sofosbuvir/velpatasvir/voxilaprevir (Rx)

>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

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
  • Frequent monitoring of relevant laboratory parameters (eg, International Normalized Ratio [INR] in patients taking warfarin, blood glucose levels in diabetic patients) or drug concentrations of concomitant medications such as cytochrome P450 substrates with a narrow therapeutic index (eg, certain immunosuppressants) is recommended to ensure safe and effective use; dose adjustments of concomitant medications may be necessary
  • 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

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.

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)

Oral Administration

Take with food

Storage

Store below 30°C (86°F)

Dispense only in original container