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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)

Special Alerts:

[Posted 10/04/2016]

AUDIENCE: Infectious Disease, Gastroenterology, Patient

ISSUE: The FDA is warning about the risk of hepatitis B virus (HBV) becoming an active infection again in any patient who has a current or previous infection with HBV and is treated with certain direct-acting antiviral (DAA) medicines for hepatitis C virus. In a few cases, HBV reactivation in patients treated with DAA medicines resulted in serious liver problems or death. HBV reactivation usually occurred within 4-8 weeks.

As a result, FDA is requiring a Boxed Warning, our most prominent warning, about the risk of HBV reactivation to be added to the drug labels of these DAAs directing health care professionals to screen and monitor for HBV in all patients receiving DAA treatment. This warning will also be included in the patient information leaflet or Medication Guides for these medicines.

BACKGROUND: Direct-acting antiviral medicines are used to treat chronic hepatitis C virus (HCV) infection, an infection that can last a lifetime. These medicines reduce the amount of HCV in the body by preventing HCV from multiplying, and in most cases, they cure HCV. Without treatment, HCV can lead to serious liver problems including cirrhosis, liver cancer, and death (see List of Direct-Acting Antivirals in the FDA Drug Safety Communication, available at: ).

FDA identified 24 cases of HBV reactivation reported to FDA and from the published literature in HCV/HBV co-infected patients treated with DAAs during the 31 months from November 22, 2013 to July 18, 2016. This number includes only cases submitted to FDA, so there are likely additional cases about which FDA is unaware. Of the cases reported, two patients died and one required a liver transplant. HBV reactivation was not reported as an adverse event in the clinical trials submitted for the DAA approvals because patients with HBV co-infection were excluded from the trials. See the data summary section in the Drug Safety Communication, available at: , for more detailed information.

RECOMMENDATION: Health care professionals should screen all patients for evidence of current or prior HBV infection before starting treatment with DAAs, and monitor patients using blood tests for HBV flare-ups or reactivation during treatment and post-treatment follow-up.

Patients should tell your health care professional if you have a history of hepatitis B infection or other liver problems before being treated for hepatitis C. Do not stop taking your DAA medicine without first talking to your health care professional. Stopping treatment early could result in your virus becoming less responsive to certain hepatitis C medicines. Read the patient information leaflet or Medication Guide that comes with each new prescription because the information may have changed. Contact your health care professional immediately if you develop fatigue, weakness, loss of appetite, nausea and vomiting, yellow eyes or skin, or light-colored stools, as these may be signs of serious liver problems.

For more information visit the FDA website at: and .

Introduction

Antiviral;1 nucleotide analog HCV NS5B polymerase inhibitor.1

Uses for Sofosbuvir

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Chronic HCV Infection

Treatment of chronic HCV genotype 1, 2, 3, or 4 infection in adults, including those with HIV coinfection and those with hepatocellular carcinoma awaiting liver transplantation.1 119

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,12 119 183 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

  • 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

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Oral Administration

Administer orally without regard to food.1

If a sofosbuvir dose is missed, take it the same day as soon as remembered and then resume regular dosing schedule the next day.1 Do not take more than a single 400-mg dose on any calendar day.1

Dosage

Adults

Treatment of Chronic HCV Genotype 1 Infection
Sofosbuvir in Conjunction with Peginterferon Alfa and Ribavirin
Oral

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 patient has cirrhosis.119 183 (See Table 1.)

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

Sofosbuvir in Conjunction with Daclatasvir
Oral

Noncirrhotic: 400 mg once daily119 in conjunction with daclatasvir (60 mg once daily).119 178 Continue both drugs for 12 weeks.178

Compensated cirrhosis (Child-Pugh class A): 400 mg once daily119 in conjunction with daclatasvir (60 mg once daily).119 178 Continue both drugs for 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 decompensated cirrhosis (Child-Pugh class C).178 Experts recommend a duration of 24 weeks if sofosbuvir used in conjunction with daclatasvir (without ribavirin) in patients who cannot receive ribavirin.119

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

400 mg once daily in conjunction with ribavirin for a duration of 12 weeks.1 Experts recommend a duration of 12 weeks in those without cirrhosis and a duration of 16–24 weeks in those with compensated cirrhosis.119

Sofosbuvir in Conjunction with Daclatasvir
Oral

Noncirrhotic or with compensated cirrhosis who cannot receive ribavirin: 400 mg once daily in conjunction with daclatasvir (60 mg once daily).119 Experts recommend a 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): 400 mg once daily in conjunction with daclatasvir (60 mg once daily) and ribavirin for 12 week.119 Referral to an expert (ideally at a liver transplant center) recommended.119

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

400 mg once daily in conjunction with ribavirin for a duration of 24 weeks.1

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 duration is 12 weeks,178 but optimal duration not established.119 178 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,178 but optimal duration not established.119 178 Referral to an expert (ideally at a liver transplant center) recommended.119

Treatment of Chronic HCV Genotype 4 Infection
Sofosbuvir in Conjunction with Peginterferon Alfa and Ribavirin
Oral

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

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

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

  • 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

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 direct-acting antiviral (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 any other preparation containing sofosbuvir,1 including 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

Category B (sofosbuvir; not indicated for monotherapy).1

No adequate and well-controlled studies using sofosbuvir in pregnant women;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 and metabolites distributed into human milk.1 Predominant metabolite (GS-331007) distributed into milk in rats.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 not established in pediatric patients <18 years of age.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

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

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

Elvitegravir: 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

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

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

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

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

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

  • 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

  • If a dose of sofosbuvir is missed, advise patient to take it later in the day as soon as it is remembered and then resume regular dosing schedule the next day; do not take more than a single 400-mg dose of sofosbuvir on any calendar day.1

  • 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, 2016, American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

Date published: August 05, 2014
Last reviewed: October 12, 2016
Date modified: November 09, 2016

References

1. Gilead Sciences, Inc. Sovaldi (sofosbuvir) tablets prescribing information. Foster City, CA; 2015 Aug.

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]

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. [PubMed 25038354]

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.

119. American Association for the Study of Liver Diseases (AASLD). Recommendations for testing, managing, and treating hepatitis C. From the AASLD website. Accessed 2016 Jun 30.

176. Gilead Sciences. Epclusa (sofosbuvir and velpatasvir) tablets prescribing information. Foster City, CA; 2016 Jun.

178. Bristol-Myers Squibb. Daklinza (daclatasvir) tablets prescribing information. Princeton, NJ. 2016 Apr.

181. Gilead Sciences, Inc. Harvoni (ledipasvir and sofosbuvir) tablets prescribing information. Foster City, CA; 2016 Feb.

183. Janssen. Olysio (simeprevir) capsules prescribing information. Titusville, NJ; 2016 Feb.

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 (January 28, 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; 2016 Mar.

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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