Fingolimod (Gilenya▼): updated advice about the risks of serious liver injury and herpes meningoencephalitis

Liver monitoring requirements and discontinuation criteria for fingolimod have been updated following reports of serious liver injury. Fatal cases of encephalitis and meningitis caused by herpes simplex and varicella zoster viruses have also been reported during treatment. Advise patients to seek urgent medical attention if they develop any clinical features of liver dysfunction or meningoencephalitis. Discontinue fingolimod if significant hepatic injury or herpes meningoencephalitis is confirmed.

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

Advice for healthcare professionals:

  • a small number of cases of clinically significant liver injury, including acute hepatic failure requiring transplantation, have been reported during fingolimod treatment
  • monitor liver function tests (including bilirubin) routinely: before starting treatment; during treatment at months 1, 3, 6, 9 and 12; and then periodically until 2 months after discontinuation
  • in patients without signs and symptoms of liver injury, the updated advice is:
    • monitor liver function tests more frequently if serum aspartate aminotransferase (AST) or serum alanine aminotransferase (ALT) levels exceed 3-times the upper limit of normal (ULN) but less than 5-times ULN with a normal bilirubin level
    • discontinue fingolimod if ALT or AST levels exceed 5-times ULN or if they are at least 3-times the ULN and bilirubin is increased – fingolimod may be re-started following a careful benefit-risk assessment of the underlying cause when serum levels have returned to normal
  • in patients with symptoms or signs of hepatic dysfunction:
    • check liver function tests urgently
    • discontinue fingolimod if significant hepatic injury is confirmed; further treatment with fingolimod may be considered following recovery only if an alternative cause of hepatic dysfunction is established
  • continue to be vigilant for infections with fingolimod; information has been updated to include herpes zoster/herpes simplex infections with visceral or CNS dissemination
  • report any suspected adverse drug reactions to black triangle medicines such as fingolimod via the Yellow Card scheme

Advice to give to patients:

  • fingolimod has been associated with a risk of serious liver injury and regular blood tests are needed to identify people at risk of liver damage before, during, and after treatment
  • seek urgent medical attention if you develop any symptoms or signs of liver injury (such as feeling sick or vomiting (without another reason), tiredness, abdominal pain, jaundice (yellow skin or eyes), or dark urine
  • serious and life-threatening cases of a type of brain infection (herpes meningoencephalitis) have been reported
  • seek urgent medical attention if you experience any symptoms of a brain infection during fingolimod treatment and for 8 weeks after the last dose, including seizures (fits), headache, neck stiffness, oversensitivity to light, rash or fever
  • read carefully the information booklet from your doctor and the patient information leaflet that accompanies your medicine and keep them handy in case you need to read them again

Risk of serious liver injury

Fingolimod (Gilenya) is authorised to treat patients aged 10 years or older with highly active relapsing-remitting multiple sclerosis that has not responded to at least one disease-modifying therapy or which is severe and rapidly progressive.

In clinical trials, 8% of adult patients receiving fingolimod 0.5mg daily developed increased ALT levels that exceeded 3-times the upper limit of normal (ULN) compared with 2% receiving placebo. Fingolimod was discontinued if serum transaminases were greater than 5-times ULN. Increased transaminase levels usually occurred within the first year of treatment and returned to normal within 2 months after discontinuation of fingolimod. Re-treatment resulted in increased transaminase levels in some patients, supporting a causal relationship.

A recent European review of safety data identified 7 cases of clinically significant liver injury that developed between 10 days and 5 years after the start of fingolimod treatment, including 3 post-marketing reports of acute hepatic failure requiring liver transplantation. Liver samples showed submassive hepatic necrosis in 2 patients, and one of these samples also contained features of acute hepatitis.

As of 31 August 2020, worldwide, more than 307,200 people (836,200 patient-years) with multiple sclerosis have been treated with Gilenya in clinical trials and routine clinical practice.[footnote 1] In the UK, just under 10,000 patients have received fingolimod (Gilenya) since it was marketed in 2011.[footnote 1]

We have not received any UK reports via the Yellow Card scheme of acute hepatic failure or serious liver injury (defined as AST or ALT at 3-times ULN or higher with increased bilirubin or jaundice) considered causally related to fingolimod treatment. 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).

Due to the severity of recently reported cases, recommendations for liver monitoring and the discontinuation criteria have been strengthened to minimise the risks of liver injury. The marketing authorisation holder of Gilenya has sent a letter to prescribers to inform of this new advice.

New information on risk of meningoencephalitis

Advice in the product information regarding the risks of herpes zoster/herpes simplex infections with fingolimod has also been updated following the review’s consideration of reported cases of infections with visceral or CNS dissemination, some of which were fatal.

Remind patients to seek immediate medical attention if they have a fever or signs of infection (including influenza or shingles) or if they have symptoms of meningitis or encephalitis during fingolimod treatment and up to 2 months after the last dose. See Drug Safety Update December 2017.

Resources available to support safe use

The product information and the educational materials will be revised to include updated advice for healthcare professionals and patients on the risks of serious liver injury and of herpes meningoencephalitis and cryptococcal meningitis.

Report suspected reactions on a Yellow Card

Please continue to report suspected adverse drug reactions (ADRs) to the Yellow Card Scheme. Fingolimod is a black triangle medicine and as such all ADRs should be reported.

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: 4.

  1. Data provided by the Marketing Authorisation Holder. ↩ ↩2

Updates to this page

Published 7 January 2021
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