Dataset Information

The impact of CYP2D6 mediated drug-drug interaction: a systematic review on a combination of metoprolol and paroxetine/fluoxetine.

ABSTRACT:

Aim

Metoprolol (a CYP2D6 substrate) is often co-prescribed with paroxetine/fluoxetine (a CYP2D6 inhibitor) because the clinical relevance of this drug-drug interaction (DDI) is still unclear. This review aimed to systematically evaluate the available evidence and quantify the clinical impact of the DDI.

Method

Pubmed, Web of Science, Cochrane Library and Embase were searched for studies reporting on the effect of the DDI among adults published until April 2018. Data on pharmacokinetics, pharmacodynamics and clinical outcomes from experimental, observational and case report studies were retrieved. The protocol of this study was registered in PROSPERO (CRD42018093087).

Results

We found nine eligible articles that consisted of four experimental and two observational studies as well as three case reports. Experimental studies reported that paroxetine increased the AUC of metoprolol three to five times, and significantly decreased systolic blood pressure and heart rate of patients. Case reports concerned bradycardia and atrioventricular block due to the DDI. Results from observational studies were conflicting. A cohort study indicated that the DDI was significantly associated with the incidence of early discontinuation of metoprolol as an indicator of the emergence of metoprolol-related side effects. In a case-control study, the DDI was not significantly associated with bradycardia.

Conclusion

Despite the contradictory conclusions from the current literature, the majority of studies suggest that the DDI can lead to adverse clinical consequences. Since alternative antidepressants and beta-blockers with comparable efficacy are available, such DDIs can be avoided. Nonetheless, if prescribing the combination is unavoidable, a dose adjustment or close monitoring of the metoprolol-related side effects is necessary.

SUBMITTER: Bahar MA

PROVIDER: S-EPMC6255988 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description: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.