Biogen released a direct healthcare professional communication (DHPC) pertaining to the risk of progressive multifocal leukoencephalopathy (PML) associated with Tecfidera (dimethyl fumarate) to alert healthcare professionals for safe usage of this medicine and implementing the recommended risk minimizing measures. This DHPC released in agreement with European Medicines Agency (EMA) and national health authority of Ireland – Health Products Regulatory Authority (HPRA).

Dimethyl fumarate is an immunomodulatory and anti-inflammatory agent used in the treatment of relapsing forms of multiple sclerosis (MS). PML is a rare fatal viral infection which could result in severe disability, caused by reactivation of John Cunningham (JC) virus in brain. Altered, weakened immune system of body triggers the inactive JC virus to multiply and causes PML. Immunosuppressants, immunomodulators, anti-neoplastic agents, drugs used for treating auto-immune disorders, organ transplant rejections etc., which are involved in altering body’s immune system have potential to trigger inactive JC virus in brain. PML can be diagnosed by magnetic resonance imaging (MRI) scanning, or through lumbar puncture (spinal tap) for identification JC viral DNA from cerebrospinal fluid (CSF).

Symptoms of PML:

Initial symptoms: Clumsiness, weakness, or difficulty speaking or thinking

Progressive symptoms: Dementia, unable to speak, visual impairment.

Important information for Health care professionals:

Based on the clinical trial data for Tecfidera, it is expected to cause lymphopenia which is a decreased white blood cell count (~30 %) during the treatment.

There are total eleven case reports which presented confirmed diagnosis of PML in patients treated with Tecfidera. The underlying biological plausibility which is common amongst the 11 cases is decreased absolute lymphocyte count (ALC) – Lymphopenia.

Out of eleven cases, in three case reports, patients had mild lymphopenia and in remaining eight cases the severity reported for lymphopenia is moderate to severe.

In contrary, from recent article published by Allison LM Jordan et al., reported nine cases of dimethyl fumarate associated PML. Among the nine case reports, there are younger patients without lymphopenia diagnosed with PML.

Risk minimizing measures:

Measure the absolute lymphocyte count in patient before initiating treatment with Tecfidera and monitor the count for every three months.

Targeted vigilance should be followed for patients having less lymphocyte count than the reference/normal ranges by analyzing the additional factors that might contribute to the increased risk of PML.

Be informed about below additional risk factors that could contribute to the increased risk of PML

  • Past medical history/concurrent use of other immunosuppressive or immunomodulatory therapy
  • Therapy duration: Cases of PML have occurred after approximately 1 to 5 years of treatment
  • Profound decreases in CD4+ and especially in CD8+ T cell counts

Re-Assess the benefit-risk balance before usage of dimethyl fumarate in patients with sustained moderate reductions of absolute lymphocyte counts ≥0.5 x 109/L and <0.8 x 109/L for more than six months.

Evaluate the patients for any potential symptoms indicative of neurological dysfunction.

Suspend/discontinue the treatment with dimethyl fumarate after identification of first signs/symptoms of PML and confirm the presence of JC virus DNA in CSF by quantitative polymerase chain reaction methodology.

Inform patients and patient care providers about signs/symptoms of PML and advise them to report the same at the earliest possibility.

Disseminate this new safety information for dimethyl fumarate to your fellow professionals involved in healthcare for better awareness.

These new recommendations for safe usage of dimethyl fumarate would be updated into the product labels by the marketing authorisation holder. Meanwhile, healthcare professionals are advised to be aware and adhere to these new recommendations for early minimization of PML risk from dimethyl fumarate.

Voluntary ADR reporting

Every medicinal product has both benefits and risks. There is no single pharmaceutical product which is completely free from side effects/adverse drug reactions. Health care professionals and consumers of pharmaceutical medicinal products are encouraged to be aware of this fact and observe/monitor for any possible adverse events, reactions, medication errors, or quality complaints of medicinal products and report the same to your respective national health authority. This would accumulate safety evidence for medicinal products which in turn help health authorities to take regulatory actions at the earliest possibility for a better patient safety.

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