b'Table 15 summarizes adverse reactions in BGB-3111-212. 7 DRUG INTERACTIONSTable 15: Adverse Reactions in 10% of Patients with Relapsed or Refractory FL Who Received BRUKINSA7.1 Effect of Other Drugs on BRUKINSAin Study BGB-3111-212 Table 17: Drug Interactions that Affect ZanubrutinibBGB-3111-212 Moderate and Strong CYP3A InhibitorsBRUKINSA + Obinutuzumab Obinutuzumab Clinical Coadministration with a moderate or strong CYP3A inhibitor increases zanubrutinib C maxand System Organ Class (N=143) (N=71) Impact AUC [see Clinical Pharmacology (12.3)] which may increase the risk of BRUKINSA toxicities.Preferred Term All Grades Grade 3 or 4 All Grades Grade 3 or 4 Prevention orReduce BRUKINSA dosage when coadministered with moderate or strong CYP3A (%) (%) (%) (%) management inhibitors [see Dosage and Administration (2.3)].General disorders and administration site conditionsFatiguea,b 27 1.4 25 1.4 Moderate and Strong CYP3A InducersPyrexia 13 0 20 0 ClinicalCoadministration with a moderate or strong CYP3A inducer decreases zanubrutinib C maxMusculoskeletal and connective tissue disorders Impact and AUC [see Clinical Pharmacology (12.3)] which may reduce BRUKINSA efficacy.Musculoskeletal paina,c 22 3.5 23 1.4Avoid coadministration of BRUKINSA with strong CYP3A inducersVascular disorders Prevention or[see Dosage and Administration (2.3)].a,d managementAvoid coadministration of BRUKINSA with moderate CYP3A inducers [see Dosage and Hemorrhage 20 1.4 10 1.4Administration (2.3)]. If these inducers cannot be avoided, increase BRUKINSA dosage to Gastrointestinal disorders 320 mg twice daily [see Dosage and Administration (2.3)].Diarrhea 18 2.8 17 1.4Constipation 13 0 9 0 8 USE IN SPECIFIC POPULATIONS Abdominal paina 11 2.1 11 0 8.1 PregnancyInfections and infestations Risk Summary Based on findings in animals, BRUKINSA can cause fetal harm when administered to pregnant women. Upper respiratory tract infectiona,e 17 2.8 10 0 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 Pneumoniaa,f,* 15 13 11 7 administration of zanubrutinib to pregnant rats during the period of organogenesis was associated with fetal COVID-19a,* 13 9 11 4.2 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 Herpes virus infectiong 11 2.1 1.4 0 while taking BRUKINSA, the patient should be apprised of the potential hazard to the fetus.Urinary tract infectionh 10 1.4 7 0 The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. Respiratory, thoracic, and mediastinal disorders All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general Cougha 14 0 14 0 population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.Dyspneaa,* 11 2.1 13 0 Data Skin and subcutaneous tissue disorders Animal Data Rasha,i 11 0 14 0 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.* Includes fatal outcomes: COVID-19 (3 patients), pneumonia (2 patients), dyspnea (1 patient).Malformations in the heart (2 or 3-chambered hearts) were noted at all dose levels in the absence of maternal aI ncludes multiple related terms. toxicity. The dose of 30 mg/kg/day is approximately 5 times the exposure (AUC) in patients receiving the b Fatigue: Fatigue, asthenia, and lethargy.c recommended dose of 160 mg twice daily. 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. Administration of zanubrutinib to pregnant rabbits during the period of organogenesis at 30, 70, and 150 mg/kg/day dHemorrhage: All terms containing hematoma, hemorrhage, hemorrhagic, and related terms indicative of bleeding.resulted in postimplantation loss at the highest dose. The dose of 150 mg/kg is approximately 32 times the e Upper respiratory tract infection: Upper respiratory tract infection, sinusitis, pharyngitis, laryngitis, rhinitis, nasopharyngitis,exposure (AUC) in patients at the recommended dose and was associated with maternal toxicity.laryngopharyngitis, tonsillitis bacterial, and related terms.f Pneumonia: Pneumonia, COVID-19 pneumonia, lung infiltration, lung consolidation, and related terms including specific types of infection. In a pre and postnatal developmental toxicity study, zanubrutinib was administered orally to rats at doses g Herpes virus infection: Herpes viral infection, herpes zoster, herpes simplex, herpes simplex reactivation, varicella, and Epstein-Barr viremia. of 30, 75, and 150 mg/kg/day from implantation through weaning. The offspring from the middle and high h i Urinary tract infection: Urinary tract infection, cystitis, pyelonephritis, and related terms. dose groups had decreased body weights preweaning, and all dose groups had adverse ocular findings (e.g.,Rash: Rash, erythema, dermatitis, drug eruption, skin reaction, and related terms. cataract, protruding eye). The dose of 30 mg/kg/day is approximately 5 times the AUC in patients receiving the Clinically relevant adverse reactions in 10% of patients who received BRUKINSA in combination withrecommended dose.obinutuzumab included bruising, edema, pruritus, petechiae, vomiting, headache, arthralgia, hypertension, sepsis,8.2 Lactationcardiac arrhythmias, renal insufficiency, febrile neutropenia, transaminase elevation, and pneumonitis. Risk Summary Table 16: Select Laboratory Abnormalities (20%) that Worsened from Baseline in Patients Who ReceivedThere are no data on the presence of zanubrutinib or its metabolites in human milk, the effects on the BRUKINSA in Study BGB-3111-212 breastfed child, or the effects on milk production. Because of the potential for serious adverse reactions from BRUKINSA in a breastfed child, advise lactating women not to breastfeed during treatment with BRUKINSA and BGB-3111-212 for two weeks following the last dose.Laboratory Abnormalitya BRUKINSA + Obinutuzumab Obinutuzumab 8.3 Females and Males of Reproductive PotentialBRUKINSA can cause embryo-fetal harm when administered to pregnant women [see Use in Specific All Grades Grade 3 or 4 All Grades Grade 3 or 4 Populations (8.1)].(%) (%) (%) (%) Pregnancy Testing Hematologic abnormalities Pregnancy testing is recommended for females of reproductive potential prior to initiating BRUKINSA therapy.Platelets decreased 65 11 43 11 Contraception Neutrophils decreased 47 17 42 14 Females Advise female patients of reproductive potential to use effective contraception during treatment with BRUKINSA Hemoglobin decreased 31 0.8 23 0 and for 1 week following the last dose of BRUKINSA. If this drug is used during pregnancy, or if the patient Lymphocytes decreased 30 11 51 25 becomes pregnant while taking this drug, the patient should be informed of the potential hazard to a fetus.Chemistry Males Glucose increasedb 53 8 41 9 Advise men to avoid fathering a child while receiving BRUKINSA and for 1 week following the last dose of BRUKINSA.Alanine aminotransferase8.4 Pediatric Useincreased 23 0 28 0 Safety and effectiveness of BRUKINSA in pediatric patients have not been established.Phosphate decreased 21 0.8 14 0 8.5 Geriatric Usea Of the 1729 patients with MCL, MZL, WM, CLL/SLL, and FL in clinical studies with BRUKINSA, 59% were 65The denominator used to calculate the rate was 122 in the BRUKINSA + obinutuzumab arm, and varied from 56 to 58 in theyears of age, and 21% were 75 years of age. Patients 65 years of age had numerically higher rates of 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. Grade 3 or higher adverse reactions and serious adverse reactions (57% and 38%, respectively) than patients bNonfasting conditions. 65 years of age (51% and 29%, respectively). No overall differences in effectiveness were observed between younger and older patients.8.6 Renal ImpairmentNo dosage modification is recommended in patients with mild, moderate, or severe renal impairment(CLcr 15 mL/min, estimated by Cockcroft-Gault). Monitor for BRUKINSA adverse reactions in patientsManufactured for:on dialysis [see Clinical Pharmacology (12.3)].BeiGene USA, Inc.8.7 Hepatic Impairment1840 Gateway Dr., FL 3Dosage modification of BRUKINSA is recommended in patients with severe hepatic impairment [see Dosage San Mateo, CA 94404and Administration (2.2)]. The safety of BRUKINSA has not been evaluated in patients with severe hepatic BRUKINSA is a registered trademark owned by BeiGene, Ltd. or its affiliates.impairment. No dosage modification is recommended in patients with mild to moderate hepatic impairment.BeiGene, Ltd. 2024 0721-BRU-PRC-027-r2 3/2024 Monitor for BRUKINSA adverse reactions in patients with hepatic impairment [see Clinical Pharmacology (12.3)].'