Drug Interaction Report

GENERALLY AVOID: Quizartinib can cause dose- and concentration-dependent prolongation of the QT interval. Theoretically, coadministration with other agents that can prolong the QT interval may increase the risk of ventricular arrhythmias including torsade de pointes and sudden death. In a clinical study where 265 patients with newly diagnosed FLT3-ITD-positive acute myeloid leukemia (AML) were treated with quizartinib (38% for >=6 months; 30% for >1 year) in combination with chemotherapy, 2.3% had a Fridericia-corrected QT interval (QTcF) greater than 500 ms and 10% had a QTcF increase from baseline greater than 60 ms. Overall, QT prolongation of any grade occurred in 14% of the quizartinib patients (compared to 4.1% of patients treated with placebo and chemotherapy), and 4% required dose reductions of quizartinib due to QT prolongation. The study excluded patients with a QTcF >=450 ms or other risk factors for QT prolongation or arrhythmic events. Based on an analysis of the exposure-response relationship, quizartinib is predicted to produce a median increase of 18 and 24 ms in the QTcF at steady-state peak plasma concentration during maintenance therapy at the 26.5 mg and 53 mg dose levels, respectively. Across premarketing clinical trials, torsade de pointes arrhythmia was reported in approximately 0.2%, cardiac arrest in 0.6% (including 0.4% with a fatal outcome), and ventricular fibrillation in 0.1% of the total 1,081 patients with AML treated with quizartinib. These severe cardiac events occurred predominantly during the induction phase. 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, hypomagnesemias). 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: Coadministration of quizartinib with other drugs that can prolong the QT interval should generally be avoided. If concomitant use is required, more frequent monitoring with electrocardiograms (ECGs) is recommended to guide continued treatment. All patients treated with quizartinib should have ECGs performed as well as potassium and magnesium serum levels measured prior to initiation of treatment, at regular intervals during treatment, and when clinically indicated such as following dose escalation or during episodes of diarrhea or vomiting. Do not initiate quizartinib or escalate the dose if QTcF interval is greater than 450 ms. In addition, hypokalemia and hypomagnesemia should be corrected before and during treatment. If QTcF increases to greater than 480 ms during treatment, reduce the dose, interrupt therapy, or permanently discontinue quizartinib as clinically appropriate in accordance with the prescribing information. 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. Quizartinib should be permanently discontinued in patients who experience torsade de pointes, polymorphic ventricular tachycardia, or QT prolongation with signs or symptoms of life-threatening arrhythmia.

MONITOR: Grapefruit juice may increase the plasma concentrations of orally administered drugs that are substrates of the CYP450 3A4 isoenzyme. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruit. Because grapefruit juice inhibits primarily intestinal rather than hepatic CYP450 3A4, the magnitude of interaction is greatest for those drugs that undergo significant presystemic metabolism by CYP450 3A4 (i.e., drugs with low oral bioavailability). In general, the effect of grapefruit juice is concentration-, dose- and preparation-dependent, and can vary widely among brands. Certain preparations of grapefruit juice (e.g., high dose, double strength) have sometimes demonstrated potent inhibition of CYP450 3A4, while other preparations (e.g., low dose, single strength) have typically demonstrated moderate inhibition. Pharmacokinetic interactions involving grapefruit juice are also subject to a high degree of interpatient variability, thus the extent to which a given patient may be affected is difficult to predict.

MANAGEMENT: Patients who regularly consume grapefruit or grapefruit juice should be monitored for adverse effects and altered plasma concentrations of drugs that undergo significant presystemic metabolism by CYP450 3A4. Grapefruit and grapefruit juice should be avoided if an interaction is suspected. Orange juice is not expected to interact with these drugs.