Drug Interaction Report

MONITOR: Coadministration with letermovir may increase the plasma concentrations of drugs that are substrates of CYP450 3A4. In vitro and in vivo studies have shown that both estrogens and progestins are partially metabolized by CYP450 3A4. Studies of letermovir with midazolam, a CYP450 3A4 probe substrate, have shown the net effect of letermovir on the CYP450 3A4 isoenzyme is moderate inhibition. Theoretically, concomitant administration of letermovir with CYP450 3A4 substrates, such as estrogens and progestins, may result in clinically relevant increases in the plasma concentration of the CYP450 3A4 substrate. The interaction between letermovir and ethinyl estradiol and levonorgestrel has been evaluated in clinical drug-drug interaction studies and no clinically significant interaction was found.

MANAGEMENT: Monitor estrogen/progestin therapy for altered pharmacologic response and adjust dosage(s) accordingly whenever letermovir is added to or withdrawn from therapy. When choosing an oral contraceptive, consider choosing an ethinyl estradiol-levonorgestrel product as this combination has been studied with letermovir and no clinically significant interaction has been found.

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.