sofosbuvir/velpatasvir (Rx)

>10%

Without cirrhosis or with compensated cirrhosis

• Headache (22%)
• Fatigue (15%)

With decompensated cirrhosis

• Fatigue (32%)
• Anemia (26%)
• Hemoglobin <10 g/dL (23%)
• Nausea (15%)
• Headache 11%)
• Insomnia (11%)

1-10%

Without cirrhosis or with compensated cirrhosis

• Nausea (9%)
• Asthenia (5%)
• Insomnia (5%)
• Lipase increase >3 x ULN (3%)
• Rash (2%)
• Depression (1%)
• Increased creatinine kinase ≥10 x ULN (1%)

With decompensated cirrhosis

• Diarrhea (10%)
• Hemoglobin <3.5 g/dL (7%)
• Rash (5%)
• Increased creatinine kinase ≥10 x ULN (2%)

Postmarketing Reports

Cardiac disorders: Serious symptomatic bradycardia has been reported in patients taking amiodarone who initiated treatment with sofosbuvir in combination with another HCV direct-acting antiviral

Skin and subcutaneous tissue disorders: Angioedema

Contraindications

Sofosbuvir/velpatasvir plus ribavirin combination regimen is contraindicated in patients for whom ribavirin is contraindicated

Cautions

Hepatitis B virus reactivation

• Hepatitis B virus (HBV) reactivation reported in HCV/HBV coinfected patients undergoing or who completed treatment with HCV DDAs, and were not receiving HBV antiviral therapy
• HBV reactivation is characterized as an abrupt increase in HBV replication manifesting as a rapid increase in serum HBV DNA level (see Black Box Warnings and Dosing Considerations)
• HBV reactivation also reported in patients receiving certain immunosuppressants or chemotherapeutic agents
• Risk of HBV reactivation associated with treatment with HCV direct-acting antivirals may increase in these patients
• Reactivation of HBV replication may be accompanied by hepatitis, eg, increases in aminotransferase levels and, in severe cases, increases in bilirubin levels, liver failure, and death may occur
• In patients with serologic evidence of HBV infection, monitor for clinical and laboratory signs of hepatitis flare or HBV reactivation during HCV treatment and during post-treatment follow-up; initiate appropriate patient management for HBV infection as clinically indicated
• If administered with ribavirin, warnings and precautions for ribavirin apply to this combination; see ribavirin prescribing information

Bradycardia

• Coadministration with amiodarone is not recommended
• Postmarketing cases of symptomatic bradycardia and cases requiring pacemaker intervention reported when amiodarone coadministered with regimen
• Serious symptomatic bradycardia may occur if sofosbuvir is coadministered with amiodarone in combination with another direct-acting antiviral (eg, daclatasvir, simeprevir)
• Bradycardia has generally occurred within hours to days, but reports have been observed up to 2 weeks after initiating HCV treatment
• Patients also taking beta-blockers, or those with underlying cardiac comorbidities, and/or advanced liver disease may be at increased risk for symptomatic bradycardia with coadministration of amiodarone
• For patients taking amiodarone who have no other alternative viable treatment options and who will require coadministration, counsel patients about risk of symptomatic bradycardia and monitor cardiac activity in an in-patient setting for first 48 hours of coadministration, after which outpatient or self-monitoring of heart rate should occur on a daily basis through at least first 2 weeks of treatment
• Patients receiving therapy who need to start amiodarone therapy due to no other alternative viable treatment options should undergo similar cardiac monitoring as outlined above
• Because of amiodarone’s long half-life, patients discontinuing amiodarone just prior to starting therapy should also undergo similar cardiac monitoring

Drug interaction overview

• Drugs affecting sofosbuvir/velpatasvir

  • Sofosbuvir and velpatasvir are substrates of drug transporters P-gp and BCRP while GS-331007 (the predominant circulating metabolite of sofosbuvir) is not
  • In vitro, slow metabolic turnover of velpatasvir by CYP2B6, CYP2C8, and CYP3A4 was observed
  • Drugs that are potent P-gp inducers and/or moderate-to-potent inducers of CYP2B6, CYP2C8, or CYP3A4 (eg, rifampin, carbamazepine, St. John’s wort) may significantly decrease sofosbuvir and/or velpatasvir plasma concentrations, leading to potentially reduced therapeutic effect; avoid coadministration

• Drugs that increase gastric pH

  • Coadministration with drugs that increase gastric pH are expected to decrease velpatasvir serum concentration
  • See the Administration section for how long is needed between sofosbuvir/velpatasvir doses and drugs that increase gastric pH

• Sofosbuvir/velpatasvir effect on other drugs

  • Velpatasvir inhibits drug transporters P-gp, BCRP, OATP1B1, OATP1B3, and OATP2B1
  • Coadministration with drugs that are substrates of these transporters may increase the exposure of such drugs
  • 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) recommended to ensure safe and effective use; dose adjustments of concomitant medications may be necessary

Pregnancy

Contraindicated if administered with ribavirin in pregnant women and in men whose female partners are pregnant

There are no adequate data available to establish pregnancy risk for sofosbuvir or velpatasvir

Lactation

Unknown if sofosbuvir, velpatasvir, or their metabolites are 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

If regimen includes ribavirin, refer to ribavirin prescribing information

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

Absorption

Velpatasvir solubility decreases as gastric pH increases; practically insoluble (<0.1 mg/mL) at pH >5

Peak concentration time

• Sofosbuvir: 0.5-1 hr
• Velpatasvir: 3 hr

Peak plasma concentration

• Sofosbuvir: 567 ng/mL
• Velpatasvir: 259 ng/mL

AUC

• Sofosbuvir: 1268 ng·hr/mL
• Velpatasvir: 2980 ng·hr/mL

Distribution

Protein bound

• Sofosbuvir: 61-65%
• Velpatasvir: >99.5%

Metabolism

Sofosbuvir

• Liver metabolism by cathepsin A, CES1, and HINT1
• Substrate of P-gp transporter and breast cancer resistance protein (substrate for sofosbuvir but not metabolite GS-331007)

Velpatasvir

• Substrate of P-gp transporter, CYP2B6, 2C8, and 3A4

Elimination

Half-life

• Sofosbuvir: 0.5 hr; GS-33107 25 hr (active metabolite)
• Velpatasvir: 15 hr

Excretion

• Major route of elimination

  • Sofosbuvir: Metabolism
  • GS-33107: Glomerular filtration and active tubular secretion
  • Velpatasvir: Biliary excretion as parent compound (77%)

• Urine

  • Sofosbuvir: 80%
  • Velpatasvir: 14%

• Feces

  • Sofosbuvir: 0.4%
  • Velpatasvir: 94%

See oral pellets full instructions for use

Oral Pellet Preparation

Do not chew oral pellets to avoid a bitter aftertaste

Oral pellets can be taken directly in the mouth or mixed with food

Administer with food to increase tolerability/palatability in children aged <6 years of age

Sprinkle oral pellets on ≥1 spoonfuls of nonacidic soft food (eg, pudding, chocolate syrup, ice cream) at or below room temperature

Take oral pellets within 15 minutes of gently mixing with food and swallow the entire contents without chewing

Do not store and reuse any leftover oral pellets or mixture

Oral Administration

Take regularly at about the same time each day

May take with or without food

Oral pellets: Do not chew

If coadministered with ribavirin, take with food

Use with drugs that increase gastric pH

• Coadministration with drugs that increase gastric pH are expected to decrease velpatasvir serum concentration
• Antacids: Separate administration of sofosbuvir/velpatasvir by at least 4 hr
• H2-antagonists: May be administered simultaneously with or 12 hr apart from sofosbuvir/velpatasvir at a dose that does not exceed doses comparable to famotidine 40 mg BID
• PPIs: Coadministration with omeprazole or other PPIs is not recommended; if considered medically necessary, give sofosbuvir/velpatasvir with food 4 hr before omeprazole 20 mg; use with other PPIs has not been studied

Storage

Tablets or pellets: Store below 30°C (86 ºF)

Dispense only in original container