Dosing and uses of Epclusa (sofosbuvir/velpatasvir)
Adult dosage forms and strengths
sofosbuvir/velpatasvir
tablet
- 400mg/100mg
Chronic Hepatitis C
Indicated for adults with chronic hepatitis C virus (HCV) infection genotypes 1, 2, 3, 4, 5, and 6
1 tablet (400 mg sofosbuvir/ 100 mg velpatasvir) PO qDay
Treatment duration
- Patients without cirrhosis or with compensated cirrhosis (Child-Pugh A): Sofosbuvir/velpatasvir for 12 weeks
- Patients with decompensated cirrhosis (Child-Pugh B or C): Sofosbuvir/velpatasvir plus weight-based ribavirin with food for 12 weeks
- Weight-based ribavirin dose
- <75 kg: 1000 mg/day PO divided BID
- ≥75 kg: 1200 mg/day PO divided BID
- Ribavirin starting dose and on-treatment dosage should be modified based on hemoglobin and creatinine clearance
Dosage modifications
Renal impairment
- Severe renal impairment (eGFR <30mL/min/1.73 m²) or ESRD: No dosage recommendation can be give owing to higher exposures (up to 20-fold) of the predominant sofosbuvir metabolite
Hepatic impairment
- Mild, moderate, or severe (Child-Pugh A, B, or C): No dosage adjustment required
Pediatric dosage forms and strengths
Safety and efficacy not established
Epclusa (sofosbuvir/velpatasvir) adverse (side) effects
>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
Warnings
Black box warnings
Direct-acting antivirals (DDAs) may reactivate hepatitis B virus (HBV) in patients who have a current or previous HBV infection while being treated for hepatitis C virus
In a few cases, HBV reactivation in patients treated with DAA medicines resulted in serious liver problems or death
Patients should be screened for evidence of current or prior HBV infection before starting treatment with DAAs, and monitored for HBV flare-ups or reactivation during DAA treatment and posttreatment follow-up
Contraindications
Sofosbuvir/velpatasvir plus ribavirin combination regimen is contraindicated in patients for whom ribavirin is contraindicated
Cautions
If administered with ribavirin, warnings and precautions for ribavirin apply to this combination; see ribavirin prescribing information
Bradycardia
- Coadministration with amiodarone is not recommended
- 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
- If no alternative exists for amiodarone, inpatient cardiac monitoring is recommended for the first 48 hr and then daily home monitoring for at least the first 2 weeks
- 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
Pregnancy
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.
Pharmacology of Epclusa (sofosbuvir/velpatasvir)
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%
Administration
Oral Administration
Take regularly at about the same time each day
May take with or without food
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
Store below 30°C (86 ºF)
Dispense only in original container
