Drug Interactions between fluticasone / salmeterol and mifepristone

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).

MONITOR: Beta-2 adrenergic agonists can cause dose-related prolongation of the QT interval and potassium loss. Theoretically, coadministration with other agents that can prolong the QT interval may result in additive effects and increased risk of ventricular arrhythmias including torsade de pointes and sudden death. In general, the risk of an individual agent or a combination of agents causing ventricular arrhythmia in association with QT prolongation is largely unpredictable but may be increased by certain underlying risk factors such as congenital long QT syndrome, cardiac disease, and electrolyte disturbances (e.g., hypokalemia, hypomagnesemia). In addition, the extent of drug-induced QT prolongation is dependent on the particular drug(s) involved and dosage(s) of the drug(s). Clinically significant prolongation of QT interval and hypokalemia occur infrequently when beta-2 agonists are inhaled at normally recommended dosages. However, these effects may be more common when the drugs are administered systemically or when recommended dosages are exceeded.

MANAGEMENT: Caution is recommended if beta-2 agonists are used in combination with other drugs that can prolong the QT interval. Patients should be advised to seek prompt medical attention if they experience symptoms that could indicate the occurrence of torsade de pointes such as dizziness, lightheadedness, fainting, palpitation, irregular heart rhythm, shortness of breath, or syncope.

Although they are often combined in clinical practice, the concomitant use of beta-2 adrenergic agonists and corticosteroids may result in additive hypokalemic effects. Since beta-2 agonists can sometimes cause QT interval prolongation, the development of hypokalemia may potentiate the risk of ventricular arrhythmias including torsade de pointes. However, clinical data are limited, and the potential significance is unknown. Patients who are receiving systemic or nebulized formulations of beta-2 agonists, high dosages of inhaled beta-2 agonists, or systemic corticosteroid therapy may be at a greater risk of developing hypokalemia.