Drug Interaction Report

MONITOR: Both azithromycin and tacrolimus have rarely been associated with QT interval prolongation. Theoretically, concomitant use may result in additive effects and increased risk of ventricular arrhythmias including torsade de pointes and sudden death. In general, the risk of an individual agent or a combination of these agents causing ventricular arrhythmia in association with QT prolongation is largely unpredictable but may be increased by certain underlying risk factors such as congenital long QT syndrome, cardiac disease, and electrolyte disturbances (e.g., hypokalemia, hypomagnesemia). In addition, the extent of drug-induced QT prolongation is dependent on the particular drug(s) involved and dosage(s) of the drug(s).

MONITOR: Rarely, azithromycin has been reported to increase the plasma concentrations of tacrolimus. The exact mechanism has not been established, since azithromycin is not generally considered an inhibitor of CYP450 3A4 or P-glycoprotein, of which tacrolimus is a substrate. Supportive evidence is limited to two published case reports. In one report, a patient receiving intravenous tacrolimus had a twofold increase in his tacrolimus levels three days after the initiation of azithromycin 500 mg/day. In the other report, a heart transplant patient had increased tacrolimus blood levels following the administration of intravenous azithromycin and ceftriaxone. Tacrolimus levels decreased after the discontinuation of ceftriaxone and switch from intravenous to oral azithromycin. In contrast, a 10-day course of azithromycin reportedly had no significant effect on serum creatinine or tacrolimus levels in a bone marrow transplant patient treated with tacrolimus.

MANAGEMENT: Caution and clinical monitoring are recommended when azithromycin and tacrolimus are prescribed in combination. Patients should be advised to seek medical attention if they experience symptoms that could indicate the occurrence of torsade de pointes such as dizziness, lightheadedness, fainting, palpitations, irregular heartbeat, shortness of breath, or syncope. It may be appropriate to monitor tacrolimus levels more closely following the initiation or discontinuation of azithromycin.

ADJUST DOSING INTERVAL: Consumption of food has led to a 27% decrease in the bioavailability of orally administered tacrolimus.

MANAGEMENT: Tacrolimus should be administered at least one hour before or two hours after meals.

GENERALLY AVOID: Grapefruit juice has been reported to increase tacrolimus trough concentrations. Data are limited, but inhibition of the CYP450 enzyme system appears to be involved.

MANAGEMENT: The clinician may want to recommend that the patient avoid ingesting large amounts of grapefruit juice while taking tacrolimus.