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: According to the manufacturer, coadministration with a meal high in calories, fat, and protein reduces the absorption of indinavir. In ten patients given indinavir in this manner, the peak plasma concentration (Cmax) and area under the concentration-time curve (AUC) of indinavir decreased by an average of 84% and 77%, respectively. In contrast, grapefruit juice may have only minor effects on the oral bioavailability of indinavir. The manufacturer's package labeling states that administration of a single 400 mg dose of indinavir with 8 oz. of grapefruit juice decreased indinavir AUC by an average of 26%. Likewise, a study consisting of 14 HIV-infected subjects found no uniform nor significant changes in steady-state indinavir AUC during administration with double-strength grapefruit juice compared to water. There was, however, a delay in absorption (Tmax) due to grapefruit juice that is unlikely to be of clinical significance.

MANAGEMENT: To ensure maximal oral absorption, indinavir should be administered without food but with water 1 hour before or 2 hours after a meal. Alternatively, indinavir may be administered with other liquids such as skim milk, juice, coffee, or tea, or with a light meal (e.g., dry toast with jelly, juice, and coffee with skim milk and sugar; corn flakes, skim milk and sugar).