Drug interactions between clonazepam and olanzapine

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 CLOSELY: 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.