等待内容更新

以下资料仅供参考

【中文名称】吉二代

【印度名称】Hepcinat-LP
【英文名】Sofosbuvir
【规格】28片/瓶

【含量】Ledipasvir 90 mg and Sofosbuvir 400 mg
【包装单位】瓶
【生产厂家】印度NATCO公司

【适应证和用途】：

    HARVONI是一个ledipasvir，一种丙肝病毒(HCV)NS5A抑制剂，和sofosbuvir，一种HCV核苷酸类似物NS5B聚合酶抑制剂的固定剂量组合复方，和适用在成年中为慢性丙肝(CHC)基因型1感染的治疗。

【剂量和给药方法】：

⑴推荐剂量：1片(90 mg ledipasvir和400 mg sofosbuvir)口服每天1次有或无食物(2.1)。

⑵推荐治疗时间(2.1)：

⒈未治疗过有或无肝硬化：12周

⒉经历治疗无肝硬化：12周

⒊经历治疗有肝硬化：24周

⑶对有严重肾受损或肾病终末期患者不能做推荐剂量(2.2)

【药物相互作用】：

⑴P-gp诱导剂(如，利福平[rifampin]，圣约翰草[St.John’s wort])：可能改变ledipasvir和sofosbuvir的浓度。不建议HARVONI与P-gp诱导剂使用。(5.1，7，12.3)

⑵使用前为药物相互作用潜在咨询完整处方资料。(5.1，7，12.3)

【质量检验报告摘录】：

【临床试验经验】：

    因为临床试验是在广泛不同情况下进行的，临床试验观察到不良反应率不能与另一种药临床试验发生率直接比较而且可能不反映实践中观察到的发生率。

    HARVONI的安全性评估是根据来自三项3期临床试验有基因型1慢性丙肝(CHC)与代偿肝病(有和无肝硬化)受试者包括接受HARVONI共8，12和24周分别215，539。和326例受试者的合并数据[见临床研究(14)]。

    对受试者接受HARVONI共8，12，和24周由于不良事件永久地终止治疗受试者的比例分别为0%，<1%，和1%。

    用8，12，或24周HARVONI治疗受试者最常见不良反应(≥10%)为疲乏和头痛。

表2列出在临床试验中接受8，12，或24周治疗用HARVONI受试者观察到≥5%不良反应(由研究者评估所有级别不良事件相关原因)。在表2展示不良反应多数发生严重程度1级。并排制表是为了简化介绍；直接跨越试验比较不应由于不同试验设计造成。

    胆红素升高：用HARVONI治疗共8，12，和24周受试者观察到胆红素升高大于1.5×ULN分别为3%，<1%，和2%。

    脂肪酶升高：在用HARVONI治疗共8，12，和24周受试者分别有<1%，2%，和3%观察到短暂，无症状脂肪酶升高大于3×ULN。

    肌酸激酶：HARVONI的3期试验未评价肌酸激酶。在其他临床试验中sofosbuvir与利巴韦林或干扰素/利巴韦林联用治疗受试者曾报道孤立的，无症状肌酸激酶升高(3或4级)。

【对药物相互作用潜能】：

    因为HARVONI含ledipasvir和sofosbuvir，曾鉴定用HARVONI可能发生与这些药物个别地任何相互作用。

    口服给予HARVONI后，sofosbuvir被迅速吸收和收到广泛首过肝脏提取。在临床药理学研究中，为了药代动力学分析目的监视sofosbuvir和无活性代谢物GS-331007二者。

    Ledipasvir是一种药物转运蛋白P-gp和乳癌耐药蛋白(BCRP)的抑制剂和可能增加共同给药对这些转运蛋白底物的小肠吸收。

    Ledipasvir和sofosbuvir是药物转运蛋白P-gp和BCRP的底物而GS-331007不是。P-gp诱导剂(如，利福平或圣约翰草)可能减低ledipasvir和sofosbuvir血浆浓度，导致减低HARVONI的治疗效应,和建议用P-gp诱导剂不与HARVONI使用。

    根据用HARVONI的组分(ledipasvir或sofosbuvir)或HARVONI进行药物相互作用研究，未曾或观察到临床上显著药物相互作用或预期当HARVONI个别地与以下药物使用[见临床药理学(12.3)]：阿巴卡韦[abacavir]，阿扎那韦[atazanavir]/利托那韦[ritonavir]，环孢素[cyclosporine]，达芦那韦[darunavir]/利托那韦，依非韦伦[efavirenz]，恩曲他滨，拉米夫定，美沙酮[methadone]，口服避孕药，普伐他汀[pravastatin]，拉替拉韦，利匹韦林，他克莫司[tacrolimus]，替诺福韦诺福韦酯[disoproxil fumarate,DF]，或维拉帕米[verapamil]。见表3 HARVONI与某些HIV抗逆转录病毒方案使用[见药物相互作用(7.2)]。

【药代动力学】：

吸收

    在健康成年受试者和在慢性丙型肝炎受试者中曾评价ledipasvir，sofosbuvir，和主要循环代谢物GS-331007的药代动力学性质。口服给予HARVONI后，药后4至4.5小时观察到   ledipasvir中位峰浓度。Sofosbuvir是迅速吸收和药后~0.8至1小时观察到血浆中位峰浓度。药后3.5至4小时间观察到GS-331007的血浆中位峰浓度。

    根据在HCV-感染受试者中群体药代动力学分析，对ledipasvir(N=2113)，sofosbuvir(N=1542)，和GS-331007(N=2113)的几何均数稳态AUC0-24分别为7290，1320,和12,000 ng•hr/mL。对ledipasvir，sofosbuvir，和GS-331007稳态Cmax分别为323，618，和707 ng/mL。健康成年受试者和HCV感染受试者中Sofosbuvir和GS-331007的AUC0-24和Cmax相似。相对于健康受试者(N=191)，在HCV-感染受试者中ledipasvir的AUC0-24和Cmax是分别较低24%和较低32%。

食物的影响

    相对于口服条件。给予单次剂量HARVONI与一个中度脂肪(~600 kcal，25%至30%脂肪)或高脂肪(~1000 kcal，50%脂肪)餐增加sofosbuvir AUC0-inf约2-倍，但不显著影响sofosbuvir Cmax。餐类型存在不改变GS-331007和ledipasvir的暴露。在3期试验中HCV-感染受试者有食物或无食物接受HARVONI反应率相似。可不考虑食物给予HARVONI。

分布

    Ledipasvir是>99.8%与人血浆蛋白结合。在健康受试者单次90 mg剂量[14C]-ledipasvir后，14C-放射性的血与血浆比值范围0.51和0.66间。

    Sofosbuvir是与人血浆蛋白结合约61–65%和结合与跨越1μg/mL至20μg/mL范围药物浓度无关。在人血浆中GS-331007的蛋白结合最小。在健康受试者中单次400 mg剂量[14C]-sofosbuvir后，14C-放射性的血与血浆比值为约0.7。

代谢

    在体外，未观察到通过人CYP1A2，CYP2C8，CYP2C9，CYP 2C19，CYP2D6，和CYP3A4可检测到的ledipasvir代谢。曾观察到通过一种未知机制缓慢氧化代谢的证据。单剂量90 mg[14C]-ledipasvir后，全身暴露几乎完全与母体药物(>98%)。未变化ledipasvir是粪中存在主要种类。

    Sofosbuvir在肝脏中被广泛代谢形成药理学活性核苷三磷酸类似物GS-461203。代谢激活通路涉及被人组织蛋白酶A(CatA)或羧酸酯酶1(CES1)羧基酯部分连续水解和被组氨酸三联体核苷酸结合蛋白1(HINT1)磷酸酯裂解接着被嘧啶核苷酸的生物合成途径磷酸化。去磷酸化作用导致核苷代谢物GS-331007的形成不能有效地再磷酸化和在体外缺乏抗-HCV活性。单次400 mg口服剂量[14C]-sofosbuvir，GS-331007约占全身总暴露>90%。

消除

    单次90 mg口服剂量[14C]-ledipasvir后，在粪和尿中[14C]-放射性的均数总回收为约87%，与回收放射性剂量大多数来自粪(约86%)。在粪中排泄的未变化ledipasvir占给予剂量均数70%和氧化代谢物M19占剂量2.2%。这些数据表明未变化ledipasvir的胆道排泄是主要消除途径，与肾排泄是一个次要通路(约1%)。HARVONI的给予后ledipasvir中位末端半衰期是47小时。

    单次400 mg口服剂量[14C]-sofosbuvir后，均数总回收剂量为是大于92%，尿，粪，和呼出气回收组成分别约80%，14%，和2.5%。尿中回收sofosbuvir剂量多数为GS-331007(78%)而3.5%被回收为sofosbuvir。这些数据表明对GS-331007肾清除是主要消除途径。HARVONI的给药后sofosbuvir和GS-331007中位末端半衰期分别为0.5和27小时。

【特殊人群】：

患者有肾受损：

    在HCV阴性有严重肾受损受试者(eGFR<30 mL/min按Cockcroft-Gault)用单剂量90 mg ledipasvir研究ledipasvir的药代动力学。健康受试者和有严重肾受损受试者间未观察到ledipasvir药代动力学临床上相关差别。

    在HCV阴性有轻度(eGFR≥50和<80 mL/min/1.73m2)，中度(eGFR≥30和<50 mL/min/1.73m2)，严重肾受损(eGFR<30 400=""esrd=""egfr="">80 mL/min/1.73m2)，在轻，中度，和严重肾受损受试者sofosbuvir AUC0-inf分别为61%，107%，和171%较高，而GS331007 AUC0-inf分别为55%，88%，和451%较高。在有ESRD受试者中，相对于有正常肾功能受试者，sofosbuvir和GS-331007 AUC0-inf分别为28%和1280%较高当sofosbuvir是在血液透析前给予与之比较，当sofosbuvir是在血液透析后给予分别为60%和2070%较高。一个4小时血液透析时间去除约18%给予剂量。

种族：

    在HCV-感染受试者中群体药代动力学分析表明种族对ledipasvir，sofosbuvir，和GS331007暴露无临床上相关影响。

性别：

    在HCV-感染受试者中群体药代动力学分析表明性别对sofosbuvir和GS-331007暴露无临床上相关影响。Ledipasvir的AUC和Cmax女性比男性分别较高77%和58%；但是，性别和ledipasvir暴露间相互关系不认为是临床上相关，因为跨越3期研究在男性和女性受试者实现高反应率(SVR>90%)和在女性和男性这安全性图形相似。

老年患者：

    在HCV-感染受试者中群体药代动力学分析显示年龄范围(18至80岁)内分析，年龄对ledipasvir，sofosbuvir，和GS-331007暴露没有临床上相关影响。

有肝受损患者：

    在HCV阴性受试者有严重肝受损(Child-Pugh类别C)用单剂量90 mg ledipasvir研究ledipasvir的药代动力学。在有严重肝受损受试者和有正常肝功能对照受试者Ledipasvir血浆暴露(AUC0-inf)相似。在HCV-感染受试者中群体药代动力学分析表明肝硬化对ledipasvir的暴露无临床上相关影响。

    在HCV-感染受试者有中度和严重肝受损(Child-Pugh类别B和C)中-7天给予400 mg sofosbuvir后研究sofosbuvir的药代动力学。相对于有正常肝功能受试者，在中度和严重肝受损sofosbuvir AUC0-24分别是较高126%和143%，而GS-331007 AUC0-24是分别较高18%和9%。在HCV-感染受试者中群体药代动力学分析表明肝硬化对sofosbuvir和GS-331007的暴露无临床上相关影响。

   

【临床研究】：

 在三项3期试验1518例有基因型1慢性丙肝(CHC)与代偿肝病受试者中评价HARVONI的疗效：

●研究ION-3：非肝硬化未治疗过受试者[见临床研究(14.2)]，

●研究ION-1：肝硬化和非肝硬化未治疗过受试者[见临床研究(14.2)]，和

●研究ION-2：肝硬化和非肝硬化受试者以前用一种基于干扰素方案治疗失败，包括含一种HCV蛋白酶抑制剂方案[见临床研究(14.3)]。

    所有三项3期试验评价HARVONI的疗效(1个固定剂量片90 mg ledipasvir和400 mg sofosbuvir每天给药1次)有或无利巴韦林。每项试验固定治疗时间。为使用高纯系统临床试验期间用COBAS TaqMan HCV试验(版本2.0)测量血清HCV RNA值。分析定量低限(LLOQ)25 IU/mL。

持续病毒学反应(SVR)是主要终点和被定义为停止治疗后在12周时HCV RNA小于LLOQ。复发是次要终点，被定义为HCV RNA大于或等于LLOQ有2次连续值或治疗结束时实现HCV RNA小于LLOQ后治疗阶段后期间可得到的最末治疗后测量。
    备注：每个患者情况不同，药物因人而异，建议听取医生嘱咐服用药物！以上内容仅供参考

 

Ledipasvir and Sofosbuvir

Medically reviewed on Sep 10, 2018

 

 

Index Terms

· GS-5885

· Ledipasvir/Sofosbuvir

· Sofosbuvir and Ledipasvir

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Tablet, Oral:

Harvoni: Ledipasvir 90 mg and sofosbuvir 400 mg [contains fd&c yellow #6 aluminum lake]

Brand Names: U.S.

· Harvoni

Pharmacologic Category

· Antihepaciviral, NS5A Inhibitor

· Antihepaciviral, Polymerase Inhibitor (Anti-HCV)

· NS5A Inhibitor

· NS5B RNA Polymerase Inhibitor

Pharmacology

Ledipasvir inhibits the HCV NS5A protein necessary for viral replication; sofosbuvir is a prodrug converted to its pharmacologically active form (GS-461203), inhibits NS5B RNA-dependent RNA polymerase, also essential for viral replication, and acts as a chain terminator.

Absorption

Ledipasvir and sofosbuvir are well absorbed

Metabolism

Ledipasvir: Slow oxidative metabolism via an unknown mechanism; Sofosbuvir: Hepatic; forms pharmacologically active nucleoside (uridine) analog triphosphate GS-461203; Dephosphorylation results in the formation of nucleoside inactive metabolite GS-331007

Excretion

Ledipasvir: Feces (~86%), urine (1%); Sofosbuvir: Urine (80%), feces (14%)

Time to Peak

Ledipasvir: 4 to 4.5 hours; Sofosbuvir: ~0.8 to 1 hour

Half-Life Elimination

Ledipasvir: 47 hours; Sofosbuvir: ~0.5 hours

Protein Binding

Ledipasvir: >99.8%; Sofosbuvir: ~61% to 65%

Special Populations: Renal Function Impairment

Sofosbuvir: Following a single 400 mg dose of sofosbuvir in HCV negative subjects with mild (eGFR ≥50 and <80 mL/minute/1.73 m2), moderate (eGFR ≥30 and <50 mL/minute/1.73 m2), severe renal impairment (eGFR <30 mL/minute/1.73 m2), and subjects with ESRD requiring hemodialysis the sofosbuvir AUC0-inf was 61%, 107%, and 171% higher in mild, moderate, and severe renal impairment than in subjects with normal renal function.

Use: Labeled Indications

Chronic hepatitis C: Treatment of chronic hepatitis C virus (HCV) genotype 1, 4, 5, or 6 infection in adult and pediatric patients ≥12 years or weighing ≥35 kg, without cirrhosis or with compensated cirrhosis; genotype 1 in adult patients with decompensated cirrhosis, in combination with ribavirin; and genotype 1 or 4 in adult liver transplant patients without cirrhosis or with compensated cirrhosis, in combination with ribavirin.

Off Label UsesChronic hepatitis C, genotype 1 or 4 (kidney transplant recipients)

Based on the AASLD/IDSA Recommendations for Testing, Managing, and Treating Hepatitis C guidelines, ledipasvir and sofosbuvir is recommended and effective for treatment of hepatitis C virus genotype 1 or 4 infection in kidney transplant recipients without cirrhosis or with compensated cirrhosis. Hepatitis C treatment guidelines are constantly changing with the advent of new treatment therapies and information; consult current clinical practice guidelines for the most recent treatment recommendations.

Chronic hepatitis C, genotype 4, 5, or 6 (with decompensated cirrhosis)

Based on the AASLD/IDSA Recommendations for Testing, Managing, and Treating Hepatitis C guidelines, ledipasvir and sofosbuvir, with or without concomitant ribavirin, is recommended and effective for treatment of hepatitis C virus genotype 4, 5, or 6 infection in patients with decompensated cirrhosis, including patients who have prior sofosbuvir-based treatment failure. Hepatitis C treatment guidelines are constantly changing with the advent of new treatment therapies and information; consult current clinical practice guidelines for the most recent treatment recommendations.

Chronic hepatitis C, genotype 5 or 6 (liver transplant recipients)

Based on the AASLD/IDSA Recommendations for Testing, Managing, and Treating Hepatitis C guidelines, ledipasvir and sofosbuvir, with concomitant ribavirin, is recommended and effective for treatment of hepatitis C virus genotype 5 or 6 infection in liver transplant recipients with or without cirrhosis (including decompensated cirrhosis). Hepatitis C treatment guidelines are constantly changing with the advent of new treatment therapies and information; consult current clinical practice guidelines for the most recent treatment recommendations.

Contraindications

There are no contraindications listed in the manufacturer’s labeling. If ledipasvir/sofosbuvir is administered with ribavirin, the contraindications to ribavirin also apply. See ribavirin manufacturer's information.

Canadian labeling: Additional contraindications (not in US labeling): Hypersensitivity to any component of the formulation.

Dosing: Adult

Chronic hepatitis C (CHC) infection (monoinfection or co-infected with HIV-1) (AASLD/IDSA 2017):Oral:

Genotype 1:

Treatment-naive patients without cirrhosis or with compensated cirrhosis (Child-Pugh class A) or peginterferon/ribavirin treatment-experienced patients without cirrhosis: One tablet once daily for 12 weeks. Note: Treatment-naive patients without cirrhosis who have HCV RNA <6 million units/mL, are HIV-uninfected, and non-black may be considered for therapy of 8 weeks duration.

Peginterferon/ribavirin treatment-experienced patients with compensated cirrhosis (Child-Pugh class A) (alternative regimen): One tablet once daily with concomitant ribavirin for 12 weeks

NS3 protease inhibitor + peginterferon/ribavirin treatment-experienced patients:

Without cirrhosis: One tablet once daily for 12 weeks

With compensated cirrhosis (Child-Pugh class A) (alternative regimen): One tablet once daily with concomitant ribavirin for 12 weeks

Non-NS5A inhibitor, sofosbuvir containing regimen-experienced patients without cirrhosis (except in cases of simeprevir failure) (alternative regimen): One tablet once daily with concomitant ribavirin for 12 weeks

Decompensated cirrhosis (Child-Pugh class B or C): One tablet once daily with concomitant ribavirin for 12 weeks; if ribavirin-ineligible, one tablet once daily for 24 weeks

Decompensated cirrhosis (Child-Pugh class B or C) in patients with sofosbuvir- or NS5A-based treatment failure: One tablet once daily with concomitant ribavirin for 24 weeks

Liver transplant recipients (treatment-naive and treatment-experienced) with or without cirrhosis, including decompensated cirrhosis: One tablet once daily with concomitant ribavirin for 12 weeks

Kidney transplant recipients (treatment-naive and treatment-experienced) without cirrhosis or with compensated (Child-Pugh class A) cirrhosis (off-label use): One tablet once daily for 12 weeks

Genotype 4:

Treatment-naive patients without cirrhosis or with compensated cirrhosis (Child-Pugh class A) and peginterferon/ribavirin treatment-experienced patients without cirrhosis: One tablet once daily for 12 weeks.

Peginterferon/ribavirin treatment-experienced patients with compensated cirrhosis (Child-Pugh class A) (alternative regimen): One tablet once daily with concomitant ribavirin for 12 weeks

Decompensated cirrhosis (Child-Pugh class B or C) (off-label use): One tablet once daily with concomitant ribavirin for 12 weeks; if ribavirin-ineligible, one tablet once daily for 24 weeks

Decompensated cirrhosis (Child-Pugh class B or C) in patients with sofosbuvir- or NS5A-based treatment failure (off-label use): One tablet once daily with concomitant ribavirin for 24 weeks

Liver transplant recipients (treatment-naive and treatment-experienced) with or without cirrhosis, including decompensated cirrhosis: One tablet once daily with concomitant ribavirin for 12 weeks

Kidney transplant recipients (treatment-naive and treatment-experienced) without cirrhosis or with compensated (Child-Pugh class A) cirrhosis (off-label use): One tablet once daily for 12 weeks

Genotype 5 or 6:

Treatment-naive and peginterferon/ribavirin treatment-experienced patients without cirrhosis or with compensated cirrhosis (Child-Pugh class A): One tablet once daily for 12 weeks

Decompensated cirrhosis (Child-Pugh class B or C) (off-label use): One tablet once daily with concomitant ribavirin for 12 weeks; if ribavirin-ineligible, one tablet once daily for 24 weeks

Decompensated cirrhosis (Child-Pugh class B or C) in patients with sofosbuvir- or NS5A-based treatment failure: One tablet once daily with concomitant ribavirin for 24 weeks

Liver transplant recipients (treatment-naive and treatment-experienced) with or without cirrhosis, including decompensated cirrhosis (off-label use): One tablet once daily with concomitant ribavirin for 12 weeks

Dosing: Geriatric

Refer to adult dosing.

Dosing: Pediatric

Chronic hepatitis C (CHC) infection (monoinfection or co-infected with HIV-1): Children and Adolescents ≥12 years or weighing ≥35 kg: Oral: 1 tablet (ledipasvir 90 mg/sofosbuvir 400 mg) once daily.

Duration of therapy: Note: Treatment-experienced patients are defined as those who have failed an interferon-based regimen with or without ribavirin.

Genotype 1:

Treatment-naive patients without cirrhosis or with compensated cirrhosis (Child-Pugh class A) or treatment-experienced patients without cirrhosis: 12 weeks.

Treatment-experienced patients with compensated cirrhosis (Child-Pugh class A): 24 weeks.

Genotype 4, 5, or 6:

Treatment-naive and treatment-experienced patients without cirrhosis or with compensated cirrhosis (Child-Pugh class A): 12 weeks.

Dosing: Renal Impairment

eGFR ≥30 mL/minute/1.73 m2: No dosage adjustment necessary.

eGFR <30 mL/minute/1.73 m2: There are no dosage adjustments provided in the manufacturer's labeling. However, sofosbuvir and metabolite accumulate in patients with severely impaired renal function.

End-stage renal disease (ESRD) , including those requiring intermittent hemodialysis (IHD): There are no dosage adjustments provided in the manufacturer's labeling However, sofosbuvir and metabolite accumulate in patients with severely impaired renal function. In a 4-hour dialysis session, 18% of sofosbuvir dose was removed.

Dosing: Hepatic Impairment

Mild, moderate, or severe impairment (Child-Pugh class A, B, or C): No dosage adjustment necessary.

Administration

Oral: Administer with or without food.

Storage

Store below 30°C (86°F). Dispense in original container.

Drug Interactions

Afatinib: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Afatinib. Management: Per US labeling: reduce afatinib by 10mg if not tolerated. Per Canadian labeling: avoid combination if possible; if used, administer the P-gp inhibitor simultaneously with or after the dose of afatinib. Consider therapy modification

Amiodarone: Sofosbuvir may enhance the bradycardic effect of Amiodarone. Avoid combination

Antacids: May decrease the serum concentration of Ledipasvir. Management: Separate the administration of ledipasvir and antacids by 4 hours. Consider therapy modification

Betrixaban: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Betrixaban. Management: Decrease the betrixaban dose to an initial single dose of 80 mg followed by 40 mg once daily if combined with a P-glycoprotein inhibitor. Consider therapy modification

Bilastine: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Bilastine. Management: Consider alternatives when possible; bilastine should be avoided in patients with moderate to severe renal insufficiency who are receiving p-glycoprotein inhibitors. Consider therapy modification

Brentuximab Vedotin: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Brentuximab Vedotin. Specifically, concentrations of the active monomethyl auristatin E (MMAE) component may be increased. Monitor therapy

CarBAMazepine: May decrease the serum concentration of Ledipasvir. Avoid combination

CarBAMazepine: May decrease the serum concentration of Sofosbuvir. Avoid combination

Celiprolol: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Celiprolol. Monitor therapy

Colchicine: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Colchicine. Colchicine distribution into certain tissues (e.g., brain) may also be increased. Management: Colchicine is contraindicated in patients with impaired renal or hepatic function who are also receiving a p-glycoprotein inhibitor. In those with normal renal and hepatic function, reduce colchicine dose as directed. See full monograph for details. Consider therapy modification

Dabigatran Etexilate: P-glycoprotein/ABCB1 Inhibitors may increase serum concentrations of the active metabolite(s) of Dabigatran Etexilate. Management: Dabigatran dose reductions may be needed. Specific recommendations vary considerably according to US vs Canadian labeling, specific P-gp inhibitor, renal function, and indication for dabigatran treatment. Refer to full monograph or dabigatran labeling. Consider therapy modification

DOXOrubicin (Conventional): P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of DOXOrubicin (Conventional). Management: Seek alternatives to P-glycoprotein inhibitors in patients treated with doxorubicin whenever possible. One U.S. manufacturer (Pfizer Inc.) recommends that these combinations be avoided. Consider therapy modification

Edoxaban: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Edoxaban. Management: See full monograph for details. Reduced doses are recommended for patients receiving edoxaban for venous thromboembolism in combination with certain inhibitors. Similar dose adjustment is not recommended for edoxaban use in atrial fibrillation. Consider therapy modification

Everolimus: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Everolimus. Monitor therapy

Histamine H2 Receptor Antagonists: May decrease the serum concentration of Ledipasvir. Consider therapy modification

Lumacaftor: May decrease the serum concentration of P-glycoprotein/ABCB1 Substrates. Lumacaftor may increase the serum concentration of P-glycoprotein/ABCB1 Substrates. Monitor therapy

Modafinil: May decrease the serum concentration of Sofosbuvir. Avoid combination

Naldemedine: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Naldemedine.Monitor therapy

Naloxegol: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Naloxegol. Monitor therapy

OXcarbazepine: May decrease the serum concentration of Sofosbuvir. Avoid combination

OXcarbazepine: May decrease the serum concentration of Ledipasvir. Avoid combination

PAZOPanib: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of PAZOPanib. Avoid combination

P-glycoprotein/ABCB1 Inducers: May decrease the serum concentration of Sofosbuvir. Avoid combination

P-glycoprotein/ABCB1 Inducers: May decrease the serum concentration of Ledipasvir. Avoid combination

P-glycoprotein/ABCB1 Inhibitors: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates. P-glycoprotein inhibitors may also enhance the distribution of p-glycoprotein substrates to specific cells/tissues/organs where p-glycoprotein is present in large amounts (e.g., brain, T-lymphocytes, testes, etc.). Monitor therapy

P-glycoprotein/ABCB1 Substrates: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of P-glycoprotein/ABCB1 Substrates. P-glycoprotein inhibitors may also enhance the distribution of p-glycoprotein substrates to specific cells/tissues/organs where p-glycoprotein is present in large amounts (e.g., brain, T-lymphocytes, testes, etc.). Exceptions: Loperamide. Monitor therapy

PHENobarbital: May decrease the serum concentration of Ledipasvir. Avoid combination

PHENobarbital: May decrease the serum concentration of Sofosbuvir. Avoid combination

Primidone: May decrease the serum concentration of Ledipasvir. Avoid combination

Primidone: May decrease the serum concentration of Sofosbuvir. Avoid combination

Proton Pump Inhibitors: May decrease the serum concentration of Ledipasvir. Management: PPI doses equivalent to omeprazole 20 mg or lower may be given with ledipasvir under fasted conditions. Administration with higher doses of PPIs, 2 hours after a PPI, or in combination with food and PPIs may reduce ledipasvir bioavailability. Consider therapy modification

Prucalopride: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Prucalopride.Monitor therapy

Ranolazine: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Ranolazine. Monitor therapy

Ranolazine: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates. Monitor therapy

Rifabutin: May decrease the serum concentration of Sofosbuvir. Avoid combination

Rifabutin: May decrease the serum concentration of Ledipasvir. Avoid combination

Rifapentine: May decrease the serum concentration of Sofosbuvir. Avoid combination

Rifapentine: May decrease the serum concentration of Ledipasvir. Avoid combination

RifAXIMin: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of RifAXIMin. Monitor therapy

Rosuvastatin: Ledipasvir may increase the serum concentration of Rosuvastatin. Avoid combination

Silodosin: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Silodosin. Avoid combination

Simeprevir: May increase the serum concentration of Ledipasvir. Ledipasvir may increase the serum concentration of Simeprevir. Avoid combination

Tacrolimus (Systemic): Ledipasvir may decrease the serum concentration of Tacrolimus (Systemic). Monitor therapy

Tenofovir Alafenamide: Sofosbuvir may increase the serum concentration of Tenofovir Alafenamide. Monitor therapy

Tenofovir Disoproxil Fumarate: Ledipasvir may increase the serum concentration of Tenofovir Disoproxil Fumarate. Management: Avoidance of this combination is recommended under some circumstances. Refer to full monograph for details. Consider therapy modification

Tipranavir: May decrease the serum concentration of Ledipasvir. Avoid combination

Tipranavir: May decrease the serum concentration of Sofosbuvir. Avoid combination

Topotecan: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Topotecan. Avoid combination

Venetoclax: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Venetoclax. Management: Reduce the venetoclax dose by at least 50% in patients requiring these combinations.Consider therapy modification

VinCRIStine (Liposomal): P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of VinCRIStine (Liposomal). Avoid combination

Vitamin K Antagonists (eg, warfarin): Antihepaciviral NS5B RNA Polymerase Inhibitors may diminish the anticoagulant effect of Vitamin K Antagonists. Monitor therapy

Adverse Reactions

>10%:

Central nervous system: Headache (11% to 29%), fatigue (10% to 18%)

Neuromuscular & skeletal: Weakness (18% to 31%)

1% to 10%:

Central nervous system: Irritability (8%), insomnia (3% to 6%), dizziness (5%), depression (<5%; including in subjects with preexisting history of psychiatric illness)

Gastrointestinal: Nausea (6% to 9%), increased serum lipase (>3 x ULN: ≤9%), diarrhea (3% to 7%)

Hepatic: Hyperbilirubinemia (>1.5 x ULN: ≤3%)

Neuromuscular & skeletal: Myalgia (9%), increased creatine phosphokinase (1%)

Respiratory: Cough (5%), dyspnea (3%)

<1%, postmarketing, and/or case reports: Angioedema, reactivation of HBV, skin rash (with blisters or angioedema-like swelling)

ALERT: U.S. Boxed Warning

Hepatitis B virus reactivation:

Test all patients for evidence of current or prior hepatitis B virus (HBV) infection before initiating treatment with ledipasvir/sofosbuvir. HBV reactivation has been reported in hepatitis C virus (HCV)/HBV coinfected patients who were undergoing or had completed treatment with HCV direct acting antivirals and were not receiving HBV antiviral therapy. Some cases have resulted in fulminant hepatitis, hepatic failure, and death. Monitor HCV/HBV coinfected patients for hepatitis flare or HBV reactivation during HCV treatment and post-treatment follow-up. Initiate appropriate patient management for HBV infection as clinically indicated.

Warnings/Precautions

Disease-related concerns:

• Hepatitis B virus reactivation: [US Boxed Warning]: Hepatitis B virus (HBV) reactivation has been reported in hepatitis C virus (HCV)/HBV coinfected patients who were receiving or had completed treatment with HCV direct-acting antivirals and were not receiving HBV antiviral therapy; some cases have resulted in fulminant hepatitis, hepatic failure, and death. Test all patients for evidence of current or prior HBV infection prior to initiation of ledipasvir/sofosbuvir; monitor HCV/HBV co-infected patients for hepatitis flare or HBV reactivation during treatment and post-treatment follow-up. Initiate treatment for HBV infection as clinically indicated. HBV reactivation has been reported in HBsAg positive patients and in patients with serologic evidence of resolved HBV infection (ie, HBsAg negative and anti-HBc positive) and is characterized by an abrupt increase in HBV replication manifested as a rapid increase in serum HBV DNA level; reappearance of HBsAg may occur in patients with resolved HBV infection. Risk of HBV reactivation may be increased in patients receiving certain immunosuppressants or chemotherapeutic agents.

Concurrent drug therapy issues:

• Amiodarone: Symptomatic bradycardia (some requiring pacemaker intervention) and fatal cardiac arrest has occurred in patients receiving amiodarone and ledipasvir/sofosbuvir. Bradycardia generally occurred within hours to days following coadministration, however some cases have occurred 2 weeks following the initiation of HCV treatment. The risk of bradycardia may be increased in patients taking beta blockers or patients with underlying cardiac comorbidities and/or advanced liver disease. Bradycardia generally resolves following discontinuation of ledipasvir/sofosbuvir. Coadministration of amiodarone and ledipasvir/sofosbuvir is not recommended. However, if patients have no treatment alternatives, patients should have inpatient cardiac monitoring for the first 48 hours, followed by daily outpatient or self-monitoring of heart rate for at least the first 2 weeks of treatment. Due to the long half-life of amiodarone, cardiac monitoring (as described) is also recommended if amiodarone was discontinued just prior to beginning treatment with ledipasvir/sofosbuvir. Patients should seek medical attention immediately if they experience fainting or near-fainting, dizziness, lightheadedness, malaise, weakness, excessive tiredness, shortness of breath, chest pains, confusion or memory problems.

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Monitoring Parameters

Manufacturer’s labeling:

Bilirubin, liver enzymes, and serum creatinine at baseline and periodically when clinically indicated. If used in combination with amiodarone (or in patients who discontinued amiodarone just prior to initiating ledipasvir/sofosbuvir), inpatient cardiac monitoring for the first 48 hours of coadministration, then outpatient or self-monitoring of heart rate daily through at least the first 2 weeks of treatment.

Serum HCV-RNA at baseline, during treatment, at the end of treatment, during treatment follow-up, and when clinically indicated.

Hepatitis B surface antigen (HBsAg) and hepatitis B core antibody (anti-HBc) prior to initiation; in patients with serologic evidence of hepatitis B virus (HBV) infection, monitor for clinical and laboratory signs of hepatitis flare or HBV reactivation during treatment and during post-treatment follow-up.

Alternate recommendations (AASLD/IDSA 2015):

Baseline (within 12 weeks prior to starting antiviral therapy): CBC, INR, hepatic function panel (albumin, total and direct bilirubin, ALT, AST, and alkaline phosphatase), calculated GFR

Baseline (at any time prior to starting antiviral therapy): HCV genotype and subtype, quantitative HCV viral load

During therapy: CBC, serum creatinine, calculated GFR, hepatic function panel (after 4 weeks of therapy and as clinically indicated); quantitative HCV viral load testing (after 4 weeks of therapy and at 12 weeks after completion of therapy). If quantitative HCV viral load is detectable at treatment week 4, repeat testing is recommended after 2 additional weeks of treatment (treatment week 6).

Pregnancy Considerations

Adverse events were not observed in animal reproduction studies using ledipasvir or sofosbuvir.

Treatment of hepatitis C is not currently recommended to treat maternal infection or to decrease the risk of mother-to-child transmission during pregnancy (Tran 2016). HCV-infected females of childbearing potential should consider postponing pregnancy until therapy is complete to reduce the risk of HCV transmission (AASLD/IDSA 2017). When HCV infection is detected during pregnancy, treatment should be deferred until after delivery. Direct-acting antiviral medications should not be used in pregnant females outside of clinical trials until safety and efficacy information is available (SMFM [Hughes 2017]).

If used in combination with ribavirin, all warnings related to the use of ribavirin and pregnancy and/or contraception should be followed. Refer to the ribavirin monograph for additional information.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience loss of strength and energy, headache, nausea, diarrhea, insomnia, cough, muscle pain, irritability, or dizziness. Have patient report immediately to prescriber signs of liver problems (dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or jaundice) (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.