Introduction
Intramuscular olanzapine and parenteral benzodiazepines are commonly used agents in the ED for acute agitation. An FDA warning states that potentially fatal respiratory depression can occur when olanzapine and parenteral benzodiazepines are administered concomitantly, noting that “concomitant administration of intramuscular olanzapine and parenteral benzodiazepine has not been studied and is therefore not recommended.”
Key Context
- IM olanzapine and parenteral benzodiazepines are commonly used in the ED for acute agitation
- FDA warning of potentially fatal respiratory depression with concomitant use
- Warning initially stemmed from post-marketing adverse event monitoring data
- The clinical significance of this warning is questionable based on emerging evidence
Pharmacology
| Parameter | Olanzapine | Lorazepam | Midazolam |
|---|---|---|---|
|
Dose
|
5–10 mg with maximum of 30 mg/day | 1–4 mg PRN until adequately sedated | 2.5–5 mg PRN until adequately sedated |
|
Administration
|
IM: Reconstitute 10 mg vial with 2.1 mL SWFI. Resulting solution ~5 mg/mL. Use within 1 hour. | IM: administer undiluted. IV: dilute with equal volume of compatible diluent. | IM: administer undiluted. IV: can administer undiluted or diluted with compatible diluent. |
|
PK/PD
|
Onset: within 15 min Duration: ≥2 hours Metabolism: glucuronidation & CYP450 (1A2, 2D6) Half-life: 30 hrs (adults); ~1.5× greater in elderly Excretion: urine (57%), feces (30%) |
Onset: 15–30 min Duration: 6–8 hours Metabolism: hepatic Half-life: 13–18 hrs Excretion: urine (88%), feces (7%) |
Onset: 15 min Duration: 2–6 hours Metabolism: hepatic CYP3A4 Half-life: 2–6 hrs Excretion: urine (90%) |
|
Adverse Effects
|
Orthostatic hypotension, dizziness, drowsiness | Drowsiness, sedated state | Drowsiness, sedated state |
|
Warnings
|
Patients should remain recumbent if drowsy/dizzy until hypotension, bradycardia, and/or hypoventilation ruled out | Associated with anterograde amnesia, cardiorespiratory effects, CNS depression, hypotension, paradoxical reaction. Avoid with opioid agonists and other CNS depressants when possible. | Associated with anterograde amnesia, cardiorespiratory effects, CNS depression, hypotension, paradoxical reaction. Avoid with opioid agonists and other CNS depressants when possible. |
|
Compatibility
|
SWFI | D5W, NS, SWFI | D5W, NS |
Clinical Pearl
The FDA black box warning on concomitant use stemmed from post-marketing surveillance data. All three agents share overlapping CNS depressant effects, making careful patient selection and monitoring essential, particularly in patients with significant alcohol use.
Overview of Key Evidence
| Author / Year | Design (n) | Intervention | Key Findings |
|---|---|---|---|
| Klein, 20184 |
Prospective Observational
n=737 |
IM haloperidol 5 mg, ziprasidone 20 mg, olanzapine 10 mg, midazolam 5 mg, and haloperidol 10 mg for ED agitation |
Midazolam: 71% sedated at 15 min
Olanzapine: 61% sedated
AEs uncommon and not statistically different between groups |
| Marder, 20106 |
Post-Marketing Review
n=160 AEs / 539,000 pts |
539,000 patients received IM olanzapine over 21 months; 160 adverse events (0.03%), 83 serious (0.01%), 29 fatalities (0.0053%) |
66% of fatalities: concomitant BZD
76% had comorbidities
76% also received other concomitant antipsychotics; 12 deaths occurred >24 hrs post-injection |
| Wilson, 20109 |
Retrospective Chart Review
n=25 |
Patients receiving IM olanzapine for ED agitation with vital signs documented before and after (within 4 hours) |
40% received concomitant BZD
Decreased O₂ sats only in patients with significant alcohol use, irrespective of BZD use |
| Chan, 20125 |
RCT
n=336 |
Agitated adults randomized to saline, droperidol 5 mg, or olanzapine 5 mg; all then received midazolam 2.5–5 mg until adequately sedated |
1.6x more likely to sedate with olanzapine or droperidol
Time to sedation: droperidol −4 min, olanzapine −5 min vs placebo. Low AEs comparable across groups (O₂ desat: 7.8% control, 8% droperidol, 4.6% olanzapine) |
| Williams, 20188 |
Medication Use Evaluation
n=91 |
Patients receiving IM olanzapine and IM lorazepam within a 24-hour period |
No hypotension, bradycardia, bradypnea, or O₂ desat
41 patients received concomitant administration within 60 minutes |
Clinical Conclusions
Bottom Line
The concomitant administration of IM olanzapine and IM/IV benzodiazepines is likely not as clinically risky as was initially thought. Patient-specific factors, particularly the presence of additional CNS depressants such as alcohol, should be carefully considered.
The concomitant administration of IM olanzapine and IM/IV benzodiazepines is likely not as clinically risky as was initially thought.
Careful consideration should be used when recommending agents for the management of acute agitation to ensure the agent and dose is appropriate. Patient-specific factors, particularly the use/presence of additional CNS depressants (e.g., alcohol), should be considered.
Full Reference List
- Olanzapine. Lexicomp [online database]. Hudson, OH. Wolters Kluwer Clinical Drug Information, Inc. Accessed 2021, December 20.
- Lorazepam. Lexicomp [online database]. Hudson, OH. Wolters Kluwer Clinical Drug Information, Inc. Accessed 2021, December 20.
- Midazolam. Lexicomp [online database]. Hudson, OH. Wolters Kluwer Clinical Drug Information, Inc. Accessed 2021, December 20.
- Klein LR. Ann Emerg Med. 2018;72(4):374-385. doi:10.1016/j.annemergmed.2018.04.027
- Chan EW. Ann Emerg Med. 2013;61(1):72-81. doi:10.1016/j.annemergmed.2012.07.118
- Marder SR. J Clin Psychiatry. 2010;71(4):433-441. doi:10.4088/JCP.08m04411gry
- Olanzapine. Package insert. Eli Lilly and Company; 2009.
- Williams AM. Ment Health Clin. 2018;8(5):208-213. doi:10.9740/mhc.2018.09.208
- Wilson MP. J Emerg Med. 2012;43(5):889-896. doi:10.1016/j.jemermed.2010.04.012
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