Dimethyl fumarate (Tecfidera): updated advice on the risk of progressive multifocal leukoencephalopathy (PML) associated with mild lymphopenia

The monitoring requirements and discontinuation criteria for dimethyl fumarate (Tecfidera) have been strengthened following a small number of reports of progressive multifocal leukoencephalopathy (PML) in patients with mild lymphopenia. Continue to monitor lymphocyte counts and advise patients to seek urgent medical attention if they experience any symptoms or signs suggestive of PML.

From:
Medicines and Healthcare products Regulatory Agency
Published
7 January 2021
Therapeutic area:
Neurology

Advice for healthcare professionals:

  • a small number of patients receiving dimethyl fumarate (Tecfidera) for the treatment of multiple sclerosis have developed PML associated with mild lymphopenia (defined as lymphocyte counts between 0.8x10⁹ per litre and the lower limit of normal [per local laboratory]); until now, other reported cases of PML were reported in patients with moderate to severe lymphopenia
  • Tecfidera is contraindicated in patients with suspected or confirmed PML
  • Before starting treatment:
    • do not start treatment in patients with severe lymphopenia (lymphocyte count of less than 0.5x10⁹ per litre)
    • investigate patients with low lymphocyte counts for underlying causes of this before initiation
  • During treatment:
    • all patients should have a lymphocyte count at least every 3 months
    • conduct enhanced vigilance with close monitoring of lymphocyte counts and neurological symptoms in patients with lymphopenia and consider additional factors that may increase the risk of PML (see list below)
    • revaluate treatment in patients who have sustained moderate reductions of absolute lymphocyte counts (between 0.5x10⁹ per litre and 0.8x10⁹ per litre) for longer than 6 months
    • stop treatment in patients who have prolonged severe lymphopenia for longer than 6 months
    • Tecfidera must be permanently discontinued in any patient developing PML

Advice to give to patients:

  • Tecfidera can lower the number of immune cells (lymphocytes) in the bloodstream and increase the risk of a viral infection in the brain (progressive multifocal leukoencephalopathy or PML); symptoms of PML can resemble those of a multiple sclerosis relapse
  • be vigilant for any new or worsening neurological or psychiatric symptoms and seek urgent medical attention if they occur – these may include altered vision, weakness, confusion, speech problems, or personality changes lasting for more than a few days
  • speak to your partner or carer about the risks and the need to seek medical attention if symptoms occur – they may notice symptoms that you are not aware of
  • read carefully the patient information leaflet that comes with your medicine and keep it handy in case you need to read it again

Background

Dimethyl fumarate (Tecfidera) is authorised to treat adults with relapsing-remitting multiple sclerosis.

In clinical trials, lymphocyte counts decreased by approximately 30% from baseline values during Tecfidera treatment. We informed you of the risk of progressive multifocal leukoencephalopathy (PML) associated with prolonged moderate to severe lymphopenia caused by Tecfidera in March 2015 and April 2016.

PML is a rare serious opportunistic infection caused by the John-Cunningham virus (JCV), which may be fatal or result in severe disability. Risk factors for developing PML in the presence of JCV include an altered or weakened immune system.

Prescribers should be aware that mild lymphopenia during treatment with dimethyl fumarate is now considered a risk factor for PML and other factors may also increase the risk in the presence of lymphopenia.

Cases of PML with mild lymphopenia

A recent European review of safety data identified 11 cases of PML with lymphopenia associated with Tecfidera treatment, including 3 cases in patients with mild lymphopenia (lymphocyte counts defined as lymphocyte counts between 0.8x10⁹ per litre and the lower limit of normal [per local laboratory]). These reports were received within an estimated exposure to Tecfidera of more than 475,000 patients. [footnote 1]

The risk of PML in patients with mild lymphopenia has been added to the product information (summary of product characteristics), alongside a new contraindication for suspected or confirmed PML. The marketing authorisation holder of Tecfidera has sent a letter to prescribers to inform of this new advice.

We have not received any UK reports via the Yellow Card scheme of confirmed PML cases associated with Tecfidera. However, we ask healthcare professionals to continue to be vigilant for suspected adverse drug reactions in UK patients and report any suspected cases (see Reporting instructions below).

Patient monitoring advice

Lymphocyte counts should be checked before starting Tecfidera and continue to be monitored routinely every 3 months during treatment.

Lymphocyte counts and neurological symptoms should be monitored more closely in patients with lymphopenia. Prescribers should be aware that the following factors may further increase the risk of PML in individuals with lymphopenia:

  • duration of treatment – PML has been diagnosed after approximately 1–5 years of Tecfidera treatment
  • previous immunosuppressive or immunomodulatory treatment
  • marked reductions in CD4+ and CD8+ T cell counts

Magnetic resonance imaging (MRI) may be considered as part of increased vigilance for patients considered at increased risk of PML in accordance with local recommendations.

Physicians should continue to re-assess the balance of benefits and risks of Tecfidera treatment in patients with sustained moderate lymphopenia (defined as lymphocyte counts between 0.5x10⁹ per L and 0.8x10⁹ per L) for longer than 6 months.

Patients who have recently stopped natalizumab (Tysabri) may develop PML in the absence of lymphopenia.

Other medicines containing dimethyl fumarate

Dimethyl fumarate is also available as the medicine Skilarence, authorised to treat moderate to severe plaque psoriasis in adults. Prescribers of Skilarence should continue to follow the already stringent lymphocyte monitoring and discontinuation thresholds recommended for this medicine.

Reminder of actions required if PML is suspected

Healthcare professionals should continue to monitor patients on dimethyl fumarate for any signs of neurological dysfunction.

In any patient developing signs or symptoms suggestive of PML, dimethyl fumarate treatment should be stopped immediately and appropriate investigations conducted, including testing for John Cunningham virus (JCV) DNA in the cerebrospinal fluid using a quantitative polymerase chain reaction assay.

Report suspected reactions on a Yellow Card

Please continue to report suspected adverse drug reactions to the Yellow Card scheme.

Healthcare professionals, patients, and caregivers are asked to submit reports using the Yellow Card scheme electronically using:

When reporting please provide as much information as possible, including information about batch numbers, medical history, any concomitant medication, onset, treatment dates, and product brand name.

Report suspected side effects to medicines, vaccines or medical device and diagnostic adverse incidents used in coronavirus (COVID-19) using the dedicated Coronavirus Yellow Card reporting site or the Yellow Card app. See the MHRA website for the latest information on medicines and vaccines for COVID-19.

Article citation: Drug Safety Update volume 14, issue 6: January 2021: 3.

  1. Exposure data taken from letter to healthcare professionals. November 2020. ↩

Published 7 January 2021
Contents