Drug Interactions between amiodarone and tacrolimus

GENERALLY AVOID: Grapefruit juice may significantly increase the plasma concentrations of orally administered amiodarone. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruits. In 11 nonsmoking, healthy volunteers, grapefruit juice (300 mL with drug administration, then 3 hours and 9 hours later) increased the mean peak plasma concentration (Cmax) and area under the concentration-time curve (AUC) of amiodarone (17 mg/kg single dose) by 84% and 50%, respectively, compared to water. Formation of the pharmacologically active metabolite, N-desethylamiodarone (N-DEA), was completely inhibited. Clinically, this interaction can lead to altered efficacy of amiodarone, since antiarrhythmic properties of amiodarone and N-DEA appear to differ. In the study, mean increases in PR and QTc intervals of 17.9% and 11.3%, respectively, were observed 6 hours postdose with water, while increases of 10.2% and 3.3%, respectively, were observed after administration with grapefruit juice.

ADJUST DOSING INTERVAL: Food increases the rate and extent of absorption of amiodarone. The mechanism appears to involve the effect of food-induced physiologic changes on drug release from its formulation. In 30 healthy volunteers, administration of a single 600 mg dose of amiodarone following a high-fat meal resulted in a Cmax and AUC that were 3.8 and 2.4 times the respective values under fasting conditions. The time to reach peak plasma concentration (Tmax) was decreased by 37%, indicating an increased rate of absorption. Mean Cmax and AUC for the active metabolite, N-DEA, also increased by 32% and 55%, respectively, but there was no change in the Tmax.

MANAGEMENT: Patients treated with oral amiodarone should avoid consumption of grapefruits and grapefruit juice. In addition, oral amiodarone should be administered consistently with regard to meals.

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.