Effect of regulatory warnings on antipsychotic prescription rates among elderly patients with dementia: A population-based time-series analysis

The Department of Health Policy, Management and Evaluation, University of Toronto, Toronto, Ont.
Canadian Medical Association Journal (Impact Factor: 5.96). 09/2008; 179(5):438-46. DOI: 10.1503/cmaj.071540
Source: PubMed


Three warnings of serious adverse events associated with the use of atypical antipsychotic drugs among elderly patients with dementia were sent to health care professionals in Canada. We assessed the impact of these warnings on prescription rates of antipsychotic drugs in this patient population.
We used prescription drug claims data from Ontario to calculate prescription rates of atypical and conventional antipsychotic drugs among elderly patients with dementia from May 1, 2000, to Feb. 28, 2007. We performed a time-series analysis to estimate the effect of each warning on rates of antipsychotic drug use.
Before the first warning, growth in the use of atypical antipsychotics was responsible for an increasing rate of overall antipsychotic use. Each warning was associated with a small relative decrease in the predicted growth in the use of atypical antipsychotic drugs: a 5.0% decrease after the first warning, 4.9% after the second and 3.2% after the third (each p < 0.05). The overall prescription rate of antipsychotic drugs among patients with dementia increased by 20%, from 1512 per 100 000 elderly patients in September 2002, the month before the first warning, to 1813 per 100 000 in February 2007, 20 months after the last warning.
Although the warnings slowed the growth in the use of atypical antipsychotic drugs among patients with dementia, they did not reduce the overall prescription rate of these potentially dangerous drugs. More effective interventions are necessary to improve postmarket drug safety in vulnerable populations.

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    • "From an epidemiological standpoint, the large utilization of antipsychotics is a well known pharmaco-epidemiological burden, also for off-label indications [9]. Several studies on US and Canada prescriptions examined the impact of regulatory safety warnings and found only a slight decrease or even an increase of the antipsychotic use (especially SGAs in patients with dementia) [20-23]. Our data are also in line with a recent analysis on Australian data, which revealed a +217.7% increase in atypical antipsychotic dispensation over the 2000-2011 period, with olanzapine as the most frequently dispensed agent [53]. "
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    ABSTRACT: Antipsychotics (APs) have been associated with risk of torsade de Pointes (TdP). This has important public health implications. Therefore, (a) we exploited the public FDA Adverse Event Reporting System (FAERS) to characterize their torsadogenic profile; (b) we collected drug utilization data from 12 European Countries to assess the population exposure over the 2005-2010 period. FAERS data (2004-2010) were analyzed based on the following criteria: (1) ≥4 cases of TdP/QT abnormalities; (2) Significant Reporting Odds Ratio, ROR [Lower Limit of the 95% confidence interval>1], for TdP/QT abnormalities, adjusted and stratified (Arizona CERT drugs as effect modifiers); (3) ≥4 cases of ventricular arrhythmia/sudden cardiac death (VA/SCD); (4) Significant ROR for VA/SCD; (5) Significant ROR, combined by aggregating TdP/QT abnormalities with VA and SCD. Torsadogenic signals were characterized in terms of signal strength: from Group A (very strong torsadogenic signal: all criteria fulfilled) to group E (unclear/uncertain signal: only 2/5 criteria). Consumption data were retrieved from 12 European Countries and expressed as defined daily doses per 1,000 inhabitants per day (DID). Thirty-five antipsychotics met at least one criterium: 9 agents were classified in Group A (amisulpride, chlorpromazine, clozapine, cyamemazine, haloperidol, olanzapine, quetiapine, risperidone, ziprasidone). In 2010, the overall exposure to antipsychotics varied from 5.94 DID (Estonia) to 13.99 (France, 2009). Considerable increment of Group A agents was found in several Countries (+3.47 in France): the exposure to olanzapine increased across all Countries (+1.84 in France) and peaked 2.96 in Norway; cyamemazine was typically used only in France (2.81 in 2009). Among Group B drugs, levomepromazine peaked 3.78 (Serbia); fluphenazine 1.61 (Slovenia). This parallel approach through spontaneous reporting and drug utilization analyses highlighted drug- and Country-specific scenarios requiring potential regulatory consideration: levomepromazine (Serbia), fluphenazine (Slovenia), olanzapine (across Europe), cyamemazine (France). This synergy should be encouraged to support future pharmacovigilance activities.
    Full-text · Article · Nov 2013 · PLoS ONE
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    • "Nevertheless, the practice of prescribing antipsychotics to elderly patients has continued [29]–[31] and risperidone, the only SGA with an official indication for behavioural disturbances of dementia in Canada as well as in Europe and the US, remains the antipsychotic agent most commonly prescribed to the over-65 age group [31]. The superiority of SGAs in terms of lower incidence of movement disorders or EPS such as acute dystonia, akathisia, parkinsonism and tardive dyskinesia, has been recently challenged [32]. "
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    ABSTRACT: Despite concerns over the potential for severe adverse events, antipsychotic medications remain the mainstay of treatment of behaviour disorders and psychosis in elderly patients. Second-generation antipsychotic agents (SGAs; e.g., risperidone, olanzapine, quetiapine) have generally shown a better safety profile compared to the first-generation agents (FGAs; e.g., haloperidol and phenothiazines), particularly in terms of a lower potential for involuntary movement disorders. Risperidone, the only SGA with an official indication for the management of inappropriate behaviour in dementia, has emerged as the antipsychotic most commonly prescribed to older patients. Most clinical trials evaluating the risk of movement disorders in elderly patients receiving antipsychotic therapy have been of limited sample size and/or of relatively short duration. A few observational studies have produced inconsistent results. A population-based retrospective cohort study of all residents of the Canadian province of Manitoba aged 65 and over, who were dispensed antipsychotic medications for the first time during the time period from April 1, 2000 to March 31, 2007, was conducted using Manitoba's Department of Health's administrative databases. Cox proportional hazards models were used to determine the risk of extrapyramidal symptoms (EPS) in new users of risperidone compared to new users of FGAs. After controlling for potential confounders (demographics, comorbidity and medication use), risperidone use was associated with a lower risk of EPS compared to FGAs at 30, 60, 90 and 180 days (adjusted hazard ratios [HR] 0.38, 95% CI: 0.22-0.67; 0.45, 95% CI: 0.28-0.73; 0.50, 95% CI: 0.33-0.77; 0.65, 95% CI: 0.45-0.94, respectively). At 360 days, the strength of the association weakened with an adjusted HR of 0.75, 95% CI: 0.54-1.05. In a large population of elderly patients the use of risperidone was associated with a lower risk of EPS compared to FGAs.
    Full-text · Article · May 2013 · PLoS ONE
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    • "After the warning in 2004, there was a foreseeable increase in prescriptions of quetiapine to the detriment of risperidone and olanzapine. Another study (Valiyeva et al., 2008), using prescription drug claims data from the Ontario Drug Benefit database, evaluated the impact of three warnings of serious adverse events related to the use of atypical antipsychotics among elderly patients with dementia, and found that each warning had only a limited effect on prescription rates. However, the overall prescription rate of antipsychotics rose between the first warning and the end of the study period. "
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    ABSTRACT: The objective of the study was to assess the trend of antipsychotic prescription in elderly patients taking cholinesterase inhibitors (ChEIs) from 2002 to 2008 and the changes subsequent to two main official warnings issued by the Italian Medicines Agency to restrict their use. Elderly patients aged 65-94years who received at least one prescription of ChEIs between 1 January 2002 and 31 December 2008 were selected. We used data on prescriptions from the Lombardy Region Drug Administrative Database (Italy). The first prescription of one ChEI was used as the index day to calculate the prescription of an antipsychotic. The prescription of atypical antipsychotics in patients exposed to ChEIs declined from 21.0% in 2002 to 14.6% in 2008 (OR 0.92; 95%CI:0.90, 0.94; p<0.001), while the prescribing prevalence of typicals slightly increased (OR 1.08; 95%CI:1.03, 1.13; p=0.001). In relation to the two warnings, the prevalence of patients who received a prescription of antipsychotics was significantly lower in 2005 than 2004 (23.1% vs. 28.0%; OR 0.79; 95%CI:0.73-0.86; p<0.001) and in 2007 than 2006 (19.4% vs. 23.0%; OR 0.79; 95%CI:0.73-0.86; p<0.001). After the first safety warning the prevalence of prescriptions for risperidone and olanzapine dropped significantly, and there was a significant increase for quetiapine. Haloperidol prescriptions increased, especially after the second warning. Despite regulatory warnings issued to discourage the use of antipsychotics, they are still frequently prescribed to patients taking ChEIs. Awaiting further studies to clarify their therapeutic role, physicians should prescribe antipsychotics very cautiously and only after careful risk-benefit assessment.
    Full-text · Article · Jan 2012 · European neuropsychopharmacology: the journal of the European College of Neuropsychopharmacology
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