Drug Interactions between amitriptyline / chlordiazepoxide and armodafinil

MONITOR: Central nervous system- and/or respiratory-depressant effects may be additively or synergistically increased in patients taking multiple drugs that cause these effects, especially in elderly or debilitated patients. Sedation and impairment of attention, judgment, thinking, and psychomotor skills may increase.

MANAGEMENT: During concomitant use of these drugs, patients should be monitored for potentially excessive or prolonged CNS and respiratory depression. Cautious dosage titration may be required, particularly at treatment initiation. Ambulatory patients should be counseled to avoid hazardous activities requiring mental alertness and motor coordination until they know how these agents affect them, and to notify their physician if they experience excessive or prolonged CNS effects that interfere with their normal activities.

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effects and serum TCA levels should be monitored more closely whenever modafinil or armodafinil is added to or withdrawn from therapy, and the TCA dosage adjusted accordingly.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.

Coadministration with modafinil (the racemate) or armodafinil (the R-enantiomer) may decrease the plasma concentrations of drugs that are substrates of the CYP450 3A4 isoenzyme. Modafinil and armodafinil are modest inducers of CYP450 3A4, and pharmacokinetic studies suggest that their effects may be primarily intestinal rather than hepatic. Thus, clinically significant interactions would most likely be expected with drugs that have low oral bioavailability due to significant intestinal CYP450 3A4-mediated first-pass metabolism (e.g., buspirone, cyclosporine, lovastatin, midazolam, saquinavir, simvastatin, sirolimus, tacrolimus, triazolam, calcium channel blockers). However, the potential for interaction should be considered with any drug metabolized by CYP450 3A4, especially given the high degree of interpatient variability with respect to CYP450-mediated metabolism. Pharmacologic response to these drugs may be altered and should be monitored more closely whenever modafinil or armodafinil is added to or withdrawn from therapy. Dosage adjustments may be required if an interaction is suspected.