Dosing & Uses
Dosage Forms & Strengths
sofosbuvir/velpatasvir/voxilaprevir
tablet
- 400mg/100mg/100mg
Hepatitis C
Indicated for retreatment of chronic hepatitis C virus (HCV) infection in adults with genotype 1, 2, 3, 4, 5, or 6 previously treated with an NS5A inhibitor-containing regimen, or with genotype 1a or 3 previously treated with a sofosbuvir-containing regimen without an NS5A inhibitor
1 tablet (sofosbuvir 400 mg/velpatasvir 100 mg/voxilaprevir 100 mg) PO qDay for 12 weeks
Dosage Modifications
Hepatic impairment
- Mild (Child-Pugh A): No dosage adjustment required
- Moderate or severe (Child-Pugh B or C): Not recommended owing to higher voxilaprevir exposure
Renal impairment
- Mild or moderate: No dosage adjustment required
- Severe (eGFR <30 mL/min/1.73 m²) or ESRD: Not recommended owing to higher exposures (up to 20-fold) of the predominant sofosbuvir metabolite
Dosing Considerations
Test all patients for evidence of current or prior hepatits B virus (HBV) infection by measuring hepatitis B surface antigen (HBsAg) and hepatitis B core antibody (anti-HBc) before initiating (see Black Box Warnings)
Safety and efficacy not established
Interactions
Interaction Checker
No Results
Contraindicated
Serious - Use Alternative
Significant - Monitor Closely
Minor
Adverse Effects
>10%
Headache (21-23%)
Fatigue (17-19%)
Diarrhea (13-14%)
Nausea (10-13%)
1-10%
Asthenia (4-6%)
Insomnia (3-6%)
Postmarketing Reports
Cardiac disorders: Serious symptomatic bradycardia reported in patients taking amiodarone who initiated treatment with a sofosbuvir-containing regimen (see Cautions)
Skin and subcutaneous tissue: Rashes, sometimes with blister or angioedemalike swelling; angioedema
Warnings
Black Box Warnings
Hepatitis B reactivation
- Test all patients for evidence of current or prior HBV infection before initiating
- HBV reactivation reported in HCV/HBV-coinfected patients who were undergoing or had completed treatment with HCV direct-acting antivirals (DAA) and were not receiving HBV antiviral therapy
- Some cases resulted in fulminant hepatitis, hepatic failure, and death
- Monitor HCV/HBV-coinfected patients for hepatitis flare or HBV reactivation during HCV treatment and posttreatment follow-up
- HBV reactivation is characterized as an abrupt increase in HBV replication manifesting as a rapid increase in serum HBV DNA level
- Initiate appropriate patient management for HBV infection as clinically indicated
Contraindications
Rifampin; significantly decreases sofosbuvir, velpatasvir, and voxilaprevir serum concentrations
Cautions
HBV reactivation reported (see Black Box Warnings)
Bradycardia with amiodarone coadministration
- Serious symptomatic bradycardia may occur in patients taking amiodarone with sofosbuvir-containing regimens, particularly in patients also receiving beta blockers, or those with underlying cardiac comorbidities, and/or advanced liver disease
- Coadministration with amiodarone not recommended
- If coadministration with amiodarone required, cardiac monitoring in an inpatient setting for the first 48 hr of coadministration recommended, after which outpatient or self-monitoring of heart rate should occur on a daily basis through at least the first 2 weeks of treatment
Drug interaction overview
- Potential for other drugs to affect sofosbuvir/velpatasvir/voxilaprevir
- P-gp and BCRP substrates: Sofosbuvir, velpatasvir, and voxilaprevir; BS-331007 (predominant sofosbuvir metabolite) is not a substrate
- OATP1B1 and OATP1B3 substrates: Voxilaprevir
- In vitro, slow metabolic turnover of velpatasvir by CYP2B6, CYP2C8, and CYP3A4 and of voxilaprevir by CYP1A2, CYP2C8, and primarily CYP3A4 was observed
- Drugs that are inducers of P-gp and/or moderate to potent inducers of CYP2B6, CYP2C8, or CYP3A4 (eg, St. John’s wort, carbamazepine) may significantly decrease plasma concentrations of sofosbuvir, velpatasvir, and/or voxilaprevir, leading to potentially reduced therapeutic effect
- Coadministration with these agents is not recommended
- Potential for sofosbuvir/velpatasvir/voxilaprevir to affect other drugs
- P-gp, BCRP, OATP1B1, and OATP1B3 inhibitors: Velpatasvir, voxilaprevir
- OATP2B1 inhibitor: Velpatasvir
- Coadministration with drugs that are substrates of these transporters may alter the exposure of such drugs
- Coadministration of sofosbuvir/velpatasvir/voxilaprevir with BCRP substrates (eg, methotrexate, mitoxantrone, imatinib, irinotecan, lapatinib, rosuvastatin, sulfasalazine, topotecan) is not recommended
- Acid reducing agents
- Velpatasvir solubility decreases as pH increases; drugs that increase gastric pH are expected to decrease concentration of velpatasvir
- Separate antacid and sofosbuvir/velpatasvir/voxilaprevir administration by 4 hr
- H2-receptor antagonists may be administered simultaneously with or staggered from sofosbuvir/velpatasvir/voxilaprevir at a dose that does not exceed doses comparable with famotidine 40 mg BID
- Omeprazole 20 mg can be administered with sofosbuvir/velpatasvir/voxilaprevir; use with other PPIs has not been studied
- Antiarrhythmics
- Sofosbuvir/velpatasvir/voxilaprevir increases digoxin serum levels; monitor if coadministered; dose adjustment may be required
- Coadministration of amiodarone with sofosbuvir/velpatasvir/voxilaprevir may result in serious symptomatic bradycardia; coadministration not recommended; if coadministration is required, cardiac monitoring recommended
- Anticoagulants
- Dabigatran levels are increased by sofosbuvir/velpatasvir/voxilaprevir; dabigatran dose may require modifications, particularly with coexisting moderate renal impairment
- Anticonvulsants
- Carbamazepine, phenytoin, phenobarbital, and oxcarbazepine decrease sofosbuvir, velpatasvir, and voxilaprevir levels; coadministration not recommended
- Antimycobacterials
- Rifampin significantly decreases sofosbuvir, velpatasvir, and voxilaprevir levels; contraindicated
- Rifabutin and rifapentine decrease sofosbuvir, velpatasvir, and voxilaprevir levels; coadministration not recommended
- Antiretrovirals
- Atazanavir or lopinavir increases voxilaprevir levels; coadministration not recommended
- Tipranavir/ritonavir decreases sofosbuvir and velpatasvir levels; coadministration not recommended; effect on voxilaprevir is unknown
- Efavirenz decreases velpatasvir and voxilaprevir levels; coadministration not recommended
- Tenofovir DF is increased by sofosbuvir/velpatasvir/voxilaprevir; monitor for adverse effects, particularly renal toxicity
- Herbals
- St John’s wort decreases sofosbuvir, velpatasvir, and voxilaprevir serum concentrations
- Coadministration with St John’s wort not recommended
- HMG-CoA reductase inhibitors
- Sofosbuvir/velpatasvir/voxilaprevir increases serum concentrations of pravastatin, rosuvastatin, pitavastatin, atorvastatin, fluvastatin, lovastatin, and simvastatin
- Increased statin concentrations may increase risk of myopathy, including rhabdomyolysis
- Pravastatin: Pravastatin may be administered with sofosbuvir/velpatasvir/voxilaprevir at a dose not exceeding 40 mg/day
- Pitavastatin, rosuvastatin: Coadministration not recommended
- Atorvastatin, fluvastatin, lovastatin, simvastatin: Use the lowest approved statin dose; if higher doses are needed, use the lowest necessary statin dose based on a risk/benefit assessment
- Immunosuppressants
- Coadministration with cyclosporine increase the plasma concentration of voxilaprevir
- Coadministration with cyclosporine not recommended
- Drugs without clinically significant interactions
- No clinically significant drug interactions have been observed with the following drugs:
- Sofosbuvir/velpatasvir/voxilaprevir: Cobicistat, darunavir, elvitegravir, emtricitabine, ethinyl estradiol/norgestimate, gemfibrozil, rilpivirine, ritonavir, tenofovir alafenamide, voriconazole
- Sofosbuvir/velpatasvir: Dolutegravir, ketoconazole, raltegravir
- Sofosbuvir: Methadone, tacrolimus
Pregnancy
Pregnancy
No adequate human data are available to establish whether or not sofosbuvir/velpatasvir/voxilaprevir poses a risk to pregnancy outcomes
Animal reproduction studies
- No evidence of adverse developmental outcomes was observed with sofosbuvir, velpatasvir, or voxilaprevir at exposures greater than those in humans at the recommended human dose
Lactation
Unknown if distributed in human breast milk
Consider the developmental and health benefits of breastfeeding along with the mother’s clinical need for the drug, and any potential adverse effects on the breastfed infant from the drug or from the underlying maternal condition
Pregnancy Categories
A:Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.
B:May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.
C:Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.
D:Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.
X:Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.
NA:Information not available.
Pharmacology
Mechanism of Action
Sofosbuvir: Inhibitor of HCV NS5B RNA-dependent polymerase; its inhibition, in turn, suppresses viral replication
Velpatasvir: Pangenotypic HCV NS5A inhibitor; the NS5A protein is required for viral replication
Voxilaprevir: Pangenotypic NS3/4A protease inhibitor, which is needed for proteolytic cleavage of the HCV-encoded polyprotein into mature forms and is essential for viral replication
Absorption
Peak plasma time
- Sofosbuvir: 2 hr
- Velpatasvir: 4 hr
- Voxilaprevir: 4 hr
Peak plasma concentration
- Sofosbuvir: 678 ng/mL; 744 ng/mL (GS-331007)
- Velpatasvir: 311 ng/mL
- Voxilaprevir: 192 ng/mL
AUC
- Sofosbuvir: 1665 ng·hr/mL; 12,834 ng·hr/mL (GS-331007)
- Velpatasvir: 4041 ng·hr/mL
- Voxilaprevir: 2477 ng·hr/mL
Effect of food (relative to fasting)
- Sofosbuvir: Increased by 64-144%
- Velpatasvir: Increased by 40-166%
- Voxilaprevir: Increased by 112-435%
Distribution
Protein bound
- Sofosbuvir: 61-65%
- Velpatasvir: >99%
- Voxilaprevir: >99%
Metabolism
Sofosbuvir: Cathepsin A, CES1, HINT1
Velpatasvir: CYP2B6, CYP2C8, CYP3A4
Voxilaprevir: CYP3A4
Elimination
Sofosbuvir
- Half-life: 0.5 hr; 29 hr (GS-331007)
- Sofosbuvir metabolized in liver primarily to GS-331007
- GS-331007 eliminated by glomerular filtration and active tubular secretion
- Excretion: 80% urine; 14% feces
Velpatasvir
- Half-life: 17 hr
- Primarily eliminated by biliary excretion
- Excretion: 0.4% urine; 94% feces (77% as parent compound)
Voxilaprevir
- Half-life: 33 hr
- Primarily eliminated by biliary excretion
- Excretion: 94% feces (40% as parent compound)
Administration
Oral Administration
Take with food
Storage
Store below 30°C (86°F)
Dispense only in original container
Images
Patient Handout
Formulary
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