Drug Interactions between Endodan and mifepristone

MONITOR CLOSELY: Coadministration with inhibitors of CYP450 3A4 may increase the plasma concentrations of oxycodone, which is substantially metabolized by the isoenzyme. Increased oxycodone concentrations could conceivably increase or prolong adverse drug effects and may cause potentially fatal respiratory depression. According to some manufacturers, oxycodone systemic exposure (AUC) was, on average, approximately 2.4-times higher (range 1.5 to 3.4) during coadministration with itraconazole (200 mg orally for 5 days); 1.8 times higher (range 1.3 to 2.3) during coadministration with telithromycin (800 mg orally for 4 days); 3.6 times higher (range 2.7 to 5.6) during coadministration with voriconazole (200 mg twice daily for 4 days); and 1.7 times higher (range 1.1 - 2.1) during coadministration with grapefruit juice (200 mL three times daily for 5 days). Because oxycodone is also partially metabolized by CYP450 2D6, the magnitude of interaction may be even greater with concomitant use of a CYP450 3A4 and a CYP450 2D6 inhibitor, or concomitant use of a drug that is a dual inhibitor of both isoenzymes.

MANAGEMENT: Extreme caution is advised if oxycodone is prescribed with CYP450 3A4 inhibitors, particularly potent and moderate inhibitors (e.g., azole antifungal agents, protease inhibitors, aprepitant, ciprofloxacin, chloramphenicol, clarithromycin, cobicistat, conivaptan, crizotinib, delavirdine, diltiazem, dronedarone, erythromycin, fusidic acid, idelalisib, imatinib, mibefradil, mifepristone, nefazodone, netupitant, quinupristin-dalfopristin, telithromycin, verapamil) or weak inhibitors that also inhibit CYP450 2D6 (e.g., abiraterone, amiodarone, cimetidine, mavorixafor, pazopanib, ranolazine). Some authorities advise that the oxycodone dose may need to be adjusted. A fatal overdose may occur following the initiation of a CYP450 3A4 inhibitor in patients already receiving oxycodone. Patients should be closely monitored for signs and symptoms of sedation, respiratory depression, and hypotension. Following discontinuation of the CYP450 3A4 inhibitor, patients should be monitored for reduced efficacy of oxycodone or development of withdrawal symptoms due to reduced plasma oxycodone levels.

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).