Drug Interactions between codeine / phenylephrine / promethazine and mifepristone

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).

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MONITOR: Central nervous system- and/or respiratory-depressant effects may be additively or synergistically increased in patients taking multiple drugs that cause these effects, especially in elderly or debilitated patients. Sedation and impairment of attention, judgment, thinking, and psychomotor skills may increase.

MANAGEMENT: During concomitant use of these drugs, patients should be monitored for potentially excessive or prolonged CNS and respiratory depression. Cautious dosage titration may be required, particularly at treatment initiation. 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.

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