Drug Interactions between Di-Phen and Symbyax

MONITOR: Fluoxetine may increase serum hydantoin levels. The mechanism is unknown, but may be related to inhibition of hepatic CYP450 2C9 and 2C19 hydantoin metabolism.

MANAGEMENT: Close observation for clinical and laboratory evidence of hydantoin toxicity is recommended if these drugs must be used together. Patients should be advised to notify their physician if they experience symptoms of possible hydantoin toxicity, including drowsiness, visual disturbances, change in mental status, seizures, nausea, or ataxia.

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MONITOR: Coadministration with inducers of CYP450 1A2 may decrease the plasma concentrations of olanzapine. Data from available studies indicate that olanzapine is primarily metabolized by CYP450 1A2 and, to a lesser extent, by CYP450 2D6 and uridine diphosphate glucuronosyltransferase (UGT) 1A4. When coadministered with rifampin, a moderate CYP450 1A2 inducer that also induces UGT 1A4, olanzapine peak plasma concentration (Cmax) and systemic exposure (AUC) decreased by 11% and 48%, respectively. Coadministration with 200 mg twice daily of carbamazepine, another CYP450 1A2 inducer, caused an approximately 50% increase in the clearance of olanzapine. Higher daily dosages of carbamazepine may cause an even greater increase in olanzapine clearance.

MANAGEMENT: The potential for diminished pharmacologic effects of olanzapine should be considered during coadministration with CYP450 1A2 inducers. Alternative treatments may be required if an interaction is suspected.

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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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