Nationwide drug-dispensing data reveal important differences in adherence to drug label recommendations on CYP2D6-dependent drug interactions


Associate Professor Erik Eliasson, MD, PhD, Karolinska Institutet, Department of Laboratory Medicine, Division of Clinical Pharmacology, Karolinska University Hospital, Huddinge, SE 141 86 Stockholm, Sweden.
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• Drug–drug interactions (DDIs) may have a profound impact on the individual drug response, for instance by reducing the clearance of involved drugs and thereby causing adverse drug reactions at supratherapeutic drug exposure.

• In specific cases, such a risk with specific drug combinations is stated in the drug label, including specific recommendations on the choice of drug and/or dose.

• Less frequently, DDIs that reduce the drug effectiveness may have been recognized as well.

• The clinical adherence to these recommendations is today unknown.


• The results from this study on specific drug combinations related to cytochrome P450-dependent drug metabolism indicate that Swedish doctors avoid prescribing strong inhibitors of drug metabolism together with drugs at risk of accumulation and exposure-dependent adverse drug reactions.

• However, ‘silent’ DDIs that impact on effectiveness appear to be neglected, pointing out an area for continued medical education of drug prescribers about such DDIs.

AIMS The study aimed to investigate the clinical adherence to drug label recommendations on important drug–drug interactions (DDIs). Dispensing data on drug combinations involving selective serotonin reuptake inhibitor (SSRI) antidepressants could help to identify areas for intensified medical education.

METHODS This was a retrospective, cross-sectional analysis of individual dispensing data regarding all individuals ≥15 years old in Sweden. The study analysed the prescribing and dispensing of CYP2D6 drugs (metoprolol, donepezil, galantamine, codeine, tamoxifen) together with CYP2D6-blocking SSRIs (paroxetine/fluoxetine) or SSRIs without significant CYP2D6 inhibition (citalopram/escitalopram/sertraline), and the related prescribing of CYP2D6-independent comparator drugs (atenolol, rivastigmine, propoxyphene, anastrozole). Odds were calculated between each CYP2D6 drug and the corresponding comparator drug in patients on fluoxetine/paroxetine and citalopram/escitalopram/sertraline, respectively. The odds ratio (OR) was calculated by dividing the obtained odds in patients on fluoxetine/paroxetine by the corresponding odds in patients on citalopram/escitalopram/sertraline.

RESULTS Compared with patients that were dispensed citalopram/escitalopram/sertraline, patients dispensed fluoxetine/paroxetine had lower prescribing rates of metoprolol (adjusted OR 0.80; 95% confidence interval 0.76, 0.85), donepezil (0.65; 0.49, 0.86) and galantamine (0.58; 0.41, 0.81). In contrast, the use of prodrugs codeine (compared woth propoxyphene) or tamoxifen (compared with anastrozole) was similar among patients on fluoxetine/paroxetine and citalopram/escitalopram/sertraline (adjusted OR 1.03; 0.94, 1.12 and 1.29; 0.96, 1.73, respectively).

CONCLUSIONS Clinically important DDIs that are associated with impaired bioactivation of prodrugs might be more easily neglected in clinical practice compared with DDIs that cause drug accumulation and symptomatic adverse drug reactions.