b'Available on the IMPORTANT SAFETY INFORMATION(CONT)VA National and WARNINGS AND PRECAUTIONS(CONT)TRICARE Formularies InfectionsFatal and serious infections (including bacterial, viral, or fungal infections) and opportunistic infections have occurred in patients with hematological malignancies treated with BRUKINSA monotherapy. Grade 3 or higher infections occurred in 24% of patients, most commonly pneumonia (11%), with fatal infections occurring in 2.9% of patients. Infections due to hepatitis B virus (HBV) reactivation have occurred.BRUKINSA IS THE ONLY BTK INHIBITORConsider prophylaxis for herpes simplex virus, pneumocystis jirovecii pneumonia, and other infections according CURRENTLY APPROVED TO TREATto standard of care in patients who are at increased risk for infections. Monitor and evaluate patients for fever or FOUR DIFFERENT B-CELL MALIGNANCIES other signs and symptoms of infection and treat appropriately.CytopeniasGrade 3 or 4 cytopenias, including neutropenia (22%), thrombocytopenia (8%) and anemia (7%) based on laboratory measurements, developed in patients treated with BRUKINSA monotherapy. Grade 4 neutropenia BRUKINSA WAS DESIGNED TO MEEToccurred in 11% of patients, and Grade 4 thrombocytopenia occurred in 2.8% of patients. THE CHALLENGES OF BTK INHIBITION Monitor complete blood counts regularly during treatment and interrupt treatment, reduce the dose, or discontinue treatment as warranted. Treat using growth factor or transfusions, as needed.High potency and affinitySustainedLow off-targetSecond Primary Malignanciesfor BTK 1,2 24-hour inhibition 2 binding 2,3 Second primary malignancies, including non-skin carcinoma, have occurred in 13% of patients treated with Inhibition in PBMCs is 100% with bothConcentration levelsHigh affinity for BTKBRUKINSA monotherapy. The most frequent second primary malignancy was non-melanoma skin cancer twice-daily and once-daily dosing.continuously maintainedwith low off-targetreported in 7% of patients. Other second primary malignancies included malignant solid tumors (5%), melanoma Inhibition in lymph nodes is 100% withabove the IC 50for binding, including(1.2%), and hematologic malignancies (0.5%). Advise patients to use sun protection and monitor patients for the twice-daily and 94% with once-daily dosing. 24 hours. TEC, HER4, and JAK3. development of second primary malignancies.The clinical significance of 100% inhibition has not been established. Cardiac ArrhythmiasSerious cardiac arrhythmias have occurred in patients treated with BRUKINSA. Atrial fibrillation and atrial flutter were reported in 3.7% of 1550 patients treated with BRUKINSA monotherapy, including Grade 3 or higher cases in 1.7% of patients. Patients with cardiac risk factors, hypertension, and acute infections may be at increased risk. Grade 3 or higher ventricular arrhythmias were reported in 0.2% of patients. Monitor for signs and symptoms of cardiac arrhythmias (e.g., palpitations, dizziness, syncope, dyspnea, chest discomfort), manage appropriately, and consider the risks and benefits of continued BRUKINSA treatment.To learn more about the BTK inhibitor BRUKINSA and all itsEmbryo-Fetal Toxicityindications, visit BRUKINSA.com Based on findings in animals, BRUKINSA can cause fetal harm when administered to a pregnant woman. Administration of zanubrutinib to pregnant rats during the period of organogenesis caused embryo-fetal toxicity, including malformations at exposures that were 5 times higher than those reported in patients at the recommended dose of 160 mg twice daily. Advise women to avoid becoming pregnant while taking BRUKINSA INDICATIONS and for 1 week after the last dose. Advise men to avoid fathering a child during treatment and for 1 week after the BRUKINSA is a kinase inhibitor indicated for the treatment of adult patients with: last dose. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus.Chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) ADVERSE REACTIONS Waldenstrms macroglobulinemia (WM)In this pooled safety population, the most common adverse reactions, including laboratory abnormalities, in 30% Mantle cell lymphoma (MCL) who have received at least one prior therapy. of patients who received BRUKINSA (N=1550) included decreased neutrophil count (42%), upper respiratory tract infection (39%), decreased platelet count (34%), hemorrhage (30%), and musculoskeletal pain (30%).Relapsed or refractory marginal zone lymphoma (MZL) who have received at least one anti-CD20-based regimen.The MCL and MZL indications are approved under accelerated approval based on overall response rate.DRUG INTERACTIONSContinued approval for these indications may be contingent upon verification and description of clinical benefit in confirmatory trials. CYP3A Inhibitors: When BRUKINSA is co-administered with a strong CYP3A inhibitor, reduce BRUKINSA dose to 80 mg once daily. For coadministration with a moderate CYP3A inhibitor, reduce BRUKINSA dose to 80 mg IMPORTANT SAFETY INFORMATION twice daily.WARNINGS AND PRECAUTIONS CYP3A Inducers: Avoid coadministration with strong or moderate CYP3A inducers. Dose adjustment may be recommended with moderate CYP3A inducers.Hemorrhage SPECIFIC POPULATIONSFatal and serious hemorrhage has occurred in patients with hematological malignancies treated with BRUKINSAHepatic Impairment: The recommended dose of BRUKINSA for patients with severe hepatic impairment ismonotherapy. Grade 3 or higher hemorrhage, including intracranial and gastrointestinal hemorrhage, hematuria80 mg orally twice daily.and hemothorax have been reported in 3.6% of patients treated with BRUKINSA monotherapy in clinical trials, with fatalities occurring in 0.3% of patients. Bleeding of any grade, excluding purpura and petechiae, occurred inPlease see Brief Summary of Prescribing Information on the following pages.30% of patients. Abbreviations: BTK, Bruton tyrosine kinase; HER4, human epidermal growth factor receptor 4; IC 50 , half maximal inhibitory concentration; JAK3, Janus kinase 3; Bleeding has occurred in patients with and without concomitant antiplatelet or anticoagulation therapy.PBMC, peripheral blood mononuclear cell; TEC, tyrosine kinase expressed in hepatocellular carcinoma; VA, Veterans Affairs. Coadministration of BRUKINSA with antiplatelet or anticoagulant medications may further increase the riskReferences: 1. BRUKINSA. Package insert. BeiGene, Ltd; 2023. 2. Tam CS, Ou YC, Trotman J, Opat S. Clinical pharmacology and PK/PD translation of the second-generation of hemorrhage. Brutons tyrosine kinase inhibitor, zanubrutinib. Expert Rev Clin Pharmacol. 2021;14(11):1329-1344. doi:10.1080/17512433.2021.1978288 3. Kaptein A, de Bruin G, Emmelot-van Monitor for signs and symptoms of bleeding. Discontinue BRUKINSA if intracranial hemorrhage of any gradeHoek M, et al. Potency and selectivity of BTK inhibitors in clinical development for B-cell malignancies. Blood. 2018;132(suppl 1):1871. doi:10.1182/blood-2018-99-109973occurs. Consider the benefit-risk of withholding BRUKINSA for 3-7 days pre- and post-surgery depending upon the type of surgery and the risk of bleeding.BRUKINSA and BeiGene are registered trademarks owned by BeiGene, Ltd or its affiliates.BeiGene, Ltd. 2023 Please see Brief Summary of Prescribing Information on the following pages. All Rights Reserved. 0523-BRU-PRC-104 6/2023BeiGene Market AccessBrukinsa Trim: 7.875 x 10.75Federal Ad 2US Medicine Bleed: 0.125 all around0523-BRU-PRC-104 6/2023 Safety:0.375 all aroundSix page (3 spreads) journal ad'