Torsadogenic risk of antipsychotics: combining adverse event reports with drug utilization data across Europe

Emanuel Raschi, Elisabetta Poluzzi, Brian Godman, Ariola Koci, Ugo Moretti, Marija Kalaba, Marion Bennie, Corrado Barbui, Bjorn Wettermark, Miriam Sturkenboom, Fabrizio De Ponti

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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.

Original languageEnglish
Article numbere81208
JournalPLOS One
Volume8
Issue number11
DOIs
Publication statusPublished - 20 Nov 2013

Keywords

  • torsadogenic risk
  • antipsychotics
  • adverse event reports
  • drug utilization data
  • europe
  • torsade de pointes

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    Raschi, E., Poluzzi, E., Godman, B., Koci, A., Moretti, U., Kalaba, M., Bennie, M., Barbui, C., Wettermark, B., Sturkenboom, M., & De Ponti, F. (2013). Torsadogenic risk of antipsychotics: combining adverse event reports with drug utilization data across Europe. PLOS One, 8(11), [e81208]. https://doi.org/10.1371/journal.pone.0081208