Discontinuation and dose adjustment of metoprolol after metoprolol-paroxetine/fluoxetine co-prescription in Dutch elderly.

Muh Akbar Bahar,Yuanyuan Wang,Eelko Hak,Bob Wilffert,Jens H.J Bos

doi:10.1002/pds.4422

Abstract

PurposeCo‐prescription of paroxetine/fluoxetine (a strong CYP2D6 inhibitor) in metoprolol (a CYP2D6 substrate) users is common, but data on the clinical consequences of this drug‐drug interaction are limited and inconclusive. Therefore, we assessed the effect of paroxetine/fluoxetine initiation on the existing treatment with metoprolol on the discontinuation and dose adjustment of metoprolol among elderly.MethodsWe performed a cohort study using the University of Groningen IADB.nl prescription database (www.IADB.nl). We selected all elderly (≥60 years) who had ever been prescribed metoprolol and had a first co‐prescription of paroxetine/fluoxetine, citalopram (weak CYP2D6 inhibitor), or mirtazapine (negative control) from 1994 to 2015. The exposure group was metoprolol and paroxetine/fluoxetine co‐prescription, and the other groups acted as controls. The outcomes were early discontinuation and dose adjustment of metoprolol. Logistic regression was applied to estimate adjusted odds ratios (OR) and 95% confidence intervals (CI).ResultsCombinations of metoprolol‐paroxetine/fluoxetine, metoprolol‐citalopram, and metoprolol‐mirtazapine were started in 528, 673, and 625 patients, respectively. Compared with metoprolol‐citalopram, metoprolol‐paroxetine/fluoxetine was not significantly associated with the early discontinuation and dose adjustment of metoprolol (OR = 1.07, 95% CI:0.77‐1.48; OR = 0.87, 95% CI:0.57‐1.33, respectively). In comparison with metoprolol‐mirtazapine, metoprolol‐paroxetine/fluoxetine was associated with a significant 43% relative increase in early discontinuation of metoprolol (OR = 1.43, 95% CI:1.01‐2.02) but no difference in the risk of dose adjustment. Stratified analysis by gender showed that women have a significantly high risk of metoprolol early discontinuation (OR = 1.62, 95% CI:1.03‐2.53).ConclusionParoxetine/fluoxetine initiation in metoprolol prescriptions, especially for female older patients, is associated with the risk of early discontinuation of metoprolol.

Highlights

The number of patients included as metoprolol‐paroxetine/fluoxetine group, metoprolol‐citalopram group, and metoprolol‐mirtazapine group were 528, 673, and 625, respectively (Figure 1)
The risk of the discontinuation and dose adjustment of metoprolol was not significantly different between metoprolol‐paroxetine/fluoxetine and metoprolol‐citalopram
We found that the risk of discontinuation and dose adjustment of metoprolol in the metoprolol‐ paroxetine/fluoxetine combination is not significantly different from the metoprolol‐citalopram combination but had a 43% higher risk of early discontinuation of metoprolol compared with the metoprolol‐ mirtazapine group

Summary

Introduction

Relevant cytochrome P450 mediated drug‐drug interactions (DDI) are prevalent in geriatric patients with multiple comorbidities such as cardiovascular and psychiatric diseases.[1,2,3,4] Metoprolol and paroxetine/fluoxetine as the drugs of choice for treating these chronic illnesses consecutively are often observed to be co‐prescribed in the elderly.[5,6,7] Several studies have reported that the combination triggersPharmacoepidemiol Drug Saf. 2018;27:621–629.wileyonlinelibrary.com/journal/pds 621 cytochrome P450 2D6 (CYP2D6) mediated pharmacokinetic DDI.[8,9,10] Metoprolol is predominantly metabolized by CYP2D6, while paroxetine and fluoxetine are strong inhibitors of the enzyme.[11,12,13] co‐prescription of these drugs leads to the substantial increase of the blood concentration of metoprolol and potentially induces metoprolol‐related adverse drug reactions.[8,10,14,15]The frequent co‐administration of the drugs makes the clinical relevance of the DDI important to be determined, but so far real‐world data about its clinical consequences are sparse and conflicting. Relevant cytochrome P450 mediated drug‐drug interactions (DDI) are prevalent in geriatric patients with multiple comorbidities such as cardiovascular and psychiatric diseases.[1,2,3,4] Metoprolol and paroxetine/fluoxetine as the drugs of choice for treating these chronic illnesses consecutively are often observed to be co‐prescribed in the elderly.[5,6,7] Several studies have reported that the combination triggers. Wileyonlinelibrary.com/journal/pds 621 cytochrome P450 2D6 (CYP2D6) mediated pharmacokinetic DDI.[8,9,10] Metoprolol is predominantly metabolized by CYP2D6, while paroxetine and fluoxetine are strong inhibitors of the enzyme.[11,12,13] co‐prescription of these drugs leads to the substantial increase of the blood concentration of metoprolol and potentially induces metoprolol‐related adverse drug reactions.[8,10,14,15]. Some case reports indicated that the co‐medication of metoprolol and paroxetine/fluoxetine produces bradycardia and atrioventricular block in elderly.[10,16,17] another observational study found that the risk of bradycardia in the older population with the interacting combination is not different from those without the combination.[7]

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