Drug Interaction Report

ADDITIONAL CONTRACEPTION RECOMMENDED: Coadministration with mycophenolic acid may decrease the plasma concentrations and, theoretically, the efficacy of contraceptive hormones. The mechanism of interaction has not been established. In 18 women with psoriasis who were studied over 3 consecutive menstrual cycles, administration of combined oral contraceptives containing ethinyl estradiol (0.02 to 0.04 mg) and levonorgestrel (0.05 to 0.20 mg), desogestrel (0.15 mg), or gestodene (0.05 to 0.10 mg) during treatment with mycophenolate mofetil 1 gram twice daily resulted in a 15% reduction in mean levonorgestrel systemic exposure (AUC). No significant changes in mean AUC for ethinyl estradiol and 3-keto desogestrel were observed. However, there was a large interpatient variability in the data, especially for ethinyl estradiol. Mean serum levels of LH, FSH, and progesterone were not significantly affected in the study.

MANAGEMENT: Although clinical significance of the interaction is unknown, caution is advised when mycophenolic acid is prescribed in combination with hormonal contraceptives, including all oral, injectable, transdermal, vaginal, and implantable forms. Because use of mycophenolic acid is associated with an increased risk of pregnancy loss in the first trimester and congenital malformations, it is particularly important that female patients not become pregnant during treatment. An acceptable barrier method (e.g., diaphragm with spermicide, cervical cap with spermicide, contraceptive sponge, male condom, female condom) should be used in addition to the hormonal contraceptive of choice during the entire duration of mycophenolic acid therapy and for 6 weeks after discontinuation. Input from a gynecologist or similar expert on adequate contraception should be sought as needed. Intrauterine systems are unlikely to be significantly affected because of their local action.

ADJUST DOSING INTERVAL: Administration of enteric coated mycophenolic acid with meals may alter its pharmacokinetics relative to administration in the fasting state. When mycophenolic acid 720 mg was administered with a high-fat meal, there was a 33% decrease in the peak plasma concentration (Cmax); a 3.5-hour increase in delay time for the rise of plasma mycophenolic acid; and a 5-hour delay in the time to reach peak plasma concentration (Tmax). However, no effect was observed on the systemic exposure of mycophenolic acid.

MANAGEMENT: To avoid variability in drug absorption between doses, enteric coated formulations of mycophenolic acid should be taken on an empty stomach, one hour before or two hours after food intake. The tablets should be swallowed whole and not crushed, chewed or divided in order to maintain the integrity of the enteric coating.

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.