The Eli Lilly warning followed reports of 160 adverse events, including 29 fatalities, linked to IM olanzapine/IM benzodiazepine combinations from January 2004 to September 2005 (Marder SR et al, J Clin Psychiatry 2010;71(4):433–441). Looking closely at these cases, it is unclear that this medication combination actually caused the fatalities. Many of them occurred days after the olanzapine injection (n = 12) or involved patients with serious medical illnesses or suicide attempts (n = 14), either of which may have been the actual cause of death.

In addition, subsequent controlled trials appear to show that IV and IM olanzapine are safe when combined with benzodiazepines. A double-blind, randomized controlled study that compared IV olanzapine 5 mg combined with IV midazolam 2.5–5 mg (n = 109) to IV midazolam alone (n = 115) found that the olanzapine/midazolam combination produced more rapid sedation than midazolam alone and was safe and well tolerated (Chan EW et al, Ann Emerg Med 2013;61(1):72–81). Another study of hospital patients (n = 91) who received IM olanzapine (5–10 mg) plus IM lorazepam (1–2 mg) reported no serious adverse events, even among patients who received both medications within a five-minute interval (Williams AM, Ment Health Clin 2018;8(5):208–213). Lastly, in a study that looked at 96 patients who received IM haloperidol (n = 71) or IM olanzapine (n = 25) along with a benzodiazepine, 5% of the patients in the haloperidol plus benzodiazepine group experienced hypotension, while none of the patients in the olanzapine plus benzodiazepine group had this side effect. Also, none experienced decreased oxygen saturation, except for patients who had positive alcohol breathalyzer tests or were visibly intoxicated. The authors concluded that olanzapine plus benzodiazepine is no riskier than haloperidol plus benzodiazepine, provided patients have not ingested significant amounts of alcohol (Wilson MP et al, J Emerg Med 2012;43(5):790–797).

Should we separate the administration of these meds by some time interval? The FDA does not give a clear directive on this point, unlike the European Medicines Agency, which recommends separating olanzapine and benzodiazepines by at least one hour.

The olanzapine + benzodiazepines combination is probably safe for most agitated patients who are otherwise healthy—though it is not our first choice, given the clinical controversies. This combination is best avoided in patients with compromised respiratory function (eg, COPD) or who are intoxicated with alcohol.