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

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.

Figures

Figure 1

Olanzapine plasma concentrations across multiple injections in a patient with a PDSS event. The figure illustrates the olanzapine plasma concentration profiles after 6 different olanzapine LAI injections in one patient who experienced a PDSS event at the second injection. Arrows below the x-axis indicate injections. Higher than expected olanzapine plasma concentrations were measured at 6 and 24 hours after the second injection, with concentrations returning to the expected therapeutic range after 48 hours. Olanzapine concentrations at subsequent injections remained in the expected therapeutic range. The dashed line indicates 100 ng/mL; all of the assessed PDSS cases had maximum olanzapine concentrations higher than this value.

Figure 2

Olanzapine plasma concentrations observed over time in PDSS events. The figure shows olanzapine plasma concentrations from the time of the injection associated with the PDSS event up to 72 hours after that injection. Olanzapine plasma concentration values plotted at time 0 hour (pre-injection) that anchor the concentration curves are either based on the patient's data for measurements made before other injections or are presumed to be approximately 20 ng/mL based on the general population's typical pre-injection concentration. Only the data after injection (samples collected beyond 0 hour) are actual measurements for samples collected for these events. Case numbers correspond to the cases presented in Detke et al [2].

Figure 3

Maximum observed olanzapine plasma concentration by dose during the PDSS events. The figure illustrates the maximum observed olanzapine plasma concentration measured during the PDSS events by dose. C# = case number. Case numbers correspond to the cases presented in Detke et al [2].

Figure 4

Illustration of proposed mechanism for olanzapine LAI distribution (in yellow) after vessel damage by nicking. The figure illustrates the proposed mechanism for distribution of the olanzapine LAI suspension during a PDSS event. The first panel depicts the tip of the syringe needle piercing the wall of the blood vessel situated within the muscle bed. In the second panel, the medication (in yellow) has been injected into the muscle tissue and is leaking into the blood vessel through the punctured vessel wall.