Drug Interactions between famotidine / ibuprofen and mifepristone

MONITOR: Nonsteroidal anti-inflammatory drugs (NSAIDs) may interfere with the abortifacient effects of mifepristone given in sequential combination with a prostaglandin analog such as misoprostol. By inhibiting prostaglandin synthesis and release, NSAIDs have been associated with an increased incidence of dystocia and delayed parturition in pregnant animals when administered in late pregnancy. However, their impact on medical abortion has not been adequately studied. Limited evidence suggests that coadministration of NSAIDs on the day of prostaglandin administration does not adversely influence the effects of mifepristone or the prostaglandin on cervical ripening or uterine contractility and does not reduce the clinical efficacy of medical termination of pregnancy.

MANAGEMENT: Until more information is available, it may be advisable to avoid the use of NSAIDs in women receiving mifepristone and a prostaglandin analog for the medical termination of pregnancy.

MONITOR: Coadministration with mifepristone may increase the plasma concentrations of NSAIDs that are substrates of the CYP450 2C8 and/or 2C9 enzymes. Mifepristone has been reported to be a clinically significant inhibitor of CYP450 2C8/2C9 when given at dosages used to control hyperglycemia secondary to hypercortisolism in patients with Cushing's syndrome. When a single 40 mg dose of fluvastatin, a typical CYP450 2C8/2C9 substrate, was administered with mifepristone 1200 mg once daily for 7 days in healthy subjects, mean fluvastatin peak plasma concentration (Cmax) and systemic exposure (AUC) increased by nearly 1.8- and 3.6-fold, respectively, compared to administration of fluvastatin alone.

MANAGEMENT: Caution is advised when mifepristone is prescribed concomitantly with NSAIDs that are substrates of CYP450 2C8 and/or 2C9 such as celecoxib, diclofenac, flurbiprofen, ibuprofen, indomethacin, lornoxicam, mefenamic acid, meloxicam, naproxen, piroxicam, and tenoxicam. The lowest dosage of the NSAID should be used whenever possible. 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: Famotidine may cause QTc prolongation. 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. According to the manufacturer, prolongation of the QT interval has been reported very rarely in patients with impaired renal function whose dose/dosing interval of famotidine may not have been adjusted appropriately. In general, the risk of an individual agent or a combination of these 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).

MANAGEMENT: Caution and clinical monitoring are recommended if famotidine is 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.

H2 antagonists may alter the pharmacokinetic disposition of some nonsteroidal anti-inflammatory drugs (NSAIDs), resulting in increased or decreased plasma concentrations. Data have been varied, even for the same NSAID. The mechanism may involve inhibition of metabolism, changes in gastric pH resulting in altered absorption, and/or reduced urinary elimination of the affected NSAIDs. Statistically significant changes have been small and of limited clinical significance when interactions have been observed.