-experienced patients were included.5
A sustained virologic response was observed in 93% of genotype 2 patients and in 85% of genotype 3 patients treated for 24 weeks. In total, 27% of genotype 3 patients treated for 12 weeks achieved a sustained virologic response.5
Safety profile
Treatment with sofosbuvir was generally well tolerated in clinical studies, with low rates of treatment discontinuation due to adverse events.1
The safety profile in patients co-infected with HCV/HIV was similar, with no decrease in CD4 T-cell percentage observed.4

SOVALDI Rx
Generic Name and Formulations:
Sofosbuvir 400mg; tabs.

Company:
Gilead Sciences, Inc.

RECENT UPDATES
02/10/14
Monograph added.
Indications for SOVALDI:
As a component of a combination antiviral treatment regimen for chronic hepatitis C (CHC) genotype 1, 2, 3, or 4 infection, including those with hepatocellular carcinoma meeting Milan criteria (awaiting liver transplant), and those with HCV/HIV-1 co-infection. Not for use as monotherapy.

Adult Dose for SOVALDI:
400mg once daily. Genotype 1: treat for 12 wks (with PegIFN alfa + RBV) or 24 wks (with RBV) if interferon-based regimen ineligible. Genotype 2: treat for 12 wks (with RBV). Genotype 3: treat for 24 wks (with RBV). Genotype 4: treat for 12 wks (with PegIFN alfa + RBV). Hepatocellular carcinoma: treat up to 48 wks (with RBV) or until time of liver transplant, whichever occurs first. Dose reduction of sofosbuvir is not recommended. Other dose modifications: see full labeling. If peginterferon alfa or ribavirin are discontinued, sofosbuvir should also be discontinued.

Children's Dose for SOVALDI:
<18yrs: not established.

Pharmacological Class:
HCV NS5B polymerase inhibitor.

Contraindications:
Pregnant women and in men whose partners are pregnant (note: ribavirin is Cat. X). Peginterferon and ribavirin contraindications also apply to combination therapy with sofosbuvir.

Warnings/Precautions:
Female patients/partners of male patients must have (–) pregnancy test before initiating therapy; use 2 effective non-hormonal methods of contraception during and for 6 months after treatment completion; perform routine monthly pregnancy test. Severe renal impairment or ESRD. Decompensated cirrhosis. Post-liver transplant recipients. Pregnancy (Cat. B). Nursing mothers: not recommended.

Interactions:
Avoid concomitant strong P-gp inducers (eg, rifampin, St. John’s wort). Antagonized by carbamazepine, phenytoin, phenobarbital, oxcarbazepine, rifabutin, rifapentine, tipranavir/ritonavir; avoid concomitant use. May be co-administered with P-gp and/or BCRP inhibitors (see full labeling).

Adverse Reactions:
Fatigue, headache, nausea, insomnia, anemia, pruritus, rash.

Note:
For peginterferon alfa and ribavirin specific dosing and safety information, refer to their respective PI.

How Supplied:
Tabs—28

FDA批准Sovaldi用于治疗慢性丙型肝炎病毒感染
2013年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。