Sofosbuvir (Monograph)

Brand name: Sovaldi
Drug 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

Medically reviewed by Drugs.com on Jan 23, 2024. Written by ASHP.

Introduction

Antiviral; nucleotide analog HCV NS5B polymerase inhibitor.

Uses for Sofosbuvir

Chronic HCV Infection

Treatment of chronic HCV genotype 1, 2, 3, or 4 infection in treatment-naive (have not previously received HCV treatment) or previously treated adults without cirrhosis or with compensated cirrhosis (Child-Pugh class A), including those with HIV coinfection and those with hepatocellular carcinoma awaiting liver transplantation.

Treatment of chronic HCV genotype 2 or 3 infection in treatment-naive or previously treated pediatric patients ≥3 years of age without cirrhosis or with compensated cirrhosis (Child-Pugh class A).

Single-entity sofosbuvir must be used in conjunction with other antivirals; do not use alone.

Single-entity sofosbuvir usually used in multiple-drug regimen that includes sofosbuvir and ribavirin (with or without peginterferon alfa).

Fixed combination of ledipasvir and sofosbuvir (ledipasvir/sofosbuvir), fixed combination of sofosbuvir and velpatasvir (sofosbuvir/velpatasvir), and fixed combination of sofosbuvir, velpatasvir, and voxilaprevir (sofosbuvir/velpatasvir/voxilaprevir) also commercially available.

Treatment of chronic HCV infection is complex and rapidly evolving; consult a specialist to obtain the most up-to-date information. Information from the American Association for the Study of Liver Diseases (AASLD) and IDSA regarding diagnosis and management of HCV infection, including recommendations for initial treatment, is available at [Web].

Related/similar drugs

Harvoni, Vosevi, Epclusa, Mavyret, ribavirin, Sovaldi

Sofosbuvir Dosage and Administration

General

Pretreatment Screening

• 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).

• In patients with serologic evidence of HBV infection, measure baseline HBV DNA level.

• When sofosbuvir is used in conjunction with ribavirin or in conjunction with peginterferon alfa and ribavirin, women of childbearing potential should have a negative pregnancy test immediately prior to initiating ribavirin therapy; perform pregnancy tests periodically during and for 6 months after completion of ribavirin therapy.

Patient Monitoring

• Patients with evidence of current or prior HBV infection: Monitor for clinical and laboratory signs (i.e., HBsAg, HBV DNA levels, serum aminotransferase concentrations, bilirubin concentrations) of hepatitis flare or HBV reactivation during and after treatment with HCV DAAs, including sofosbuvir.

• If amiodarone is used concomitantly with a regimen containing sofosbuvir and another DAA, perform cardiac monitoring in an inpatient setting during the first 48 hours of concomitant use; perform heart rate monitoring daily (outpatient or self-monitoring) through at least the first 2 weeks of concomitant use. Similar cardiac monitoring is recommended in patients who discontinue amiodarone just prior to initiation of a regimen containing sofosbuvir with another DAA.

Other General Considerations

• Single-entity sofosbuvir must be used in conjunction with other antivirals; do not use alone.

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

• Do not reduce sofosbuvir dosage for any reason.

• 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. If other antivirals in the multiple-drug regimen are discontinued for any reason, sofosbuvir also should be discontinued.

Administration

Oral Administration

Administer orally with or without food.

Available as film-coated tablets and pellets for oral administration; use the pellets in pediatric patients who cannot swallow tablets.

Sofosbuvir pellets taken with food: Add one or more spoonfuls of nonacidic soft food at or below room temperature (e.g., pudding, chocolate syrup, mashed potato, ice cream) to a bowl; sprinkle entire contents of the appropriate number of single-dose packets of pellets (see Table 1) onto the food and gently mix with a spoon. Ensure that no pellets remain in the packet(s). Ingest entire mixture containing the pellets within 30 minutes after preparation; swallow pellets in the mixture whole without chewing to avoid a bitter aftertaste.

Sofosbuvir pellets taken without food: Pour entire contents of single-dose packet of pellets directly into the mouth and swallow pellets without chewing to avoid a bitter aftertaste. May drink water after swallowing the pellets, if needed. If 2 packets of pellets are indicated (see Table 1), repeat the process. Ensure that no pellets remain in the packet(s).

Dosage

Pediatric Patients

Treatment of Chronic HCV Genotype 2 or 3 Infection

Sofosbuvir in Conjunction with Ribavirin

Oral

Treatment-naive or previously treated (defined as failed interferon-based regimen with or without ribavirin) pediatric patients ≥3 years of age without cirrhosis or with compensated cirrhosis (Child-Pugh class A): Dosage based on weight. (See Table 1.)

Treatment duration depends on HCV genotype. (See Table 2.)

Adults

Treatment of Chronic HCV Genotype 1 Infection

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 treatment duration of 12 weeks.

Sofosbuvir in Conjunction with Ribavirin

Oral

Treatment-naive without cirrhosis or with compensated cirrhosis (Child-Pugh class A): 400 mg once daily in conjunction with ribavirin for a treatment duration of 24 weeks; consider only in patients who cannot receive peginterferon alfa.

Treatment of Chronic HCV Genotype 2 Infection

Sofosbuvir in Conjunction with Ribavirin

Oral

Treatment-naive or previously treated (defined as 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 treatment duration of 12 weeks.

Treatment of Chronic HCV Genotype 3 Infection

Sofosbuvir in Conjunction with Ribavirin

Oral

Treatment-naive or previously treated (defined as 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 treatment duration of 24 weeks.

Treatment of Chronic HCV Genotype 4 Infection

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 treatment duration of 12 weeks.

HCV-infected Coinfected with HIV

Oral

HCV genotype 1, 2, 3, or 4 infection: Use same sofosbuvir dosage and same sofosbuvir multiple-drug treatment regimen and duration recommended for adults without HIV infection.

HCV-infected with Hepatocellular Carcinoma Awaiting Liver Transplantation

Sofosbuvir in Conjunction with Ribavirin

Oral

Treatment of chronic HCV infection 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).

Special Populations

Hepatic Impairment

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

Renal Impairment

Mild or moderate renal impairment: Dosage adjustments not needed.

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

Geriatric Patients

Dosage adjustments not needed.

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. (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. (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 HCV DAAs were used for treatment of HCV infection in patients with HBV coinfection; fulminant hepatitis, hepatic failure, and death reported in some cases.

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. HBV reactivation usually occurred within 4–8 weeks after initiation of HCV treatment.

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

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

Mechanism for HBV reactivation in coinfected patients receiving HCV DAAs unknown. 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.

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. If there is serologic evidence of HBV infection, measure baseline HBV DNA level.

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. Initiate appropriate management for HBV infection as clinically indicated.

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

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 (no longer available in US), ledipasvir, or an investigational HCV NS5A replication complex inhibitor. Fatal cardiac arrest reported in a patient receiving amiodarone concomitantly with ledipasvir/sofosbuvir.

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. Mechanism for this adverse cardiovascular effect unknown.

Patients who may be at increased risk for symptomatic bradycardia if amiodarone used concomitantly with regimen of sofosbuvir with another HCV 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 HCV DAA not recommended.

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

Advise patients receiving amiodarone concomitantly with regimen of sofosbuvir with another HCV 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.

Hematologic Effects

Anemia reported. 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.

Interactions

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

Precautions Related to Multiple-drug Treatment Regimens

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

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

Specific Populations

Pregnancy

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

When used in conjunction with ribavirin, consider that ribavirin is contraindicated in pregnant women and male partners of pregnant women. (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. Predominant metabolite (GS-331007) distributed into milk in rats; no apparent effects on the nursing pups.

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

When used in conjunction with ribavirin, consider potential for adverse reactions to ribavirin in nursing infants and discontinue nursing or the ribavirin-containing regimen. (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 <3 years of age.

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

Safety, efficacy, and pharmacokinetics of sofosbuvir in pediatric patients ≥3 years of age with HCV genotype 2 or 3 infection established in an open-label clinical study. Safety, efficacy, and pharmacokinetics of the drug in pediatric patients ≥3 years of age comparable to those in adults.

Safety and efficacy of sofosbuvir for treatment of HCV genotype 2 or 3 infection in pediatric patients ≥3 years of age with compensated cirrhosis are supported by data indicating that sofosbuvir and GS-331007 exposures in pediatric patients are comparable to those in adults and that such exposures in adults without cirrhosis are comparable to those in adults with compensated cirrhosis. Therefore, efficacy in pediatric patients with compensated cirrhosis is expected to be similar to that in adults with compensated cirrhosis.

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

Geriatric Use

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

Hepatic Impairment

Decompensated cirrhosis: Safety and efficacy not established.

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

HCV-infected adults 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.

Renal Impairment

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

Common Adverse Effects

Sofosbuvir in conjunction with ribavirin (≥20%): Fatigue, headache, decreased appetite.

Sofosbuvir in conjunction with peginterferon alfa and ribavirin (≥20%): Fatigue, headache, nausea, insomnia, anemia.

Drug Interactions

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

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

Drugs Affecting P-glycoprotein Transport System

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

Drugs Affecting Breast Cancer Resistance Protein

BCRP inhibitors: Possible increased sofosbuvir plasma concentrations without increase in plasma concentrations of GS-331007.

Specific Drugs

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.

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

Food

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

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.

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. Population pharmacokinetics analysis in HCV-infected patients indicates that cirrhosis does not substantially affect sofosbuvir or GS-331007 exposure.

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; GS-331007 AUC is 55, 88, or 451% higher, respectively.

Pharmacokinetics in pediatric patients ≥3 years of age with HCV genotype 2 or 3 infection similar to those in adults. Pharmacokinetics not established in pediatric patients <3 years of age.

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

Distribution

Plasma Protein Binding

Sofosbuvir: Approximately 61–65%.

GS-331007: Minimal protein binding.

Elimination

Metabolism

Sofosbuvir is a prodrug. 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). Results in formation of pharmacologically active metabolite, GS-461203.

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

Elimination Route

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

Half-life

Sofosbuvir: 0.4 hours.

GS-331007: 27 hours.

Special Populations

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

Stability

Storage

Oral

Film-coated Tablets

Room temperature <30ºC.

Dispense only in original container.

Pellets

Single-use packets: Room temperature <30ºC.

After mixing with soft food, use within 30 minutes; do not store or use any leftover mixture. (See Administration under Dosage and Administration.)

Actions and Spectrum

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

• 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.

• 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.

• 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. Treatment-emergent amino acid substitutions were detected in clinical trials (e.g., L159F, S282T, V321A); clinical importance not known.

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

Advice to Patients

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

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

• Sofosbuvir may be taken with or without food.

• Inform patients that reactivation of HBV infection has occurred in coinfected patients being treated for HCV infection. Importance of informing clinician of any history of HBV infection or other liver problems (e.g., cirrhosis). 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. (See Risk of HBV Reactivation in Patients Coinfected with HCV and HBV under Cautions.)

• If regimen containing sofosbuvir with another HCV 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. (See Cardiovascular Effects under Cautions.)

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

• 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.

• Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed. If used in multiple-drug regimen that includes ribavirin, advise men and women of importance of using effective contraception during and for 6 months after ribavirin therapy. (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.

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Frequently asked questions

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