Drug Interaction Report

GENERALLY AVOID: Coadministration with potent CYP450 inducers may significantly reduce the systemic exposure to roflumilast and its pharmacologically active N-oxide metabolite, the former of which is metabolized by CYP450 1A2 and 3A4, and the latter of which is metabolized by CYP450 2C19 and 3A4. In 15 healthy volunteers, administration of a single 500 mcg oral dose of roflumilast in combination with the potent CYP450 3A4 inducer rifampin (600 mg once daily for 11 days) resulted in a 68% reduction of roflumilast peak plasma concentration (Cmax) and 80% reduction of systemic exposure (AUC) compared to administration of roflumilast alone. In addition, rifampin increased the Cmax of roflumilast N-oxide by 30% and decreased its AUC and half-life by 56% and 2.5-fold (from 24 to 9.9 hours), respectively. Total phosphodiesterase 4 inhibitory activity (i.e., combined effect of both roflumilast and roflumilast N-oxide) decreased by 58% in association with these changes.

MANAGEMENT: Due to the potential for reduced therapeutic effectiveness of roflumilast, concomitant use with potent CYP450 enzyme inducers such as carbamazepine, phenobarbital, phenytoin, rifampin, and St. John's wort is not recommended.

Food intake does not affect the total exposure to roflumilast and its pharmacologically active N-oxide metabolite, but delays the time to maximum concentration (Tmax) of roflumilast by one hour and reduces its peak plasma concentration (Cmax) by approximately 40%. The Tmax and Cmax of
roflumilast N-oxide are unaffected. Roflumilast may be taken with or without food.