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Tecfidera: risk of progressive multifocal leukoencephalopathy associated with mild lymphopenia


A small number of patients receiving Dimethyl fumarate ( Tecfidera ) for the treatment of multiple sclerosis have developed progressive multifocal leukoencephalopathy ( 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, physicians must exclude patients with severe lymphopenia ( lymphocyte count of less than 0.5x10⁹ per litre ), and 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; 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.

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.

MHRA ( Medicines and Healthcare products Regulatory Agency ) has informed of the risk of progressive multifocal leukoencephalopathy associated with prolonged moderate to severe lymphopenia caused by Tecfidera in March 2015 and April 2016.

Progressive multifocal leukoencephalopathy 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 progressive multifocal leukoencephalopathy and other factors may also increase the risk in the presence of 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.

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.

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 progressive multifocal leukoencephalopathy in the absence of lymphopenia. ( Xagena )

Source: MHRA, 2021

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