Eltrombopag (Revolade) can cause severe hepatotoxicity and potentially fatal liver injury

August 26, 2016 – Eltrombopag is a medication that has been developed for certain conditions that lead to thrombocytopenia (abnormally low platelet counts). It is a small molecule agonist of the c-mpl (TpoR) receptor, which is the physiological target of the hormone thrombopoietin. Eltrombopag is approved and on the market under the trade name Promacta in the US and as Revolade throughout the European Union (EU), in Canada, in Switzerland, in Australia, in New Zealand, in Japan, and many other countries worldwide.

The approved indications for Eltrombopag (Revolade) in Canada are as follows:

  • For adult chronic immune thrombocytopenia purpura (cITP) to increase platelet counts in splenectomized patients who are refractory to first-line treatments (e.g. corticosteroids, immunoglobulins). Eltrombopag (Revolade) may be considered as second line treatment for adult non-splenectomized patients where surgery is contraindicated,
  • To increase platelet counts in thrombocytopenic patients with chronic hepatitis C virus (HCV) infection to allow the initiation and maintenance of interferon-based therapy, and
  • For the treatment of adult patients with severe aplastic anemia who have had an insufficient response to immunosuppressive therapy.
Eltrombopag (Revolade)

Eltrombopag (Revolade)

From a Health Canada MedEffect e-Notice based Health Product Risk Communication, we learn that a systematic analysis of different trials in the clinical database (across the entire Eltrombopag (Revolade) development program) and the post-marketing safety database, performed by Novartis Pharmaceuticals Canada Inc.), revealed cases fulfilling Hy’s Law criteria for drug-induced liver injury.

In the course of this review, two (2) cases fulfilling Hy’s law criteria were identified in adult cITP patients; three (3) further cases were identified in patients treated for other, non-approved indications. The elevation of laboratory values typically occurred within three (3) months of initiation; in all five (5) cases the event resolved following Eltrombopag (Revolade) discontinuation. In clinical trials in patients with chronic HCV infection, 11 patients (i.e., 1% of patients treated with Eltrombopag (Revolade)) experienced drug-induced severe liver injury.

Based on these findings, Health Canada communicates the following key messages to healthcare professionals (medical hematologists, hepatologists, and pharmacists), pharmacy associations, nurse associations, medical associations, chiefs of medicine in hospitals, hospital pharmacy chiefs, patients, and patient groups:

  • Eltrombopag (Revolade) administration can cause severe hepatotoxicity and potentially fatal liver injury. Cases of severe drug-induced liver injury with Eltrombopag (Revolade) have been reported in patients during clinical trials and post-marketing.
  • To mitigate the risk of severe hepatotoxicity and potentially fatal liver injury, healthcare professionals should:
    • measure serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) and bilirubin prior to initiation of Eltrombopag (Revolade), every 2 weeks during the dose adjustment phase, and then monthly following establishment of a stable dose.
    • discontinue Eltrombopag (Revolade) if ALT levels:
      • increase greater than or equal to 3x upper limit of normal (ULN) in patients with normal liver function or;
      • increase greater than or equal to 3x baseline or greater than 5x ULN, whichever is the lower, in patients with elevations in transaminases before treatment.
  • The Canadian Product Monograph for Eltrombopag (Revolade) has been updated to reflect this new safety information.

Consumers (patients) should talk to their doctor, pharmacist or nurse before taking Eltrombopag (Revolade) and let them know if they have liver problems, as this can increase the risk of liver injury. Eltrombopag (Revolade) should not be used if they have severe liver impairment. Patients must have blood tests to check their liver before starting to take Eltrombopag (Revolade) and during treatment. Patient’s doctor will order the blood tests and any other tests required. In some cases, Eltrombopag (Revolade) treatment may need to be stopped.

For healthcare professionals, the Canadian Product Monograph for Eltrombopag (Revolade) has been updated to reflect the risk of severe hepatotoxicity (i.e., severe hepatotoxicity and potentially fatal liver injury) in the existing Hepatotoxicity section under the Warnings and Precautions and to add an adverse drug reaction to the Adverse Reactions section.

In addition, an upper limit on the extent of ALT elevation in patients with elevated ALT at baseline was added, to prohibit continuation of Eltrombopag (Revolade) in patients with pre-existing hepatic disease, and in line with discontinuation criteria in the pivotal trials conducted in the approved indications.

Healthcare professionals should measure serum ALT, AST and bilirubin prior to initiation of Eltrombopag (Revolade), every 2 weeks during the dose adjustment phase, and then monthly following establishment of a stable dose. Healthcare professionals should discontinue Eltrombopag (Revolade) if ALT levels:

  • increase greater than or equal to 3x ULN in patients with normal liver function or;
  • increase  greater than or equal to 3x baseline or greater than 5x ULN, whichever is the lower, in patients with elevations in transaminases before treatment and that are:
    • progressive, or
    • persistent for greater than or equal to 4 weeks, or
    • accompanied by increased direct bilirubin, or
    • accompanied by clinical symptoms of liver injury or evidence for hepatic decompensation
 

Note added in proof: Based on this report, it would probably be a good idea for patients worldwide who are taking or who will be started on medicines which contain Eltrombopag as the pharmacologically active ingredient to talk to their treating physicians about the risk of severe liver toxicity with this medicine. Currently, it is also not clear if some patients carry genetic predispositions which make them more vulnerable than others. This latter possibility is likely because only a relatively small fraction of treated patients (i.e., about 1%) seems to suffer from the observed adverse effect.

 
thassodotcom

Ph.D.; Professor in Pharmacology and Toxicology. Senior expert in theragenomic and personalized medicine and individualized drug safety. Senior expert in pharmaco- and toxicogenetics. Senior expert in human safety of drugs, chemicals, environmental pollutants, and dietary ingredients.

Posted in Adverse Drug Reaction [ADR], Regulatory Announcement, Thasso Post, Theragenomic Medicine
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