Gastrointestinal Tolerability of Delayed-Release Dimethyl Fumarate in a Multicenter, Open-Label Study of Patients with Relapsing Forms of Multiple Sclerosis (MANAGE)

Abstract

Background: In phase 3 trials, delayed-release dimethyl fumarate (DMF; also known as gastroresistant DMF) demonstrated efficacy in relapsing-remitting multiple sclerosis (MS). Gastrointestinal (GI) events were associated with DMF treatment. The single-arm, open-label MANAGE study examined the incidence, severity, duration, and management of GI events in adults with relapsing MS initiating DMF treatment in clinical practice in the United States shortly after marketing approval. Patients and Methods: Patients (N = 233) took DMF for up to 12 weeks and recorded information regarding GI events using an eDiary and numerical rating scales. Results: Overall, 54.1% of patients used symptomatic therapy and had GI symptoms. The incidence of GI events was highest in the first month of treatment. The duration of GI events varied by event type, and severity was generally mild to moderate. Decreased severity was seen in patients treated with antacids, bismuth subsalicylate, acid-secretion blockers, antidiarrheals, and antiemetics. Less than 10% of patients were using symptomatic therapy for GI events by week 12 of DMF treatment. A modest reduction in severe GI events was observed in patients who regularly took DMF with food compared with patients who did not. The incidence of GI-related events was comparable in patients with or without a history of GI abnormalities and in patients who did or did not use alcohol or tobacco. Conclusions: Gastrointestinal events associated with DMF are generally transient, mild to moderate in severity, and manageable. Symptomatic therapy and dosing with food may mitigate these events.

Dimethyl Fumarate

“…7,8 During treatment with DMF in the clinical trial and real-world settings, patients commonly experienced transient mildto-moderate flushing and gastrointestinal (GI) AEs, particularly nausea, vomiting, abdominal pain, and diarrhea, especially in the first month of therapy. [7][8][9][10] These AEs associated with DMF can be particularly bothersome for some patients, with the potential to compromise patient acceptance of and adherence to treatment.…”

“…Delayed-release dimethyl fumarate has a wellcharacterized GI AE profile in the treatment of RRMS based on its use in DEFINE 8 9 In both settings, DMF treatment-emergent GI AEs were generally mild or moderate in severity, occurred most frequently in the first month of treatment before decreasing thereafter, had a variable duration, and were manageable with standard medical interventions. 9,10 In DEFINE and CONFIRM, the mean duration of exposure to study treatment was 77 weeks in both treatment groups, and a comparable proportion of patients in the DMF (70%) and placebo (65%) groups completed 2 years of the study.…”

“…9,10 In DEFINE and CONFIRM, the mean duration of exposure to study treatment was 77 weeks in both treatment groups, and a comparable proportion of patients in the DMF (70%) and placebo (65%) groups completed 2 years of the study. 10 Except during the first month of treatment, the incidence of GI AEs was low for the duration of the study period.…”

“…More than half (54%) of the patients who reported GI AEs used symptomatic therapy, and these patients tended to have a higher incidence of and more severe GI AEs than nonusers of symptomatic therapy. 9 Patients in MANAGE tended to use the same symptomatic therapies as those used in DEFINE and CON-FIRM. 9,10 Except for constipation (duration, 16 hours), all GI AEs had a duration of less than 10 hours.…”

“…9,10 Except for constipation (duration, 16 hours), all GI AEs had a duration of less than 10 hours. 9 The duration of GI AEs was similar among users and nonusers of symptomatic therapy.…”