Drug Interactions between letrozole / ribociclib and roflumilast topical

MONITOR: Coadministration with ribociclib may increase the plasma concentrations and pharmacologic effects of drugs that are substrates of CYP450 3A4. The proposed mechanism is decreased clearance due to ribociclib-mediated inhibition of CYP450 3A4 metabolism. In healthy study subjects, administration of midazolam, a sensitive CYP450 3A4 substrate, with multiple 400 mg daily doses of ribociclib increased the midazolam peak plasma concentration (Cmax) and systemic exposure (AUC) by 2.1-fold and 3.8-fold, respectively, compared to midazolam administered alone. When given at a clinically relevant dose of 600 mg daily, ribociclib is predicted to increase midazolam Cmax and AUC by 2.4-fold and 5.2-fold, respectively.

MANAGEMENT: Caution is advised when ribociclib is used concomitantly with drugs that undergo metabolism by CYP450 3A4, particularly those with a narrow therapeutic range. Dosage adjustments as well as clinical and laboratory monitoring may be appropriate for some drugs whenever ribociclib is added to or withdrawn from therapy.

MONITOR: Coadministration with CYP450 3A4 inhibitors or dual CYP450 3A4/1A2 inhibitors may increase the systemic exposure (AUC) to roflumilast following topical administration. According to the prescribing information, N-oxidation of roflumilast by CYP450 3A4 and 1A2 is a major step in the metabolism of the drug. In vitro, roflumilast is 3 times more potent than its N-oxide metabolite at inhibition of the phosphodiesterase 4 (PDE4) enzyme, but on average, the roflumilast N-oxide AUC is approximately 8-fold greater than the parent drug AUC following IV or topical administration and about 10-fold greater following oral administration. In a pharmacokinetic study of 18 adults and 6 adolescents with plaque psoriasis and a mean body surface area involvement of 26.8% (adults) and 13.0% (adolescents), the mean AUC of roflumilast and roflumilast N-oxide following application of 3 to 6.5 g once daily for 15 days was 72.7 and 628 h*ng/mL, respectively, for adults and 25.1 and 140 h*ng/mL, respectively, for adolescents. Data regarding concomitant use of CYP450 3A4 or dual CYP450 3A4/1A2 inhibitors have been reported for oral roflumilast (500 mcg single dose). When coadministered with the potent CYP450 3A4 inhibitor ketoconazole (200 mg twice daily for 13 days), roflumilast peak plasma concentration (Cmax) and AUC increased by 23% and 99%, respectively, while roflumilast N-oxide Cmax decreased by 38% and AUC increased by 3%. When coadministered with erythromycin (500 mg three times daily for 13 days), a moderate CYP450 3A4 inhibitor, roflumilast Cmax and AUC increased by 40% and 70%, respectively, while roflumilast N-oxide Cmax decreased by 34% and AUC increased by 4%. When coadministered with the dual CYP450 3A4/1A2 inhibitors fluvoxamine (50 mg daily for 14 days) or cimetidine (400 mg twice daily for 7 days), roflumilast Cmax increased by 12% and 46% and its AUC increased by 156% and 85%, respectively, while the roflumilast N-oxide Cmax decreased by 210% and 4% and its AUC increased by 52% and 27%, respectively.

MANAGEMENT: Treatment with topical roflumilast should be re-evaluated if an interaction is suspected and persistent intolerability occurs. Patients should be advised to contact their physician if they experience increased frequency and/or severity of side effects such as diarrhea, headache, insomnia, nausea, upper respiratory tract infection, or urinary tract infection.