Drug Interactions between Onmel and tacrolimus

ADJUST DOSE: Coadministration with azole antifungal agents may significantly increase the oral bioavailability of tacrolimus. The proposed mechanism is inhibition of tacrolimus metabolism via intestinal CYP450 3A4. In healthy volunteers, administration of a single 0.05 mg/kg oral dose of tacrolimus in combination with posaconazole suspension (400 mg twice a day for 7 days) increased mean tacrolimus peak plasma concentration (Cmax) and systemic exposure (AUC) by 2.2- and 4.5-fold, respectively. Likewise, voriconazole given orally at therapeutic dosages for 7 days increased the Cmax and AUC of a single 0.1 mg/kg dose of tacrolimus by an average of 2.2- and 3.2-fold, respectively. Another study found that ketoconazole (200 mg orally at bedtime for 12 days) increased the oral bioavailability of tacrolimus from 14% to 30% in six healthy volunteers, and decreased the apparent oral clearance of tacrolimus by 66%. In a study of transplant patients, median tacrolimus trough plasma concentration (Cmin) increased 3.1-fold in eight subjects treated with oral fluconazole 200 mg/day and 1.4-fold in twelve subjects who received fluconazole 100 mg/day. These increases were seen on day 1 after fluconazole administration and were associated with acute renal dysfunction and mental status changes in several patients. A median reduction of 56% in the tacrolimus dosage was subsequently required. In 17 post-transplant patients treated with clotrimazole troches (10 mg three times a day), significantly higher blood tacrolimus trough levels were observed by the third day compared to 18 patients treated with nystatin (5 mL four times a day). Levels were still higher in the clotrimazole group by day 7, although mean tacrolimus doses were significantly lower than in the nystatin group. Various case reports have also implicated itraconazole in the interaction, usually resulting in 2- to 3-fold increases in tacrolimus concentrations. A retrospective study of transplant patients from one hospital found that mean tacrolimus dosage was three times lower and mean trough blood concentration-to-dose ratio six times higher in seven patients on tacrolimus with itraconazole (750 mg +/- 300 mg/day) compared to seven patients not on itraconazole. In general, the interaction appears to occur primarily in the gut. In one study, high-dose fluconazole (400 mg/day) increased the mean steady-state concentration of intravenously administered tacrolimus by just 16% in 21 allogeneic bone marrow transplant patients. Ketoconazole also did not significantly affect the intravenous clearance of tacrolimus in one study, although it was highly variable between patients. Rare cases of hemolytic uremic syndrome, thrombotic thrombocytopenic purpura, and pulmonary embolus have been reported in patients receiving tacrolimus and posaconazole for the management of transplant rejection or graft-versus-host disease.

MONITOR CLOSELY: Tacrolimus can cause concentration-dependent prolongation of the QT interval. Theoretically, coadministration with other agents that can prolong the QT interval including some azole antifungal agents 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 if tacrolimus is used concomitantly with azole antifungal agents. When initiating therapy with posaconazole or voriconazole in patients already receiving tacrolimus, the manufacturers recommend that tacrolimus dosage be reduced by about one-third initially. No specific dosing recommendations are available for use with other azole antifungal agents, although a dosage reduction for tacrolimus should also be considered. Frequent monitoring of tacrolimus whole blood levels should be performed during and after discontinuation of azole antifungal therapy, and the tacrolimus dosage adjusted accordingly. 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.