The potential for clinically significant drug-drug interactions in patients receiving CYP 2D6 model substrate/drugs and fluoxetine/paroxetine or sertraline

Abstract

While fluoxetine, paroxetine, and sertraline are all SSRI antidepressants, they are markedly different in their inhibitory effect on the human drug-metabolizing enzyme, CYP 2D6. Fluoxetine and paroxetine, at their lowest usually effective antidepressant dose, produce comparable and substantial inhibition of this enzyme while sertraline does not [1]. Previous studies found combined treatment with drugs capable of decreasing the seizure threshold and drugs capable of inhibiting the metabolism of the former drugs to be an important risk factor for seizures/myoclonus [2]. The current study determined the relative frequency of the combined use of fluoxetine/paroxetine versus sertraline with drugs principally cleared via 2D6 in a Midwestern US Veterans Affairs health care network. Method The medication regimens of 461 outpatients being treated with fluoxetine or paroxetine and 435 with sertraline were examined to determine whether they were also receiving a drug whose clearance was preferentially dependent upon 2D6. In each drug combination, substantial inhibition of 2D6 function had the potential for causing a clinically significant drug-drug interaction (DDI). A sub-analysis was conducted on patients in whom the 2D6 substrate/drug had a narrow therapeutic index, to determine whether the dose was potentially dangerous, given substantial inhibition of 2D6. Finally, the drug alert system was examined to determine whether it would have predicted a significant and/or serious DDI. Results 39.7% (183 patients: 90 fluoxetine, 92 paroxetine and 1 on both) of patients being treated with fluoxetine/paroxetine were also receiving a 2D6 model substrate/drug versus 34.2% (149 patients) of patients on sertraline. In 8.4% of patients being treated with fluoxetine/paroxetine and 8.0% with sertraline, the coadministered 2D6-model substrate/drug had a narrow therapeutic index. 21.3% of the patients being treated concomitantly with either fluoxetine or paroxetine and a 2D6 model substrate/drug were receiving a dose of the latter high enough to be a significant risk for a serious DDI. In 50% of the drug combinations, the DDI was not identified by the drug information system employed. Conclusion There was no significant difference in frequency of fluoxetine/paroxetine or sertraline use in combination with 2D6 model substrate/drugs. 50% of the 16 potentially serious adverse drug combinations were not in the drug alert system employed, suggesting the need to move from a system based on published studies to one based on mechanisms underlying DDIs. Clinical Pharmacology & Therapeutics (2004) 75, P71–P71; doi: 10.1016/j.clpt.2003.11.266