Drug Interactions between conjugated estrogens / medroxyprogesterone and rufinamide

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response to medroxyprogesterone should be monitored more closely whenever a CYP450 3A4 inducer is added to or withdrawn from therapy, and the dosage adjusted as necessary.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.

MONITOR: Rufinamide may modestly or moderately decrease the plasma concentrations and therapeutic effects of drugs that are CYP450 3A4 substrates. The mechanism is enhanced metabolism by CYP450 3A4 enzyme induction. Enzyme induction is more pronounced with larger doses of rufinamide. After treatment with rufinamide 400 mg twice daily for 11 days, the clearance of triazolam was increased by 55% and the exposure was decreased by 36%.

MANAGEMENT: During concomitant treatment with rufinamide and drugs that are CYP450 3A4 substrates, it is recommended that patients should be monitored for 2 weeks when rufinamide is added to or withdrawn from therapy, or after increases of the dose. Dose adjustments of the coadministered drug may be required if an interaction is suspected. The manufacturer also recommends that monitoring should be considered during concomitant use of drugs with a narrow therapeutic index, including digoxin and warfarin.