Fingolimod (Gilenya▼): risks of progressive multifocal leukoencephalopathy, basal-cell carcinoma, and opportunistic infections

The immunomodulatory effects of fingolimod increase the risk of progressive multifocal leukoencephalopathy and opportunistic infections.

• From: Medicines and Healthcare products Regulatory Agency
• Published: 18 April 2016

• Therapeutic area: Cancer, Dermatology, Infectious disease, Neurology

Post-publication note:

In January 2021, advice on the risks of herpes zoster/herpes simplex infections with fingolimod was updated following reported cases of infections with visceral or CNS dissemination, some of which were fatal. Please see Drug Safety Update for more information

New advice has been issued about the risk of infections and cancers associated with fingolimod, see Drug Safety Update volume 11 issue 5; December 2017: 6.

Following a 2017 routine EU review, fingolimod is contraindicated in patients with some pre-existing cardiac conditions, see Drug Safety Update volume 11 issue 5; December 2017: 5.

Fingolimod (Gilenya) is authorised to treat relapsing-remitting multiple sclerosis in patients whose disease has failed to respond to beta-interferon or is severe and getting worse rapidly.

Risk of PML

There have been reports of progressive multifocal leukoencephalopathy (PML) in patients taking fingolimod (none in the UK). PML is a rare, progressive, and demyelinating disease of the central nervous system that can be fatal. It is caused by activation of John Cunningham virus (JCV), which usually remains latent and typically only causes PML in immunocompromised patients.

New advice for healthcare professionals

Before starting fingolimod treatment:

• Perform a full blood count including lymphocyte subsets
• Perform a baseline cranial MRI scan as a reference, usually within 3 months of starting fingolimod treatment
• Counsel patients and carers on the risk of PML; advise them on the symptoms to watch out for and to get medical help urgently if they occur
• If testing for JCV is undertaken, consider that the influence of lymphopenia on the accuracy of the anti-JCV antibody test has not been studied in fingolimod-treated patients

During fingolimod treatment

• If PML is suspected, stop fingolimod treatment immediately and investigate appropriately, eg MRI scan; ultrasensitive polymerase chain reaction (PCR) assay for JCV DNA
• Monitor full blood count 3 months after starting fingolimod treatment and at least yearly thereafter
• We remind you to interrupt fingolimod treatment if lymphocyte count falls below 0.2x10⁹/L, do not restart treatment until lymphocyte levels have recovered
• When analysing routine MRI scans, pay attention to PML-suggestive lesions
• Consider further MRI scans as part of increased vigilance in patients considered at high risk of PML, in accordance with national and local recommendations
• Monitor patients for signs and symptoms or appearance of new neurological dysfunction (eg motor, cognitive, or psychiatric symptoms), bearing in mind that PML can present with features similar to multiple sclerosis
• Note that patients might still develop a JCV infection, even if they have a normal lymphocyte count and previously tested negative for anti-JCV antibodies

Reports of PML worldwide

As of December 2015, 3 confirmed cases of PML had been reported in patients taking fingolimod who had not received natalizumab. In fingolimod patients previously treated with natalizumab, 17 suspected cases of PML had been reported. It is estimated that approximately 20,000 patients had received fingolimod after previous natalizumab treatment.^{[footnote 1]}

Other multiple sclerosis treatments—natalizumab (Tysabri) and dimethyl fumarate (Tecfidera)—have also been linked to a risk of PML.

Risk of basal-cell carcinoma

Basal-cell carcinoma has been reported in patients taking fingolimod in clinical trials and in clinical practice. Up to 28 February 2015, 151 cases had been reported worldwide (exposure estimated at approximately 219,000 patient-years at this time).^{[footnote 1]} Up to 30 March 2016, we had received 2 Yellow Card reports of basal-cell carcinoma in patients taking fingolimod.

New advice for healthcare professionals

• Do not prescribe fingolimod to any patient with an active malignancy
• Patients’ skin should be evaluated before starting fingolimod treatment and then at least yearly during treatment
• Inform patients about the common signs of basal-cell carcinoma and the need to seek medical advice if they occur. These include skin nodules (eg shiny pearly nodules), patches, or open sores that do not heal within weeks
• Refer patients with any signs of basal-cell carcinoma to a dermatologist

Risk of other opportunistic infections

The immunomodulatory effects of fingolimod can increase the risk of other central nervous system infections. These can be viral (eg herpes simplex, varicella zoster), fungal (eg cryptococcal meningitis), or bacterial (eg atypical mycobacterium). Up to 30 March 2016, we had received 49 Yellow Card reports of opportunistic infections in patients taking fingolimod.

Reminder of previous advice for healthcare professionals

• Do not start fingolimod in any patient with severe infection
• Monitor full blood count 3 months after starting fingolimod treatment, at least yearly thereafter, and in case of any signs of infection
• Stop fingolimod treatment if a patient develops a serious infection; before restarting fingolimod treatment:
  • ensure the infection has resolved
  • carefully balance the benefit of fingolimod treatment against the risk of another infection
• Fingolimod can take up to 2 months to be eliminated from the body after the last dose, so remain vigilant for infections during this period

Further information

Letters sent to health professionals in January 2016 and April 2015

Article citation: Drug Safety Update Vol 9 issue 9 April 2016: 4.

1. European Medicines Agency announcement December 2015 ↩ ↩²

Published 18 April 2016