EPCLUSA Tablet (Sofosbuvir plus Velpatasvir)
|Mechanism of Action||It is a fixed-dose combination of sofosbuvir and velpatasvir which are direct-acting antiviral agents against the hepatitis C virus Sofosbuvir is a nucleotide analog HCV NS5B polymerase inhibitor and velpatasvir is an NS5A inhibitor.|
|Pharmacodynamics (PD)||At a dose three times the recommended dose, sofosbuvir does not prolong QTc to any clinically relevant extent. At a dose five times the recommended dose, velpatasvir does not prolong QTc interval to any clinically relevant extent.|
|Pharmacokinetics (PK)||Tmax (median): Sofosbuvir: 0.5-1 hour; velpatasvir: 3 hours
Effect of high fat meal: Sofosbuvir is up by 78% and velpatasvir is up by 21%.
Plasma protein binding: Sofosbuvir: 61-65%; velpatasvir: greater than 99.5%
Elimination Half-life (mean): Sofosbuvir: 0.5 hour; GS-331007 (Gilead Sciences- 331007; primary circulating nucleoside metabolite of sofosbuvir): 25 hours; velpatasvir: 15 hours
Metabolism: Sofosbuvir: Cathepsin A, CES1, and HINT1; Velpatasvir: CYP2B6, CYP2C8, and CYP3A4
Elimination: The primary route of elimination is metabolism for sofosbuvir; passive and glomerular filtration and active tubular secretion for GS-331007; and biliary excretion (of unchanged drug) for velpatasvir.
|PK-PD Analysis||No exposure-response relationships for safety or efficacy were identified for either of the components of EPCLUSA at the recommended dosage.|
|Population PK||Age had no clinically relevant effect on the exposure to sofosbuvir, GS-331007 or velpatasvir was reported in HCV-infected subjects (18 to 82 years).
Race had no clinically relevant effect on the exposure of sofosbuvir, GS-331007 or velpatasvir was reported.
Gender had no clinically relevant effect on the exposure of sofosbuvir, GS-331007 or velpatasvir
|Special Populations|| No dosage adjustment of EPCLUSA is required for patients with mild or moderate renal impairment. The safety and efficacy of EPCLUSA have not been established in patients with severe renal impairment (eGFR less than 30 mL/min/1.73 m2) or end-stage-renal disease (ESRD) requiring hemodialysis.
No dosage adjustment of EPCLUSA is required for patients with mild, moderate, or severe hepatic impairment (Child-Pugh Class A, B, or C).
|The pharmacokinetics in pediatric patients has not been established.|
|Drug Interactions||Sofosbuvir and velpatasvir are substrates of drug transporters P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) while GS-331007 is not. Drugs that are inducers of P-gp may decrease plasma concentrations of sofosbuvir and velpatasvir leading to reduced therapeutic effect of EPCLUSA. Use of these agents with EPCLUSA is not recommended.
Drugs that are moderate to potent inducers of CYP3A4 (e.g., rifampin, St. John’s wort, carbamazepine), CYP2B6, or CYP2C8 may decrease plasma concentrations of velpatasvir leading to reduced therapeutic effect of EPCLUSA. Use of these agents with EPCLUSA is not recommended.
Velpatasvir is an inhibitor of drug transporters P-gp, BCRP, OATP1B1 and OATP1B3. Coadministration of EPCLUSA with drugs that are substrates of these transporters may increase the exposure of such drugs.
Coadministration of EPCLUSA with atorvastatin is expected to increase the concentrations of atorvastatin, which is associated with increased risk of myopathy, including rhabdomyolysis. Monitor closely for HMG-CoA reductase inhibitor-associated adverse events, such as myopathy.
Serious symptomatic bradycardia has been observed when amiodarone is coadministered with a sofosbuvir-containing regimen (with another HCV direct acting antiviral). Therefore, coadministration of amiodarone with EPCLUSA may also result in serious symptomatic bradycardia. The mechanism of this effect is unknown. Coadministration of amiodarone with EPCLUSA is not recommended; if coadministration is required, cardiac monitoring is recommended.
Velpatasvir solubility decreases as pH increases. Drugs that increase gastric pH are expected to decrease systemic concentrations of velpatasvir.
Antacids: Separate antacid and EPCLUSA administration by 4 hours.
H2-receptor antagonists: H2-receptor antagonists may be administered simultaneously with or 12 hours apart from EPCLUSA at a dose that does not exceed doses comparable to famotidine 40 mg twice daily.
Proton-pump inhibitors: Coadministration of omeprazole or other proton pump inhibitors is not recommended. If it is considered medically necessary to coadminister, EPCLUSA should be administered with food and taken 4 hours before omeprazole 20 mg. Use with other proton pump inhibitors has not been studied.