b'BRIEF SUMMARY OF PRESCRIBING INFORMATION 6 ADVERSE REACTIONS Other clinically significant adverse reactions that occurred in 10% of patients with mantle cell lymphoma includefMusculoskeletal pain includes back pain, arthralgia, pain in extremity, musculoskeletal pain, myalgia, bone pain, spinal pain,FOR BRUKINSA (zanubrutinib) major hemorrhage (defined asGrade 3 hemorrhage or CNS hemorrhage of any grade) (5%) and headache (4.2%). musculoskeletal chest pain, neck pain, arthritis, musculoskeletal discomfort. SEE PACKAGE INSERT FOR FULL PRESCRIBING INFORMATION The following clinically significant adverse reactions are discussed in more detail in other sections of the labeling: a gHemorrhage includes epistaxis, hematuria, conjunctival hemorrhage, hematoma, rectal hemorrhage, periorbital hemorrhage, Hemorrhage [see Warnings and Precautions (5.1)] Table 4: Selected Laboratory Abnormalities (20%) in Patients with MCL mouth hemorrhage, post procedural hemorrhage, hemoptysis, skin hemorrhage, hemorrhoidal hemorrhage, ear hemorrhage, eye 1 INDICATIONS AND USAGEInfections [see Warnings and Precautions (5.2)] in Studies BGB-3111-206 and BGB-3111-AU-003 hemorrhage, hemorrhagic diathesis, periorbital hematoma, subdural hemorrhage, wound hemorrhage, gastric hemorrhage, lowerCytopenias [see Warnings and Precautions (5.3)] Percent of Patients (N=118) gastrointestinal hemorrhage, spontaneous hematoma, traumatic hematoma, traumatic intracranial hemorrhage, tumor hemorrhage, 1.1 Mantle Cell Lymphoma Laboratory Parameter retinal hemorrhage, hematochezia, diarrhea hemorrhagic, hemorrhage, melena, post-procedural hematoma, subdural hematoma, BRUKINSA is indicated for the treatment of adult patients with mantle cell lymphoma (MCL) who have received at Second Primary Malignancies [see Warnings and Precautions (5.4)] All Grades (%) Grade 3 or 4 (%) anal hemorrhage, hemorrhagic disorder, pericardial hemorrhage, postmenopausal hemorrhage, stoma site hemorrhage, subarachnoid least one prior therapy.Cardiac Arrhythmias [see Warnings and Precautions (5.5)] Hematologic abnormalities hemorrhage.This indication is approved under accelerated approval based on overall response rate [see Clinical Studies6.1 Clinical Trials Experience Neutrophils decreased 45 20 Clinically relevant adverse reactions in 10% of patients who received BRUKINSA included localized infection, (14.1)]. Continued approval for this indication may be contingent upon verification and description of clinical Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in theb atrial fibrillation or atrial flutter, and hematuria.benefit in a confirmatory trial. clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not Lymphocytosis 41 16 Table 6 summarizes the laboratory abnormalities in ASPEN.1.2 Waldenstrms Macroglobulinemia reflect the rates observed in practice. Platelets decreased 40 7 Table 6: Select Laboratory Abnormalitiesa (20%) that Worsened from Baseline in Patients with WM BRUKINSA is indicated for the treatment of adult patients with Waldenstrms macroglobulinemia (WM) [seeThe data in the WARNINGS AND PRECAUTIONS reflect exposure to BRUKINSA in nine monotherapy and 2Hemoglobin decreased 27 6 Who Received BRUKINSA in Cohort 1Clinical Studies (14.2)]. combination clinical trials, administered at 160 mg twice daily in 1608 patients and at 320 mg once daily in 121Chemistry abnormalities BRUKINSAb Ibrutinibb1.3 Marginal Zone Lymphoma patients. Among these 1729 patients, the median duration of exposure was 27.6 months, 78% of patients wereBlood uric acid increased 29 2.6 Laboratory Abnormality All Grades (%) Grade 3 or 4 (%) All Grades (%) Grade 3 or 4 (%)BRUKINSA is indicated for the treatment of adult patients with relapsed or refractory marginal zone lymphomaexposed for at least 12 months, and 60% of patients were exposed for at least 24 months.ALT increased 28 0.9(MZL) who have received at least one antiCD20-based regimen. In this pooled safety population, the most common adverse reactions (30%), including laboratory abnormalities,Hematologic abnormalitieswere neutrophil count decreased (51%), platelet count decreased (41%), upper respiratory tract infection (38%),Bilirubin increased 24 0.9 Neutrophils decreased 50 24 34 9This indication is approved under accelerated approval based on overall response rate [see Clinical Studies aBased on laboratory measurements.hemorrhage (32%), and musculoskeletal pain (31%). b Platelets decreased 35 8 39 5(14.3)]. Continued approval for this indication may be contingent upon verification and description of clinicalAsymptomatic lymphocytosis is a known effect of BTK inhibition.benefit in a confirmatory trial. Mantle Cell Lymphoma (MCL) Hemoglobin decreased 20 7 20 71.4 Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma The safety of BRUKINSA was evaluated in 118 patients with MCL who received at least one prior therapy Waldenstrms Macroglobulinemia (WM) Chemistry abnormalitiesThe safety of BRUKINSA was investigated in two cohorts of Study BGB-3111-302 (ASPEN). Cohort 1 includedBRUKINSA is indicated for the treatment of adult patients with chronic lymphocytic leukemia (CLL) or smallin two single-arm clinical trials, BGB-3111-206 [NCT03206970] and BGB-3111-AU-003 [NCT02343120] MUT Glucose increased 45 2.3 33 2.3) WM, randomized to and treated with either BRUKINSA (101 patients) or lymphocytic lymphoma (SLL) [see Clinical Studies (14.4)]. [see Clinical Studies (14.1)]. The median age of patients who received BRUKINSA in studies BGB-3111-206 199 patients with MYD88 mutation (MYD88 WTand BGB-3111-AU-003 was 62 years (range: 34 to 86), 75% were male, 75% were Asian, 21% were White, ibrutinib (98 patients). The trial also included a non-randomized arm, Cohort 2, with 26 wild type MYD88 (MYD88 ) WMCreatinine increased 31 1 21 11.5 Follicular Lymphoma and 94% had an ECOG performance status of 0 to 1. Patients had a median of 2 prior lines of therapy (range: 1 to 4). patients and 2 patients with unknown MYD88 status [see Clinical Studies (14.2)]. Calcium decreased 27 2 26 0BRUKINSA is indicated for the treatment of adult patients with relapsed or refractory follicular lymphoma (FL), The BGB-3111-206 trial required a platelet count 75109/L and an absolute neutrophil count 1109/LAmong patients who received BRUKINSA, 93% were exposed for 6 months or longer, and 89% were exposed for in combination with obinutuzumab, after two or more lines of systemic therapy. independent of growth factor support, hepatic enzymes 2.5upper limit of normal, total bilirubin 1.5ULN.greater than 1 year.Potassium increased 24 2 12 0This indication is approved under accelerated approval based on response rate and durability of response [seeThe BGB-3111-AU-003 trial required a platelet count 50109/L and an absolute neutrophil count 1109/LPhosphate decreased 20 3.1 18 0Clinical Studies (14.5)]. Continued approval for this indication may be contingent upon verification and descriptionindependent of growth factor support, hepatic enzymes 3upper limit of normal, total bilirubin 1.5ULN. In Cohort 1 of the ASPEN study safety population (N=101), the median age of patients who received BRUKINSAUrate increased 16 3.2 34 6of clinical benefit in a confirmatory trial. Both trials required a creatinine clearance (CLcr) 30 mL/min. Both trials excluded patients with priorwas 70 years (45-87 years old); 67% were male, 86% were White, 4% were Asian, and 10% were not allogeneic hematopoietic stem cell transplant, exposure to a BTK inhibitor, known infection with HIV, andreported (unknown race). In Cohort 2 of the ASPEN study safety population (N=28), the median age of patientsBilirubin increased 12 1 33 1who received BRUKINSA was 72 (39-87 years old); 50% were male, 96% were White, and 4% were not reporteda4 CONTRAINDICATIONSserologic evidence of active hepatitis B or hepatitis C infection, and patients requiring strong CYP3A inhibitorsbBased on laboratory measurements.None. or strong CYP3A inducers. Patients received BRUKINSA 160 mg twice daily or 320 mg once daily. Among(unknown race).The denominator used to calculate the rate varied from 86 to 101 based on the number of patients with a baseline value patients receiving BRUKINSA, 79% were exposed for 6 months or longer, and 68% were exposed for greaterIn Cohort 1, serious adverse reactions occurred in 44% of patients who received BRUKINSA. Serious adverseand at least one post-treatment value.5 WARNINGS AND PRECAUTIONS than one year. reactions in 2% of patients included influenza (3%), pneumonia (4%), neutropenia and neutrophil countMarginal Zone Lymphoma 5.1 Hemorrhage decreased (3%), hemorrhage (4%), pyrexia (3%), and febrile neutropenia (3%). In Cohort 2, serious adverseThe safety of BRUKINSA was evaluated in 88 patients with previously treated MZL in two single-arm clinical Fatal and serious hemorrhage has occurred in patients with hematological malignancies treated withFatal adverse reactions within 30 days of the last dose of BRUKINSA occurred in 8 (7%) of 118 patients with MCL.reactions occurred in 39% of patients. Serious adverse reactions in 2 patients included pneumonia (14%). studies, BGB-3111-214 and BGB-3111-AU-003 [see Clinical Studies (14.3)]. The trials required an absolute BRUKINSA. Grade 3 or higher hemorrhage including intracranial and gastrointestinal hemorrhage, hematuria,Fatal cases included pneumonia in 2 patients and cerebral hemorrhage in one patient. Permanent discontinuation of BRUKINSA due to an adverse reaction occurred in 2% of patients in Cohort 1 andneutrophil count 1109/L, platelet count 50 or 75109/L and adequate hepatic function and excluded and hemothorax was reported in 3.8% of patients treated with BRUKINSA in clinical trials, with fatalitiesSerious adverse reactions were reported in 36 patients (31%). The most frequent serious adverse reactions thatincluded hemorrhage (1 patient), neutropenia and neutrophil count decreased (1 patient); in Cohort 2, permanentpatients requiring a strong CYP3A inhibitor or inducer. Patients received BRUKINSA 160 mg twice daily (97%) occurring in 0.2% of patients. Bleeding of any grade, excluding purpura and petechiae, occurred in 32% ofoccurred were pneumonia (11%) and hemorrhage (5%). discontinuation of BRUKINSA due to an adverse reaction occurred in 7% of patients and included subduralor 320 mg once daily (3%). The median age in both studies combined was 70 years (range: 37 to 95), 52% were patients. Of the 118 patients with MCL treated with BRUKINSA, 8 (7%) patients discontinued treatment due to adversehemorrhage (1 patient) and diarrhea (1 patient).male, 64% were White, and 19% were Asian. Most patients (92%) had an ECOG performance status of 0 to 1. Bleeding has occurred in patients with and without concomitant antiplatelet or anticoagulation therapy.reactions in the trials. The most frequent adverse reaction leading to treatment discontinuation was pneumoniaDosage interruptions of BRUKINSA due to an adverse reaction occurred in 32% of patients in Cohort 1 andEighty percent received BRUKINSA for 6 months or longer, and 67% received treatment for more than one year.Coadministration of BRUKINSA with antiplatelet or anticoagulant medications may further increase the risk(3.4%). One (0.8%) patient experienced an adverse reaction leading to dose reduction (hepatitis B). in 29% in Cohort 2. Adverse reactions which required dosage interruption in 2% of patients includedTwo fatal adverse reactions (2.3%) occurred within 30 days of the last dose of BRUKINSA, including myocardial of hemorrhage. Table 3 summarizes the adverse reactions in BGB-3111-206 and BGB-3111-AU-003. neutropenia, vomiting, hemorrhage, thrombocytopenia, and pneumonia in Cohort 1. Adverse reactions leadinginfarction and a Covid-19related death.Monitor for signs and symptoms of bleeding. Discontinue BRUKINSA if intracranial hemorrhage of any gradeto dosage interruption in 2 patients in Cohort 2 included pneumonia and pyrexia. Serious adverse reactions occurred in 40% of patients. The most frequent serious adverse reactions were occurs. Consider the benefit-risk of withholding BRUKINSA for 3-7 days before and after surgery depending uponTable 3: Adverse Reactions (10%) in Patients Receiving BRUKINSA in BGB-3111-206 and Dose reductions of BRUKINSA due to an adverse reaction occurred in 11% of patients in Cohort 1 and in 7% in Cohort 2.pyrexia (8%) and pneumonia (7%). the type of surgery and the risk of bleeding. BGB-3111-AU-003 Trials Adverse reactions which required dose reductions in 2% of patients included neutropenia in Cohort 1. AdverseAdverse reactions lead to treatment discontinuation in 6% of patients, dose reduction in 2.3%, and dose Percent of Patientsreaction leading to dose reduction occurred in 2 patients in Cohort 2 (each with one event: diarrhea and pneumonia). interruption in 34%. The leading cause of dose modification was respiratory tract infections (13%).5.2 Infections Body System Adverse Reaction (N=118) Table 5 summarizes the adverse reactions in Cohort 1 in ASPEN. Table 7 summarizes selected adverse reactions in BGB-3111-214 and BGB-3111-AU-003.Fatal and serious infections (including bacterial, viral, or fungal infections) and opportunistic infections have occurredAll GradesGrade 3 or in patients with hematological malignancies treated with BRUKINSA. Grade 3 or higher infections occurred in 26% a % Higher % Table 5: Adverse Reactions (10%) Occurring in Patients with WM Who Received BRUKINSA in Cohort 1Table 7: Adverse Reactions Occurring in 10% Patients with MZL Who Received BRUKINSA of patients, most commonly pneumonia (7.9%), with fatal infections occurring in 3.2% of patients. Infections due to Upper respiratory tract infection 39 0hepatitis B virus (HBV) reactivation have occurred. BRUKINSA (N=101) Ibrutinib (N=98) BRUKINSA (N=88)Consider prophylaxis for herpes simplex virus, pneumocystis jirovecii pneumonia, and other infections according Infections and infestations Pneumoniab 1510c Body System Adverse Reaction All GradesGrade 3 All GradesGrade 3 Body System Adverse Reaction All GradesGrade 3to standard of care in patients who are at increased risk for infections. Monitor and evaluate patients for fever orUrinary tract infection 11 0.8 (%) or 4 (%) (%) or 4 (%) (%) or 4 (%)d Upper respiratoryaother signs and symptoms of infection and treat appropriately. Rash 36 0 tract infectiona 44 0 40 2 Upper respiratory tract infection 26 3.45.3 Cytopenias Skin and subcutaneous tissue disorders Bruisinge 14 0 Infections and infestations Pneumoniab 12 4 26 10 Infections and infestations Urinary tract infectionb 11 2.3Grade 3 or 4 cytopenias, including neutropenia (21%), thrombocytopenia (8%), and anemia (8%) based on laboratoryDiarrhea 23 0.8 Urinary tract infection 11 0 13 2 Pneumoniac,d 10 6measurements, developed in patients treated with BRUKINSA [see Adverse Reactions (6.1)]. Grade 4 neutropenia Gastrointestinal disorders Constipation 13 0 Diarrhea 22 3 34 2 Diarrheae 25 3.4 occurred in 10% of patients, and Grade 4 thrombocytopenia occurred in 2.5% of patients.Monitor complete blood counts regularly during treatment and interrupt treatment, reduce the dose, or discontinueHypertension 12 3.4 Nausea 18 0 13 1 Gastrointestinal disorders Abdominal painf 14 2.3treatment as warranted [see Dosage and Administration (2.4)]. Treat using growth factor or transfusions, as needed. Vascular disorders Hemorrhagef113.4c Gastrointestinal disorders Constipation 16 0 7 0 Nausea 13 05.4 Second Primary Malignancies Musculoskeletal and connective g 14 3.4 Vomiting 12 0 14 1 Skin and subcutaneous tissue disorders Bruisingg 24 0Second primary malignancies, including non-skin carcinoma, have occurred in 14% of patients treated withtissue disorders Musculoskeletal pain Fatiguec 31 1 25 1 Rashh 21 0BRUKINSA. The most frequent second primary malignancy was non-melanoma skin cancers (8%), followed byRespiratory, thoracic, and Cough 12 0 General disordersPyrexia 16 4 13 2 Musculoskeletal and connectiveiother solid tumors in 7% of the patients (including melanoma in 1% of patients) and hematologic malignanciesmediastinal disorders tissue disorders Musculoskeletal pain 27 1.1(0.7%). Advise patients to use sun protection and monitor patients for the development of second primaryaUpper respiratory tract infection includes upper respiratory tract infection, upper respiratory tract infection viral. Edema peripheral 12 0 20 0 jmalignancies. bPneumonia includes pneumonia, pneumonia fungal, pneumonia cryptococcal, pneumonia streptococcal, atypical pneumonia, lung Bruisingd 20 0 34 0 Vascular disorders Hemorrhage23 1.15.5 Cardiac Arrhythmias c infection, lower respiratory tract infection, lower respiratory tract infection bacterial, lower respiratory tract infection viral. Skin and subcutaneous tissueRashe 29 0 32 0 General disorders Fatiguek 21 2.3Serious cardiac arrhythmias have occurred in patients treated with BRUKINSA. Atrial fibrillation and atrial flutterd Includes fatal adverse reaction. disorders Respiratory, thoracic, and le Rash includes all related terms containing rash. Pruritus 11 1 6 0 Cough 10 0were reported in 4.4% of patients treated with BRUKINSA, including Grade 3 or higher cases in1.9%of patients.Bruising includes all related terms containing bruise, bruising, contusion, ecchymosis. f mediastinal disordersPatients with cardiac risk factors, hypertension, and acute infections may be at increased risk. Grade 3 or higher fHemorrhage includes all related terms containing hemorrhage, hematoma. Musculoskeletal and connectiveMusculoskeletal pain 45 9 39 1 aventricular arrhythmias were reported in 0.3% of patients. gMusculoskeletal pain includes musculoskeletal pain, musculoskeletal discomfort, myalgia, back pain, arthralgia, arthritis. tissue disorders Muscle spasms 10 0 28 1Upper respiratory tract infection includes upper respiratory tract infection, nasopharyngitis, sinusitis, tonsillitis, rhinitis, viral upper respiratory tract infection.Monitor for signs and symptoms of cardiac arrhythmias (e.g., palpitations, dizziness, syncope, dyspnea, chest Headache 18 1 14 1 bUrinary tract infection includes urinary tract infection, cystitis, Escherichia urinary tract infection, pyelonephritis, cystitis.discomfort), manage appropriately [see Dosage and Administration (2.4)], and consider the risks and benefits of Nervous system disorders Dizziness 13 1 12 0 cPneumonia includes COVID-19 pneumonia, pneumonia, bronchopulmonary aspergillosis, lower respiratory tract infection,continued BRUKINSA treatment. d organizing pneumonia.Respiratory, thoracic, andCough 16 0 18 0 Includes 2 fatalities from COVID-19 pneumonia.5.6 Embryo-Fetal Toxicity mediastinal disorders Dyspnea 14 0 7 0 e f Diarrhea includes diarrhea and diarrhea hemorrhagic.Based on findings in animals, BRUKINSA can cause fetal harm when administered to a pregnant woman.Abdominal pain includes abdominal pain, abdominal pain upper, abdominal discomfort.Hemorrhageg 42 4 43 9 gBruising includes contusion, ecchymosis, increased tendency to bruise, post procedural contusion.Administration of zanubrutinib to pregnant rats during the period of organogenesis caused embryo-fetalVascular disorders hRash includes rash, rash maculo-papular, rash pruritic, dermatitis, dermatitis allergic, dermatitis atopic, dermatitis contact, drug reaction toxicity, including malformations at exposures that were 5 times higher than those reported in patients at theHypertension 14 9 19 14with eosinophilia and systemic symptoms, erythema, photosensitivity reaction, rash erythematous, rash papular, seborrheic dermatitis.recommended dose of 160 mg twice daily. Advise women to avoid becoming pregnant while taking BRUKINSAa iMusculoskeletal pain includes back pain, arthralgia, musculoskeletal pain, myalgia, pain in extremity, musculoskeletal chest pain,Upper respiratory tract infection includes upper respiratory tract infection, laryngitis, nasopharyngitis, sinusitis, rhinitis, viral upper and for 1 week after the last dose. Advise men to avoid fathering a child during treatment and for 1 week afterrespiratory tract infection, pharyngitis, rhinovirus infection, upper respiratory tract congestion. bone pain, musculoskeletal discomfort, neck pain. the last dose. If thisdrug is used during pregnancy, or if the patient becomes pregnant while taking this drug,bPneumonia includes lower respiratory tract infection, lung infiltration, pneumonia, pneumonia aspiration, pneumonia viral.j Hemorrhage includes epistaxis, hematuria, hemorrhoidal hemorrhage, hematoma, hemoptysis, conjunctival hemorrhage, diarrhea the patient should be apprised of the potential hazard to a fetus [see Use in Specific Populations (8.1)]. cFatigue includes asthenia, fatigue, lethargy. hemorrhagic, hemorrhage urinary tract, mouth hemorrhage, pulmonary hematoma, subcutaneous hematoma, gingival bleeding, dBruising includes all related terms containing bruise, contusion, or ecchymosis. melena, upper gastrointestinal hemorrhage.eRash includes all related terms rash, maculo-papular rash, erythema, rash erythematous, drug eruption, dermatitis allergic, dermatitis atopic,Fatigue includes fatigue, lethargy, asthenia.krash pruritic, dermatitis, photodermatoses, dermatitis acneiform, stasis dermatitis, vasculitic rash, eyelid rash, urticaria, skin toxicity.l Cough includes cough and productive cough.'