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Fatal and serious infections (including bacterial, viral, or fungal infections) and opportunistic infections have occurred in patients treated with pirtobrutinib. In the clinical trial, Grade 3 or higher infections occurred in 24% of 593 patients, most commonly pneumonia (14%), with fatal infections occurring in 4.4% of patients. Sepsis occurred in 6% of patients and febrile neutropenia in 4%. In patients with CLL/SLL, Grade 3 or higher infections occurred in 32% of patients, with fatal infections occurring in 8%. Opportunistic infections after treatment with pirtobrutinib have included, but are not limited to, Pneumocystis jirovecii pneumonia and fungal infection.
Fatal and serious hemorrhage has occurred with pirtobrutinib. Major hemorrhage (defined as Grade 3 or higher bleeding or any central nervous system bleeding) occurred in 3% of 593 patients treated with pirtobrutinib, including gastrointestinal hemorrhage; fatal hemorrhage occurred in 0.3% of patients. Bleeding of any grade, excluding bruising and petechiae, occurred in 17% of patients.
pirtobrutinib can cause cytopenias, including neutropenia, thrombocytopenia, and anemia.
Cardiac arrhythmias, including atrial fibrillation and atrial flutter, were reported in recipients of pirtobrutinib. Atrial fibrillation or flutter were reported in 3.2% of patients, with Grade 3 or 4 atrial fibrillation or flutter reported in 1.5% of 593 patients in the clinical trial. Other serious cardiac arrhythmias such as supraventricular tachycardia and cardiac arrest occurred in 0.5% of patients. Patients with cardiac risk factors, such as hypertension, or previous arrhythmias may be at increased risk.
Second primary malignancies, including non-skin carcinomas, developed in 9% of 593 patients treated with pirtobrutinib monotherapy. The most frequent malignancy was non-melanoma skin cancer, reported in 4.6% of 593 patients. Other second primary malignancies included solid tumors (including genitourinary and breast cancers) and melanoma. Advise patients to use sun protection and monitor patients for the development of second primary malignancies.
Hepatotoxicity, including severe, life-threatening, and potentially fatal cases of drug-induced liver injury (DILI), has occurred in patients treated with Bruton tyrosine kinase inhibitors, including pirtobrutinib.
Based on findings in animals, pirtobrutinib can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, administration of pirtobrutinib to pregnant rats during the period of organogenesis caused embryo-fetal toxicity including embryo-fetal mortality and malformations at maternal exposures (AUC) approximately 3-times the recommended dose of 200 mg once daily. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with pirtobrutinib and for one week after the last dose.
from FDA，2024.06
