Drug Interactions between fluoxetine / olanzapine and imatinib

MONITOR: It is uncertain whether olanzapine causes clinically significant prolongation of the QT interval. In pooled studies of adults as well as pooled studies of adolescents, there were no significant differences between olanzapine and placebo in the proportion of patients experiencing potentially important changes in ECG parameters, including QT, QTcF (Fridericia-corrected), and PR intervals. In clinical trials, clinically meaningful QTc prolongations (QTcF >=500 msec at any time post-baseline in patients with baseline QTcF <500 msec) occurred in 0.1% to 1% of patients treated with olanzapine, with no significant differences in associated cardiac events compared to placebo. Published studies have generally reported no significant effect of olanzapine on QTc interval, although both QTc prolongation and QTc shortening have also been reported. There have been a few isolated case reports of QT prolongation in patients receiving olanzapine. However, causality is difficult to establish due to confounding factors such as concomitant use of drugs that cause QT prolongation and underlying conditions that may predispose to QT prolongation (e.g., hypokalemia, congenital long QT syndrome, preexisting conduction abnormalities).

MANAGEMENT: Some authorities recommend caution when olanzapine is used with drugs that are known to cause QT prolongation. ECG monitoring may be advisable in some cases, such as in patients with a history of cardiac arrhythmias or congenital or family history of long QT syndrome. 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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MONITOR: Imatinib is a substrate of the CYP450 3A4 isoenzyme as well as a potent competitive inhibitor of the CYP450 2C9, 2D6 and 3A4 isoenzymes. Some drugs that are known inhibitors of CYP450 3A4 are also metabolized by one or more of the isoenzymes inhibited by imatinib. Theoretically, coadministration of imatinib with those drugs may result in mutually elevated plasma drug concentrations due to competitive and noncompetitive inhibition of CYP450 activities.

MANAGEMENT: The possibility of prolonged and/or increased pharmacologic effects of imatinib, including serious adverse effects such as edema, hematologic toxicity and immunosuppression, should be considered during concomitant therapy, particularly with potent CYP450 3A4 inhibitors such as ketoconazole, itraconazole, ritonavir, nefazodone, and erythromycin. In addition, clinical and laboratory monitoring for potentially increased pharmacologic effects of coadministered medications is recommended, especially those with a narrow therapeutic range.

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MONITOR: Coadministration with imatinib may increase the plasma concentrations of drugs that are substrates of CYP450 2C9, 2D6 and/or 3A4. The mechanism is decreased clearance due to inhibition of these isoenzymes by imatinib. According to the manufacturer, imatinib increased the mean peak plasma concentration (Cmax) and systemic exposure (AUC) of simvastatin, a sensitive CYP450 3A4 substrate, by 2- and 3.5-fold, respectively. Data for other substrates are limited, although human liver microsome studies indicate that imatinib is a potent competitive inhibitor of all three isoenzymes.

MANAGEMENT: Caution is advised when imatinib is used concomitantly with drugs that undergo metabolism by CYP450 2C9, 2D6 and/or 3A4, particularly those with a narrow therapeutic range. Dosage adjustments as well as clinical and laboratory monitoring may be appropriate for some drugs whenever imatinib is added to or withdrawn from therapy.

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