Drug Interaction Report

CONTRAINDICATED: Mifepristone is a potent antiglucocorticoid and may antagonize the effects of corticosteroids. In animals, mifepristone at dosages of 10 to 25 mg/kg inhibited the action of dexamethasone. In human, the antiglucocorticoid action occurred at dosages of 4.5 mg/kg or greater, as indicated by a compensatory elevation of adrenocorticotropic hormone (ACTH) and cortisol. The efficacy of chronic corticosteroid therapy, including inhaled corticosteroids, may be reduced for 3 to 4 days after a single dose of mifepristone. Pharmacokinetically, mifepristone may increase the plasma concentrations of corticosteroids by inhibiting their metabolism via CYP450 3A4. However, the clinical impact has not been studied. Dexamethasone, specifically, may also decrease the blood levels of mifepristone by inducing its metabolism via CYP450 3A4.

MANAGEMENT: The use of mifepristone is considered contraindicated in patients on long-term corticosteroid therapy. When intended for daily use to control hyperglycemia secondary to hypercortisolism in patients with endogenous Cushing's syndrome, mifepristone is also contraindicated in those patients who require systemic corticosteroids for serious medical conditions or illnesses, such as immunosuppression after organ transplantation. 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.