title: Comparative safety of antipsychotics in the WHO pharmacovigilance database: the haloperidol case.
abstract: BACKGROUND
  Starting in 2007, regulatory agencies strengthened label warnings for intravenous haloperidol. Based on adverse drug reaction (ADR) reports of QT prolongation and torsades de pointes, regulatory agencies recommended the use of continuous telemetry or advising against the intravenous administration in general. Intravenous haloperidol is commonly used as a first line treatment for acute delirium. Consequently, the extended warning has caused uncertainty among health care professionals.
  
  
  OBJECTIVE
  The aim of this study is to critically evaluate the WHO global individual case safety report (ICSR) database VigiBase for QT prolongation, torsades and/or cardiac arrest involving intravenous haloperidol compared to other routes of administration and the antipsychotics olanzapine and quetiapine.
  
  
  METHODS
  All WHO safety reports (1972-2010) of cardiac reactions associated with haloperidol, quetiapine and olanzapine were evaluated, including dose, route of administration and patient risk factors. Reporting odds ratios for the 3 antipsychotics were calculated. Main outcome measure Number of submitted reports on different antipsychotics.
  
  
  RESULTS
  The absolute number of ICSR regarding QT prolongation, torsades and/or cardiac arrest were: haloperidol (365 cases), olanzapine (489) and quetiapine (520). Reporting rates of haloperidol did not increase over the last two decades. 32% of the haloperidol cases involved oral, 16.4% intramuscular and 22.7% intravenous administration. The difference of the reporting odds ratios of haloperidol and quetiapine were not statistically significant. Olanzapine was associated with a slightly lower reporting odds ratio.
  
  
  CONCLUSIONS
  While regulatory agencies advise against the use of intravenous haloperidol, review of VigiBase does not reveal that the intravenous route is any more likely to be associated with cardiac adverse events. Furthermore, our results do not demonstrate any additional risk associated with haloperidol when compared with alternative agents. Although pharmacovigilance data does not routinely include a denominator regarding frequency of use, regulatory agencies are currently advising against the use of intravenous haloperidol based on pharmacovigilance, but the number of overall reports is greater for quetiapine and olanzapine when compared to haloperidol. Improved pharmacovigilance approaches are needed to more accurately address the safe, effective use of medicines.
authors.affiliation: Clinical Pharmacy and Epidemiology, Department of Pharmaceutical Sciences, University of Basel, Basel, Switzerland. carla.meyer@unibas.ch
authors.forename: Carla
authors.initials: C
authors.lastname: Meyer-Massetti
authors.forename: Simone
authors.initials: S
authors.lastname: Vaerini
authors.forename: Alexandra E
authors.initials: AE
authors.lastname: Rätz Bravo
authors.forename: Christoph R
authors.initials: CR
authors.lastname: Meier
authors.forename: B Joseph
authors.initials: BJ
authors.lastname: Guglielmo
mesh_terms: D000368:Aged; D014150:Antipsychotic Agents / Q000008:administration & dosage / Q000009:adverse effects*; D001569:Benzodiazepines / Q000008:administration & dosage / Q000009:adverse effects; D016208:Databases, Factual / Q000706:statistics & numerical data*; D003987:Dibenzothiazepines / Q000008:administration & dosage / Q000009:adverse effects; D004305:Dose-Response Relationship, Drug; D004333:Drug Administration Routes; D005260:Female; D006220:Haloperidol / Q000008:administration & dosage / Q000009:adverse effects*; D006801:Humans; D008297:Male; D008875:Middle Aged; D000077152:Olanzapine; D060735:Pharmacovigilance; D000069348:Quetiapine Fumarate; D012307:Risk Factors; D014944:World Health Organization
chemical_list: D014150:Antipsychotic Agents; D003987:Dibenzothiazepines; D001569:Benzodiazepines; D000069348:Quetiapine Fumarate; D006220:Haloperidol; D000077152:Olanzapine