Drug Interactions between ethinyl estradiol / norelgestromin and roflumilast topical

MONITOR: Coadministration with oral contraceptives containing ethinyl estradiol and gestodene may increase the systemic exposure (AUC) to roflumilast following topical administration. The proposed mechanism is inhibition of CYP450 3A4 and 1A2 by the oral contraceptive. 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. In 20 healthy adult volunteers, administration of a single 500 mcg oral dose of roflumilast following repeated doses of a fixed combination oral contraceptive containing 0.075 mg gestodene and 0.03 mg ethinyl estradiol to steady state resulted in a 38% increase in roflumilast peak plasma concentration (Cmax) and a 51% increase in AUC. The Cmax of roflumilast N-oxide was reduced by 12%, while AUC increased by 14%.

MANAGEMENT: Caution is advised when topical roflumilast is used in combination with oral contraceptives containing ethinyl estradiol and gestodene. Treatment with 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.