Sofosbuvirinteractions

P-gp inducers and/or moderate to strong CYP inducers (e.g., rifampin, St. John's wort, carbamazepine): May decrease concentrations of sofosbuvir and/or velpatasvir. Use of EPCLUSA with P-gp inducers and/or moderate to strong CYP inducers is not recommended. Consult the full prescribing information prior to use for potential drug interactions. Clearance of HCV infection with direct acting antivirals may lead to changes in hepatic function, which may impact safe and effective use of concomitant medications. Frequent monitoring of relevant laboratory parameters (INR or blood glucose) and dose adjustments of certain concomitant medications may be necessary.

7.1 Potential for

Other Drugs to Affect EPCLUSA 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 inducers of P-gp and/or moderate to strong inducers of CYP2B6, CYP2C8, or CYP3A4 (e.g., rifampin, St. John's wort, carbamazepine) may decrease plasma concentrations of sofosbuvir and/or velpatasvir, leading to reduced therapeutic effect of EPCLUSA. The use of these agents with EPCLUSA is not recommended. EPCLUSA may be coadministered with P-gp, BCRP, and CYP inhibitors.

7.2 Potential for EPCLUSA to

Affect Other Drugs Velpatasvir is an inhibitor of drug transporters P-gp, breast cancer resistance protein (BCRP), OATP1B1, OATP1B3, and OATP2B1. Coadministration of EPCLUSA with drugs that are substrates of these transporters may increase the exposure of such drugs.

7.3 Established and

Potentially Significant Drug Interactions Clearance of HCV infection with direct acting antivirals may lead to changes in hepatic function, which may impact the safe and effective use of concomitant medications. For example, altered blood glucose control resulting in serious symptomatic hypoglycemia has been reported in diabetic patients in postmarketing case reports and published epidemiological studies. Management of hypoglycemia in these cases required either discontinuation or dose modification of concomitant medications used for diabetes treatment. Frequent monitoring of relevant laboratory parameters (e.g., International Normalized Ratio [INR] in patients taking warfarin, blood glucose levels in diabetic patients) or drug concentrations of concomitant medications such as cytochrome P450 substrates with a narrow therapeutic index (e.g., certain immunosuppressants) is recommended to ensure safe and effective use. Dose adjustments of concomitant medications may be necessary. Table 4 provides a listing of established or potentially clinically significant drug interactions. The drug interactions described are based on studies conducted with either EPCLUSA, the components of EPCLUSA (sofosbuvir and velpatasvir) as individual agents, or are predicted drug interactions that may occur with EPCLUSA. Table 4 Potentially Significant Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Studies or Predicted Interaction This table is not all inclusive.

Concomitant Drug Class: Drug Name Effect on Concentration ↓ = decrease, ↑ = increase. Clinical Effect/Recommendation DF = disoproxil fumarate.

Acid Reducing Agents: ↓ velpatasvir Velpatasvir solubility decreases as pH increases. Drugs that increase gastric pH are expected to decrease concentration of velpatasvir. Antacids (e.g., aluminum and magnesium hydroxide) Separate antacid and EPCLUSA administration by 4 hours. H 2 -receptor antagonists These interactions have been studied in healthy adults. (e.g., famotidine) H 2 -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 (e.g., omeprazole) 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.

Antiarrhythmics: amiodarone Effect on amiodarone, sofosbuvir, and velpatasvir concentrations unknown Coadministration of amiodarone with a sofosbuvir-containing regimen may 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. digoxin ↑ digoxin Therapeutic concentration monitoring of digoxin is recommended when coadministered with EPCLUSA. Refer to digoxin prescribing information for monitoring and dose modification recommendations for concentration increases of less than 50%.

Anticancers: topotecan ↑ topotecan Coadministration is not recommended.

Anticonvulsants: carbamazepine phenytoin phenobarbital ↓ sofosbuvir ↓ velpatasvir Coadministration is not recommended.

Antimycobacterials: rifabutin rifampin rifapentine ↓ sofosbuvir ↓ velpatasvir Coadministration is not recommended.

HIV Antiretrovirals: efavirenz ↓ velpatasvir Coadministration of EPCLUSA with efavirenz-containing regimens is not recommended. Regimens containing tenofovir DF ↑ tenofovir Monitor for tenofovir-associated adverse reactions in patients receiving EPCLUSA concomitantly with a regimen containing tenofovir DF. Refer to the prescribing information of the tenofovir DF-containing product for recommendations on renal monitoring. tipranavir/ritonavir ↓ sofosbuvir ↓ velpatasvir Coadministration is not recommended.

Herbal Supplements: St. John's wort (Hypericum perforatum) ↓ sofosbuvir ↓ velpatasvir Coadministration is not recommended.

HMG-CoA Reductase Inhibitors: rosuvastatin ↑ rosuvastatin Coadministration of EPCLUSA with rosuvastatin may significantly increase the concentration of rosuvastatin, which is associated with increased risk of myopathy, including rhabdomyolysis. Rosuvastatin may be administered with EPCLUSA at a dose that does not exceed 10 mg. atorvastatin ↑ atorvastatin Coadministration of EPCLUSA with atorvastatin may be associated with increased risk of myopathy, including rhabdomyolysis. Monitor closely for HMG-CoA reductase inhibitor-associated adverse reactions, such as myopathy and rhabdomyolysis.

7.4 Drugs without

Clinically Significant Interactions with EPCLUSA Based on drug interaction studies conducted with the components of EPCLUSA (sofosbuvir or velpatasvir) or EPCLUSA, no clinically significant drug interactions have been observed or are expected with the following drugs: EPCLUSA: atazanavir/ritonavir, buprenorphine/naloxone, cyclosporine, darunavir/ritonavir, dolutegravir, elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide, emtricitabine, methadone, naltrexone, raltegravir, or rilpivirine.

Sofosbuvir: ethinyl estradiol/norgestimate, or tacrolimus.

Velpatasvir: ethinyl estradiol/norgestimate, ketoconazole, or pravastatin. See Table 4 for use of EPCLUSA with certain HIV antiretroviral regimens.