Cladribine (Mavenclad): new advice to minimise risk of serious liver injury

Liver monitoring requirements for cladribine in the treatment of multiple sclerosis have been introduced following uncommon cases of serious liver injury. Advise patients to seek urgent medical attention if they develop any clinical features of liver dysfunction. Discontinue or interrupt cladribine if significant hepatic injury is confirmed.

From:
Medicines and Healthcare products Regulatory Agency
Published
15 March 2022
Therapeutic area:
Neurology

Advice for healthcare professionals:

  • a small number of cases of clinically significant liver injury have been reported during cladribine treatment for multiple sclerosis
  • most events occurred within 8 weeks of the start of the first treatment course of cladribine
  • before starting cladribine check if there is a history of liver disorders, including hepatic injury related to other medicines
  • monitor liver function tests (including total bilirubin) before each treatment course in years 1 and 2; and, if clinically necessary, during treatment
  • urgently check liver function tests (including bilirubin) in patients with symptoms or signs of liver injury
  • discontinue or interrupt cladribine treatment in patients with hepatic dysfunction or unexplained increases in liver enzymes
  • report any suspected adverse drug reactions associated with cladribine on a Yellow Card

Advice for healthcare professionals to give to patients and carers

  • cladribine treatment for multiple sclerosis has been associated with a risk of serious liver injury – these serious events are uncommon and have most commonly happened in the 8 weeks after starting the first treatment
  • blood tests to check your liver function are needed before the start of each treatment course; you may also need tests during each treatment if your doctor thinks they are needed
  • talk to your doctor straight away if you develop any signs of liver problems such as pain in the upper right area of your stomach, yellowing of your skin or the white part of your eyes, loss of appetite, feeling or being sick, dark urine, or widespread itching
  • read carefully the Patient Guide from your doctor and the Patient Information Leaflet that accompanies your medicine; keep them handy in case you need to read them again

Cladribine for multiple sclerosis

Cladribine (Mavenclad) is a nucleoside analogue that causes lymphocyte depletion. It is authorised in the UK for the treatment of adults with highly active relapsing multiple sclerosis as defined by clinical or imaging features.

The recommended cumulative dose of cladribine for multiple sclerosis is 3.5 mg/kg bodyweight over 2 years, divided into 2 treatment courses of 1.75 mg/kg per year. Each treatment course is given over 2 separate weeks: 1 week at the start of the first month and the next week at the start of the following month. Single daily doses are given on 4 or 5 days of each week.

Review of serious liver injury

A recent European review of safety data has identified 16 cases of liver injury post-marketing, including serious cases requiring discontinuation and one fatal case of hepatic failure in a patient with alcohol-related liver disease and who was undergoing tuberculosis treatment with isoniazid. Within the cases of liver injury reviewed, there were rare reports of jaundice and serum transaminase levels greater than 1000 IU/L. However, the majority of cases had mild clinical symptoms.

A small number of cases of liver injury have also been seen in clinical trials. In some of these cases, patients developed significantly increased serum transaminase levels related to treatment. These serious events resolved within 4 months after cladribine was discontinued (in the cases reporting a final outcome). Alternative causes were excluded in one patient, and none required a liver biopsy. Data from clinical trials did not suggest a dose-dependent effect.

Time to onset of liver injury varied, with most cases occurring within 8 weeks after start of the first treatment course. Some patients had underlying hepatic disorders or a history of hepatic injury related to other medicines. A causal mechanism has not been identified.

Updated advice and frequency information

The product information and the educational materials will be revised to include updated advice for healthcare professionals and patients on the risk of serious liver injury. Liver injury will be included as an adverse drug reaction of uncommon frequency (may affect up to 1 in 100 patients). A letter from the manufacturer has also been sent to UK healthcare professionals.

As of 30 June 2021, worldwide, more than 37,600 patients have been treated with Mavenclad in clinical trials and routine clinical practice.[footnote 1] In the UK, just under 2200 patients have received Mavenclad since it was marketed in September 2017.

In the UK, up to 25 January 2022, we have received 2 reports of hepatic injury in patients receiving cladribine for multiple sclerosis via the Yellow Card scheme. Both patients developed liver injury within a month of starting cladribine treatment and in one case the alanine aminotransferase (ALT) level exceeded 1000 IU/L. 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).

Other medicines containing cladribine

Cladribine is also available in other medicines. Leustat injection and Litak 2mg/ml solution for injection are authorised to treat patients with hairy cell leukaemia and Leustat injection is also approved for the treatment of B-cell chronic lymphocytic leukaemia. Prescribers of these medicines should continue to follow the current recommendations on patient monitoring.

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 timing, treatment dates, and product brand name.

Report suspected side effects to medicines, vaccines, medical device and test kit incidents used in coronavirus (COVID-19) testing and treatment 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 15, issue 8: March 2022: 1.

  1. Data provided with the permission of the Marketing Authorisation Holder. February 2022. ↩

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Published 15 March 2022
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