In June 2016, the FDA approved Epclusa, a fixed-dose combination product containing sofosbuvir, an HCV NS5B polymerase inhibitor, and velpatasvir, an HCV NS5A inhibitor, for treatment of chronic hepatitis C genotypes 1, 2, 3, 4, 5, or 6. With its approval, Epclusa became the first antiviral indicated for all 6 major forms of HCV.
This article highlights several key therapeutics areas with Epclusa that every pharmacist should know.
According to the National Institutes of Health website DailyMed: "Epclusa is indicated for the treatment of adult patients with HCV genotype 1, 2, 3, 4, 5, or 6. It can be used in those with compensated cirrhosis, decompensated cirrhosis, or without cirrhosis."2
Mechanism of Action
Epclusa is a combination of 2 direct-acting antiviral agents with distinct mechanisms of action. Sofosbuvir is an inhibitor of the HCV NS5B RNA-dependent RNA polymerase, which is required for viral replication. Velpatasvir is an inhibitor of the HCV NS5A protein, which is required for viral replication and virion assembly.
Formulation and Storage
DailyMed notes that "Each Epclusa tablet contains 400 mg of sofosbuvir and 100 mg of velpatasvir. The tablets are pink, diamond-shaped, and film-coated. Each bottle contains 28 tablet and is closed with a child-resistant closure. Epclusa should be stored below 30°C (86ºF) and dispensed in the original container."2
Epclusa is administered as one tablet taken orally once daily with or without food. The recommended treatment duration is 12 weeks in all individuals. In patients with decompensated cirrhosis (Child-Pugh B or C) Epclusa should be administered with weigh-based ribavirin.
No dosage recommendation are made for patients with severe renal impairment (estimated Glomerular Filtration Rate [eGFR] less than 30 mL/min/1.73 m2) or with end stage renal disease (ESRD), due to higher exposures (up to 20-fold) of the predominant sofosbuvir metabolite.
The efficacy of Epclusa for the treatment of chronic HCV was established in 4 randomized clinical trials in over 1800 subjects. The studies were conducted in both treatment-naive and treatment-experienced patients infected with HCV genotype 1, 2, 3, 4, 5, or 6. Sustained virologic response (SVR12), defined as HCV RNA less than lower limit of quantification (LLOQ) at 12 weeks after the cessation of treatment, was the primary endpoint in all the trials.
ASTRAL-1, -2, and -3 enrolled patients with or without cirrhosis, but excluded those with decompensated cirrhosis. In these studies, the SVR12 for a 12 week duration of Epclusa ranged from 94% to 99%. The 24 week treatment group had a numerically lower SVR12 rate of 80%, and therefore is not a recommended treatment regimen.
ASTRAL-4 enrolled only patients with moderate (Child-Pugh B) decompensated cirrhosis. SVR12 ranged from 83% to 94%. The group treated with Epclusa plus ribavirin for 12 weeks had a higher success rate compared to Epclusa alone for 12 weeks or 24 weeks (SVR12 94%, 83%, 86% respectively). Therefore, a 12 week treatment duration with ribavirin is recommended in this patient population.
In all studies, SVR12 rates were equally high among all six genotypes; no major differences were observed.
The most common adverse reactions of Epclusa are headache and fatigue. In patients receiving Epclusa with ribavirin, the most commonly reported adverse reactions were fatigue, anemia, neausea, headache, insomnia, and diarrhea.
If Epclusa is administered with ribavirin, the combination regimen is contraindicated in pregnant women and in men whose female partners are pregnant. Additionally, the safety and effectiveness of Epclusa have not been established in pediatric patients.
Sofosbuvir and velpatasvir are substrates of drug transporters P-gp and BCRP. In vitro, slow metabolic turnover of velpatasvir by CYP2B6, CYP2C8, and CYP3A4 was observed. Drugs that are inducers of P-gp and/or moderate to potent inducers of CYP2B6, CYP2C8, or CYP3A4 (e.g., rifampin, phenytoin, St. John’s wort, carbamazepine) may decrease plasma concentrations of sofosbuvir and/or velpatasvir, leading to reduced therapeutic effect of Epclusa. Therefore, the use of these agents with Epclusa is not recommended.
Co-administration of amiodarone with Epclusa may result in serious symptomatic bradycardia and is not recommended. Acid reducing agents may decrease velpatasvir concentrations and therefore administration of Epclusa should be separated by 4 hours with antacids and avoided completely with proton pump inhibitors.
|FDA Indication||Dosing||# Tablets/ Day||
|GT 1, 2, 3, 4, 5, 6||QD x 12 weeks||1||$29,904|
|GT 1, 4, 5, 6||QD x 12-24 weeks||1||$37,800|
|GT 1, 4||QD x 12-16 weeks||1||$21,840|
(ombitasvir/paritaprevir/ ritonavir and dasabuvir)
|GT 1||BID x 12-24 weeks||4||$33,328|
Viekira Pak XR
(ombitasvir/paritaprevir/ ritonavir and dasabuvir)
|GT 1||QD x 12-24 weeks||3||$33,328|
|Daklinza (daclatasvir) + Sovaldi (sofosbuvir)||GT 1, 3||QD x 12-24 weeks||2||$58,800|
|Olysio (simeprevir) + Sovaldi (sofosbuvir)||GT 1||QD x 12-24 weeks||2||$60,144|
|GT 4||QD x 12 weeks||2||$32,851|
Cost based on AWP, per Lexi-Drugs. Cost to the patient will vary based on individual insurance coverage.
Current guidelines from the American Association for the Study of Liver Diseases (AASLD) and the Infectious Diseases Society of America (IDSA) recommend Epclusa as a first line treatment option in HCV genotypes 1, 2, 3, 4, 5, and 6.3 Epclusa is currently the preferred first-line treatment agent for genotype 2 naïve or experienced patients with or without cirrhosis. No treatment preferences are made regarding the different direct acting antivirals within the guidelines for all other genotypes.
In clinical studies Epclusa was shown to be highly effective in treating HCV genotypes 1, 2, 3, 4, 5, and 6, and was well-tolerated.4 Unlike other HCV medications, Epclusa is only given as one tablet once a day, and does not require a 24 week treatment duration in more complicated patients.4
- Viral Hepatitis - Hepatitis C. Centers for Disease Control and Prevention. http://www.cdc.gov/hepatitis/hcv/. Accessed January 3, 2017.
- Label: Epclusa-velpatasvir and sofosbuvir tablet, film coated. NIH National Library of Medicine Dailymed website. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=7f30631a-ee3b-4cfe-866b-964df3f0a44f. Accessed January 3, 2017.
- AASLD/IDSA/IAS–USA. Recommendations for testing, managing, and treating hepatitis C. http://www.hcvguidelines.org. Accessed January 3, 2017.
- Epclusa [Prescribing Information]. Gilead Sciences, Inc. Foster City, California. June 2016.
Timothy O'Shea, MS, PharmD
Timothy O'Shea, MS, PharmD, is a Clinical Pharmacist working at a regional health insurance plan on the east coast. Additionally he works per diem at a nationwide retail pharmacy chain. He graduated from MCPHS University - Boston in 2015 and subsequently completed a PGY-1 Managed Care Pharmacy Residency. He completed his M.S. in Health Services Administration, with a focus on Health Economics and Outcomes, in 2018. His professional interests include pharmacy legislation and managed care pharmacy. He can be followed on Twitter at @toshea125.