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DIR Return to: TECFIDERA (dimethyl fumarate, BG-12, Fumaderm)
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#Post#: 340--------------------------------------------------
Gastro effects still a problem with Tecfidera
By: agate Date: June 1, 2014, 6:57 pm
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From MedPage Today, May 31, 2014:
[quote](Meeting Coverage)
Gastro Effects Dog Oral MS Drug Tecfidera
By John Gever, Deputy Managing Editor, MedPage Today
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
Kirstin Nygren, NP, and Barbara Giesser, MD, 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.
Claudia Chaves, MD, 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 Elliott Frohman, MD,
PhD, 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 Edward Fox, MD, 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 J. Theodore Phillips, MD, 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.
__________________________
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.[/quote]
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