Sofosbuvir, Velpatasvir, And Voxilaprevir (Monograph)

Brand name: Vosevi
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: C₂₂H₂₉FN₃O₉PC₄₉H₅₄N₈O₈C₄₀H₅₂F₄N₆O₉S
CAS number: 1190307-88-0

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

Warning

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. (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).
Monitor patients coinfected with HCV and HBV for hepatitis flare or HBV reactivation during and after HCV treatment. Initiate appropriate management for HBV infection as clinically indicated.

Introduction

HCV antiviral; 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).

Uses for Sofosbuvir, Velpatasvir, And Voxilaprevir

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 without cirrhosis or with compensated cirrhosis (Child-Pugh class A).

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 without cirrhosis or with compensated cirrhosis (Child-Pugh class A).

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

Sofosbuvir, Velpatasvir, And Voxilaprevir Dosage and Administration

General

Pretreatment Screening

Prior to initiating HCV treatment, test all patients for evidence of current or prior HBV infection by measuring hepatitis B surface antigen (HBsAg), hepatitis B surface antibody (anti-HBs), and hepatitis B core antibody (anti-HBc).
In patients with serologic evidence of HBV infection, measure baseline HBV DNA level.
Perform appropriate laboratory tests to evaluate liver function.

Patient Monitoring

Perform appropriate laboratory tests to evaluate liver function during therapy.
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.

Other General Considerations

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

Administration

Oral Administration

Administer orally once daily with food.

Dosage

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

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.

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.

Special Populations

Hepatic Impairment

Mild hepatic impairment (Child-Pugh class A): Dosage adjustments not needed. Monitor for signs and symptoms of hepatic decompensation. (See Hepatic Impairment under Cautions.)

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

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. (See Geriatric Use under Cautions.)

Cautions for Sofosbuvir, Velpatasvir, And Voxilaprevir

Contraindications

Concomitant use with rifampin.

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 were 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/voxilaprevir, screen all patients for evidence of current or prior HBV infection by measuring HBsAg, anti-HBs, and anti-HBc. If there is serologic evidence of HBV infection, measure baseline HBV DNA level.

In all patients with evidence of current or prior HBV infection, monitor for clinical and laboratory signs (i.e., HBsAg, HBV DNA levels, serum aminotransferase and bilirubin concentrations) of hepatitis flare or HBV reactivation during and after treatment with HCV DAAs. Initiate appropriate management for HBV infection as clinically indicated

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

When making decisions regarding HBV monitoring or HBV treatment in coinfected patients, consult a clinician with expertise in managing HBV infection.

Other Warnings/Precautions

Risk of Hepatic Decompensation or Failure in Patients with Evidence of Advanced Liver Disease

Postmarketing reports of hepatic decompensation or failure, including some fatalities, in patients receiving HCV treatment regimens that contain an HCV NS3/4A protease inhibitor, including sofosbuvir/velpatasvir/voxilaprevir. Data insufficient to estimate frequency of such events; causal relationship not established. Hepatic decompensation or failure usually occurred within first 4 weeks of HCV treatment.

Many of the reported cases of hepatic decompensation or failure occurred in patients with evidence of advanced liver disease with moderate or severe hepatic impairment (Child-Pugh class B or C) prior to initiation of HCV treatment. Some cases occurred in patients reported as noncirrhotic or as having compensated cirrhosis with mild liver impairment (Child-Pugh class A) at baseline, but with a history of a decompensation event or evidence of portal hypertension or decreased platelet counts at baseline. Some cases also reported in patients who had confounding factors (e.g., serious liver-related comorbidities).

If sofosbuvir/velpatasvir/voxilaprevir used in patients who have compensated cirrhosis (Child-Pugh class A) or evidence of advanced liver disease (e.g., portal hypertension), perform hepatic function tests as clinically indicated and monitor for signs and symptoms of hepatic decompensation (e.g., jaundice, ascites, hepatic encephalopathy, variceal hemorrhage).

Sofosbuvir/velpatasvir/voxilaprevir not recommended in patients with moderate or severe hepatic impairment (Child-Pugh class B or C) or any history of hepatic decompensation.

Discontinue the drug in patients who develop evidence of hepatic decompensation or failure. (See Hepatic Impairment under Cautions.)

Advise patients to contact a clinician if they develop any signs or symptoms of worsening liver disease. (See Advice to Patients.)

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 daclatasvir or simeprevir (no longer commercially available). Fatal cardiac arrest reported in one patient receiving 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 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.

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

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

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.

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. (See Interactions.)

Precautions Related to Fixed Combinations

Consider cautions, precautions, contraindications, and drug interactions associated with each drug in the fixed combination. 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.

Specific Populations

Pregnancy

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

Lactation

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

Pediatric Use

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

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

Mild hepatic impairment or compensated cirrhosis (Child-Pugh class A): Monitor for signs and symptoms of hepatic decompensation (e.g., jaundice, ascites, hepatic encephalopathy, variceal hemorrhage).

Moderate or severe hepatic impairment (Child-Pugh class B or C) or any history of hepatic decompensation: Not recommended. Postmarketing reports of hepatic decompensation or failure in such patients. (See Risk of Hepatic Decompensation or Failure in Patients with Evidence of Advanced Liver Disease under Cautions.)

Increased sofosbuvir and voxilaprevir exposures in patients with hepatic impairment. (See Pharmacokinetics.)

Renal Impairment

Mild, moderate, or severe renal impairment, including ESRD undergoing dialysis: Dosage adjustments not needed. (See Pharmacokinetics.)

Common Adverse Effects

Adverse reactions occurring in ≥10% of patients: Headache, fatigue, diarrhea, nausea, asthenia, insomnia.

Drug Interactions

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.

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

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

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

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. When sofosbuvir/velpatasvir/voxilaprevir used, consider interactions associated with each drug in the fixed combination.

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

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

Drugs Affecting or Affected by P-glycoprotein Transport System

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

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

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

Drugs Affecting or Affected by Breast Cancer Resistance Protein

BCRP substrates: Possible altered exposure of such substrates.

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

Drugs Affecting or Affected by Organic Anion Transporting Polypeptides

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

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

Specific Drugs

Drug	Interaction	Comments
Antacids (aluminum and magnesium hydroxides)	Decreased velpatasvir concentrations expected; increased gastric pH decreases velpatasvir solubility	Take antacids 4 hours before or after sofosbuvir/velpatasvir/voxilaprevir
Antiarrhythmic agents (amiodarone)	Amiodarone: Concomitant use with sofosbuvir/velpatasvir/voxilaprevir may result in serious symptomatic bradycardia; effect on amiodarone, sofosbuvir, velpatasvir, and voxilaprevir concentrations unknown	Amiodarone: Concomitant use with sofosbuvir/velpatasvir/voxilaprevir not recommended; if concomitant use necessary, patient counseling and cardiac monitoring required (see Cardiovascular Effects under Cautions)
Anticonvulsants (carbamazepine, oxcarbazepine, phenobarbital, phenytoin)	Carbamazepine, oxcarbazepine, phenobarbital, phenytoin: Decreased sofosbuvir, velpatasvir, and voxilaprevir concentrations expected	Carbamazepine, oxcarbazepine, phenobarbital, phenytoin: Concomitant use with sofosbuvir/velpatasvir/voxilaprevir not recommended
Antifungals, azoles (ketoconazole, voriconazole)	Ketoconazole: No clinically important pharmacokinetic interactions with sofosbuvir or velpatasvir Voriconazole: No clinically important pharmacokinetic interactions
Antimycobacterial agents (rifabutin, rifampin, rifapentine)	Rifabutin, rifapentine: Decreased sofosbuvir, velpatasvir, and voxilaprevir concentrations expected Rifampin: Decreased sofosbuvir, velpatasvir, and voxilaprevir concentrations and AUCs; increased voxilaprevir concentrations when a single dose used concomitantly with single dose of rifampin	Rifabutin, rifapentine: Concomitant use with sofosbuvir/velpatasvir/voxilaprevir not recommended Rifampin: Concomitant use with sofosbuvir/velpatasvir/voxilaprevir contraindicated
Antineoplastic agents (imatinib, irinotecan, lapatinib, methotrexate, mitoxantrone, topotecan)		Imatinib, irinotecan, lapatinib, methotrexate, mitoxantrone, topotecan: Concomitant use with sofosbuvir/velpatasvir/voxilaprevir not recommended
Antiretrovirals, HIV entry and fusion inhibitors	Maraviroc: Clinically important effect on maraviroc pharmacokinetics not expected	Maraviroc: Dosage adjustments not needed
Antiretrovirals, HIV integrase inhibitors (INSTIs)	Bictegravir: Pharmacokinetic interactions not expected Dolutegravir: No clinically important pharmacokinetic interactions with sofosbuvir/velpatasvir Cobicistat-boosted elvitegravir: Increased sofosbuvir and voxilaprevir AUCs; no effect on velpatasvir concentrations Fixed combination of elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide fumarate (EVG/c/FTC/TAF): No clinically important pharmacokinetic interactions Fixed combination of elvitegravir, cobicistat, emtricitabine, and tenofovir disoproxil fumarate (EVG/c/FTC/TDF): Possible increased tenofovir concentrations Raltegravir: No clinically important pharmacokinetic interactions when used with sofosbuvir/velpatasvir HIV antiretroviral regimen of raltegravir in conjunction with emtricitabine/TDF: When used concomitantly with sofosbuvir/velpatasvir, no clinically important effect on raltegravir or emtricitabine pharmacokinetics; increased tenofovir plasma concentrations and AUC	Bictegravir: Dosage adjustments not needed Dolutegravir: Dosage adjustments not needed Cobicistat-boosted elvitegravir: Dosage adjustments not needed EVG/c/FTC/TDF: Monitor for tenofovir-associated adverse effects Raltegravir: Dosage adjustments not needed HIV antiretroviral regimens that include raltegravir and TDF: Monitor for tenofovir-associated adverse effects
Antiretrovirals, HIV nonnucleoside reverse transcriptase inhibitors (NNRTIs)	Doravirine: Clinically important pharmacokinetic interactions not expected Efavirenz: Decreased velpatasvir and voxilaprevir concentrations expected Fixed combination of efavirenz, emtricitabine, and TDF (efavirenz/emtricitabine/TDF): When used concomitantly with sofosbuvir/velpatasvir, no clinically important effect on sofosbuvir pharmacokinetics; decreased velpatasvir concentrations and AUC; increased tenofovir concentrations and AUC Etravirine: Decreased velpatasvir and voxilaprevir concentrations expected Nevirapine: Decreased velpatasvir and voxilaprevir concentrations expected Rilpivirine: No clinically important pharmacokinetic interactions with sofosbuvir/velpatasvir/voxilaprevir Fixed combination of emtricitabine, rilpivirine, and TAF: No clinically important effect on pharmacokinetics of sofosbuvir, velpatasvir, or voxilaprevir Fixed combination of emtricitabine, rilpivirine, and TDF (emtricitabine/rilpivirine/TDF): No clinically important effect on emtricitabine or rilpivirine pharmacokinetics; increased tenofovir concentrations and AUC	Doravirine: Dosage adjustments not needed Efavirenz: Concomitant use with sofosbuvir/velpatasvir/voxilaprevir not recommended Etravirine: Concomitant use with sofosbuvir/velpatasvir/voxilaprevir not recommended Nevirapine: Concomitant use with sofosbuvir/velpatasvir/voxilaprevir not recommended Rilpivirine: Dosage adjustments not needed HIV antiretroviral regimens that include rilpivirine and TDF: Monitor for tenofovir-associated adverse effects
Antiretrovirals, HIV nucleoside and nucleotide reverse transcriptase inhibitors (NRTIs)	Emtricitabine: No clinically important pharmacokinetic interactions with sofosbuvir/velpatasvir/voxilaprevir TAF: No clinically important pharmacokinetic interactions with sofosbuvir/velpatasvir/voxilaprevir TDF and HIV antiretroviral regimens that include TDF: Possible increased tenofovir concentrations and AUC	TAF: Dosage adjustments not needed if used with sofosbuvir/velpatasvir/voxilaprevir TDF and HIV antiretroviral regimens that include TDF: If used with sofosbuvir/velpatasvir/voxilaprevir, monitor for tenofovir-associated adverse effects; some experts state consider TAF instead of TDF in patients at risk of TDF-associated adverse effects
Antiretrovirals, HIV protease inhibitors (PIs)	Ritonavir-boosted atazanavir: Substantially increased voxilaprevir concentrations and AUC Darunavir: No clinically important pharmacokinetic interactions HIV antiretroviral regimen of ritonavir-boosted darunavir in conjunction with fixed combination of emtricitabine and TDF (emtricitabine/TDF): Decreased sofosbuvir and velpatasvir concentrations and AUC; increased voxilaprevir and tenofovir concentrations and AUC Fixed combination of lopinavir and ritonavir (lopinavir/ritonavir): Increased voxilaprevir concentrations expected Ritonavir-boosted tipranavir: Decreased sofosbuvir and velpatasvir concentrations expected; effect on voxilaprevir concentrations unknown	Ritonavir-boosted, cobicistat-boosted, or unboosted atazanavir: Concomitant use with sofosbuvir/velpatasvir/voxilaprevir not recommended Ritonavir-boosted or cobicistat-boosted darunavir: Dosage adjustments not needed if used with sofosbuvir/velpatasvir/voxilaprevir HIV antiretroviral regimens that include ritonavir-boosted darunavir and TDF: Monitor for tenofovir-associated adverse effects Lopinavir/ritonavir: Concomitant use with sofosbuvir/velpatasvir/voxilaprevir not recommended Ritonavir-boosted tipranavir: Concomitant use with sofosbuvir/velpatasvir/voxilaprevir not recommended
Dabigatran	Concomitant use with sofosbuvir/velpatasvir/voxilaprevir results in increased dabigatran concentrations and AUC	Monitor dabigatran clinical effects
Digoxin	Increased digoxin concentrations and AUC when used concomitantly with velpatasvir	Digoxin therapeutic concentration monitoring recommended if used concomitantly with sofosbuvir/velpatasvir/voxilaprevir
Estrogens/progestins	Oral contraceptive containing ethinyl estradiol and norgestimate: No clinically important effects on pharmacokinetics of ethinyl estradiol or norgestimate
Gemfibrozil	No clinically important pharmacokinetic interactions with sofosbuvir/velpatasvir/voxilaprevir
Histamine H₂-receptor antagonists	Decreased velpatasvir concentrations expected; increased gastric pH decreases velpatasvir solubility	Administer H₂-antagonists concurrently with or staggered with sofosbuvir/velpatasvir; do not exceed H₂-antagonist dosages comparable to famotidine 40 mg twice daily
HMG-CoA reductase inhibitors (statins)	Atorvastatin: Increased atorvastatin concentrations and AUC when used with sofosbuvir/velpatasvir; increased risk of myopathy and rhabdomyolysis Fluvastatin, lovastatin, simvastatin: Possible increased statin concentrations with increased risk of myopathy and rhabdomyolysis Pitavastatin: Possible increased pitavastatin concentrations with increased risk of myopathy and rhabdomyolysis Pravastatin: Increased pravastatin concentrations and AUC; increased risk of myopathy and rhabdomyolysis Rosuvastatin: Increased rosuvastatin concentrations and AUC; increased risk of myopathy and rhabdomyolysis	Atorvastatin: If used with sofosbuvir/velpatasvir/voxilaprevir, use lowest atorvastatin dosage; if higher dosage required, use lowest necessary dosage taking into account risks and benefits Fluvastatin, lovastatin, simvastatin: If used with sofosbuvir/velpatasvir/voxilaprevir, use lowest statin dosage; if higher statin dosages required, use lowest necessary dosage taking into account risks and benefits Pitavastatin: Concomitant use with sofosbuvir/velpatasvir/voxilaprevir not recommended Pravastatin: If used concomitantly with sofosbuvir/velpatasvir/voxilaprevir, do not exceed pravastatin dose of 40 mg Rosuvastatin: Concomitant use with sofosbuvir/velpatasvir/voxilaprevir not recommended
Immunosuppressants (cyclosporine, tacrolimus)	Cyclosporine: Substantially increased voxilaprevir exposures when used with voxilaprevir; increased sofosbuvir or velpatasvir exposures with sofosbuvir or velpatasvir Tacrolimus: No clinically important pharmacokinetic interactions with sofosbuvir	Cyclosporine: Concomitant use with sofosbuvir/velpatasvir/voxilaprevir not recommended
Methadone	No clinically important pharmacokinetic interactions with sofosbuvir
Proton-pump inhibitors	Omeprazole: Decreased velpatasvir exposure when 20 mg administered 2 hours before or 4 hours after sofosbuvir/velpatasvir/voxilaprevir Other proton-pump inhibitors: Decreased velpatasvir concentrations expected; increased gastric pH decreases velpatasvir solubility	Omeprazole: If used concomitantly with sofosbuvir/velpatasvir/voxilaprevir, use omeprazole dosage of 20 mg Other proton-pump inhibitors: Concomitant use not studied
St. John's wort (Hypericum perforatum)	Possible decreased sofosbuvir, velpatasvir, and voxilaprevir concentrations	Concomitant use with sofosbuvir/velpatasvir/voxilaprevir not recommended
Sulfasalazine		Concomitant use with sofosbuvir/velpatasvir/voxilaprevir not recommended
Warfarin	Possible INR fluctuations in patients receiving warfarin and sofosbuvir/velpatasvir/voxilaprevir; subtherapeutic INR reported after initiation of sofosbuvir-containing regimens in patients receiving warfarin	Frequently monitor INR during initiation, treatment, and after discontinuance of sofosbuvir-containing regimens; may need to adjust warfarin dosage

Sofosbuvir, Velpatasvir, And Voxilaprevir 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.

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%.

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

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. Population pharmacokinetic analysis in HCV-infected individuals indicates compensated cirrhosis (Child-Pugh class A) does not substantially affect velpatasvir exposures.

Voxilaprevir: In individuals with moderate or severe hepatic impairment (Child-Pugh class B or C) without HCV infection, voxilaprevir AUC is 299 or 500% higher, respectively, compared with individuals with normal hepatic function. 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.

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.

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.

HCV-infected individuals with ESRD requiring dialysis receiving fixed combination of sofosbuvir and velpatasvir (sofosbuvir/velpatasvir): Pharmacokinetics of sofosbuvir, GS-331007, and velpatasvir similar to that reported in those without HCV infection with ESRD requiring dialysis. Pharmacokinetics of voxilaprevir not studied in individuals with ESRD; voxilaprevir exposures in HCV-infected individuals with ESRD requiring dialysis receiving sofosbuvir/velpatasvir/voxilaprevir not expected to be affected to any clinically important extent compared with exposures in those with normal renal function.

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.

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

Distribution

Plasma Protein Binding

Sofosbuvir: Approximately 61–65%.

Velpatasvir: >99%.

Voxilaprevir: >99%.

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.

Voxilaprevir: Metabolized by CYP3A4.

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 single 100-mg oral dose, 94% eliminated in feces and 0.4% in urine.

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

Half-life

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

Velpatasvir: 17 hours.

Voxilaprevir: 33 hours.

Special Populations

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

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

Stability

Storage

Oral

Film-coated Tablets

<30ºC.

Dispense only in original container.

Actions and Spectrum

Sofosbuvir/velpatasvir/voxilaprevir is a fixed combination of 3 HCV antivirals. Sofosbuvir is a nucleotide analog HCV NS5B polymerase inhibitor , velpatasvir is an HCV NS5A replication complex inhibitor (NS5A inhibitor), and voxilaprevir is an HCV nonstructural 3/4A (NS3/4A) protease inhibitor.
Sofosbuvir, velpatasvir, and voxilaprevir are all DAAs with activity against HCV. No in vitro evidence of antagonistic anti-HCV effects between sofosbuvir and velpatasvir or voxilaprevir; no in vitro evidence of antagonistic anti-HCV effects between velpatasvir and voxilaprevir.
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 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 15–110 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).
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). In vitro studies using biochemical assays indicate that voxilaprevir has activity against HCV genotypes 1b and 3a. 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).
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 not detected in patients who experienced virologic failure or relapsed with sofosbuvir/velpatasvir/voxilaprevir in phase 3 clinical trials (POLARIS-1, POLARIS-4).
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/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. Some of these patients also had baseline NS5A polymorphisms at resistance-associated amino acid positions.
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. Combinations of these NS3 substitutions often resulted in greater reductions in susceptibility to voxilaprevir compared with a single NS3 substitution. 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.
Sofosbuvir, velpatasvir, and voxilaprevir are each active against HCV with substitutions associated with resistance to other HCV DAAs with different mechanisms of action. Possibility of cross-resistance among HCV NS3/4A inhibitors and among HCV NS5A inhibitors.

Advice to Patients

Importance of reading patient information provided by the manufacturer.
Advise patients to take sofosbuvir/velpatasvir/voxilaprevir once daily with food on a regular dosing schedule.
Importance of taking the recommended dosage of sofosbuvir/velpatasvir/voxilaprevir 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. (See Risk of HBV Reactivation in Patients Coinfected with HCV and HBV under Cautions.)
Advise patients to immediately contact a clinician if they have symptoms of worsening liver problems (e.g., nausea, tiredness, yellowing of skin or white part of the eyes, bleeding or bruising more easily than normal, confusion, loss of appetite, diarrhea, dark or brown urine, dark or bloody stool, abdominal swelling, pain in upper right side of stomach area, sleepiness, vomiting of blood). (See Risk of Hepatic Decompensation or Failure in Patients with Evidence of Advanced Liver Disease 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. (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.
Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.
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.