Lenalidomide (Revlimid): risk of serious hepatic adverse drug reactions
- Medicines and Healthcare products Regulatory Agency
- 29 January 2013
- Therapeutic area:
Routine monitoring of liver function now recommended.
Article date: January 2013
Lenalidomide (Revlimid) is authorised in combination with dexamethasone for treatment of multiple myeloma in patients who have received at least one previous treatment. Lenalidomide is an immunomodulatory agent similar to thalidomide, and has antineoplastic, antiangiogenic, and proerythropoietic properties. Lenalidomide was introduced in the UK in June 2007.
Risk of hepatic adverse drug reactions
Suspected adverse hepatic reactions have been reported overall in <1% of patients treated. Of these reactions, abnormal liver investigation results, and clinical signs and symptoms of hepatic disorders are the most common (58.7%). The spectrum of hepatic suspected adverse reactions reported also includes hepatic failure, fibrosis, and cirrhosis (17.2%); and cholestasis and jaundice of hepatic origin (13.8%). The remaining reports (10%) describe non-infectious hepatitis, liver-related coagulation and bleeding disorders, and neoplasms. The outcome was fatal in 5% of cases.
In many of the cases, including most with a fatal outcome, there were confounding risk factors for liver disease such as history of hepatic and renal disorders including:
- viral hepatitis
- progression of myeloma
- myeloma involvement of the liver
- prior chemotherapy
- infection or sepsis
- concomitant medications known to cause liver injury, particularly antibiotics
Out of 9 liver biopsies performed in patients with hepatic reactions, six showed histological evidence of drug-induced liver injury. In addition, there have also been a substantial number of cases where liver function has improved on discontinuation of lenalidomide, some cases of positive rechallenge, and some cases of negative rechallenge at a lower dose.
Clinical implications of the evidence for drug-induced liver injury with lenalidomide
The evidence suggests that lenalidomide may be associated with drug-induced liver injury. The most compelling evidence of a causal association derives from the results of liver biopsies, and cases in which there has been a positive dechallenge or a positive rechallenge.
The most common hepatic reactions observed in patients treated with lenalidomide are abnormalities of liver enzymes presenting as hepatocellular injury, and/or with a cholestatic pattern. Elevations of liver enzymes frequently occur relatively soon after the start of treatment with lenalidomide; the median time to onset appears to be 41 days, but reactions have been reported from one day to more than three years after the start of treatment. Early elevations in liver enzymes are usually moderate and may normalise without progression to major liver toxicity.
Serious liver injury due to lenalidomide has been reported in relatively small numbers of patients and appears to be idiosyncratic. Predisposing factors that may increase the risk of serious liver injury with lenalidomide include elevated baseline liver enzymes; pre-existing viral liver disease; concomitant treatment with known hepatotoxic medicines; and older age.
Advice for healthcare professionals
Routine monitoring of liver function with the same frequency as haematological monitoring* is recommended for patients receiving lenalidomide. This is particularly important in patients with a history of, or concurrent, viral liver infection, or when lenalidomide is given at the same time as other medications known to be associated with liver injury.
Prescribers should consider the possibility of lenalidomide-induced liver injury in patients presenting with otherwise unexplained deterioration of liver function.
Impairment of liver function generally resolves when lenalidomide treatment is stopped. Once abnormal liver function parameters return to baseline, resumption of treatment with lenalidomide at a lower dose may be considered.
Lenalidomide is excreted predominantly by the kidney. It is important to adjust the dose of lenalidomide in patients with renal impairment to avoid high plasma levels which may increase the risk of severe hepatotoxicity, as well as haematological side effects.
The haematological monitoring recommendations for lenalidomide are as follows: a complete blood cell count, including white blood cell count with differential count, platelet count, haemoglobin, and haematocrit should be performed at baseline, every week for the first 8 weeks of lenalidomide treatment and monthly thereafter to monitor for cytopenias.
See updated summary of product characteristics and patient information leaflet on the European Medicines Agency website.
Report suspected adverse reactions via the Yellow Card Scheme
BNF section 8.2.4 Other immunomodulating drugs
Article citation: Drug Safety Update January 2013, vol 6 issue 6: A2
Published: 29 January 2013
Therapeutic area: Cancer