title: The burden and management of cytochrome P450 2D6 (CYP2D6)-mediated drug-drug interaction (DDI): co-medication of metoprolol and paroxetine or fluoxetine in the elderly.
abstract: OBJECTIVE
  Metoprolol and paroxetine/fluoxetine are inevitably co-prescribed because cardiovascular disorders and depression often coexist in the elderly. This leads to CYP2D6-mediated drug-drug interactions (DDI). Because systematic evaluations are lacking, we assessed the burden of metoprolol-paroxetine/fluoxetine interaction in the elderly and how these interactions are managed in Dutch community pharmacies.
  
  
  METHODS
  Dispensing data were collected from the University of Groningen pharmacy database (IADB.nl, 1999-2014) for elderly patients (≥60 years) starting beta-blockers and/or antidepressants. Based on the two main DDI alert systems (G-Standard and Pharmabase), incidences were divided between signalled (metoprolol-fluoxetine/paroxetine) and not-signalled (metoprolol-alternative antidepressants and alternative beta-blockers-paroxetine/fluoxetine) combinations. Incident users were defined as patients starting at least one signalled or a non-signalled combination. G-Standard signalled throughout the study period, whereas Pharmabase stopped after 2005.
  
  
  RESULTS
  A total of 1763 patients had 2039 metoprolol-paroxetine/fluoxetine co-prescriptions, despite DDI alert systems, and about 57.3% were signalled. The number of metoprolol-alternative antidepressant combinations (incidences = 3150) was higher than alternative beta-blocker-paroxetine/fluoxetine combinations (incidences = 1872). Metoprolol users are more likely to be co-medicated with an alternative antidepressant (incidences = 2320) than paroxetine/fluoxetine users (incidences = 1232) are. The number of paroxetine/fluoxetine users co-prescribed with alternative beta-blockers was comparable to those co-medicated with metoprolol (about 50%). Less than 5% of patients received a substitute therapy after using metoprolol-paroxetine/fluoxetine. Most of the metoprolol users (90%) received a low dose (mean DDD = 0.47) regardless whether they were prescribed paroxetine/fluoxetine.
  
  
  CONCLUSIONS
  Despite the signalling software, metoprolol-paroxetine/fluoxetine combinations are still observed in the elderly population. The clinical impact of these interactions needs further investigation. Copyright © 2017 John Wiley & Sons, Ltd.
authors.affiliation: University of Groningen, Groningen Research Institute of Pharmacy, Department of PharmacoTherapy, -Epidemiology & -Economics, Groningen, The Netherlands.|Hasanuddin University, Faculty of Pharmacy, Makassar, Indonesia.
authors.forename: Muh Akbar
authors.identifier: http://orcid.org/0000-0002-6582-5615
authors.initials: MA
authors.lastname: Bahar
authors.affiliation: University of Groningen, Groningen Research Institute of Pharmacy, Department of PharmacoTherapy, -Epidemiology & -Economics, Groningen, The Netherlands.
authors.forename: Eelko
authors.initials: E
authors.lastname: Hak
authors.affiliation: University of Groningen, Groningen Research Institute of Pharmacy, Department of PharmacoTherapy, -Epidemiology & -Economics, Groningen, The Netherlands.
authors.forename: Jens H J
authors.initials: JHJ
authors.lastname: Bos
authors.affiliation: Health Base Foundation, Department of Clinical Decision Support, Houten, The Netherlands.
authors.forename: Sander D
authors.initials: SD
authors.lastname: Borgsteede
authors.affiliation: University of Groningen, Groningen Research Institute of Pharmacy, Department of PharmacoTherapy, -Epidemiology & -Economics, Groningen, The Netherlands.|University of Groningen, University Medical Center Groningen, Department of Clinical Pharmacy and Pharmacology, Groningen, The Netherlands.
authors.forename: Bob
authors.initials: B
authors.lastname: Wilffert
mesh_terms: D000368:Aged; D000889:Anti-Arrhythmia Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use; D019389:Cytochrome P-450 CYP2D6 / Q000378:metabolism*; D004347:Drug Interactions; D005260:Female; D005473:Fluoxetine / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D006801:Humans; D008297:Male; D008790:Metoprolol / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D008875:Middle Aged; D017374:Paroxetine / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D017367:Selective Serotonin Reuptake Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use
chemical_list: D000889:Anti-Arrhythmia Agents; D019389:Cytochrome P-450 CYP2D6; D005473:Fluoxetine; D008790:Metoprolol; D017374:Paroxetine; D017367:Selective Serotonin Reuptake Inhibitors
keywords: CYP2D6; antidepressants; beta-blockers; cytochrome P450 (CYP)-based drug-drug interactions (DDI); metoprolol; paroxetine/fluoxetine; pharmacoepidemiology