Recommendations outline how to improve dimethyl fumarate tolerability

ORLANDO – The flushing frequently reported in conjunction with oral dimethyl fumarate therapy for relapsing forms of multiple sclerosis is greatly reduced by aspirin pretreatment, Dr. J. Theodore Phillips said at the fifth Cooperative Meeting of the Consortium of Multiple Sclerosis Centers and the Americas Committee for Treatment and Research in Multiple Sclerosis.

In contrast, slowed titration of dimethyl fumarate (Tecfidera) does not diminish the gastrointestinal adverse effects which are the other common side effect encountered during the first month or two of therapy, added Dr. Phillips, a neurologist in the multiple sclerosis research program at the Baylor Institute for Immunology Research, Dallas.

Dr. Phillips was part of an expert consensus panel which presented recommendations for maximizing the tolerability of dimethyl fumarate, approved earlier this year as the third oral agent for treatment of MS.

In an interview, he said the recommendations are largely based upon expert opinion rather than being rigorously evidence-based guidelines. After the pivotal phase III DEFINE and CONFIRM clinical trials were completed, he and four other study leaders decided to poll the investigators who had enrolled at least 10 patients in the trials as to how they managed the flushing and GI upset problems which arose. The flushing and GI 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 in 2.5% of patients, while another 4.3% discontinued due to GI adverse events.

Thirty of the 84 invited clinical investigators completed the questionnaire. Meanwhile, investigators at Biogen Idec, which markets Tecfidera, conducted their own randomized, double-blind, phase IIIb study in 172 healthy volunteers, the results of which have been incorporated into the expert panel’s recommendations. Participants in the 8-week trial were randomized to one of four treatment arms: dimethyl fumarate titrated in standard fashion over 1 week plus 325 mg of non–enteric-coated aspirin taken 30 minutes beforehand during weeks 1-4, replaced by aspirin placebo in weeks 5-8; dimethyl fumarate plus aspirin placebo during weeks 1-4; dimethyl fumarate slow-titrated over the course of 3 weeks; and double placebo.

Roughly 80% of subjects on dimethyl fumarate without aspirin experienced flushing events, self-assessed as mild-to-moderate. In contrast, while subjects were on both dimethyl fumarate and aspirin, their flushing frequency and severity were similar to participants on double-placebo.

Slow titration of dimethyl fumarate had no impact on GI symptoms or flushing frequency or severity.

Given that slow titration of dimethyl fumarate proved ineffective in reducing GI symptoms in the phase IIIb study, the expert panel’s recommendations for managing nausea/vomiting or abdominal pain were to take 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/vomiting. For patients who experience medication-related diarrhea, the panel advised loperamide or other standard antidiarrheal agents.

"Vasocutaneous flushing and GI upset in association with dosing of Tecfidera could for obvious reasons affect a person’s enthusiasm for going on," Dr. Phillips observed. "The main thing is for the physician to set expectations by up-front acknowledging 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."

The investigator survey that formed the basis for the expert panel recommendations was funded by Biogen Idec. Dr. Phillips is on the company’s medical advisory board. He has also received honoraria from Avanir, Genzyme, Novartis, and Teva.

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ORLANDO – The flushing frequently reported in conjunction with oral dimethyl fumarate therapy for relapsing forms of multiple sclerosis is greatly reduced by aspirin pretreatment, Dr. J. Theodore Phillips said at the fifth Cooperative Meeting of the Consortium of Multiple Sclerosis Centers and the Americas Committee for Treatment and Research in Multiple Sclerosis.

In contrast, slowed titration of dimethyl fumarate (Tecfidera) does not diminish the gastrointestinal adverse effects which are the other common side effect encountered during the first month or two of therapy, added Dr. Phillips, a neurologist in the multiple sclerosis research program at the Baylor Institute for Immunology Research, Dallas.

Dr. Phillips was part of an expert consensus panel which presented recommendations for maximizing the tolerability of dimethyl fumarate, approved earlier this year as the third oral agent for treatment of MS.

In an interview, he said the recommendations are largely based upon expert opinion rather than being rigorously evidence-based guidelines. After the pivotal phase III DEFINE and CONFIRM clinical trials were completed, he and four other study leaders decided to poll the investigators who had enrolled at least 10 patients in the trials as to how they managed the flushing and GI upset problems which arose. The flushing and GI 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 in 2.5% of patients, while another 4.3% discontinued due to GI adverse events.

Thirty of the 84 invited clinical investigators completed the questionnaire. Meanwhile, investigators at Biogen Idec, which markets Tecfidera, conducted their own randomized, double-blind, phase IIIb study in 172 healthy volunteers, the results of which have been incorporated into the expert panel’s recommendations. Participants in the 8-week trial were randomized to one of four treatment arms: dimethyl fumarate titrated in standard fashion over 1 week plus 325 mg of non–enteric-coated aspirin taken 30 minutes beforehand during weeks 1-4, replaced by aspirin placebo in weeks 5-8; dimethyl fumarate plus aspirin placebo during weeks 1-4; dimethyl fumarate slow-titrated over the course of 3 weeks; and double placebo.

Roughly 80% of subjects on dimethyl fumarate without aspirin experienced flushing events, self-assessed as mild-to-moderate. In contrast, while subjects were on both dimethyl fumarate and aspirin, their flushing frequency and severity were similar to participants on double-placebo.

Slow titration of dimethyl fumarate had no impact on GI symptoms or flushing frequency or severity.

Given that slow titration of dimethyl fumarate proved ineffective in reducing GI symptoms in the phase IIIb study, the expert panel’s recommendations for managing nausea/vomiting or abdominal pain were to take 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/vomiting. For patients who experience medication-related diarrhea, the panel advised loperamide or other standard antidiarrheal agents.

"Vasocutaneous flushing and GI upset in association with dosing of Tecfidera could for obvious reasons affect a person’s enthusiasm for going on," Dr. Phillips observed. "The main thing is for the physician to set expectations by up-front acknowledging 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."

The investigator survey that formed the basis for the expert panel recommendations was funded by Biogen Idec. Dr. Phillips is on the company’s medical advisory board. He has also received honoraria from Avanir, Genzyme, Novartis, and Teva.

[email protected]

ORLANDO – The flushing frequently reported in conjunction with oral dimethyl fumarate therapy for relapsing forms of multiple sclerosis is greatly reduced by aspirin pretreatment, Dr. J. Theodore Phillips said at the fifth Cooperative Meeting of the Consortium of Multiple Sclerosis Centers and the Americas Committee for Treatment and Research in Multiple Sclerosis.

In contrast, slowed titration of dimethyl fumarate (Tecfidera) does not diminish the gastrointestinal adverse effects which are the other common side effect encountered during the first month or two of therapy, added Dr. Phillips, a neurologist in the multiple sclerosis research program at the Baylor Institute for Immunology Research, Dallas.

Dr. Phillips was part of an expert consensus panel which presented recommendations for maximizing the tolerability of dimethyl fumarate, approved earlier this year as the third oral agent for treatment of MS.

In an interview, he said the recommendations are largely based upon expert opinion rather than being rigorously evidence-based guidelines. After the pivotal phase III DEFINE and CONFIRM clinical trials were completed, he and four other study leaders decided to poll the investigators who had enrolled at least 10 patients in the trials as to how they managed the flushing and GI upset problems which arose. The flushing and GI 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 in 2.5% of patients, while another 4.3% discontinued due to GI adverse events.

Thirty of the 84 invited clinical investigators completed the questionnaire. Meanwhile, investigators at Biogen Idec, which markets Tecfidera, conducted their own randomized, double-blind, phase IIIb study in 172 healthy volunteers, the results of which have been incorporated into the expert panel’s recommendations. Participants in the 8-week trial were randomized to one of four treatment arms: dimethyl fumarate titrated in standard fashion over 1 week plus 325 mg of non–enteric-coated aspirin taken 30 minutes beforehand during weeks 1-4, replaced by aspirin placebo in weeks 5-8; dimethyl fumarate plus aspirin placebo during weeks 1-4; dimethyl fumarate slow-titrated over the course of 3 weeks; and double placebo.

Roughly 80% of subjects on dimethyl fumarate without aspirin experienced flushing events, self-assessed as mild-to-moderate. In contrast, while subjects were on both dimethyl fumarate and aspirin, their flushing frequency and severity were similar to participants on double-placebo.

Slow titration of dimethyl fumarate had no impact on GI symptoms or flushing frequency or severity.

Given that slow titration of dimethyl fumarate proved ineffective in reducing GI symptoms in the phase IIIb study, the expert panel’s recommendations for managing nausea/vomiting or abdominal pain were to take 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/vomiting. For patients who experience medication-related diarrhea, the panel advised loperamide or other standard antidiarrheal agents.

"Vasocutaneous flushing and GI upset in association with dosing of Tecfidera could for obvious reasons affect a person’s enthusiasm for going on," Dr. Phillips observed. "The main thing is for the physician to set expectations by up-front acknowledging 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."

The investigator survey that formed the basis for the expert panel recommendations was funded by Biogen Idec. Dr. Phillips is on the company’s medical advisory board. He has also received honoraria from Avanir, Genzyme, Novartis, and Teva.

[email protected]