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Sofosbuvir, Velpatasvir, and Voxilaprevir

Pronunciation

(soe FOS bue vir, vel PAT as vir, & vox i LA pre vir)

Index Terms

  • Velpatasvir, Voxilaprevir, and Sofosbuvir
  • Voxilaprevir, Velpatasvir, and Sofosbuvir

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Tablet, Oral:

Vosevi: Sofosbuvir 400 mg, velpatasvir 100 mg, and voxilaprevir 100 mg

Brand Names: U.S.

  • Vosevi

Pharmacologic Category

  • Antihepaciviral, NS5A Inhibitor
  • Antihepaciviral, Polymerase Inhibitor (Anti-HCV)
  • NS3/4A Inhibitor
  • NS5A Inhibitor
  • NS5B RNA Polymerase Inhibitor

Pharmacology

Sofosbuvir is an inhibitor of the HCV NS5B RNA-dependent RNA polymerase, which is required for viral replication and acts a s a chain terminator.

Velpatasvir is an inhibitor of the HCV NS5A protein, which is also required for viral replication.

Voxilaprevir is a noncovalent, reversible inhibitor of the NS3/4A protease, which is necessary for the proteolytic cleavage of the HCV-encoded polyprotein (into mature forms of the NS3, NS4A, NS4B, NS5A, and NS5B proteins) and is essential for viral replication.

Use: Labeled Indications

Chronic hepatitis C: Treatment of adults with chronic hepatitis C virus (HCV) infection without cirrhosis or with compensated cirrhosis (Child-Pugh class A) who have genotype 1, 2, 3, 4, 5, or 6 infection and have previously been treated with an HCV regimen containing an NS5A inhibitor or who have genotype 1a or 3 infection and have previously been treated with an HCV regimen containing sofosbuvir without an NS5A inhibitor

Limitations of use: Additional benefit of sofosbuvir/velpatasvir/voxilaprevir over sofosbuvir/velpatasvir was not shown with genotype 1b, 2, 4, 5, or 6 infection previously treated with sofosbuvir without an NS5A inhibitor.

Contraindications

Concurrent use with rifampin

Dosing: Adult

Chronic hepatitis C (without cirrhosis or with compensated cirrhosis [Child-Pugh class A]): Oral:

Genotype 1, 2, 3, 4, 5, or 6 (previously treated with a regimen containing an NS5A inhibitor): One tablet once daily for 12 weeks.

Genotype 1a or 3 (previously treated with a regimen containing sofosbuvir without an NS5A inhibitor): One tablet once daily for 12 weeks.

Dosing: Geriatric

Refer to adult dosing.

Dosing: Renal Impairment

eGFR ≥30 mL/minute/1.73 m2: No dosage adjustment necessary.

eGFR <30 mL/minute/1.73 m2: There are no dosage adjustments provided in the manufacturer's labeling; predominate sofosbuvir metabolite accumulates with impaired renal function.

ESRD requiring hemodialysis: There are no dosage adjustments provided in the manufacturer's labeling; predominate sofosbuvir metabolite accumulates with impaired renal function.

Dosing: Hepatic Impairment

Mild impairment (Child-Pugh class A): No dosage adjustment necessary.

Moderate or severe impairment (Child-Pugh class B or C): Use is not recommended (due to higher voxilaprevir exposure).

Administration

Administer with food.

Storage

Store below 30°C (86ºF); dispense in original container.

Drug Interactions

Afatinib: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Afatinib. Management: Per US labeling: reduce afatinib by 10mg if not tolerated. Per Canadian labeling: avoid combination if possible; if used, administer the P-gp inhibitor simultaneously with or after the dose of afatinib. Consider therapy modification

Amiodarone: Sofosbuvir may enhance the bradycardic effect of Amiodarone. Avoid combination

Antacids: May decrease the serum concentration of Velpatasvir. Management: Separate administration of velpatasvir and antacids by at least 4 hours. Consider therapy modification

Asunaprevir: OATP1B1/SLCO1B1 Inhibitors may increase the serum concentration of Asunaprevir. Avoid combination

Atazanavir: May increase the serum concentration of Voxilaprevir. Avoid combination

BCRP/ABCG2 Substrates: Voxilaprevir may increase the serum concentration of BCRP/ABCG2 Substrates. Avoid combination

Betrixaban: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Betrixaban. Management: Decrease the betrixaban dose to an initial single dose of 80 mg followed by 40 mg once daily if combined with a P-glycoprotein inhibitor. Consider therapy modification

Bilastine: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Bilastine. Management: Consider alternatives when possible; bilastine should be avoided in patients with moderate to severe renal insufficiency who are receiving p-glycoprotein inhibitors. Consider therapy modification

Brentuximab Vedotin: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Brentuximab Vedotin. Specifically, concentrations of the active monomethyl auristatin E (MMAE) component may be increased. Monitor therapy

CarBAMazepine: May decrease the serum concentration of Sofosbuvir. Avoid combination

Celiprolol: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Celiprolol. Monitor therapy

Colchicine: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Colchicine. Colchicine distribution into certain tissues (e.g., brain) may also be increased. Management: Colchicine is contraindicated in patients with impaired renal or hepatic function who are also receiving a p-glycoprotein inhibitor. In those with normal renal and hepatic function, reduce colchicine dose as directed. Consider therapy modification

CYP2B6 Inducers (Moderate): May decrease the serum concentration of Velpatasvir. Avoid combination

CYP2C8 Inducers (Strong): May decrease the serum concentration of Velpatasvir. Avoid combination

CYP3A4 Inducers (Moderate): May decrease the serum concentration of Velpatasvir. Avoid combination

CYP3A4 Inducers (Strong): May decrease the serum concentration of Velpatasvir. Avoid combination

CYP3A4 Inducers (Strong): May decrease the serum concentration of Voxilaprevir. Avoid combination

Dabigatran Etexilate: P-glycoprotein/ABCB1 Inhibitors may increase serum concentrations of the active metabolite(s) of Dabigatran Etexilate. Management: Dabigatran dose reductions may be needed. Specific recommendations vary considerably according to US vs Canadian labeling, specific P-gp inhibitor, renal function, and indication for dabigatran treatment. Refer to full monograph or dabigatran labeling. Consider therapy modification

Deferasirox: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Digoxin: Velpatasvir may increase the serum concentration of Digoxin. Monitor therapy

DOXOrubicin (Conventional): P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of DOXOrubicin (Conventional). Management: Seek alternatives to P-glycoprotein inhibitors in patients treated with doxorubicin whenever possible. One U.S. manufacturer (Pfizer Inc.) recommends that these combinations be avoided. Consider therapy modification

Edoxaban: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Edoxaban. Management: See full monograph for details. Reduced doses are recommended for patients receiving edoxaban for venous thromboembolism in combination with certain inhibitors. Similar dose adjustment is not recommended for edoxaban use in atrial fibrillation. Consider therapy modification

Everolimus: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Everolimus. Management: Everolimus dose reductions are required for patients being treated for subependymal giant cell astrocytoma or renal cell carcinoma. See prescribing information for specific dose adjustment and monitoring recommendations. Consider therapy modification

Grazoprevir: OATP1B1/SLCO1B1 Inhibitors may increase the serum concentration of Grazoprevir. Avoid combination

H2-Antagonists: May decrease the serum concentration of Velpatasvir. Monitor therapy

HMG-CoA Reductase Inhibitors: Voxilaprevir may increase the serum concentration of HMG-CoA Reductase Inhibitors. Management: Use the lowest statin dose possible if combined with voxilaprevir and monitor patients for increased statin effects/toxicities. Avoid concomitant use of voxilaprevir with rosuvastatin or pitavastatin, and limit pravastatin doses to 40 mg daily. Consider therapy modification

Lopinavir: May increase the serum concentration of Voxilaprevir. Avoid combination

Modafinil: May decrease the serum concentration of Sofosbuvir. Avoid combination

Naldemedine: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Naldemedine. Monitor therapy

Naloxegol: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Naloxegol. Monitor therapy

Nilotinib: May decrease the serum concentration of CYP2B6 Substrates. Monitor therapy

OATP1B1/SLCO1B1 Inhibitors: May increase the serum concentration of Voxilaprevir. Avoid combination

OXcarbazepine: May decrease the serum concentration of Sofosbuvir. Avoid combination

PAZOPanib: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of PAZOPanib. Avoid combination

PAZOPanib: BCRP/ABCG2 Inhibitors may increase the serum concentration of PAZOPanib. Avoid combination

P-glycoprotein/ABCB1 Inducers: May decrease the serum concentration of Sofosbuvir. Avoid combination

P-glycoprotein/ABCB1 Inducers: May decrease the serum concentration of Velpatasvir. Avoid combination

P-glycoprotein/ABCB1 Inhibitors: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates. P-glycoprotein inhibitors may also enhance the distribution of p-glycoprotein substrates to specific cells/tissues/organs where p-glycoprotein is present in large amounts (e.g., brain, T-lymphocytes, testes, etc.). Monitor therapy

P-glycoprotein/ABCB1 Substrates: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of P-glycoprotein/ABCB1 Substrates. P-glycoprotein inhibitors may also enhance the distribution of p-glycoprotein substrates to specific cells/tissues/organs where p-glycoprotein is present in large amounts (e.g., brain, T-lymphocytes, testes, etc.). Monitor therapy

PHENobarbital: May decrease the serum concentration of Sofosbuvir. Avoid combination

Pitavastatin: Voxilaprevir may increase the serum concentration of Pitavastatin. Avoid combination

Primidone: May decrease the serum concentration of Sofosbuvir. Avoid combination

Proton Pump Inhibitors: May decrease the serum concentration of Velpatasvir. Avoid combination

Prucalopride: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Prucalopride. Monitor therapy

Ranolazine: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Ranolazine. Monitor therapy

Ranolazine: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates. Monitor therapy

Rifabutin: May decrease the serum concentration of Sofosbuvir. Avoid combination

RifAMPin: May increase the serum concentration of Voxilaprevir. Specifically, a single dose of rifampin may increase voxilaprevir concentrations, while chronic daily use of rifampin may decrease voxilaprevir concentrations. RifAMPin may decrease the serum concentration of Voxilaprevir. Avoid combination

Rifapentine: May decrease the serum concentration of Sofosbuvir. Avoid combination

RifAXIMin: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of RifAXIMin. Monitor therapy

Ritonavir: May decrease the serum concentration of Velpatasvir. Ritonavir may increase the serum concentration of Velpatasvir. Consider therapy modification

Rosuvastatin: Voxilaprevir may increase the serum concentration of Rosuvastatin. Avoid combination

Sarilumab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Silodosin: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Silodosin. Avoid combination

Siltuximab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Tenofovir Disoproxil Fumarate: Velpatasvir may increase the serum concentration of Tenofovir Disoproxil Fumarate. Monitor therapy

Tipranavir: May decrease the serum concentration of Sofosbuvir. Avoid combination

Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Topotecan: Velpatasvir may increase the serum concentration of Topotecan. Avoid combination

Venetoclax: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Venetoclax. Management: Reduce the venetoclax dose by at least 50% in patients requiring these combinations. Consider therapy modification

VinCRIStine (Liposomal): P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of VinCRIStine (Liposomal). Avoid combination

Vitamin K Antagonists (eg, warfarin): Antihepaciviral NS5B RNA Polymerase Inhibitors may diminish the anticoagulant effect of Vitamin K Antagonists. Monitor therapy

Voxilaprevir: OATP1B1/SLCO1B1 Inhibitors may increase the serum concentration of Voxilaprevir. Avoid combination

Adverse Reactions

Also see Sofosbuvir monograph.

>10%:

Central nervous system: Headache (21% to 23%), fatigue (17% to 19%)

Gastrointestinal: Diarrhea (13% to 14%), nausea (10% to 13%)

Hepatic: Increased serum bilirubin (4% to 13%)

1% to 10%:

Central nervous system: Insomnia (3% to 6%), depression (≤1%)

Dermatologic: Skin rash (2%)

Gastrointestinal: Increased serum lipase (2%)

Neuromuscular & skeletal: Weakness (4% to 6%)

<1%, postmarketing, and/or case reports: Increased creatine phosphokinase

ALERT: U.S. Boxed Warning

Hepatitis B virus reactivation:

Test all patients for evidence of current or prior hepatitis B virus (HBV) infection before initiating treatment with sofosbuvir/velpatasvir/voxilaprevir. HBV reactivation has been reported in hepatitis C virus (HCV)/HBV coinfected patients who were undergoing or had completed treatment with HCV direct-acting antivirals and were not receiving HBV antiviral therapy. Some cases have resulted in fulminant hepatitis, hepatic failure, and death. Monitor HCV/HBV coinfected patients for hepatitis flare or HBV reactivation during HCV treatment and post-treatment follow-up. Initiate appropriate patient management for HBV infection as clinically indicated.

Warnings/Precautions

Concerns related to adverse effects:

• Hepatitis B virus reactivation: [US Boxed Warning]: Hepatitis B virus (HBV) reactivation has been reported in hepatitis C virus (HCV)/HBV co-infected patients who were receiving or had completed treatment with HCV direct-acting antivirals and were not receiving HBV antiviral therapy; some cases have resulted in fulminant hepatitis, hepatic failure, and death. Test all patients for evidence of current or prior HBV infection prior to initiation of sofosbuvir/velpatasvir/voxilaprevir; monitor HCV/HBV co-infected patients for hepatitis flare or HBV reactivation during treatment and post-treatment follow-up. Initiate treatment for HBV infection as clinically indicated. HBV reactivation has been reported in HBsAg-positive patients and in patients with serologic evidence of resolved HBV infection (ie, HBsAg negative and anti-HBc positive) and is characterized by an abrupt increase in HBV replication manifested as a rapid increase in serum HBV DNA level; reappearance of HBsAg may occur in patients with resolved HBV infection. Risk of HBV reactivation may be increased in patients receiving certain immunosuppressants or chemotherapeutic agents.

Disease-related concerns:

• Hepatic impairment: Use is not recommended in patients with moderate or severe hepatic impairment (Child-Pugh class B or C).

Concurrent drug therapy issues:

• Amiodarone: Symptomatic bradycardia (some requiring pacemaker intervention) has occurred in patients receiving amiodarone and sofosbuvir in combination with daclatasvir or simeprevir. A fatal cardiac arrest was reported in a patient taking amiodarone with sofosbuvir/ledipasvir-containing regimen. Bradycardia generally occurred within hours to days following coadministration; however, some cases have occurred 2 weeks following the initiation of HCV treatment. The risk of bradycardia may be increased in patients taking beta blockers or patients with underlying cardiac comorbidities and/or advanced liver disease. Bradycardia generally resolves following discontinuation. Coadministration of amiodarone and sofosbuvir/velpatasvir/voxilaprevir is not recommended. However, if patients have no treatment alternatives, patients should have inpatient cardiac monitoring for the first 48 hours, followed by daily outpatient or self-monitoring of heart rate for at least the first 2 weeks of treatment. Due to the long half-life of amiodarone, cardiac monitoring (as described) is also recommended if amiodarone was discontinued just prior to beginning treatment with sofosbuvir/velpatasvir/voxilaprevir. Patients should seek medical attention immediately if they experience fainting or near-fainting, dizziness, light-headedness, malaise, weakness, excessive tiredness, shortness of breath, chest pains, confusion, or memory problems.

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions for more detailed information.

Monitoring Parameters

Baseline (within 12 weeks prior to starting antiviral therapy) CBC, INR, hepatic function panel (albumin, total and direct bilirubin, ALT, AST, and alkaline phosphatase), and calculated GFR; repeat CBC, serum creatinine, calculated GFR, and hepatic function panel after 4 weeks of therapy and as clinically indicated; baseline (at any time prior to starting therapy) HCV genotype and subtype and quantitative HCV viral load; repeat quantitative HCV viral load testing (after 4 weeks of therapy and at 12 weeks after completion of therapy). If quantitative HCV viral load is detectable at treatment week 4, repeat testing is recommended after 2 additional weeks of treatment (treatment week 6) (AASLD/IDSA 2017). Hepatitis B surface antigen (HBsAg) and hepatitis B core antibody (anti-HBc) prior to initiation; in patients with serologic evidence of hepatitis B virus (HBV) infection, monitor for clinical and laboratory signs of hepatitis flare or HBV reactivation during treatment and during post-treatment follow-up.

If used in combination with amiodarone (or in patients who discontinued amiodarone just prior to initiating sofosbuvir/velpatasvir), inpatient cardiac monitoring for the first 48 hours of coadministration, then outpatient or self-monitoring of heart rate daily through at least the first 2 weeks of treatment.

Pregnancy Considerations

Adverse events were not observed in animal reproduction studies using individual components of this combination. Also refer to sofosbuvir monograph.

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