Co-prescription of metoprolol and CYP2D6-inhibiting antidepressants before and after implementation of an optimized drug interaction database in Norway

Abstract

Purpose To compare the co-prescription of metoprolol and potent CYP2D6-inhibiting antidepressants before and during a 10-year period after implementation of an optimized drug interaction database into clinical decision support systems in Norway. Methods The study was a retrospective, cross-sequential nationwide analysis of drug-dispensing data retrieved from the Norwegian Prescription Database over a 1-year period before (2007) and two 1-year periods after (2012 and 2017) implementation of a drug interaction database providing recommendations on non-interacting alternative medications. Primary outcome was changes in co-prescription rates of metoprolol and the potent CYP2D6-inhibiting antidepressants fluoxetine, paroxetine, or bupropion relative to alternative antidepressants with no or limited CYP2D6 inhibitory potential. To control for potential secular trend bias, a comparison group consisting of atenolol/bisoprolol users was included. Results The co-prescription rate of metoprolol with potent CYP2D6 inhibitors declined following implementation of the optimized database, by 21% (P < 0.001) after 5 years and by 40% (P < 0.001) after 10 years. Compared with atenolol/bisoprolol users, patients treated with metoprolol had significantly reduced likelihood of being prescribed a CYP2D6-inhibiting antidepressant in the two post-implementation periods (OR 0.61 (95% CI 0.54–0.69) and OR 0.45 (95% CI 0.40–0.51), respectively, versus OR 0.84 (95% CI 0.74–0.94) prior to implementation). Small and mostly insignificant differences in average daily metoprolol dosage were found between patients treated with the various antidepressants. Conclusion The present study suggests that implementation of a drug interaction database providing recommendations on non-interacting drug alternatives contributes to reduced co-prescribing of drug combinations associated with potentially serious adverse effects.

Advancing CYP2D6 Pharmacogenetics through a Pharmacoequity Lens

“…The DPWG has also developed numerous recommendations for more than 40 CYP2D6-metabolized medications (Figure 1). Several are published [10][11][12][13][14] and those not included in publications are provided on the Pharmacogenomics Knowledgebase (PharmGKB; https://www.pharm gkb.org). Moreover, consensus has been reached between the CPIC and DPWG in terms of diplotype to phenotype translation.…”

Mechanism-Based Inactivation of CYP2D6 by Phellopterin and Related Drug–Drug Interaction with Metoprolol

“…For example, administration of paroxetine increased plasma concentrations of metoprolol by more than five-fold, and severe bradycardia and atrioventricular block have been reported in patients taking both drugs. 17 The objectives of the present study were to investigate the interaction of PLP with cytochrome P450 enzymes and to determine the pharmacokinetic alteration of metoprolol resulting from pretreatment with PLP. methorphan, 4-hydroxytolbutamide, 4-nitrophenol, and omeprazole were purchased from Sigma-Aldrich Chemical (St. Louis, MO).…”

“…Studies have shown that the plasma concentration of metoprolol can increase by multiple fold and even cause bradycardia after taking drugs with CYP2D6 inhibitory properties. For example, administration of paroxetine increased plasma concentrations of metoprolol by more than five-fold, and severe bradycardia and atrioventricular block have been reported in patients taking both drugs …”