VOSEVI

Clinical safety rating: caution

Comprehensive clinical and safety monograph for VOSEVI (VOSEVI).

How it works

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.

What the body does with it

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.

Classification & Brands

Dosing & administration

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.

Use during pregnancy

1st trimester	Consult provider
2nd trimester	Consult provider
3rd trimester	Consult provider

Clinical note

Comprehensive clinical and safety monograph for VOSEVI (VOSEVI).

Breastfeeding	No data on presence in human milk; animal studies indicate excretion. M/P ratio unknown. Risk of adverse effects in infant not excluded; advise against breastfeeding during therapy.
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

Warnings & precautions

■ 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.

Side Effect Profile

Serious Effects

Absolute Contraindications

["Concomitant use with rifampin (CYP2B6 and P-gp inducer) due to significant decrease in voxilaprevir concentrations","Concomitant use with St. John's wort (Hypericum perforatum) due to decreased drug concentrations","Coadministration with rosuvastatin is contraindicated due to increased risk of myopathy/rhabdomyolysis","Severe hepatic impairment (Child-Pugh C)"]

Clinical Precautions

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"]

Clinical Tips & Counseling

Drug interactions

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VOSEVI

Clinical safety rating: caution

Comprehensive clinical and safety monograph for VOSEVI (VOSEVI).

How it works

What the body does with it

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.

Classification & Brands

Dosing & administration

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.

Use during pregnancy

1st trimester	Consult provider
2nd trimester	Consult provider
3rd trimester	Consult provider

Clinical note

Comprehensive clinical and safety monograph for VOSEVI (VOSEVI).

Breastfeeding	No data on presence in human milk; animal studies indicate excretion. M/P ratio unknown. Risk of adverse effects in infant not excluded; advise against breastfeeding during therapy.
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