title: Pro-arrhythmic potential of oral antihistamines (H1): combining adverse event reports with drug utilization data across Europe.
abstract: BACKGROUND
  There is appreciable utilisation of antihistamines (H1) in European countries, either prescribed by physician and purchased by patients for self-medication. Terfenadine and astemizole underwent regulatory restrictions in '90 because of their cardiac toxicity, but only scarce clinical data are available on other antihistamines.
  
  
  OBJECTIVE
  To investigate the pro-arrhythmic potential of antihistamines by combining safety reports of the FDA Adverse Event Reporting System (FAERS) with drug utilization data from 13 European Countries.
  
  
  METHODS
  We identified signals of antihistamine arrhythmogenic potential by analyzing FAERS database for all cases of Torsades de Pointes (TdP), QT abnormalities (QTabn), ventricular arrhythmia (VA) and sudden cardiac death/cardiac arrest (SCD/CA). Number of cases ≥3 and disproportionality were used to define alert signals: TdP and QTabn identified stronger signals, whereas SCD/CA identified weaker signals. Drug utilization data from 2005 to 2010 were collected from administrative databases through health authorities and insurance.
  
  
  RESULTS
  Antihistamines were reported in 109 cases of TdP/QT prolongation, 278 VA and 610 SCD/CA. Five agents resulted in stronger signals (cetirizine, desloratadine, diphenhydramine, fexofenadine, loratadine) and 6 in weaker signals (alimemazine, carbinoxamine, cyclizine, cyproeptadine, dexchlorpheniramine and doxylamine). Exposure to antihistamines with stronger signal was markedly different across European countries and was at least 40% in each Country. Cetirizine was >29 Defined Daily Doses per 1000 inhabitants per day (DID) in Norway, desloratadine >11 DID in France and loratadine >9 DID in Sweden and Croatia. Drugs with weaker signals accounted for no more than 10% (in Sweden) and in most European countries their use was negligible.
  
  
  CONCLUSIONS
  Some second-generation antihistamines are associated with signal of torsadogenicity and largely used in most European countries. Although confirmation by analytical studies is required, regulators and clinicians should consider risk-minimisation activities. Also antihistamines without signal but with peculiar use in a few Countries (e.g., levocetirizine) or with increasing consumption (e.g., rupatadine) deserve careful surveillance.
authors.affiliation: Department of Medical and Surgical Sciences, Alma Mater Studiorum-University of Bologna, Bologna, Italy.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Poluzzi
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.affiliation: Division of Clinical Pharmacology, Karolinska Institutet, Stockholm, Sweden; Strathclyde Institute of Pharmacy and Biomedical Sciences, Strathclyde University, Glasgow, United Kingdom.
authors.forename: Brian
authors.initials: B
authors.lastname: Godman
authors.affiliation: Department of Medical and Surgical Sciences, Alma Mater Studiorum-University of Bologna, Bologna, Italy.
authors.forename: Ariola
authors.initials: A
authors.lastname: Koci
authors.affiliation: Clinical Pharmacology Unit, University of Verona, Verona, Italy.
authors.forename: Ugo
authors.initials: U
authors.lastname: Moretti
authors.affiliation: Republic Fund for Health Insurance, Belgrade, Serbia.
authors.forename: Marija
authors.initials: M
authors.lastname: Kalaba
authors.affiliation: Division of Clinical Pharmacology, Karolinska Institutet, Stockholm, Sweden; Centre for Pharmacoepidemiology, Karolinska University Hospital, Solna, Stockholm, Sweden; Stockholm, County Council, Stockholm, Sweden.
authors.forename: Bjorn
authors.initials: B
authors.lastname: Wettermark
authors.affiliation: Erasmus University Medical Centre, Rotterdam, Netherlands.
authors.forename: Miriam
authors.initials: M
authors.lastname: Sturkenboom
authors.affiliation: Department of Medical and Surgical Sciences, Alma Mater Studiorum-University of Bologna, Bologna, Italy.
authors.forename: Fabrizio
authors.initials: F
authors.lastname: De Ponti
mesh_terms: D000284:Administration, Oral; D016907:Adverse Drug Reaction Reporting Systems / Q000706:statistics & numerical data; D001145:Arrhythmias, Cardiac / Q000139:chemically induced*; D016208:Databases, Factual; D004363:Drug Utilization / Q000706:statistics & numerical data; D005060:Europe; D006634:Histamine H1 Antagonists / Q000008:administration & dosage* / Q000009:adverse effects*; D006801:Humans; D060735:Pharmacovigilance
chemical_list: D006634:Histamine H1 Antagonists