What are the adverse effects of Ibrutinib (Imbruvica)?

From the Guidelines

Ibrutinib is associated with a significant risk of atrial fibrillation, occurring in 6-16% of patients, and this adverse effect can have serious consequences, including increased risk of mortality and serious complications, such as ischemic stroke and heart failure. The incidence of atrial fibrillation with ibrutinib increases over time, with a median exposure time of 13 months, and can be as high as 16% after 2 years of therapy 1. The mechanisms of ibrutinib-associated atrial fibrillation are not well established, but may be related to off-target inhibition of cardiac Tec protein kinase and PI3K, and enhanced automaticity related to abnormal Ca2+ handling 1.

Management of Atrial Fibrillation

The treatment of ibrutinib-induced atrial fibrillation is complicated due to the antiplatelet properties of ibrutinib, which increases the risk of major and clinically relevant non-major bleeds, and its interactions with several drugs utilized in the management of atrial fibrillation, including oral anticoagulants 1. However, atrial fibrillation and bleeding are manageable, and preexisting atrial fibrillation should not represent a contraindication to ibrutinib therapy 1.

Monitoring and Prevention

Patients should be advised to report unusual bleeding, heart palpitations, shortness of breath, or signs of infection promptly, and blood pressure should be monitored regularly 1. Concomitant medications that increase bleeding risk, such as anticoagulants and NSAIDs, should be used cautiously, and testing for von Willebrand activity in patients with a history of bleeding diathesis before starting ibrutinib is reasonable 1.

Alternative Treatment Options

Newer BTK inhibitors, such as acalabrutinib and zanubrutinib, with higher BTK selectivity, present a lower incidence of atrial fibrillation than ibrutinib, and may be considered as alternative treatment options for patients at high risk of atrial fibrillation 1.

From the FDA Drug Label

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Hemorrhage [see Warnings and Precautions (5. 1)] Infections [see Warnings and Precautions (5.2)] Cardiac Arrhythmias, Cardiac Failure, and Sudden Death [see Warnings and Precautions (5.3)] Hypertension [see Warnings and Precautions (5.4)] Cytopenias [see Warnings and Precautions (5.5)] Second Primary Malignancies [see Warnings and Precautions (5.6)] Hepatotoxicity, including DILI [see Warnings and Precautions (5. 7)] Tumor Lysis Syndrome [see Warnings and Precautions (5.8)]

1. 1 Clinical Trials Experience Because clinical trials are conducted under widely variable conditions, adverse reaction rates observed in clinical trials of a drug cannot be directly compared with rates of clinical trials of another drug and may not reflect the rates observed in practice Unless otherwise specified, the pooled safety population described in the WARNINGS AND PRECAUTIONS reflects exposure to IMBRUVICA in 6 trials. IMBRUVICA was administered as a single agent at 420 mg orally once daily (475 patients), as a single agent at 560 mg orally once daily [1. 3 times the recommended adult dosage (174 patients)], and in combination with other drugs at 420 mg orally once daily (827 patients) in patients with B-cell malignancies. In this pooled safety population of 1,476 patients, 87% were exposed for 6 months or longer and 68% were exposed for greater than one year The most common adverse reactions (≥ 30%) were thrombocytopenia, diarrhea, fatigue, musculoskeletal pain, neutropenia, rash, anemia, bruising, and nausea.

The common adverse reactions of ibrutinib include:

• thrombocytopenia
• diarrhea
• fatigue
• musculoskeletal pain
• neutropenia
• rash
• anemia
• bruising
• nausea 2

From the Research

Ibrutinib Adverse Effects

• The most common side effects of ibrutinib are diarrhea, upper respiratory tract infection, bleeding, fatigue, and cardiac side effects, which are generally mild (grade I-II) 3.
• However, atrial fibrillation (AF) and bleeding are important and may be grade III or higher side effects that require strict monitoring 3.
• Other adverse events associated with ibrutinib include dysrhythmias, infections, and constitutional symptoms, which can result in dose reduction or discontinuation of ibrutinib 4.
• Unique adverse events related to ibrutinib have been reported, including palindromic rheumatoid arthritis, diffuse spongiotic dermatitis, bullous pemphigoid, recurrent hemorrhagic stroke, peripheral neuropathy, and pulmonary aspergillosis 5.
• Ibrutinib has been associated with a high risk of abdominal manifestations, including diarrhea, compared to control groups 6.
• The management of ibrutinib's adverse events often requires individualized approaches and may involve dose reduction or transition to alternative therapies 7.

Management of Adverse Events

• Regular monitoring for adverse events and proactive treatment are essential to minimize side effects and avoid disruption of ibrutinib therapy 4.
• Strategies for managing common adverse events associated with ibrutinib, such as atrial fibrillation, bleeding, and infections, are crucial in real-world clinical practice 7.
• Investigation of the pathogenesis of adverse events with ibrutinib and clinical trials examining therapeutic approaches for complications arising during therapy are needed 7.