Abstract
BackgroundOlanzapine 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.MethodsHealthcare 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.ResultsInjection 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.ConclusionsManufacturing 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 RegistrationClinicalTrials.gov ID; URL: http://http//www.clinicaltrials.gov/: NCT00094640, NCT00088478, NCT00088491, NCT00088465, and NCT00320489
Highlights
Olanzapine long-acting injection (LAI) is a salt-based depot antipsychotic combining olanzapine and pamoic acid
Post-injection delirium/sedation syndrome (PDSS), known as post injection syndrome, is a serious adverse event observed in a small percentage of patients treated with olanzapine long-acting injection (LAI), following approximately 0.07% of injections [1]
Hypothesized root causes included product quality issues, errors in reconstitution, inappropriate dosing or administration of the medication, or unanticipated behavior of the formulation under certain physiological conditions, such as accidental intravascular injection. We investigated these potential causes through the following: 1) review of product quality controls, 2) analysis of unused suspension remaining in the product vials of the post-injection delirium/sedation syndrome" (PDSS) cases, 3) review of information from the injection administrators and healthcare personnel involved in the cases for any notable occurrences during the injection process or apparent proximate causes of the event, 4) analysis of plasma samples collected during the PDSS events, and 5) analysis of both the solubility and intrinsic in-vitro dissolution rate of olanzapine pamoate in various media representative of physiological fluids
Summary
Olanzapine long-acting injection (LAI) is a salt-based depot antipsychotic combining olanzapine and pamoic acid. Hypotheses emerged and were evaluated regarding the possible mechanism or mechanisms behind these events Because the first such PDSS case revealed unexpectedly high olanzapine concentrations at the time of the PDSS event, it was hypothesized from that first case and those subsequently observed that these events were likely the result of too much olanzapine entering the systemic circulation more rapidly than intended. Similar solubility-limited salt-based depot formulations are known to be advantageous because they provide a slow extended dissolution over a prolonged time while permitting the dissolution process to begin quickly, allowing for an immediate onset of action from absorption of the disassociated components (in this case, olanzapine and pamoic acid) into the bloodstream [4,5]. Olanzapine concentrations increase slowly after the olanzapine LAI injection, and the slow depot release maintains the olanzapine concentration within a range of approximately 5 to 73 ng/mL (10th percentile for 150 mg/2 weeks to 90th percentile for 300 mg/2 weeks at steady state) [5], which is within the range resulting from within-label oral olanzapine doses [7,8,9]
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