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Sofosbuvir

Class: HCV Polymerase Inhibitors
Chemical Name: N-[[P(S),2′R]-2′-Deoxy-2′-fluoro-2′-methyl-P-phenyl-5′-uridylyl]-l-alanine 1-methylethyl ester
Molecular Formula: C22H29FN3O9P
CAS Number: 1190307-88-0
Brands: Sovaldi

Warning(s)

    Risk of HBV Reactivation in Patients Coinfected with HCV and HBV
  • HBV reactivation, including cases resulting in fulminant hepatitis, hepatic failure, and death, reported in patients coinfected with HCV and HBV who were receiving or had completed treatment with HCV direct-acting antivirals (DAAs) and were not receiving HBV antiviral therapy.1 25 (See Risk of HBV Reactivation in Patients Coinfected with HCV and HBV under Cautions.)

  • Test all patients for evidence of current or prior HBV infection before initiating sofosbuvir.1 25

  • Monitor patients coinfected with HCV and HBV for hepatitis flare or HBV reactivation during and after HCV treatment.1 25 Initiate appropriate management for HBV infection as clinically indicated.1

Introduction

Antiviral;1 nucleotide analog HCV NS5B polymerase inhibitor.1

Uses for Sofosbuvir

Chronic HCV Infection

Treatment of chronic HCV genotype 1, 2, 3, or 4 infection in treatment-naive (previously untreated) or previously treated adults without cirrhosis or with compensated cirrhosis, including those with HIV coinfection and those with hepatocellular carcinoma awaiting liver transplantation.1 119

Treatment of chronic HCV genotype 2 or 3 infection in treatment-naive or previously treated pediatric patients ≥12 years of age without cirrhosis or with compensated cirrhosis.1

Treatment of chronic HCV infection caused by genotype 5 or 6;1 2 119 only limited data available.1 2 119

Must be used in conjunction with other antivirals;1 119 do not use alone.1 119

Used in multiple-drug regimen that includes sofosbuvir and ribavirin (with or without peginterferon alfa),1 2 3 4 5 11 multiple-drug regimen that includes sofosbuvir and simeprevir,12 15 16 119 183 or multiple-drug regimen that includes sofosbuvir and daclatasvir (with or without ribavirin).8 9 10 119 178

Used in conjunction with ledipasvir;119 181 fixed combination containing ledipasvir and sofosbuvir (ledipasvir/sofosbuvir) commercially available.181

Used in conjunction with velpatasvir;176 fixed combination containing sofosbuvir and velpatasvir (sofosbuvir/velpatasvir) commercially available.176

Specific multiple-drug treatment regimen and duration of treatment with sofosbuvir and other antivirals depend on HCV genotype and patient population.1

Treatment of chronic HCV infection is complex and rapidly evolving; consult a specialist to obtain the most up-to-date information.119 Information from the American Association for the Study of Liver Diseases (AASLD), Infectious Diseases Society of America (IDSA), and International Antiviral Society–USA (IAS–USA) regarding diagnosis and management of HCV infection, including recommendations for initial treatment, is available at .119

Sofosbuvir Dosage and Administration

General

  • Must be used in conjunction with other antivirals;1 do not use alone.1

  • Specific multiple-drug regimen and duration of treatment depend on HCV genotype and patient population.1

  • Prior to initiating HCV treatment, test all patients for evidence of current or prior HBV infection by measuring hepatitis B surface antigen (HBsAg), hepatitis B surface antibody (anti-HBs), and hepatitis B core antibody (anti-HBc).1 25 119 (See Risk of HBV Reactivation in Patients Coinfected with HCV and HBV under Cautions.)

  • Do not reduce sofosbuvir dosage for any reason.1

  • If adverse reactions potentially related to other antivirals in the multiple-drug regimen occur, adjust dosage (dosage modification) or discontinue these drugs according to respective manufacturer’s prescribing information.1 If other antivirals in the multiple-drug regimen are discontinued for any reason, sofosbuvir also should be discontinued.1

Administration

Oral Administration

Administer orally without regard to food.1

Dosage

Pediatric Patients

Treatment of Chronic HCV Genotype 2 Infection
Sofosbuvir in Conjunction with Ribavirin
Oral

Pediatric patients ≥12 years of age weighing ≥35 kg without cirrhosis or with compensated cirrhosis (Child-Pugh class A): 400 mg once daily in conjunction with ribavirin for a duration of 12 weeks.1

Treatment of Chronic HCV Genotype 3 Infection
Sofosbuvir in Conjunction with Ribavirin
Oral

Pediatric patients ≥12 years of age weighing ≥35 kg without cirrhosis or with compensated cirrhosis (Child-Pugh class A): 400 mg once daily in conjunction with ribavirin for a duration of 24 weeks.1

Adults

Treatment of Chronic HCV Genotype 1 Infection
Sofosbuvir in Conjunction with Daclatasvir
Oral

Noncirrhotic: 400 mg once daily119 in conjunction with daclatasvir (60 mg once daily) for a duration of 12 weeks.119 178

Compensated cirrhosis (Child-Pugh class A): 400 mg once daily119 in conjunction with daclatasvir (60 mg once daily).119 178 Manufacturer of daclatasvir recommends a duration of 12 weeks.178 Experts recommend a duration of 24 weeks and state consider adding ribavirin to the sofosbuvir and daclatasvir regimen.119

Decompensated cirrhosis (Child-Pugh class B or C): 400 mg once daily119 in conjunction with daclatasvir (60 mg once daily) and ribavirin.119 178 Usual duration is 12 weeks,119 178 but optimal duration not established in those with cirrhosis.178 If regimen of sofosbuvir and daclatasvir (without ribavirin) used in patients who cannot receive ribavirin, experts recommend a duration of 24 weeks.119 Referral to an expert (ideally at a liver transplant center) recommended.119

Sofosbuvir in Conjunction with Peginterferon Alfa and Ribavirin
Oral

Treatment-naive without cirrhosis or with compensated cirrhosis (Child-Pugh class A): 400 mg once daily in conjunction with peginterferon alfa and ribavirin for a duration of 12 weeks.1

Sofosbuvir in Conjunction with Ribavirin
Oral

400 mg once daily in conjunction with ribavirin for a duration of 24 weeks;1 consider only in patients who cannot receive peginterferon alfa.1

Sofosbuvir in Conjunction with Simeprevir
Oral

400 mg once daily119 with simeprevir (150 mg once daily with food).119 183 Continue both drugs for 12 or 24 weeks, depending on whether or not patient has compensated cirrhosis (Child-Pugh class A).119 183 (See Table 1.) For patients with compensated cirrhosis, experts state consider adding ribavirin to the 24-week regimen of sofosbuvir and simeprevir.119

Previously treated defined as patients with prior relapses, prior partial response, or prior null response who failed prior interferon-based treatment.183

Table 1. Recommended Treatment Duration of Sofosbuvir in Conjunction with Simeprevir in Adults with HCV Genotype 1 Infection.119183

Patient Type

Duration of Sofosbuvir in Conjunction with Simeprevir

Treatment-naive or previously treated adults (without cirrhosis)

12 weeks

Treatment-naive or previously treated adults (with compensated cirrhosis)

24 weeks

Treatment of Chronic HCV Genotype 2 Infection
Sofosbuvir in Conjunction with Daclatasvir
Oral

Noncirrhotic or with compensated cirrhosis (Child-Pugh class A): Some experts recommend 400 mg once daily in conjunction with daclatasvir (60 mg once daily).119 These experts recommend treatment duration of 12 weeks in those without cirrhosis and a duration of 16–24 weeks in those with compensated cirrhosis.119

Decompensated cirrhosis (Child-Pugh class B or C): Experts recommend 400 mg once daily in conjunction with daclatasvir (60 mg once daily) and ribavirin for a duration of 12 weeks.119 Referral to an expert (ideally at a liver transplant center) recommended.119

Sofosbuvir in Conjunction with Ribavirin
Oral

Treatment-naive or previously treated (i.e., failed interferon-based regimen with or without ribavirin) without cirrhosis or with compensated cirrhosis (Child-Pugh class A): 400 mg once daily in conjunction with ribavirin for a duration of 12 weeks.1

Treatment of Chronic HCV Genotype 3 Infection
Sofosbuvir in Conjunction with Daclatasvir
Oral

Noncirrhotic: 400 mg once daily119 in conjunction with daclatasvir (60 mg once daily) for a duration of 12 weeks.119 178

Compensated cirrhosis (Child-Pugh class A): 400 mg once daily119 in conjunction with daclatasvir (60 mg once daily) and ribavirin.119 178 Usual treatment duration is 12 weeks, but optimal duration not established.178 Experts recommend a duration of 24 weeks and state that use of sofosbuvir and daclatasvir without ribavirin can be considered.119

Decompensated cirrhosis (Child-Pugh class B or C): 400 mg once daily119 in conjunction with daclatasvir (60 mg once daily) and ribavirin.119 178 Usual duration is 12 weeks, but optimal duration not established.178 Referral to an expert (ideally at a liver transplant center) recommended.119

Sofosbuvir in Conjunction with Ribavirin
Oral

Treatment-naive or previously treated (i.e., failed interferon-based regimen with or without ribavirin) without cirrhosis or with compensated cirrhosis (Child-Pugh class A): 400 mg once daily in conjunction with ribavirin for a duration of 24 weeks.1

Treatment of Chronic HCV Genotype 4 Infection
Sofosbuvir in Conjunction with Daclatasvir
Oral

Decompensated cirrhosis (Child-Pugh class B or C): Some experts recommend 400 mg once daily in conjunction with daclatasvir (60 mg once daily) and ribavirin for a duration of 12 weeks.119 If a regimen of daclatasvir and sofosbuvir (without ribavirin) used in patients who cannot receive ribavirin, experts recommend a duration of 24 weeks.119 Referral to an expert (ideally at a liver transplant center) recommended.119

Sofosbuvir in Conjunction with Peginterferon Alfa and Ribavirin
Oral

Treatment-naive without cirrhosis or with compensated cirrhosis: 400 mg once daily in conjunction with peginterferon alfa and ribavirin for a duration of 12 weeks.1

Treatment of Chronic HCV Genotype 5 or 6 Infection
Sofosbuvir in Conjunction with Peginterferon Alfa and Ribavirin
Oral

Manufacturer states data insufficient to make dosage recommendations.1 Experts recommend 400 mg once daily in conjunction with peginterferon alfa and ribavirin for a duration of 12 weeks.119

HCV-infected Coinfected with HIV
Oral

HCV genotype 1, 2, 3, or 4 infection: Generally, use same sofosbuvir dosage and same sofosbuvir multiple-drug treatment regimens and duration of therapy recommended for adults without HIV infection.1 119

HCV-infected with Hepatocellular Carcinoma Awaiting Liver Transplantation
Sofosbuvir in Conjunction with Ribavirin
Oral

Treatment and prevention of post-transplantation HCV reinfection: 400 mg once daily in conjunction with ribavirin for up to 48 weeks or until time of liver transplantation (whichever occurs first).1

Prescribing Limits

Pediatric Patients

Treatment of Chronic HCV Infection
Oral

≥12 years of age weighing ≥35 kg: Maximum 400 mg daily.1

Adults

Treatment of Chronic HCV Infection
Oral

Maximum 400 mg daily.1

Special Populations

Hepatic Impairment

Mild, moderate, or severe hepatic impairment (Child-Pugh class A, B, or C): Dosage adjustments not needed.1

Renal Impairment

Mild or moderate renal impairment: Dosage adjustments not needed.1

Severe renal impairment (estimated GFR <30 mL/minute per 1.73 m2) or end-stage renal disease (ESRD): Dosage recommendations not available;1 safety and efficacy not established in such patients.1 (See Renal Impairment under Cautions.)

Geriatric Patients

Dosage adjustments not needed.1

Cautions for Sofosbuvir

Contraindications

  • Because sofosbuvir must be used in conjunction with other antivirals, consider contraindications for all antivirals included in the multiple-drug regimen.1 (See Precautions Related to Multiple-drug Treatment Regimens under Cautions.)

  • Sofosbuvir used in conjunction with ribavirin or in conjunction with peginterferon alfa and ribavirin is contraindicated in women who are or may become pregnant and in male partners of pregnant women.1 (See Precautions Related to Multiple-drug Treatment Regimens under Cautions.)

Warnings/Precautions

Warnings

Risk of HBV Reactivation in Patients Coinfected with HCV and HBV

Postmarketing reports of reactivation of HBV infection when DAAs were used for treatment of HCV infection in patients with HBV coinfection;1 25 fulminant hepatitis, hepatic failure, and death reported in some cases.1 25

HBV reactivation (abrupt increase in HBV replication manifested as rapid increase in serum HBV DNA levels or detection of HBsAg in an individual who was previously HBsAg negative and anti-HBc positive) reported in patients with HCV and HBV coinfection receiving HCV treatment with a regimen that included HCV DAAs without interferon alfa.1 25 HBV reactivation usually occurred within 4–8 weeks after initiation of HCV treatment.25

Patients with HBV reactivation heterogeneous in terms of HCV genotype and baseline HBV disease.25 Some patients were HBsAg positive; others had serologic evidence of resolved HBV infection (i.e., HBsAg negative and anti-HBc positive).1 25

HBV reactivation also reported in patients receiving certain immunosuppressant or chemotherapeutic drugs;1 risk of reactivation associated with HCV DAAs may be increased in such patients.1

Mechanism for HBV reactivation in coinfected patients receiving HCV DAAs unknown.25 Although HCV DAAs not known to cause immunosuppression, HBV reactivation in coinfected patients may result from a complex interplay of host immunologic responses in the setting of infection with 2 hepatitis viruses.25

Prior to initiating treatment with an HCV DAA, including sofosbuvir, screen all patients for evidence of current or prior HBV infection by measuring HBsAg, anti-HBs, and anti-HBc.1 25 119 If there is serologic evidence of HBV infection, measure baseline HBV DNA level.25 119

In all patients with evidence of current or prior HBV infection, monitor for clinical and laboratory signs (i.e., HBsAg, HBV DNA levels, serum aminotransferase and bilirubin concentrations) of hepatitis flare or HBV reactivation during and after treatment with HCV DAAs.1 25 119 Initiate appropriate management for HBV infection as clinically indicated.1 119

Advise coinfected patients to immediately contact a clinician if they develop any signs or symptoms of serious liver injury.25 (See Advice to Patients.)

When making decisions regarding HBV monitoring or HBV treatment in coinfected patients, consult a clinician with expertise in managing HBV infection.25 119

Other Warnings/Precautions

Cardiovascular Effects

Postmarketing reports of symptomatic bradycardia, including cases requiring pacemaker intervention, in patients receiving amiodarone concomitantly with HCV treatment regimen containing sofosbuvir in conjunction another HCV DAA, including simeprevir, ledipasvir, or an investigational HCV NS5A replication complex inhibitor.1 23 Fatal cardiac arrest reported in a patient receiving amiodarone concomitantly with ledipasvir/sofosbuvir.1

In most reported cases, bradycardia occurred within hours to days after HCV treatment initiated in patients receiving amiodarone (also has been observed up to 2 weeks after initiation of HCV treatment) and resolved after HCV treatment discontinued.1 Mechanism for this adverse cardiovascular effect unknown.1

Patients who may be at increased risk for symptomatic bradycardia if amiodarone used concomitantly with regimen of sofosbuvir with another DAA include those also receiving a β-adrenergic blocking agent, those with underlying cardiac comorbidities, and/or those with advanced liver disease.

Concomitant use of amiodarone and regimen of sofosbuvir with another DAA not recommended.1

If there are no alternative HCV treatment options and regimen of sofosbuvir with another DAA must be used in a patient receiving amiodarone, advise patient about the risk of serious symptomatic bradycardia before initiating HCV treatment.1 Perform cardiac monitoring in an inpatient setting during first 48 hours of concomitant use of amiodarone and regimen of sofosbuvir with another DAA;1 heart rate monitoring should then be performed daily (outpatient or self-monitoring) through at least the first 2 weeks of concomitant use.1 Similar cardiac monitoring recommended in patients who discontinued amiodarone just prior to initiation of sofosbuvir with another DAA or if there are no other treatment options and amiodarone must be initiated in a patient already receiving sofosbuvir with another DAA.1

Advise patients receiving amiodarone concomitantly with regimen of sofosbuvir with another DAA to immediately contact clinician if signs or symptoms of bradycardia (e.g., near-fainting or fainting, dizziness, lightheadedness, malaise, weakness, excessive tiredness, shortness of breath, chest pain, confusion, memory problems) develop.1

Hematologic Effects

Anemia reported.1 In clinical trials, anemia reported in 21% and hemoglobin concentration <10 g/dL reported in 23% of patients who received 12 weeks of sofosbuvir, peginterferon alfa, and ribavirin.1

Interactions

Concomitant use with certain drugs not recommended (e.g., rifampin, St. John's wort).1 (See Specific Drugs under Interactions.)

Precautions Related to Multiple-drug Treatment Regimens

Sofosbuvir must be used in conjunction with other antivirals.1 Consider cautions, precautions, contraindications, and drug interactions associated with each drug in the multiple-drug regimen.1 Consider cautionary information applicable to specific populations (e.g., pregnant or nursing women, individuals with hepatic or renal impairment, geriatric patients) for each drug.1

Do not use concomitantly with ledipasvir/sofosbuvir181 or sofosbuvir/velpatasvir.176

When used in conjunction with ribavirin,1 consider that ribavirin may cause fetal toxicity and/or death.349 377 Extreme care must be taken to avoid pregnancy in female patients and female partners of male patients receiving a ribavirin-containing regimen.349 377 Obtain a negative pregnancy test for female patients of childbearing potential immediately prior to initiating ribavirin;349 377 perform pregnancy tests monthly during and for 6 months after ribavirin treatment is completed.349 377 Women of childbearing potential (and their male partners) and male patients (and their female partners) must use at least 2 forms of effective contraception during and for 6 months after ribavirin treatment is completed.349 377

Specific Populations

Pregnancy

Adequate data regarding use of sofosbuvir in pregnant women not available;1 animal studies did not reveal evidence of fetal harm.1

When used in conjunction with ribavirin,1 consider that ribavirin is contraindicated in pregnant women and male partners of pregnant women.349 377 (See Precautions Related to Multiple-drug Treatment Regimens under Cautions and see Contraindications under Cautions.)

Lactation

Not known whether sofosbuvir or its metabolites distributed into human milk.1 Predominant metabolite (GS-331007) distributed into milk in rats;1 no apparent effects on the nursing pups.1

Consider benefits of breast-feeding and importance of sofosbuvir to the woman;1 also consider potential adverse effects on the breast-fed child from the drug or from underlying maternal condition.1

When used in conjunction with ribavirin,1 consider potential for adverse reactions to ribavirin in nursing infants and discontinue nursing or the ribavirin-containing regimen.349 377 (See Precautions Related to Multiple-drug Treatment Regimens under Cautions.)

Pediatric Use

Safety and efficacy for treatment of HCV genotype 2 or 3 infection not established in pediatric patients <12 years of age or weighing <35 kg.1

Safety and efficacy for treatment of HCV genotype 1 or 4 infection not established in pediatric patients of any age.1

Adverse effects and pharmacokinetics of sofosbuvir in pediatric patients ≥12 years of age with HCV genotype 2 or 3 infection are similar to those in adults.1

Geriatric Use

No clinically important differences in efficacy in patients ≥65 years of age compared with younger adults.1

Hepatic Impairment

Decompensated cirrhosis: Safety and efficacy not established.1

Post-liver transplant patients: Safety and efficacy not established.1

HCV-infected patients with hepatocellular carcinoma awaiting liver transplantation: Safety profile of sofosbuvir used in conjunction with ribavirin is similar to that observed in HCV-infected adults in clinical trials.1

Renal Impairment

Severe renal impairment (estimated GFR <30 mL/minute per 1.73 m2) or ESRD requiring hemodialysis: Safety and efficacy not established.1 Substantially increased plasma concentrations of predominant metabolite (GS-331007).1

Common Adverse Effects

Sofosbuvir in conjunction with ribavirin: Fatigue, headache.1

Sofosbuvir in conjunction with peginterferon alfa and ribavirin: Fatigue, headache, nausea, insomnia, anemia.1

Sofosbuvir in conjunction with simeprevir: Fatigue, headache, nausea, dizziness, diarrhea, insomnia, pruritus, rash.183

Sofosbuvir in conjunction with daclatasvir: Headache,178 fatigue,178 nausea,178 diarrhea,178 insomnia.178

Interactions for Sofosbuvir

Substrate of P-glycoprotein (P-gp) transport system;1 predominant metabolite (GS-331007) not a P-gp substrate.1 Sofosbuvir and GS-331007 do not inhibit P-gp.1

Substrate of breast cancer resistance protein (BCRP);1 GS-331007 is not a BCRP substrate.1 Sofosbuvir and GS-331007 do not inhibit BCRP.1

Drugs Affecting P-glycoprotein Transport System

P-gp inducers: Possible decreased sofosbuvir plasma concentrations leading to reduced therapeutic effect.1

Drugs Affecting Breast Cancer Resistance Protein

BCRP inhibitors: Possible increased sofosbuvir plasma concentrations without increase in plasma concentrations of GS-331007.1

Specific Drugs

Drug

Interaction

Comments

Antiarrhythmic agents (amiodarone)

Amiodarone: Concomitant use with regimen containing sofosbuvir in conjunction with another DAA (e.g., ledipasvir, simeprevir) may result in serious symptomatic bradycardia1 23 (mechanism unknown);1 effect on amiodarone and sofosbuvir concentrations unknown1

Amiodarone: Concomitant use with regimen containing sofosbuvir with another DAA not recommended;1 if concomitant use required, patient counseling and cardiac monitoring required 1 (see Cardiovascular Effects under Cautions)

Anticonvulsants (e.g., carbamazepine, oxcarbazepine, phenobarbital, phenytoin)

Decreased sofosbuvir concentrations expected;1 may result in decreased therapeutic effect1

Concomitant use not recommended1

Antimycobacterial agents (e.g., rifabutin, rifampin, rifapentine)

Rifabutin, rifampin, rifapentine: Decreased sofosbuvir concentrations expected; may result in decreased therapeutic effect1

Rifabutin, rifampin, rifapentine: Concomitant use not recommended1

Atazanavir

Elevated total bilirubin in 94% of HCV patients coinfected with HIV receiving atazanavir and other antiretrovirals, but in only 1.5% of those not receiving atazanavir1

Daclatasvir

No clinically important changes in daclatasvir pharmacokinetics178

Dolutegravir

Clinically important pharmacokinetic interactions not expected200

Dosage adjustments not needed200

Darunavir

Ritonavir-boosted darunavir: No clinically important pharmacokinetic interactions1

Dosage adjustments not needed for either drug1

Efavirenz

No clinically important pharmacokinetic interactions1

Dosage adjustments not needed for either drug1

Elbasvir and grazoprevir

Fixed combination of elbasvir and grazoprevir (elbasvir/grazoprevir): No clinically important pharmacokinetic interactions177

Dosage adjustments not needed177

Elvitegravir

Elvitegravir: Clinically important pharmacokinetic interactions not expected200

Fixed combination of elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide (EVG/c/FTC/TAF): Clinically important interactions not expected243

Dosage adjustments not needed200

Emtricitabine

No clinically important pharmacokinetic interactions1

Dosage adjustments not needed for either drug1

Estrogens/progestins

Oral contraceptive containing ethinyl estradiol and norgestimate: No clinically important effects on pharmacokinetics of ethinyl estradiol or norgestimate and its active metabolites (norelgestromin, norgestrel) when used concomitantly with sofosbuvir;1 13 efficacy of the oral contraceptive not expected to be affected13

Oral contraceptives containing ethinyl estradiol and norgestimate: Dosage adjustments not needed for either drug1

Immunosuppressants (cyclosporine, tacrolimus)

Cyclosporine: Increased sofosbuvir exposure1

Tacrolimus: No clinically important pharmacokinetic interaction1

Cyclosporine, tacrolimus: Dosage adjustments not needed for either drug1

Interferon alfa

No in vitro evidence of antagonistic anti-HCV effects1

Maraviroc

Clinically important pharmacokinetic interactions not expected200

Use maraviroc dosage of 300 mg twice daily in patients receiving sofosbuvir200

Methadone

No clinically important pharmacokinetic interactions1

Dosage adjustments not needed for either drug1

Raltegravir

No clinically important pharmacokinetic interactions1

Dosage adjustments not needed for either drug1 200

Ribavirin

No in vitro evidence of antagonistic anti-HCV effects1

Rilpivirine

No clinically important pharmacokinetic interactions1

Dosage adjustments not needed for either drug1

Simeprevir

Slightly increased sofosbuvir concentrations and AUC;183 no clinically important effect on simeprevir pharmacokinetics183

No in vitro evidence of antagonistic anti-HCV effects between simeprevir and NS5B polymerase inhibitors183

Dosage adjustments not needed for either drug183

St. John's wort (Hypericum perforatum)

Possible decreased sofosbuvir concentrations;1 may result in decreased therapeutic effect1

Do not use concomitantly1

Tenofovir

Tenofovir disoproxil fumarate: No clinically important pharmacokinetic interactions1

Tenofovir disoproxil fumarate: Dosage adjustments not needed for either drug1

Tipranavir

Ritonavir-boosted tipranavir: Decreased sofosbuvir concentrations expected;1 may result in decreased therapeutic effect1

Ritonavir-boosted tipranavir: Concomitant use not recommended1

Warfarin

Subtherapeutic INR reported after initiation of sofosbuvir-containing regimens in patients receiving warfarin26 27 28

Closely monitor INR when initiating or discontinuing sofosbuvir-containing regimens26 27 28

Sofosbuvir Pharmacokinetics

Absorption

Bioavailability

Following oral administration, peak plasma concentrations of sofosbuvir and predominant metabolite (GS-331007) occur approximately 0.5–2 and 2–4 hours, respectively, after a dose.1

Sofosbuvir and GS-331007 account for approximately 4 and 90% of systemic exposure, respectively, after a single 400-mg dose.1

Food

High-fat meal does not substantially affect sofosbuvir or GS-331007 peak plasma concentrations or AUC relative to fasting state.1

Special Populations

Compared with healthy individuals receiving sofosbuvir alone, sofosbuvir AUC is 39% higher and GS-331007 AUC is 39% lower in HCV-infected individuals.1

In patients with moderate or severe hepatic impairment (Child-Pugh class B or C), sofosbuvir AUC is 126 or 143% higher, respectively, compared with patients with normal hepatic function; GS-331007 AUC is 18 or 9% higher, respectively.1 Population pharmacokinetics analysis in HCV-infected patients indicates that cirrhosis does not substantially affect sofosbuvir or GS-331007 exposure.1

In patients with mild, moderate, or severe renal impairment, sofosbuvir AUC is 61, 107, or 171% higher, respectively, compared with patients with normal renal function;1 GS-331007 AUC is 55, 88, or 451% higher, respectively.1

Pharmacokinetics in pediatric patients ≥12 years of age with HCV genotype 2 or 3 infection similar to adults.1

Population pharmacokinetic analysis indicates age (range 19–75 years), race, and gender do not have clinically important effects on sofosbuvir pharmacokinetics.1

Distribution

Plasma Protein Binding

Sofosbuvir: Approximately 61–65%.1

GS-331007: Minimal protein binding.1

Elimination

Metabolism

Sofosbuvir is a prodrug.1 Undergoes intracellular metabolic activation in the liver (hydrolysis by human cathepsin A [CatA] or carboxylesterase 1 [CES1], phosphoramidate cleavage by histidine triad nucleotide-binding protein 1 [HINT1], and phosphorylation by pyrimidine nucleotide biosynthesis pathway).1 7 Results in formation of pharmacologically active metabolite, GS-461203.1

Desphosphorylation subsequently occurs leading to formation of GS-331007 (the predominant circulating metabolite) which has no anti-HCV activity.1

Elimination Route

Eliminated in urine (80%, mainly as GS-331007), in feces (14%), and in expired air (2.5%).1

Half-life

Sofosbuvir: 0.4 hours.1

GS-331007: 27 hours.1

Special Populations

Hemodialysis (4-hour session) removes approximately 18% of dose.1

Stability

Storage

Oral

Film-coated Tablets

Room temperature <30ºC.1

Dispense only in original container.1

Actions and Spectrum

  • Nucleotide analog HCV NS5B polymerase inhibitor.1 Direct-acting antiviral (DAA) with activity against HCV.1

  • Sofosbuvir is a prodrug that undergoes metabolic activation in the liver to a pharmacologically active uridine analog triphosphate (GS-461203), which can be incorporated into HCV RNA by NS5B polymerase; acts as RNA chain terminator.1

  • In vitro studies using biochemical and cell-based replicon assays indicate GS-461203 has activity against HCV genotypes 1a, 1b, 2a, 2b, 3a, 4a, 5a, and 6a.1

  • Certain amino acid substitutions in NS5B polymerase (e.g., S282T) of HCV genotypes 1b, 2a, 2b, 3a, 4a, 5a, and 6a have been selected in cell culture and have been associated with reduced susceptibility to sofosbuvir in vitro in replicon studies.1 Treatment-emergent amino acid substitutions were detected in clinical trials (e.g., L159F, S282T, V321A); clinical importance not known.1

  • In replicon studies, the S282T substitution associated with reduced susceptibility to sofosbuvir did not affect susceptibility to ribavirin or HCV NS5A inhibitors.1 In addition, sofosbuvir was active against HCV replicons with substitutions associated with resistance to other drugs (e.g., ribavirin, HCV NS3/4A protease inhibitors).1

Advice to Patients

  • Importance of using sofosbuvir in conjunction with other antivirals;1 do not use alone.1

  • Advise patient not to reduce sofosbuvir dosage;1 if other antivirals in the multiple-drug regimen discontinued for any reason, sofosbuvir also should be discontinued.1

  • Sofosbuvir may be taken with or without food.1

  • Inform patients that reactivation of HBV infection has occurred in coinfected patients being treated for HCV infection.1 25 Importance of informing clinician of any history of HBV infection or other liver problems (e.g., cirrhosis).1 25 Importance of immediately contacting a clinician if any signs or symptoms of serious liver injury (e.g., fatigue, weakness, loss of appetite, nausea and vomiting, yellowing of the eyes or skin, light-colored bowel movements) occur.25 (See Risk of HBV Reactivation in Patients Coinfected with HCV and HBV under Cautions.)

  • If regimen containing sofosbuvir with another DAA is used in a patient receiving amiodarone, advise patient about the risk of serious symptomatic bradycardia and importance of immediately contacting clinician if signs or symptoms of bradycardia (e.g., near-fainting or fainting, dizziness, lightheadedness, malaise, weakness, excessive tiredness, shortness of breath, chest pain, confusion, memory problems) occur.1 (See Cardiovascular Effects under Cautions.)

  • Inform patients that the effect of HCV treatment on transmission of HCV unknown;1 patients should take appropriate precautions to prevent transmission of the virus during treatment or in the event of treatment failure.1

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.1

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1 If used in multiple-drug regimen that includes ribavirin, advise men and women of importance of using 2 forms of effective contraception during and for 6 months after ribavirin therapy.1 (See Precautions Related to Multiple-drug Treatment Regimens under Cautions.)

  • Importance of informing patients of other important precautionary information. (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Sofosbuvir

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets, film-coated

400 mg

Sovaldi

Gilead

Sofosbuvir Combinations

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets, film-coated

400 mg with Ledipasvir 90 mg

Harvoni

Gilead

Tablets, film-coated

400 mg with Velpatasvir 100 mg

Epclusa

Gilead

AHFS DI Essentials. © Copyright 2017, Selected Revisions October 9, 2017. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References

1. Gilead Sciences, Inc. Sovaldi (sofosbuvir) tablets prescribing information. Foster City, CA; 2017 Apr.

2. Lawitz E, Mangia A, Wyles D et al. Sofosbuvir for previously untreated chronic hepatitis C infection. N Engl J Med. 2013; 368:1878-87. [PubMed 23607594]

3. Gilead Sciences, Inc. A phase 3, multicenter, open-label study to investigate the efficacy and safety of GS-7977 with peginterferon alfa 2a and ribavirin for 12 weeks in treatment-naïve subjects with chronic genotype 1, 4, 5, or 6 HCV infection . Protocol No. GS-US-334-0110. Foster City, CA: Gilead Sciences, Inc.; 2012.

4. Pharmasset, Inc. A multicenter, blinded, randomized, placebo-controlled, study to investigate the safety and efficacy of PSI-7977 in combination with pegylated interferon and ribavirin for 12 weeks compared to pegylated interferon and ribavirin for 24 weeks in treatment-naive patients with chronic genotype 2 or 3 HCV infection . Protocol No. P7977-1231. Princeton, NJ: Pharmasset, Inc.; 2011.

5. Jacobson IM, Gordon SC, Kowdley KV et al. Sofosbuvir for hepatitis C genotype 2 or 3 in patients without treatment options. N Engl J Med. 2013; 368:1867-77. [PubMed 23607593]

6. Pineda JA, Aguilar-Guisado M, Rivero A et al. Natural history of compensated hepatitis C virus-related in HIV-infected patients. Clin Infect Dis. 2009; 49:1274-82. [PubMed 19772387]

7. Murakami E, Tolstykh T, Bao H et al. Mechanism of activation of PSI-7851 and its diastereoisomer PSI-7977. J Biol Chem. 2010; 285:34337-47. [PubMed 20801890]

8. Poordad F, Schiff ER, Vierling JM et al. Daclatasvir With Sofosbuvir and Ribavirin for HCV Infection With Advanced Cirrhosis or Post-Liver Transplant Recurrence. Hepatology. 2016; :. [PubMed 26754432]

9. Wyles DL, Ruane PJ, Sulkowski MS et al. Daclatasvir plus Sofosbuvir for HCV in Patients Coinfected with HIV-1. N Engl J Med. 2015; 373:714-25. [PubMed 26196502]

10. Nelson DR, Cooper JN, Lalezari JP et al. All-oral 12-week treatment with daclatasvir plus sofosbuvir in patients with hepatitis C virus genotype 3 infection: ALLY-3 phase III study. Hepatology. 2015; 61:1127-35. [PubMed 25614962]

11. Zeuzem S, Dusheiko GM, Salupere R et al. Sofosbuvir and ribavirin in HCV genotypes 2 and 3. N Engl J Med. 2014; 370:1993-2001. [PubMed 24795201]

12. Lawitz E, Sulkowski MS, Ghalib R et al. Simeprevir plus sofosbuvir, with or without ribavirin, to treat chronic infection with hepatitis C virus genotype 1 in non-responders to pegylated interferon and ribavirin and treatment-naive patients: the COSMOS randomised study. Lancet. 2014; 384:1756-65. [PubMed 25078309]

13. German P, Moorehead L, Pang P et al. Lack of a clinically important pharmacokinetic interaction between sofosbuvir or ledipasvir and hormonal oral contraceptives norgestimate/ethinyl estradiol in HCV-uninfected female subjects. J Clin Pharmacol. 2014; 54:1290-8. [PubMed 24925712]

14. Mangia A, Arleo A, Copetti M et al. The combination of daclatasvir and sofosbuvir for curing genotype 2 patients who cannot tolerate ribavirin. Liver Int. 2016; :. [PubMed 26786792]

15. Kwo P, Gitlin N, Nahass R et al. Simeprevir plus sofosbuvir (12 and 8 weeks) in hepatitis C virus genotype 1-infected patients without cirrhosis: OPTIMIST-1, a phase 3, randomized study. Hepatology. 2016; 64:370-80. [PubMed 26799692]

16. Lawitz E, Matusow G, DeJesus E et al. Simeprevir plus sofosbuvir in patients with chronic hepatitis C virus genotype 1 infection and cirrhosis: A phase 3 study (OPTIMIST-2). Hepatology. 2016; 64:360-9. [PubMed 26704148]

20. Genentech. Pegasys (peginterferon alfa-2a) injection for subcutaneous use prescribing information. South San Francisco, CA; 2013 Jul.

21. Sulkowski MS, Naggie S, Lalezari J et al. Sofosbuvir and ribavirin for hepatitis C in patients with HIV coinfection. JAMA. 2014 Jul 23-30; 312:353-61.

22. Molina JM, Orkin C, Iser DM et al. Sofosbuvir plus ribavirin for treatment of hepatitis C virus in patients co-infected with HIV (PHOTON-2): a multicentre, open-label, non-randomised, phase 3 study. Lancet. 2015; 385:1098-106. [PubMed 25659285]

23. US Food and Drug Administration. FDA drug safety communication: FDA warns of serious slowing of the heart rate when antiarrhythmic drug amiodarone is used with hepatitis C treatments containing sofosbuvir (Harvoni) or Sovaldi in combination with another direct acting antiviral. 2015 Mar 24. From FDA website.

25. US Food and Drug Administration. FDA drug safety communication: FDA warns about the risk of hepatitis B reactivating in some patients treated with direct-acting antivirals for hepatitis C. 2016 Oct 4. From FDA website.

26. Britnell SR, Willets AE, Vanderman AJ et al. Influence of Successful Chronic Hepatitis C Virus Treatment with Ledipasvir/Sofosbuvir on Warfarin Dosing Requirements in Four Veterans. Pharmacotherapy. 2016; 36:1173-1179. [PubMed 27716978]

27. DeCarolis DD, Westanmo AD, Chen YC et al. Evaluation of a Potential Interaction Between New Regimens to Treat Hepatitis C and Warfarin. Ann Pharmacother. 2016; 50:909-917. [PubMed 27465881]

28. Peterson D, Van Ermen A. Increased warfarin requirements in a patient with chronic hepatitis C infection receiving sofosbuvir and ribavirin. Am J Health Syst Pharm. 2017; 74:888-892. [PubMed 28596225]

119. American Association for the Study of Liver Diseases (AASLD). Recommendations for testing, managing, and treating hepatitis C. From the AASLD website. Accessed 2017 May 8.

176. Gilead Sciences. Epclusa (sofosbuvir and velpatasvir) tablets prescribing information. Foster City, CA; 2017 Feb.

177. Merck & Co., Inc. Zepatier (elbasvir and grazoprevir) tablets prescribing information. Whitehouse Station, NJ; 2017 Feb.

178. Bristol-Myers Squibb. Daklinza (daclatasvir) tablets prescribing information. Princeton, NJ. 2017 Feb.

181. Gilead Sciences, Inc. Harvoni (ledipasvir and sofosbuvir) tablets prescribing information. Foster City, CA; 2017 Apr.

183. Janssen. Olysio (simeprevir) capsules prescribing information. Titusville, NJ; 2017 May.

200. Panel on Antiretroviral Guidelines for Adults and Adolescents, US Department of Health and Human Services (HHS). Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents (July 14, 2016). Updates may be available at HHS AIDS Information (AIDSinfo) website.

243. Gilead Sciences. Genvoya (elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide) tablets prescribing information. Foster City, CA; 2017 Apr.

349. Merck Sharp & Dohme Corporation. Rebetol (ribavirin) capsules and oral solution prescribing information. Whitehouse Station, NJ; 2013 Nov.

377. Genentech. Copegus (ribavirin) tablets prescribing information. South San Francisco, CA; 2013 Feb.

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