Drug Interaction Report

MONITOR: Coadministration of mifepristone with a drug that is both a substrate as well as inhibitor of CYP450 3A4 may result in increased plasma concentrations of both drugs. Mifepristone itself is also a substrate and moderate inhibitor of CYP450 3A4. Theoretically, competitive and/or noncompetitive metabolic inhibition may occur. Because mifepristone is associated with dose-dependent prolongation of the QT interval, increased levels may potentiate the risk of ventricular arrhythmias such as torsade de pointes and sudden death.

MANAGEMENT: Due to its potent antiglucocorticoid effects and potential to cause dose-related prolongation of the QT interval, caution is advised if mifepristone is prescribed in combination with a CYP450 3A4 inhibitor, particularly when used daily to control hyperglycemia secondary to hypercortisolism in patients with endogenous Cushing's syndrome. When the coadministered drug is also a CYP450 3A4 substrate, clinical and/or laboratory monitoring may be appropriate following the addition or withdrawal of mifepristone, and the dosage adjusted as necessary. Because mifepristone is eliminated slowly from the body, drug interactions may be observed for a prolonged period following discontinuation (approximately 2 to 3 weeks if mifepristone had been administered chronically to steady state).

ADJUST DOSING INTERVAL: Food may significantly increase the plasma concentrations of mifepristone.

GENERALLY AVOID: Grapefruit juice may increase the plasma concentrations of mifepristone. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruit. Because pharmacokinetic interactions involving grapefruit juice are often subject to a high degree of interpatient variability, the extent to which a given patient may be affected is difficult to predict.

MANAGEMENT: When mifepristone is used daily to control hyperglycemia secondary to hypercortisolism in patients with endogenous Cushing's syndrome, it should be taken with food to achieve consistent plasma drug levels. Patients should be advised to avoid consuming grapefruit or grapefruit juice during treatment with mifepristone, as it may cause increased adverse effects such as headache, dizziness, fatigue, nausea, vomiting, cramping, diarrhea, hypokalemia, adrenal insufficiency, vaginal bleeding, arthralgia, peripheral edema, and hypertension. Because mifepristone is eliminated slowly from the body, the interaction with grapefruit juice may be observed for a prolonged period.