Risperidone long-acting injection in the treatment of schizophrenia: 24-month results from the electronic Schizophrenia Treatment Adherence Registry in Canada.

OBJECTIVE: To assess outcomes over 24 months in Canadian patients with schizophrenia initiated on risperidone long-acting injection (RLAI) and participating in the electronic Schizophrenia Treatment Adherence Registry (e-STAR). MATERIALS AND METHODS: Patients with schizophrenia or schizoaffective disorder were enrolled from 24 sites after an independent decision to initiate RLAI. Subsequent patient management was based on usual clinical practice at each site and was not protocol-driven. Relevant data were collected retrospectively by chart review for 12 months prior to RLAI and prospectively for 24 months following RLAI initiation. RESULTS: Patients (n=188) had a mean age of 39.2 years, were 66.3% male, and 27.7% were inpatients at baseline. Twenty-four months after initiating therapy (initial dose =28.7 mg), 34.1% (95% confidence interval 27.2%-42.2%) of patients had discontinued RLAI with a mean time to discontinuation of 273.4±196 days. Over the treatment period, there were significant (P<0.001) changes from baseline in Clinical Global Impression-Severity (CGI-S; 3.48 versus [vs] 4.31 at baseline), Global Assessment of Functioning (GAF; 56.1 vs 48.1), and Personal and Social Performance (PSP; 59.1 vs 46.9) scale scores. In addition, after 12 months, there were significant (P<0.001) decreases in the percentage of patients hospitalized (23.9% vs 58.5% pre-RLAI), mean length of stay (11.4 vs 30.4 days), and number of hospitalizations (0.32 vs 0.87) compared to the 12-month pre-RLAI period. Reductions in hospitalization continued into the second 12 months of therapy, when only 9% of patients were hospitalized and mean length of stay was 2.0 days. CONCLUSION: In a routine clinical practice setting, patients switched to RLAI showed significant improvements in clinical outcomes and in global and social functioning, and hospitalization was significantly reduced. The data confirm that RLAI provides effective long-term management of schizophrenia in Canada.

Differences in the in vitro and in vivo pharmacokinetic profiles of once-daily modified-release methylphenidate formulations in Canada: examination of current bioequivalence criteria.

BACKGROUND: Current Canadian bioequivalence criteria rely on rate and extent of drug exposure, that is, C(max) and AUC. In the case of complex modified-release formulations, these criteria may not address pharmacokinetic differences with potential therapeutic and tolerability implications. OBJECTIVE: This study was performed to characterize in vitro dissolution and in vivo pharmacokinetic profiles of three modified-release formulations of methylphenidate (MPH) marketed in Canada, two of which meet the criteria for assuming bioequivalence as defined by Health Canada: MPH extended-release (ER-C) and osmotic controlled-release oral-delivery-system (OROS-MPH). METHODS: In vitro dissolution tests were performed using 54-mg OROS-MPH, 54-mg MPH ER-C, and 20-mg MPH sustained-release (SR) tablets. In vivo pharmacokinetics of single oral doses of 54 mg OROS-MPH, 54 mg MPH ER-C, and 60 mg MPH-SR were evaluated in an open-label, randomized, crossover study in healthy subjects. Plasma samples were collected up to 24 hours after administration of the drug. RESULTS: In vitro dose-corrected release profiles of MPH ER-C and MPH-SR tablets were similar (<10% difference), whereas OROS-MPH exhibited a profile distinct from that of the other formulations. Twenty-four subjects completed the pharmacokinetic study and were included in the analyses. Analysis of C(max) and AUC of MPH showed that OROS-MPH and MPH ER-C met the criteria for assumed bioequivalence according to Health Canada guidelines. However, partial AUCs exhibited significant differences between the two formulations, which were supported by ratios of MPH concentrations over time. Comparison of MPH ER-C with MPH-SR (dose corrected) also satisfied bioequivalence criteria. CONCLUSIONS: The pharmacokinetic data suggest that in vitro and in vivo profiles of OROS-MPH and MPH ER-C are distinct. However, using traditional criteria for bioequivalence, MPH ER-C would be assumed bioequivalent to both OROS-MPH and MPH-SR. Inclusion of partial AUCs as additional criteria could aid in ensuring therapeutic equivalence. ClinicalTrials.gov identifier: NCT01118702.

Risk of discontinuation of risperidone after exposure to potentially interacting drugs: a nested case-control study in patients with schizophrenia.

BACKGROUND: The cytochrome P450 (CYP) 2D6 and 3A4 isozymes play an important role in the metabolism of risperidone. Concurrent use of drugs that inhibit or induce the action of these enzymes may increase or decrease levels of risperidone, thereby increasing the risk for discontinuation of risperidone or the need for supplemental treatment to control disease symptoms. OBJECTIVE: This study examined the association between exposure to potentially interacting drugs and nonpersistence in a cohort of patients with schizophrenia newly starting treatment with risperidone. METHODS: The data for this nested case-control study were obtained from the administrative health databases of the Régie de l'Assurance Maladie de Québec. The base cohort included patients aged > or = 15 years who began treatment with risperidone between July 2001 and December 2004. Cases consisted of those who were nonpersistent with risperidone either through drug discontinuation or the addition of/switch to a different atypical antipsychotic; noncases were those who persisted with risperidone through the end of their follow-up period. Exposure to CYP-inhibiting or CYP-inducing medications in the 1-, 3-, and 6-month windows before nonpersistence was compared between cases and noncases. The association between exposure to interacting medications and nonpersistence was analyzed using conditional logistic regression models to account for matching by time on treatment. RESULTS: The base cohort included 20,840 patients, of whom 59.2% were female and 57.7% were aged > or = 65 years. Nonpersistence occurred in 10,913 patients (52.4%) during the study period. Between 40% and 50% of patients were exposed to potential CYP inhibitors, and 6% to 10% were exposed to potential CYP inducers. Exposure to CYP inhibitors over 3 and 6 months was associated with an increase in risk for nonpersistence of approximately 10% (odds ratio [OR] for 3-month exposure = 1.10 [95% CI, 1.06-1.14]; OR for 6-month exposure = 1.11 [95% CI, 1.07-1.15]), whereas exposure to CYP inducers was not associated with a significant change in risk. Exposure to potentially interacting drugs was more likely to lead to nonpersistence while patients were still new to risperidone (ie, in the first month of treatment). For instance, the OR for 6-month exposure to inhibiting drugs was 1.20 (95% CI, 1.04-1.39) in the 1st month of treatment and 1.11 (95% CI, 1.01-1.20) between the 6th and 12th months. CONCLUSION: In this study, use of medications that are potential inhibitors of CYP2D6 and CYP3A4 appeared to be associated with an increased risk of nonpersistence with risperidone, particularly while patients were still new to treatment.

Canadian Outcomes Study in Dementia: study methods and patient characteristics.

OBJECTIVE: To describe the methods and patient characteristics of the Canadian Outcomes Study in Dementia (COSID). METHODS: COSID is a 3-year prospective study of dementia patients living in the community at the time of study registration. We assessed patients' cognition, behaviour, and functioning every 6 months, using the Modified Mini-Mental State Examination (3MS), the Neuropsychiatric Inventory (NPI), and the Functional Autonomy Measurement System (SMAF), respectively. We assessed caregivers, using the Zarit Burden Interview (ZBI). Additional information included the Global Deterioration Scale (GDS), patients' driving status, and clinical information including family history, dementia type, concomitant medications, and comorbid conditions. From the patient or caregiver, we collected details of inpatient and outpatient resources used by the patient and (or) caregiver. RESULTS: We enrolled 766 patients from 31 Canadian sites. Overall mean age was 76.8 years, and mean age of onset was 73.1 years. Of the total patients, 98% were white, 54% were women, and 84% were diagnosed with Alzheimer's disease. Mean baseline 3MS was 66.5, NPI was 9.5, and SMAF was 18.30. Of these patients, 48% reported a GDS score of 3 (that is, moderate), 16% reported a GDS score of 4 (that is, moderately severe), and the remaining 36% reported a GDS score of 1 or 2 (that is, mild or very mild). At baseline, 83% of patients received cholinesterase inhibitors, 46% received nonsteroidal antiinflammatory drugs, 39% received vitamin E, and 25% received antidepressants. Adult day care and home help were the largest cost factors in this population, with mean monthly costs of $65 and $64, respectively. We found interesting differences in the resources used among geographic regions and care settings. CONCLUSIONS: COSID is already generating valuable information about treatment patterns, outcomes, and resource use in Canadian patients with dementia. As the data mature, it will be possible to build robust models on treatment effectiveness and costs of care.