Vosevi - Drug Monograph

Introduction

Vosevi (sofosbuvir/velpatasvir/voxilaprevir) is a fixed-dose combination antiviral medication approved by the FDA in July 2017 for the treatment of chronic hepatitis C virus (HCV) infection. It represents the first single-tablet regimen approved for patients who have previously failed certain direct-acting antiviral (DAA) therapies. Vosevi combines three potent antiviral agents targeting different stages of the HCV lifecycle, offering a salvage therapy option for difficult-to-treat populations.

Mechanism of Action

Vosevi contains three distinct antiviral agents with complementary mechanisms:

• Sofosbuvir: A nucleotide analog NS5B polymerase inhibitor that acts as a chain terminator during viral RNA replication
• Velpatasvir: An NS5A inhibitor that disrupts HCV replication complex formation and virion assembly
• Voxilaprevir: An NS3/4A protease inhibitor that prevents cleavage of the HCV polyprotein into mature viral proteins

This triple combination provides synergistic antiviral activity against HCV genotypes 1-6, with each component targeting different non-structural proteins essential for viral replication.

Indications

Vosevi is indicated for:

• Treatment of chronic HCV genotype 1, 2, 3, 4, 5, or 6 infection in adults:

- Without cirrhosis or with compensated cirrhosis (Child-Pugh A) - Who have previously been treated with an HCV regimen containing an NS5A inhibitor - Who have previously been treated with an HCV regimen containing sofosbuvir without an NS5A inhibitor

Dosage and Administration

• 12 weeks for all approved indications

• Renal impairment: No dosage adjustment required in any degree of renal impairment, including end-stage renal disease requiring hemodialysis
• Hepatic impairment: Not recommended in patients with moderate to severe hepatic impairment (Child-Pugh B or C)
• Elderly: No dosage adjustment required
• Pediatric: Safety and effectiveness not established in patients under 18 years

Pharmacokinetics

• Peak plasma concentrations reached in 0.5-5 hours for components
• Food increases voxilaprevir exposure approximately 2-fold

• Sofosbuvir and velpatasvir >99% plasma protein bound
• Voxilaprevir >99% plasma protein bound
• Extensive tissue distribution

• Sofosbuvir: Activated in hepatocytes to pharmacologically active GS-461203
• Velpatasvir: Metabolized primarily by CYP2B6, CYP2C8, and CYP3A4
• Voxilaprevir: Metabolized primarily by CYP3A4

• Sofosbuvir: Renal elimination (80%) and fecal elimination (14%)
• Velpatasvir: Primarily biliary excretion (>99%)
• Voxilaprevir: Primarily biliary excretion (>99%)
• Half-lives: Sofosbuvir 0.5 hr, GS-461203 27 hr, velpatasvir 15 hr, voxilaprevir 33 hr

Contraindications

• Hypersensitivity to any component of Vosevi
• Concomitant use with strong inducers of CYP3A4 (e.g., rifampin, St. John's wort, carbamazepine, phenytoin)
• Concomitant use with certain drugs that are highly dependent on CYP3A4 for clearance and have narrow therapeutic indices (e.g., alfuzosin, ergot derivatives)

Warnings and Precautions

Drug Interactions

• Strong CYP3A inducers: Contraindicated (significantly decrease voxilaprevir and velpatasvir concentrations)
• Moderate CYP3A inducers: Not recommended (may decrease concentrations)
• Strong CYP3A inhibitors: Not recommended (may increase voxilaprevir concentrations)
• P-gp inducers: May decrease sofosbuvir concentrations
• OATP1B1/1B3 inhibitors: May increase voxilaprevir concentrations
• Acid-reducing agents: May decrease velpatasvir concentrations

• Anticonvulsants: Carbamazepine, phenytoin, phenobarbital
• Antimicrobials: Rifampin, rifabutin, clarithromycin
• Herbal products: St. John's wort
• HIV medications: Efavirenz, etravirine, nevirapine

Adverse Effects

• Headache
• Fatigue
• Diarrhea
• Nausea

• Hepatotoxicity
• Bradycardia (with amiodarone coadministration)
• Hepatitis B reactivation

Monitoring Parameters

• HCV RNA levels at baseline, during treatment, and post-treatment to assess virologic response
• Liver function tests (ALT, AST, bilirubin) at baseline and during treatment
• HBV screening before initiation
• Serum creatinine and estimated GFR
• Signs and symptoms of hepatic decompensation
• Medication adherence assessment

Patient Education

• Take exactly as prescribed: one tablet daily with food
• Do not discontinue without consulting healthcare provider
• Inform all healthcare providers about all medications being taken, including over-the-counter drugs and herbal supplements
• Report any symptoms of liver problems (fatigue, weakness, loss of appetite, nausea, vomiting, yellowing of skin/eyes)
• Use effective contraception during treatment and for extended period after treatment as recommended
• Keep all follow-up appointments for monitoring
• Do not share medication with others

References

1. FDA prescribing information for Vosevi. (2022). Accessible at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/209195s009lbl.pdf 2. Bourlière M, et al. Sofosbuvir, Velpatasvir, and Voxilaprevir for Previously Treated HCV Infection. N Engl J Med. 2017;376(22):2134-2146. 3. AASLD/IDSA HCV Guidance Panel. Hepatitis C guidance 2019 update: AASLD-IDSA recommendations for testing, managing, and treating hepatitis C virus infection. Hepatology. 2020;71(2):686-721. 4. Poordad F, et al. Glecaprevir and pibrentasvir for 12 weeks for hepatitis C virus genotype 1 infection and prior direct-acting antiviral treatment. Hepatology. 2017;66(2):389-397. 5. Jacobson IM, et al. Safety and efficacy of elbasvir/grazoprevir in patients with hepatitis C virus infection and compensated cirrhosis: an integrated analysis. Gastroenterology. 2017;152(6):1372-1382.