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Switching to olanzapine long-acting injection from either oral olanzapine or any other antipsychotic: comparative post hoc analyses.

ABSTRACT: A considerable proportion of patients suffering from schizophrenia show suboptimal responses to oral antipsychotics due to inadequate adherence. Hence, they are likely to benefit from switching to a long-acting injectable formulation. These post hoc analyses assessed the clinical effects of switching to olanzapine long-acting injection (OLAI) from either oral olanzapine (OLZ) or other antipsychotics (non-OLZ).Post hoc analyses were done based on two randomized studies (one short-term, one long-term) conducted in patients suffering from schizophrenia and treated with OLAI. The short-term study was an 8-week placebo-controlled, double-blind trial in acute patients, and the long-term study was a 2-year, oral olanzapine-controlled, open-label, follow-up of stabilized outpatients.These analyses used data from 62 OLAI-treated patients (12 switched from OLZ, 50 from non-OLZ) from the short-term study and 190 OLAI-treated patients (56 switched from OLZ, 134 from non-OLZ) from the long-term study. Kaplan-Meier survival analyses of time to all-cause discontinuation of OLAI treatment did not differ significantly between OLZ and non-OLZ patients in the short-term study (P=0.209) or long-term study (P=0.448). Similarly, the proportions of OLZ and non-OLZ patients that discontinued OLAI were not statistically different in the short-term (16.7% versus 36.0%, respectively; P=0.198) or long-term (57.1% versus 47.8% respectively; P=0.238) studies. In the short-term study, no significant differences were detected between the patient groups in mean change in Positive and Negative Syndrome Scale (PANSS) total score (-13.4 OLZ versus -20.8 non-OLZ; P=0.166). In the long-term study, mean change in PANSS total score (3.9 OLZ versus -3.6 non-OLZ; P=0.008) was significantly different between the non-OLZ and OLZ groups. Rates of treatment-emergent adverse events were similar in OLZ and non-OLZ groups per study.These post hoc analyses suggest that no significant differences in clinical effectiveness were seen after switching from non-OLZ or OLZ to OLAI. However, these findings should be interpreted with care, due to small sample sizes and differences in patients' clinical profiles.

SUBMITTER: Ciudad A

PROVIDER: S-EPMC3825698 | biostudies-other | 2013

REPOSITORIES: biostudies-other

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Switching to olanzapine long-acting injection from either oral olanzapine or any other antipsychotic: comparative post hoc analyses.

Ciudad Antonio A Anand Ernie E Berggren Lovisa L Casillas Marta M Schacht Alexander A Perrin Elena E

Neuropsychiatric disease and treatment 20131108

<h4>Background</h4>A considerable proportion of patients suffering from schizophrenia show suboptimal responses to oral antipsychotics due to inadequate adherence. Hence, they are likely to benefit from switching to a long-acting injectable formulation. These post hoc analyses assessed the clinical effects of switching to olanzapine long-acting injection (OLAI) from either oral olanzapine (OLZ) or other antipsychotics (non-OLZ).<h4>Methods</h4>Post hoc analyses were done based on two randomized ...[more]

PMID: 24235837

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Project description:Hospitalization is a costly and distressing event associated with relapse during schizophrenia treatment. No information is available on the predictors of psychiatric hospitalization during maintenance treatment with olanzapine long-acting injection (olanzapine-LAI) or how the risk of hospitalization differs between olanzapine-LAI and oral olanzapine. This study aimed to identify the predictors of psychiatric hospitalization during maintenance treatment with olanzapine-LAI and assessed four parameters: hospitalization prevalence, incidence rate, duration, and the time to first hospitalization. Olanzapine-LAI was also compared with a sub-therapeutic dose of olanzapine-LAI and with oral olanzapine.This was a post hoc exploratory analysis of data from a randomized, double-blind study comparing the safety and efficacy of olanzapine-LAI (pooled active depot groups: 405 mg/4 weeks, 300 mg/2 weeks, and 150 mg/2 weeks) with oral olanzapine and sub-therapeutic olanzapine-LAI (45 mg/4 weeks) during 6 months' maintenance treatment of clinically stable schizophrenia outpatients (n=1064). The four psychiatric hospitalization parameters were analyzed for each treatment group. Within the olanzapine-LAI group, patients with and without hospitalization were compared on baseline characteristics. Logistic regression and Cox's proportional hazards models were used to identify the best predictors of hospitalization. Comparisons between the treatment groups employed descriptive statistics, the Kaplan-Meier estimator and Cox's proportional hazards models.Psychiatric hospitalization was best predicted by suicide threats in the 12 months before baseline and by prior hospitalization. Compared with sub-therapeutic olanzapine-LAI, olanzapine-LAI was associated with a significantly lower hospitalization rate (5.2% versus 11.1%, p < 0.01), a lower mean number of hospitalizations (0.1 versus 0.2, p = 0.01), a shorter mean duration of hospitalization (1.5 days versus 2.9 days, p < 0.01), and a similar median time to first hospitalization (35 versus 60 days, p = 0.48). Olanzapine-LAI did not differ significantly from oral olanzapine on the studied hospitalization parameters.In clinically stable schizophrenia outpatients receiving olanzapine-LAI maintenance treatment, psychiatric hospitalization was best predicted by a history of suicide threats and prior psychiatric hospitalization. Olanzapine-LAI was associated with a significantly lower incidence of psychiatric hospitalization and shorter duration of hospitalization compared with sub-therapeutic olanzapine-LAI. Olanzapine-LAI did not differ significantly from oral olanzapine on hospitalization parameters.ClinicalTrials.gov: NCT00088491.

Project description:An advance in the treatment of schizophrenia is the development of long-acting intramuscular formulations of antipsychotics, such as olanzapine long-acting injection (LAI). During clinical trials, a post-injection syndrome characterized by signs of delirium and/or excessive sedation was identified in a small percentage of patients following injection with olanzapine LAI.Safety data from all completed and ongoing trials of olanzapine LAI were reviewed for possible cases of this post-injection syndrome. Descriptive analyses were conducted to characterize incidence, clinical presentation, and outcome. Regression analyses were conducted to assess possible risk factors.Based on approximately 45,000 olanzapine LAI injections given to 2054 patients in clinical trials through 14 October 2008, post-injection delirium/sedation syndrome occurred in approximately 0.07% of injections or 1.4% of patients (30 cases in 29 patients). Symptomatology was consistent with olanzapine overdose (e.g., sedation, confusion, slurred speech, altered gait, or unconsciousness). However, no clinically significant decreases in vital signs were observed. Symptom onset ranged from immediate to 3 to 5 hours post injection, with a median onset time of 25 minutes post injection. All patients recovered within 1.5 to 72 hours, and the majority continued to receive further olanzapine LAI injections following the event. No clear risk factors were identified.Post-injection delirium/sedation syndrome can be readily identified based on symptom presentation, progression, and temporal relationship to the injection, and is consistent with olanzapine overdose following probable accidental intravascular injection of a portion of the olanzapine LAI dose. Although there is no specific antidote for olanzapine overdose, patients can be treated symptomatically as needed. Special precautions include use of proper injection technique and a post-injection observation period.ClinicalTrials.gov ID; URL: http://http//www.clinicaltrials.gov/: NCT00094640, NCT00088478, NCT00088491, NCT00088465, and NCT00320489.

Project description: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.

Project description:OBJECTIVE:First-month data of a 13-week acute schizophrenia study were used to compare paliperidone palmitate to oral risperidone during initiation of long-acting injectable risperidone. DESIGN:Double-blind, randomized study. SETTING:Outpatient or inpatient. PARTICIPANTS:Adults with established (?1 year) schizophrenia. Those assigned to risperidone long-acting injectable (n=460) received 25mg on Days 8 and 22 with oral risperidone (l-6mg) supplementation for the first 28 days. The paliperidone palmitate group (n=453) received 150mg eq. on Day 1, l00mg eq. on Day 8, and oral placebo supplementation for the first 28 days. MEASUREMENTS:Positive and Negative Syndrome Scale, Personal and Social Performance Scale, Clinical Global Impression-Severity score, and responder rate (percentage of patients with ?30% reduction in PANSS total score). An analysis of covariance model estimated least-square mean differences between treatment groups. A post-hoc analysis of efficacy data for the period of interest, i.e., at the time points before and after the first 28 days, was conducted. RESULTS:Positive and Negative Syndrome Scale, Personal and Social Performance Scale, Clinical global Impression-Severity scores showed similar efficacy between the treatment groups during the first weeks of treatment, corresponding to the risperidone long-acting injection initiation period. Mean Positive and Negative Syndrome Scale total score at baseline was 84.7 for paliperidone palmitate and 84.4 for oral risperidone, on Day 22 was 73.6 and 74.1, respectively, and on Day 36 was 71.8 and 72.8, respectively. Overall incidence of adverse events in the first 28 days was generally similar (45% for paliperidone palmitate vs. 35% for oral risperidone), except for injection site pain (4.6% vs. 0.7%). Similar active moiety plasma concentrations were obtained during this period. CONCLUSION:During the first month, paliperidone palmitate without oral supplementation has similar efficacy and safety to oral risperidone (during initiation of risperidone long-acting injectable) in acutely exacerbated schizophrenia.

Project description:To treat acute schizophrenia, a long-acting injectable antipsychotic needs a rapid onset of action and therapeutic profile similar to that of oral agents. The present post-hoc analyses compared results from a randomized, double-blind, placebo-controlled trial of olanzapine long-acting injection (LAI) for acute schizophrenia with those observed in similarly designed trials of oral olanzapine.Six-week results from the olanzapine LAI study (N?=?404) were compared with those of 3 oral studies (study 1: olanzapine vs. haloperidol vs. placebo [N?=?335]; study 2: olanzapine vs. haloperidol vs. low-dose olanzapine [N?=?431]; study 3: olanzapine vs. placebo vs. low-dose olanzapine [N?=?152]). All patients had baseline Brief Psychiatric Rating Scale (BPRS) scores ?24 (0-6 scale). Six-week effect sizes were calculated. Efficacy onset, pharmacokinetics, discontinuations, weight gain, and extrapyramidal symptoms were also assessed.At 6?weeks, mean BPRS scores decreased by 14 to 15 points for olanzapine LAI (405?mg/4?weeks, 210 or 300?mg/2?weeks), by 8 to 16 for oral olanzapine (10?±?2.5 or 15?±?2.5?mg/day), and by 12 to 13 for haloperidol (15?±?5?mg/day). For those same dose groups, effect sizes vs. placebo for the BPRS were 0.7 to 0.8 for olanzapine LAI, 0.5 to 0.7 for oral olanzapine, and 0.6 for haloperidol. The first statistically significant separation from placebo on the BPRS occurred at 3?days for the olanzapine LAI groups and at 1?week for oral olanzapine and haloperidol (15?±?5?mg/day) in oral study 1 although as late as week 6 for the 10-mg/day olanzapine dose in oral study 3. Olanzapine concentrations were similar across studies. Weight gain ?7% of baseline occurred in up to 35% of olanzapine LAI and oral patients versus up to 12% of haloperidol and placebo patients. Extrapyramidal symptoms were lowest in the olanzapine LAI groups and significantly greater in the haloperidol groups. No post-injection delirium/sedation syndrome events occurred in the olanzapine LAI study.Patients treated acutely with olanzapine LAI showed a similar pattern of improvement to that seen historically with oral olanzapine. With the exception of injection-related adverse events, the efficacy and tolerability profile of olanzapine LAI is similar to oral olanzapine.ClinicalTrials.gov ID; URL: http://http//www.clinicaltrials.gov/: NCT00088478; ClinicalStudyResults.org ID; URL: http://www.clinicalstudyresults.org/: 917, 978, 982, and 5984.

Project description:BACKGROUND:Depot antipsychotic injections are an important tool for the management of patients with schizophrenia who have difficulty with adherence to oral medication. However, pain and discomfort at the injection site can be a potential impediment to the use of these long-acting formulations. We report here the results of a pooled analysis of injection site-related adverse events (AEs) collected during treatment with the olanzapine long-acting injection (olanzapine LAI). METHODS:Unsolicited injection site-related AEs were pooled from 7 olanzapine LAI clinical trials conducted in patients between March 2001 and December 2010. All patients had a Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) or Fourth Edition, Text Revision (DSM-IV-TR) diagnosis of schizophrenia or schizoaffective disorder and were between the ages of 18 and 75. Doses ranged from 45 to 405 mg olanzapine LAI, and injection intervals were 2, 3, or 4 weeks. Events were evaluated for severity, timing, possible risk factors, and outcome. A criterion of p < .05 for statistical significance was used for all tests. RESULTS:A total of 1752 patients received at least 1 olanzapine LAI injection. Of these, 92 patients (5.3%) reported at least 1 injection site-related AE, with "pain" being the most common type (2.9%). Most events were mild (81.4%) and the median duration was 3 days. Four patients (0.2%) discontinued due to injection site-related AEs. Dose volume and body mass index did not appear to affect the probability of injection site-related AEs. However, patients who experienced a post-injection delirium/sedation syndrome event (n = 37) were more likely to have or have had an injection site-related AE at some time during the study. Incidence of injection site-related AEs appeared to decrease over time. In 94.2% of the injection site-related AEs, no specific treatment or concomitant medication was reported; in 9 cases, patients received pharmacologic treatment for reaction, mass, abscess, rash, or pain. CONCLUSIONS:Injection site-related AEs with olanzapine LAI were generally mild. The incidence and nature of these injection site-related AEs were generally similar to those occurring during treatment with other injectable antipsychotics. TRIAL REGISTRATION:ClinicalTrials.gov ID; URL: NCT00094640, NCT00088478, NCT00088491, NCT00088465, and NCT00320489.

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Switching to olanzapine long-acting injection from either oral olanzapine or any other antipsychotic: comparative post hoc analyses.

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Switching to olanzapine long-acting injection from either oral olanzapine or any other antipsychotic: comparative post hoc analyses.

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