BRUKINSA

1 INDICATIONS AND USAGE BRUKINSA is a kinase inhibitor indicated for the treatment of adult patients with: Mantle cell lymphoma (MCL) who have received at least one prior therapy. ( 1.1 ) This indication is approved under accelerated approval based on overall response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial. Waldenström's macroglobulinemia (WM). ( 1.2 ) Relapsed or refractory marginal zone lymphoma (MZL) who have received at least one anti–CD20-based regimen. ( 1.3 ) This indication is approved under accelerated approval based on overall response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial. Chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). ( 1.4 ) Relapsed or refractory follicular lymphoma (FL), in combination with obinutuzumab, after two or more lines of systemic therapy. ( 1.5 ) This indication is approved under accelerated approval based on response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial. 1.1 Mantle Cell Lymphoma BRUKINSA is indicated for the treatment of adult patients with mantle cell lymphoma (MCL) who have received at least one prior therapy. This indication is approved under accelerated approval based on overall response rate [see Clinical Studies (14.1) ] . Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial. 1.2 Waldenström's Macroglobulinemia BRUKINSA is indicated for the treatment of adult patients with Waldenström's macroglobulinemia (WM) [see Clinical Studies (14.2) ] . 1.3 Marginal Zone Lymphoma BRUKINSA is indicated for the treatment of adult patients with relapsed or refractory marginal zone lymphoma (MZL) who have received at least one anti–CD20-based regimen. This indication is approved under accelerated approval based on overall response rate [see Clinical Studies (14.3) ] . Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial. 1.4 Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma BRUKINSA is indicated for the treatment of adult patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) [see Clinical Studies (14.4) ] . 1.5 Follicular Lymphoma BRUKINSA is indicated for the treatment of adult patients with relapsed or refractory follicular lymphoma (FL), in combination with obinutuzumab, after two or more lines of systemic therapy. This indication is approved under accelerated approval based on response rate and durability of response [see Clinical Studies (14.5) ] . Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.

2 DOSAGE AND ADMINISTRATION Recommended dosage: 160 mg orally twice daily or 320 mg orally once daily with or without food; swallow whole with water. Tablets can be split in half as prescribed by the healthcare provider. ( 2.1 ) Reduce BRUKINSA dose in patients with severe hepatic impairment. ( 2.2 , 8.7 ) Advise patients not to open, break, or chew capsules. ( 2.1 ) Advise patients not to chew or crush tablets. ( 2.1 ) Manage toxicity using treatment interruption, dose reduction, or discontinuation. ( 2.4 ) 2.1 Recommended Dosage The recommended dosage of BRUKINSA for monotherapy or in combination with obinutuzumab is 160 mg taken orally twice daily or 320 mg taken orally once daily until disease progression or unacceptable toxicity. Capsule Administration Instructions Administer BRUKINSA capsules with or without food [see Clinical Pharmacology (12.3) ] . Advise patients to swallow capsules whole with water and not to open, break, or chew capsules. Tablet Administration Instructions Administer BRUKINSA tablets with or without food [see Clinical Pharmacology (12.3) ] . Advise patients to swallow tablets whole with water and not to chew or crush the tablets. The tablets can be split in half as prescribed by the healthcare provider. Missed Dose If a dose of BRUKINSA is missed, it should be taken as soon as possible on the same day with a return to the normal schedule the following day. 2.2 Dosage Modification for Use in Hepatic Impairment The recommended dosage of BRUKINSA for patients with severe hepatic impairment (Child-Pugh class C) is 80 mg orally twice daily; no dosage modification is recommended for patients with mild or moderate hepatic impairment (Child-Pugh class A or B) [see Use in Specific Populations (8.7) and Clinical Pharmacology (12.3) ] . 2.3 Dosage Modifications for Drug Interactions Recommended dosage modifications of BRUKINSA for drug interactions are provided in Table 1 [see Drug Interactions (7.1) ] . Table 1: Dosage Modifications for Use with CYP3A Inhibitors or Inducers Coadministered Drug Recommended BRUKINSA Dosage (Starting Dose: 160 mg twice daily or 320 mg once daily) Clarithromycin 250 mg twice daily Since clarithromycin 250 mg twice daily acts as a moderate CYP3A inhibitor, it is recommended that patients be administered clarithromycin 250 mg twice daily with 80 mg BRUKINSA twice daily [see Clinical Pharmacology (12.3) ] . 80 mg twice daily Modify or interrupt zanubrutinib dose as recommended for adverse reactions [see Dosage and Administration (2.4) ] . Clarithromycin 500 mg twice daily 80 mg once daily Posaconazole suspension 100 mg once daily 80 mg twice daily Posaconazole suspension dosage higher than 100 mg once daily Posaconazole delayed-release tablets 300 mg once daily Posaconazole intravenous 300 mg once daily 80 mg once daily Other strong CYP3A inhibitor 80 mg once daily Moderate CYP3A inhibitor 80 mg twice daily Strong CYP3A inducer Avoid concomitant use. Moderate CYP3A inducer Avoid concomitant use. If these inducers cannot be avoided, increase BRUKINSA dose to 320 mg twice daily. After discontinuation of a CYP3A inhibitor or moderate CYP3A inducer, resume previous dose of BRUKINSA [see Dosage and Administration (2.1 , 2.2) and Drug Interactions (7.1) ] . 2.4 Dosage Modifications for Adverse Reactions Recommended dosage modifications of BRUKINSA for Grade 3 or higher adverse reactions are provided in Table 2. Table 2: Recommended Dosage Modifications for Adverse Reaction Adverse Reaction Adverse Reaction Occurrence Dosage Modification (Starting Dose: 160 mg twice daily or 320 mg once daily) Hematological toxicities [see Warnings and Precautions (5.3) ] Grade 3 or Grade 4 febrile neutropenia Platelet count decreased to 25,000-50,000/mm 3 with significant bleeding Neutrophil count decreased to <500/mm 3 (lasting more than 10 consecutive days) Platelet count decreased to <25,000/mm 3 (lasting more than 10 consecutive days) First Interrupt BRUKINSA Once toxicity has resolved to Grade 1 or lower or baseline: Resume at 160 mg twice daily or 320 mg once daily. Second Interrupt BRUKINSA Once toxicity has resolved to Grade 1 or lower or baseline: Resume at 80 mg twice daily or 160 mg once daily. Third Interrupt BRUKINSA Once toxicity has resolved to Grade 1 or lower or baseline: Resume at 80 mg once daily. Fourth Discontinue BRUKINSA Nonhematological toxicities [see Warnings and Precautions (5.5) and Adverse Reactions (6.1) ] Severe or life-threatening nonhematological toxicities Evaluate the benefit-risk before resuming treatment at the same dosage for Grade 4 nonhematological toxicity. First Interrupt BRUKINSA Once toxicity has resolved to Grade 1 or lower or baseline: Resume at 160 mg twice daily or 320 mg once daily. Second Interrupt BRUKINSA Once toxicity has resolved to Grade 1 or lower or baseline: Resume at 80 mg twice daily or 160 mg once daily. Third Interrupt BRUKINSA Once toxicity has resolved to Grade 1 or lower or baseline: Resume at 80 mg once daily. Fourth Discontinue BRUKINSA Asymptomatic lymphocytosis in CLL and MCL should not be regarded as an adverse reaction, and these patients should continue taking BRUKINSA. Refer to the obinutuzumab prescribing information for management of obinutuzumab toxicities.

4 CONTRAINDICATIONS None. None. ( 4 )

5 WARNINGS AND PRECAUTIONS Hemorrhage : Monitor for bleeding and manage appropriately. ( 5.1 ) Infections : Monitor patients for signs and symptoms of infection, including opportunistic infections, and treat as needed. ( 5.2 ) Cytopenias : Monitor complete blood counts during treatment. ( 5.3 ) Second Primary Malignancies : Other malignancies have developed including skin cancers and non-skin carcinomas. Monitor and advise patients to use sun protection. ( 5.4 ) Cardiac Arrhythmias : Monitor for signs and symptoms of arrhythmias and manage appropriately. ( 5.5 ) Hepatotoxicity, Including Drug-Induced Liver Injury : Monitor hepatic function throughout treatment. ( 5.6 ) Embryo-Fetal Toxicity : Can cause fetal harm. Advise women of the potential risk to a fetus and to use effective contraception. ( 5.7 ) 5.1 Hemorrhage Fatal and serious hemorrhage has occurred in patients with hematological malignancies treated with BRUKINSA. Grade 3 or higher hemorrhage including intracranial and gastrointestinal hemorrhage, hematuria, and hemothorax was reported in 3.8% of patients treated with BRUKINSA in clinical trials, with fatalities occurring in 0.2% of patients. Bleeding of any grade, excluding purpura and petechiae, occurred in 32% of patients. Bleeding has occurred in patients with and without concomitant antiplatelet or anticoagulation therapy. Coadministration of BRUKINSA with antiplatelet or anticoagulant medications may further increase the risk of hemorrhage. Monitor for signs and symptoms of bleeding. Discontinue BRUKINSA if intracranial hemorrhage of any grade occurs. Consider the benefit-risk of withholding BRUKINSA for 3-7 days before and after surgery depending upon the type of surgery and the risk of bleeding. 5.2 Infections Fatal and serious infections (including bacterial, viral, or fungal infections) and opportunistic infections have occurred in patients with hematological malignancies treated with BRUKINSA. Grade 3 or higher infections occurred in 26% of patients, most commonly pneumonia (7.9%), with fatal infections occurring in 3.2% of patients. Infections due to hepatitis B virus (HBV) reactivation have occurred. Consider prophylaxis for herpes simplex virus, pneumocystis jirovecii pneumonia, and other infections according to standard of care in patients who are at increased risk for infections. Monitor and evaluate patients for fever or other signs and symptoms of infection and treat appropriately. 5.3 Cytopenias Grade 3 or 4 cytopenias, including neutropenia (21%), thrombocytopenia (8%), and anemia (8%) based on laboratory measurements, developed in patients treated with BRUKINSA [see Adverse Reactions (6.1) ]. Grade 4 neutropenia 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 discontinue treatment as warranted [see Dosage and Administration (2.4) ] . Treat using growth factor or transfusions, as needed. 5.4 Second Primary Malignancies Second primary malignancies, including non-skin carcinoma, have occurred in 14% of patients treated with BRUKINSA. The most frequent second primary malignancy was non-melanoma skin cancers (8%), followed by other solid tumors in 7% of the patients (including melanoma in 1% of patients) and hematologic malignancies (0.7%). Advise patients to use sun protection and monitor patients for the development of second primary malignancies. 5.5 Cardiac Arrhythmias Serious cardiac arrhythmias have occurred in patients treated with BRUKINSA. Atrial fibrillation and atrial flutter were reported in 4.4% of patients treated with BRUKINSA, including Grade 3 or higher cases in 1.9% 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 0.3% of patients. Monitor for signs and symptoms of cardiac arrhythmias (e.g., palpitations, dizziness, syncope, dyspnea, chest discomfort), manage appropriately [see Dosage and Administration (2.4) ] , and consider the risks and benefits of continued BRUKINSA treatment. 5.6 Hepatotoxicity, Including Drug-Induced Liver Injury 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 BRUKINSA. Evaluate bilirubin and transaminases at baseline and throughout treatment with BRUKINSA. For patients who develop abnormal liver tests after BRUKINSA, monitor more frequently for liver test abnormalities and clinical signs and symptoms of hepatic toxicity. If DILI is suspected, withhold BRUKINSA. Upon confirmation of DILI, discontinue BRUKINSA. 5.7 Embryo-Fetal Toxicity 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 and for 1 week after the last dose. Advise men to avoid fathering a child during treatment and for 1 week after the 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 [see Use in Specific Populations (8.1) ] .

7 DRUG INTERACTIONS CYP3A Inhibitors: Modify BRUKINSA dose with moderate or strong CYP3A inhibitors as described. ( 2.3 , 7.1 ) CYP3A Inducers: Avoid coadministration with strong or moderate CYP3A inducers. Dose adjustment may be recommended with moderate CYP3A inducers. ( 2.3 , 7.1 ) 7.1 Effect of Other Drugs on BRUKINSA Table 17: Drug Interactions that Affect Zanubrutinib Moderate and Strong CYP3A Inhibitors Clinical Impact Coadministration with a moderate or strong CYP3A inhibitor increases zanubrutinib C max and AUC [see Clinical Pharmacology (12.3) ] which may increase the risk of BRUKINSA toxicities. Prevention or management Reduce BRUKINSA dosage when coadministered with moderate or strong CYP3A inhibitors [see Dosage and Administration (2.3) ] . Moderate and Strong CYP3A Inducers Clinical Impact Coadministration with a moderate or strong CYP3A inducer decreases zanubrutinib C max and AUC [see Clinical Pharmacology (12.3) ] which may reduce BRUKINSA efficacy. Prevention or management Avoid coadministration of BRUKINSA with strong CYP3A inducers [see Dosage and Administration (2.3) ] . Avoid coadministration of BRUKINSA with moderate CYP3A inducers [see Dosage and Administration (2.3) ] . If these inducers cannot be avoided, increase BRUKINSA dosage to 320 mg twice daily [see Dosage and Administration (2.3) ] .

6 ADVERSE REACTIONS The following clinically significant adverse reactions are discussed in more detail in other sections of the labeling: Hemorrhage [see Warnings and Precautions (5.1) ] Infections [see Warnings and Precautions (5.2) ] Cytopenias [see Warnings and Precautions (5.3) ] Second Primary Malignancies [see Warnings and Precautions (5.4) ] Cardiac Arrhythmias [see Warnings and Precautions (5.5) ] Hepatotoxicity, including DILI [see Warnings and Precautions (5.6) ] The most common adverse reactions (≥30%), including laboratory abnormalities, are neutrophil count decreased, platelet count decreased, upper respiratory tract infection, hemorrhage, and musculoskeletal pain. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact BeOne Medicines at 1-877-828-5596 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The data in the WARNINGS AND PRECAUTIONS reflect exposure to BRUKINSA in nine monotherapy and 2 combination clinical trials, administered at 160 mg twice daily in 1608 patients and at 320 mg once daily in 121 patients. Among these 1729 patients, the median duration of exposure was 27.6 months, 78% of patients were exposed for at least 12 months, and 60% of patients were exposed for at least 24 months. In this pooled safety population, the most common adverse reactions (≥30%), including laboratory abnormalities, were neutrophil count decreased (51%), platelet count decreased (41%), upper respiratory tract infection (38%), hemorrhage (32%), and musculoskeletal pain (31%). Mantle Cell Lymphoma (MCL) The safety of BRUKINSA was evaluated in 118 patients with MCL who received at least one prior therapy in two single-arm clinical trials, BGB-3111-206 [NCT03206970] and BGB-3111-AU-003 [NCT02343120] [see Clinical Studies (14.1) ] . The median age of patients who received BRUKINSA in studies BGB-3111-206 and BGB-3111-AU-003 was 62 years (range: 34 to 86), 75% were male, 75% were Asian, 21% were White, 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). The BGB-3111-206 trial required a platelet count ≥75 × 10 9 /L and an absolute neutrophil count ≥1 × 10 9 /L independent of growth factor support, hepatic enzymes ≤2.5 × upper limit of normal, total bilirubin ≤1.5 × ULN. The BGB-3111-AU-003 trial required a platelet count ≥50 × 10 9 /L and an absolute neutrophil count ≥1 × 10 9 /L independent of growth factor support, hepatic enzymes ≤3 × upper limit of normal, total bilirubin ≤1.5 × ULN. Both trials required a creatinine clearance (CLcr) ≥30 mL/min. Both trials excluded patients with prior allogeneic hematopoietic stem cell transplant, exposure to a BTK inhibitor, known infection with HIV, and serologic evidence of active hepatitis B or hepatitis C infection, and patients requiring strong CYP3A inhibitors or strong CYP3A inducers. Patients received BRUKINSA 160 mg twice daily or 320 mg once daily. Among patients receiving BRUKINSA, 79% were exposed for 6 months or longer, and 68% were exposed for greater than one year. Fatal adverse reactions within 30 days of the last dose of BRUKINSA occurred in 8 (7%) of 118 patients with MCL. Fatal cases included pneumonia in 2 patients and cerebral hemorrhage in one patient. Serious adverse reactions were reported in 36 patients (31%). The most frequent serious adverse reactions that occurred were pneumonia (11%) and hemorrhage (5%). Of the 118 patients with MCL treated with BRUKINSA, 8 (7%) patients discontinued treatment due to adverse reactions in the trials. The most frequent adverse reaction leading to treatment discontinuation was pneumonia (3.4%). One (0.8%) patient experienced an adverse reaction leading to dose reduction (hepatitis B). Table 3 summarizes the adverse reactions in BGB-3111-206 and BGB-3111-AU-003. Table 3: Adverse Reactions (≥10%) in Patients Receiving BRUKINSA in BGB-3111-206 and BGB-3111-AU-003 Trials Body System Adverse Reaction Percent of Patients (N=118) All Grades % Grade 3 or Higher % Infections and infestations Upper respiratory tract infection Upper respiratory tract infection includes upper respiratory tract infection, upper respiratory tract infection viral. 39 0 Pneumonia Pneumonia includes pneumonia, pneumonia fungal, pneumonia cryptococcal, pneumonia streptococcal, atypical pneumonia, lung infection, lower respiratory tract infection, lower respiratory tract infection bacterial, lower respiratory tract infection viral. 15 10 Includes fatal adverse reaction. Urinary tract infection 11 0.8 Skin and subcutaneous tissue disorders Rash Rash includes all related terms containing rash. 36 0 Bruising Bruising includes all related terms containing bruise, bruising, contusion, ecchymosis. 14 0 Gastrointestinal disorders Diarrhea 23 0.8 Constipation 13 0 Vascular disorders Hypertension 12 3.4 Hemorrhage Hemorrhage includes all related terms containing hemorrhage, hematoma. 11 3.4 Musculoskeletal and connective tissue disorders Musculoskeletal pain Musculoskeletal pain includes musculoskeletal pain, musculoskeletal discomfort, myalgia, back pain, arthralgia, arthritis. 14 3.4 Respiratory, thoracic, and mediastinal disorders Cough 12 0 Other clinically significant adverse reactions that occurred in <10% of patients with mantle cell lymphoma include major hemorrhage (defined as ≥ Grade 3 hemorrhage or CNS hemorrhage of any grade) (5%) and headache (4.2%). Table 4: Selected Laboratory Abnormalities Based on laboratory measurements. (>20%) in Patients with MCL in Studies BGB-3111-206 and BGB-3111-AU-003 Laboratory Parameter Percent of Patients (N=118) All Grades (%) Grade 3 or 4 (%) Hematologic abnormalities Neutrophils decreased 45 20 Lymphocytosis Asymptomatic lymphocytosis is a known effect of BTK inhibition. 41 16 Platelets decreased 40 7 Hemoglobin decreased 27 6 Chemistry abnormalities Blood uric acid increased 29 2.6 ALT increased 28 0.9 Bilirubin increased 24 0.9 Waldenström's Macroglobulinemia (WM) The safety of BRUKINSA was investigated in two cohorts of Study BGB-3111-302 (ASPEN). Cohort 1 included 199 patients with MYD88 mutation ( MYD88 MUT ) WM, randomized to and treated with either BRUKINSA (101 patients) or ibrutinib (98 patients). The trial also included a non-randomized arm, Cohort 2, with 26 wild type MYD88 ( MYD88 WT ) WM patients and 2 patients with unknown MYD88 status [see Clinical Studies (14.2) ] . Among patients who received BRUKINSA, 93% were exposed for 6 months or longer, and 89% were exposed for greater than 1 year. In Cohort 1 of the ASPEN study safety population (N=101), the median age of patients who received BRUKINSA was 70 years (45-87 years old); 67% were male, 86% were White, 4% were Asian, and 10% were not reported (unknown race). In Cohort 2 of the ASPEN study safety population (N=28), the median age of patients who received BRUKINSA was 72 (39-87 years old); 50% were male, 96% were White, and 4% were not reported (unknown race). In Cohort 1, serious adverse reactions occurred in 44% of patients who received BRUKINSA. Serious adverse reactions in >2% of patients included influenza (3%), pneumonia (4%), neutropenia and neutrophil count decreased (3%), hemorrhage (4%), pyrexia (3%), and febrile neutropenia (3%). In Cohort 2, serious adverse reactions occurred in 39% of patients. Serious adverse reactions in >2 patients included pneumonia (14%). Permanent discontinuation of BRUKINSA due to an adverse reaction occurred in 2% of patients in Cohort 1 and included hemorrhage (1 patient), neutropenia and neutrophil count decreased (1 patient); in Cohort 2, permanent discontinuation of BRUKINSA due to an adverse reaction occurred in 7% of patients and included subdural hemorrhage (1 patient) and diarrhea (1 patient). Dosage interruptions of BRUKINSA due to an adverse reaction occurred in 32% of patients in Cohort 1 and in 29% in Cohort 2. Adverse reactions which required dosage interruption in >2% of patients included neutropenia, vomiting, hemorrhage, thrombocytopenia, and pneumonia in Cohort 1. Adverse reactions leading to dosage interruption in >2 patients in Cohort 2 included pneumonia and pyrexia. Dose reductions of BRUKINSA due to an adverse reaction occurred in 11% of patients in Cohort 1 and in 7% in Cohort 2. Adverse reactions which required dose reductions in >2% of patients included neutropenia in Cohort 1. Adverse reaction leading to dose reduction occurred in 2 patients in Cohort 2 (each with one event: diarrhea and pneumonia). Table 5 summarizes the adverse reactions in Cohort 1 in ASPEN. Table 5: Adverse Reactions (≥10%) Occurring in Patients with WM Who Received BRUKINSA in Cohort 1 Body System Adverse Reaction BRUKINSA (N=101) Ibrutinib (N=98) All Grades (%) Grade 3 or 4 (%) All Grades (%) Grade 3 or 4 (%) Infections and infestations Upper respiratory tract infection Upper respiratory tract infection includes upper respiratory tract infection, laryngitis, nasopharyngitis, sinusitis, rhinitis, viral upper respiratory tract infection, pharyngitis, rhinovirus infection, upper respiratory tract congestion. 44 0 40 2 Pneumonia Pneumonia includes lower respiratory tract infection, lung infiltration, pneumonia, pneumonia aspiration, pneumonia viral. 12 4 26 10 Urinary tract infection 11 0 13 2 Gastrointestinal disorders Diarrhea 22 3 34 2 Nausea 18 0 13 1 Constipation 16 0 7 0 Vomiting 12 0 14 1 General disorders Fatigue Fatigue includes asthenia, fatigue, lethargy. 31 1 25 1 Pyrexia 16 4 13 2 Edema peripheral 12 0 20 0 Skin and subcutaneous tissue disorders Bruising Bruising includes all related terms containing bruise, contusion, or ecchymosis. 20 0 34 0 Rash Rash includes all related terms rash, maculo-papular rash, erythema, rash erythematous, drug eruption, dermatitis allergic, dermatitis atopic, rash pruritic, dermatitis, photodermatoses, dermatitis acneiform, stasis dermatitis, vasculitic rash, eyelid rash, urticaria, skin toxicity. 29 0 32 0 Pruritus 11 1 6 0 Musculoskeletal and connective tissue disorders Musculoskeletal pain Musculoskeletal pain includes back pain, arthralgia, pain in extremity, musculoskeletal pain, myalgia, bone pain, spinal pain, musculoskeletal chest pain, neck pain, arthritis, musculoskeletal discomfort. 45 9 39 1 Muscle spasms 10 0 28 1 Nervous system disorders Headache 18 1 14 1 Dizziness 13 1 12 0 Respiratory, thoracic, and mediastinal disorders Cough 16 0 18 0 Dyspnea 14 0 7 0 Vascular disorders Hemorrhage Hemorrhage includes epistaxis, hematuria, conjunctival hemorrhage, hematoma, rectal hemorrhage, periorbital hemorrhage, mouth hemorrhage, post procedural hemorrhage, hemoptysis, skin hemorrhage, hemorrhoidal hemorrhage, ear hemorrhage, eye hemorrhage, hemorrhagic diathesis, periorbital hematoma, subdural hemorrhage, wound hemorrhage, gastric hemorrhage, lower gastrointestinal hemorrhage, spontaneous hematoma, traumatic hematoma, traumatic intracranial hemorrhage, tumor hemorrhage, retinal hemorrhage, hematochezia, diarrhea hemorrhagic, hemorrhage, melena, post-procedural hematoma, subdural hematoma, anal hemorrhage, hemorrhagic disorder, pericardial hemorrhage, postmenopausal hemorrhage, stoma site hemorrhage, subarachnoid hemorrhage. 42 4 43 9 Hypertension 14 9 19 14 Clinically relevant adverse reactions in <10% of patients who received BRUKINSA included localized infection, atrial fibrillation or atrial flutter, and hematuria. Table 6 summarizes the laboratory abnormalities in ASPEN. Table 6: Select Laboratory Abnormalities Based on laboratory measurements. (≥20%) that Worsened from Baseline in Patients with WM Who Received BRUKINSA in Cohort 1 Laboratory Abnormality BRUKINSA The denominator used to calculate the rate varied from 86 to 101 based on the number of patients with a baseline value and at least one post-treatment value. Ibrutinib All Grades (%) Grade 3 or 4 (%) All Grades (%) Grade 3 or 4 (%) Hematologic abnormalities Neutrophils decreased 50 24 34 9 Platelets decreased 35 8 39 5 Hemoglobin decreased 20 7 20 7 Chemistry abnormalities Glucose increased 45 2.3 33 2.3 Creatinine increased 31 1 21 1 Calcium decreased 27 2 26 0 Potassium increased 24 2 12 0 Phosphate decreased 20 3.1 18 0 Urate increased 16 3.2 34 6 Bilirubin increased 12 1 33 1 Marginal Zone Lymphoma The safety of BRUKINSA was evaluated in 88 patients with previously treated MZL in two single-arm clinical studies, BGB-3111-214 and BGB-3111-AU-003 [see Clinical Studies (14.3) ] . The trials required an absolute neutrophil count ≥1 × 10 9 /L, platelet count ≥50 or ≥75 × 10 9 /L and adequate hepatic function and excluded patients requiring a strong CYP3A inhibitor or inducer. Patients received BRUKINSA 160 mg twice daily (97%) or 320 mg once daily (3%). The median age in both studies combined was 70 years (range: 37 to 95), 52% were male, 64% were White, and 19% were Asian. Most patients (92%) had an ECOG performance status of 0 to 1. Eighty percent received BRUKINSA for 6 months or longer, and 67% received treatment for more than one year. Two fatal adverse reactions (2.3%) occurred within 30 days of the last dose of BRUKINSA, including myocardial infarction and a Covid-19–related death. Serious adverse reactions occurred in 40% of patients. The most frequent serious adverse reactions were pyrexia (8%) and pneumonia (7%). Adverse reactions lead to treatment discontinuation in 6% of patients, dose reduction in 2.3%, and dose interruption in 34%. The leading cause of dose modification was respiratory tract infections (13%). Table 7 summarizes selected adverse reactions in BGB-3111-214 and BGB-3111-AU-003. Table 7: Adverse Reactions Occurring in ≥10% Patients with MZL Who Received BRUKINSA Body System Adverse Reaction BRUKINSA (N=88) All Grades (%) Grade 3 or 4 (%) Infections and infestations Upper respiratory tract infection Upper respiratory tract infection includes upper respiratory tract infection, nasopharyngitis, sinusitis, tonsillitis, rhinitis, viral upper respiratory tract infection. 26 3.4 Urinary tract infection Urinary tract infection includes urinary tract infection, cystitis, Escherichia urinary tract infection, pyelonephritis, cystitis. 11 2.3 Pneumonia Pneumonia includes COVID-19 pneumonia, pneumonia, bronchopulmonary aspergillosis, lower respiratory tract infection, organizing pneumonia. , Includes 2 fatalities from COVID-19 pneumonia. 10 6 Gastrointestinal disorders Diarrhea Diarrhea includes diarrhea and diarrhea hemorrhagic. 25 3.4 Abdominal pain Abdominal pain includes abdominal pain, abdominal pain upper, abdominal discomfort. 14 2.3 Nausea 13 0 Skin and subcutaneous tissue disorders Bruising Bruising includes contusion, ecchymosis, increased tendency to bruise, post procedural contusion. 24 0 Rash Rash includes rash, rash maculo-papular, rash pruritic, dermatitis, dermatitis allergic, dermatitis atopic, dermatitis contact, drug reaction with eosinophilia and systemic symptoms, erythema, photosensitivity reaction, rash erythematous, rash papular, seborrheic dermatitis. 21 0 Musculoskeletal and connective tissue disorders Musculoskeletal pain Musculoskeletal pain includes back pain, arthralgia, musculoskeletal pain, myalgia, pain in extremity, musculoskeletal chest pain, bone pain, musculoskeletal discomfort, neck pain. 27 1.1 Vascular disorders Hemorrhage Hemorrhage includes epistaxis, hematuria, hemorrhoidal hemorrhage, hematoma, hemoptysis, conjunctival hemorrhage, diarrhea hemorrhagic, hemorrhage urinary tract, mouth hemorrhage, pulmonary hematoma, subcutaneous hematoma, gingival bleeding, melena, upper gastrointestinal hemorrhage. 23 1.1 General disorders Fatigue Fatigue includes fatigue, lethargy, asthenia. 21 2.3 Respiratory, thoracic, and mediastinal disorders Cough Cough includes cough and productive cough. 10 0 Clinically relevant adverse reactions in <10% of patients who received BRUKINSA included peripheral neuropathy, second primary malignancies, dizziness, edema, headache, petechiae, purpura, and atrial fibrillation or flutter. Table 8 summarizes select laboratory abnormalities. Table 8: Select Laboratory Abnormalities (≥20%) that Worsened from Baseline in Patients with MZL Laboratory Abnormality The denominator used to calculate the rate varied from 87 to 88 based on the number of patients with a baseline value and at least one post-treatment value. BRUKINSA All Grades (%) Grade 3 or 4 (%) Hematologic abnormalities Neutrophils decreased 43 15 Platelets decreased 33 10 Lymphocytes decreased 32 8 Hemoglobin decreased 26 6 Chemistry abnormalities Glucose increased 54 4.6 Creatinine increased 34 1.1 Phosphate decreased 27 2.3 Calcium decreased 23 0 ALT increased 22 1.1 Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma The safety data described below reflect exposure to BRUKINSA (160 mg twice daily) in 675 patients with CLL from two randomized controlled clinical trials [see Clinical Studies (14.4) ] . The trials required patients to be unsuitable for fludarabine, cyclophosphamide, and rituximab (FCR) therapy defined as age ≥65 years, or age 18 to <65 years with either a total Cumulative Illness Rating Scale (CIRS) >6, CLcr 30 to 69 mL/min, or history of serious or frequent infections. The trial excluded patients with AST or ALT ≥2 times the upper limit of normal (ULN) or bilirubin ≥3 times (ULN) and patients requiring a strong CYP3A inhibitor or inducer. SEQUOIA The safety of BRUKINSA monotherapy in patients with previously untreated CLL/SLL was evaluated in a randomized, multicenter, open-label, actively controlled trial [see Clinical Studies (14.4) ] . Patients without deletion of chromosome 17p13.1 (17p deletion) (Cohort 1) received either BRUKINSA 160 mg twice daily until disease progression or unacceptable toxicity (n=240) or bendamustine plus rituximab (BR) for 6 cycles (n=227). Bendamustine was dosed at 90 mg/m 2 /day intravenously on the first 2 days of each cycle, and rituximab was dosed at 375 mg/m 2 on day 1 of Cycle 1 and 500 mg/m 2 on day 1 of Cycles 2 to 6. Additionally, the same BRUKINSA regimen was evaluated in 111 patients with previously untreated CLL/SLL with 17p deletion in a non-randomized single arm (Cohort 2). Randomized Cohort: Previously Untreated CLL/SLL without 17p Deletion In patients with previously untreated CLL/SLL without 17p deletion, the median age was 70, 62% were male, 89% were White, 2% were Asian, and 2% were Black. Most patients (93%) had an ECOG performance status of 0 to 1. The median duration of exposure to BRUKINSA was 26 months, with 71% exposed for more than 2 years. Serious adverse reactions occurred in 36% of patients who received BRUKINSA. Serious adverse reactions that occurred in ≥5% of patients were COVID-19, pneumonia, and second primary malignancy (5% each). Fatal adverse reactions occurred in 11 (4.6%) patients with the leading cause of death being COVID-19 (2.1%). Adverse reactions led to permanent discontinuation of BRUKINSA in 8% of patients, dose reduction in 8%, and dose interruption in 46%. The most common adverse reactions leading to permanent discontinuation were second primary malignancy and COVID-19. The leading causes of dose modification (≥5% of all patients) were respiratory infections (COVID-19, pneumonia) and hemorrhage. Table 9 summarizes select adverse reactions in this randomized cohort. Table 9: Adverse Reactions in ≥10% Patients with Previously Untreated CLL/SLL without 17p Deletion in SEQUOIA CLL/SLL without 17p deletion BRUKINSA (N=240) BR (N=227) System Organ Class Preferred Term All Grades (%) Grade 3 or 4 (%) All Grades (%) Grade 3 or 4 (%) Musculoskeletal and connective tissue disorders Musculoskeletal pain Musculoskeletal pain: musculoskeletal pain, arthralgia, back pain, pain in extremity, myalgia, neck pain, spinal pain, musculoskeletal discomfort, bone pain. 33 1.7 17 0.4 Infections and infestations Upper respiratory tract infection Upper respiratory tract infection: upper respiratory tract infection, nasopharyngitis, sinusitis, rhinitis, pharyngitis, upper respiratory tract congestion, laryngitis, tonsillitis and upper respiratory tract inflammation, and related terms. 28 1.3 15 0.9 Pneumonia Pneumonia: pneumonia, COVID-19 pneumonia, lower respiratory tract infection, lung infiltration, and related terms including specific types of infection. 13 Includes 3 fatal outcomes. 5 8 Includes 2 fatal outcomes. 4 Vascular disorders Hemorrhage Hemorrhage: all terms containing hematoma, hemorrhage, hemorrhagic, and related terms indicative of bleeding. 27 4 4 0.4 Hypertension Includes multiple similar adverse reaction terms. 14 7 5 2.6 Skin and subcutaneous tissue disorders Rash Rash: Rash, dermatitis, drug eruption, and related terms. 24 1.3 30 5 Bruising Bruising: all terms containing bruise, bruising, contusion, or ecchymosis. 24 0 2.6 0 Respiratory, thoracic, and mediastinal disorders Cough 15 0 10 0 Gastrointestinal disorders Diarrhea 14 0.8 12 0.9 Constipation 10 0.4 18 0 Nausea 10 0 33 1.3 General disorders Fatigue Fatigue: fatigue, asthenia, and lethargy. 14 1.3 21 1.8 Neoplasms Second primary malignancy Second primary malignancy: includes non-melanoma skin cancer, malignant solid tumors (including lung, renal, genitourinary, breast, ovarian, and rectal), and chronic myeloid leukemia. 13 6 1.3 0.4 Nervous system disorders Headache 12 0 8 0 Dizziness Dizziness: dizziness and vertigo. 11 0.8 5 0 Other clinically significant adverse reactions occurring in <10% of BRUKINSA recipients in this cohort included COVID-19 (9%), edema (8%), abdominal pain (8%), urinary tract infection (7%), and atrial fibrillation or flutter (3.3%). Table 10 summarizes select laboratory abnormalities in this cohort. Table 10: Select Laboratory Abnormalities (≥20%) that Worsened from Baseline in Patients with Previously Untreated CLL/SLL without 17p Deletion in SEQUOIA Laboratory Abnormality The denominator used to calculate the rate was 239 in the BRUKINSA arm and 227 in the BR arm, based on the number of patients with a baseline value and at least one post-treatment value. Grading is based on NCI CTCAE criteria. BRUKINSA BR All Grades (%) Grade 3 or 4 (%) All Grades (%) Grade 3 or 4 (%) Hematologic abnormalities Neutrophils decreased 37 15 80 53 Hemoglobin decreased 29 2.5 66 8 Platelets decreased 27 1.7 61 11 Leukocytes increased 21 Lymphocytes increased in 15%. 21 0.4 0.4 Chemistry abnormalities Glucose increased Nonfasting conditions. 55 7 67 10 Creatinine increased 22 0.8 18 0.4 Magnesium increased 22 0 14 0.4 Alanine aminotransferase increased 21 2.1 23 2.2 Single-Arm Cohort: Previously Untreated CLL/SLL and 17p Deletion In 111 patients with previously untreated, 17p del CLL/SLL, the median age was 70, 71% were male, 95% were White, and 1% were Asian. Most patients (87%) had an ECOG performance status of 0 to 1. The median duration of exposure to BRUKINSA was 30 months. Fatal adverse reactions occurred in 3 (2.7%) patients, including pneumonia, renal insufficiency, and aortic dissection (1 patient each). Serious adverse reactions occurred in 41% of patients treated with BRUKINSA. Serious adverse reactions reported in ≥5% of patients were pneumonia (8%) and second primary malignancy (7%). Adverse reactions led to treatment discontinuation in 5% of patients, dose reduction in 5%, and dose interruption in 51%. The leading causes of dose modification (≥5% of all patients) were pneumonia, neutropenia, second primary malignancy, and diarrhea. Table 11 summarizes select adverse reactions in this cohort. Table 11: Adverse Reactions in ≥10% of Patients with Previously Untreated CLL/SLL and 17p Deletion in SEQUOIA CLL/SLL with 17p Deletion BRUKINSA (N=111) System Organ Class Preferred Term All Grades (%) Grade 3 or 4 (%) Infections and infestations Upper respiratory tract infection Upper respiratory tract infection: upper respiratory tract infection, nasopharyngitis, sinusitis, rhinitis, pharyngitis, upper respiratory tract congestion, upper respiratory tract inflammation, viral upper respiratory tract infection, and related terms. 38 0 Pneumonia Pneumonia: pneumonia, COVID-19 pneumonia, lower respiratory tract infection, and related terms including specific types of infection. 20 Includes 1 fatal outcome. 8 Musculoskeletal and connective tissue disorders Musculoskeletal pain Musculoskeletal pain: musculoskeletal pain, arthralgia, back pain, pain in extremity, myalgia, neck pain, bone pain. 38 2.7 Skin and subcutaneous tissue disorders Rash Rash: Rash, dermatitis, toxic skin eruption, and related terms. 28 0 Bruising Bruising: all terms containing bruise, bruising, contusion, or ecchymosis. 26 0.9 Vascular disorders Hemorrhage Hemorrhage: all terms containing hematoma, hemorrhage, hemorrhagic, and related terms indicative of bleeding. 28 4.5 Hypertension 11 5.4 Neoplasms Second primary malignancy Second primary malignancy: includes non-melanoma skin cancer, malignant solid tumors (including bladder, lung, renal, breast, prostate, ovarian, pelvis, and ureter), and malignant melanoma. 22 Includes non-melanoma skin cancer in 13%. 6 Gastrointestinal disorders Diarrhea 18 0.9 Nausea 16 0 Constipation 15 0 Abdominal pain 12 1.8 Respiratory, thoracic, and mediastinal disorders Cough Includes multiple similar adverse reaction terms. 18 0 Dyspnea 13 0 General disorders and administration site conditions Fatigue Fatigue: fatigue, asthenia, and lethargy. 14 0.9 Nervous system disorders Headache 11 1.8 Clinically significant adverse reactions occurring in <10% of BRUKINSA recipients in this cohort included urinary tract infection (8%), edema (7%), atrial fibrillation or flutter (4.5%), and COVID-19 (3.6%). Table 12 summarizes select laboratory abnormalities in this cohort. Table 12: Select Laboratory Abnormalities (≥20%) that Worsened from Baseline in Patients with Previously Untreated CLL/SLL and 17p Deletion in SEQUOIA Laboratory Abnormality The denominator used to calculate the rate varied from 110 to 111 based on the number of patients with a baseline value and at least one post-treatment value. Grading is based on NCI CTCAE criteria. BRUKINSA All Grades (%) Grade 3 or 4 (%) Hematologic abnormalities Neutrophils decreased 42 19 Grade 4, 9%. Hemoglobin decreased 26 3.6 Platelets decreased 23 0.9 Chemistry abnormalities Glucose increased Nonfasting conditions. 52 6 Magnesium increased 31 0 Creatinine increased 27 0.9 ALPINE The safety of BRUKINSA monotherapy was evaluated in patients with previously treated CLL/SLL in a randomized, multicenter, open-label, actively controlled trial [see Clinical Studies (14.4) ] . In ALPINE, 324 patients received BRUKINSA monotherapy, 160 mg orally twice daily and 324 patients received ibrutinib monotherapy, 420 mg orally daily until disease progression or unacceptable toxicity. In ALPINE, the median duration of exposure was 24 months for BRUKINSA. Adverse reactions leading to death in the BRUKINSA arm occurred in 24 (7%) patients. Adverse reactions leading to death that occurred in >1% of patients were pneumonia (2.8%) and COVID-19 infection (1.9%). One hundred and four patients in the BRUKINSA arm (32%) reported ≥1 serious adverse reaction. Serious adverse reactions occurring in ≥5% of patients were pneumonia (10%), COVID-19 (7%), and second primary malignancies (5%). Adverse reactions led to treatment discontinuation in 13% of patients, dose reduction in 11%, and dose interruption in 42%. The leading cause of treatment discontinuation was pneumonia. The leading causes of dose modification (≥5% of all patients) were respiratory infections (COVID-19, pneumonia) and neutropenia. Table 13 summarizes select adverse reactions in ALPINE. Table 13: Adverse Reactions in ≥10% of Patients with Relapsed or Refractory CLL/SLL Who Received BRUKINSA in ALPINE System Organ Class Preferred Term BRUKINSA (N=324) Ibrutinib (N=324) All Grades (%) Grade 3 or 4 (%) All Grades (%) Grade 3 or 4 (%) Infections and infestations Upper respiratory tract infection Upper respiratory tract infection: upper respiratory tract infection, sinusitis, pharyngitis, rhinitis, nasopharyngitis, laryngitis, tonsillitis, and related terms. 27 1.2 22 1.2 Pneumonia Pneumonia: Pneumonia, COVID-19 pneumonia, lower respiratory tract infection, lung infiltration, and related terms including specific types of infection. 18 Includes fatal outcomes: pneumonia (9 patients), COVID-19 (8 patients), and hemorrhage (1 patient). 9 19 Includes fatal outcomes: pneumonia (10 patients), COVID-19 (9 patients), and hemorrhage (2 patients). 11 COVID-19 COVID-19: COVID-19, COVID-19 pneumonia, postacute COVID-19 syndrome, SARS-CoV-2 test positive. 14 7 10 4.6 Musculoskeletal and connective tissue disorders Musculoskeletal pain Musculoskeletal pain: musculoskeletal pain, arthralgia, back pain, pain in extremity, myalgia, neck pain, spinal pain, bone pain, and musculoskeletal discomfort. 26 0.6 28 0.6 Vascular disorders Hemorrhage Hemorrhage: all terms containing hematoma, hemorrhage, hemorrhagic, and related terms indicative of bleeding. 24 2.5 26 3.7 Hypertension Includes multiple similar adverse reaction terms. 19 13 20 13 Skin and subcutaneous tissue disorders Rash Rash: Rash, Dermatitis, and related terms. 20 1.2 21 0.9 Bruising Bruising: all terms containing bruise, bruising, contusion, or ecchymosis. 16 0 14 0 Gastrointestinal disorders Diarrhea 14 1.5 22 0.9 General disorders Fatigue Fatigue: asthenia, fatigue, lethargy. 13 0.9 14 0.9 Respiratory, thoracic, and mediastinal disorders Cough 11 0.3 11 0 Nervous system disorders Dizziness 10 0 7 0 Clinically relevant adverse reactions in <10% of patients who received BRUKINSA included urinary tract infection (9%), supraventricular arrhythmias (9%) including atrial fibrillation or flutter (4.6%), abdominal pain (8%), headache (8%), pruritus (6.2%), constipation (5.9%), and edema (4.6%). Table 14 summarizes select laboratory abnormalities in ALPINE. Table 14: Select Laboratory Abnormalities (≥20%) that Worsened from Baseline in Patients Who Received BRUKINSA in ALPINE Laboratory Abnormality The denominator used to calculate the rate was 321 in the BRUKINSA arm, and varied from 320 to 321 in the ibrutinib arm, based on the number of patients with a baseline value and at least one post-treatment value. Grading is based on NCI CTCAE criteria. BRUKINSA Ibrutinib All Grades (%) Grade 3 or 4 (%) All Grades (%) Grade 3 or 4 (%) Hematologic abnormalities Neutrophils decreased 43 15 33 16 Hemoglobin decreased 28 4 32 3.7 Lymphocytes increased 24 19 26 19 Platelets decreased 22 4 24 3.4 Chemistry abnormalities Glucose increased 52 5 29 2.8 Creatinine increased 26 0 23 0 Phosphate decreased 21 2.5 13 2.2 Calcium decreased 21 0.6 29 0 Follicular Lymphoma The safety of BRUKINSA in combination with obinutuzumab was evaluated in 143 adult patients with relapsed or refractory follicular lymphoma (FL) in study BGB-3111-212 (ROSEWOOD), a randomized, multicenter, open-label trial [see Clinical Studies (14.5) ] . The trial required an absolute neutrophil count ≥1 × 10 9 /L, platelet count ≥50 × 10 9 /L, and CLcr ≥30 mL/min and excluded patients requiring a strong CYP3A inhibitor or inducer. Patients were randomized to receive either BRUKINSA 160 mg twice daily until disease progression or unacceptable toxicity plus obinutuzumab (n=143) or obinutuzumab monotherapy (n=71). Obinutuzumab was dosed at 1,000 mg intravenously on Days 1, 8, and 15 of Cycle 1; on Day 1 of Cycles 2 to 6; and then every 8 weeks for up to 20 doses. At the discretion of the investigator, obinutuzumab was administered intravenously on Day 1 (100 mg) and on Day 2 (900 mg) of Cycle 1 instead of 1,000 mg on Day 1 of Cycle 1. In patients who received BRUKINSA in combination with obinutuzumab, the median age was 63, 49% were female, 63% were White, and 21% were Asian. Most patients (97%) had an ECOG performance status of 0 to 1. The median duration of BRUKINSA treatment was 12 months, with 24% of patients treated for at least 2 years. Serious adverse reactions occurred in 35% of patients who received BRUKINSA in combination with obinutuzumab. Serious adverse reactions in ≥5% of patients included pneumonia (11%) and COVID-19 (10%). Fatal adverse reactions occurred in 4.2% of patients, with the leading cause of death being COVID-19 (2.1%). Adverse reactions led to permanent discontinuation of BRUKINSA in 17% of patients, dose reduction in 9%, and dose interruption in 40%. Adverse reactions leading to permanent discontinuation in ≥2% of patients were pneumonia, COVID-19, and second primary malignancy. The leading causes of BRUKINSA dosage modification (42% of all patients) were pneumonia, COVID-19, thrombocytopenia, and neutropenia. Table 15 summarizes adverse reactions in BGB-3111-212. Table 15: Adverse Reactions in ≥10% of Patients with Relapsed or Refractory FL Who Received BRUKINSA in Study BGB-3111-212 System Organ Class Preferred Term BGB-3111-212 BRUKINSA + Obinutuzumab (N=143) Obinutuzumab (N=71) All Grades (%) Grade 3 or 4 (%) All Grades (%) Grade 3 or 4 (%) General disorders and administration site conditions Fatigue Includes multiple related terms. , Fatigue: Fatigue, asthenia, and lethargy. 27 1.4 25 1.4 Pyrexia 13 0 20 0 Musculoskeletal and connective tissue disorders Musculoskeletal pain , Musculoskeletal pain: Back pain, musculoskeletal pain, musculoskeletal discomfort, noncardiac chest pain, neck pain, pain in extremity, myalgia, spinal pain, bone pain, arthralgia, and related terms. 22 3.5 23 1.4 Vascular disorders Hemorrhage , Hemorrhage: All terms containing hematoma, hemorrhage, hemorrhagic, and related terms indicative of bleeding. 20 1.4 10 1.4 Gastrointestinal disorders Diarrhea 18 2.8 17 1.4 Constipation 13 0 9 0 Abdominal pain 11 2.1 11 0 Infections and infestations Upper respiratory tract infection , Upper respiratory tract infection: Upper respiratory tract infection, sinusitis, pharyngitis, laryngitis, rhinitis, nasopharyngitis, laryngopharyngitis, tonsillitis bacterial, and related terms. 17 2.8 10 0 Pneumonia , Pneumonia: Pneumonia, COVID-19 pneumonia, lung infiltration, lung consolidation, and related terms including specific types of infection. , Includes fatal outcomes: COVID-19 (3 patients), pneumonia (2 patients), dyspnea (1 patient). 15 13 11 7 COVID-19 , 13 9 11 4.2 Herpes virus infection Herpes virus infection: Herpes viral infection, herpes zoster, herpes simplex, herpes simplex reactivation, varicella, and Epstein-Barr viremia. 11 2.1 1.4 0 Urinary tract infection Urinary tract infection: Urinary tract infection, cystitis, pyelonephritis, and related terms. 10 1.4 7 0 Respiratory, thoracic, and mediastinal disorders Cough 14 0 14 0 Dyspnea , 11 2.1 13 0 Skin and subcutaneous tissue disorders Rash , Rash: Rash, erythema, dermatitis, drug eruption, skin reaction, and related terms. 11 0 14 0 Clinically relevant adverse reactions in <10% of patients who received BRUKINSA in combination with obinutuzumab included bruising, edema, pruritus, petechiae, vomiting, headache, arthralgia, hypertension, sepsis, cardiac arrhythmias, renal insufficiency, febrile neutropenia, transaminase elevation, and pneumonitis. Table 16: Select Laboratory Abnormalities (≥20%) that Worsened from Baseline in Patients Who Received BRUKINSA in Study BGB-3111-212 Laboratory Abnormality The denominator used to calculate the rate was 122 in the BRUKINSA + obinutuzumab arm, and varied from 56 to 58 in the obinutuzumab arm, based on the number of patients with a baseline value and at least one post-treatment value. Grading is based on NCI CTCAE criteria. BGB-3111-212 BRUKINSA + Obinutuzumab Obinutuzumab All Grades (%) Grade 3 or 4 (%) All Grades (%) Grade 3 or 4 (%) Hematologic abnormalities Platelets decreased 65 11 43 11 Neutrophils decreased 47 17 42 14 Hemoglobin decreased 31 0.8 23 0 Lymphocytes decreased 30 11 51 25 Chemistry Glucose increased Nonfasting conditions. 53 8 41 9 Alanine aminotransferase increased 23 0 28 0 Phosphate decreased 21 0.8 14 0 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of BRUKINSA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Hepatobiliary disorder: drug-induced liver injury

8.1 Pregnancy Risk Summary Based on findings in animals, BRUKINSA can cause fetal harm when administered to pregnant women. There are no available data on BRUKINSA use in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. In animal reproduction studies, oral administration of zanubrutinib to pregnant rats during the period of organogenesis was associated with fetal heart malformation at approximately 5-fold human exposures (see Data ) . Women should be advised to avoid pregnancy while taking BRUKINSA. If BRUKINSA is used during pregnancy, or if the patient becomes pregnant while taking BRUKINSA, the patient should be apprised of the potential hazard to the fetus. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Animal Data Embryo-fetal development toxicity studies were conducted in both rats and rabbits. Zanubrutinib was administered orally to pregnant rats during the period of organogenesis at doses of 30, 75, and 150 mg/kg/day. Malformations in the heart (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 approximately 5 times the exposure (AUC) in patients receiving the recommended dose of 160 mg twice daily. Administration of zanubrutinib to pregnant rabbits during the period of organogenesis at 30, 70, and 150 mg/kg/day resulted in postimplantation loss at the highest dose. The dose of 150 mg/kg is approximately 32 times the exposure (AUC) in patients at the recommended dose and was associated with maternal toxicity. In a pre and postnatal developmental toxicity study, zanubrutinib was administered orally to rats at doses of 30, 75, and 150 mg/kg/day from implantation through weaning. The offspring from the middle and high dose groups had decreased body weights preweaning, and all dose groups had adverse ocular findings (e.g., cataract, protruding eye). The dose of 30 mg/kg/day is approximately 5 times the AUC in patients receiving the recommended dose.