Drug Interaction Report

MONITOR: Coadministration with inducers of CYP450 3A4 may decrease the plasma concentrations of elbasvir and grazoprevir, both of which are substrates of the isoenzyme. In 10 study subjects, administration of elbasvir 50 mg once daily with efavirenz 600 mg once daily decreased elbasvir peak plasma concentration (Cmax), systemic exposure (AUC) and trough plasma concentration (Cmin) by 45%, 54% and 59%, respectively, compared to administration of elbasvir alone. Likewise, when grazoprevir 200 mg once daily and efavirenz 600 mg once daily were given together to 12 study subjects, grazoprevir Cmax, AUC and Cmin decreased by 87%, 83% and 69%, respectively. Efavirenz is generally considered a moderate inducer of CYP450 3A4. The extent to which other, less potent inducers of CYP450 3A4 may interact with elbasvir and grazoprevir is unknown.

MANAGEMENT: The potential for diminished pharmacologic effects of elbasvir-grazoprevir should be considered during coadministration with CYP450 3A4 inducers. Alternative treatments may be required if an interaction is suspected.

MONITOR: Coadministration with inducers of CYP450 3A4 may decrease the plasma concentrations of elbasvir and grazoprevir, both of which are substrates of the isoenzyme. In 10 study subjects, administration of elbasvir 50 mg once daily with efavirenz 600 mg once daily decreased elbasvir peak plasma concentration (Cmax), systemic exposure (AUC) and trough plasma concentration (Cmin) by 45%, 54% and 59%, respectively, compared to administration of elbasvir alone. Likewise, when grazoprevir 200 mg once daily and efavirenz 600 mg once daily were given together to 12 study subjects, grazoprevir Cmax, AUC and Cmin decreased by 87%, 83% and 69%, respectively. Efavirenz is generally considered a moderate inducer of CYP450 3A4. The extent to which other, less potent inducers of CYP450 3A4 may interact with elbasvir and grazoprevir is unknown.

MANAGEMENT: The potential for diminished pharmacologic effects of elbasvir-grazoprevir should be considered during coadministration with CYP450 3A4 inducers. Alternative treatments may be required if an interaction is suspected.

ADJUST DOSING INTERVAL: Food may enhance the oral bioavailability of bexarotene. In one clinical study, bexarotene peak plasma concentration (Cmax) and systemic exposure (AUC) resulting from a 75 to 300 mg dose were 35% and 48% higher, respectively, when administered after a fat-containing meal relative to a glucose solution. In all clinical trials, patients were instructed to take bexarotene with or immediately following a meal.

Coadministration with inhibitors of CYP450 3A4 such as grapefruit juice may theoretically increase the plasma concentrations of bexarotene. In vitro studies suggest that bexarotene is metabolized by CYP450 3A4. However, concomitant administration with multiple doses of ketoconazole, a potent CYP450 3A4 inhibitor, did not alter bexarotene plasma concentrations, which would imply that bexarotene elimination is not substantially dependent on CYP450 3A4 metabolism in vivo.

MANAGEMENT: Because safety and efficacy data are based upon administration with food, bexarotene should be administered once daily with a meal. Patients may want to avoid consuming large amounts of grapefruit or grapefruit juice.

Food does not appear to have clinically significant effects on the pharmacokinetics of elbasvir and grazoprevir. When a single 50 mg-100 mg dose of elbasvir-grazoprevir was administered to healthy study subjects with a high-fat meal (900 kcal; 500 kcal from fat), elbasvir peak plasma concentration (Cmax) and systemic exposure (AUC) decreased by 15% and 11%, respectively, while grazoprevir Cmax and AUC increased by 2.8- and 1.5-fold, respectively, compared to administration under fasting conditions. According to the product labeling, elbasvir-grazoprevir may be administered with or without food.