Drug Interactions between fluoxetine / olanzapine and halazepam

MONITOR: Several studies have suggested that the effects of benzodiazepines, particularly their effects on psychomotor performance, may be increased by fluoxetine. The mechanism may be related to additive CNS depressant effects and/or inhibition of CYP450 2C19 and/or 3A4 benzodiazepine metabolism by fluoxetine. The clinical implications are uncertain, but effects may be more pronounced in the elderly.

MANAGEMENT: Patients should be monitored for excessive CNS depression and psychomotor impairment. Dose reductions may be required. Ambulatory patients should be made aware of the possibility of additive CNS effects (e.g., drowsiness, dizziness, lightheadedness, confusion) and counseled to avoid activities requiring mental alertness until they know how these agents affect them. Patients should also be advised to notify their physician if they experience excessive or prolonged CNS effects that interfere with their normal activities.

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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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GENERALLY AVOID: The safety and efficacy of intramuscular olanzapine administered in combination with benzodiazepines have not been established. Deaths have been reported in patients who received IM olanzapine during postmarketing use. The cause has not been determined but in many of the deaths, patients were treated with multiple concomitant drugs including IM benzodiazepines and other IM antipsychotics that are known to have the potential to induce hypotension, bradycardia, and respiratory or CNS depression. In addition, IM olanzapine may have been administered to some patients in a manner that was inconsistent with product labeling and also to patients with significant medical comorbidities or other medical conditions associated with potentially fatal outcomes. As of September 30, 2005, there have been 29 cases of spontaneously reported fatalities temporally associated with the use of IM olanzapine. Nineteen of these fatal cases had been or were concurrently being treated with benzodiazepines (seven with more than one benzodiazepine; six with IM or IV benzodiazepines; five treated within 2 hours of death). Based on estimated exposure, the incidence of fatal reports was less than 0.01%, which is similar to that reported for other parenteral agents used to treat patients with acute agitation associated with mental illness. A causal relationship is difficult to establish because there tends to be a higher risk of mortality associated with this particular patient population regardless of treatment.

MONITOR: CNS- and/or cardiorespiratory-depressant effects may be increased during concomitant use of olanzapine and benzodiazepines, especially in elderly or debilitated patients. In clinical trials of elderly patients with dementia-related psychosis, the incidence of death in olanzapine-treated patients was significantly greater than in placebo-treated patients (3.5% vs. 1.5%). Risk factors for the increased mortality with olanzapine include age greater than 80 years, dysphagia, sedation, malnutrition and dehydration, concomitant use of benzodiazepines, and presence of pulmonary conditions such as pneumonia. Limited data in 15 healthy subjects receiving IM olanzapine followed by an IM benzodiazepine (lorazepam) found that the combination prolonged somnolence by 3.3 hours compared to IM olanzapine alone and 5.8 hours compared to IM lorazepam alone.

MANAGEMENT: Caution is necessary when olanzapine is used in combination with benzodiazepines. Ambulatory patients should be made aware of the possibility of additive CNS effects and counseled to avoid activities requiring mental alertness until they know how these agents affect them. They should also be advised to avoid rising abruptly from a sitting or recumbent position and to contact their physician if they experience symptoms of hypotension such as dizziness, lightheadedness, or fainting. Concomitant administration of IM olanzapine and parenteral benzodiazepine has not been studied and is therefore not recommended. Patients given this combination when necessary should be closely monitored for excessive sedation and cardiorespiratory depression.

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