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Potential for Epclusa to affect other medicinal products: Velpatasvir is an inhibitor of drug transporter P-gp, breast cancer resistance protein (BCRP), organic anion-transporting polypeptide (OATP) 1B1 and OATP1B3. Co-administration of Epclusa with medicinal products that are substrates of these transporters may increase the exposure of such medicinal products. See Table 20 for examples of interactions with sensitive substrates of P-gp (digoxin), BCRP (rosuvastatin), and OATP (pravastatin).
Potential for other medicinal products to affect Epclusa: Sofosbuvir and velpatasvir are substrates of drug transporters P-gp and BCRP. Velpatasvir is also a substrate of drug transporter OATP1B. In vitro, slow metabolic turnover of velpatasvir by CYP2B6, CYP2C8 and CYP3A4 was observed. Medicinal products that are strong inducers of P-gp and/or strong inducers of CYP2B6, CYP2C8, or CYP3A4 (e.g. carbamazepine, phenobarbital and phenytoin, rifampicin, rifabutin and St. John's wort) may decrease plasma concentrations of sofosbuvir or velpatasvir leading to reduced therapeutic effect of sofosbuvir/velpatasvir. The use of such medicinal products with Epclusa is contraindicated (see Contraindications). Medicinal products that are moderate P-gp inducers and/or moderate CYP inducers (e.g. efavirenz, modafinil, oxcarbazepine or rifapentine) may decrease sofosbuvir or velpatasvir plasma concentration leading to reduced therapeutic effect of Epclusa. Co-administration with such medicinal products is not recommended with Epclusa (see Precautions). Co-administration with medicinal products that inhibit P-gp or BCRP may increase sofosbuvir or velpatasvir plasma concentrations. Medicinal products that inhibit OATP, CYP2B6, CYP2C8, or CYP3A4 may increase plasma concentration of velpatasvir. Clinically significant medicinal product interactions with Epclusa mediated by P-gp, BCRP, OATP, or CYP450 inhibitors are not expected; Epclusa may be co-administered with P-gp, BCRP, OATP and CYP inhibitors.
Patients treated with vitamin K antagonists: As liver function may change during treatment with Epclusa, a close monitoring of International Normalised Ratio (INR) values is recommended.
Impact of DAA therapy on medicinal products metabolized by the liver: The pharmacokinetics of medicinal products that are metabolized by the liver (e.g. immunosuppressive agents such as calcineurin inhibitors) may be impacted by changes in liver function during DAA therapy, related to clearance of HCV.
Interactions between Epclusa and other medicinal products: Table 20 provides a listing of established or potentially clinically significant medicinal product interactions (where 90% confidence interval [CI] of the geometric least-squares mean [GLSM] ratio were within "↔", extended above "↑", or extended below "↓" the predetermined interaction boundaries). The medicinal product interactions described are based on studies conducted with either sofosbuvir/velpatasvir or velpatasvir and sofosbuvir as individual agents, or are predicted medicinal product interactions that may occur with sofosbuvir/velpatasvir. The table is not all-inclusive. (See Tables 20a, 20b, 20c, and 20d.)
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