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

• Published in: Pharmacoepidemiology and drug safety 2017-07, Vol.26 (7), p.752-765
• Main Authors: Bahar, Muh. Akbar, Hak, Eelko, Bos, Jens H.J., Borgsteede, Sander D., Wilffert, Bob
• Format: Article
• Language: English
• Subjects: Aged; Anti-Arrhythmia Agents - administration & dosage; Anti-Arrhythmia Agents - pharmacokinetics; Anti-Arrhythmia Agents - therapeutic use; Antidepressants; beta‐blockers; Computer programs; CYP2D6; CYP2D6 protein; Cytochrome P-450 CYP2D6 - metabolism; Cytochrome P450; cytochrome P450 (CYP)‐based drug–drug interactions (DDI); Drug interaction; Drug Interactions; Female; Fluoxetine; Fluoxetine - administration & dosage; Fluoxetine - pharmacokinetics; Fluoxetine - therapeutic use; Geriatrics; Humans; Male; Mental depression; Metoprolol; Metoprolol - administration & dosage; Metoprolol - pharmacokinetics; Metoprolol - therapeutic use; Middle Aged; Older people; Paroxetine; Paroxetine - administration & dosage; Paroxetine - pharmacokinetics; Paroxetine - therapeutic use; paroxetine/fluoxetine; pharmacoepidemiology; Serotonin Uptake Inhibitors - administration & dosage; Serotonin Uptake Inhibitors - pharmacokinetics; Serotonin Uptake Inhibitors - therapeutic use; Software
• ISSN: 1053-8569; 1099-1557
• DOI: 10.1002/pds.4200

Purpose 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. Method 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. Conclusion 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.