Drug Interactions between indinavir and Prograf

GENERALLY AVOID: Grapefruit and/or grapefruit juice may increase the plasma concentrations of tacrolimus. The proposed mechanism for the interaction is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruit. Inhibition of hepatic CYP450 3A4 may also contribute. Although clinical data are lacking, this interaction may result in increased risk of serious adverse reactions such as nephro- and neurotoxicity, as well as other adverse effects associated with tacrolimus such as malignancies, infections, diabetes, hyperkalemia, hypertension, and QT prolongation.

GENERALLY AVOID: Alcohol may modify the rate of tacrolimus release from extended release formulations, thereby potentially increasing the risk of serious adverse reactions.

ADJUST DOSING INTERVAL: Coadministration with food decreases the rate and extent of tacrolimus absorption. This effect is greatest after a high-fat meal.

MANAGEMENT: Patients should avoid consumption of food or drink containing grapefruit during treatment with tacrolimus. Concomitant use of tacrolimus, especially extended release formulations, with alcohol should also be avoided. Tacrolimus extended release formulations should be administered on an empty stomach, at least 1 hour before or 2 hours after a meal, and tacrolimus immediate release formulations should be taken consistently every day with or without food.

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).