b'BRIEF SUMMARY OF PRESCRIBING INFORMATION 6.1 Clinical Trials Experience Table 3: Adverse Reactions ( 10%) in Patients Receiving BRUKINSA The estimated background risk of major birth defects and miscarriage for the indicated FOR BRUKINSA (zanubrutinib) Because clinical trials are conducted under widely varying conditions, adverse reactionin BGB-3111-206 and BGB-3111-AU-003 Trials (continued) population is unknown. All pregnancies have a background risk of birth defect, loss, or SEE PACKAGE INSERT FOR FULL PRESCRIBING INFORMATION rates observed in the clinical trials of a drug cannot be directly compared to rates inMusculoskeletal andMusculoskeletal pain 14 3.4 other adverse outcomes. In the U.S. general population, the estimated background risk of 1 INDICATIONS AND USAGE the clinical trials of another drug and may not reflect the rates observed in practice. connective tissuemajor birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and BRUKINSA is indicated for the treatment of adult patients with mantle cell lymphomaThe data in the WARNINGS AND PRECAUTIONS reflect exposure to BRUKINSA as adisorders 15% to 20%, respectively.(MCL) who have received at least one prior therapy.single agent at 160 mg twice daily in 524 patients in clinical trials BGB-3111-AU-003,Metabolism andHypokalemia 14 1.7 DataThis indication is approved under accelerated approval based on overall response rateBGB-3111-206, BGB-3111-205, BGB-3111-210, and BGB-3111-1002 and to BRUKINSAnutrition disorders Animal Data[see Clinical Studies (14.1)]. Continued approval for this indication may be contingentat 320 mg once daily in 105 patients in trials BGB-3111-AU-003 and BGB-3111-1002.Embryo-fetal development toxicity studies were conducted in both rats and upon verification and description of clinical benefit in a confirmatory trial. Among 629 patients receiving BRUKINSA, 79% were exposed for 6 months or longer andRespiratory, thoracicCough 12 0 rabbits. Zanubrutinib was administered orally to pregnant rats during the period of 4 CONTRAINDICATIONS: None. 61% were exposed for greater than one year. and mediastinalorganogenesis at doses of 30, 75, and 150 mg/kg/day. Malformations in the heart In this pooled safety population, the most common adverse reactions in 10% of patientsdisorders (2- or 3-chambered hearts) were noted at all dose levels in the absence of maternal 5 WARNINGS AND PRECAUTIONSwho received BRUKINSA were neutrophil count decreased (53%), platelet count decreased^ Includes fatal adverse reaction toxicity. The dose of 30 mg/kg/day is approximately 5 times the exposure (AUC) in 5.1 Hemorrhage (39%), upper respiratory tract infection (38%), white blood cell count decreased (30%),* Bruising includes all related terms containing bruise, bruising, contusion, ecchymosispatients receiving the recommended dose of 160 mg twice daily.Fatal and serious hemorrhagic events have occurred in patients with hematologicalhemoglobin decreased (29%), rash (25%), bruising (23%), diarrhea (20%), cough (20%), Hemorrhage includes all related terms containing hemorrhage, hematoma Administration of zanubrutinib to pregnant rabbits during the period of organogenesisMusculoskeletal pain includes musculoskeletal pain, musculoskeletal discomfort, myalgia, back pain,malignancies treated with BRUKINSA monotherapy. Grade 3 or higher bleeding eventsmusculoskeletal pain (19%), pneumonia (18%), urinary tract infection (13%), hematuriaarthralgia, arthritis at 30, 70, and 150 mg/kg/day resulted in post-implantation loss at the highest dose. including intracranial and gastrointestinal hemorrhage, hematuria, and hemothorax have(12%), fatigue (11%), constipation (11%), and hemorrhage (10%).Pneumonia includes pneumonia, pneumonia fungal, pneumonia cryptococcal, pneumonia streptococcal,The dose of 150 mg/kg is approximately 32 times the exposure (AUC) in patients at thebeen reported in 2% of patients treated with BRUKINSA monotherapy. Bleeding eventsMantle Cell Lymphoma (MCL) atypical pneumonia, lung infection, lower respiratory tract infection, lower respiratory tract infection bacterial,recommended dose and was associated with maternal toxicity.of any grade, including purpura and petechiae, occurred in 50% of patients treated withlower respiratory tract infection viralBRUKINSA monotherapy.The safety of BRUKINSA was evaluated in 118 patients with MCL who received at leastII Rash includes all related terms containing rash In a pre- and post-natal developmental toxicity study, zanubrutinib was administered orally to one prior therapy in two single-arm clinical trials, BGB-3111-206 [NCT03206970] andUpper respiratory tract infection includes upper respiratory tract infection, upper respiratory tract infection viralrats at doses of 30, 75, and 150 mg/kg/day from implantation through weaning. The offspringBleeding events have occurred in patients with and without concomitant antiplateletBGB-3111-AU-003 [NCT02343120] [see Clinical Studies (14.1)]. The median age offrom the middle and high dose groups had decreased body weights preweaning, and all dose or anticoagulation therapy. Co-administration of BRUKINSA with antiplatelet orpatients who received BRUKINSA in studies BGB-3111-206 and BGB-3111-AU-003Other clinically significant adverse reactions that occurred in 10% of patients withgroups had adverse ocular findings (e.g. cataract, protruding eye). The dose of 30 mg/kg/day anticoagulant medications may further increase the risk of hemorrhage. was 62 years (range: 34 to 86), 75% were male, 75% were Asian, 21% were White, andmantle cell lymphoma include major hemorrhage (defined asGrade 3 hemorrhageis approximately 5 times the AUC in patients receiving the recommended dose. Monitor for signs and symptoms of bleeding. Discontinue BRUKINSA if intracranial94% had an ECOG performance status of 0 to 1. Patients had a median of 2 prior lines ofor CNS hemorrhage of any grade) (5%), hyperuricemia (6%) and headache (4.2%).hemorrhage of any grade occurs. Consider the benefit-risk of withholding BRUKINSA for therapy (range: 1 to 4). The BGB-3111-206 trial required a platelet count75 x 109/L andTable 4: Selected Laboratory Abnormalities* ( 20%) in Patients with MCL 8.2 Lactation3-7 days pre- and post-surgery depending upon the type of surgery and the risk of bleeding. an absolute neutrophil count1 x 109/L independent of growth factor support, hepaticin Studies BGB-3111-206 and BGB-3111-AU-003 Risk Summaryenzymes2.5 x upper limit of normal, total bilirubin1.5 x ULN. The BGB-3111-AU-003There are no data on the presence of zanubrutinib or its metabolites in human milk, 5.2 Infections trial required a platelet count50 x 109/L and an absolute neutrophil count1 x 109/LLaboratory Parameter Percent of Patients (N=118) the effects on the breastfed child, or the effects on milk production. Because of the Fatal and serious infections (including bacterial, viral, or fungal) and opportunisticindependent of growth factor support, hepatic enzymes3 x upper limit of normal,All Grades (%) Grade 3 or 4 (%) potential for serious adverse reactions from BRUKINSA in a breastfed child, advise infections have occurred in patients with hematological malignancies treated withtotal bilirubin1.5 x ULN. Both trials required a CLcr30 mL/min. Both trials excludedlactating women not to breastfeed during treatment with BRUKINSA and for at least BRUKINSA monotherapy. Grade 3 or higher infections occurred in 23% of patientspatients with prior allogeneic hematopoietic stem cell transplant, exposure to a BTKNeutrophils decreased 45 20 two weeks following the last dose.treated with BRUKINSA monotherapy. The most common Grade 3 or higher infectioninhibitor, known infection with HIV, and serologic evidence of active hepatitis B or hepatitisPlatelets decreased 40 7 8.3 Females and Males of Reproductive Potential was pneumonia. Infections due to hepatitis B virus (HBV) reactivation have occurred.C infection and patients requiring strong CYP3A inhibitors or strong CYP3A inducers.Hemoglobin decreased 27 6 Pregnancy Testing Consider prophylaxis for herpes simplex virus, pneumocystis jiroveci pneumonia, Patients received BRUKINSA 160 mg twice daily or 320 mg once daily. Among patients Pregnancy testing is recommended for females of reproductive potential prior to and other infections according to standard of care in patients who are at increased receiving BRUKINSA, 79% were exposed for 6 months or longer and 68% were exposedLymphocytosis 41 16 initiating BRUKINSA therapy.risk for infections. Monitor and evaluate patients for fever or other signs and symptomsfor greater than one year. Chemistry abnormalitiesof infection and treat appropriately. Fatal events within 30 days of the last dose of BRUKINSA occurred in 8 (7%) ofBlood uric acid increased 29 2.6 Contraception 5.3 Cytopenias 118 patients with MCL. Fatal cases included pneumonia in 2 patients and cerebralFemaleshemorrhage in one patient. ALT increased 28 0.9 BRUKINSA can cause embryo-fetal harm when administered to pregnant womenGrade 3 or 4 cytopenias, including neutropenia (27%), thrombocytopenia (10%), Bilirubin increased 24 0.9 [see Use in Specific Populations (8.1)]. Advise female patients of reproductive potential and anemia (8%) based on laboratory measurements, were reported in patientsSerious adverse reactions were reported in 36 patients (31%). The most frequent seriousto use effective contraception during treatment with BRUKINSA and for at least 1 week treated with BRUKINSA monotherapy. adverse reactions that occurred were pneumonia (11%) and hemorrhage (5%). * Based on laboratory measurements.following the last dose of BRUKINSA. If this drug is used during pregnancy, or if theAsymptomatic lymphocytosis is a known effect of BTK inhibition.Monitor complete blood counts during treatment and treat using growth factor orOf the 118 patients with MCL treated with BRUKINSA, 8 (7%) patients discontinuedpatient becomes pregnant while taking this drug, the patient should be informed oftransfusions, as needed. treatment due to adverse reactions in the trials. The most frequent adverse reaction7 DRUG INTERACTIONS the potential hazard to a fetus.5.4 Second Primary Malignancies leading to treatment discontinuation was pneumonia (3.4%). One (0.8%) patient7.1 Effect of Other Drugs on BRUKINSAMalesSecond primary malignancies, including non-skin carcinoma, have occurred in 9%experienced an adverse reaction leading to dose reduction (hepatitis B). Table 5: Drug Interactions that Affect Zanubrutinib Advise men to avoid fathering a child while receiving BRUKINSA and for at leastof patients treated with BRUKINSA monotherapy. The most frequent second primaryTable 3 summarizes the adverse reactions in BGB-3111-206 and BGB-3111-AU-003. Moderate and Strong CYP3A Inhibitors 1 week following the last dose of BRUKINSA.malignancy was skin cancer (basal cell carcinoma and squamous cell carcinoma ofTable 3: Adverse Reactions ( 10%) in Patients Receiving BRUKINSA Clinical ImpactCo-administration with a moderate or strong CYP3A8.4 Pediatric Useskin), reported in 6% of patients. Advise patients to use sun protection.in BGB-3111-206 and BGB-3111-AU-003 Trials inhibitor increases zanubrutinib C maxand AUC [seeSafety and effectiveness in pediatric patients have not been established.5.5 Cardiac Arrhythmias Body System Adverse Reaction Percent of PatientsClinical Pharmacology (12.3)] which may increase the8.5 Geriatric UseAtrial fibrillation and atrial flutter have occurred in 2% of patients treated with(N=118) risk of BRUKINSA toxicities. Of the 641 patients in clinical studies with BRUKINSA, 49% were65 years of age, BRUKINSA monotherapy. Patients with cardiac risk factors, hypertension, and acutePrevention or Reduce BRUKINSA dosage when co-administered with All GradesGrade 3 orwhile 16% were75 years of age. No overall differences in safety or effectiveness infections may be at increased risk. Grade 3 or higher events were reported in 0.6% % Higher % management moderate or strong CYP3A inhibitors [see Dosage andwere observed between younger and older patients.of patients treated with BRUKINSA monotherapy. Monitor signs and symptoms for Administration (2.3)].atrial fibrillation and atrial flutter and manage as appropriate. Blood and lymphaticNeutropenia and38 15 Moderate and Strong CYP3A Inducers 8.6 Renal Impairment5.6 Embryo-Fetal Toxicity system disorders Neutrophil count decreased No dosage modification is recommended in patients with mild to moderate renal Based on findings in animals, BRUKINSA can cause fetal harm when administered to aThrombocytopenia and27 5Clinical ImpactCo-administration with a moderate or strong CYP3Aimpairment (CLcr30 mL/min, estimated by Cockcroft-Gault). Monitor for BRUKINSA pregnant woman. Administration of zanubrutinib to pregnant rats during the period ofPlatelet count decreased inducer decreases zanubrutinib C maxand AUC [seeadverse reactions in patients with severe renal impairment (CLcr 30 mL/min) or on organogenesis caused embryo-fetal toxicity, including malformations at exposures thatClinical Pharmacology (12.3)] which may reducedialysis [see Clinical Pharmacology (12.3)].were 5 times higher than those reported in patients at the recommended dose of 160 mgLeukopenia and White25 5 BRUKINSA efficacy. 8.7 Hepatic Impairmenttwice daily. Advise women to avoid becoming pregnant while taking BRUKINSA and for atblood count decreased Prevention or Avoid co-administration of BRUKINSA with moderate Dosage modification of BRUKINSA is recommended in patients with severe hepaticleast 1 week after the last dose. Advise men to avoid fathering a child during treatmentAnemia and Hemoglobin14 8 management or strong CYP3A inducers [see Dosage andimpairment [see Dosage and Administration (2.2)]. The safety of BRUKINSA has not and for at least 1 week after the last dose. If this drug is used during pregnancy, or if thedecreased Administration (2.3)]. been evaluated in patients with severe hepatic impairment. No dosage modification is patient becomes pregnant while taking this drug, the patient should be apprised of therecommended in patients with mild to moderate hepatic impairment. Monitor for BRUKINSA potential hazard to a fetus [see Use in Specific Populations (8.1)]. Infections andUpper respiratory tract39 0 8 USE IN SPECIFIC POPULATIONSadverse reactions in patients with hepatic impairment [see Clinical Pharmacology (12.3)]. 6 ADVERSE REACTIONS infestations infection 8.1 PregnancyThe following clinically significant adverse reactions are discussed in more detail inPneumonia 15 10^ Risk Summaryother sections of the labeling: Based on findings in animals, BRUKINSA can cause fetal harm when administered to Urinary tract infection 11 0.8 pregnant women. There are no available data on BRUKINSA use in pregnant womenHemorrhage [see Warnings and Precautions (5.1)] Skin and subcutaneousRashII 36 0 to evaluate for a drug-associated risk of major birth defects, miscarriage or adverseInfections [see Warnings and Precautions (5.2)] tissue disorders Bruising* 14 0 maternal or fetal outcomes. In animal reproduction studies, oral administration ofDistributed and Marketed by: Cytopenias [see Warnings and Precautions (5.3)] zanubrutinib to pregnant rats during the period of organogenesis was associated withBeiGene USA, Inc. Second Primary Malignancies [see Warnings and Precautions (5.4)] GastrointestinalDiarrhea 23 0.8 fetal heart malformation at approximately 5-fold human exposures (see Data). WomenSan Mateo, CA 94403 Cardiac Arrhythmias [see Warnings and Precautions (5.5)] disorders Constipation 13 0 should be advised to avoid pregnancy while taking BRUKINSA. If BRUKINSA is usedBRUKINSA and BeiGene are trademarks owned by BeiGene, Ltd. during pregnancy, or if the patient becomes pregnant while taking BRUKINSA,Vascular disorders Hypertension 12 3.4 the patient should be apprised of the potential hazard to the fetus. BeiGene, Ltd. 2019 All Rights Reserved. 0919-BRU-PRC-046 11/2019Hemorrhage11 3.4^15434_3_Brukinsa_BrandedHCP_PostApproval_Compendium_0620_RL.indd 3-4 5/1/20 11:53 AM'