Drug Interaction Report

MONITOR: Coadministration with inhibitors of CYP450 3A4 may increase the plasma concentrations of grazoprevir, which is a substrate of the isoenzyme. In 8 study subjects, administration of a single 100 mg dose of grazoprevir with the potent CYP450 3A4 inhibitor ketoconazole (400 mg once daily) increased grazoprevir peak plasma concentration (Cmax), systemic exposure (AUC) and trough plasma concentration (Cmin) by 13%, 200% and 100%, respectively, compared to administration of grazoprevir alone. High plasma levels of grazoprevir may increase the risk of adverse effects such as alanine aminotransferase (ALT) elevations. Ketoconazole also increased the Cmax, AUC and Cmin of a single 50 mg dose of elbasvir by 29%, 80% and 89%, respectively. The extent to which other, less potent inhibitors of CYP450 3A4 may interact with elbasvir and grazoprevir is unknown.

MANAGEMENT: Caution is advised if elbasvir-grazoprevir is prescribed in combination with CYP450 3A4 inhibitors. Patients should be monitored for increased adverse effects such as nausea, vomiting, and ALT elevations.

GENERALLY AVOID: Grapefruit juice may increase the plasma concentrations of crizotinib. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruits. Because crizotinib is associated with concentration-dependent prolongation of the QT interval, increased levels may potentiate the risk of ventricular arrhythmias such as torsade de pointes and sudden death.

Food has no significant effect on the gastrointestinal absorption of crizotinib. According to the product labeling, a high-fat meal reduced crizotinib peak plasma concentration (Cmax) and systemic exposure (AUC) by approximately 14%.

MANAGEMENT: Patients treated with crizotinib should avoid consumption of grapefruit, grapefruit juice, and any supplement containing grapefruit extract. Crizotinib may be taken without regards to food.

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.