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.

GENERALLY AVOID: Food does not significantly affect the oral bioavailability of diroximel fumarate. Administration of diroximel fumarate with a high-fat, high-calorie (900 to 1000 calories; 50% from fat) meal did not affect the systemic exposure (AUC) of its active metabolite, monomethyl fumarate (MMF), but decreased its peak plasma concentration (Cmax) by 44% and prolonged the time to reach peak concentration (Tmax) from 2.5 to 7.0 hours relative to administration in the fasted state. In comparison, administration of diroximel fumarate with low-fat, low-calorie (350 to 400 calories; 10 to 15 g fat) and medium-fat, medium-calorie (650 to 700 calories; 25 to 30 g fat) meals decreased the MMF Cmax by approximately 12% and 25%, respectively, while also leaving the AUC unaffected.

GENERALLY AVOID: Coadministration of diroximel fumarate with ethanol may reduce the plasma concentrations of monomethyl fumarate (MMF). The mechanism has not been reported. Following coadministration with 240 mL of 5% v/v and 40% v/v ethanol, the mean Cmax of MMF was reduced by 9% and 21%, respectively, relative to coadministration with water. The AUC of MMF was not significantly altered, indicating that ethanol did not induce dose dumping.

MANAGEMENT: Diroximel fumarate may be taken with or without food; however, high-fat, high-calorie meals or snacks should be avoided. The manufacturer recommends meals or snacks containing no more than 700 calories and no more than 30 grams of fat. Taking diroximel fumarate with food may improve tolerability for patients experiencing flushing or gastrointestinal adverse reactions. The manufacturer also recommends avoiding concomitant use of diroximel fumarate with ethanol.

ADJUST DOSING INTERVAL: Food enhances the oral bioavailability of umbralisib. When a single oral dose of umbralisib was administered with a high-fat, high-calorie meal (approximately 917 calories; 171 calories from protein, 232 calories from carbohydrate, 502 calories from fat) in healthy subjects, umbralisib peak plasma concentration (Cmax) and systemic exposure (AUC) increased by 115% and 61%, respectively, compared to administration under fasted conditions.

MANAGEMENT: Umbralisib should be administered with food at approximately the same time each day.