Drug Interaction Report

GENERALLY AVOID: The concomitant use of roflumilast with immunosuppressive agents has not been adequately studied. Roflumilast is a selective phosphodiesterase 4 (PDE4) inhibitor and a nonsteroidal anti-inflammatory agent. In experimental models and in vitro studies, roflumilast has exhibited immunomodulatory effects. Specifically, roflumilast and its active metabolite, roflumilast N-oxide, suppress the release of inflammatory mediators including leukotriene B4, reactive oxygen species, tumor necrosis factor alpha, interferon gamma, and granzyme B. Roflumilast also reduces sputum neutrophils and attenuates influx of neutrophils and eosinophils into the airways.

MANAGEMENT: According to the product labeling for roflumilast in some countries such as Canada and the U.K., concomitant use with immunosuppressive agents such as methotrexate, azathioprine, infliximab, etanercept, and systemic corticosteroids (except when used short-term, e.g., in the treatment of COPD exacerbations) should be avoided if possible. Due to a lack of clinical experience, treatment with roflumilast should not be initiated, or existing treatment should be stopped, in patients receiving immunosuppressive agents and in patients with severe acute infectious diseases, cancers (except basal cell carcinoma), or severe immunological diseases (e.g., HIV infection, multiple sclerosis, lupus erythematosus, progressive multifocal leukoencephalopathy).

MONITOR: Grapefruit juice may increase the plasma concentrations of orally administered drugs that are substrates of the CYP450 3A4 isoenzyme, such as cobimetinib. However, the interaction seems to affect primarily those drugs that undergo significant presystemic metabolism by CYP450 3A4 (i.e., drugs with low oral bioavailability), presumably due to the fact that grapefruit juice inhibits primarily intestinal rather than hepatic CYP450 3A4. Because pharmacokinetic interactions involving grapefruit juice are often subject to a high degree of interpatient variability, the extent to which a given patient may be affected is difficult to predict.

MANAGEMENT: Patients who regularly consume grapefruit or grapefruit juice should be monitored for adverse effects and altered plasma concentrations of cobimetinib. Grapefruit and grapefruit juice should be avoided if an interaction is suspected. Orange juice is not expected to interact with these drugs.

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.