Drug Interaction Report

CONTRAINDICATED: Coadministration with potent inhibitors of CYP450 3A4 may significantly increase the plasma concentrations of ticagrelor, which is primarily metabolized by the isoenzyme. In healthy volunteers, administration of ticagrelor in combination with the potent CYP450 3A4 inhibitor ketoconazole resulted in increased ticagrelor peak plasma concentration (Cmax) and systemic exposure (AUC) by 2.4-fold and 7.3-fold, respectively, and reduced Cmax and AUC of the active metabolite by 89% and 56%, respectively.

MANAGEMENT: Concomitant use of ticagrelor with potent CYP450 3A4 inhibitors is considered contraindicated by some foreign authorities. The U.S. labeling for ticagrelor recommends avoiding use with potent CYP450 3A4 inhibitors. Labeling for itraconazole, a potent CYP450 3A4 inhibitor, specifically contraindicates use with ticagrelor during and for 2 weeks after treatment with itraconazole.

ADJUST DOSING INTERVAL: Food increases the absorption of itraconazole capsules but decreases the absorption of itraconazole oral solution. Cola beverages may increase the bioavailability of itraconazole capsules. Itraconazole capsules require an acidic gastric pH for adequate dissolution and subsequent absorption. Cola beverages help lower gastric pH and improve absorption.

GENERALLY AVOID: Grapefruit juice may impair the absorption of itraconazole capsules, resulting in decreased antifungal effects. In a small, randomized, crossover study, the administration of itraconazole capsules with double-strength grapefruit juice (compared to water) was associated with significantly decreased (43%) plasma concentrations of itraconazole and its pharmacologically active hydroxy metabolite, as well as delayed times to reach peak concentrations of both. The exact mechanism of interaction is unknown but may involve reduced absorption of itraconazole secondary to enhanced activity of intestinal P-glycoprotein drug efflux pumps and delayed gastric emptying induced by certain compounds present in grapefruits. Another study reported no pharmacokinetic changes with single-strength grapefruit juice. Whether or not these observations apply to itraconazole oral solution is unknown.

MANAGEMENT: The manufacturer recommends that the capsules be taken immediately after a full meal and the solution be taken on an empty stomach to ensure maximal absorption. Cola beverages may help increase the bioavailability of itraconazole capsules, particularly in patients with hypochlorhydria or those treated concomitantly with gastric acid suppressants. Until more information is available, it may be advisable to avoid the consumption of grapefruits and grapefruit juice during itraconazole therapy.