ORLANDO—The flushing frequently reported in conjunction with oral dimethyl fumarate therapy for relapsing forms of multiple sclerosis (MS) is greatly reduced by aspirin pretreatment, J. Theodore Phillips, MD, PhD, reported at the Fifth Cooperative Meeting of the Consortium of MS Centers and the Americas Committee for Treatment and Research in MS.
In contrast, slowed titration of dimethyl fumarate does not diminish the gastrointestinal adverse effects, which are common during the first two months of therapy, noted Dr. Phillips, Research Investigator at the MS Research Program, Baylor Institute for Immunology Research in Dallas.
Dr. Phillips was part of a consensus panel that presented recommendations for maximizing the tolerability of dimethyl fumarate, which was approved earlier this year as the third oral agent for the treatment of MS.
In an interview, Dr. Phillips said that the recommendations are largely based on expert opinion rather than on rigorous, evidence-based guidelines. After the pivotal phase III DEFINE and CONFIRM clinical trials were completed, he and four other study leaders decided to ask the investigators who had enrolled at least 10 patients in the trials how they had managed flushing and gastrointestinal upset problems. The flushing and gastrointestinal side effects were reported by 36% and 42%, respectively, of study patients randomized to the drug. The incidence decreased after the first month. These side effects were generally rated by investigators as mild to moderate in nature. Flushing resulted in study dropout of 2.5% of patients, and 4.3% discontinued because of gastrointestinal adverse events.
Thirty of the 84 invited clinical investigators completed the questionnaire. Investigators at Biogen Idec conducted their own randomized, double-blind, phase IIIb study in 172 healthy volunteers, the results of which have been incorporated into the panel’s recommendations. Participants in the eight-week trial were randomized to one of four treatment arms: dimethyl fumarate titrated in standard fashion for one week plus 325 mg of non–enteric-coated aspirin taken 30 minutes beforehand during weeks 1 to 4, replaced by aspirin placebo in weeks 5 to 8; dimethyl fumarate plus aspirin placebo during weeks 1 to 4; dimethyl fumarate slow-titrated during the course of three weeks; and double placebo.
Roughly 80% of subjects who received dimethyl fumarate without aspirin experienced flushing events self-assessed as mild to moderate. Although participants were taking both dimethyl fumarate and aspirin, their flushing frequency and severity were similar to those of participants receiving double placebo. Slow titration of dimethyl fumarate had no impact on gastrointestinal symptoms or flushing frequency or severity.
The panel’s recommendations for managing nausea or vomiting or abdominal pain were to advise taking the drug with food and consider prescribing a proton pump inhibitor or H2 receptor antagonist. Metoclopramide or domperidone is another recommended option for those with nausea or vomiting. For patients who experience medication-related diarrhea, the panel advised loperamide or other standard antidiarrheal agents.
“Vasocutaneous flushing and gastrointestinal upset in association with dosing of [dimethyl fumarate] could for obvious reasons affect a person’s enthusiasm for going on,” Dr. Phillips commented. “The main thing is for the physician to set expectations by acknowledging up front these issues as part of the risk–benefit discussion prior to initiating the drug. Tell the patient that if those side effects were to happen, we’ve got game plans to deal with them.”
—Bruce Jancin
IMNG Medical News