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Cited by 96Schizophrenia research and treatmentIntramuscular injections and effectsPharmacovigilance and Adverse Drug Reactions

Post-injection delirium/sedation syndrome in patients with schizophrenia treated with olanzapine long-acting injection, II: investigations of mechanism

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McDonnell, David P, Detke, Holland C, Bergstrom, Richard F, Kothare, Prajakti, Johnson, Jason, Stickelmeyer, Mary, Sanchez-Felix, Manuel V, Sorsaburu, Sebastian +1 more·2010·BMC Psychiatry
DOI 10.1186/1471-244x-10-45PMC PMC2895590
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Abstract

BACKGROUND: Olanzapine long-acting injection (LAI) is a salt-based depot antipsychotic combining olanzapine and pamoic acid. The slow intramuscular dissolution of this practically insoluble salt produces an extended release of olanzapine lasting up to 4 weeks. However, in a small number of injections (< 0.1%), patients experienced symptoms suggestive of olanzapine overdose, a phenomenon that has been termed "post-injection delirium/sedation syndrome" (PDSS). The authors conducted a series of parallel investigations into the possible reasons PDSS events occur. METHODS: Healthcare providers involved in the PDSS cases were queried for clinical information around the events. Plasma samples from patients experiencing PDSS were collected when possible (12/30 cases) and olanzapine concentrations compared with the known pharmacokinetic profile for olanzapine LAI. Product batches and used vials from the PDSS cases were evaluated for compliance with established manufacturing standards and/or possible user error. Because this depot formulation depends upon slow dissolution at the intramuscular injection site, in-vitro experiments were conducted to assess solubility of olanzapine pamoate in various media. RESULTS: Injection administrators reported no unusual occurrences during the injection. No anomalies were found with the product batches or the remaining suspension in the used vials. Olanzapine concentrations during PDSS events were higher than the expected 5-73 ng/mL range, with concentrations exceeding 100 ng/mL and in some cases reaching >600 ng/mL during the first hours after injection but then returning to the expected therapeutic range within 24 to 72 hours. Solubility and dissolution rate of olanzapine pamoate were also found to be substantially greater in plasma than in other media such as those approximating the environment in muscle tissue. CONCLUSIONS: Manufacturing irregularities, improper drug reconstitution, and inappropriate dosing were ruled out as possible causes of PDSS. In-vitro solubility and in-vivo pharmacokinetic investigations suggest that PDSS is related to exposure of the injected product to a substantial volume of blood. This exposure is most likely the result of unintended partial intravascular injection or blood vessel injury during the injection (occurring even with proper injection technique) with subsequent seepage of the medication into the vasculature, which would produce higher than intended olanzapine concentrations and symptoms consistent with PDSS. TRIAL REGISTRATION: ClinicalTrials.gov ID; URL: http://http//www.clinicaltrials.gov/: NCT00094640, NCT00088478, NCT00088491, NCT00088465, and NCT00320489.

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  • Post-injection delirium/sedation syndrome (PDSS) may occur with higher doses of olanzapine pamoate.

    “When dosing olanzapine pamoate, consider the risks of PDSS, which may occur with higher doses [112].”

    From Pharmacokinetic Characteristics of Long-Acting Injectable Antipsychotics for Schizophrenia: An Overview (2021) · cites this paper as [112]

    The Discussion (Pharmacokinetic analyses; page unavailable) reports PDSS after doses up to 405 mg, so it can occur at higher doses. But the Results state that PDSS can occur across the therapeutic dose range and that dose size is not a principal factor; the citation does not support an implication that higher doses carry a particular PDSS risk. (LLM, conf=0.85)

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Research works printed but not linked: 8

  1. Electronic Medicines Compendium: Summary of product characteristics for ZYPADHERA 210 mg, 300 mg, and 405 mg, powder and solvent for prolonged release suspension for injection. 2009, [ http://www.medicines.org.uk/emc/medicine/21361/SPC/ZYPADHERA ]
  2. Shrewsbury R: Applied pharmaceutics in contemporary compounding. 2008, Englewood: Morton Publishing Company, 2
  3. Bergstrom R, Callaghan J, Cerimele J, Kurtz D, Hatcher B: Population pharmacokinetics and plasma concentrations of olanzapine. Olanzapine (Zyprexa): A novel antipsychotic. Edited by: Tran P, Bymaster F, Tye N, Herra J, Breier A, Tollefson G. 2000, Philadelphia: Lippincott, Williams, and Wilkins, 232-252.
  4. Eli Lilly and Company: Zyprexa [package insert]. 2009
  5. Kurtz D, Bergstrom R, McDonnell DP, Mitchell M: Pharmacokinetics of multiple doses of olanzapine long-acting injection, an intramuscular formulation of olanzapine, in stabilized patients with schizophrenia [abstract]. Biol Psychiatry. 2008, 63 (suppl 1): 288S-
  6. Novocol Pharmaceuticals of Canada, Inc: Septocaine with epinephrine [package insert]. 2005
  7. Institute for Safe Medication Practices: ISMP medication safety alert: Bicillin products: syringe enhancements may help to prevent IV administration. 2004, [ http://www.ismp.org/Newsletters/acutecare/articles/20040506_2.asp ]
  8. Institute for Safe Medication Practices: ISMP medication safety alert: Action needed to prevent serious tissue injury with IV promethazine. 2006, [ http://www.ismp.org/Newsletters/acutecare/articles/20060810.asp ]

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Authors
McDonnell, D. P., Detke, H. C., Bergstrom, R. F., Kothare, P., Johnson, J., Stickelmeyer, M., Sanchez-Felix, M. V., Sorsaburu, S., & Mitchell, M. I.
Affiliations
Eli Lilly (United States) (US)
Corresponding author
McDonnell, David P
ORCID
Venue
BMC Psychiatry
Publisher
Springer Science and Business Media LLC
Published
2010-06-10
Volume
10
Issue
1
Pages
45-45
ISSN
1471-244X (ISSN-L)
DOI
10.1186/1471-244x-10-45
PMC
PMC2895590
OpenAlex
W2009416404
Semantic Scholar
41b4879b26c47f4c1b1d4d7b34d7a02f2386f6b9
Cited by
96
References
13
Citations by year
2026: 5 · 2025: 3 · 2024: 7 · 2023: 4 · 2022: 10 · 2021: 4 · 2020: 1 · 2019: 5 · 2017: 8 · 2016: 5 · 2015: 4 · 2014: 9 · 2013: 10 · 2012: 8
FWCI
6.76
Type
journal article
Language
en
Open access
Licence
Locations
  • BMC Psychiatry (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
Funders
Eli Lilly and Company
Topics
  • Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
  • Health Sciences › Medicine › Emergency Medicine › Intramuscular injections and effects
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Toxicology › Pharmacovigilance and Adverse Drug Reactions
Keywords
olanzapine pamoate, long-acting injectable antipsychotics, schizophrenia, plasma drug concentration, drug solubility, dissolution rate, intramuscular injection, intravascular injection, vascular injury, pharmacokinetics
MeSH terms
Olanzapine, Benzodiazepines, Clinical Trials as Topic, Delayed-Action Preparations, Humans, Injections, Intramuscular, Schizophrenia, Syndrome, Antipsychotic Agents, Treatment Outcome, Drug Overdose, Drug-Related Side Effects and Adverse Reactions

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