Drug Interaction Report

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.

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GENERALLY AVOID: One case series has suggested that benzodiazepines may amplify the teratogenic effects of valproate in the offspring of epileptic women. Both drugs individually have been associated with adverse effects to the fetus. Another study has suggested that valproate may displace diazepam from plasma protein binding sites and inhibit its metabolism; however, the clinical significance has not been established. Other benzodiazepines may interact with valproate in a similar fashion.

MANAGEMENT: Both valproate and benzodiazepines should be avoided during pregnancy unless the potential benefits outweigh the risks to the fetus. In other patients, close observation for clinical evidence of benzodiazepine toxicity (excessive sedation) is recommended if valproate and a benzodiazepine must be used together.

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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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GENERALLY AVOID: Alcohol may potentiate some of the pharmacologic effects of CNS-active agents. Use in combination may result in additive central nervous system depression and/or impairment of judgment, thinking, and psychomotor skills.

MANAGEMENT: Patients receiving CNS-active agents should be warned of this interaction and advised to avoid or limit consumption of alcohol. Ambulatory patients should be counseled to avoid hazardous activities requiring complete mental alertness and motor coordination until they know how these agents affect them, and to notify their physician if they experience excessive or prolonged CNS effects that interfere with their normal activities.

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GENERALLY AVOID: Acute alcohol ingestion may potentiate the CNS depression and other CNS effects of many benzodiazepines. Tolerance may develop with chronic ethanol use. The mechanism may be decreased clearance of the benzodiazepines because of CYP450 hepatic enzyme inhibition. Also, it has been suggested that the cognitive deficits induced by benzodiazepines may be increased in patients who chronically consume large amounts of alcohol.

MONITOR: Grapefruit juice may increase the plasma concentrations of orally administered drugs that are substrates of the CYP450 3A4 isoenzyme. However, the interaction seems to affect primarily those drugs that undergo significant presystemic metabolism by CYP450 3A4 (i.e., drugs with low oral bioavailability), presumably due to the fact that grapefruit juice inhibits intestinal rather than hepatic CYP450 3A4. Because pharmacokinetic interactions involving grapefruit juice are often subject to a high degree of interpatient variability, the extent to which a given patient may be affected is difficult to predict.

MANAGEMENT: Patients should be advised to avoid alcohol during benzodiazepine therapy. Patients who regularly consume grapefruit or grapefruit juice should be monitored for adverse effects and altered plasma concentrations of drugs that undergo significant presystemic metabolism by CYP450 3A4. Grapefruit and grapefruit juice should be avoided if an interaction is suspected. Orange juice is not expected to interact with these drugs.

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GENERALLY AVOID: Alcohol may potentiate some of the pharmacologic effects of CNS-active agents. Use in combination may result in additive central nervous system depression and/or impairment of judgment, thinking, and psychomotor skills.

MANAGEMENT: Patients receiving CNS-active agents should be warned of this interaction and advised to avoid or limit consumption of alcohol. Ambulatory patients should be counseled to avoid hazardous activities requiring complete mental alertness and motor coordination until they know how these agents affect them, and to notify their physician if they experience excessive or prolonged CNS effects that interfere with their normal activities.

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One study has reported a 22% reduction in diazepam plasma levels when coadministered with caffeine. The exact mechanism of this interaction has not been specified. Physicians and patients should be aware that changes to caffeine consumption habits may impact the efficacy of diazepam therapy.

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