Drug Interactions between mifepristone and MKO Melt Dose Pack

MONITOR CLOSELY: Coadministration of ketamine with other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death. In addition, opioid analgesics, barbiturates, and benzodiazepines may prolong the time to complete recovery from anesthesia.

MANAGEMENT: During concomitant use of ketamine with other CNS depressants, including alcohol, close monitoring of neurologic status and respiratory parameters, including respiratory rate and pulse oximetry, is recommended. Dosage adjustments should be considered according to the patient's clinical situation. Ambulatory patients should be counseled to avoid hazardous activities requiring mental alertness and motor coordination until they know how these agents affect them, and to notify their physician if they experience excessive or prolonged CNS effects that interfere with their normal activities.

CONTRAINDICATED: Coadministration with mifepristone may significantly increase the plasma concentrations of drugs that are primarily metabolized by the CYP450 3A4 isoenzyme. The mechanism is decreased clearance due to inhibition of CYP450 3A4 activity by mifepristone. When a single 80 mg dose of simvastatin, a sensitive CYP450 3A4 substrate, was administered following pretreatment with mifepristone 1200 mg once daily for 10 days, simvastatin peak plasma concentration (Cmax) and systemic exposure (AUC) increased by approximately 7- and 10-fold, respectively. Likewise, the Cmax and AUC of simvastatin acid, the pharmacologically active metabolite, increased by approximately 18- and 16-fold, respectively.

MANAGEMENT: When mifepristone is used daily to control hyperglycemia secondary to hypercortisolism in patients with endogenous Cushing's syndrome, concomitant use of CYP450 3A4 substrates with narrow therapeutic ranges and high first-pass effect is considered contraindicated. These drugs include lovastatin, simvastatin, cyclosporine, ergot derivatives, fentanyl, oral midazolam, triazolam, pimozide, quinidine, sildenafil, sirolimus, and tacrolimus. The contraindication does not apply when mifepristone is used on a limited basis to terminate a pregnancy, but caution and close monitoring are advisable. 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).

GENERALLY AVOID: Mifepristone may prolong the QTc interval in a dose-related manner. 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. Mifepristone and its metabolites have been found to inhibit the hERG-encoded cardiac potassium channels responsible for the rapid delayed rectifier K+ (IKr) repolarizing current. However, there is little or no experience with high exposure, concomitant dosing with other QT-prolonging drugs, or potassium channel variants resulting in a long QT interval. 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). Since mifepristone can commonly cause hypokalemia during prolonged use, this should also be considered during coadministration with other QT-prolonging drugs. In a study of patients with Cushing's syndrome, hypokalemia was observed in 44% of subjects treated with mifepristone. The hypokalemia responded to treatment with potassium supplementation and/or mineralocorticoid antagonist therapy (e.g., spironolactone or eplerenone).

MANAGEMENT: When mifepristone is used daily to control hyperglycemia secondary to hypercortisolism in patients with endogenous Cushing's syndrome, coadministration with other drugs that can prolong the QT interval should generally be avoided. Caution is recommended if no alternatives exist and concomitant use is required. Serum potassium should be assessed prior to starting mifepristone and 1 to 2 weeks following initiation of therapy or an increase in dosage, and periodically as needed. Hypokalemia must be corrected prior to initiation of mifepristone. Patients should be advised to seek medical attention if they experience potential signs and symptoms of hypokalemia such as fatigue, weakness, myalgia, muscle cramps, numbness, tingling, abdominal pain, constipation, palpitation, and irregular heart rhythm. 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: Based on in vitro inhibition data, coadministration with mifepristone may increase the plasma concentrations of drugs that are substrates of the CYP450 3A4 isoenzyme. The mechanism is decreased clearance due to inhibition of CYP450 3A4 activity by mifepristone.

MANAGEMENT: Caution is advised if mifepristone must be used concomitantly with medications that undergo metabolism by CYP450 3A4, particularly those with a narrow therapeutic range. Dosage adjustments as well as clinical and laboratory monitoring may be appropriate for some drugs whenever mifepristone is added to or withdrawn from therapy. 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).