Abstract
BackgroundAntipsychotics (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.MethodsFAERS 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).Results 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).ConclusionsThis 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.
Highlights
Antipsychotics (APs) represent a heterogeneous pharmacological class in terms of molecular targets [1], several studies have challenged whether this multifaceted profile translates into clinical differences between first- and second- generation agents (FGAs and SGAs), in the past referred to as “typical” and “atypical” drugs, respectively [2,3,4]
Only cyamemazine is not included in any Arizona CERT lists
The 7-year-period analysis of FDA Adverse Event Reporting System (FAERS) characterized 35 antipsychotics with potential torsadogenic signal: 9 of them fulfilled all pharmacovigilance criteria to be labeled as very strong torsadogenic signals (i.e., Group A), with cyamemazine as the only agent currently not included in Arizona CERT lists
Summary
Antipsychotics (APs) represent a heterogeneous pharmacological class in terms of molecular targets [1], several studies have challenged whether this multifaceted profile translates into clinical differences (i.e., effectiveness) between first- and second- generation agents (FGAs and SGAs), in the past referred to as “typical” and “atypical” drugs, respectively [2,3,4] This uncertainty poses emerging clinical implications for psychiatrists when considering the appropriate therapy, which should be tailored to the individual [5,6,7]. Conclusions: This parallel approach through spontaneous reporting and drug utilization analyses highlighted drugand 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
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