Olanzapine long-acting injection: a review of first experiences of post-injection delirium/sedation syndrome in routine clinical practice.

BACKGROUND: Olanzapine long-acting injection (LAI) for the treatment of schizophrenia was associated with a cluster of symptoms termed post-injection delirium/sedation syndrome (PDSS) in a small percentage (~2%) of patients during clinical trials. The objective of this analysis was to evaluate the rate and clinical characteristics of PDSS since olanzapine LAI entered commercial use. METHODS: Cases of PDSS were identified from all reported adverse events during worldwide commercial use of olanzapine LAI through to 1 March 2014. Data sources included two ongoing post-marketing safety studies as well as spontaneously reported adverse events from routine clinical practice over a 5-year period (1 March 2009 to 1 March 2014). RESULTS: A total of 338 PDSS events were identified. Of these, 91% occurred within 1 hour of injection, and 52% of these occurred within 15 minutes. None of the PDSS events in this analysis were fatal, and most resolved within 72 hours. The most common symptoms (occurring in >30% of cases) were sedation (61%), confusion (56%), dysarthria (54%), somnolence (46%), dizziness (45%) and disorientation (35%). Overall, PDSS occurred with approximately 0.07% of injections and in 0.46-1.03% of patients (reporting and incidence rates from spontaneous reports and post-marketing safety studies, respectively). CONCLUSIONS: The PDSS events reported during routine clinical use of olanzapine LAI are generally similar in incidence and presentation to those reported in clinical trials. Caution should be applied when interpreting spontaneously reported rates of adverse events, however, due to potential under-reporting. Implemented risk-minimisation activities may contribute substantially to the identification and appropriate management of patients with PDSS in clinical practice.

Postinjection delirium/sedation syndrome in patients with schizophrenia receiving olanzapine long-acting injection: results from a large observational study.

BACKGROUND: Postinjection delirium/sedation syndrome (PDSS) has been reported uncommonly during treatment with olanzapine long-acting injection (LAI), a sustained-release formulation of olanzapine. AIMS: The primary aim of the study was to estimate the incidence per injection and per patient of PDSS events in adult patients with schizophrenia who were receiving olanzapine LAI in real-world clinical practice. Secondary aims were to further characterise the clinical presentation of PDSS events, to identify potential risk factors associated with PDSS events and to characterise hospitalisations at baseline and post-baseline. METHOD: A prospective observational study of adult patients with schizophrenia receiving olanzapine LAI from 24 countries. Data were collected on patient characteristics, olanzapine LAI treatment and any adverse events (AEs). All AEs were reviewed and adjudicated for PDSS using predetermined criteria. RESULTS: There were 46 confirmed PDSS events (0.044% of the 103 505 injections) in 45 patients (1.17% of the 3858 patients). Based on 45 confirmed events with time-to-onset information, 91.1% (n=41) occurred within 1 h of injection. Time-to-recovery from the event was within 72 h for 95.6% of patients (range 6 h to 11 days). Risk factors for PDSS (per-injection) included high dose (odds ratio (OR)high/low=3.95; P=0.006) and male gender (ORfemale/male=0.42; P=0.017). CONCLUSIONS: Results of this study confirm previously reported PDSS rates, time to onset and recovery, and the severity of PDSS events, and suggest that higher doses and male gender are potential risk factors associated with PDSS. DECLARATION OF INTEREST: All authors are full-time employees and hold stock/stock options in Eli Lilly, which funded this study. This post-authorisation safety study (PASS) was proposed by Eli Lilly when submitting the original marketing authorisation application for olanzapine LAI in 2007. The protocol and final study report for this European Union regulatory commitment are publicly accessible via the European Network of Centres for Pharmacoepidemiology and Pharmacovigilance (ENCePP) European Union PASS Register (www.encepp.eu/encepp/viewResource.htm?id=16847). The current manuscript describes the results within the final study report. COPYRIGHT AND USAGE: © The Royal College of Psychiatrists 2017. This is an open access article distributed under the terms of the Creative Commons Non-Commercial, No Derivatives (CC BY-NC-ND) license.

A double-blind, randomized trial to evaluate the pharmacokinetics and tolerability of 30 or 40 mg/d oral olanzapine relative to 20 mg/d oral olanzapine in stable psychiatric subjects.

BACKGROUND: Prescription monitoring in the United States suggests that oral olanzapine is prescribed in doses that exceed the approved range of 5 to 20 mg/d. OBJECTIVE: In this double-blind, randomized study, the pharmacokinetics and tolerability of higher-dose (30 or 40 mg/d) olanzapine were examined relative to the highest approved dose (20 mg/d) among non-treatment-resistant patients with psychiatric illnesses. METHODS: After a 10-day period in which all patients were stabilized on 20 mg/d olanzapine, 37 patients with schizophrenia, schizoaffective disorder, or bipolar I disorder were randomized to receive treatment with olanzapine 20 mg/d for 20 days (group A, n=12), 30 mg/d for 10 days followed by 40 mg/d for 10 days (group B, n=11), or 40 mg/d for 20 days (group C, n=14). On days 10, 20, and 30, blood samples were collected before dosing and at 1, 2, 5, 6, 10, 14, 18, and 24 hours after dosing. Plasma olanzapine concentrations were assayed using high-performance liquid chromatography with electrochemical detection. Tolerability was assessed by spontaneously reported treatment-emergent adverse events; changes from baseline in vital signs, electrocardiograms, and standard laboratory test values; incidences of categorically defined treatment-emergent akathisia and parkinsonism; and 2-hour standard oral glucose tolerance tests. RESULTS: Of the 53 subjects who entered the study, 16 were excluded (7 because entry criteria were not met, 6 because of subject's decision, and 3 for other reasons). Subjects were primarily men (group A, 75%; group B, 55%; group C, 79%), approximately 40 years old (mean [SD] age: group A, 40.6 [8.6]; group B, 37.9 [8.6]; group C, 39.4 [9.2] years), and black (group A, 83%; group B, 55%; group C, 64% [the remainder were white]). Mean (SD) baseline weight was 84.0 (17.5) kg for group A, 82.1 (12.0) kg for group B, and 100.9 (23.3) kg for group C. By day 20, dose-proportional increases were observed in plasma olanzapine Cmax,ss and AUC. Geometric mean (percent coefficient of variation) values for groups A, B, and C at day 20 were as follows: Cmax,ss 57.8 (40.2), 75.6 (86.7), and 94.1 (50.2) ng/mL, respectively; and AUC: 997 (38.5), 1220 (88.0), and 1630 (53.9) ng . h/mL, respectively. The most frequently reported adverse events were weight gain (group A, 2/12 [17%]; group B, 3/11 [27%]; group C, 2/14 [14%]) and sedation (group A, 3/12 [25%]; group B, 2/11 [18%]; group C, 2/14 [14%]). Mean (SD) weight gain from baseline to end point was 3.5 (2.81) kg for group A, 3.0 (3.15) kg for group B, and 3.1 (2.22) kg for group C. Changes in glucose tolerance, vital signs, or laboratory parameters did not appear to be dose dependent. During double-blind therapy, 7 subjects experienced akathisia (spontaneously reported, n=3 [group C]; categorically defined, n=3 [group B]; both, n=1 [group C]). Of the subjects with categorically defined akathisia, 2 had a history of akathisia and the other had a score of 1 (questionable) on the Barnes Akathisia Scale at baseline. No cases of parkinsonism were observed at any time. CONCLUSIONS: Among these subjects with psychiatric illnesses, olanzapine at doses of 30 and 40 mg/d displayed a pharmacokinetic profile consistent with that of 20 mg/d. Higher-dose olanzapine exhibited a tolerance profile similar to that of 20 mg/d; however, akathisia may be more likely to occur at higher doses, particularly in subjects with a history of akathisia.

Olanzapine in pregnancy and breastfeeding: a review of data from global safety surveillance.

BACKGROUND: Olanzapine use has been reported during pregnancy and breastfeeding, but there are no controlled clinical trials assessing the safety of olanzapine exposure to infants and fetuses. The purpose of this report was to review and analyze prospective post-marketing cases of pregnancy and breastfeeding with olanzapine, in order to guide clinicians and women on the use of olanzapine therapy during pregnancy and/or breastfeeding. METHODS: A worldwide safety database maintained by Eli Lilly and Company was searched for all spontaneous-reported data regarding olanzapine use during pregnancy and/or breastfeeding. Cases reported prior to pregnancy outcome were considered to be prospective, and follow-up was pursued after the delivery date to assess outcome. RESULTS: Outcome data were available for 610 prospectively identified pregnancies during which olanzapine was used. The majority of women had normal births (66%), although premature births were reported in 9.8% and perinatal conditions in 8% of the pregnancies. A total of 102 pregnancies reported olanzapine treatment during breastfeeding. In these infants, the most commonly reported adverse events were somnolence (3.9%), irritability (2%), tremor (2%), and insomnia (2%), although the majority of pregnancies reported no adverse events (82.3%). CONCLUSIONS: The frequency of fetal outcomes in these prospectively identified pregnancies exposed to olanzapine did not differ from rates of outcomes reported in the general population. These data may be useful to help guide clinicians and women decide to continue, or discontinue, olanzapine therapy during pregnancy and/or breastfeeding, but should be considered within the limitations associated with spontaneously reported data. Women should notify their clinicians if they become pregnant or intend to become pregnant while being treated with olanzapine. Because of limited experience in humans, olanzapine should be used in pregnancy only when potential benefit justifies potential risk to the fetus. Olanzapine should only be considered during breastfeeding when the potential benefit justifies the potential risk to the infant.

Case reports of postmarketing adverse event experiences with olanzapine intramuscular treatment in patients with agitation.

OBJECTIVE: Agitation is a medical emergency with increased risk for poor outcome. Successful treatment often requires intramuscular (IM) psychotropics. Safety data from the first 21 months of olanzapine IM, approved in the United States for the treatment of agitation associated with schizophrenia and bipolar disorder, are presented. METHOD: A Lilly-maintained safety database was searched for all spontaneous adverse events (AEs) reported in temporal association with olanzapine IM treatment. RESULTS: The estimated worldwide patient exposure to olanzapine IM from January 1, 2004, through September 30, 2005, was 539,000; 160 cases containing AEs were reported from patients with schizophrenia (30%), bipolar disorder (21%), unspecified psychosis (10%), dementia (8%), and depression (5%). Many reported concomitant treatment with benzodiazepines (39%) or other antipsychotics (54%). The most frequently reported events involved the following organ systems: central nervous (21%), cardiac (12%), respiratory (6%), vascular (6%), and psychiatric (5%). Eighty-three cases were considered serious, including 29 fatalities. In these fatalities, concomitant benzodiazepines or other antipsychotics were reported in 66% and 76% of cases, respectively. The most frequently reported events in the fatal cases involved the following organ systems: cardiovascular (41%), respiratory (21%), general (17%), and central nervous (10%). The majority of fatal cases (76%) included comorbid conditions and potentially clinically significant risk factors for AEs. CONCLUSIONS: Clinicians should use care when treating agitated patients, especially when they present with concurrent medical conditions and are treated with multiple medications, which may increase the risk of poor or even fatal outcomes. Clinicians should use caution when using olanzapine IM and parenteral benzodiazepines simultaneously.