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Sofosbuvir and Velpatasvir

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
Brands: Epclusa

Warning

    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 fixed combination of sofosbuvir and velpatasvir (sofosbuvir/velpatasvir).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

HCV antiviral;1 fixed combination containing sofosbuvir (nucleotide analog HCV NS5B polymerase inhibitor) and velpatasvir (HCV NS5A replication complex inhibitor [NS5A inhibitor]).1

Uses for Sofosbuvir and Velpatasvir

Chronic HCV Infection

Treatment of chronic HCV genotype 1, 2, 3, 4, 5, or 6 infection in treatment-naive (previously untreated) or previously treated adults, including those with cirrhosis (compensated or decompensated).1 2 3 4 119

Used alone or in conjunction with ribavirin, depending on certain patient factors (e.g., presence of decompensated cirrhosis).1 2 3 4 119

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 and Velpatasvir Dosage and Administration

General

  • For treatment of chronic HCV infection, sofosbuvir/velpatasvir is used alone or in conjunction with ribavirin.1

  • Base specific regimen on certain patient factors (e.g., presence of decompensated cirrhosis).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.)

Administration

Oral Administration

Administer orally once daily without regard to food.1

Dosage

Available as fixed-combination tablets containing 400 mg of sofosbuvir and 100 mg of velpatasvir.1

Adults

Treatment of Chronic HCV Infection
HCV Genotype 1, 2, 3, 4, 5, or 6 Infection
Oral

1 tablet (sofosbuvir 400 mg and velpatasvir 100 mg) once daily.1 119

Noncirrhotic or with compensated cirrhosis (Child-Pugh class A): Use alone for a duration of 12 weeks.1 119

Decompensated cirrhosis (Child-Pugh class B or C): Use in conjunction with ribavirin for a duration of 12 weeks.1 119 If sofosbuvir/velpatasvir (without ribavirin) is 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.119 Referral to an expert (ideally at a liver transplant center) recommended.119

Special Populations

Hepatic Impairment

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

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 and Velpatasvir

Contraindications

  • If sofosbuvir/velpatasvir used in conjunction with ribavirin, the contraindications to ribavirin also apply.1 (See Precautions Related to Fixed Combinations and 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/velpatasvir, 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 with another HCV DAA (e.g., daclatasvir, ledipasvir, simeprevir).1 23 Fatal cardiac arrest reported in one patient receiving fixed combination of ledipasvir and sofosbuvir (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 sofosbuvir/velpatasvir include those also receiving a β-adrenergic blocking agent, those with underlying cardiac comorbidities, and/or those with advanced liver disease.1

Concomitant use of amiodarone with sofosbuvir/velpatasvir not recommended.1

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.1 Perform cardiac monitoring in an inpatient setting during first 48 hours of concomitant use of amiodarone and sofosbuvir/velpatasvir;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/velpatasvir or if there are no other treatment options and amiodarone must be initiated in a patient already receiving sofosbuvir/velpatasvir.1

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.1

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.1 (See Interactions.)

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.1 Consider cautionary information applicable to specific populations (e.g., pregnant or nursing women, individuals with hepatic or renal impairment, geriatric patients) for both sofosbuvir and velpatasvir.1

When used in conjunction with ribavirin, 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 not available regarding use in pregnant women.1 In animal studies, no evidence that sofosbuvir or velpatasvir affected fetal development at dosages tested.1

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

Lactation

Not known whether sofosbuvir/velpatasvir and metabolites distributed into human milk.1

Predominant metabolite of sofosbuvir (GS-331007) distributed into milk in rats;1 velpatasvir distributed into milk in rats and detected in plasma of suckling rat pups.1 GS-331007 and velpatasvir had no apparent effects on nursing pups.1

Consider benefits of breast-feeding and importance of the drug to the woman;1 also consider potential adverse effects on the breast-fed child from the drug or 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 Fixed Combinations and Multiple-drug Treatment Regimens under Cautions.)

Pediatric Use

Safety and efficacy not established in pediatric patients <18 years of age.1

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.1

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.1

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.1

When velpatasvir/sofosbuvir is used in conjunction with ribavirin in patients with decompensated cirrhosis (Child-Pugh class B or C), clinical and hepatic laboratory monitoring is recommended as clinically indicated.1

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.1

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.1

Severe renal impairment without HCV infection: Velpatasvir exposure similar to exposure in healthy individuals.1

Common Adverse Effects

Sofosbuvir/velpatasvir in patients without cirrhosis or with compensated cirrhosis: Headache,1 2 4 fatigue,1 2 4 nasopharyngitis,2 4 nausea,2 4 insomnia.4

Sofosbuvir/velpatasvir in conjunction with ribavirin in patients with decompensated cirrhosis: Fatigue,1 3 anemia,1 3 nausea,1 3 headache,1 3 insomnia,1 3 diarrhea,1 3 muscle spasm,3 dyspnea,3 cough.3

Interactions for Sofosbuvir and Velpatasvir

In vitro studies indicate slow metabolic turnover of velpatasvir by CYP2B6, 2C8, and 3A4.1

Velpatasvir inhibits P-gp transport system;1 sofosbuvir and velpatasvir are substrates of P-gp.1

Velpatasvir inhibits breast cancer resistance protein (BCRP);1 sofosbuvir and velpatasvir are substrates of BCRP.1

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

The following drug interactions are based on studies using sofosbuvir/velpatasvir, sofosbuvir alone, or velpatasvir alone, or are predicted to occur.1 When sofosbuvir/velpatasvir used, consider interactions associated with both drugs in the fixed combination.1

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;1 concomitant use of sofosbuvir/velpatasvir with such inducers not recommended.1

CYP2B6, 2C8, or 3A4 inhibitors: Possible increased velpatasvir plasma concentrations;1 sofosbuvir/velpatasvir may be used concomitantly with such inhibitors.1

Drugs Affecting or Affected by P-glycoprotein Transport System

P-gp substrates: Intestinal absorption may be affected resulting in increased exposure of such substrates.1

P-gp inducers: Possible decreased sofosbuvir and/or velpatasvir plasma concentrations leading to reduced therapeutic effect;1 concomitant use of sofosbuvir/velpatasvir with P-gp inducers not recommended.1

P-gp inhibitors: Possible increased sofosbuvir and/or velpatasvir concentrations;1 sofosbuvir/velpatasvir may be used concomitantly with P-gp inhibitors.1

Drugs Affecting or Affected by Breast Cancer Resistance Protein

BCRP substrates: Intestinal absorption may be affected resulting in increased exposure of such substrates.1

BCRP inhibitors: Possible increased sofosbuvir and/or velpatasvir concentrations;1 sofosbuvir/velpatasvir may be used concomitantly with BCRP inhibitors.1

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.1

Specific Drugs

Drug

Interaction

Comments

Antacids (aluminum and magnesium hydroxides)

Decreased velpatasvir concentrations expected;1 increased gastric pH decreases velpatasvir solubility1

Take antacids 4 hours before or after sofosbuvir/velpatasvir1

Antiarrhythmic agents (amiodarone)

Amiodarone: Concomitant use with sofosbuvir/velpatasvir may result in serious symptomatic bradycardia;1 23 effect on amiodarone, sofosbuvir, and velpatasvir concentrations unknown1

Amiodarone: Concomitant use with sofosbuvir/velpatasvir not recommended;1 if concomitant use necessary, patient counseling and cardiac monitoring required1 (see Cardiovascular Effects under Cautions)

Anticonvulsants (carbamazepine, oxcarbazepine, phenobarbital, phenytoin)

Carbamazepine, oxcarbazepine, phenobarbital, phenytoin: Decreased sofosbuvir and velpatasvir concentrations expected1

Carbamazepine, oxcarbazepine, phenobarbital, phenytoin: Concomitant use with sofosbuvir/velpatasvir not recommended1

Antifungals, azoles (ketoconazole)

Ketoconazole: No clinically important pharmacokinetic interactions with velpatasvir1

Antimycobacterial agents (rifabutin, rifampin, rifapentine)

Rifabutin, rifapentine: Decreased sofosbuvir and velpatasvir concentrations expected1

Rifampin: Decreased sofosbuvir and velpatasvir concentrations and AUCs1 6

Rifabutin, rifampin, rifapentine: Concomitant use with sofosbuvir/velpatasvir not recommended1

Atazanavir

Ritonavir-boosted atazanavir: No clinically important pharmacokinetic interactions1

HIV antiretroviral regimen of ritonavir-boosted atazanavir in conjunction with fixed combination of emtricitabine and tenofovir disoproxil fumarate (emtricitabine/tenofovir DF): Increased velpatasvir and tenofovir concentrations and AUC1

HIV antiretroviral regimens that include ritonavir-boosted atazanavir and tenofovir DF: Monitor for tenofovir-associated adverse effects1

Darunavir

Ritonavir-boosted darunavir: No clinically important pharmacokinetic interactions1

HIV antiretroviral regimen of ritonavir-boosted darunavir in conjunction with emtricitabine/tenofovir DF: Decreased sofosbuvir and velpatasvir concentrations and AUC;1 increased tenofovir concentrations and AUC1

HIV antiretroviral regimens that include ritonavir-boosted darunavir and tenofovir DF: Monitor for tenofovir-associated adverse effects1

Digoxin

Increased digoxin concentrations and AUC when used concomitantly with velpatasvir1

Digoxin therapeutic concentration monitoring recommended if used concomitantly with sofosbuvir/velpatasvir1

Dolutegravir

No clinically important pharmacokinetic interactions with sofosbuvir/velpatasvir1

Efavirenz

Fixed combination of efavirenz, emtricitabine, and tenofovir DF (efavirenz/emtricitabine/tenofovir DF): No clinically important effect on sofosbuvir pharmacokinetics;1 decreased velpatasvir concentrations and AUC; increased tenofovir concentrations and AUC1

HIV antiretroviral regimens containing efavirenz: Concomitant use with sofosbuvir/velpatasvir not recommended1

Elvitegravir

Fixed combination of elvitegravir, cobicistat, emtricitabine, and tenofovir DF (EVG/c/FTC/TDF): No clinically important effect on sofosbuvir, velpatasvir, elvitegravir, cobicistat, or emtricitabine pharmacokinetics;1 increased tenofovir concentrations and AUC1

Fixed combination of elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide (EVG/c/FTC/TAF): No clinically important pharmacokinetic interactions1

EVG/c/FTC/TDF: Monitor for tenofovir-associated adverse effects1

Emtricitabine

No clinically important pharmacokinetic interactions with sofosbuvir/velpatasvir1

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)1

Histamine H2-receptor antagonists

Decreased velpatasvir concentrations expected;1 increased gastric pH decreases velpatasvir solubility1

Administer H2-antagonists concurrently with or 12 hours apart from sofosbuvir/velpatasvir;1 do not exceed H2-antagonist dosages comparable to famotidine 40 mg twice daily1

HMG-CoA reductase inhibitors (statins)

Atorvastatin: Increased atorvastatin concentrations expected; increased risk of myopathy and rhabdomyolysis1

Pravastatin: No clinically important interactions1 6

Rosuvastatin: Increased rosuvastatin concentrations; increased risk of myopathy and rhabdomyolysis1 6

Atorvastatin: Closely monitor for statin-associated adverse effects (e.g., myopathy, rhabdomyolysis)1

Rosuvastatin: Do not exceed rosuvastatin dosage of 10 mg daily1

Immunosuppressants (cyclosporine, tacrolimus)

Cyclosporine: No clinically important pharmacokinetic interactions with sofosbuvir or velpatasvir1

Tacrolimus: No clinically important pharmacokinetic interactions with sofosbuvir1

Interferons

Interferon alfa: No in vitro evidence of antagonistic anti-HCV effects with sofosbuvir or velpatasvir1 188

Lopinavir

Fixed combination of lopinavir and ritonavir (lopinavir/ritonavir): No clinically important effect on sofosbuvir or velpatasvir pharmacokinetics1

Methadone

No clinically important pharmacokinetic interactions with sofosbuvir1

Proton-pump inhibitors

Decreased velpatasvir concentrations expected;1 increased gastric pH decreases velpatasvir solubility1

Concomitant use with sofosbuvir/velpatasvir not recommended1

If concomitant use necessary, administer sofosbuvir/velpatasvir with food 4 hours before omeprazole 20 mg;1 use with other proton-pump inhibitors not studied1

Raltegravir

HIV antiretroviral regimen of raltegravir in conjunction with emtricitabine/tenofovir DF: No clinically important effect on raltegravir or emtricitabine pharmacokinetics;1 increased tenofovir plasma concentrations and AUC1

HIV antiretroviral regimens that include raltegravir and tenofovir DF: Monitor for tenofovir-associated adverse effects1

Ribavirin

No in vitro evidence of antagonistic anti-HCV effects with sofosbuvir or velpatasvir1 188

Rilpivirine

Fixed combination of emtricitabine, rilpivirine, and tenofovir DF (emtricitabine/rilpivirine/tenofovir DF): No clinically important effect on emtricitabine or rilpivirine pharmacokinetics;1 increased tenofovir concentrations and AUC1

HIV antiretroviral regimens that include rilpivirine and tenofovir DF: Monitor for tenofovir-associated adverse effects1

St. John's wort (Hypericum perforatum)

Possible decreased sofosbuvir and velpatasvir concentrations1

Concomitant use with sofosbuvir/velpatasvir not recommended1

Tenofovir

HIV antiretroviral regimens that include tenofovir DF: Possible increased tenofovir concentrations1

HIV antiretroviral regimens that include tenofovir DF: Monitor for tenofovir-associated adverse effects1

Tipranavir

Ritonavir-boosted tipranavir: Decreased sofosbuvir and velpatasvir concentrations expected1

Ritonavir-boosted tipranavir: Concomitant use with sofosbuvir/velpatasvir not recommended1

Topotecan

Increased topotecan concentrations expected1

Concomitant use with sofosbuvir/velpatasvir 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 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.1 7 Peak plasma concentrations and AUC of sofosbuvir and GS-331007 are similar in HCV-infected and healthy adults.1

Following oral administration of sofosbuvir/velpatasvir, peak plasma concentrations of velpatasvir occur 3 hours after the dose.1 7 Peak plasma concentrations and AUC of velpatasvir are 42 and 37% lower, respectively, in HCV-infected adults compared with healthy adults.1

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,1 and increased velpatasvir exposures by 34 or 21%, respectively.1 7

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;1 GS-331007 AUC is 18 or 9% higher, respectively.1

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.1

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;1 GS-331007 AUC is 55, 88, or 451% higher, respectively.1

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.1

Population pharmacokinetic analysis in HCV-infected individuals indicates cirrhosis does not substantially affect sofosbuvir, GS-331007, or velpatasvir exposures.1

Population pharmacokinetic analysis in HCV-infected individuals indicates that gender and race do not affect sofosbuvir, GS-331007, or velpatasvir exposures.1

Distribution

Plasma Protein Binding

Sofosbuvir: Approximately 61–65%.1

Velpatasvir: >99.5%.1

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).1 181 Results in formation of pharmacologically active metabolite, GS-461203.1 181 Desphosphorylation subsequently occurs leading to formation of GS-331007 (the predominant circulating metabolite);1 181 GS-331007 has no anti-HCV activity.1 181

Velpatasvir: Metabolized by CYP2B6, 2C8, and 3A4.1

Elimination Route

Sofosbuvir: Major route of elimination is renal clearance.1 Following single 400-mg oral dose, 80% eliminated in urine (mainly as GS-331007), 14% in feces, and 2.5% in expired air.1 181

Velpatasvir: Major route of elimination is biliary excretion (approximately 77% of a dose eliminated as parent drug).1 Following a single 100-mg oral dose, 94% eliminated in feces and 0.4% in urine.1 7

Half-life

Sofosbuvir: 0.5 hours;1 GS-331007 has half-life of 25 hours.1

Velpatasvir: 15 hours.1

Special Populations

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

Stability

Storage

Oral

Film-coated Tablets

<30ºC.1

Dispense only in original container.1

Actions and Spectrum

  • Sofosbuvir/velpatasvir is a fixed combination of 2 HCV antivirals.1 Sofosbuvir is a nucleotide analog HCV NS5B polymerase inhibitor1 and velpatasvir is an HCV NS5A replication complex inhibitor (NS5A inhibitor).1

  • Sofosbuvir and velpatasvir are both DAAs with activity against HCV.1 No in vitro evidence of antagonistic anti-HCV effects between the drugs in HCV replicon studies.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;1 acts as RNA chain terminator.1 In vitro studies using biochemical and cell-based replicon assays indicate that GS-461203 has activity against HCV genotypes 1b, 2a, 3a, and 4a.1 5 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).1 5

  • Velpatasvir inhibits the HCV NS5A protein, which is required for viral replication.1 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).1 5

  • 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.1 In all replicon genotypes tested, the S282T substitution was associated with reduced susceptibility to sofosbuvir;1 in genotypes 2a, 5, and 6 replicons, an M289L substitution developed along with the S282T substitution.1 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.1

  • 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.1 Combinations of these NS5A substitutions often resulted in greater reductions in susceptibility to velpatasvir compared with a single NS5A substitution.1 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.1 3 5 Some of these patients also had baseline NS5A polymorphisms at resistance-associated amino acid positions.1 3 5

  • 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).1 Efficacy of sofosbuvir/velpatasvir not established in patients in whom previous treatment with a regimen that included an HCV NS5A inhibitor failed.1

Advice to Patients

  • Importance of reading patient information provided by the manufacturer.1

  • Advise patients to take sofosbuvir/velpatasvir once daily (with or without food) on a regular dosing schedule.1

  • Importance of taking the recommended dosage of sofosbuvir/velpatasvir for the recommended duration of treatment;1 importance of not missing doses.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 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.1 (See Cardiovascular Effects under Cautions.)

  • 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 conjunction with ribavirin, advise men and women of importance of using 2 forms of effective contraception during and for 6 months after ribavirin therapy.1 349 377 (See Precautions Related to Fixed Combinations and Multiple-drug Treatment Regimens under Cautions.)

  • Importance of informing patients of other important precautionary information.1 (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 and Velpatasvir

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets, film-coated

Sofosbuvir 400 mg and 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.

References

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

2. Feld JJ, Jacobson IM, Hézode C et al. Sofosbuvir and velpatasvir for HCV genotype 1, 2, 4, 5, and 6 infection. N Engl J Med. 2015; 373:2599-607. [PubMed 26571066]

3. Curry MP, O'Leary JG, Bzowej N et al. Sofosbuvir and velpatasvir for HCV in patients with decompensated cirrhosis. N Engl J Med. 2015; 373:2618-28. [PubMed 26569658]

4. Foster GR, Afdhal N, Roberts SK et al. Sofosbuvir and velpatasvir for HCV genotype 2 and 3 infection. N Engl J Med. 2015; 373:2608-17. [PubMed 26575258]

5. US Food and Drug Administration. Center for Drug Evaluation and Research. Application number 208341Orig1s000: Microbiology review(s). From FDA website.

6. Mogalian E, German P, Kearney BP et al. Use of Multiple Probes to Assess Transporter- and Cytochrome P450-Mediated Drug-Drug Interaction Potential of the Pangenotypic HCV NS5A Inhibitor Velpatasvir. Clin Pharmacokinet. 2016; 55:605-13. [PubMed 26519191]

7. US Food and Drug Administration. Center for Drug Evaluation and Research. Application number 208341Orig1s000: Clinical pharmacology and biopharmaceutics review. From FDA website.

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.

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

188. Gilead Sciences, Inc. Sovaldi (sofosbuvir) 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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