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Vosevi

Generic Name: Sofosbuvir, Velpatasvir, And Voxilaprevir
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: C22H29FN3O9PC49H54N8O8C40H52F4N6O9S
CAS Number: 1190307-88-0

Medically reviewed on Sep 3, 2018

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, velpatasvir, and voxilaprevir (sofosbuvir/velpatasvir/voxilaprevir).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

See also: Mavyret

HCV antiviral;1 fixed combination containing sofosbuvir (nucleotide analog HCV NS5B polymerase inhibitor), velpatasvir (HCV NS5A replication complex inhibitor [NS5A inhibitor]), and voxilaprevir (HCV NS3/4A protease inhibitor).1

Uses for Vosevi

Chronic HCV Infection

Treatment of chronic HCV genotype 1, 2, 3, 4, 5, or 6 infection in adults previously treated with an HCV regimen containing an HCV NS5A inhibitor, including those with compensated cirrhosis.1 2 119

Treatment of chronic HCV genotype 1a or 3 infection in adults previously treated with an HCV regimen containing sofosbuvir without an HCV NS5A inhibitor, including those with compensated cirrhosis.1 2 119

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) and Infectious Diseases Society of America (IDSA) regarding diagnosis and management of HCV infection, including recommendations for initial treatment, is available at [Web].119

Vosevi Dosage and Administration

General

  • 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.)

  • Prior to and during treatment, perform appropriate laboratory tests to evaluate liver function.119 (See Hepatic Impairment under Cautions.)

Administration

Oral Administration

Administer orally once daily with food.1

Dosage

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

Adults

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

Failed previous treatment with HCV regimen containing an HCV NS5A inhibitor (noncirrhotic or compensated cirrhosis [Child-Pugh class A]): 1 tablet (sofosbuvir 400 mg, velpatasvir 100 mg, and voxilaprevir 100 mg) once daily for 12 weeks.1 119

HCV Genotype 1a or 3 Infection
Oral

Failed previous treatment with sofosbuvir without an HCV NS5A inhibitor (noncirrhotic or with compensated cirrhosis [Child-Pugh class A]): 1 tablet (sofosbuvir 400 mg, velpatasvir 100 mg, and voxilaprevir 100 mg) once daily for 12 weeks.1 119

Special Populations

Hepatic Impairment

Mild hepatic impairment (Child-Pugh class A): Dosage adjustments not needed.1

Moderate or severe hepatic impairment (Child-Pugh class B or C): Not recommended.1 (See Hepatic Impairment under Cautions.)

Renal Impairment

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

Severe renal impairment (eGFR <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 (See Geriatric Use under Cautions.)

Cautions for Vosevi

Contraindications

  • Concomitant use with rifampin.1

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 were 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/voxilaprevir, 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 is used concomitantly with sofosbuvir/velpatasvir/voxilaprevir 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/voxilaprevir not recommended.1

If there are no alternative HCV treatment options and regimen of sofosbuvir/velpatasvir/voxilaprevir 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/voxilaprevir;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/voxilaprevir or if there are no other treatment options and amiodarone must be initiated in a patient already receiving sofosbuvir/velpatasvir/voxilaprevir.1

Advise patients receiving amiodarone concomitantly with sofosbuvir/velpatasvir/voxilaprevir 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/voxilaprevir 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, St. John's wort) may lead to reduced therapeutic effect and is not recommended.1 (See Interactions.)

Precautions Related to Fixed Combinations

Consider cautions, precautions, contraindications, and drug interactions associated with each drug 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 sofosbuvir, velpatasvir, and voxilaprevir.1

Specific Populations

Pregnancy

Adequate data not available regarding use of sofosbuvir/velpatasvir/voxilaprevir in pregnant women.1 In animal studies, no evidence that sofosbuvir, velpatasvir, or voxilaprevir affected fetal development at dosages tested.1

Lactation

Not known whether sofosbuvir/velpatasvir/voxilaprevir or 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 voxilaprevir detected in plasma of suckling rat pups.1 GS-331007, velpatasvir, and voxilaprevir 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 breast-fed child from the drug or underlying maternal condition.1

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

Moderate or severe hepatic impairment (Child-Pugh class B or C): Safety and efficacy not established; use not recommended in such patients.1 (See Pharmacokinetics.)

Renal Impairment

Severe renal impairment (eGFR <30 mL/minute per 1.73 m2) or ESRD requiring hemodialysis: Safety and efficacy not established; dosage recommendation not available for such patients.1 (See Pharmacokinetics.)

Common Adverse Effects

Headache,1 2 fatigue,1 2 diarrhea,1 2 nausea,1 2 asthenia,1 2 insomnia.1 2

Interactions for Vosevi

In vitro studies indicate slow metabolic turnover of velpatasvir by CYP2B6, 2C8, and 3A4 and slow metabolic turnover of voxilaprevir by CYP1A2, 2C8, and 3A4.1

Velpatasvir and voxilaprevir inhibit P-gp transport system;1 sofosbuvir, velpatasvir, and voxilaprevir are substrates of P-gp.1

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

Voxilaprevir and, to a lesser extent, velpatasvir are transported by organic anion transporting polypeptide (OATP) 1B1 and 1B3;1 velpatasvir and voxilaprevir inhibit OATP1B1 and 1B3; velpatasvir also inhibits OATP2B1.1

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

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Moderate or potent CYP2B6, 2C8, or 3A4 inducers: Possible decreased sofosbuvir, velpatasvir, and/or voxilaprevir plasma concentrations potentially leading to reduced therapeutic effect;1 concomitant use of sofosbuvir/velpatasvir/voxilaprevir with such inducers not recommended.1

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

Drugs Affecting or Affected by P-glycoprotein Transport System

P-gp substrates: Possible altered exposure of such substrates.1

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

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

Drugs Affecting or Affected by Breast Cancer Resistance Protein

BCRP substrates: Possible altered exposure of such substrates.1

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

Drugs Affecting or Affected by Organic Anion Transporting Polypeptides

OATP1B1, 1B3, or 2B1 substrates: Possible altered exposure of such substrates.1

OATP inhibitors: Possible substantially increased voxilaprevir concentrations;1 concomitant use of sofosbuvir/velpatasvir/voxilaprevir and OATP inhibitors not recommended.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/velpatasvir/voxilaprevir1

Antiarrhythmic agents (amiodarone)

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

Amiodarone: Concomitant use with sofosbuvir/velpatasvir/voxilaprevir 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, velpatasvir, and voxilaprevir concentrations expected1

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

Antifungals, azoles (ketoconazole, voriconazole)

Ketoconazole: No clinically important pharmacokinetic interactions with sofosbuvir or velpatasvir1

Voriconazole: No clinically important pharmacokinetic interactions1

Antimycobacterial agents (rifabutin, rifampin, rifapentine)

Rifabutin, rifapentine: Decreased sofosbuvir, velpatasvir, and voxilaprevir concentrations expected1

Rifampin: Decreased sofosbuvir, velpatasvir, and voxilaprevir concentrations and AUCs;1 6 increased voxilaprevir concentrations when a single dose used concomitantly with single dose of rifampin1

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

Rifampin: Concomitant use with sofosbuvir/velpatasvir/voxilaprevir contraindicated1

Antineoplastic agents (imatinib, irinotecan, lapatinib, methotrexate, mitoxantrone, topotecan)

Imatinib, irinotecan, lapatinib, methotrexate, mitoxantrone, topotecan: Concomitant use with sofosbuvir/velpatasvir/voxilaprevir not recommended1

Atazanavir

Ritonavir-boosted atazanavir: Substantially increased voxilaprevir concentrations and AUC1

Ritonavir-boosted, cobicistat-boosted, or unboosted atazanavir: Concomitant use with sofosbuvir/velpatasvir/voxilaprevir not recommended1 200

Dabigatran

Concomitant use with sofosbuvir/velpatasvir/voxilaprevir results in increased dabigatran concentrations and AUC1

Monitor dabigatran clinical effects1

Darunavir

Darunavir: No clinically important pharmacokinetic interactions1

HIV antiretroviral regimen of ritonavir-boosted darunavir in conjunction with fixed combination of emtricitabine and tenofovir disoproxil fumarate (emtricitabine/tenofovir DF): Decreased sofosbuvir and velpatasvir concentrations and AUC;1 increased voxilaprevir and tenofovir concentrations and AUC1

Ritonavir-boosted or cobicistat-boosted darunavir: Dosage adjustments not needed if used with sofosbuvir/velpatasvir/voxilaprevir200

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/velpatasvir/voxilaprevir1

Dolutegravir

No clinically important pharmacokinetic interactions with sofosbuvir/velpatasvir1

Dosage adjustments not needed200

Efavirenz

Efavirenz: Decreased velpatasvir and voxilaprevir concentrations expected1 200

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

Efavirenz: Concomitant use with sofosbuvir/velpatasvir/voxilaprevir not recommended1 200

Elvitegravir

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

EVG/c/FTC/TAF: Dosage adjustments not needed;200 consider monitoring for hepatotoxicity200

EVG/c/FTC/TDF: Dosage adjustments not needed;200 monitor for tenofovir-associated adverse effects;200 consider monitoring for hepatotoxicity200

Emtricitabine

No clinically important pharmacokinetic interactions with sofosbuvir/velpatasvir/voxilaprevir1

Estrogens/progestins

Oral contraceptive containing ethinyl estradiol and norgestimate: No clinically important effects on pharmacokinetics of ethinyl estradiol or norgestimate1

Etravirine

Decreased velpatasvir and voxilaprevir concentrations expected200

Concomitant use with sofosbuvir/velpatasvir/voxilaprevir not recommended200

Gemfibrozil

No clinically important pharmacokinetic interactions with sofosbuvir/velpatasvir/voxilaprevir1

Histamine H2-receptor antagonists

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

Administer H2-antagonists concurrently with or staggered with 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 and AUC when used with sofosbuvir/velpatasvir; increased risk of myopathy and rhabdomyolysis1

Fluvastatin, lovastatin, simvastatin: Possible increased statin concentrations with increased risk of myopathy and rhabdomyolysis1

Pitavastatin: Possible increased pitavastatin concentrations with increased risk of myopathy and rhabdomyolysis1

Pravastatin: Increased pravastatin concentrations and AUC; increased risk of myopathy and rhabdomyolysis1

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

Atorvastatin: If used with sofosbuvir/velpatasvir/voxilaprevir, use lowest atorvastatin dosage;1 if higher dosage required, use lowest necessary dosage taking into account risks and benefits1

Fluvastatin, lovastatin, simvastatin: If used with sofosbuvir/velpatasvir/voxilaprevir, use lowest statin dosage;1 if higher statin dosages required, use lowest necessary dosage taking into account risks and benefits1

Pitavastatin: Concomitant use with sofosbuvir/velpatasvir/voxilaprevir not recommended1

Pravastatin: If used concomitantly with sofosbuvir/velpatasvir/voxilaprevir, do not exceed pravastatin dose of 40 mg1

Rosuvastatin: Concomitant use with sofosbuvir/velpatasvir/voxilaprevir not recommended1

Immunosuppressants (cyclosporine, tacrolimus)

Cyclosporine: Substantially increased voxilaprevir exposures when used with voxilaprevir; increased sofosbuvir or velpatasvir exposures with sofosbuvir or velpatasvir1

Tacrolimus: No clinically important pharmacokinetic interactions with sofosbuvir1

Cyclosporine: Concomitant use with sofosbuvir/velpatasvir/voxilaprevir not recommended1

Lopinavir

Fixed combination of lopinavir and ritonavir (lopinavir/ritonavir): Increased voxilaprevir concentrations expected1

Concomitant use with sofosbuvir/velpatasvir/voxilaprevir not recommended1 200

Maraviroc

Clinically important pharmacokinetic interactions not expected200

Dosage adjustments not needed200

Methadone

No clinically important pharmacokinetic interactions with sofosbuvir1

Nevirapine

Decreased velpatasvir and voxilaprevir concentrations expected200

Concomitant use with sofosbuvir/velpatasvir/voxilaprevir not recommended200

Proton-pump inhibitors

Omeprazole: Decreased velpatasvir exposure when 20 mg administered 2 hours before or 4 hours after sofosbuvir/velpatasvir/voxilaprevir1

Other proton-pump inhibitors: Decreased velpatasvir concentrations expected;1 increased gastric pH decreases velpatasvir solubility1

Omeprazole: If used concomitantly with sofosbuvir/velpatasvir/voxilaprevir, use omeprazole dosage of 20 mg1

Other proton-pump inhibitors: Concomitant use not studied1

Raltegravir

Raltegravir: No clinically important pharmacokinetic interactions when used with sofosbuvir/velpatasvir1

HIV antiretroviral regimen of raltegravir in conjunction with emtricitabine/tenofovir DF: When used concomitantly with sofosbuvir/velpatasvir, no clinically important effect on raltegravir or emtricitabine pharmacokinetics;1 increased tenofovir plasma concentrations and AUC1

Raltegravir: Dosage adjustments not needed200

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

Rilpivirine

Rilpivirine: No clinically important pharmacokinetic interactions with sofosbuvir/velpatasvir/voxilaprevir1

Fixed combination of emtricitabine, rilpivirine, and tenofovir alafenamide: No clinically important effect on pharmacokinetics of sofosbuvir, velpatasvir, or voxilaprevir1

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

Rilpivirine: Dosage adjustments not needed1 200

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

St. John's wort (Hypericum perforatum)

Possible decreased sofosbuvir, velpatasvir, and voxilaprevir concentrations1

Concomitant use with sofosbuvir/velpatasvir/voxilaprevir not recommended1

Sulfasalazine

Concomitant use with sofosbuvir/velpatasvir/voxilaprevir not recommended1

Tenofovir

Tenofovir alafenamide: No clinically important pharmacokinetic interactions with sofosbuvir/velpatasvir/voxilaprevir1

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

Tenofovir alafenamide: Dosage adjustments not needed if used with sofosbuvir/velpatasvir/voxilaprevir200

Tenofovir DF: Dosage adjustments not needed if used with sofosbuvir/velpatasvir/voxilaprevir;200 monitor for tenofovir-associated adverse effects1

Tipranavir

Ritonavir-boosted tipranavir: Decreased sofosbuvir and velpatasvir concentrations expected;1 effect on voxilaprevir concentrations unknown1

Ritonavir-boosted tipranavir: Concomitant use with sofosbuvir/velpatasvir/voxilaprevir not recommended1 200

Warfarin

INR fluctuations reported in patients receiving warfarin and sofosbuvir/velpatasvir/voxilaprevir;1 subtherapeutic INR reported after initiation of sofosbuvir-containing regimens in patients receiving warfarin26 27 28

Frequently monitor INR during initiation, treatment, and after discontinuation of sofosbuvir-containing regimens1 26 27 28

Vosevi Pharmacokinetics

Absorption

Bioavailability

Following oral administration of sofosbuvir/velpatasvir/voxilaprevir, peak plasma concentrations of sofosbuvir, velpatasvir, and voxilaprevir occur at 2, 4, and 4 hours, respectively, after the dose.1

Food

Administration of sofosbuvir/velpatasvir/voxilaprevir with food increased sofosbuvir exposures by 64–144%, velpatasvir exposures by 40–166%, and voxilaprevir exposures by 112–435%.1

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 Population pharmacokinetic analysis in HCV-infected individuals indicates compensated cirrhosis (Child-Pugh class A) does not substantially affect sofosbuvir or GS-331007 exposures.1

Velpatasvir: In individuals with moderate or severe hepatic impairment (Child-Pugh class B or C) without HCV infection, velpatasvir AUC after single 100-mg dose is similar to that observed in individuals with normal hepatic function.1 Population pharmacokinetic analysis in HCV-infected individuals indicates compensated cirrhosis (Child-Pugh class A) does not substantially affect velpatasvir exposures.1

Voxilaprevir: In HCV-infected individuals with moderate or severe hepatic impairment (Child-Pugh class B or C), sofosbuvir AUC is 299 or 500% higher, respectively, compared with individuals with normal hepatic function.1 Population pharmacokinetic analysis in HCV-infected individuals indicates voxilaprevir exposures are 73% higher in those with compensated cirrhosis (Child-Pugh class A) compared with those 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

Voxilaprevir: In individuals with severe renal impairment without HCV infection, no clinically important differences in voxilaprevir pharmacokinetics after single 100-mg dose compared with healthy individuals.1

Population pharmacokinetic analysis in HCV-infected adults ≤85 years of age indicates age does not have a clinically important effect on sofosbuvir, GS-331007, velpatasvir, or voxilaprevir exposures.1

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

Distribution

Plasma Protein Binding

Sofosbuvir: Approximately 61–65%.1

Velpatasvir: >99%.1

Voxilaprevir: >99%.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

Voxilaprevir: Metabolized by CYP3A4.1

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) and 14% in feces.1 181

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

Voxilaprevir: Major route of elimination is biliary excretion (approximately 40% of a dose eliminated as parent drug).1 Following single 100-mg oral dose, 94% eliminated in feces and no drug in urine.1

Half-life

Sofosbuvir: 0.5 hours;1 GS-331007 has half-life of 29 hours.1

Velpatasvir: 17 hours.1

Voxilaprevir: 33 hours.1

Special Populations

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

Velpatasvir and voxilaprevir: Not expected to be removed to any clinically important extent by hemodialysis.1

Stability

Storage

Oral

Film-coated Tablets

<30ºC.1

Dispense only in original container.1

Actions and Spectrum

  • Sofosbuvir/velpatasvir/voxilaprevir is a fixed combination of 3 HCV antivirals.1 Sofosbuvir is a nucleotide analog HCV NS5B polymerase inhibitor1 , velpatasvir is an HCV NS5A replication complex inhibitor (NS5A inhibitor),1 and voxilaprevir is an HCV nonstructural 3/4A (NS3/4A) protease inhibitor.1

  • Sofosbuvir, velpatasvir, and voxilaprevir are all DAAs with activity against HCV.1 No in vitro evidence of antagonistic anti-HCV effects between sofosbuvir and velpatasvir or voxilaprevir;1 no in vitro evidence of antagonistic anti-HCV effects between velpatasvir and voxilaprevir.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 7 acts as RNA chain terminator.1 In vitro studies using biochemical assays indicate that GS-461203 has activity against HCV genotypes 1b, 2a, 3a, and 4a.1 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 15–110 nM).1

  • Velpatasvir inhibits the HCV NS5A protein, which is required for viral replication.1 7 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

  • Voxilaprevir reversibly binds to the active site of HCV NS3/4A protease, thereby blocking enzyme activity essential for viral replication (i.e., blocking cleavage of the HCV-encoded polyproteins into mature forms of NS3, NS4A, NS4B, NS5A, and NS5B).1 4 5 7 In vitro studies using biochemical assays indicate that voxilaprevir has activity against HCV genotypes 1b and 3a.1 Voxilaprevir has shown in vitro activity against full-length or chimeric replicons of HCV genotypes 1a, 1b, 2a, 2b, 3a, 4a, 4d, 4r, 5a, 6a, 6e, and 6n (median EC50 ranges from 0.2–6.6 nM).1 4

  • 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 not detected in patients who experienced virologic failure or relapsed with sofosbuvir/velpatasvir/voxilaprevir in phase 3 clinical trials (POLARIS-1, POLARIS-4).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/voxilaprevir in patients with HCV genotype 1a (e.g., L31M, Y93H, K24R), genotype 3a (e.g., E92K), or genotype 4 (e.g., Y93H) infection who relapsed or experienced virologic failure.1 Some of these patients also had baseline NS5A polymorphisms at resistance-associated amino acid positions.1

  • Certain amino acid substitutions in NS3/4A protease inhibitor resistance-associated positions of HCV genotypes 1a (e.g., A156 L/T), 1b (e.g., A156T/V), 2a (e.g., A156L/V), 3a (e.g., A156T/V), 4a (e.g., A156L/T/V), 5a, and 6a have been selected in cell culture and have been associated with reduced susceptibility to voxilaprevir in vitro in replicon studies.1 Combinations of these NS3 substitutions often resulted in greater reductions in susceptibility to voxilaprevir compared with a single NS3 substitution.1 Treatment-emergent NS3 resistance-associated substitutions were detected in phase 3 clinical trials evaluating sofosbuvir/velpatasvir/voxilaprevir in patients with HCV genotype 1a (e.g., V36A) or genotype 3a (e.g., Q41K, V55A, R155M) infection who relapsed.1

  • Sofosbuvir, velpatasvir, and voxilaprevir are each active against HCV with substitutions associated with resistance to other HCV DAAs with different mechanisms of action.1 Possibility of cross-resistance among HCV NS3/4A inhibitors and among HCV NS5A inhibitors.1

Advice to Patients

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

  • Advise patients to take sofosbuvir/velpatasvir/voxilaprevir once daily with food on a regular dosing schedule.1

  • Importance of taking the recommended dosage of sofosbuvir/velpatasvir/voxilaprevir 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/voxilaprevir 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

  • 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, Velpatasvir, and Voxilaprevir

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets, film-coated

Sofosbuvir 400 mg, Velpatasvir 100 mg, and Voxilaprevir 100 mg

Vosevi

Gilead

AHFS DI Essentials™. © Copyright 2018, Selected Revisions September 3, 2018. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

References

1. Gilead Sciences, Inc. Vosevi (sofosbuvir, velpatasvir, and voxilaprevir) tablets prescribing information. Foster City, CA; 2017 Nov.

2. Bourlière M, Gordon SC, Flamm SL et al. Sofosbuvir, Velpatasvir, and Voxilaprevir for Previously Treated HCV Infection. N Engl J Med. 2017; 376:2134-2146. http://www.ncbi.nlm.nih.gov/pubmed/28564569?dopt=AbstractPlus

3. Jacobson IM, Lawitz E, Gane EJ et al. Efficacy of 8 Weeks of Sofosbuvir, Velpatasvir, and Voxilaprevir in Patients With Chronic HCV Infection: 2 Phase 3 Randomized Trials. Gastroenterology. 2017; 153:113-122. http://www.ncbi.nlm.nih.gov/pubmed/28390869?dopt=AbstractPlus

4. Lawitz E, Yang JC, Stamm LM et al. Characterization of HCV resistance from a 3-day monotherapy study of voxilaprevir, a novel pangenotypic NS3/4A protease inhibitor. Antivir Ther. 2017; http://www.ncbi.nlm.nih.gov/pubmed/29063860?dopt=AbstractPlus

5. Chahine EB, Kelley D, Childs-Kean LM. Sofosbuvir/Velpatasvir/Voxilaprevir: A Pan-Genotypic Direct-Acting Antiviral Combination for Hepatitis C. Ann Pharmacother. 2017; :1060028017741508. http://www.ncbi.nlm.nih.gov/pubmed/29115151?dopt=AbstractPlus

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. http://www.ncbi.nlm.nih.gov/pubmed/26519191?dopt=AbstractPlus

7. Soriano V, Benítez-Gutiérrez L, Arias A et al. Evaluation of sofosbuvir, velpatasvir plus voxilaprevir as fixed-dose co-formulation for treating hepatitis C. Expert Opin Drug Metab Toxicol. 2017; 13:1015-1022. http://www.ncbi.nlm.nih.gov/pubmed/28753040?dopt=AbstractPlus

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. http://www.fda.gov/downloads/Drugs/DrugSafety/UCM439492.pdf

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. http://www.fda.gov/Drugs/DrugSafety/ucm522932.htm

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. http://www.ncbi.nlm.nih.gov/pubmed/27716978?dopt=AbstractPlus

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. http://www.ncbi.nlm.nih.gov/pubmed/27465881?dopt=AbstractPlus

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. http://www.ncbi.nlm.nih.gov/pubmed/28596225?dopt=AbstractPlus

119. American Association for the Study of Liver Diseases (AASLD) and the Infectious Diseases Society of America. HCV guidance: Recommendations for testing, managing, and treating hepatitis C. From the AASLD website. Accessed 2018 February 15. http://www.hcvguidelines.org

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

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 adults and adolescents living with HIV (October 17, 2017). Updates may be available at HHS AIDS Information (AIDSinfo) website. http://www.aidsinfo.nih.gov

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