Vosevi is a fixed-dose combination of the three antiviral drugs - Sofosbuvir, Velpatasvir, and Voxilaprevir) 400/100/100 mg - that is being marketed by Gilead's Sciences for the treatment of chronic hepatitis C infection.
Vosevi (Sofosbuvir, Velpatasvir, and Voxilaprevir) Uses:
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Chronic hepatitis C:
- With chronic hepatitis C virus (HCV) infection, treatment of adults without cirrhosis or with compensated cirrhosis (Child-Pugh class A) who have genotype 1, 2, 3, 4, 5, or 6 infections and have previously been treated with an HCV regimen containing an NS5A inhibitor or who have genotype 1a or 3 infections and have previously been treated with an HCV regimen containing sofosbuvir without an NS5A inhibitor
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Off-Label Use of Vosevi (Sofosbuvir, velpatasvir, and voxilaprevir) in Adults:
- Chronic hepatitis C, genotype 3, treatment-naive or peginterferon + ribavirin treatment-experienced
Vosevi (Sofosbuvir, Velpatasvir, and Voxilaprevir) Dose in Adults
Vosevi (Sofosbuvir, Velpatasvir, and Voxilaprevir) Dose in the treatment of chronic hepatitis C:
(without cirrhosis or with compensated cirrhosis [Child-Pugh class A]):
P/O:
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Genotype 1, 2, 3, 4, 5, or 6 (previously treated with a regimen containing a direct-acting antiviral [including NS5A inhibitors]):
- For 12 weeks, 1 tablet once daily.
- With prior NS5A inhibitor failure and cirrhosis for patients with genotype 3, concomitant ribavirin should be used (AASLD/IDSA 2018).
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Genotype 1a (previously treated with a regimen containing sofosbuvir without an NS5A inhibitor):
- For 12 weeks, 1 tablet once daily (AASLD/IDSA 2018)
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Genotype 3 treatment-naive with compensated cirrhosis (Child-Pugh class A) when Y93H substitution is present (alternative regimen) (off-label use):
- For 12 weeks, 1 tablet once daily (AASLD/IDSA 2018)
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Genotype 3 peginterferon/ribavirin-experienced without cirrhosis (alternative regimen) or with compensated cirrhosis (Child-Pugh class A) (off-label use):
- For 12 weeks, 1 tablet once daily.
Note:
- In patients without cirrhosis, use is only recommended when Y93H substitution is present (AASLD/IDSA 2018).
Vosevi (Sofosbuvir, Velpatasvir, and Voxilaprevir) Use in Chidren:
The safety and efficacy of the drug in children have not been established.
Vosevi Pregnancy Risk Category: B
- Animal reproduction studies did not show adverse effects from the use of any individual component of the combination.
- Refer to the sofosbuvir monograph for more information.
- Treatment of hepatitis C cannot be used to treat maternal infections or reduce the chance of mother-to child transmission during pregnancy.
- HCV-infected women with childbearing potential who are not yet on treatment to reduce the risk of HCV transmission should postpone pregnancy.
- Treatment should be delayed until after birth if HCV infection is discovered during pregnancy.
- Direct-acting antiviral medication should not be administered to pregnant women unless safety and efficacy data are available.
Use of sofosbuvir and velpatasvir during breastfeeding
- It is unknown if sofosbuvir or velpatasvir are found in breast milk.
- When deciding whether to breastfeed during therapy, you should consider the risks to infants, the benefits to the mother, and the benefits to the mother.
- The spread of the hepatitis C viruses is not associated with breastfeeding.
- Breastfeeding is not recommended if the nipples are cracked, bleeding or swollen.
- Breastfeeding is not recommended in the case of HIV co-infection.
Vosevi (Sofosbuvir, Velpatasvir, and Voxilaprevir) Dose in Kidney Disease:
-
eGFR ≥30 mL/minute/1.73 m2:
- No dosage adjustment necessary.
-
eGFR <30 mL/minute/1.73 m2:
- In the manufacturer's labeling, there are no dosage adjustments provided.
- Predominate sofosbuvir metabolite accumulates with impaired renal function.
-
ESRD requiring hemodialysis:
- In the manufacturer's labeling, there are no dosage adjustments provided.
- Predominate sofosbuvir metabolite accumulates with impaired renal function.
Vosevi (Sofosbuvir, Velpatasvir, and Voxilaprevir) Dose in Liver disease:
-
Mild impairment (Child-Pugh class A):
- No dosage adjustment is necessary.
-
Moderate or severe impairment (Child-Pugh class B or C):
- Use is not recommended (due to higher voxilaprevir exposure).
Also, see the Sofosbuvir monograph.
Common Side Effects of Vosevi (Sofosbuvir, Velpatasvir, and Voxilaprevir):
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Central nervous system:
- Headache
- Fatigue
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Gastrointestinal:
- Diarrhea
- Nausea
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Hepatic:
- Increased serum bilirubin
Less Common Side Effects of Vosevi (Sofosbuvir, Velpatasvir, and Voxilaprevir):
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Central nervous system:
- Insomnia
- Depression
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Dermatologic:
- Skin rash
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Gastrointestinal:
- Increased serum lipase
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Neuromuscular & skeletal:
- Weakness
Contraindications to Vosevi (Sofosbuvir, Velpatasvir, and Voxilaprevir):
- Concurrent use of rifampin
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Canadian labeling:Additional contraindications not listed in the US labeling:
- Hypersensitivity to sofosbuvir, velpatasvir, voxilaprevir, or any component of the formulation.
- Concurrent use of dabigatran or phenobarbital and phenytoin, rosuvastatin or St John's Wort
Warnings and precautions
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Hepatitis B virus reactivation:
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[US Boxed Warning]
- Hepatitis B virus reactivation (HBV), has been reported in hepatitis C viral (HCV) co-infected patients receiving or having completed treatment with HCV direct acting antivirals but not receiving HBV antiviral treatment.
- Some cases can lead to fulminant liver disease, hepatic failure and even death.
- Prior to initiation of sofosbuvir/velpatasvir/voxilaprevir, test all patients for evidence of current or prior HBV infection.
- Examine HCV/HBV coinfected patients during treatment for hepatitis flare, HBV reactivation and posttreatment follow up.
- If HBV infection is clinically indicated, you should start treatment.
- HBV reactivation was reported in HBsAg positive patients and in patients with serologic evidence that resolved HBV infection (i.e. HBsAg positive & anti-HBc negative). It is characterized as an abrupt increase of HBV replication, manifested by a rapid rise in serum HBV DNA levels.
- Patients with a resolved HBV infection may experience HBsAg recurrence.
- Patients who are taking immunosuppressants and chemotherapeutic drugs may have a higher risk of HBV reactivation.
-
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Diabetes:
- Patients with diabetes may experience rapid reductions in viral load due to direct-acting antiviral therapy (DAA). If antidiabetic drugs are used at the same dosage, this could lead to symptomatic hypoglycemia.
- Assess for changes in glucose tolerance and inform patients about the possibility of hypoglycemia during DAA therapy, especially within the first three months.
- Modifications to anti-diabetic therapy might be required.
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Hepatic impairment
- Patients with severe or moderate hepatic impairment should not use this product (Child-Pugh Class B or C).
Sofosbuvir, velpatasvir, and voxilaprevir: Drug Interaction
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Antidiabetic Agents |
Direct Acting Antiviral Agents (HCV) may enhance the hypoglycemic effect of Antidiabetic Agents. |
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Brentuximab Vedotin |
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Celiprolol |
P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Celiprolol. |
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Deferasirox |
May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). |
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Digoxin |
Velpatasvir may increase the serum concentration of Digoxin. |
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Erdafitinib |
May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). |
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Erdafitinib |
May increase the serum concentration of P-glycoprotein/ABCB1 Substrates. |
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Everolimus |
P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Everolimus. |
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Histamine H2 Receptor Antagonists |
May decrease the serum concentration of Velpatasvir. |
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Ivosidenib |
May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). |
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Larotrectinib |
P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Larotrectinib. |
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Naldemedine |
P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Naldemedine. |
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Naloxegol |
P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Naloxegol. |
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P-glycoprotein/ABCB1 Inhibitors |
May increase the serum concentration of Pglycoprotein/ABCB1 Substrates. P-glycoprotein inhibitors may also enhance the distribution of pglycoprotein substrates to specific cells/tissues/organs where p-glycoprotein is present in large amounts (e.g., brain, T-lymphocytes, testes, etc.). |
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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.). Exceptions: Loperamide. |
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Prucalopride |
P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Prucalopride. |
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Ranolazine |
P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Ranolazine. |
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Ranolazine |
May increase the serum concentration of P-glycoprotein/ABCB1 Substrates. |
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RifAXIMin |
P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of RifAXIMin. |
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Sarilumab |
May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). |
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Silodosin |
P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Silodosin. |
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Siltuximab |
May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). |
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Tacrolimus (Systemic) |
Sofosbuvir may decrease the serum concentration of Tacrolimus (Systemic). |
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Talazoparib |
P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Talazoparib. Management: These listed exceptions are discussed in detail in separate interaction monographs. |
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Talazoparib |
BCRP/ABCG2 Inhibitors may increase the serum concentration of Talazoparib. |
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Tegaserod |
P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Tegaserod. |
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Tenofovir Alafenamide |
Sofosbuvir may increase the serum concentration of Tenofovir Alafenamide. |
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Tenofovir Disoproxil Fumarate |
Velpatasvir may increase the serum concentration of Tenofovir Disoproxil Fumarate. |
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Tenofovir Disoproxil Fumarate |
May increase the serum concentration of Voxilaprevir. |
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Tocilizumab |
May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). |
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Vitamin K Antagonists (eg, warfarin) |
Antihepaciviral NS5B RNA Polymerase Inhibitors may diminish the anticoagulant effect of Vitamin K Antagonists. |
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Risk Factor D (Consider therapy modification) |
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Afatinib |
P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Afatinib. Management: Reduce afatinib by 10 mg if not tolerated. Some non-US labeling recommends avoiding combination if possible. Iif used, administer the P-gp inhibitor simultaneously with or after the dose of afatinib. |
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Alpelisib |
BCRP/ABCG2 Inhibitors may increase the serum concentration of Alpelisib. Management: Avoid coadministration of BCRP/ABCG2 inhibitors and alpelisib due to the potential for increased alpelisib concentrations and toxicities. If coadministration cannot be avoided, closely monitor for increased alpelisib adverse reactions. |
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Antacids |
May decrease the serum concentration of Velpatasvir. Management: Separate administration of velpatasvir and antacids by at least 4 hours. |
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Betrixaban |
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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. |
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Cladribine |
BCRP/ABCG2 Inhibitors may increase the serum concentration of Cladribine. Management: Avoid concomitant use of BCRP inhibitors during the 4 to 5 day oral cladribine treatment cycles whenever possible. If combined, consider dose reduction of the BCRP inhibitor and separation in the timing of administration. |
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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. See full monograph for details. |
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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. |
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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. |
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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 P-gp inhibitors. Similar dose adjustment is not recommended for edoxaban use in atrial fibrillation. |
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HMG-CoA Reductase Inhibitors (Statins) |
Voxilaprevir may increase the serum concentration of HMG-CoA Reductase Inhibitors (Statins). 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. |
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Lefamulin |
P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Lefamulin. Management: Avoid concomitant use of lefamulin tablets with P-glycoprotein/ABCB1 inhibitors. If concomitant use is required, monitor for lefamulin adverse effects. |
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Ritonavir |
May decrease the serum concentration of Velpatasvir. Ritonavir may increase the serum concentration of Velpatasvir. |
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Tolvaptan |
May increase the serum concentration of OATP1B1/1B3 (SLCO1B1/1B3) Substrates. |
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Venetoclax |
P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Venetoclax. Management: Consider a venetoclax dose reduction by at least 50% in patients requiring concomitant treatment with P-glycoprotein (P-gp) inhibitors. |
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Risk Factor X (Avoid combination) |
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Amiodarone |
Sofosbuvir may enhance the bradycardic effect of Amiodarone. |
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Asunaprevir |
OATP1B1/1B3 (SLCO1B1/1B3) Inhibitors may increase the serum concentration of Asunaprevir. |
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Atazanavir |
May increase the serum concentration of Voxilaprevir. |
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BCRP/ABCG2 Substrates |
Voxilaprevir may increase the serum concentration of BCRP/ABCG2 Substrates. |
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CYP2B6 Inducers (Moderate) |
May decrease the serum concentration of Velpatasvir. |
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CYP3A4 Inducers (Moderate) |
May decrease the serum concentration of Velpatasvir. |
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CYP3A4 Inducers (Strong |
May decrease the serum concentration of Velpatasvir. |
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CYP3A4 Inducers (Strong) |
May decrease the serum concentration of Voxilaprevir. |
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Elagolix |
OATP1B1/1B3 (SLCO1B1/1B3) Inhibitors may increase the serum concentration of Elagolix. |
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Grazoprevir |
OATP1B1/1B3 (SLCO1B1/1B3) Inhibitors may increase the serum concentration of Grazoprevir. |
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Lopinavir |
May increase the serum concentration of Voxilaprevir. |
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Modafinil |
May decrease the serum concentration of Sofosbuvir. |
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OATP1B1/1B3 (SLCO1B1/1B3) Inhibitors |
May increase the serum concentration of Voxilaprevir. |
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Oxcarbazepine |
May decrease the serum concentration of Sofosbuvir. |
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PAZOPanib |
P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of PAZOPanib. |
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PAZOPanib |
BCRP/ABCG2 Inhibitors may increase the serum concentration of PAZOPanib. |
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P-glycoprotein/ABCB1 Inducers |
May decrease the serum concentration of Sofosbuvir. |
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P-glycoprotein/ABCB1 Inducers |
May decrease the serum concentration of Velpatasvir. |
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PHENobarbital |
May decrease the serum concentration of Sofosbuvir. |
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Pitavastatin |
Voxilaprevir may increase the serum concentration of Pitavastatin. |
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Primidone |
May decrease the serum concentration of Sofosbuvir. |
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Proton Pump Inhibitors |
May decrease the serum concentration of Velpatasvir. |
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Revefenacin |
OATP1B1/1B3 (SLCO1B1/1B3) Inhibitors may increase serum concentrations of the active metabolite(s) of Revefenacin. |
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Rifabutin |
May decrease the serum concentration of Sofosbuvir. |
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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. |
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Rifapentine |
May decrease the serum concentration of Sofosbuvir. |
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Rosuvastatin |
Voxilaprevir may increase the serum concentration of Rosuvastatin. |
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Tipranavir |
May decrease the serum concentration of Sofosbuvir. |
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Topotecan |
Velpatasvir may increase the serum concentration of Topotecan. |
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VinCRIStine (Liposomal) |
P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of VinCRIStine (Liposomal). |
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Voxilaprevir |
OATP1B1/1B3 (SLCO1B1/1B3) Inhibitors may increase the serum concentration of Voxilaprevir. |
Vosevi 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) & calculated GFR.
- After 4 weeks of therapy and as clinically indicated, repeat CBC, serum creatinine, calculated GFR, and hepatic function panel.
- Baseline (at any time prior to starting therapy) HCV genotype & subtype & 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 2018).
- Prior to initiation, Hepatitis B surface antigen (HBsAg) & hepatitis B core antibody (anti-HBc).
- Monitor for clinical and laboratory signs of hepatitis flare or HBV reactivation during treatment and during post-treatment follow-up in patients with serologic evidence of hepatitis B virus (HBV) infection.
- Monitor blood glucose and for signs/symptoms of hypoglycemia in patients with diabetes.
- 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.
How to administer Vosevi (Sofosbuvir, Velpatasvir, and Voxilaprevir)?
- Administer with food.
Mechanism of action of Vosevi (Sofosbuvir, Velpatasvir, and Voxilaprevir):
- Sofosbuvir is an inhibitor of the HCV NS5B RNA-dependent RNA polymerase, which is required for viral replication and acts as a chain terminator.
- Velpatasvir, an inhibitor of HCV NS5A proteins, is required for viral replication.
- Voxilaprevir, a noncovalent, reversible inhibitor of the NS3/4A proteinase is required for the proteolytic cleavage (into mature forms the NS3A, NS4B and NS5A proteins) and is vital for viral replication.
See individual agents.
International Brands of Sofosbuvir, velpatasvir, and voxilaprevir:
- Vosevi
Sofosbuvir, velpatasvir, and voxilaprevir Brand Names in Pakistan:
No Brands Available in Pakistan.
