Could Lower Dose of Imbruvica Help Mitigate Adverse Events?
Written by: Lauren Schwab, Legal Assistant
Law Offices of Thomas J. Lamb, P.A.
Imbruvica (ibrutinib) has been associated with cardiotoxic properties, and in some cases, even death. A recent November 2020 article, "Ibrutinib’s Cardiotoxicity - An Opportunity for Postmarketing Regulation” published in JAMA Oncology, highlights a study of chronic lymphocytic leukemia (CLL) in relation to Imbruvica. The study found a significant increase in death rate for those using Imbruvica when compared to the controlled factor:
This drug is known to have cardiotoxic properties, probably due to off-target inhibition of another kinase. While in randomized trials ibrutinib [Imbruvica] has been demonstrated to increase survival, some studies have demonstrated fatal toxic effects associated with the drug. This was most obvious in a 3-arm study of CLL in which the 2 ibrutinib [Imbruvica] arms were associated with a 7% rate of death during treatment or within 30 days after treatment cessation, compared with a 1% rate of death in the control arm.
Similar toxicity reports have been found in another Bruton tyrosine kinase (BTK) inhibitor drug, Calquence (acalabrutinib), although the labeling for this drug does include a warning regarding the risk of atrial fibrillation and flutter. Another study conducted by the World Health Organization (WHO), and analyzed by the Food and Drug Administration (FDA) reviews the 303 Imbruvica deaths and their causes from 2015-2017:
This analysis included 13,572 reports involving ibrutinib [Imbruvica] as of January 2018, primarily in patients receiving treatment for CLL. More than 97% of the events were from 2015-2017 and included 303 ibrutinib [Imbruvica] associated deaths. Of total deaths, 103 were due to arrhythmias, and 90 were due to central nervous system hemorrhage. Conduction disorders (mainly high-grade atrioventricular block) were also notable.
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Could Lowering Imbruvica's Recommended Dosage Impact Adverse Events?
Some discussion has occurred over whether a lower dosage of Imbruvica would have any affect on the adverse events and deaths associated with the drug. According to the same November 2020 article, "Ibrutinib’s Cardiotoxicity - An Opportunity for Postmarketing Regulation”:
In analyzing the original application, the FDA reviewers included the following comment to the sponsor: “We recommend you evaluate lower doses in future clinical development as data from the phase 1 trial PCYC-04753 showed that maximum BTK occupancy and maximum response were achieved at doses of 2.5mg/kg.”
Furthermore, a 2019 study reiterated the need for a lower dosage of Imbruvica:
A 2019 preclinical study that tested the effects of ibrutinib [Imbruvica] on stem cell–derived cardiomyocytes differentiated into “atrial-like” cardiomyocytes found that ibrutinib [Imbruvica] caused a dose-dependent decrease in action potential duration and cardiomyocyte viability that was associated with an increase in calcium transient duration. These preclinical results are consistent with recent evidence regarding the serious cardiac adverse events associated with ibrutinib [Imbruvica] use.
However, no further studies have been performed by the manufacturer, despite FDA recommendations for additional testing of Imbruvica at lower doses. Due to a lack of data on the effects of Imbruvica dosage and the role it plays in the adverse events cause by the drug, it is currently unclear if the lower dose would have an impact, and susceptible patients may still have an adverse reaction, despite taking Imbruvica at a lower dose.
We will continue to monitor the drug safety profile of Imbruvica and report significant developments, including any additional Imbruvica drug label changes, here.
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