Sofosbuvir and Velpatasvir (Monograph)

Brand name: Epclusa
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: C₂₂H₂₉FN₃O₉PC₄₉H₅₄N₈O₈
CAS number: 1190307-88-0

Medically reviewed by Drugs.com on Aug 19, 2024. Written by ASHP.

Introduction

HCV antiviral; fixed combination containing sofosbuvir (nucleotide analog HCV NS5B polymerase inhibitor) and velpatasvir (HCV NS5A replication complex inhibitor [NS5A inhibitor]).

Uses for Sofosbuvir and Velpatasvir

Chronic HCV Infection

Treatment of chronic HCV genotype 1, 2, 3, 4, 5, or 6 infection in adults and pediatric patients ≥3 years of age without cirrhosis or with compensated or decompensated cirrhosis (Child-Pugh class A, B, or C), including those with HIV coinfection and those who have undergone liver transplantation.

Used alone for treatment of chronic HCV infection in patients without cirrhosis or with compensated cirrhosis (Child-Pugh class A); used in conjunction with ribavirin in patients with decompensated cirrhosis (Child-Pugh class B or C).

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].

Sofosbuvir and Velpatasvir Dosage and Administration

General

Pretreatment Screening

• Prior to initiating sofosbuvir/velpatasvir, test all patients for evidence of current or prior hepatitis B virus (HBV) infection by measuring hepatitis B surface antigen (HBsAg), hepatitis B surface antibody (anti-HBs), and hepatitis B core antibody (anti-HBc).

Patient Monitoring

• Monitor for signs of reactivation of HBV infection and hepatitis flare both during and after treatment with sofosbuvir/velpatasvir.

• Perform clinical and liver function monitoring (including direct bilirubin), when indicated, for patients who have decompensated cirrhosis and are receiving concomitant therapy with sofosbuvir/velpatasvir and ribavirin.

Other General Considerations

• For the treatment of chronic HCV infection, sofosbuvir/velpatasvir is used alone or in conjunction with ribavirin. The specific regimen depends on certain patient factors (e.g., presence of decompensated cirrhosis).

Administration

Oral Administration

Sofosbuvir/velpatasvir is commercially available as fixed-combination film-coated tablets and pellets.

Administer orally once daily without regard to food. Swallow whole; do not chew.

Preparation and Administration of Sofosbuvir/Velpatasvir Oral Pellets

Sofosbuvir/velpatasvir oral pellets are supplied as single-use packets. Do not open packets until ready to use.

May administer oral pellets with or without food.

Administration without food: administer entire contents of prescribed number of packets directly into mouth and swallow without chewing to avoid a bitter aftertaste.

Administration with food: Pour entire contents of prescribed number of packets into a bowl containing 1 or more spoonfuls of a non-acidic, soft food that is at or below room temperature (e.g., pudding, chocolate syrup, ice cream); gently mix with a spoon. Take oral pellets/food mixture within 15 minutes without chewing to avoid a bitter aftertaste. Water may be swallowed after the pellets if needed. No pellets should remain in the packet(s) or in the food.

In patients <6 years of age, administration of pellets with food is recommended to improve palatability and increase tolerability.

Dosage

Available as fixed-combination tablets containing 200 mg of sofosbuvir and 50 mg of velpatasvir, fixed-combination tablets containing 400 mg of sofosbuvir and 100 mg of velpatasvir, fixed-combination pellets containing 150 mg of sofosbuvir and 37.5 mg of velpatasvir, and fixed-combination pellets containing 200 mg of sofosbuvir and 50 mg of velpatasvir.

Pediatric Patients

Treatment of Chronic HCV Infection

HCV Genotype 1, 2, 3, 4, 5, or 6 Infection

Oral

Treatment-naive or previously treated pediatric patients ≥3 years of age: Dosage is based on weight. Recommended treatment duration is 12 weeks. (See Table 1 and Table 2.)

Pediatric patients ≥3 years of age without cirrhosis or with compensated cirrhosis (Child-Pugh class A): See Table 2 for recommended sofosbuvir/velpatasvir dosage. Use alone for a treatment duration of 12 weeks.

Pediatric patients ≥3 years of age with decompensated cirrhosis (Child-Pugh class B or C): Use in conjunction with ribavirin. See Table 2 and Table 3 for recommended sofosbuvir/velpatasvir and ribavirin dosages. Give both drugs for treatment duration of 12 weeks.

Two tablets containing sofosbuvir 200 mg/velpatasvir 50 mg once daily can be administered for patients who cannot swallow the sofosbuvir 400 mg/velpatasvir 100 mg tablet.

Give each dose with food.

HCV-infected with HIV Coinfection.

Oral

Use same dosage, treatment regimen, and treatment duration recommended for HCV-infected patients without HIV coinfection.

Liver Transplant Recipients

Oral

Use same dosage, treatment regimen, and treatment duration recommended for HCV-infected patients who have not undergone liver transplantation.

Adults

Treatment of Chronic HCV Infection

HCV Genotype 1, 2, 3, 4, 5, or 6 Infection

Oral

Treatment-naive or previously treated adults: 1 tablet (sofosbuvir 400 mg and velpatasvir 100 mg) once daily.

Noncirrhotic or with compensated cirrhosis (Child-Pugh class A): Use alone for treatment duration of 12 weeks. (See Table 4.)

Decompensated cirrhosis (Child-Pugh class B or C): Use in conjunction with ribavirin. Give both drugs for treatment duration of 12 weeks. (See Table 4.)

If sofosbuvir/velpatasvir (without ribavirin) used for treatment of HCV genotype 1, 4, 5, or 6 infection in patients who cannot receive ribavirin, some experts recommend treatment duration of 24 weeks. Referral to an expert (ideally at a liver transplant center) recommended.

In clinical trials, previously treated adults had received regimens containing peginterferon alfa and ribavirin with or without an HCV nonstructural 3/4A (NS3/4A) protease inhibitor (boceprevir, simeprevir, or telaprevir; drugs no longer available in US).

Use weight-based ribavirin dosage in adults (1 g daily for patients <75 kg or 1.2 g daily for those ≥75 kg); give ribavirin daily dosage in 2 divided doses with food. May decrease initial and on-treatment dosages of ribavirin based on hemoglobin concentration and creatinine clearance.

HCV-infected with HIV Coinfection.

Oral

Use same dosage, treatment regimen, and treatment duration recommended for HCV-infected patients without HIV coinfection.

Liver Transplant Recipients

Oral

Use same dosage, treatment regimen, and treatment duration recommended for HCV-infected patients who have not undergone liver transplantation.

Special Populations

Hepatic Impairment

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

Renal Impairment

Mild, moderate, or severe renal impairment, including end-stage renal disease (ESRD) requiring dialysis: Dosage adjustments not needed.

Geriatric Patients

Dosage adjustments not needed.

Cautions for Sofosbuvir and Velpatasvir

Contraindications

• If sofosbuvir/velpatasvir used in conjunction with ribavirin, the contraindications to ribavirin also apply.

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; 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/velpatasvir, 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.

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 with another HCV DAA (e.g., daclatasvir, simeprevir; drugs no longer available in US). Fatal cardiac arrest reported in one patient receiving amiodarone with fixed combination of ledipasvir and sofosbuvir (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 sofosbuvir/velpatasvir 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 with sofosbuvir/velpatasvir not recommended.

If there are no alternative HCV treatment options and regimen of sofosbuvir/velpatasvir must be used in a patient receiving amiodarone, advise patient about the risk of serious bradycardia before initiating HCV treatment. Perform cardiac monitoring in an inpatient setting during first 48 hours of concomitant use of amiodarone and sofosbuvir/velpatasvir; 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/velpatasvir or if there are no other treatment options and amiodarone must be initiated in a patient already receiving sofosbuvir/velpatasvir.

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

Interactions

Concomitant use of sofosbuvir/velpatasvir and inducers of the P-glycoprotein (P-gp) transport system and/or moderate to potent inducers of CYP2B6, 2C8, or 3A4 (e.g., carbamazepine and other anticonvulsants, rifampin, St. John's wort) not recommended.

Precautions Related to Fixed Combinations and Multiple-drug Treatment Regimens

Consider cautions, precautions, contraindications, and drug interactions associated with both drugs in the fixed combination (i.e., sofosbuvir, velpatasvir). Consider cautionary information applicable to specific populations (e.g., pregnant or nursing women, individuals with hepatic or renal impairment, geriatric patients) for both drugs.

When used in conjunction with ribavirin, consider the usual cautions, precautions, and contraindications associated with ribavirin in addition to those associated with sofosbuvir/velpatasvir.

Specific Populations

Pregnancy

Adequate data not available regarding use in pregnant women. In animal studies, no evidence that sofosbuvir or velpatasvir affected fetal development at dosages tested.

When used in conjunction with ribavirin, consider that ribavirin is contraindicated in pregnant women and male partners of pregnant women.

Lactation

Not known whether sofosbuvir/velpatasvir and metabolites distributed into human milk.

Predominant metabolite of sofosbuvir (GS-331007) distributed into milk in rats; velpatasvir distributed into milk in rats and detected in plasma of suckling rat pups. GS-331007 and velpatasvir had no apparent effects on nursing pups.

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

When used in conjunction with ribavirin, consider potential for adverse reactions to ribavirin in nursing infants in addition to those associated with sofosbuvir/velpatasvir.

Pediatric Use

Safety and efficacy not established in pediatric patients <3 years of age.

Safety and efficacy for treatment of HCV genotype 1, 2, 3, 4, or 6 infection in treatment-naive and previously treated pediatric patients ≥6 years of age weighing ≥17 kg without cirrhosis or with compensated cirrhosis (Child-Pugh class A) have been established based on an open-label, phase 2 study.

Safety and efficacy for treatment of HCV genotype 5 infection in pediatric patients ≥3 years of age without cirrhosis or with compensated cirrhosis (Child-Pugh class A) are supported by similar sofosbuvir, GS-331007 (predominant metabolite of sofosbuvir), and velpatasvir exposures in adults and pediatric patients. Similar rationale used to support dosage recommendations for pediatric patients with HCV genotype 1, 2, 3, 4, 5, or 6 infection who have decompensated cirrhosis (Child-Pugh class B or C).

Adverse effects reported in pediatric patients ≥3 years of age are similar to those observed in adults.

Data not available regarding safety of sofosbuvir/velpatasvir in pediatric patients with renal impairment.

Geriatric Use

No overall differences in safety and efficacy in patients ≥65 years of age compared with younger adults, but increased sensitivity in some older individuals cannot be ruled out.

Hepatic Impairment

HCV-infected individuals with moderate or severe hepatic impairment (Child-Pugh class B or C): Increased sofosbuvir and GS-331007 exposures compared with those in individuals with normal hepatic function.

Moderate or severe hepatic impairment (Child-Pugh class B or C) without HCV infection: Velpatasvir exposure similar to exposure in individuals with normal hepatic function.

When velpatasvir/sofosbuvir used in conjunction with ribavirin in patients with decompensated cirrhosis (Child-Pugh class B or C), clinical and hepatic laboratory monitoring (including direct bilirubin) recommended as clinically indicated.

Data not available regarding safety of sofosbuvir/velpatasvir in patients with decompensated cirrhosis and severe renal impairment.

Renal Impairment

Mild, moderate, or severe renal impairment without HCV infection: Increased sofosbuvir and GS-331007 exposures compared with those in individuals with normal renal function.

ESRD without HCV infection: Increased sofosbuvir and GS-331007 exposures when administered 1 hour before or 1 hour after hemodialysis compared with exposures in individuals with normal renal function.

Severe renal impairment without HCV infection: Velpatasvir exposure similar to exposure in healthy individuals.

HCV-infected with ESRD requiring dialysis: Increased sofosbuvir, GS-331007, and velpatasvir exposures compared with those with normal renal function.

Data not available regarding safety of sofosbuvir/velpatasvir in patients with severe renal impairment (including those with ESRD requiring dialysis) who also have decompensated cirrhosis.

Liver Transplant Recipients

Adverse reactions in liver transplant recipients are consistent with the known safety profile of sofosbuvir/velpatasvir.

Common Adverse Effects

Sofosbuvir/velpatasvir in adult and pediatric patients ≥6 years of age or older (≥10%): Headache and fatigue.

Sofosbuvir/velpatasvir in pediatric patients <6 years of age: (≥10%): Vomiting and product use issue (spitting up the drug).

Sofosbuvir/velpatasvir in conjunction with ribavirin in adults with decompensated cirrhosis (≥10%): Fatigue, anemia, nausea, headache, insomnia, and diarrhea.

Drug Interactions

In vitro studies indicate slow metabolic turnover of velpatasvir by CYP2B6, 2C8, and 3A4.

Velpatasvir inhibits P-gp transport system; sofosbuvir and velpatasvir are substrates of P-gp.

Velpatasvir inhibits breast cancer resistance protein (BCRP); sofosbuvir and velpatasvir are substrates of BCRP.

Velpatasvir transported by organic anion transporting polypeptide (OATP) 1B1 and 1B3; velpatasvir inhibits OATP1B1, 1B3, and 2B1.

The following drug interactions are based on studies using sofosbuvir/velpatasvir, sofosbuvir alone, or velpatasvir alone, or are predicted to occur. When sofosbuvir/velpatasvir used, consider interactions associated with both drugs in the fixed combination.

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Moderate or potent CYP2B6, 2C8, or 3A4 inducers: Possible decreased sofosbuvir and/or velpatasvir plasma concentrations leading to reduced therapeutic effect; concomitant use of sofosbuvir/velpatasvir with such inducers not recommended.

CYP2B6, 2C8, or 3A4 inhibitors: Possible increased velpatasvir plasma concentrations; sofosbuvir/velpatasvir may be used concomitantly with such inhibitors.

Drugs Affecting or Affected by P-glycoprotein Transport System

P-gp substrates: Intestinal absorption may be affected resulting in increased exposure of such substrates.

P-gp inducers: Possible decreased sofosbuvir and/or velpatasvir plasma concentrations leading to reduced therapeutic effect; concomitant use of sofosbuvir/velpatasvir with P-gp inducers not recommended.

P-gp inhibitors: Possible increased sofosbuvir and/or velpatasvir concentrations; sofosbuvir/velpatasvir may be used concomitantly with P-gp inhibitors.

Drugs Affecting or Affected by Breast Cancer Resistance Protein

BCRP substrates: Intestinal absorption may be affected resulting in increased exposure of such substrates.

BCRP inhibitors: Possible increased sofosbuvir and/or velpatasvir concentrations; sofosbuvir/velpatasvir may be used concomitantly with BCRP inhibitors.

Drugs Affecting or Affected by Organic Anion Transporting Polypeptides

OATP1B1, 1B3, or 2B1 substrates: Intestinal absorption may be affected resulting in increased exposure of such substrates.

Specific Drugs

Sofosbuvir and Velpatasvir Pharmacokinetics

Absorption

Bioavailability

Following oral administration of sofosbuvir/velpatasvir, peak plasma concentrations of sofosbuvir occur approximately 0.5–1 hour after the dose. Peak plasma concentrations and AUC of sofosbuvir and GS-331007 are similar in HCV-infected and healthy adults.

Following oral administration of sofosbuvir/velpatasvir, peak plasma concentrations of velpatasvir occur 3 hours after the dose. Peak plasma concentrations and AUC of velpatasvir are 42 and 37% lower, respectively, in HCV-infected adults compared with healthy adults.

Food

Administration of sofosbuvir/velpatasvir with moderate-fat (approximately 600 kcal, 30% fat) or high-fat (approximately 800 kcal, 50% fat) meal increased sofosbuvir exposures by 60 or 78%, respectively, and increased velpatasvir exposures by 34 or 21%, respectively.

Special Populations

Sofosbuvir: In HCV-infected individuals with moderate or severe hepatic impairment (Child-Pugh class B or C), sofosbuvir AUC is 126 or 143% higher, respectively, compared with individuals with normal hepatic function; GS-331007 AUC is 18 or 9% higher, respectively.

Velpatasvir: In individuals with moderate or severe hepatic impairment (Child-Pugh class B or C) without HCV infection, AUC of velpatasvir after single 100-mg dose is similar to that observed in individuals with normal hepatic function.

Sofosbuvir: In individuals with mild, moderate, or severe renal impairment without HCV infection, sofosbuvir AUC after single 400-mg dose is 61, 107, or 171% higher, respectively, compared with individuals with normal renal function; GS-331007 AUC is 55, 88, or 451% higher, respectively.

Velpatasvir: In individuals with severe renal impairment without HCV infection, no clinically important differences in velpatasvir pharmacokinetics after single 100-mg dose compared with healthy individuals.

Sofosbuvir/velpatasvir: In HCV-infected individuals with ESRD requiring dialysis, AUCs of sofosbuvir, GS-331007, and velpatasvir are 81, 1719, and 418% higher, respectively, than AUCs in HCV-infected patients with normal renal function.

Population pharmacokinetic analysis in HCV-infected individuals indicates cirrhosis does not substantially affect sofosbuvir, GS-331007, or velpatasvir exposures.

Population pharmacokinetic analysis in HCV-infected individuals indicates that sex and race do not affect sofosbuvir, GS-331007, or velpatasvir exposures.

Pediatric patients ≥3 years of age: No clinically important differences in pharmacokinetics compared with adults.

Distribution

Plasma Protein Binding

Sofosbuvir: Approximately 61–65%.

Velpatasvir: >99.5%.

Elimination

Metabolism

Sofosbuvir: Prodrug that 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); GS-331007 has no anti-HCV activity.

Velpatasvir: Metabolized by CYP2B6, 2C8, and 3A4.

Elimination Route

Sofosbuvir: Major route of elimination is renal clearance. Following single 400-mg oral dose, 80% eliminated in urine (mainly as GS-331007) and 14% in feces.

Velpatasvir: Major route of elimination is biliary excretion (approximately 77% of a dose eliminated as parent drug). Following a single 100-mg oral dose, 94% eliminated in feces and 0.4% in urine.

Half-life

Sofosbuvir: 0.5 hours; GS-331007 has half-life of 25 hours.

Velpatasvir: 15 hours.

Special Populations

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

Stability

Storage

Oral

Film-coated Pellets

<30ºC.

Do not use oral pellets if packet or tamper-evident seal is opened or damaged.

Film-coated Tablets

<30ºC.

Dispense tablets only in original container.

Actions and Spectrum

• Sofosbuvir/velpatasvir is a fixed combination of 2 HCV antivirals. Sofosbuvir is a nucleotide analog HCV NS5B polymerase inhibitor and velpatasvir is an HCV NS5A replication complex inhibitor (NS5A inhibitor).

• Sofosbuvir and velpatasvir are both DAAs with activity against HCV. No in vitro evidence of antagonistic anti-HCV effects between the drugs in HCV replicon studies.

• 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 that GS-461203 has activity against HCV genotypes 1b, 2a, 3a, and 4a. Sofosbuvir has shown in vitro activity against full-length or chimeric replicons of HCV genotypes 1a, 1b, 2a, 2b, 3a, 4a, 4d, 5a, and 6a (mean drug concentration required to inhibit viral replication by 50% [EC₅₀] ranges from 14–110 nM).

• Velpatasvir inhibits the HCV NS5A protein, which is required for viral replication. Velpatasvir has shown in vitro activity against full-length or chimeric replicons of HCV genotypes 1a, 1b, 2a, 2b, 3a, 4a, 4d, 5a, 6a, and 6e (mean EC₅₀ ranges from 0.002–0.13 nM).

• Certain amino acid substitutions in NS5B polymerase 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. In all replicon genotypes tested, the S282T substitution was associated with reduced susceptibility to sofosbuvir; in genotypes 2a, 5, and 6 replicons, an M289L substitution developed along with the S282T substitution. Treatment-emergent NS5B resistance-associated substitutions were detected in phase 3 clinical trials evaluating sofosbuvir/velpatasvir in patients with HCV genotype 3a infection (e.g., L314F, L314I, L314P) who experienced virologic failure.

• Certain amino acid substitutions in NS5A of HCV genotype 1a (e.g., L31V, Y93H/N), genotype 1b (e.g., L31V, Y93H), genotype 2a (e.g., F28S, Y93H), genotype 3a (e.g., Y93H/S), genotype 4a (e.g., Y93H), and genotype 6 (e.g., L31V, P32A/L/Q/R) have been selected in cell culture and have been associated with reduced susceptibility to velpatasvir in vitro in replicon studies. Combinations of these NS5A substitutions often resulted in greater reductions in susceptibility to velpatasvir compared with a single NS5A substitution. Treatment-emergent NS5A resistance-associated substitutions were detected in phase 3 clinical trials evaluating sofosbuvir/velpatasvir in patients with HCV genotype 1a (e.g., Y93N, Q30R, H58D), genotype 1b (e.g., L31M/V, Y93H), genotype 1c/h (e.g., Y93H, K24M/T, L31I/V), or genotype 3a (e.g., Y93H, M28T/V, S38P/Y, P58L, A30V, H58T) infection who experienced virologic failure. Some of these patients also had baseline NS5A polymorphisms at resistance-associated amino acid positions.

• Sofosbuvir and velpatasvir are active against HCV with substitutions associated with resistance to other HCV DAAs with different mechanisms of action (e.g., HCV NS5B polymerase inhibitors, HCV NS3 protease inhibitors). Efficacy of sofosbuvir/velpatasvir not established in patients in whom previous treatment with a regimen that included an HCV NS5A inhibitor failed.

Advice to Patients

• Importance of reading patient information provided by the manufacturer.

• Advise patients to take sofosbuvir/velpatasvir once daily (with or without food) on a regular dosing schedule.

• Advise patients or their caregivers to read and follow the manufacturer's instructions to prepare the correct dose of sofosbuvir/velpatasvir oral pellets.

• Importance of taking the recommended dosage of sofosbuvir/velpatasvir for the recommended duration of treatment; importance of not missing doses.

• 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.

• If sofosbuvir/velpatasvir is used in a patient receiving amiodarone, advise the patient about the risk of serious symptomatic bradycardia and the importance of immediately contacting a 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.

• 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 females informing clinicians if they are or plan to become pregnant or plan to breast-feed. If used in conjunction with ribavirin, advise males and females of importance of using effective contraception during and for 6 months after ribavirin therapy.

• 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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