Drug Interactions between Astagraf XL and E S P

ADJUST DOSE: Coadministration with certain macrolide or ketolide antibiotics may significantly increase the oral bioavailability of tacrolimus. The proposed mechanism is inhibition of tacrolimus metabolism via intestinal CYP450 3A4. Inhibition of P-glycoprotein (P-gp) efflux transporter in gut wall may also contribute. There have been case reports of nephrotoxicity and other adverse effects (e.g., hyperkalemia, hyperglycemia, hemolytic anemia, hemolytic uremic syndrome, neurotoxicity) in association with significantly elevated tacrolimus blood levels within days following the addition of clarithromycin or erythromycin, which necessitated either a dosing adjustment or interruption of tacrolimus and/or discontinuation of the macrolide. Greater than 10-fold increases in tacrolimus blood levels have been observed in some cases. These reports are consistent with data derived from pharmacokinetic studies involving tacrolimus and other potent CYP450 3A4 inhibitors such as azole antifungal agents. Although data are not available for telithromycin, it is expected to interact similarly with tacrolimus due to its status as a potent CYP450 3A4/P-gp inhibitor.

MONITOR CLOSELY: Tacrolimus can cause concentration-dependent prolongation of the QT interval. Theoretically, coadministration with other agents that can prolong the QT interval such as macrolide and ketolide antibiotics 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 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).

MANAGEMENT: Caution is advised when tacrolimus is used with macrolide or ketolide antibiotics that significantly inhibit CYP450 3A4 such as clarithromycin, erythromycin, josamycin, and telithromycin. A preemptive dosage reduction for tacrolimus may be appropriate in some cases. Frequent monitoring of tacrolimus whole blood levels should be performed during and after discontinuation of macrolide antibiotic therapy, and the tacrolimus dosage adjusted accordingly. In addition, patients should be closely monitored for development of serious adverse effects such as nephrotoxicity, lymphoma and other malignancies, infections, diabetes, neurotoxicity (tremor, paraesthesia, encephalopathy, delirium, coma), hyperkalemia, QT prolongation, myocardial hypertrophy, and hypertension. Patients should be advised to seek prompt medical attention if they experience symptoms that could indicate the occurrence of torsade de pointes such as dizziness, lightheadedness, fainting, palpitation, irregular heart rhythm, shortness of breath, or syncope.

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