Background: A 68-year-old male taking ibrutinib 560 mg daily for mantle cell lymphoma presented to ED with shortness of breath, chest pain and dizziness. He was subsequently admitted and diagnosis included atrial fibrillation (AF), attributed to ibrutinib therapy. Metoprolol, digoxin, and diltiazem were started for rate control. Ibrutinib was withheld but then recommenced on discharge. Three months post-discharge the patient had a cardiac arrest, and died three days later.
Aim: To determine the optimal dosing of ibrutinib in patients commenced on diltiazem for treatment of AF.
Method: A literature review was conducted to determine ibrutinib dosing in the context of diltiazem and to identify interactions. The patient’s records were reviewed and causality analysis, using the Naranjo algorithm, was conducted to identify the likelihood of ibrutinib toxicity causing the fatal reaction.
Results: The Naranjo algorithm score was 7 (probable reaction) for the ibrutinib and diltiazem interaction causing ibrutinib toxicity. The patient’s arrhythmias and cardiac arrest were secondary to ibrutinib toxicity due to concomitant treatment with diltiazem. As diltiazem is a moderate inhibitor of CYP3A4 and ibrutinib is a substrate of this enzyme, prolonged co-administration of the two drugs is likely to result in reduced ibrutinib clearance and subsequent cardiotoxicity. For patients who present with AF requiring rate control while taking ibrutinib, the recommended treatment sequence is a beta-blocker, then digoxin if required (space doses six hours apart from ibrutinib to minimise P-glycoprotein interactions in the gastrointestinal tract). If further rate control therapy is needed and diltiazem is prescribed, the dose of ibrutinib should be reduced by 50% to 75%, depending on the patient’s clinical requirements.1,2
Conclusion: Medication review is essential for high-risk patients at every transition of care. This case highlights the need for clear guidelines with recommendations on cardiac assessments for high-risk patients and management of new onset cardiac toxicities.