Drug Interactions between diroximel fumarate and Kisqali Femara Co-Pack

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as well as clinical and laboratory monitoring may be appropriate for some drugs whenever ribociclib is added to or withdrawn from therapy.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 use of monomethyl fumarate (MMF) or its prodrugs, dimethyl fumarate and diroximel fumarate, with other immunosuppressive or myelosuppressive agents may increase the risk of infections. Treatment with MMF or its prodrugs can cause lymphopenia as well as serious and potentially life-threatening opportunistic infections (e.g., progressive multifocal leukoencephalopathy (PML), herpes zoster, herpes simplex, West Nile virus, cytomegalovirus, Candida, Aspergillus, Nocardia, Listeria monocytogenes, Mycobacterium tuberculosis), and the risk may be theoretically potentiated in the presence of other agents that also suppress the immune system or bone marrow function. In multiple sclerosis studies, the concomitant treatment of relapses with a short course of intravenous corticosteroids was not associated with a clinically relevant increase of infection.

MANAGEMENT: The safety and efficacy of monomethyl fumarate (MMF), dimethyl fumarate, or diroximel fumarate in combination with other immunosuppressive or myelosuppressive agents have not been evaluated. Until further information is available, concomitant use should be avoided if possible. Short courses of intravenous corticosteroids may be used in combination with MMF or its prodrugs for the treatment of multiple sclerosis relapses. When switching patients from one immunosuppressive or myelosuppressive agent to another, the half-life and mode of action of each therapy should be considered to avoid unintended additive effects on the immune system while simultaneously reducing the risk of reactivation of multiple sclerosis.