Clinical Pharmacology Corner: FDA Approves EPCLUSA (Sofosbuvir and Velpatasvir) for the Treatment of Chronic Hepatitis C Infection

FDA Approves EPCLUSA^® (Sofosbuvir and Velpatasvir) for the Treatment of Chronic Hepatitis C Infection

 On June 28, 2016, the U.S. Food and Drug Administration (FDA) approved EPCLUSA^® (a combination tablet that includes Sofosbuvir and Velpatasvir) for the treatment of adult patients with chronic hepatitis C virus genotype 1, 2, 3, 4, 5, or 6 infection without cirrhosis, with compensated cirrhosis, or with decompensated cirrhosis for use in combination with ribavirin. The approved recommended dosage of EPCLUSA is one tablet (sofosbuvir 400 mg and velpatasvir 100 mg) taken orally once daily with or without food for 12 weeks. In patients with decompensated cirrhosis (Child-Pugh B and C), EPCLUSA should be administered in combination with ribavirin (RBV). Serious symptomatic bradycardia may occur when EPCLUSA is coadministered with amiodarone. 

Mechanism of Action (MOA), General Pharmacokinetics (PK) and Pharmacodynamics (PD) of EPCLUSA

• MOA: Sofosbuvir is an inhibitor of hepatitis C virus (HCV) NS5B polymerase and velpatasvir is an inhibitor of HCV NS5A protein
• Absorption (median Tmax): Sofosbuvir: 0.5-1 hour; velpatasvir: 3 hours 
• Plasma protein binding: Sofosbuvir: 61-65%; velpatasvir: greater than 99.5%
• Elimination Half-life (mean): Sofosbuvir: 0.5 hour; GS-331007 (primary circulating nucleoside metabolite ofsofosbuvir): 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.
• Exposure-Response: No exposure-response relationships for safety or efficacy were identified for either of the components of EPCLUSA at the recommended dosage. 

Drug Interaction Potential

• 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.
• 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.
• In vitro, slow metabolic turnover of velpatasvir by CYP2B6, CYP2C8, and CYP3A4 was observed. 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.

Use in Specific Populations

• Renal Impairment: 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 recommendation can be given for patients with severe renal impairment or ESRD.
• Hepatic Impairment: No dosage adjustment of EPCLUSA is required for patients with mild, moderate, or severe hepatic impairment (Child-Pugh Class A, B, or C).

Safety and Efficacy

The efficacy and safety of EPCLUSA were established in four clinical trials: 3 trials were conducted in subjects with genotypes 1 through 6 HCV infection with or without compensated cirrhosis and a fourth trial was conducted in subjects with genotypes 1 through 6 HCV infection with decompensated cirrhosis.

For subjects with or without compensated cirrhosis, the sustained virologic response (SVR12) rates were greater than 95% (range: 95% to 100% across all HCV genotypes). Among subjects with compensated cirrhosis, the SVR12 rates were greater than 91% (range: 91.3% to 100.0% across HCV genotypes) and among subjects with prior treatment experience, the SVR12 rates were greater than 90% (range: 90.1% to 100.0% across HCV genotypes). For subjects with decompensated cirrhosis, numerically higher SVR12 rates were achieved following treatment with EPCLUSA+RBV for 12 weeks (SVR12: 94%) as compared to treatment with EPCLUSA alone for 12 weeks or 24 weeks.

The most common adverse reactions (incidence at least 10%) were headache and fatigue in subjects treated with EPCLUSA for 12 weeks. The most common adverse reactions (all grades with frequency of at least 10%) in subjects with decompensated cirrhosis who received EPCLUSA plus RBV for 12 weeks were fatigue (32%), anemia (26%), nausea (15%), headache (11%), insomnia (11%), and diarrhea (10%).

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 Full prescribing information is available at http://go.usa.gov/xrjNd. 

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This bulletin was prepared by Office of Clinical Pharmacology, Office of Translational Sciences, CDER, FDA.

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FDA/Center for Drug Evaluation and Research (CDER)
Office of Translational Sciences
Office of Clinical Pharmacology
Email: ocp@fda.hhs.gov