Precautions of Acalabrutinib

1. Severe and Opportunistic Infections

Fatal and severe infections, including opportunistic infections, have occurred in patients with hematologic malignancies receiving acalabrutinib treatment.

Among 1,764 patients exposed to acalabrutinib in clinical trials, 32% experienced severe or Grade 3 or higher infections (bacterial, viral, or fungal). The most common cause was respiratory tract infections (19% of all patients, including 9% with pneumonia). These infections mainly occurred in the absence of Grade 3 or 4 neutropenia, and neutropenic infections were reported in 2.7% of all patients. Opportunistic infections in acalabrutinib recipients include, but are not limited to, hepatitis B virus reactivation, fungal pneumonia, Pneumocystis jirovecii pneumonia, Epstein-Barr virus reactivation, cytomegalovirus, and progressive multifocal leukoencephalopathy. Prophylaxis should be considered for patients at increased risk of opportunistic infections. Monitor patients for signs and symptoms of infection and treat promptly.

2. Bleeding

Fatal and severe bleeding events have occurred in patients receiving acalabrutinib treatment.

Among 1,764 patients exposed to acalabrutinib in clinical trials, major bleeding (severe or Grade 3 or higher bleeding, or any central nervous system bleeding) occurred in 4.4% of patients, and fatal bleeding occurred in 0.2% of patients. Bleeding events of any grade (excluding bruising and petechiae) occurred in 40% of patients.

Concomitant use of antithrombotic drugs with acalabrutinib may further increase the risk of bleeding. In clinical trials, the incidence of major bleeding was 7% in patients not taking antithrombotic drugs and 4% in patients taking antithrombotic drugs. When administered concomitantly with acalabrutinib, the risks and benefits of antithrombotic drugs should be considered. Monitor patients for signs of bleeding.

Depending on the type of surgery and bleeding risk, consider the benefit-risk of discontinuing acalabrutinib for 3 to 7 days before and after surgery.

3. Cytopenias

Acalabrutinib can cause Grade 3 or 4 cytopenias. Among patients receiving acalabrutinib monotherapy or in combination with obinutuzumab, Grade 3 or 4 cytopenias included decreased absolute neutrophil count (26%), thrombocytopenia (10%), decreased hemoglobin (10%), and decreased absolute lymphocyte count (10%); the incidence of Grade 4 neutropenia was 14%.

Monitor complete blood counts regularly during treatment. Interrupt treatment, reduce the dose, or discontinue treatment as appropriate.

4. Second Primary Malignancies

Among 1,764 patients exposed to acalabrutinib in clinical trials, 18% developed second primary malignancies, including skin cancer and other solid tumors. The most common second primary malignancy was non-melanoma skin cancer, reported in 10% of patients, followed by other solid tumors (9%, including melanoma, lung cancer, gastrointestinal cancer, and genitourinary cancer) and hematologic malignancies (1%). Monitor patients for the development of second cancers and advise avoiding sun exposure.

5. Cardiac Arrhythmias

Fatal and severe cardiac arrhythmias have occurred in patients receiving acalabrutinib treatment.

Among 1,764 patients treated with acalabrutinib, the reporting rate of Grade 3 or 4 atrial fibrillation or flutter was 2.6%, and the reporting rate of atrial fibrillation or flutter of all grades was 7%. The reporting rate of Grade 3 or higher ventricular arrhythmia events was 0.6%, including fatal cases accounting for 0.3% of all patients. Patients with cardiac risk factors, hypertension, previous arrhythmias, and acute infections may have an increased risk of developing arrhythmias. Monitor for symptoms of arrhythmias (e.g., palpitations, dizziness, syncope, dyspnea) and manage appropriately.

6. Hepatotoxicity, Including Drug-Induced Liver Injury

Hepatotoxicity, including severe, life-threatening, and potentially fatal cases of drug-induced liver injury, has occurred in patients receiving Bruton’s Tyrosine Kinase (BTK) inhibitors, including acalabrutinib.

Assess bilirubin and transaminases before and during acalabrutinib treatment. For patients who develop abnormal liver function tests after using acalabrutinib, more frequent monitoring of abnormal liver function tests and clinical signs and symptoms of hepatotoxicity is recommended. If drug-induced liver injury is suspected, discontinue acalabrutinib temporarily. After confirming drug-induced liver injury, discontinue acalabrutinib permanently.

FDA，2025.01