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

Bahar, M. A., Hak, E., Bos, J. H. J., Borgsteede, S. D. & Wilffert, B., Jul-2017, In : Pharmcoepidemiology and Drug Safety. 26, 7, p. 752-765 14 p.

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  • The burden and management of cytochrome P450 2D6 (CYP2D6)-mediated drug–drug interaction (DDI)

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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 (, 1999-2014) for elderly patients (60years) 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.

Original languageEnglish
Pages (from-to)752-765
Number of pages14
JournalPharmcoepidemiology and Drug Safety
Issue number7
Publication statusPublished - Jul-2017


  • cytochrome P450 (CYP)-based drug-drug interactions (DDI), CYP2D6, paroxetine, fluoxetine, metoprolol, beta-blockers, antidepressants, pharmacoepidemiology, ACUTE MYOCARDIAL-INFARCTION, INTERACTION ALERTS, HEART-FAILURE, CARDIOVASCULAR-DISEASE, ENZYME-INHIBITOR, PHARMACOKINETICS, PRESCRIPTION, DEPRESSION, RELEASE, IADB

ID: 41850555