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


BACKGROUND
ClinicalTrials.gov ID; URL: http://http//www.clinicaltrials.gov/: NCT00094640, NCT00088478, NCT00088491, NCT00088465, and NCT00320489.
McDonnell
David P
DP
Lilly Research Laboratories, Indianapolis, Indiana, USA. mcdonnelldp@lilly.com
Detke
Holland C
HC
Bergstrom
Richard F
RF
Kothare
Prajakti
P
Johnson
Jason
J
Stickelmeyer
Mary
M
Sanchez-Felix
Manuel V
MV
Sorsaburu
Sebastian
S
Mitchell
Malcolm I
MI
D014150:Antipsychotic Agents / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics; D001569:Benzodiazepines / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics; D002986:Clinical Trials as Topic / Q000706:statistics & numerical data; D003692:Delayed-Action Preparations; D062787:Drug Overdose / Q000209:etiology / Q000378:metabolism; D064420:Drug-Related Side Effects and Adverse Reactions / Q000175:diagnosis / Q000378:metabolism; D006801:Humans; D007273:Injections, Intramuscular; D000077152:Olanzapine; D012559:Schizophrenia / Q000188:drug therapy*; D013577:Syndrome; D016896:Treatment Outcome
D014150:Antipsychotic Agents; D003692:Delayed-Action Preparations; D001569:Benzodiazepines; D000077152:Olanzapine