Drug Interaction Report

MONITOR: Coadministration with inhibitors of CYP450 3A4 may increase the plasma concentrations and pharmacologic effects of dasatinib, which is primarily metabolized by the isoenzyme. In a drug interaction study of 18 patients with solid tumors, coadministration of dasatinib (20 mg once a day) with the potent inhibitor ketoconazole (200 mg twice a day) increased the dasatinib peak plasma concentration (Cmax) and systemic exposure (AUC) by approximately 4- and 5-fold, respectively, compared to administration without ketoconazole. Data are not available for dasatinib in combination with other CYP450 3A4 inhibitors. Theoretically, a reverse interaction may also occur, since many CYP450 3A4 inhibitors are also substrates of the isoenzyme and dasatinib is an inhibitor.

MANAGEMENT: Caution is advised if dasatinib is used in combination with moderate CYP450 3A4 inhibitors. Close monitoring for toxicity (e.g., myelosuppression, bleeding complications, fluid retention) is recommended, and the dasatinib dosage adjusted as necessary. Patients should also be monitored for altered efficacy and safety of the concomitant administered drug.

GENERALLY AVOID: Grapefruit and grapefruit juice may significantly increase the plasma concentrations of dasatinib. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall induced by certain compounds present in grapefruit. Because grapefruit juice inhibits primarily intestinal rather than hepatic CYP450 3A4, the magnitude of interaction is greatest for those drugs that undergo significant presystemic metabolism by CYP450 3A4 (i.e., drugs with low oral bioavailability). In general, the effect of grapefruit juice is concentration-, dose- and preparation-dependent, and can vary widely among brands. Certain preparations of grapefruit juice (e.g., high dose, double strength) have sometimes demonstrated potent inhibition of CYP450 3A4, while other preparations (e.g., low dose, single strength) have typically demonstrated moderate inhibition. Pharmacokinetic interactions involving grapefruit juice are also subject to a high degree of interpatient variability, thus the extent to which a given patient may be affected is difficult to predict. Because dasatinib prolongs the QT interval, high plasma levels of dasatinib may increase the risk of ventricular arrhythmias such as torsade de pointes and sudden death.

MANAGEMENT: Patients treated with dasatinib should avoid consumption of grapefruit, grapefruit juice, and any supplement containing grapefruit extract. Some authorities recommend close monitoring for toxicity (e.g., myelosuppression, bleeding complications, fluid retention, bradycardia or other conduction disturbances) and a reduction of dasatinib dosage to a range of 20 to 40 mg daily should be considered if there are no alternatives and concomitant use with a potent CYP450 3A4 inhibitor is necessary.