VOSEVI
Clinical safety rating: caution
Comprehensive clinical and safety monograph for VOSEVI (VOSEVI).
VOSEVI (sofosbuvir, velpatasvir, and voxilaprevir) is a fixed-dose combination of a nucleotide analog NS5B polymerase inhibitor (sofosbuvir), an NS5A inhibitor (velpatasvir), and a NS3/4A protease inhibitor (voxilaprevir). The combination inhibits hepatitis C virus replication by targeting multiple viral proteins.
| Metabolism | Sofosbuvir is metabolized by cathepsin A and CES1 to the active metabolite GS-461203, followed by dephosphorylation. Velpatasvir and voxilaprevir are metabolized by CYP2B6, CYP2C8, CYP3A4 (minor). Voxilaprevir is also a substrate of OATP1B1/1B3. |
| Excretion | Sofosbuvir: 80% renal, 14% fecal; Velpatasvir: 94% fecal, 0.4% renal; Voxilaprevir: 40% renal, 47% fecal. VOSEVI components are eliminated primarily via biliary/fecal (velpatasvir, voxilaprevir) and renal (sofosbuvir) pathways. |
| Half-life | Sofosbuvir: 0.5 h (parent), 27 h (GS-331007 metabolite); Velpatasvir: 17 h; Voxilaprevir: 33 h. Terminal half-lives support once-daily dosing; metabolite GS-331007 accumulates but is less active. |
| Protein binding | Sofosbuvir: ~85% bound; Velpatasvir: >99.5% bound; Voxilaprevir: >99% bound. Primarily to albumin. |
| Volume of Distribution | Sofosbuvir: ~1.8 L/kg; Velpatasvir: ~4.9 L/kg; Voxilaprevir: ~3.9 L/kg. Large Vd indicates extensive tissue distribution, including liver (target organ). |
| Bioavailability | Oral: sofosbuvir ~92%, velpatasvir ~29%, voxilaprevir ~44% (fasted). Administer with food to increase absorption (especially voxilaprevir AUC 2- to 4-fold). |
| Onset of Action | Oral: rapid absorption; sofosbuvir peak at 0.5-2 h, velpatasvir peak at 3 h, voxilaprevir peak at 4 h. Antiviral effect begins within hours of first dose, with viral RNA decline detectable by day 1. |
| Duration of Action | Sustained viral suppression for 12 weeks (standard course). Clinical cure (SVR12) achieved post-treatment. Duration of action is prolonged due to high potency and barrier to resistance. |
| Molecular Weight | Sofosbuvir: 529.45; Velpatasvir: 883.0; Voxilaprevir: 1321.0; combination product average ~600-900 overall. |
One tablet (sofosbuvir 400 mg/velpatasvir 100 mg/voxilaprevir 100 mg) orally once daily with food for 8 weeks.
| Dosage form | TABLET |
| Renal impairment | No dose adjustment required for mild to moderate renal impairment (eGFR ≥30 mL/min/1.73 m²). For severe renal impairment (eGFR <30 mL/min/1.73 m²) or end-stage renal disease, safety and efficacy not established; use not recommended. |
| Liver impairment | Contraindicated in Child-Pugh class B or C decompensated cirrhosis due to increased voxilaprevir exposure. No dose adjustment required for Child-Pugh class A cirrhosis. |
| Pediatric use | Safety and efficacy in pediatric patients <18 years have not been established; no specific dosing recommendations. |
| Geriatric use | No dose adjustment required based on age. Clinical studies included patients ≥65 years with no overall differences in safety or efficacy; consider renal function monitoring. |
| 1st trimester | Contraindicated due to risk of teratogenicity (ribavirin component). |
| 2nd trimester | Contraindicated due to ribavirin risk; avoid in pregnancy. |
| 3rd trimester | Contraindicated due to ribavirin risk; avoid in pregnancy. |
Clinical note
Comprehensive clinical and safety monograph for VOSEVI (VOSEVI).
| Placental transfer | Ribavirin has significant placental transfer and accumulates in fetal tissue; sofosbuvir and velpatasvir transfer to a lesser degree. |
| Breastfeeding | Excretion in human milk unknown; not recommended due to potential adverse effects in nursing infant. |
| Lactation Rating |
■ FDA Black Box Warning
Risk of hepatitis B virus reactivation in patients coinfected with HCV and HBV. Test all patients for evidence of current or prior HBV infection before starting treatment. Monitor HCV/HBV coinfected patients for hepatitis B reactivation during treatment and post-treatment follow-up.
| Serious Effects |
PregnancyCoadministration with rifampinSevere hepatic impairment (Child-Pugh C)
| Precautions | Risk of HBV reactivation, Risk of bradycardia when coadministered with amiodarone; avoid use unless alternatives are not available, Decompensated hepatic impairment: not recommended for use in patients with moderate or severe hepatic impairment (Child-Pugh B or C), Drug interactions: potential for reduced therapeutic effect if given with P-gp inducers (e.g., rifampin) or moderate/strong CYP inducers |
| Food/Dietary | VOSEVI should be taken with food to ensure adequate absorption. A high-fat meal (approximately 800–1000 calories, 50% fat) increases absorption of velpatasvir and voxilaprevir. Avoid concurrent use with St. John's wort, rifampin, and other P-glycoprotein inducers, as they may reduce VOSEVI efficacy. |
Loading safety data…
| L5 - Avoid |
| Teratogenic Risk | VOSEVI is contraindicated in pregnancy due to risk of fetal harm. No adequate human data; animal studies show developmental toxicity at clinically relevant exposures. Use effective contraception during treatment and for 6 months after completion. |
| Fetal Monitoring | Pregnancy test before initiation and monthly during treatment. Monitor for drug interactions (e.g., with hormonal contraceptives). Hepatic function should be monitored per standard of care. |
| Fertility Effects | No effects on fertility demonstrated in animal studies. Human data insufficient. No impact on spermatogenesis or oogenesis anticipated based on mechanism. |
| Clinical Pearls | VOSEVI is a fixed-dose combination of sofosbuvir (NS5B inhibitor), velpatasvir (NS5A inhibitor), and voxilaprevir (NS3/4A protease inhibitor) indicated for treatment-naive and treatment-experienced patients with chronic HCV genotype 1–6 without cirrhosis or with compensated cirrhosis. It is particularly useful for patients who have failed prior NS5A inhibitor-containing regimens, including those with genotype 3 and compensated cirrhosis. Monitor for hepatitis B reactivation in HBV co-infected patients. Dose adjustment not required for mild or moderate renal impairment, but safety not established in severe renal impairment or ESRD. Caution with amiodarone due to risk of serious bradycardia. Check for drug interactions with P-gp inducers, CYP2B6, CYP2C8, and CYP3A4 substrates. |
| Patient Advice | Take VOSEVI exactly as prescribed, usually one tablet once daily with food. · Do not skip doses or stop taking VOSEVI without talking to your doctor. · If you have hepatitis B co-infection, your doctor will monitor you for HBV reactivation during and after treatment. · Tell your doctor about all medications, including over-the-counter drugs, herbal supplements, and vitamins, as VOSEVI may interact with them. · Common side effects include headache, fatigue, diarrhea, and nausea. Contact your doctor if you experience severe abdominal pain, jaundice, or signs of liver injury. · VOSEVI does not prevent transmission of HCV. Practice safe sex and avoid sharing needles to reduce the risk of spreading the virus. |