Dimethyl Fumarate for MS: Liver Injury Warning Strengthened

February 01, 2017

The prescribing information for the oral multiple sclerosis (MS) medication dimethyl fumarate (Tecfidera, Biogen) has been updated to include a warning of potential liver injury that could require hospitalization.

The new information notes that clinically significant cases of liver injury have been reported in patients treated with the drug in the postmarketing setting. The onset has ranged from a few days to several months after initiation of treatment.

Signs and symptoms of liver injury, including elevation of serum aminotransferases to greater than 5-fold the upper limit of normal and elevation of total bilirubin to greater than 2-fold the upper limit of normal, have been observed. These abnormalities resolved upon treatment discontinuation. Some cases required hospitalization.

While none of the reported cases resulted in liver failure, liver transplant, or death, the prescribing information states that the combination of new serum aminotransferase elevations with increased levels of bilirubin caused by drug-induced hepatocellular injury is an important predictor of serious liver injury that may lead to acute liver failure, liver transplant, or death in some patients.

It recommends obtaining serum aminotransferase, alkaline phosphatase, and total bilirubin levels before treatment with dimethyl fumarate and during treatment, as clinically indicated, and that the drug be discontinued if clinically significant liver injury is suspected.

Biogen said that 14 cases of liver injury have occurred among approximately 230,000 patients treated with the drug. The company added that the label changes were finalized with the US Food and Drug Administration on January 19.

Tecfidera is Biogen's top-selling drug, with 2016 sales recently reported as close to $4 billion.

Analysts have had mixed reactions to the updated label. RBC Capital Markets analyst Michael Yee is quoted in a Reuters report as saying he did not think this would materially change market share or future sales projections because there was already mention of some rare cases of elevated liver enzymes in the initial label. But other analysts have suggested the new liver safety update could create some pressure on the drug in terms of its ability to compete for first-line use.

MS experts contacted by Medscape Medical News did not think the labeling change would make much difference to its use.

"The incidence of liver function abnormalities appears to be rare, but the new labeling informs prescribers that monitoring will be necessary," said Edward Fox, MD, MS Clinic of Central Texas, Round Rock. "I would expect that this will lead to more frequent laboratory testing early in the course of treatment, but would be very unlikely to affect prescribing patterns. Personally, it won't change what I have already been doing. Most disease-modifying treatments for MS, including all approved oral therapies, have labeling reflecting a risk of hepatic injury." 

Jeffrey Cohen, MD, Cleveland Clinic, Ohio, added: "We already routinely monitor blood counts and liver enzymes with dimethyl fumarate and have not encountered any liver issues in our patients.  As a result, this revision of the prescribing information will not cause a major change in our practice."

But Mark S. Freedman, MD, Ottawa Hospital, Ontario, Canada, noted that this was another side effect to have shown up with the drug since it reached the market.

"Tecfidera is not the 'honey' it was reported to be from the clinical trials," he commented. "Progressive multifocal leukoencephalopathy and other opportunistic infections (herpes), hepatotoxicity, renal toxicity, and other issues have all surfaced since the trials were reported."

Dr Cohen has received fees from EMD Serono, Genentech, Genzyme, Innate Immunotherapeutics, and Vaccinex. Dr Fox has received personal consulting fees from Novartis, Biogen Idec, GlaxoSmithKline, MedDay, Questcor, Teva, and XenoPort; has served on advisory committees for Biogen Idec and Novartis; and has received research grant funding from Novartis. Dr Freedman has received honoraria for consultancy/advisory board activity from Bayer Healthcare, Biogen Idec, Chugai, EMD Canada, Genzyme, Novartis, Sanofi-Aventis, and Teva Canada Innovation.

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