New EMA Advice on PML Prevention With Dimethyl Fumarate (Tecfidera) in MS

Susan Jeffrey


October 23, 2015

The European Medicines Agency (EMA) today issued updated recommendations on ways to minimize the risk for progressive multifocal leukoencephalopathy with dimethyl fumarate (Tecfidera, Biogen).

To date, three cases of PML have occurred in patients treated with dimethyl fumarate who had not previously received other drugs, such as natalizumab, known to be associated with a risk for PML. These cases occurred after long treatment in patients who had very low lymphocyte counts over an extended period, a known effect of the drug in a small proportion of patients, the EMA statement notes.

The EMA's Committee for Medicinal Products for Human Use (CHMP) conducted this review in the context of a procedure known as a type II variation, beginning in November 2014, when the first case of PML was reported. During its assessment, the CHMP sought the advice of experts in neurology, virology, and immunology and from patients' representatives, the release said.

New recommendations include performing a complete blood count before starting treatment with dimethyl fumarate and every 3 months during treatment. Further, a baseline MRI scan should be available, usually within 3 months, as a reference. If during treatment lymphocyte counts become very low for more than 6 months, physicians should consider stopping treatment. If treatment is continued, patients should be closely monitored, the EMA statement notes.

EMA also reviewed cases of PML that occurred with two other fumarate-containing drugs, Fumaderm (Biogen) and Psorinovo (Mierlo-Hout), used to treat psoriasis. Related recommendations were issued for these medications.


Lymphopenia is a known and common adverse effect with dimethyl fumarate, the EMA release points out. "Three unconfounded cases of progressive multifocal leukoencephalopathy (PML) have occurred so far with Tecfidera in the setting of prolonged (over six months) severe lymphopenia," they write.

After reviewing the available information on the risk of PML, EMA recommended the following steps to minimize the risk:

  • "Prior to initiating treatment with Tecfidera, a complete blood count including a lymphocyte count should be performed and a baseline MRI scan should be available (usually within three months) as a reference. After starting therapy, complete blood counts including lymphocytes should be performed every three months.

  • If during treatment with Tecfidera the lymphocyte count drops below 0.5x109/L for more than 6 months, the benefit-risk of continued treatment with Tecfidera should be re-considered in the context of other therapeutic options available. Clinical factors and evaluation of any laboratory and imaging investigations could be included as part of this re-consideration. If Tecfidera is discontinued, the lymphocyte count should be closely monitored until recovery.

  • PML can only occur in the presence of JC virus infection. If an anti-JC virus antibody test is done, it should be considered that the influence of lymphopenia on the accuracy of such tests has not been studied in patients treated with Tecfidera. Doctors should also note that a negative antibody test (in the presence of normal lymphocyte counts) does not preclude the possibility of subsequent JC virus infection.

  • During treatment with Tecfidera, the need for further MRI scans should be considered in accordance with national and local recommendations. MRI imaging may be considered as part of increased vigilance in patients considered at increased risk of PML. In case of clinical suspicion of PML, MRI should be performed immediately for diagnostic purposes.

  • If therapy is continued in patients with severe prolonged lymphopenia, these patients should be considered at increased risk for PML and should be monitored closely for signs and symptoms of new neurological dysfunction (e.g. motor dysfunction, cognitive or psychiatric symptoms).

  • In case PML is suspected, treatment with Tecfidera should be withheld immediately and further evaluations performed.

  • No studies have been performed evaluating the efficacy and safety of Tecfidera when switching patients from other disease-modifying therapies to Tecfidera. The contribution of prior immunosuppressive therapy to the development of PML in patients treated with Tecfidera is unknown. When switching patients from other disease-modifying therapy to Tecfidera, the half-life and mode of action of the other therapy must be considered in order to avoid an additive immune effect whilst at the same time reducing the risk of disease reactivation."

The product information will be updated in line with these recommendations, the EMA statement said.


EMA also reviewed cases of PML that occurred with two other fumarate drugs, Fumaderm and Psorinovo, both used to treat psoriasis. Cases of PML have also occurred in patients with prolonged lymphopenia who were treated with these drugs, and the following recommendations were issued for Fumaderm, currently marketed only in Germany:

  • "Before starting treatment, a complete blood count should be performed; in the presence of values outside the normal range, treatment should not be started.

  • During treatment, blood cell counts should be monitored every four weeks; if the lymphocyte count drops below 0.7x109/L, the dose should be halved. If during a follow-up check after 4 weeks the lymphocyte count remains below this value, then treatment must be discontinued. If therapy is continued in presence of a lymphocyte count below 0.7x109/L, the risk of PML cannot be ruled out.

  • If the lymphocyte count drops below 0.5x109/L, treatment should be discontinued."

The CHMP opinion will now be sent to the European Commission for a legally binding decision valid throughout the European Union, the statement notes.

The US Food and Drug Administration (FDA) issued a warning in November 2014 about a fatal case of PML seen in a patient taking dimethyl fumarate and added information on this case to the Tecfidera label at that time.

In August, Novartis reported that a third case of PML had been seen in patients with MS treated with another oral agent, fingolimod (Gilenya). In these cases, the patients had not received previous treatment with natalizumab. Information on PML risk was added to the label by the FDA.


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