title: Generic switching of warfarin and risk of excessive anticoagulation: a Danish nationwide cohort study.
abstract: OBJECTIVE
  Generic switching of warfarin was recently repealed in Denmark, as adverse drug reaction (ADR) reports suggested risk of excessive anticoagulation following switches from branded to generic warfarin. We investigated this putative association in a formalized pharmacoepidemiological analysis.
  
  
  METHODS
  We conducted a nationwide cohort study based on Danish healthcare registries, including data from the introduction of generic warfarin until the repeal (January 2011-April 2015). We followed Danish warfarin users over time and compared the rate of incident hospitalizations due to excessive anticoagulation (i.e. increased INR or any bleeding requiring hospitalization) in periods following a recent switch to generic warfarin to the rate in periods without a recent switch.
  
  
  RESULTS
  We included 105,751 warfarin users, filling a total of 1,539,640 prescriptions for warfarin (2.5% for generic warfarin). This constituted 89.0% of all warfarin prescriptions in Denmark during the study period. We observed 19,362 switches to generic warfarin during the study period. The adjusted hazard ratio for excessive anticoagulation following a recent switch from branded to generic warfarin was 1.1 (95%CI, 0.8-1.4). The result was robust within subgroups and several sensitivity analyses.
  
  
  CONCLUSIONS
  Switching from branded to generic warfarin is not associated with an increased risk of hospitalization with excessive anticoagulation. However, a minor excess risk of transient INR increase cannot be excluded. Pharmacoepidemiological studies provide an effective method for swift evaluation of hypotheses generated by ADR-reports.
authors.affiliation: Clinical Pharmacology, Department of Public Health, University of Southern Denmark, Denmark.
authors.forename: Maja
authors.initials: M
authors.lastname: Hellfritzsch
authors.affiliation: Department of Clinical Chemistry and Pharmacology, Odense University Hospital, Denmark.
authors.forename: Jette
authors.initials: J
authors.lastname: Rathe
authors.affiliation: Clinical Pharmacology, Department of Public Health, University of Southern Denmark, Denmark.
authors.forename: Tore Bjerregaard
authors.initials: TB
authors.lastname: Stage
authors.affiliation: Department of Drug Design and Pharmacology, University of Copenhagen, Denmark.|NDA Advisory Services Ltd, United Kingdom.
authors.forename: Steffen
authors.initials: S
authors.lastname: Thirstrup
authors.affiliation: Department of Cardiology, Aarhus University Hospital, Denmark.
authors.forename: Erik L
authors.initials: EL
authors.lastname: Grove
authors.affiliation: Clinical Pharmacology, Department of Public Health, University of Southern Denmark, Denmark.|Department of Clinical Chemistry and Pharmacology, Odense University Hospital, Denmark.
authors.forename: Per
authors.initials: P
authors.lastname: Damkier
authors.affiliation: Clinical Pharmacology, Department of Public Health, University of Southern Denmark, Denmark.
authors.forename: Anton
authors.initials: A
authors.lastname: Pottegård
mesh_terms: D016907:Adverse Drug Reaction Reporting Systems / Q000706:statistics & numerical data*; D000925:Anticoagulants / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use; D015331:Cohort Studies; D003718:Denmark / Q000453:epidemiology; D016568:Drugs, Generic / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use; D006470:Hemorrhage / Q000097:blood / Q000139:chemically induced / Q000453:epidemiology*; D006801:Humans; D019934:International Normalized Ratio; D017891:Pharmacoepidemiology / Q000379:methods*; D014859:Warfarin / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use
chemical_list: D000925:Anticoagulants; D016568:Drugs, Generic; D014859:Warfarin
keywords: Denmark; adverse drug reaction reports; excessive anticoagulation; generic drugs; oral anticoagulants; pharmacoepidemiology; warfarin