Drug Interactions between Depakote and fluoxetine / olanzapine

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: Concurrent use of olanzapine and valproic acid may potentiate the risk of hepatotoxicity. The exact mechanism of interaction is unknown. In a retrospective study of 52 children, combined treatment with olanzapine and divalproex was associated with more frequent elevations of hepatic enzymes than either agent alone, and mean and peak hepatic enzyme levels during the observed course of treatment were also higher. All 12 patients who received combined treatment had at least one peak enzyme elevation above the normal range, versus 10 of 17 who received olanzapine alone and 6 of 23 who received divalproex alone. With the exception of 2 patients who required discontinuation of combination treatment (due to development of pancreatitis in one and steatohepatitis in the other), the observed peak and mean enzyme levels were less than 3 times the upper limit of normal (ULN) and were asymptomatic. The long-term significance of these findings is unknown.

MANAGEMENT: The authors of the study recommend monitoring liver function tests every 3 to 4 months during the first year of treatment with either olanzapine or valproic acid, at least in pediatric patients. If no elevations of liver enzymes or marked weight gain occur after one year, a decrease in frequency of monitoring to every 6 months can be considered. Patients should be advised to notify their physician if they experience signs and symptoms of hepatotoxicity such as fever, rash, anorexia, nausea, vomiting, fatigue, right upper quadrant pain, dark urine, and jaundice.

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Individual case reports suggest that fluoxetine may increase valproate levels, perhaps by inhibiting the hepatic metabolism of valproate. Another study of two patients suggests that valproate may enhance the therapeutic effects of fluoxetine. The mechanism is unknown. Patients should be monitored for altered pharmacologic effects and increased valproic acid levels if these drugs are administered concomitantly.

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