b'Table 9 summarizes select adverse reactions in this randomized cohort. interruption in 51%. The leading causes of dose modification (5% of all patients) were pneumonia,Table 13 summarizes select adverse reactions in ALPINE. 8 USE IN SPECIFIC POPULATIONS Table 9: Adverse Reactions in 10% Patients with Previously Untreated CLL/SLL Without 17p Deletionneutropenia, second primary malignancy, and diarrhea. Table 13: Adverse Reactions in 10% of Patients with Relapsed or Refractory CLL/SLL Who Received8.1 Pregnancyin SEQUOIA Table 11 summarizes select adverse reactions in this cohort. BRUKINSA in ALPINE Risk Summary CLL/SLL without 17p deletion Table 11: Adverse Reactions in 10% of Patients with Previously Untreated CLL/SLL and 17p DeletionBRUKINSA Ibrutinib Based on findings in animals, BRUKINSA can cause fetal harm when administered to pregnant women. BRUKINSA (N=240) BR (N=227) in SEQUOIA (N=324) (N=324) There are no available data on BRUKINSA use in pregnant women to evaluate for a drug-associated risk of CLL/SLL with 17p Deletion System Organ Class All Grades Grade 3 or 4 All Grades Grade 3 or 4 major birth defects, miscarriage or adverse maternal or fetal outcomes. In animal reproduction studies, oral System Organ ClassAll Grades Grade 3 or 4 All Grades Grade 3 or 4 Preferred Term (%) (%) (%) (%) administration of zanubrutinib to pregnant rats during the period of organogenesis was associated with fetal Preferred Term (%) (%) (%) (%) BRUKINSA (N=111) Infections and infestations heart malformation at approximately 5-fold human exposures (see Data). Women should be advised to avoid Musculoskeletal and connective tissue disorders System Organ Class All Grades Grade 3 or 4 Upper respiratory tract infectiona 27 1.2 22 1.2 pregnancy while taking BRUKINSA. If BRUKINSA is used during pregnancy, or if the patient becomes pregnant Musculoskeletal paina 33 1.7 17 0.4 Preferred Term (%) (%) Pneumoniab 18* 9 19 11 while taking BRUKINSA, the patient should be apprised of the potential hazard to the fetus.Infections and infestations The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. Infections and infestations Upper respiratory tract infectiona 38 0.0 COVID-19c 14* 7 10 4.6 All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general Upper respiratory tract infectionb 28 1.3 15 0.9 b Musculoskeletal and connective tissue disorders population, the estimated background risk of major birth defects and miscarriage in clinically recognized Pneumoniac 13* 5 8 4 Pneumonia 20* 8 Musculoskeletal paind 26 0.6 28 0.6 pregnancies is 2% to 4% and 15% to 20%, respectively.Musculoskeletal and connective tissue disorders Vascular disorders Data Vascular disorders Musculoskeletal painc 38 2.7 eAnimal Data Hemorrhaged 27* 4 4 0.4 Hemorrhage 24* 2.5 26 3.7 Embryo-fetal development toxicity studies were conducted in both rats and rabbits. Zanubrutinib was Skin and subcutaneous tissue disorders fe d Hypertension 19 13 20 13 administered orally to pregnant rats during the period of organogenesis at doses of 30, 75, and 150 mg/kg/day.Hypertension 14 7 5 2.6 Rash 28 0.0 Skin and subcutaneous tissue disorders Malformations in the heart (2 or 3-chambered hearts) were noted at all dose levels in the absence of maternal Skin and subcutaneous tissue disorders Bruisinge 26 0.9 Rashg 20 1.2 21 0.9 toxicity. The dose of 30 mg/kg/day is approximately 5 times the exposure (AUC) in patients receiving the Rashf 24 1.3 30 5 Vascular disorders h recommended dose of 160 mg twice daily.g Hemorrhagef 28 4.5 Bruising 16 0.0 14 0.0 Administration of zanubrutinib to pregnant rabbits during the period of organogenesis at 30, 70, and 150 mg/kg/day Bruising 24 0 2.6 0 Gastrointestinal disorders resulted in post-implantation loss at the highest dose. The dose of 150 mg/kg is approximately 32 times the Respiratory, thoracic and mediastinal disorders Hypertensiong 11 5.4 Diarrhea 14 1.5 22 0.9 exposure (AUC) in patients at the recommended dose and was associated with maternal toxicity.Coughe 15 0 10 0 Neoplasms General disorders In a pre and postnatal developmental toxicity study, zanubrutinib was administered orally to rats at doses Gastrointestinal disorders Second primary malignancyh 22 6 Fatiguei 13 0.9 14 0.9 of 30, 75, and 150 mg/kg/day from implantation through weaning. The offspring from the middle and highGastrointestinal disorders Respiratory, thoracic and mediastinal disorders dose groups had decreased body weights preweaning, and all dose groups had adverse ocular findings (e.g., Diarrhea 14 0.8 12 0.9 cataract, protruding eye). The dose of 30 mg/kg/day is approximately 5 times the AUC in patients receiving the Constipation 10 0.4 18 0.0 Diarrhea 18 0.9 Coughf 11 0.3 11 0.0 recommended dose.Nausea 10 0 33 1.3 Nausea 16 0.0 Nervous system disorders f 8.2 LactationConstipation 15 0.0 Dizziness 10 0.0 7 0.0 Risk Summary General disorders Abdominal paing 12 1.8 *Includes fatal outcomes: pneumonia (9 patients), COVID-19 (8 patients), and hemorrhage (1 patient). There are no data on the presence of zanubrutinib or its metabolites in human milk, the effects on the Fatigueh 14 1.3 21 1.8 Includes fatal outcomes: pneumonia (10 patients), COVID-19 (9 patients), and hemorrhage (2 patients). breastfed child, or the effects on milk production. Because of the potential for serious adverse reactions from Respiratory, thoracic and mediastinal disorders aUpper respiratory tract infection: upper respiratory tract infection, sinusitis, pharyngitis, rhinitis, nasopharyngitis, laryngitis, BRUKINSA in a breastfed child, advise lactating women not to breastfeed during treatment with BRUKINSA and Neoplasms Coughg 18 0.0 b tonsillitis, and related terms. for two weeks following the last dose.i P neumonia: Pneumonia, COVID-19 pneumonia, lower respiratory tract infection, lung infiltration, and related terms including specific Second primary malignancy 13* 6 1.3 0.4 Dyspneag 13 0.0 types of infection. 8.3 Females and Males of Reproductive PotentialcCOVID-19: COVID-19, COVID-19 pneumonia, post-acute COVID-19 syndrome, SARS-CoV-2 test positive.Nervous system disorders General disorders and administration site conditions d Musculoskeletal pain: musculoskeletal pain, arthralgia, back pain, pain in extremity, myalgia, neck pain, spinal pain, bone pain, andBRUKINSA can cause embryo-fetal harm when administered to pregnant women [see Use in Specific Headachee 12 0 8 0 Fatiguei 14 0.9 e musculoskeletal discomfort. Populations (8.1)].j f Hemorrhage: all terms containing hematoma, hemorrhage, hemorrhagic, and related terms indicative of bleeding. Pregnancy Testing Dizziness 11 0.8 5 0 Nervous system disorders g Includes multiple similar adverse reaction terms. Pregnancy testing is recommended for females of reproductive potential prior to initiating BRUKINSA therapy.Rash: Rash, Dermatitis, and related terms.* Includes 3 fatal outcomes. Headache 11 1.8 hBruising: all terms containing bruise, bruising, contusion, or ecchymosis. Contraception Includes 2 fatal outcomes. iFatigue: asthenia, fatigue, lethargy.aMusculoskeletal pain: musculoskeletal pain, arthralgia, back pain, pain in extremity, myalgia, neck pain, spinal pain, * Includes 1 fatal outcome. Females musculoskeletal discomfort, bone pain. Includes non-melanoma skin cancer in 13%. Clinically relevant adverse reactions in 10% of patients who received BRUKINSA included urinary tract infectionAdvise female patients of reproductive potential to use effective contraception during treatment with BRUKINSA bUpper respiratory tract infection: upper respiratory tract infection, nasopharyngitis, sinusitis, rhinitis, pharyngitis, upper a Upper respiratory tract infection: upper respiratory tract infection, nasopharyngitis, sinusitis, rhinitis, pharyngitis, upper(9%), supraventricular arrhythmias (9%) including atrial fibrillation or flutter (4.6%), abdominal pain (8%), headacheand for 1 week following the last dose of BRUKINSA. If this drug is used during pregnancy, or if the patient respiratory tract congestion, upper respiratory tract inflammation, viral upper respiratory tract infection, and related terms.c respiratory tract congestion, laryngitis, tonsillitis and upper respiratory tract inflammation, and related terms. b Pneumonia: pneumonia, COVID-19 pneumonia, lower respiratory tract infection, and related terms including specific types of infection. (8%), pruritus (6.2%), constipation (5.9%), and edema (4.6%). becomes pregnant while taking this drug, the patient should be informed of the potential hazard to a fetus.Musculoskeletal pain: musculoskeletal pain, arthralgia, back pain, pain in extremity, myalgia, neck pain, bone pain.Pneumonia: pneumonia, COVID-19 pneumonia, lower respiratory tract infection, lung infiltration, and related terms includingcspecific types of infection. d Table 14 summarizes select laboratory abnormalities in ALPINE. Males d Hemorrhage: all terms containing hematoma, hemorrhage, hemorrhagic, and related terms indicative of bleeding. e Rash: Rash, dermatitis, toxic skin eruption, and related terms.eIncludes multiple similar adverse reaction terms. f Bruising: all terms containing bruise, bruising, contusion, or ecchymosis. Table 14: Select Laboratory Abnormalities (20%) that Worsened from Baseline in Patients Who ReceivedAdvise men to avoid fathering a child while receiving BRUKINSA and for 1 week following the last dose of BRUKINSA.f Rash: Rash, dermatitis, drug eruption, and related terms. g Hemorrhage: all terms containing hematoma, hemorrhage, hemorrhagic, and related terms indicative of bleeding. BRUKINSA in ALPINE8.4 Pediatric Useg Bruising: all terms containing bruise, bruising, contusion, or ecchymosis.h Includes multiple similar adverse reaction terms.h Fatigue: fatigue, asthenia, and lethargy Second primary malignancy: includes non-melanoma skin cancer, malignant solid tumors (including bladder, lung, renal, breast,a BRUKINSA Ibrutinib Safety and effectiveness in pediatric patients have not been established.iSecond primary malignancy: includes non-melanoma skin cancer, malignant solid tumors (including lung, renal, genitourinary,i prostate, ovarian, pelvis, and ureter), and malignant melanoma. Laboratory Abnormality All Grades (%) Grade 3 or 4 (%) All Grades (%) Grade 3 or 4 (%) 8.5 Geriatric UseFatigue: fatigue, asthenia, and lethargy.breast, ovarian, and rectal), and chronic myeloid leukemia.jDizziness: dizziness and vertigo. Clinically significant adverse reactions occurring in 10% of BRUKINSA recipients in this cohort includedHematologic abnormalities Of the 1550 patients with MCL, MZL, WM, and CLL/SLL in clinical studies with BRUKINSA, 61% were 65 urinary tract infection (8%), edema (7%), atrial fibrillation or flutter (4.5%), and COVID-19 (3.6%). Neutrophils decreased 43 15 33 16 years of age, and 22% were 75 years of age. Patients 65 years of age had numerically higher rates of Other clinically significant adverse reactions occurring in 10% of BRUKINSA recipients in this cohort includedGrade 3 or higher adverse reactions and serious adverse reactions (63% and 47%, respectively) than patients COVID-19 (9%), edema (8%), abdominal pain (8%), urinary tract infection (7%), and atrial fibrillation or flutterTable 12 summarizes select laboratory abnormalities in this cohort. Hemoglobin decreased 28 4 32 3.7 65 years of age (57% and 36%, respectively). No overall differences in effectiveness were observed between (3.3%). Table 12: Select Laboratory Abnormalities (20%) that Worsened from Baseline in Patients withLymphocytes increased 24 19 26 19 younger and older patients.Table 10 summarizes select laboratory abnormalities in this cohort. Previously Untreated CLL/SLL and 17p Deletion in SEQUOIAPlatelets decreased 22 4 24 3.4 8.6 Renal ImpairmentTable 10: Select Laboratory Abnormalities (20%) that Worsened from Baseline in Patients with PreviouslyBRUKINSA Chemistry abnormalities No dosage modification is recommended in patients with mild, moderate, or severe renal impairmentUntreated CLL/SLL without 17p Deletion in SEQUOIA Laboratory Abnormalitya All Grades (%) Grade 3 or 4 (%) Glucose increased 52 5 29 2.8 (CLcr 15 mL/min, estimated by Cockcroft-Gault). Monitor for BRUKINSA adverse reactions in patientsa BRUKINSA BR Creatinine increased 26 0.0 23 0.0 on dialysis [see Clinical Pharmacology (12.3)].Laboratory Abnormality All Grades (%) Grade 3 or 4 (%) All Grades (%) Grade 3 or 4 (%) Hematologic abnormalities 8.7 Hepatic ImpairmentHematologic abnormalities Neutrophils decreased 42 19b Phosphate decreased 21 2.5 13 2.2 Dosage modification of BRUKINSA is recommended in patients with severe hepatic impairment [see Dosage Hemoglobin decreased 26 3.6 Calcium decreased 21 0.6 29 0.0 and Administration (2.2)]. The safety of BRUKINSA has not been evaluated in patients with severe hepatic Neutrophils decreased 37 15 80 53 aT he denominator used to calculate the rate was 321 in the BRUKINSA arm, and varied from 320 to 321 in the ibrutinib arm, basedimpairment. No dosage modification is recommended in patients with mild to moderate hepatic impairment. Hemoglobin decreased 29 2.5 66 8 Platelets decreased 23 0.9 on the number of patients with a baseline value and at least one post-treatment value. Grading is based on NCI CTCAE criteria. Monitor for BRUKINSA adverse reactions in patients with hepatic impairment [see Clinical Pharmacology (12.3)].Platelets decreased 27 1.7 61 11 Chemistry abnormalities 7 DRUG INTERACTIONS Manufactured for: Leukocytes increased 21b 21 0.4 0.4 Glucose increasedc 52 6 BeiGene USA, Inc. Chemistry abnormalities Magnesium increased 31 0 7.1 Effect of Other Drugs on BRUKINSA1840 Gateway Dr., FL 3 c Table 15: Drug Interactions that Affect ZanubrutinibSan Mateo, CA 94404 Glucose increased 55 7 67 10 Creatinine increased 27 0.9 Moderate and Strong CYP3A Inhibitors BRUKINSA is a registered trademark owned by BeiGene, Ltd. or its affiliates. Creatinine increased 22 0.8 18 0.4 aThe denominator used to calculate the rate varied from 110 to 111 based on the number of patients with a baseline value and at BeiGene, Ltd. 2023 0721-BRU-PRC-027-r1 1/2023 least one post-treatment value. Grading is based on NCI CTCAE criteria. Clinical Coadministration with a moderate or strong CYP3A inhibitor increases zanubrutinib C maxand Magnesium increased 22 0 14 0.4 bGrade 4, 9%.Impact AUC [see Clinical Pharmacology (12.3)] which may increase the risk of BRUKINSA toxicities.Alanine aminotransferase increased 21 2.1 23 2.2 cNon-fasting conditions.Prevention orReduce BRUKINSA dosage when coadministered with moderate or strong CYP3A aThe denominator used to calculate the rate was 239 in the BRUKINSA arm and 227 in the BR arm, based on the number ofALPINE management inhibitors [see Dosage and Administration (2.3)]. patients with a baseline value and at least one post-treatment value. Grading is based on NCI CTCAE criteria. The safety of BRUKINSA monotherapy was evaluated in patients with previously treated CLL/SLL in a randomized, bLymphocytes increased in 15%.Moderate and Strong CYP3A Inducersc multicenter, open-label, actively controlled trial [see Clinical Studies (14.4)]. In ALPINE, 324 patients received Non-fasting conditions. BRUKINSA monotherapy, 160 mg orally twice daily and 324 patients received ibrutinib monotherapy, 420 mgClinicalCoadministration with a moderate or strong CYP3A inducer decreases zanubrutinib C max Single-arm cohort: Previously untreated CLL/SLL and 17p deletion orally daily until disease progression or unacceptable toxicity. Impact and AUC [see Clinical Pharmacology (12.3)] which may reduce BRUKINSA efficacy.In 111 patients with previously untreated, 17p del CLL/SLL, the median age was 70, 71% were male, 95%In ALPINE, the median duration of exposure was 24 months for BRUKINSA. Adverse reactions leading to deathPrevention or Avoid coadministration of BRUKINSA with strong CYP3A inducers were White, and 1% were Asian. Most patients (87%) had an ECOG performance status of 0 to 1. The medianin the BRUKINSA arm occurred in 24 (7%) patients. Adverse reactions leading to death that occurred in 1% ofmanagement [see Dosage and Administration (2.3)].duration of exposure to BRUKINSA was 30 months. patients were pneumonia (2.8%) and COVID-19 infection (1.9%).Avoid coadministration of BRUKINSA with moderate CYP3A4 inducers [see Dosage andFatal adverse reactions occurred in 3 (2.7%) patients, including pneumonia, renal insufficiency, and aorticOne hundred and four patients in the BRUKINSA arm (32%) reported 1 serious adverse reaction. SeriousAdministration (2.3)]. If these inducers cannot be avoided, increase BRUKINSA dosage to dissection (1 patient each). adverse reactions occurring in 5% of patients were pneumonia (10%), COVID-19 (7%), and second primary320 mg twice daily [see Dosage and Administration (2.3)].malignancies (5%).Serious adverse reactions occurred in 41% of patients treated with BRUKINSA. Serious adverse reactionsAdverse reactions led to treatment discontinuation in 13% of patients, dose reduction in 11%, and dose reported in 5% of patients were pneumonia (8%) and second primary malignancy (7%). interruption in 42%. The leading cause of treatment discontinuation was pneumonia. The leading causes of dose Adverse reactions led to treatment discontinuation in 5% of patients, dose reduction in 5%, and dosemodification (5% of all patients) were respiratory infections (COVID-19, pneumonia) and neutropenia.BEBR23BLNY2082_M11_Brief_Summary_Updt_PP.indd 3 2/2/23 3:09 PM BEBR23BLNY2082_M11_Brief_Summary_Updt_PP.indd 4 2/2/23 3:09 PM'