Cladribine: advice to minimise risk of serious liver injury
Cladribine is a nucleoside analogue that causes lymphocyte depletion
- Cladribine is a deoxyadenosine analogue prodrug that preferentially depletes lymphocytes, key cells underlying multiple sclerosis (MS) pathogenesis (2):
- cladribine has a prolonged intracellular residence time (due to its resistance to the purine-degrading enzyme, adenosine deaminase) and is phosphorylated to its active triphosphate moiety (CdATP) by intracellular deoxycytidine kinase (DCK)
- process occurs especially well in lymphocytes, due to their high DCK levels and low levels of 5-nucleotidase (5-NTase; an enzyme that dephosphorylates and inactivates CdATP)
It is authorised in the UK for the treatment of adults with highly active relapsing multiple sclerosis as defined by clinical or imaging features
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 (1)
- 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
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
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