Drug Interactions between armodafinil and conjugated estrogens / medroxyprogesterone

MONITOR: Coadministration with inducers of CYP450 3A4 may decrease the plasma concentrations and pharmacologic effects of medroxyprogesterone, which is primarily metabolized by the isoenzyme. Aminoglutethimide, a CYP450 3A4 inducer, has been shown to significantly decrease the serum levels of medroxyprogesterone by 50% or more when administered at 250 mg two to four times daily to women with breast cancer receiving high-dose medroxyprogesterone orally. The decrease was accompanied by an increase in serum cortisol level, which suggests diminished adrenal suppressive effect of medroxyprogesterone. The interaction has not been studied with depot formulations of medroxyprogesterone. Because the clearance of medroxyprogesterone is approximately equal to the rate of hepatic blood flow, drugs that induce CYP450 3A4 are not expected to significantly affect the pharmacokinetics of medroxyprogesterone administered parenterally. In one study, no interaction was reported when medroxyprogesterone was administered intravenously with aminoglutethimide.

MANAGEMENT: Pharmacologic response to medroxyprogesterone should be monitored more closely whenever a CYP450 3A4 inducer is added to or withdrawn from therapy, and the dosage adjusted as necessary. When administered as the depot formulation for contraception, no dosage adjustment for medroxyprogesterone is currently recommended during coadministration with CYP450 3A4 inducers. However, consideration may be given to decreasing the dosing interval (e.g., from one injection every 12 weeks to every 10 weeks) if an interaction is suspected.

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.