Drug Interaction Report

MONITOR: Coadministration with valdecoxib may increase the plasma concentrations of ethinylestradiol and norethisterone. The mechanism of interaction has not been described, although valdecoxib has been shown to be a weak inhibitor of CYP450 3A4, an isoenzyme of which ethinylestradiol and norethisterone are substrates. According to product labeling, coadministration of valdecoxib (40 mg twice a day) and norethisterone-ethinylestradiol (1 mg-35 mcg oral contraceptive combination) resulted in a 20% and 34% increase, respectively, in the systemic exposure (AUC) of the hormones. The clinical significance of these changes in terms of safety is unknown. However, an increase in ethinylestradiol exposure can increase the incidence of adverse reactions associated with oral contraceptives such as venous thromboembolic complications and certain cancers.

MANAGEMENT: The potential increase in ethinylestradiol concentration should be considered when selecting an oral contraceptive for use with valdecoxib.

MONITOR: Coadministration of ethinyl estradiol may increase the plasma concentrations of drugs that are primarily metabolized by CYP450 1A2. In a study of 30 healthy volunteers administered the CYP450 1A2 substrate tizanidine, the systemic exposure (AUC) of tizanidine was 3.9 times greater in women using an oral contraceptive containing ethinyl estradiol.

MANAGEMENT: Patients should be monitored for increased adverse effects of the CYP450 1A2 substrate during concomitant use with ethinyl estradiol. Product labeling for the specific CYP450 1A2 substrate should be consulted for additional recommendations.

Coadministration with grapefruit juice may increase the bioavailability of oral estrogens. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall induced by certain compounds present in grapefruits. In a small, randomized, crossover study, the administration of ethinyl estradiol with grapefruit juice (compared to herbal tea) increased peak plasma drug concentration (Cmax) by 37% and area under the concentration-time curve (AUC) by 28%. Based on these findings, grapefruit juice is unlikely to affect the overall safety profile of ethinyl estradiol. However, as with other drug interactions involving grapefruit juice, the pharmacokinetic alterations are subject to a high degree of interpatient variability. Also, the effect on other estrogens has not been studied.

The central nervous system effects and blood levels of ethanol may be increased in patients taking oral contraceptives, although data are lacking and reports are contradictory. The mechanism may be due to enzyme inhibition. Consider counseling women about this interaction which is unpredictable.