Drug Interaction Report

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as well as clinical and laboratory monitoring may be appropriate for some drugs whenever ribociclib is added to or withdrawn from therapy.

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).

GENERALLY AVOID: Pomegranates and grapefruit may increase the systemic exposure to ribociclib. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in these fruits. Increased exposure to ribociclib may increase the risk of adverse effects such as infections, neutropenia, leukopenia, anemia, thrombocytopenia, anorexia, nausea, vomiting, diarrhea, stomatitis, alopecia, fatigue, headache, and abnormal liver function may be increased.

MANAGEMENT: Patients receiving ribociclib should avoid consumption of pomegranates or pomegranate juice and grapefruit or grapefruit juice during treatment.

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.