Drug Interactions between clonidine / ketorolac / ropivacaine 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).

Coadministration with inhibitors of CYP450 3A4 may modestly increase the plasma concentrations of ropivacaine. Although ropivacaine is primarily metabolized by CYP450 1A2, it has been shown to undergo some metabolism via CYP450 3A4. In eight healthy volunteers, pretreatment with the 3A4 inhibitor erythromycin (500 mg three times a day for 6 days) was found to have only minor effects on the pharmacokinetics of a single dose of ropivacaine (0.6 mg/kg IV over 30 minutes) compared to placebo. However, in combination with the potent 1A2 inhibitor fluvoxamine (100 mg daily), erythromycin further increased the area under the plasma concentration-time curve (AUC) of ropivacaine by 50% compared to fluvoxamine alone, which increased the ropivacaine AUC by 3.7-fold. Fluvoxamine alone prolonged the elimination half-life of ropivacaine from 2.3 to 7.4 hours, while the addition of erythromycin further increased the half-life to 11.9 hours. In another study, pretreatment with the potent 3A4 inhibitor ketoconazole (100 mg twice daily for 2 days) decreased the mean total plasma clearance of ropivacaine (40 mg IV over 20 minutes) by just 15% in 12 healthy volunteers. Thus, it appears that CYP450 3A4 inhibitors may only have a significant effect on the pharmacokinetics of ropivacaine in the presence of a CYP450 1A2 inhibitor such as fluvoxamine, ciprofloxacin, or mexiletine.