Background

Treatment of acute agitation often involves combining antipsychotics and benzodiazepines. Injectable olanzapine, a second-generation antipsychotic, uniquely carries a warning against concomitant use with parenteral benzodiazepines. The olanzapine prescribing information states that “concomitant administration of intramuscular (IM) olanzapine and parenteral benzodiazepines is not recommended due to the potential for excessive sedation and cardiorespiratory compromise”. The European Medicines Agency (similar to the United States FDA) cautions against use of the two within 60 minutes of each other using similar language.  

The above warnings were based on a 2010 publication of 160 adverse event reports from a post-marketing database maintained by the drug manufacturer, and have resulted in many institutions prohibiting co-administration of IM olanzapine and parenteral benzodiazepines. The publication cited 29 fatal adverse events involving injectable olanzapine, concluding that caution should be exercised when using IM olanzapine and parenteral benzodiazepines simultaneously. However, 25 of the 29 patients received other sedating medications in addition to olanzapine and benzodiazepines, and the majority of fatalities were >12 hours after the last dose of olanzapine. Following this publication, a 2013 randomized controlled trial by Chan et al. found no difference in adverse event rates between patients receiving IV midazolam alone and patients receiving IV midazolam plus IV olanzapine for acute agitation.

This December 2024 study by Cole et al. aimed to re-evaluate the risks of cardiorespiratory compromise with concomitant injectable olanzapine and injectable benzodiazepine administration.  

Study design

This was a single-center retrospective cohort study of 693 patients who received 2 parenteral doses of eligible sedating medications within 60 minutes of each other. A total of 549 patients received 2 doses of olanzapine, and 144 received olanzapine and a benzodiazepine (midazolam, lorazepam, or diazepam). To avoid cohorts with a higher baseline risk of sedation, patients who received other sedating medications and patients who received more than 2 doses of olanzapine or 1 dose of a benzodiazepine were excluded. 

Patient Population

• Average age of 35
• Mostly male
• Most patients were intoxicated with alcohol
  • 65% in olanzapine + olanzapine group
  • 88% of patients in olanzapine + benzodiazepine group
  • Median blood alcohol concentration of 210 mg/dL for both groups
• Average time between medications was about 30 minutes for both groups
• Most medications were given via IM route

Results

*One death during hospitalization was due to missed occlusion myocardial infarction

• No significant difference in rates of intubation
• No significant difference in rates of hypoxemia or hypotension at any time after drug administration while in the ED
• No significant differences in primary or secondary outcomes when inclusion criteria was expanded to 2 doses within 120 minutes of each other in pre-specified sensitivity analysis

Study Critique:

• Well-designed study that attempted to address limitations of prior studies by excluding patients who received additional sedatives or multiple doses
• Median time of 30 minutes between doses aligns with real-world practice and pharmacokinetics of each medication
• May not be generalizable to all institutions and types of agitation, as most patients were agitated secondary to alcohol intoxication
• Study was slightly underpowered

Key Takeaways

• The concomitant administration of IM olanzapine with parenteral benzodiazepines may pose less risk than labeled warnings suggest.
• With the increasing pool of literature showing improved safety, it may be time to re-evaluate our practices surrounding these agents.

References

1. Olanzapine prescribing information (2009). U.S. Food and Drug Administration. Published 2009. Accessed January 10, 2025. 
2. Zyprexa product information. European Medicines Agency. Published October 1, 2022. Accessed January 10 2025.
3. Marder SR, Sorsaburu, S, Dunayevich E, et al. Case reports of postmarketing adverse event experiences with olanzapine intramuscular treatment in patients with agitation. J Clin Psychiatry; 2010; 71: 433-441. 
4. Cole JB, Stang JL, Collins JD et al. Comparing intubation rates in patients receiving parenteral olanzapine with and without a parenteral benzodiazepine in the emergency department. Ann Emerg Med. 84(6): 658-667.
5. Chan EW, Taylor DM, Knott JC et al. Intravenous droperidol or olanzapine as an adjunct to midazolam for the acutely agitated patient: a multi-center, randomized, double-blind, placebo-controlled trial. Ann Emerg Med. 2013;61:72-81.