b'BRIEF SUMMARY OF PRESCRIBING INFORMATION Fatal events within 30 days of the last dose of BRUKINSA occurred in 8 (7%) of 118 patients with MCL. Fatal cases includedTable 5 summarizes the adverse reactions in Cohort 1 in ASPEN. * Includes 2 fatal events of COVID-19 pneumonia.aUpper respiratory tract infections includes upper respiratory tract infection, nasopharyngitis, sinusitis, tonsillitis, rhinitis, viral upper FOR BRUKINSA (zanubrutinib) pneumonia in 2 patients and cerebral hemorrhage in one patient. Table 5: Adverse Reactions ( 10%) Occurring in Patients with WM Who Received BRUKINSA in Cohort 1respiratory tract infection.SEE PACKAGE INSERT FOR FULL PRESCRIBING INFORMATION Serious adverse reactions were reported in 36 patients (31%). The most frequent serious adverse reactions that occurredBody System Adverse Reaction BRUKINSA (N=101) Ibrutinib (N=98) b Urinary tract infection includes urinary tract infection, cystitis, Escherichia urinary tract infection, pyelonephritis, cystitis.were pneumonia (11%) and hemorrhage (5%). dPneumonia includes COVID-19 pneumonia, pneumonia, bronchopulmonary aspergillosis, lower respiratory tract infection, organizing pneumonia.c 1 INDICATIONS AND USAGE All GradesGrade 3 All GradesGrade 3Diarrhea includes diarrhea and diarrhea hemorrhagic.Of the 118 patients with MCL treated with BRUKINSA, 8 (7%) patients discontinued treatment due to adverse reactions in (%) or 4 (%) (%) or 4 (%) efAbdominal pain includes abdominal pain, abdominal pain upper, abdominal discomfort.1.1 Mantle Cell Lymphoma the trials. The most frequent adverse reaction leading to treatment discontinuation was pneumonia (3.4%). One (0.8%)gBruising includes contusion, ecchymosis, increased tendency to bruise, post procedural contusion.BRUKINSA is indicated for the treatment of adult patients with mantle cell lymphoma (MCL) who have received at least Infections and infestations Upper respiratory44 0 40 2 Rash includes rash, rash maculo-papular, rash pruritic, dermatitis, dermatitis allergic, dermatitis atopic, dermatitis contact, drug reaction one prior therapy. patient experienced an adverse reaction leading to dose reduction (hepatitis B). tract infection h with eosinophilia and systemic symptoms, erythema, photosensitivity reaction, rash erythematous, rash papular, seborrheic dermatitis.Table 3 summarizes the adverse reactions in BGB-3111-206 and BGB-3111-AU-003.Musculoskeletal pain includes back pain, arthralgia, musculoskeletal pain, myalgia, pain in extremity, musculoskeletal chest pain, bone This indication is approved under accelerated approval based on overall response rate [see Clinical Studies (14.1)]. ContinuedPneumonia 12 4 26 10i pain, musculoskeletal discomfort, neck pain. approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial. Table 3: Adverse Reactions ( 10%) in Patients Receiving BRUKINSA in BGB-3111-206 and BGB-3111-AU-003 Trials Urinary tract infection 11 0 13 2 Hemorrhage includes epistaxis, hematuria, hemorrhoidal hemorrhage, hematoma, hemoptysis, conjunctival hemorrhage, diarrhea hemorrhagic, hemorrhage urinary tract, mouth hemorrhage, pulmonary hematoma, subcutaneous hematoma, gingival bleeding, melena, 1.2 Waldenstrms Macroglobulinemia Body System Adverse Reaction Percent of PatientsGastrointestinal disorders Diarrhea 22 3 34 2j upper gastrointestinal hemorrhage.BRUKINSA is indicated for the treatment of adult patients with Waldenstrms macroglobulinemia (WM). (N=118) Nausea 18 0 13 1 kFatigue includes fatigue, lethargy, asthenia.All GradesGrade 3 or Cough includes cough and productive cough.1.3 Marginal Zone Lymphoma % Higher % Constipation 16 0 7 0 Clinically relevant adverse reactions in 10% of patients who received BRUKINSA included peripheral neuropathy, second BRUKINSA is indicated for the treatment of adult patients with relapsed or refractory marginal zone lymphoma (MZL) Vomiting 12 0 14 1 primary malignancies, dizziness, edema, headache, petechiae, purpura and atrial fibrillation or flutter. who have received at least one anti-CD20-based regimen. Blood and lymphatic system disorders Neutropenia and38 15 # Table 8 summarizes selected laboratory abnormalities.Neutrophil count decreased General disorders Fatigue 31 1 25 1This indication is approved under accelerated approval based on overall response rate [see Clinical Studies (14.3)]. Continuedand administration site conditions Table 8: Select Laboratory Abnormalities ( 20%) That Worsened from Baseline in Patients with MZLapproval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial. Thrombocytopenia and 27 5 Pyrexia 16 4 13 2 Laboratory Abnormality1 BRUKINSAPlatelet count decreased Edema peripheral 12 0 20 04 CONTRAINDICATIONS: None. Leukopenia and25 5 Skin and subcutaneous tissueBruising* 20 0 34 0 All Grades (%) Grade 3 or 4 (%)5 WARNINGS AND PRECAUTIONS White blood count decreased disorders Rashll 29 0 32 0 Hematologic abnormalities5.1 Hemorrhage Anemia and Hemoglobin decreased 14 8 Pruritus 11 1 6 0 Neutrophils decreased 43 15Fatal and serious hemorrhagic events have occurred in patients with hematological malignancies treated with BRUKINSA Musculoskeletal and connective tissueMusculoskeletal pain 45 9 39 1 Platelets decreased 33 10monotherapy. Grade 3 or higher hemorrhage including intracranial and gastrointestinal hemorrhage, hematuria andInfections and infestations Upper respiratory tract infection 39 0 disorders Lymphocytes decreased 32 8hemothorax have been reported in 3.4% of patients treated with BRUKINSA monotherapy. Hemorrhage events of any grade,Pneumonia 15 10^ Muscle spasms 10 0 28 1 Hemoglobin decreased 26 6excluding purpura and petechiae, occurred in 35% of patients. Urinary tract infection 11 0.8 Nervous system disorders Headache 18 1 14 1 Chemistry abnormalitiesBleeding events have occurred in patients with and without concomitant antiplatelet or anticoagulation therapy. Skin and subcutaneous tissue disorders RashII 36 0 Dizziness 13 1 12 0 Glucose increased 54 4.6Co-administration of BRUKINSA with antiplatelet or anticoagulant medications may further increase the risk of hemorrhage. Respiratory, thoracic and mediastinalCough 16 0 18 0 Creatinine increased 34 1.1Monitor for signs and symptoms of bleeding. Discontinue BRUKINSA if intracranial hemorrhage of any grade occurs. ConsiderBruising* 14 0 disorders Dyspnea 14 0 7 0the benefit-risk of withholding BRUKINSA for 3-7 days pre- and post-surgery depending upon the type of surgery and theGastrointestinal disorders Diarrhea 23 0.8 Vascular disorders Hemorrhage 42 4 43 9 Phosphate decreased 27 2.3risk of bleeding. Calcium decreased 23 05.2 Infections Constipation 13 0 Hypertension 14 9 19 14 ALT increased 22 1.1Fatal and serious infections (including bacterial, viral, or fungal) and opportunistic infections have occurred in patients withVascular disorders Hypertension 12 3.4* Bruising includes all related terms containing bruise, contusion, or ecchymosis.Hemorrhage includes epistaxis, hematuria, conjunctival hemorrhage, hematoma, rectal hemorrhage, periorbital hemorrhage, mouthThe denominator used to calculate the rate varied from 87 to 88 based on the number of patients with a baseline value and at least hematological malignancies treated with BRUKINSA monotherapy. Grade 3 or higher infections occurred in 27% of patients,Hemorrhage11 3.4^ hemorrhage,post procedural hemorrhage, hemoptysis, skin hemorrhage, hemorrhoidal hemorrhage, ear hemorrhage, eye hemorrhage,one post-treatment value. most commonly pneumonia. Infections due to hepatitis B virus (HBV) reactivation have occurred.hemorrhagic diathesis, periorbital hematoma, subdural hemorrhage, wound hemorrhage, gastric hemorrhage, lower gastrointestinal Musculoskeletal and connective tissue disorders Musculoskeletal pain 14 3.4 hemorrhage, spontaneous hematoma, traumatic hematoma, traumatic intracranial hemorrhage, tumor hemorrhage, retinal hemorrhage,7 DRUG INTERACTIONSConsider prophylaxis for herpes simplex virus, pneumocystis jiroveci pneumonia, and other infections according to standardhematochezia, diarrhea hemorrhagic, hemorrhage, melena, post procedural hematoma, subdural hematoma, anal hemorrhage,7.1 Effect of Other Drugs on BRUKINSA of care in patients who are at increased risk for infections. Monitor and evaluate patients for fever or other signs andhemorrhagic disorder, pericardial hemorrhage, postmenopausal hemorrhage, stoma site hemorrhage, subarachnoid hemorrhage. Table 9: Drug Interactions that Affect Zanubrutinibsymptoms of infection and treat appropriately. Metabolism and nutrition disorders Hypokalemia 14 1.7 # Fatigue includes asthenia, fatigue, lethargy. Musculoskeletal pain includes back pain, arthralgia, pain in extremity, musculoskeletal pain, myalgia, bone pain, spinal pain,Moderate and Strong CYP3A Inhibitors 5.3 Cytopenias musculoskeletal chest pain, neck pain, arthritis, musculoskeletal discomfort.Grade 3 or 4 cytopenias, including neutropenia (26%), thrombocytopenia (11%) and anemia (8%) based on laboratoryRespiratory, thoracic and mediastinal disorders Cough 12 0 Pneumonia includes lower respiratory tract infection, lung infiltration, pneumonia, pneumonia aspiration, pneumonia viral.Clinical ImpactCo-administration with a moderate or strong CYP3A inhibitor increases zanubrutinib C maxandash includes all related terms rash, maculo-papular rash, erythema, rash erythematous, drug eruption, dermatitis allergic, dermatitisAUC [see Clinical Pharmacology (12.3)] which may increase the risk of BRUKINSA toxicities.measurements, developed in patients treated with BRUKINSA monotherapy [see Adverse Reactions (6.1)]. Grade 4ll R neutropenia occurred in 13% of patients, and Grade 4 thrombocytopenia occurred in 3.6% of patients.atopic, rash pruritic, dermatitis, photodermatosis, dermatitis acneiform, stasis dermatitis, vasculitic rash, eyelid rash, urticaria, skin toxicity.Prevention or Reduce BRUKINSA dosage when co-administered with moderate or strong CYP3A inhibitors ^ Includes fatal adverse reaction. Upper respiratory tract infection includes upper respiratory tract infection, laryngitis, nasopharyngitis, sinusitis, rhinitis, viral uppermanagement [see Dosage and Administration (2.3)].Monitor complete blood counts regularly during treatment and interrupt treatment, reduce the dose, or discontinue treatment * Bruising includes all related terms containing bruise, bruising, contusion, ecchymosis.respiratory tract infection, pharyngitis, rhinovirus infection, upper respiratory tract congestion.as warranted [see Dosage and Administration (2.4)]. Treat using growth factor or transfusions, as needed.Hemorrhage includes all related terms containing hemorrhage, hematoma. Clinically relevant adverse reactions in 10% of patients who received BRUKINSA included localized infection, atrial fibrillation or atrialModerate and Strong CYP3A Inducers5.4 Second Primary Malignancies Musculoskeletal pain includes musculoskeletal pain, musculoskeletal discomfort, myalgia, back pain, arthralgia, arthritis. flutter and hematuria. Clinical ImpactCo-administration with a moderate or strong CYP3A inducer decreases zanubrutinib C maxSecond primary malignancies, including non-skin carcinoma, have occurred in 14% of patients treated with BRUKINSA P neumonia includes pneumonia, pneumonia fungal, pneumonia cryptococcal, pneumonia streptococcal, atypical pneumonia, lung infection,Table 6 summarizes the laboratory abnormalities in ASPEN. and AUC [see Clinical Pharmacology (12.3)] which may reduce BRUKINSA efficacy.monotherapy. The most frequent second primary malignancy was non-melanoma skin cancer reported in 8% of patients.lower respiratory tract infection, lower respiratory tract infection bacterial, lower respiratory tract infection viral. Table 6: Select Laboratory Abnormalities* ( 20%) That Worsened from Baseline in Patients with WM Who ReceivedPrevention or Avoid co-administration of BRUKINSA with moderate or strong CYP3A inducers Other second primary malignancies included malignant solid tumors (4.0%), melanoma (1.7%) and hematologic II Rash includes all related terms containing rash. BRUKINSA in Cohort 1 management [see Dosage and Administration (2.3)].malignancies (1.2%). Advise patients to use sun protection and monitor patients for the development of second primary U pper respiratory tract infection includes upper respiratory tract infection, upper respiratory tract infection viral.1 1malignancies. Other clinically significant adverse reactions that occurred in 10% of patients with mantle cell lymphoma include Laboratory Abnormality BRUKINSA Ibrutinib 8 USE IN SPECIFIC POPULATIONS major hemorrhage (defined asGrade 3 hemorrhage or CNS hemorrhage of any grade) (5%), hyperuricemia (6%) All Grades (%) Grade 3 or 4 (%) All Grades (%) Grade 3 or 4 (%) 8.1 Pregnancy 5.5 Cardiac Arrhythmias Risk Summary Atrial fibrillation and atrial flutter were reported in 3.2% of patients treated with BRUKINSA monotherapy. Patients withand headache (4.2%). Hematologic Abnormalities Based on findings in animals, BRUKINSA can cause fetal harm when administered to pregnant women. There are no available cardiac risk factors, hypertension and acute infections may be at increased risk. Grade 3 or higher events were reported Table 4: Selected Laboratory Abnormalities* ( 20%) in Patients with MCL Neutrophils decreased 50 24 34 9 data on BRUKINSA use in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage or adverse in 1.1% of patients treated with BRUKINSA monotherapy. Monitor signs and symptoms for atrial fibrillation and atrial flutter in Studies BGB-3111-206 and BGB-3111-AU-003 Platelets decreased 35 8 39 5 maternal or fetal outcomes. In animal reproduction studies, oral administration of zanubrutinib to pregnant rats during the period and manage as appropriate [see Dosage and Administration (2.4)]. of organogenesis was associated with fetal heart malformation at approximately 5-fold human exposures (see Data). Women Laboratory Parameter Percent of Patients (N=118) Hemoglobin decreased 20 7 20 7 should be advised to avoid pregnancy while taking BRUKINSA. If BRUKINSA is used during pregnancy, or if the patient becomes 5.6 Embryo-Fetal Toxicity All Grades (%) Grade 3 or 4 (%) Chemistry Abnormalities pregnant while taking BRUKINSA, the patient should be apprised of the potential hazard to the fetus.Based on findings in animals, BRUKINSA can cause fetal harm when administered to a pregnant woman. Administration Hematologic abnormalities The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies of zanubrutinib to pregnant rats during the period of organogenesis caused embryo-fetal toxicity, including malformations Bilirubin increased 12 1.0 33 1.0 have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background at exposures that were 5 times higher than those reported in patients at the recommended dose of 160 mg twice daily.Neutrophils decreased 45 20 Calcium decreased 27 2.0 26 0 risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.Advise women to avoid becoming pregnant while taking BRUKINSA and for 1 week after the last dose. Advise men to avoidPlatelets decreased 40 7 Data fathering a child during treatment and for 1 week after the last dose. If this drug is used during pregnancy, or if the patientCreatinine increased 31 1.0 21 1.0 Animal Data becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus [see Use inHemoglobin decreased 27 6 Embryo-fetal development toxicity studies were conducted in both rats and rabbits. Zanubrutinib was administered orally Specific Populations (8.1)]. Lymphocytosis 41 16 Glucose increased 45 2.3 33 2.3 to pregnant rats during the period of organogenesis at doses of 30, 75, and 150 mg/kg/day. Malformations in the heart Potassium increased 24 2.0 12 0 (2- or 3-chambered hearts) were noted at all dose levels in the absence of maternal toxicity. The dose of 30 mg/kg/day is 6 ADVERSE REACTIONS Chemistry abnormalities approximately 5 times the exposure (AUC) in patients receiving the recommended dose of 160 mg twice daily.Blood uric acid increased 29 2.6 Urate increased 16 3.2 34 6 Administration of zanubrutinib to pregnant rabbits during the period of organogenesis at 30, 70, and 150 mg/kg/day resulted The following clinically significant adverse reactions are discussed in more detail in other sections of the labeling: Phosphate decreased 20 3.1 18 0 in post-implantation loss at the highest dose. The dose of 150 mg/kg is approximately 32 times the exposure (AUC) inHemorrhage [see Warnings and Precautions (5.1)] ALT increased 28 0.9 patients at the recommended dose and was associated with maternal toxicity.Bilirubin increased 24 0.9* Based on laboratory measurements. In a pre- and post-natal developmental toxicity study, zanubrutinib was administered orally to rats at doses of 30, 75, andInfections [see Warnings and Precautions (5.2)]1 The denominator used to calculate the rate varied from 86 to 101 based on the number of patients with a baseline value *Based on laboratory measurements. and at least one post-treatment value. 150 mg/kg/day from implantation through weaning. The offspring from the middle and high dose groups had decreased bodyCytopenias [see Warnings and Precautions (5.3)] Asymptomatic lymphocytosis is a known effect of BTK inhibition.weights preweaning, and all dose groups had adverse ocular findings (e.g., cataract, protruding eye). The dose of 30 mg/kg/Marginal Zone Lymphomaday is approximately 5 times the AUC in patients receiving the recommended dose. Second Primary Malignancies [see Warnings and Precautions (5.4)] Waldenstrms Macroglobulinemia (WM) The safety of BRUKINSA was evaluated in 88 patients with previously treated MZL in two single-arm clinical studies, BGB-3111-2148.2 Lactation and BGB-3111-AU-003 [see Clinical Studies (14.3)]. The trials required an absolute neutrophil count1 x 109/L, platelet count50Cardiac Arrhythmias [see Warnings and Precautions (5.5)] The safety of BRUKINSA was investigated in two cohorts of Study BGB-3111-302 (ASPEN). Cohort 1 included 199 patients9 Risk Summary MUT or75 x 10/L and adequate hepatic function and excluded patients requiring a strong CYP3A inhibitor or inducer. Patients receivedThere are no data on the presence of zanubrutinib or its metabolites in human milk, the effects on the breastfed child, or the 6.1 Clinical Trials Experience with MYD88 mutation (MYD88 ) WM, randomized to and treated with either BRUKINSA (101 patients) or ibrutinib BRUKINSA 160 mg twice daily (97%) or 320 mg once daily (3%). The median age in both studies combined was 70 years (range: 37 WT effects on milk production. Because of the potential for serious adverse reactions from BRUKINSA in a breastfed child, advise Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials (98 patients). The trial also included a non-randomized arm, Cohort 2, with 26 wild type MYD88 (MYD88 ) WM patients to 95), 52% were male, 64% were Caucasian and 19% were Asian. Most patients (92%) had an ECOG performance status of 0 to 1.lactating women not to breastfeed during treatment with BRUKINSA and for two weeks following the last dose.of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed and 2 patients with unknown MYD88 status [see Clinical Studies (14.2)]. Eighty percent received BRUKINSA for 6 months or longer, and 67% received treatment for more than one year. 8.3 Females and Males of Reproductive Potential in practice. Among patients who received BRUKINSA, 93% were exposed for 6 months or longer, and 89% were exposed for greaterTwo fatal adverse reactions (2.3%) occurred within 30 days of the last dose of BRUKINSA, including myocardial infarction andPregnancy Testing The data in the WARNINGS AND PRECAUTIONS reflect exposure to BRUKINSA in seven clinical trials, administered as a singlethan 1 year. a Covid-19 related death. Pregnancy testing is recommended for females of reproductive potential prior to initiating BRUKINSA therapy.agent at 160 mg twice daily in 730 patients, at 320 mg once daily in 105 patients, and at 40 mg to 160 mg once daily In Cohort 1 of the ASPEN study safety population (N=101), the median age of patients who received BRUKINSA was Serious adverse reactions occurred in 40% of patients. The most frequent serious adverse reactions were pyrexia (8%) and pneumonia (7%).Contraception (0.125 to 0.5 times the recommended dosage) in 12 patients. Among 847 patients receiving BRUKINSA, 73% were exposed70 years (45-87 years old); 67% were male, 86% were White, 4% were Asian and 10% were not reported (unknown race). Adverse reactions lead to treatment discontinuation in 6% of patients, dose reduction in 2.3%, and dose interruption in 34%.Females for at least 1 year, 57% were exposed for at least 2 years and 26% were exposed for at least 3 years.In Cohort 2 of the ASPEN study safety population (N=28), the median age of patients who received BRUKINSA was 72 The leading cause of dose modification was respiratory tract infections (13%). BRUKINSA can cause embryo-fetal harm when administered to pregnant women [see Use in Specific Populations (8.1)]. Advise female patients of reproductive potential to use effective contraception during treatment with BRUKINSA and forIn this pooled safety population, the most common adverse reactions, including laboratory abnormalities, in30% of(39-87 years old); 50% were male, 96% were White and 4% were not reported (unknown race). Table 7 summarizes selected adverse reactions in BGB-3111-214 and BGB-3111-AU-003. 1 week following the last dose of BRUKINSA. If this drug is used during pregnancy, or if the patient becomes pregnantpatients included neutrophil count decreased (54%), upper respiratory tract infection (47%), platelet count decreased In Cohort 1, serious adverse reactions occurred in 44% of patients who received BRUKINSA. Serious adverse reactions Table 7: Adverse Reactions Occurring in10% Patients with MZL Who Received BRUKINSAwhile taking this drug, the patient should be informed of the potential hazard to a fetus.(41%), hemorrhage (35%), lymphocyte count decreased (31%), rash (31%) and musculoskeletal pain (30%). in 2% of patients included influenza (3%), pneumonia (4%), neutropenia and neutrophil count decreased (3%), Body System Adverse Reaction BRUKINSA (N=88) Males Mantle Cell Lymphoma (MCL) hemorrhage (4%), pyrexia (3%) and febrile neutropenia (3%). In Cohort 2, serious adverse reactions occurred in 39% All GradesGrade 3 Advise men to avoid fathering a child while receiving BRUKINSA and for 1 week following the last dose of BRUKINSA.of patients. Serious adverse reactions in 2 patients included pneumonia (14%). 8.4 Pediatric Use The safety of BRUKINSA was evaluated in 118 patients with MCL who received at least one prior therapy in two % or 4 (%) Safety and effectiveness in pediatric patients have not been established.single-arm clinical trials, BGB-3111-206 [NCT03206970] and BGB-3111-AU-003 [NCT02343120] [see Clinical StudiesPermanent discontinuation of BRUKINSA due to an adverse reaction occurred in 2% of patients in Cohort 1 and includedInfections and infestations Upper respiratory tract infectionsa 26 3.4 8.5 Geriatric Use (14.1)]. The median age of patients who received BRUKINSA in studies BGB-3111-206 and BGB-3111-AU-003 was hemorrhage (1 patient), neutropenia and neutrophil count decreased (1 patient); in Cohort 2, permanent discontinuation b Of the 847 patients in clinical studies with BRUKINSA, 53% were65 years of age, and 20% were75 years of age.of BRUKINSA due to an adverse reaction occurred in 7% of patients and included subdural hemorrhage (1 patient) andUrinary tract infection 11 2.362 years (range: 34 to 86), 75% were male, 75% were Asian, 21% were White, and 94% had an ECOG performance status c No overall differences in safety or effectiveness were observed between younger and older patients.of 0 to 1. Patients had a median of 2 prior lines of therapy (range: 1 to 4). The BGB-3111-206 trial required a platelet count diarrhea (1 patient).Pneumonia 10 6 8.6 Renal Impairment75 x 109/L and an absolute neutrophil count1 x 109/L independent of growth factor support, hepatic enzymes2.5 xDosage interruptions of BRUKINSA due to an adverse reaction occurred in 32% of patients in Cohort 1 and in 29% in Gastrointestinal disorders Diarrhead 25 3.4No dosage modification is recommended in patients with mild, moderate, or severe renal impairment (CLcr15 mL/min,upper limit of normal, total bilirubin1.5 x ULN. The BGB-3111-AU-003 trial required a platelet count50 x 109/L and anCohort 2. Adverse reactions which required dosage interruption in 2% of patients included neutropenia, vomiting,e estimated by Cockcroft-Gault). Monitor for BRUKINSA adverse reactions in patients on dialysis [see Clinical Pharmacology (12.3)].absolute neutrophil count1 x 109/L independent of growth factor support, hepatic enzymes3 x upper limit of normal,hemorrhage, thrombocytopenia and pneumonia in Cohort 1. Adverse reactions leading to dosage interruption in Abdominal pain 14 2.3 8.7 Hepatic Impairment total bilirubin1.5 x ULN. Both trials required a CLcr30 mL/min. Both trials excluded patients with prior allogeneic 2 patients in Cohort 2 included pneumonia and pyrexia. Nausea 13 0 Dosage modification of BRUKINSA is recommended in patients with severe hepatic impairment [see Dosage and hematopoietic stem cell transplant, exposure to a BTK inhibitor, known infection with HIV and serologic evidence of activeDose reductions of BRUKINSA due to an adverse reaction occurred in 11% of patients in Cohort 1 and in 7% in Cohort 2.Skin and subcutaneous tissue disorders Bruisingf 24 0 Administration (2.2)]. The safety of BRUKINSA has not been evaluated in patients with severe hepatic impairment.hepatitis B or hepatitis C infection and patients requiring strong CYP3A inhibitors or strong CYP3A inducers. Patients receivedAdverse reactions which required dose reductions in 2% of patients included neutropenia in Cohort 1. Adverse reactionRashg 21 0 No dosage modification is recommended in patients with mild to moderate hepatic impairment. Monitor for BRUKINSA BRUKINSA 160 mg twice daily or 320 mg once daily. Among patients receiving BRUKINSA, 79% were exposed for 6 monthsleading to dose reduction occurred in 2 patients in Cohort 2 (each with one event: diarrhea and pneumonia). h adverse reactions in patients with hepatic impairment [see Clinical Pharmacology (12.3)].or longer, and 68% were exposed for greater than one year. Musculoskeletal and connective tissue disorders Musculoskeletal pain 27 1.1 Distributed and Marketed by: Vascular disorders Hemorrhagei23 1.1 BeiGene USA, Inc. j 2955 Campus Drive, Suite 200 General disorders Fatigue 21 2.3 San Mateo, CA 94403 Respiratory, thoracic and mediastinal disorders Coughk 10 0 BRUKINSA is a registered trademark owned by BeiGene, Ltd.BeiGene, Ltd. 2021 All Rights Reserved. 0721-BRU-PRC-027 09/202122065_2_WM_HCPJournalAd_Fed_Pract_7-875x10-75_RL.indd 3-4 11/2/21 5:00 PM'