Drug Interactions between doxepin topical and modafinil

MONITOR: Coadministration with modafinil (the racemate) or armodafinil (the R-enantiomer) may increase the plasma concentrations of tricyclic antidepressants (TCAs) in patients who are deficient in CYP450 2D6 (approximately 7% to 10% of the Caucasian population; similar or lower in other populations). Modafinil and armodafinil are modest inhibitors of CYP450 2C19, an isoenzyme that provides an ancillary pathway for the metabolism of certain TCAs normally metabolized by CYP450 2D6 such as clomipramine or desipramine. In a study of healthy volunteers, coadministration of a single 50 mg dose of clomipramine on the first three days of modafinil therapy (200 mg/day) showed no effect on the pharmacokinetics of either drug. However, increased levels of clomipramine and its active metabolite desmethylclomipramine have been reported in a patient receiving modafinil for narcolepsy. The patient was a CYP450 2D6 poor metabolizer.

MANAGEMENT: Caution is advised if tricyclic antidepressants are coadministered with modafinil or armodafinil in CYP450 2D6-deficient patients. Pharmacologic effects and serum TCA levels should be monitored more closely whenever modafinil or armodafinil is added to or withdrawn from therapy, and the TCA dosage adjusted accordingly. Patients should be advised to notify their physician if they experience possible signs of TCA toxicity such as excessive drowsiness, restlessness, agitation, ataxia, blurred vision, tachycardia, arrhythmia, and seizures.