Drug Interaction Report

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.

ADJUST DOSING INTERVAL: Food increases the systemic exposure of givinostat. An open-label, randomized, crossover, single dose food effect study conducted in 12 healthy males used givinostat liquid filled capsules. Subjects received a single oral dose of givinostat (100 mg) in the fasting state or after a high-fat standard meal, with a washout period of at least 1 week in between. The high-fat standard meal resulted in an increase in systemic exposure (AUC) and maximum plasma concentration (Cmax) of about 40% and 23%, respectively, when compared to the fasted state. Additionally, the time to maximum concentration (Tmax) was delayed slightly from 2 to 3 hours.

MANAGEMENT: Givinostat should be administered with food to increase its absorption. In the case of the oral suspension, this can also help mask its bitter taste.

Food does not significantly affect the oral bioavailability of dimethyl fumarate. Administration of dimethyl fumarate with a high-fat, high-calorie meal did not affect the systemic exposure (AUC) to its active metabolite, monomethyl fumarate (MMF), but decreased its peak plasma concentration (Cmax) by 40% and prolonged the time to reach peak concentration (Tmax) from 2.0 hours to 5.5 hours. In the study, the incidence of flushing was reduced by approximately 25% in the fed state. Dimethyl fumarate may be taken with or without food; however, taking it with food may help reduce flushing.