Olanzapine

- 5mg and 10mg tablets (sublingual)
- 10mg lyophilized powder (IM)

Emergency Medicine Executive Summary

(Summary version version, Updated September 2021)

Olanzapine is a second generation (atypical) antipsychotic with a potent antagonism of serotonin 5-HT2A, 5-HT2C, dopamine D1-4, histamine H1 and alpha1-adrenergic receptors. It also has a moderate antagonism of muscarinic M1-5 receptors, as well as a weak agonism to GABA-A, BZD and beta-adrenergic receptors.

In the ED, olanzapine is frequently indicated as a first-line antipsychotic for acute agitation associated with psychiatric disorders (US FDA and EMA approved for agitation in individuals with schizophrenia and bipolar disorder)(7, 9). Agitation in the ED is a very complex situation that includes a variety of dissimilar scenarios with a wide range of therapeutic options. Many clinical guidelines have been proposed with substantial differences between them; as emergency physicians, it is of great importance to be familiarized with the available therapeutic arsenal for agitation, such as haloperidol, droperidol, benzodiazepines, propofol, ketamine, etc.

  • Adult dose for severe agitation:
    5 to 10mg IM, repeated every 20 min if necessary, with a maximum of 30mg/day for intramuscular administration.

There are significant differences among first and second generation antipsychotics, and there is an abundant amount of literature available that compare olanzapine with haloperidol as well as other therapies to treat agitation. Clinically relevant data is summarized below:

Olanzapine vs haloperidol; extrapyramidal effects: olanzapine had a reduced risk of nearterm side effects such as dystonia or akathisia, with rates being less than 1%; 10 times less than haloperidol. (1, 2).

Olanzapine vs haloperidol; adequate sedation within 15 min: olanzapine showed better results (61% vs 42%)(6).

Olanzapine vs haloperidol; need of rescue medication: olanzapine needed less rescue medication (21% vs 33% in the entire encounter)(6).

Olanzapine vs haloperidol + benzodiazepine; sedation in 2 hours: either intervention showed similar results (3).

Olanzapine vs droperidol; time to sedation: no significant difference (16 min vs 17.5 min)(10).

Olanzapine vs droperidol; need of rescue medication: olanzapine needed more rescue medication (24% vs 17%)(10).

Olanzapine vs droperidol; extrapyramidal effects: olanzapine had a significantly lower risk (0.1% vs 6.1%)(10).

Therefore, olanzapine is currently recommended as the first-line antipsychotic for an agitated psychiatric adult patient (2). In the pediatric population it is considered to be safe and effective (8), but is not yet US-FDA nor EMA approved for agitation (7, 9).

Cautions

  • When olanzapine is administered by oral formulation, it can be combined with a benzodiazepine; nonetheless, parenteral administration with a benzodiazepine is not recommended due to the risk of respiratory depression (2, 6, 7).

  • In eldery patients, the half-life of olanzapine is 1.5 times longer compared to young adults, consequently, consider a starting dose of 5mg im for agitation (7).

  • There is an association between antipsychotics (1st and 2nd generation) and an increased mortality risk when used to treat dementia-related psychosis at long term (4, 7). Haloperidol has an NNH of 26 and olanzapine an NNH 40 (4).

  • Olanzapine is associated with an increased risk of hypotension (4.5% for 5-10mg im) (1, 7), orthostatism, and the potential consequence of syncope (6). Use with caution when other factors of cardiocirculatory depression are present.

  • Avoid olanzapine in suspected or confirmed intoxications with anticholinergic medications. Other agents should be used preferentially in some intoxications (eg, stimulants) or alcohol withdrawal.

Adult dose

Acute agitation associated with psychiatric disorders (2, 7):

  • Severe agitation (aggressive/threatening, non-cooperative):
    IM: 5-10mg; may repeat in 20 min if needed, max 30 mg/day for intramuscular route.
    Consider 5mg im as a starting dose in eldery patients (50% increase in half life in elder population).

  • Mild or moderate agitation (cooperative or disruptive):
    Sublingual: 5-10mg, may repeat every 2 hours if needed; max 20mg/day for oral/sublingual route.
    Consider 5mg sublingual as a starting dose in eldery patients (50% increase in half life in elder population).

Pediatric dose

  • Severe agitation (aggressive/threatening, non-cooperative):
    IM: 0.1mg/kg, max 30mg/day for intramuscular administration.

Usual dosing:

  • Child: 2.5mg IM, may repeat every 20-30min if needed

  • Adolescent: 5-10mg IM, may repeat every 20-30min if needed

  • Mild or moderate agitation (cooperative):
    Sublingual: 0.1mg/kg, max 20mg/day for oral/sublingual administration

Usual dosing:

  • Child: 2.5mg sublingual, may repeat every 30-45min if needed

  • Adolescent: 5-10mg sublingual, may repeat every 30-45min if needed

References

  1. Breier A, Meehan K, Birkett M, et al. A double-blind, placebo-controlled dose-response comparison of intramuscular olanzapine and haloperidol in the treatment of acute agitation in schizophrenia. Arch Gen Psychiatry. 2002;59(5):441-448. doi:10.1001/archpsyc.59.5.441.
    Pubmed

  2. Wilson MP, Pepper D, Currier GW, Holloman GH Jr, Feifel D. The psychopharmacology of agitation: consensus statement of the american association for emergency psychiatry project Beta psychopharmacology workgroup. West J Emerg Med. 2012;13(1):26-34. doi:10.5811/westjem.2011.9.6866.
    Pubmed

  3. Huang CL, Hwang TJ, Chen YH, et al. Intramuscular olanzapine versus intramuscular haloperidol plus lorazepam for the treatment of acute schizophrenia with agitation: An open-label, randomized controlled trial. J Formos Med Assoc. 2015;114(5):438-445. doi:10.1016/j.jfma.2015.01.018.
    Pubmed

  1. Maust DT, Kim HM, Seyfried LS, et al. Antipsychotics, other psychotropics, and the risk of death in patients with dementia: number needed to harm. JAMA Psychiatry. 2015;72(5):438-445. doi:10.1001/jamapsychiatry.2014.3018.
    Pubmed

  2. Chun TH, Mace SE, Katz ER; American Academy of Pediatrics; Committee on Pediatric Emergency Medicine, and American College of Emergency Physicians; Pediatric Emergency Medicine Committee. Evaluation and Management of Children and Adolescents With Acute Mental Health or Behavioral Problems. Part I: Common Clinical Challenges of Patients With Mental Health and/or Behavioral Emergencies. Pediatrics. 2016;138(3):e20161570. doi:10.1542/peds.2016-1570.
    Pubmed

  3. Klein LR, Driver BE, Miner JR, et al. Intramuscular Midazolam, Olanzapine, Ziprasidone, or Haloperidol for Treating Acute Agitation in the Emergency Department. Ann Emerg Med. 2018;72(4):374-385. doi:10.1016/j.annemergmed.2018.04.027.
    Pubmed

  1. NIH-NLM (National Institutes of Health National Library of Medicine). DailyMed. Label: Zyprexa- olanzapine tablet, Zyprexa Zydis- olanzapine tablet, orally disintegrating, Zyprexa Intramuscular- olanzapine injection, powder, for solution. Updated in April 2020. Visited in September 2021.
    DailyMed

  2. Cole JB, Klein LR, Strobel AM, Blanchard SR, Nahum R, Martel ML. The Use, Safety, and Efficacy of Olanzapine in a Level I Pediatric Trauma Center Emergency Department Over a 10-Year Period. Pediatr Emerg Care. 2020;36(2):70-76. doi:10.1097/PEC.0000000000001231.
    Pubmed

  3. EMA (European Medicines Agency), Zyprexa, olanzapine: EPAR (European Public Assessment Report) - Product Information. Date of issue of marketing authorisation valid throughout the European Union: 1996. Last updated March 2020. Visited in September 2021.
    EMA

  4. Cole JB, Stang JL, DeVries PA, Martel ML, Miner JR, Driver BE. A Prospective Study of Intramuscular Droperidol or Olanzapine for Acute Agitation in the Emergency Department: A Natural Experiment Owing to Drug Shortages. Ann Emerg Med. 2021;78(2):274-286. doi:10.1016/j.annemergmed.2021.01.005.
    Pubmed

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