title: Torsadogenic risk of antipsychotics: combining adverse event reports with drug utilization data across Europe.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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).
  
  
  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).
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Medical and Surgical Sciences, Alma Mater Studiorum - University of Bologna, Bologna, Italy.
authors.forename: Emanuel
authors.initials: E
authors.lastname: Raschi
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Poluzzi
authors.forename: Brian
authors.initials: B
authors.lastname: Godman
authors.forename: Ariola
authors.initials: A
authors.lastname: Koci
authors.forename: Ugo
authors.initials: U
authors.lastname: Moretti
authors.forename: Marija
authors.initials: M
authors.lastname: Kalaba
authors.forename: Marion
authors.initials: M
authors.lastname: Bennie
authors.forename: Corrado
authors.initials: C
authors.lastname: Barbui
authors.forename: Bjorn
authors.initials: B
authors.lastname: Wettermark
authors.forename: Miriam
authors.initials: M
authors.lastname: Sturkenboom
authors.forename: Fabrizio
authors.initials: F
authors.lastname: De Ponti
mesh_terms: D016907:Adverse Drug Reaction Reporting Systems; D014150:Antipsychotic Agents / Q000009:adverse effects* / Q000627:therapeutic use; D004363:Drug Utilization; D005060:Europe; D006801:Humans; D060735:Pharmacovigilance; D012306:Risk; D016171:Torsades de Pointes / Q000139:chemically induced* / Q000453:epidemiology*; D014481:United States; D014486:United States Food and Drug Administration
chemical_list: D014150:Antipsychotic Agents