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DALLAS -- Large proportions of patients starting on dimethyl fumarate (Tecfidera) for multiple sclerosis appear to need additional medications to manage the drug's gastrointestinal and other adverse effects, and a substantial minority are ultimately unable to tolerate the drug, multiple studies reported here found.
These findings were confirmed in the manufacturer's own studies -- for example, more than half of patients in an open-label study took over-the-counter medications to control stomach upset and diarrhea -- although symptoms eventually abated in those who stayed on the drug beyond 2 months.
On the other hand, one-quarter of patients switching to dimethyl fumarate from another MS medication in an independent study had stopped the drug within 3 months.
These and other reports on dimethyl fumarate's safety were presented during a poster session at the joint meeting of the Consortium of Multiple Sclerosis Centers and the Americas Committee for Treatment and Research in Multiple Sclerosis (CMSC-ACTRIMS).
The drug's safety has always been a concern. Serious adverse events have been rare -- no cases of progressive multifocal leukoencephalopathy (PML) have been reported with dimethyl fumarate in MS patients, although a handful of cases have been seen with a close chemical cousin marketed for many years in Europe for psoriasis.
But more mundane side effects such as flushing, gastrointestinal complaints, and itching were common in the MS trials and, according to the studies reported at CMSC-ACTRIMS, in real-world experience as well.
Groups at three major medical centers -- in Los Angeles, the Boston area, and here in Dallas -- each reported their experiences in patients starting on dimethyl fumarate either de novo or after switching from some other medication.
University of California Los Angeles
, and , reviewed outcomes in 30 patients starting on dimethyl fumarate from April 2013 (immediately after its FDA approval) through January of this year. All patients were switched to the drug because they were failing on other therapies.
Of these, five (17%) stopped the drug, primarily because of its adverse GI effects, the researchers said. One of these patients developed splenomegaly within a week of starting on the agent, which resolved after it was withdrawn.
Of the remaining 25, 12 reported either minimal or no adverse effects. The other 13 indicated significant side effects, mainly nausea, vomiting, bloating, and/or diarrhea, but not severe enough that they stopped taking the drug. These were treated with dietary strategies (e.g., taking the medication with fat-containing foods and use of probiotics) as well as over-the-counter medications such as simethicone.
Nygren and Giesser indicated that, midway through the study period, they adopted a slower up-titration schedule than the 1-week period currently recommended in the drug's label (starting dose 120 mg twice daily, then 240 mg thereafter). Their new strategy involved starting patients at 120 mg once daily for the first week and gradually stepping the dose up to 240 mg twice daily over 4 weeks. The researchers indicated that this seemed to reduce the incidence of side effects.
They also reported a novel finding -- in three patients who discontinued and for whom lab data were available, all showed high eosinophil counts. This was not seen in other patients (number unspecified) who found the drug more tolerable.
Lahey Outpatient Center, Lexington, Mass.
, and colleagues tracked 104 patients who were put on dimethyl fumarate. They found that 57% developed GI symptoms during the first month of treatment, but when reevaluated after 3 months, only 11% were still reporting such effects.
Flushing, another common side effect of dimethyl fumarate, was seen in 51% during month one, declining by about half in subsequent months.
More seriously, grade 2 leukopenia or grade 3-4 lymphopenia was detected at month six in 25%, after only a small percentage had shown such effects in earlier evaluations.
Treatment was discontinued in 13 patients, "the vast majority due to the GI side effects," Chaves and colleagues reported.
University of Texas Southwestern Medical Center
In this chart review, researchers led by , examined adverse effects in 66 patients starting on dimethyl fumarate following its approval.
They found that only 18% had no adverse effects. Flushing affected 44%, while 51% reported GI symptoms. Another 12% reported itching.
These were generally treated with OTC medications -- low-dose aspirin for flushing, bismuth agents or loperamide for abdominal discomfort, and antihistamines for pruritus.
In patients with persistent side effects, medications were stepped up to the prescription category, including montelukast (Singulair) for itching and glycopyrrolate for GI symptoms, the researchers indicated.
Nevertheless, they reported, 26% eventually stopped dimethyl fumarate because of intolerability.
Manufacturer-Sponsored Studies
The drug's manufacturer, Biogen Idec, funded a series of post-marketing analyses of dimethyl fumarate's safety reported at CMSC-ACTRIMS. One of these, called MANAGE, focused specifically on GI effects.
Led by , of Central Texas Neurology Consultants in Round Rock, Texas, the open-label study recruited 233 MS patients (mean disease duration 9 years, SD 7) who agreed to start on dimethyl fumarate.
Nearly all -- 206 -- reported some type of GI event during the 16-week study -- and 126 took some type of OTC medication to treat GI symptoms, the researchers found. Most of these uses occurred early in treatment, as fewer than 10% of patients were still taking such medications when asked at week 12.
Fox and colleagues reported that 10% discontinued dimethyl fumarate because of adverse effects, of whom three-quarters cited GI problems as the main reason.
Patients in MANAGE were asked to keep daily diaries during the first 12 weeks of the study, recording among other things whether they had taken the drug with food as recommended. Severe GI events appeared to be more common in participants whose diaries indicated that they didn't always follow the instruction -- these were seen in 15.5% of such patients, versus 7.7% of those always taking the drug with meals -- but compliance with the food instruction did not seem to affect the risk of either "extreme" GI difficulties or mild-moderate symptoms.
Interim results from a longer, larger study called ENDORSE generally followed the same pattern. This is a planned 5-year extension study involving some 1,700 participants in earlier pivotal trials, including some originally assigned to placebo or glatiramer acetate (Copaxone) and therefore new to dimethyl fumarate.
Discontinuation rates in those patients because of adverse effects have ranged from 14% to 23%, according to investigators led by , of Baylor Institute for Immunology Research in Dallas. Among those continuing on dimethyl fumarate after 2 or more years on the drug during the placebo-controlled trials, discontinuations because of adverse effects were in the range of 4%-6%.
In the patients continuing on the drug from the earlier trials, MS relapse was the most common reason for discontinuing. But for those who switched from placebo or glatiramer acetate, reasons were mostly the same as in the other studies, led by GI complaints and flushing.
Another analysis sponsored by Biogen Idec confirmed that lymphopenia incidence grew with extended treatment (up to 3.6% of patients staying on the drug for 96 weeks).
Limitations to these analyses, especially the retrospective "real-world" studies, included variable and often unspecified methods for diagnosing and categorizing adverse effects, as well as reliance on patient reports for those with subjective symptoms.
Disclosures
The retrospective chart reviews had no external funding. Authors of the Lahey and UCLA reviews declared they had no relevant financial interests. Some authors of the UT Southwestern study reported relationships with Biogen Idec, Teva, Acorda, Genzyme, Novartis, and Abbott.
The Biogen Idec-sponsored studies included company employees as authors. Other authors reported extensive relationships with commercial entities, including Biogen Idec as well as Acorda, Genzyme, Novartis, Teva, XenoPort, Roche, Synthon, Merck Serono, and others.