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

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

Post-Injection Delirium/Sedation Syndrome in Patients Treated with Olanzapine Pamoate: Mechanism, Incidence, and Management

“…Unexpected high olanzapine plasma concentrations in people with PDSS led to the assumption that these would be responsible for the symptoms described; in particular, parallels with orally overdosed patients hinted at a connection in this manner [21]. Higher solubility of olanzapine pamoate monohydrate in plasma than solubility in muscle tissue was shown by McDonnell et al [34] and substantiated the hypothesis that false injections into the bloodstream lead to high concentrations of olanzapine in plasma and are thereby causative of PDSS. The mean time to onset of symptoms was 49 min, with a median of 25 min [23], which can be explained by the chemical features of olanzapine pamoate monohydrate salt and the fact that it has to dissolve first and then dissociate into its components olanzapine base and pamoic acid.…”

“…McDonnell et al [34] were able to closely follow up on 12 of the 30 cases reported by Detke et al [21] and detected elevated olanzapine concentrations in all of those patients. When collecting plasma samples at about six fixed time slots until resolution of the clinical symptoms, the initial concentrations within the first 6 h after injection never showed results below 100 ng/mL and would reach peak concentrations above 650 ng/mL.…”

“…Considering the probable mechanism of PDSS, the most obvious precaution is using the proper injection technique in order to prevent olanzapine pamoate monohydrate from contacting the blood system [35]. For the recommended gluteal injection a 1.5-inch (or 35 mm) 19-gauge needle or a 2-inch (or 50 mm) needle for obese patients, allowing an application deep into the muscle, were used during clinical trials and did not show any differences in outcome [34]. Emphasis lies on the proper aspiration in order to allow removal of the syringe when blood is visible.…”

“…The analysis of further potential causes, such as product quality and inappropriate dosing or administration of the medication, were considered and investigated for but did not show any irregularities [34].…”

A review of the efficacy and tolerability of antipsychotic long-acting injections

“…However, it remains unpredictable and is not thought to be related to the dose or dosing frequency or number of doses administered, or patient or medical factors (eg injection technique). 14,21 If it is to be used, olanzapine pamoate LAI should be initiated only for patients who have demonstrated response and tolerability to oral olanzapine. The SPC clearly states that the recommended starting doses and maintenance doses (after two months of treatment) of olanzapine LAI should be based on equivalent doses of oral olanzapine.…”