Drug Interaction Report

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.

GENERALLY AVOID: Coadministration of imatinib with strong CYP450 3A4 inhibitors such as grapefruit juice, may significantly increase the plasma concentrations of imatinib, a known substrate of CYP450 3A4. The proposed mechanism is inhibition of CYP450 3A4-mediated metabolism of imatinib by certain compounds present in grapefruits. Because grapefruit juice inhibits primarily intestinal rather than hepatic CYP450 3A4, the magnitude of interaction is greatest for those drugs that undergo significant presystemic metabolism by CYP450 3A4 (i.e., drugs with low oral bioavailability). In general, the effect of grapefruit juice is concentration-, dose- and preparation-dependent, and can vary widely among brands. Certain preparations of grapefruit juice (e.g., high dose, double strength) have sometimes demonstrated potent inhibition of CYP450 3A4, while other preparations (e.g., low dose, single strength) have typically demonstrated moderate inhibition. Pharmacokinetic interactions involving grapefruit juice are also subject to a high degree of interpatient variability, thus the extent to which a given patient may be affected is difficult to predict. In a single-dose study, coadministration of imatinib with ketoconazole (a strong CYP450 3A4 inhibitor) increased imatinib peak plasma concentration (Cmax) and systemic exposure (AUC) by 26% and 40%, respectively.

MANAGEMENT: Patients treated with imatinib should preferably avoid the consumption of grapefruit or grapefruit juice. If coadministration is unavoidable, monitor for prolonged and/or increased pharmacologic effects of imatinib, including edema, hematologic toxicity and immunosuppression.