Drug Interaction Report

GENERALLY AVOID: Coadministration of deferiprone and other drugs that can cause neutropenia or agranulocytosis may increase the risk and/or severity of hematologic toxicity. Serious infection and death have been reported. The mechanism by which deferiprone leads to neutropenia or agranulocytosis is unknown. In pooled clinical trials of 642 patients with thalassemia syndromes, neutropenia occurred in 6.2% and agranulocytosis in 1.7% of deferiprone-treated patients. Similarly, agranulocytosis occurred in 1.5% of deferiprone-treated patients in pooled clinical trials of 196 patients with sickle cell disease or other anemias. Pediatric patients experienced a higher rate of decreases in neutrophil count when compared to adults being treated with deferiprone for the same condition. Neutropenia and agranulocytosis generally resolve upon discontinuation of deferiprone.

MANAGEMENT: Concomitant use of deferiprone with other drugs known to be associated with neutropenia or agranulocytosis should generally be avoided. Some authorities consider this combination to be contraindicated. If coadministration is unavoidable, the patient's baseline absolute neutrophil count (ANC) should be measured and then closely monitored during deferiprone therapy according to the manufacturer's product labeling. If neutropenia or infection develops, deferiprone and any other concomitant therapy associated with neutropenia or agranulocytosis should be discontinued. A complete blood cell (CBC) count, including a white blood cell (WBC) count corrected for the presence of nucleated red blood cells, an ANC, and a platelet count should be obtained daily until recovery. Patients should be advised to seek immediate medical assistance if they develop symptoms of infection (e.g., fever, sore throat, flu-like symptoms). For patients who develop agranulocytosis (ANC less than 0.5 x 10^9/L), hospitalization should be considered, and deferiprone should not be resumed following recovery unless potential benefits outweigh the risks. Likewise, patients who develop neutropenia with deferiprone should not be rechallenged unless potential benefits outweigh the risks.

GENERALLY AVOID: Grapefruit juice may increase the plasma concentrations of nilotinib. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruits. Because nilotinib is associated with concentration-dependent prolongation of the QT interval, increased levels may potentiate the risk of ventricular arrhythmias such as torsade de pointes and sudden death.

ADJUST DOSING INTERVAL: Food increases the oral bioavailability of nilotinib. The mechanism of interaction is unknown. Compared to the fast state, nilotinib systemic exposure (AUC) increased by 82% when the dose was given 30 minutes after a high-fat meal. Because nilotinib is associated with concentration-dependent prolongation of the QT interval, increased levels may potentiate the risk of ventricular arrhythmias such as torsade de pointes and sudden death.

MANAGEMENT: Patients treated with nilotinib should avoid consumption of grapefruit, grapefruit juice, and any supplement containing grapefruit extract. In addition, no food should be consumed for at least 2 hours before and 1 hour after a nilotinib dose.