Post-publication note: December 2019
At the time of publication of this article, data showed a risk of falsely low/normal results with bilirubin during eltrombopag treatment. Through personal correspondence, the MHRA has been made aware of further recent data suggesting a risk also of falsely high bilirubin results with eltrombopag. Clinicians should continue to follow the advice in the article to request re-testing using another method to determine the validity of the result if bilirubin and/or creatinine laboratory results are inconsistent with clinical observations.
Actions for healthcare professionals:
- eltrombopag is highly coloured (reddish-brown) and can cause serum discolouration and interference with the test results of creatinine and bilirubin
- be aware that interference with bilirubin (falsely low/normal results) and creatinine (falsely high/normal results) may occur in patients taking eltrombopag
- if bilirubin and/or creatinine laboratory results are inconsistent with clinical observations, request re-testing using another method to determine the validity of the result
- the laboratory may consider susceptibility to serum discolouration and other factors that may be relevant when selecting an alternative test method
- report suspected adverse drug reactions, including any harm that occurs from a medicine interfering with laboratory test results, to the Yellow Card Scheme
Eltrombopag is a small-molecule thrombopoietin receptor (TPO-R) agonist indicated for:
- chronic idiopathic thrombocytopenia (cITP) in patients who are refractory to other treatments
- thrombocytopenia in patients with chronic hepatitis C virus (HCV) infection
- the treatment of cytopenias in patients with severe aplastic anaemia who have had an insufficient response to immunosuppressive therapy.
Due to a risk of abnormal liver function and severe hepatotoxicity with eltrombopag, serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), and bilirubin should be measured before initiation, every 2 weeks during the dose-adjustment phase, and monthly following establishment of a stable dose. See Summary of Product Characteristics for more information, including recommendations for stopping treatment in cases of ALT elevations.
Reports of interference with bilirubin and creatinine test values
An EU review of data considered the available evidence of laboratory test interference (ie, bilirubin and creatinine) associated with eltrombopag. Up to 30 September 2017, the licence holder of Revolade received 9 reports worldwide of serum discolouration and interference with bilirubin and creatinine test values.
Six reports were of suspected interactions with bilirubin test values, of which 2 reported falsely low/normal bilirubin values (false-negative) despite clinically noticeable jaundice. Daily doses of eltrombopag were reported to be 75 mg in 4 cases, 150 mg in 1 case, and 300 mg in 1 case.
Three reports were of suspected interactions with creatinine test values leading to falsely high/normal values (false-positive). All 3 cases of a positive interaction with serum creatinine values were in patients with paediatric severe aplastic anaemia on high doses of eltrombopag (to 5 mg/kg and 7.5 mg/kg per day; equivalent to 375 mg).
Of the 9 reported cases of interference, 2 resulted in eltrombopag dose reductions and 2 led to temporarily discontinuation of the medicine. In 1 case eltrombopag was discontinued 4 days after suspected interference with a biological test due to lack of response. Two cases did not result in eltrombopag dose reductions and the action taken with eltrombopag was not reported in the remaining 2 cases.
In addition, several publications describe potential negative interference from eltrombopag on bilirubin testing and positive interference on creatinine test values. Two publications report that eltrombopag did not interfere with aminotransferases and blood urea testing findings.
Mechanism and clinical consequences
The mechanism for the eltrombopag interference with bilirubin and creatinine test values appears to be pH-dependent and method- or reagent-specific and related to the colour of eltrombopag in serum.
The false-positive interference with creatinine may result in a misleading clinical picture of apparent renal deterioration.
The interference with bilirubin is less likely to have clinically significant consequences since the stopping criteria for hepatic disorders are based on rises in ALT levels and clinical symptoms/evidence of hepatic decompensation, rather than bilirubin values alone.
Call for reporting
Please continue to report suspected adverse drug reactions to eltrombopag on a Yellow Card.
Article citation: Drug Safety Update volume 11, issue 12; July 2018: 3.