WARNINGS AND PRECAUTIONS SECTION.


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 occurred in patients including skin cancers. Advise patients to use sun protection. (5.4)Cardiac Arrhythmias: Monitor for atrial fibrillation and atrial flutter and manage appropriately. (5.5)Embryo-Fetal Toxicity: Can cause fetal harm. Advise women of the potential risk to fetus and to avoid pregnancy. (5.6). 5.1Hemorrhage. Fatal and serious hemorrhagic events have occurred in patients with hematological malignancies treated with BRUKINSA monotherapy. Grade or higher bleeding events including intracranial and gastrointestinal hemorrhage, hematuria, and hemothorax have been reported in 2% of patients treated with BRUKINSA monotherapy. Bleeding events of any grade, including purpura and petechiae, occurred in 50% of patients treated with BRUKINSA monotherapy.Bleeding events have occurred in patients with and without concomitant antiplatelet or anticoagulation therapy. Co-administration 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 pre- and post-surgery depending upon the type of surgery and the risk of bleeding.. 5.2Infections. Fatal and serious infections (including bacterial, viral, or fungal) and opportunistic infections have occurred in patients with hematological malignancies treated with BRUKINSA monotherapy. Grade or higher infections occurred in 23% of patients treated with BRUKINSA monotherapy. The most common Grade or higher infection was pneumonia. Infections due to hepatitis virus (HBV) reactivation have occurred.Consider prophylaxis for herpes simplex virus, pneumocystis jiroveci 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.. 5.3Cytopenias. Grade or cytopenias, including neutropenia (27%), thrombocytopenia (10%), and anemia (8%) based on laboratory measurements, were reported in patients treated with BRUKINSA monotherapy.Monitor complete blood counts during treatment and treat using growth factor or transfusions, as needed.. 5.4Second Primary Malignancies. Second primary malignancies, including non-skin carcinoma, have occurred in 9% of patients treated with BRUKINSA monotherapy. The most frequent second primary malignancy was skin cancer (basal cell carcinoma and squamous cell carcinoma of skin), reported in 6% of patients. Advise patients to use sun protection.. 5.5Cardiac Arrhythmias. Atrial fibrillation and atrial flutter have occurred in 2% of patients treated with BRUKINSA monotherapy. Patients with cardiac risk factors, hypertension, and acute infections may be at increased risk. Grade or higher events were reported in 0.6% of patients treated with BRUKINSA monotherapy. Monitor signs and symptoms for atrial fibrillation and atrial flutter and manage as appropriate.. 5.6Embryo-Fetal Toxicity. Based on findings in animals, BRUKINSA can cause fetal harm when administered to pregnant woman. Administration of zanubrutinib to pregnant rats during the period of organogenesis caused embryo-fetal toxicity, including malformations at exposures that were 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 at least week after the last dose. Advise men to avoid fathering child during treatment and for at least 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 fetus [see Use in Specific Populations (8.1)].

HEPATIC IMPAIRMENT SUBSECTION.


8.7Hepatic Impairment. Dosage modification of BRUKINSA is recommended in patients with severe hepatic impairment [see Dosage and Administration (2.2)]. The safety of BRUKINSA has not been evaluated in patients with severe hepatic impairment. No dosage modification is recommended in patients with mild to moderate hepatic impairment. Monitor for BRUKINSA adverse reactions in patients with hepatic impairment [see Clinical Pharmacology (12.3)].

HOW SUPPLIED SECTION.


16 HOW SUPPLIED/STORAGE AND HANDLING. How SuppliedPackage SizeContentNDC Number120-countBottle with child-resistant cap containing 120 capsules72579-011-0280 mg, white to off-white opaque capsule, marked with ZANU 80 in black ink. StorageStore at 20C to 25C (68F to 77F); excursions permitted between 15C to 30C (59F to 86F) [See USP Controlled Room Temperature].

SPL UNCLASSIFIED SECTION.


2.1Recommended Dosage. The recommended dose of BRUKINSA is 160 mg taken orally twice daily or 320 mg taken orally once daily until disease progression or unacceptable toxicity.BRUKINSA can be taken with or without food. Advise patients to swallow capsules whole with water. Advise patients not to open, break, or chew the capsules. If dose of BRUKINSA is missed, it should be taken as soon as possible on the same day with return to the normal schedule the following day.

STORAGE AND HANDLING SECTION.


StorageStore at 20C to 25C (68F to 77F); excursions permitted between 15C to 30C (59F to 86F) [See USP Controlled Room Temperature].

USE IN SPECIFIC POPULATIONS SECTION.


8 USE IN SPECIFIC POPULATIONS. Lactation: Advise not to breastfeed. (8.2). 8.1 Pregnancy. Risk SummaryBased 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 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 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 DataEmbryo-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 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 post-implantation 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 pre- and post-natal 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 times the AUC in patients receiving the recommended dose.. 8.2 Lactation. Risk SummaryThere are no data on the presence of zanubrutinib or its metabolites in human milk, the effects on the breastfed child, or the effects on milk production. Because of the potential for serious adverse reactions from BRUKINSA in breastfed child, advise lactating women not to breastfeed during treatment with BRUKINSA and for at least two weeks following the last dose.. 8.3 Females and Males of Reproductive Potential. Pregnancy TestingPregnancy testing is recommended for females of reproductive potential prior to initiating BRUKINSA therapy.. Contraception. FemalesBRUKINSA can cause embryo-fetal harm when administered to pregnant women [see Use in Specific Populations (8.1)]. Advise female patients of reproductive potential to use effective contraception during treatment with BRUKINSA and for at least week following the last dose of BRUKINSA. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be informed of the potential hazard to fetus.. MalesAdvise men to avoid fathering child while receiving BRUKINSA and for at least week following the last dose of BRUKINSA.. 8.4 Pediatric Use. Safety and effectiveness in pediatric patients have not been established.. 8.5 Geriatric Use. Of the 641 patients in clinical studies with BRUKINSA, 49% were >= 65 years of age, while 16% were >= 75 years of age. No overall differences in safety or effectiveness were observed between younger and older patients.. 8.6Renal Impairment. No dosage modification is recommended in patients with mild to moderate renal impairment (CLcr >= 30 mL/min, estimated by Cockcroft-Gault). Monitor for BRUKINSA adverse reactions in patients with severe renal impairment (CLcr 30 mL/min) or on dialysis [see Clinical Pharmacology (12.3)].. 8.7Hepatic Impairment. Dosage modification of BRUKINSA is recommended in patients with severe hepatic impairment [see Dosage and Administration (2.2)]. The safety of BRUKINSA has not been evaluated in patients with severe hepatic impairment. No dosage modification is recommended in patients with mild to moderate hepatic impairment. Monitor for BRUKINSA adverse reactions in patients with hepatic impairment [see Clinical Pharmacology (12.3)].

ADVERSE REACTIONS SECTION.


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)] 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)] The most common adverse reactions (>= 20%) included neutrophil count decreased, platelet count decreased, upper respiratory tract infection, white blood cell count decreased, hemoglobin decreased, rash, bruising, diarrhea and cough. (6.1)To report SUSPECTED ADVERSE REACTIONS, contact BeiGene at 1-877-828-5596 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.. 6.1Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of 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 as single agent at 160 mg twice daily in 524 patients in clinical trials BGB-3111-AU-003, BGB-3111-206, BGB-3111-205, BGB-3111-210, and BGB-3111-1002 and to BRUKINSA at 320 mg once daily in 105 patients in trials BGB-3111-AU-003 and BGB-3111-1002. Among 629 patients receiving BRUKINSA, 79% were exposed for months or longer and 61% were exposed for greater than one year.In this pooled safety population, the most common adverse reactions in 10% of patients who received BRUKINSA were neutrophil count decreased (53%), platelet count decreased (39%), upper respiratory tract infection (38%), white blood cell count decreased (30%), hemoglobin decreased (29%), rash (25%), bruising (23%), diarrhea (20%), cough (20%), musculoskeletal pain (19%), pneumonia (18%), urinary tract infection (13%), hematuria (12%), fatigue (11%), constipation (11%), and hemorrhage (10%).. 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 to 1. Patients had median of prior lines of therapy (range: to 4). The BGB-3111-206 trial required platelet count >= 75 109/L and an absolute neutrophil count >= x 109/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 platelet count >= 50 109/L and an absolute neutrophil count >= x 109/L independent of growth factor support, hepatic enzymes <= x upper limit of normal, total bilirubin <= 1.5 ULN. Both trials required CLcr >= 30 mL/min. Both trials excluded patients with prior allogeneic hematopoietic stem cell transplant, exposure to BTK inhibitor, known infection with HIV, and serologic evidence of active hepatitis or hepatitis 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 months or longer and 68% were exposed for greater than one year.Fatal events within 30 days of the last dose of BRUKINSA occurred in (7%) of 118 patients with MCL. Fatal cases included pneumonia in 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, (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 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 TrialsBody SystemAdverse ReactionPercent of Patients (N=118)All Grades %Grade or Higher %Blood and lymphatic system disordersNeutropenia and Neutrophil count decreased3815Thrombocytopenia and Platelet count decreased275Leukopenia and White blood count decreased255Anemia and Hemoglobin decreased148Infections and infestationsUpper respiratory tract infection Upper respiratory tract infection includes upper respiratory tract infection, upper respiratory tract infection viral 390Pneumonia 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 1510Includes fatal adverse reaction Urinary tract infection110.8Skin and subcutaneous tissue disordersRash Rash includes all related terms containing rash 360Bruising Bruising includes all related terms containing bruise, bruising, contusion, ecchymosis 140Gastrointestinal disordersDiarrhea230.8Constipation130Vascular disordersHypertension123.4Hemorrhage Hemorrhage includes all related terms containing hemorrhage, hematoma 113.4 Musculoskeletal and connective tissue disordersMusculoskeletal pain Musculoskeletal pain includes musculoskeletal pain, musculoskeletal discomfort, myalgia, back pain, arthralgia, arthritis 143.4Metabolism and nutrition disordersHypokalemia141.7Respiratory, thoracic and mediastinal disordersCough120Other clinically significant adverse reactions that occurred in 10% of patients with mantle cell lymphoma include major hemorrhage (defined as >= Grade hemorrhage or CNS hemorrhage of any grade) (5%), hyperuricemia (6%) and headache (4.2%).Table 4:Selected Laboratory AbnormalitiesBased on laboratory measurements. (> 20%) in Patients with MCL in Studies BGB-3111-206 and BGB-3111-AU-003Laboratory ParameterPercent of Patients (N=118)All Grades (%)Grade or (%) Neutrophils decreased4520 Platelets decreased407 Hemoglobin decreased276 Lymphocytosis Asymptomatic lymphocytosis is known effect of BTK inhibition. 4116Chemistry abnormalities Blood uric acid increased292.6 ALT increased280.9 Bilirubin increased240.9.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.


13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. Carcinogenicity studies have not been conducted with zanubrutinib.Zanubrutinib was not mutagenic in bacterial mutagenicity (Ames) assay, was not clastogenic in chromosome aberration assay in mammalian (CHO) cells, nor was it clastogenic in an in vivo bone marrow micronucleus assay in rats.A combined male and female fertility and early embryonic development study was conducted in rats at oral zanubrutinib doses of 30 to 300 mg/kg/day. Male rats were dosed weeks prior to mating and through mating and female rats were dosed weeks prior to mating and to gestation day 7. No effect on male or female fertility was noted but at the highest dose tested, morphological abnormalities in sperm and increased post-implantation loss were noted. The high dose of 300 mg/kg/day is approximately 10 times the human recommended dose, based on body surface area.

CLINICAL PHARMACOLOGY SECTION.


12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Zanubrutinib is small-molecule inhibitor of BTK. Zanubrutinib forms covalent bond with cysteine residue in the BTK active site, leading to inhibition of BTK activity. BTK is signaling molecule of the B-cell antigen receptor (BCR) and cytokine receptor pathways. In B-cells, BTK signaling results in activation of pathways necessary for B-cell proliferation, trafficking, chemotaxis, and adhesion. In nonclinical studies, zanubrutinib inhibited malignant B-cell proliferation and reduced tumor growth.. 12.2 Pharmacodynamics. BTK Occupancy in PBMCs and Lymph NodesThe median steady-state BTK occupancy in peripheral blood mononuclear cells was maintained at 100% over 24 hours at total daily dose of 320 mg in patients with B-cell malignancies. The median steady-state BTK occupancy in lymph nodes was 94% to 100% following the approved recommended dosage.. Cardiac ElectrophysiologyAt the approved recommended doses (160 mg twice daily or 320 mg once daily), there were no clinically relevant effects on the QTc interval. The effect of BRUKINSA on the QTc interval above the therapeutic exposure has not been evaluated.. 12.3 Pharmacokinetics. Zanubrutinib maximum plasma concentration (Cmax) and area under the plasma drug concentration over time curve (AUC) increase proportionally over dosage range from 40 mg to 320 mg (0.13 to time the recommended total daily dose). Limited systemic accumulation of zanubrutinib was observed following repeated administration.The geometric mean (%CV) zanubrutinib steady-state daily AUC is 2,295 (37%) ngh/mL following 160 mg twice daily and 2,180 (41%) ngh/mL following 320 mg once daily. The geometric mean (%CV) zanubrutinib steady-state Cmax is 314 (46%) ng/mL following 160 mg twice daily and 543 (51%) ng/mL following 320 mg once daily.. AbsorptionThe median tmax of zanubrutinib is hours.. Effect of FoodNo clinically significant differences in zanubrutinib AUC or Cmax were observed following administration of high-fat meal (approximately 1,000 calories with 50% of total caloric content from fat) in healthy subjects.. DistributionThe geometric mean (%CV) apparent steady-state volume of distribution of zanubrutinib is 881 (95%) L. The plasma protein binding of zanubrutinib is approximately 94% and the blood-to-plasma ratio is 0.7 to 0.8.. EliminationThe mean half-life (t 1/2 of zanubrutinib is approximately to hours following single oral zanubrutinib dose of 160 mg or 320 mg. The geometric mean (%CV) apparent oral clearance (CL/F) of zanubrutinib is 182 (37%) L/h.. MetabolismZanubrutinib is primarily metabolized by cytochrome P450(CYP)3A.. ExcretionFollowing single radiolabeled zanubrutinib dose of 320 mg to healthy subjects, approximately 87% of the dose was recovered in feces (38% unchanged) and 8% in urine (less than 1% unchanged).. Specific PopulationsNo clinically significant differences in the pharmacokinetics of zanubrutinib were observed based on age (19 to 90 years), sex, race (Asian, Caucasian, and Other), body weight (36 to 140 kg), or mild or moderate renal impairment (creatinine clearance [CLcr] >= 30 mL/min as estimated by Cockcroft-Gault). The effect of severe renal impairment (CLcr 30 mL/min) and dialysis on zanubrutinib pharmacokinetics is unknown.. Hepatic ImpairmentThe total AUC of zanubrutinib increased by 11% in subjects with mild hepatic impairment (Child-Pugh class A), by 21% in subjects with moderate hepatic impairment (Child-Pugh class B), and by 60% in subjects with severe hepatic impairment (Child-Pugh class C) relative to subjects with normal liver function. The unbound AUC of zanubrutinib increased by 23% in subjects with mild hepatic impairment (Child-Pugh class A), by 43% in subjects with moderate hepatic impairment (Child-Pugh class B), and by 194% in subjects with severe hepatic impairment (Child-Pugh class C) relative to subjects with normal liver function. Drug Interaction Studies. Clinical Studies and Model-Informed Approaches. CYP3A Inhibitors: Co-administration of multiple doses of CYP3A inhibitors increases zanubrutinib Cmax and AUC (Table 6).Table 6:Observed or Predicted Increase in Zanubrutinib Exposure After Co-Administration of CYP3A InhibitorsCo-administered CYP3A InhibitorIncrease in Zanubrutinib Cmax Increase in Zanubrutinib AUCObservedItraconazole (200 mg once daily)157%278%PredictedClarithromycin (250 mg twice daily)175%183%Diltiazem (60 mg three times daily)151%157%Erythromycin (500 mg four times daily)284%317%Fluconazole (200 mg once daily)179%177%Fluconazole (400 mg once daily)270%284%. CYP3A Inducers: Co-administration of multiple doses of rifampin (strong CYP3A inducer) decreased the zanubrutinib Cmax by 92% and AUC by 93%.Co-administration of multiple doses of efavirenz (moderate CYP3A inducer) is predicted to decrease zanubrutinib Cmax by 58% and AUC by 60%.. CYP3A Substrates: Co-administration of multiple doses of zanubrutinib decreased midazolam (CYP3A substrate) Cmax by 30% and AUC by 47%.. CYP2C19 Substrates: Co-administration of multiple doses of zanubrutinib decreased omeprazole (CYP2C19 substrate) Cmax by 20% and AUC by 36%.. Other CYP Substrates: No clinically significant differences were observed with warfarin (CYP2C9 substrate) pharmacokinetics or predicted with rosiglitazone (CYP2C8 substrate) pharmacokinetics when co-administered with zanubrutinib.. Transporter Systems: Co-administration of multiple doses of zanubrutinib increased digoxin (P-gp substrate) Cmax by 34% and AUC by 11%. No clinically significant differences in the pharmacokinetics of rosuvastatin (BCRP substrate) were observed when co-administered with zanubrutinib.. Gastric Acid Reducing Agents: No clinically significant differences in zanubrutinib pharmacokinetics were observed when co-administered with gastric acid reducing agents (proton pump inhibitors, H2-receptor antagonists).. In Vitro Studies. CYP Enzymes: Zanubrutinib is an inducer of CYP2B6.. Transporter Systems: Zanubrutinib is likely to be substrate of P-gp. Zanubrutinib is not substrate or inhibitor of OAT1, OAT3, OCT2, OATP1B1, or OATP1B3.

CLINICAL STUDIES SECTION.


14 CLINICAL STUDIES. 14.1Mantle Cell Lymphoma. The efficacy of BRUKINSA was assessed in BGB-3111-206 [NCT03206970], Phase 2, open-label, multicenter, single-arm trial of 86 previously treated patients with MCL who had received at least one prior therapy. BRUKINSA was given orally at dose of 160 mg twice daily until disease progression or unacceptable toxicity.The median age of patients was 60.5 years (range: 34 to 75) and the majority were male (78%). The median time since diagnosis to study entry was 30 months (range: to 102) and the median number of prior therapies was (range: to 4). The most common prior regimens were CHOP-based (91%) followed by rituximab-based (74%). The majority of patients had extranodal involvement (71%) and refractory disease (52%). Blastoid variant of MCL was present in 14% of patients. The MIPI score was low in 58%, intermediate in 29%, and high risk in 13%.The efficacy of BRUKINSA was also assessed in BGB-3111-AU-003 [NCT02343120], Phase 1/2, open-label, dose-escalation, global, multicenter, single-arm trial of B-cell malignancies including 32 previously treated MCL patients treated with BRUKINSA. BRUKINSA was given orally at doses of 160 mg twice daily or 320 mg daily. The median age of patients with previously treated MCL was 70 years (range: 42 to 86), and 38% of patients were >= 75 years old. Most patients were male (69%) and Caucasian (78%). The MIPI score was low in 28%, intermediate in 41%, and high risk in 31%.Tumor response was according to the 2014 Lugano Classification for both studies, and the primary efficacy endpoint was overall response rate as assessed by an Independent Review Committee.Table 7:Efficacy Results in Patients with MCL by Independent Review CommitteeStudy BGB-3111-206 (N=86)Study BGB-3111-AU-003 (N=32)ORR: overall response rate, CR: complete response, PR: partial response, DoR: duration of response, CI: confidence interval, NE: not estimableORR (95% CI)84% (74, 91)84% (67, 95)CR59%22%FDG-PET scans were not required for response assessment PR24%62%Median DoR in months (95% CI)19.5 (16.6, NE)18.5 (12.6, NE).

CLINICAL TRIALS EXPERIENCE SECTION.


6.1Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of 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 as single agent at 160 mg twice daily in 524 patients in clinical trials BGB-3111-AU-003, BGB-3111-206, BGB-3111-205, BGB-3111-210, and BGB-3111-1002 and to BRUKINSA at 320 mg once daily in 105 patients in trials BGB-3111-AU-003 and BGB-3111-1002. Among 629 patients receiving BRUKINSA, 79% were exposed for months or longer and 61% were exposed for greater than one year.In this pooled safety population, the most common adverse reactions in 10% of patients who received BRUKINSA were neutrophil count decreased (53%), platelet count decreased (39%), upper respiratory tract infection (38%), white blood cell count decreased (30%), hemoglobin decreased (29%), rash (25%), bruising (23%), diarrhea (20%), cough (20%), musculoskeletal pain (19%), pneumonia (18%), urinary tract infection (13%), hematuria (12%), fatigue (11%), constipation (11%), and hemorrhage (10%).. 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 to 1. Patients had median of prior lines of therapy (range: to 4). The BGB-3111-206 trial required platelet count >= 75 109/L and an absolute neutrophil count >= x 109/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 platelet count >= 50 109/L and an absolute neutrophil count >= x 109/L independent of growth factor support, hepatic enzymes <= x upper limit of normal, total bilirubin <= 1.5 ULN. Both trials required CLcr >= 30 mL/min. Both trials excluded patients with prior allogeneic hematopoietic stem cell transplant, exposure to BTK inhibitor, known infection with HIV, and serologic evidence of active hepatitis or hepatitis 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 months or longer and 68% were exposed for greater than one year.Fatal events within 30 days of the last dose of BRUKINSA occurred in (7%) of 118 patients with MCL. Fatal cases included pneumonia in 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, (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 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 TrialsBody SystemAdverse ReactionPercent of Patients (N=118)All Grades %Grade or Higher %Blood and lymphatic system disordersNeutropenia and Neutrophil count decreased3815Thrombocytopenia and Platelet count decreased275Leukopenia and White blood count decreased255Anemia and Hemoglobin decreased148Infections and infestationsUpper respiratory tract infection Upper respiratory tract infection includes upper respiratory tract infection, upper respiratory tract infection viral 390Pneumonia 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 1510Includes fatal adverse reaction Urinary tract infection110.8Skin and subcutaneous tissue disordersRash Rash includes all related terms containing rash 360Bruising Bruising includes all related terms containing bruise, bruising, contusion, ecchymosis 140Gastrointestinal disordersDiarrhea230.8Constipation130Vascular disordersHypertension123.4Hemorrhage Hemorrhage includes all related terms containing hemorrhage, hematoma 113.4 Musculoskeletal and connective tissue disordersMusculoskeletal pain Musculoskeletal pain includes musculoskeletal pain, musculoskeletal discomfort, myalgia, back pain, arthralgia, arthritis 143.4Metabolism and nutrition disordersHypokalemia141.7Respiratory, thoracic and mediastinal disordersCough120Other clinically significant adverse reactions that occurred in 10% of patients with mantle cell lymphoma include major hemorrhage (defined as >= Grade hemorrhage or CNS hemorrhage of any grade) (5%), hyperuricemia (6%) and headache (4.2%).Table 4:Selected Laboratory AbnormalitiesBased on laboratory measurements. (> 20%) in Patients with MCL in Studies BGB-3111-206 and BGB-3111-AU-003Laboratory ParameterPercent of Patients (N=118)All Grades (%)Grade or (%) Neutrophils decreased4520 Platelets decreased407 Hemoglobin decreased276 Lymphocytosis Asymptomatic lymphocytosis is known effect of BTK inhibition. 4116Chemistry abnormalities Blood uric acid increased292.6 ALT increased280.9 Bilirubin increased240.9.

CONTRAINDICATIONS SECTION.


4 CONTRAINDICATIONS. None.. None. (4).

DESCRIPTION SECTION.


11 DESCRIPTION. BRUKINSA (zanubrutinib) is Brutons tyrosine kinase (BTK) inhibitor. The empirical formula of zanubrutinib is C27H29N5O3 and the chemical name is (S)-7-(1-acryloylpiperidin-4-yl)-2-(4-phenoxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide. Zanubrutinib is white to off-white powder, with pH of 7.8 in saturated solution. The aqueous solubility of zanubrutinib is pH dependent, from very slightly soluble to practically insoluble.The molecular weight of zanubrutinib is 471.55 Daltons.Zanubrutinib has the following structure:Each BRUKINSA capsule for oral administration contains 80 mg zanubrutinib and the following inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, magnesium stearate, microcrystalline cellulose, and sodium lauryl sulfate. The capsule shell contains edible black ink, gelatin, and titanium dioxide.. Chemical Structure.

DOSAGE & ADMINISTRATION SECTION.


2 DOSAGE AND ADMINISTRATION. Recommended dose: 160 mg orally twice daily or 320 mg orally once daily; swallow whole with water and with or without food. (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)Manage toxicity using treatment interruption, dose reduction, or discontinuation. (2.4). Recommended dose: 160 mg orally twice daily or 320 mg orally once daily; swallow whole with water and with or without food. (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). Manage toxicity using treatment interruption, dose reduction, or discontinuation. (2.4). 2.1Recommended Dosage. The recommended dose of BRUKINSA is 160 mg taken orally twice daily or 320 mg taken orally once daily until disease progression or unacceptable toxicity.BRUKINSA can be taken with or without food. Advise patients to swallow capsules whole with water. Advise patients not to open, break, or chew the capsules. If dose of BRUKINSA is missed, it should be taken as soon as possible on the same day with return to the normal schedule the following day.. 2.2Dosage Modification for Use in Hepatic Impairment. The recommended dose of BRUKINSA for patients with severe hepatic impairment is 80 mg orally twice daily [see Use in Specific Populations (8.7) and Clinical Pharmacology (12.3)].. 2.3Dosage Modifications for Drug Interactions. Recommended dose modifications of BRUKINSA for drug interactions are provided in Table [see Drug Interactions (7.1)]. Table 1:Dose Modifications for Use With CYP3A Inhibitors or InducersCo-administered DrugRecommended BRUKINSA DoseStrong CYP3A inhibitor 80 mg once dailyInterrupt dose as recommended for adverse reactions [see Dosage and Administration (2.4)]. Moderate CYP3A inhibitor 80 mg twice dailyModify dose as recommended for adverse reactions [see Dosage and Administration (2.4)]. Moderate or strong CYP3A inducerAvoid concomitant use.After discontinuation of CYP3A inhibitor, resume previous dose of BRUKINSA [see Dosage and Administration (2.1, 2.2) and Drug Interactions (7.1)].. 2.4Dosage Modifications for Adverse Reactions. Recommended dose modifications of BRUKINSA for Grade or higher adverse reactions are provided in Table 2:Table 2:Recommended Dose Modification for Adverse ReactionEventAdverse Reaction OccurrenceDose Modification(Starting Dose: 160 mg twice daily or 320 mg once daily)Grade or higher non-hematological toxicities Grade febrile neutropenia Grade thrombocytopenia with significant bleeding Grade neutropenia (lasting more than 10 consecutive days) Grade thrombocytopenia (lasting more than 10 consecutive days)FirstInterrupt BRUKINSAOnce toxicity has resolved to recovery to Grade or lower or baseline: Resume at 160 mg twice daily or 320 mg once dailySecondInterrupt BRUKINSAOnce toxicity has resolved to recovery to Grade or lower or baseline: Resume at 80 mg twice daily or 160 mg once dailyThirdInterrupt BRUKINSAOnce toxicity has resolved to recovery to Grade or lower or baseline: Resume at 80 mg once dailyFourthDiscontinue BRUKINSAAsymptomatic lymphocytosis should not be regarded as an adverse reaction, and these patients should continue taking BRUKINSA.

DOSAGE FORMS & STRENGTHS SECTION.


3 DOSAGE FORMS AND STRENGTHS. Capsules: Each 80 mg capsule is size 0, white to off-white opaque capsule marked with ZANU 80 in black ink.. Capsules: 80 mg. (3).

DRUG INTERACTIONS SECTION.


7 DRUG INTERACTIONS. CYP3A Inhibitors: Modify BRUKINSA dose with moderate or strong CYP3A inhibitors as described. (2.3, 7.1)CYP3A Inducers: Avoid co-administration with moderate or strong CYP3A inducers. (7.1). CYP3A Inhibitors: Modify BRUKINSA dose with moderate or strong CYP3A inhibitors as described. (2.3, 7.1). CYP3A Inducers: Avoid co-administration with moderate or strong CYP3A inducers. (7.1). 7.1Effect of Other Drugs on BRUKINSA. Table 5:Drug Interactions that Affect ZanubrutinibModerate and Strong CYP3A InhibitorsClinical ImpactCo-administration with moderate or strong CYP3A inhibitor increases zanubrutinib Cmax and AUC [see Clinical Pharmacology (12.3)] which may increase the risk of BRUKINSA toxicities.Prevention or managementReduce BRUKINSA dosage when co-administered with moderate or strong CYP3A inhibitors [see Dosage and Administration (2.3)]. Moderate and Strong CYP3A InducersClinical ImpactCo-administration with moderate or strong CYP3A inducer decreases zanubrutinib Cmax and AUC [see Clinical Pharmacology (12.3)] which may reduce BRUKINSA efficacy.Prevention or managementAvoid co-administration of BRUKINSA with moderate or strong CYP3A inducers [see Dosage and Administration (2.3)].. Co-administration with moderate or strong CYP3A inhibitor increases zanubrutinib Cmax and AUC [see Clinical Pharmacology (12.3)] which may increase the risk of BRUKINSA toxicities.. Reduce BRUKINSA dosage when co-administered with moderate or strong CYP3A inhibitors [see Dosage and Administration (2.3)]. Co-administration with moderate or strong CYP3A inducer decreases zanubrutinib Cmax and AUC [see Clinical Pharmacology (12.3)] which may reduce BRUKINSA efficacy.. Avoid co-administration of BRUKINSA with moderate or strong CYP3A inducers [see Dosage and Administration (2.3)].

FEMALES & MALES OF REPRODUCTIVE POTENTIAL SECTION.


8.3 Females and Males of Reproductive Potential. Pregnancy TestingPregnancy testing is recommended for females of reproductive potential prior to initiating BRUKINSA therapy.. Contraception. FemalesBRUKINSA can cause embryo-fetal harm when administered to pregnant women [see Use in Specific Populations (8.1)]. Advise female patients of reproductive potential to use effective contraception during treatment with BRUKINSA and for at least week following the last dose of BRUKINSA. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be informed of the potential hazard to fetus.. MalesAdvise men to avoid fathering child while receiving BRUKINSA and for at least week following the last dose of BRUKINSA.

GERIATRIC USE SECTION.


8.5 Geriatric Use. Of the 641 patients in clinical studies with BRUKINSA, 49% were >= 65 years of age, while 16% were >= 75 years of age. No overall differences in safety or effectiveness were observed between younger and older patients.

INDICATIONS & USAGE SECTION.


1 INDICATIONS AND USAGE. 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 confirmatory trial.. BRUKINSA is kinase inhibitor indicated for the treatment of adult patients with mantle cell lymphoma (MCL) who have received at least one prior therapy. (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 confirmatory trial.

INFORMATION FOR PATIENTS SECTION.


17 PATIENT COUNSELING INFORMATION. Advise patients to read the FDA-approved patient labeling (Patient Information).. HemorrhageInform patients to report signs or symptoms of severe bleeding. Inform patients that BRUKINSA may need to be interrupted for major surgeries or procedures [see Warnings and Precautions (5.1)].. InfectionsInform patients to report signs or symptoms suggestive of infection [see Warnings and Precautions (5.2)].. CytopeniasInform patients that they will need periodic blood tests to check blood counts during treatment with BRUKINSA [see Warnings and Precautions (5.3)].. Second Primary MalignanciesInform patients that other malignancies have been reported in patients who have been treated with BRUKINSA, including skin cancer. Advise patients to use sun protection [see Warnings and Precautions (5.4)].. Cardiac ArrhythmiasCounsel patients to report any signs of palpitations, lightheadedness, dizziness, fainting, shortness of breath, and chest discomfort [see Warnings and Precautions (5.5)].. Embryo-Fetal ToxicityAdvise women of the potential hazard to fetus and to avoid becoming pregnant during treatment and for at least week after the last dose of BRUKINSA [see Warnings and Precautions (5.6)].Advise males with female sexual partners of reproductive potential to use effective contraception during BRUKINSA treatment and for at least week after the last dose of BRUKINSA [see Use in Specific Populations (8.3)].. LactationAdvise females not to breastfeed during treatment with BRUKINSA and for at least weeks after the last dose [see Use in Specific Populations (8.2)].. Administration InstructionsBRUKINSA may be taken with or without food. Advise patients that BRUKINSA capsules should be swallowed whole with glass of water, without being opened, broken, or chewed [see Dosage and Administration (2.1)].. Missed DoseAdvise patients that if they miss dose of BRUKINSA, they may still take it as soon as possible on the same day with return to the normal schedule the following day [see Dosage and Administration (2.1)].. Drug InteractionsAdvise patients to inform their healthcare providers of all concomitant medications, including over-the-counter medications, vitamins, and herbal products [see Drug Interactions (7)].

LACTATION SECTION.


8.2 Lactation. Risk SummaryThere are no data on the presence of zanubrutinib or its metabolites in human milk, the effects on the breastfed child, or the effects on milk production. Because of the potential for serious adverse reactions from BRUKINSA in breastfed child, advise lactating women not to breastfeed during treatment with BRUKINSA and for at least two weeks following the last dose.

MECHANISM OF ACTION SECTION.


12.1 Mechanism of Action. Zanubrutinib is small-molecule inhibitor of BTK. Zanubrutinib forms covalent bond with cysteine residue in the BTK active site, leading to inhibition of BTK activity. BTK is signaling molecule of the B-cell antigen receptor (BCR) and cytokine receptor pathways. In B-cells, BTK signaling results in activation of pathways necessary for B-cell proliferation, trafficking, chemotaxis, and adhesion. In nonclinical studies, zanubrutinib inhibited malignant B-cell proliferation and reduced tumor growth.

NONCLINICAL TOXICOLOGY SECTION.


13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. Carcinogenicity studies have not been conducted with zanubrutinib.Zanubrutinib was not mutagenic in bacterial mutagenicity (Ames) assay, was not clastogenic in chromosome aberration assay in mammalian (CHO) cells, nor was it clastogenic in an in vivo bone marrow micronucleus assay in rats.A combined male and female fertility and early embryonic development study was conducted in rats at oral zanubrutinib doses of 30 to 300 mg/kg/day. Male rats were dosed weeks prior to mating and through mating and female rats were dosed weeks prior to mating and to gestation day 7. No effect on male or female fertility was noted but at the highest dose tested, morphological abnormalities in sperm and increased post-implantation loss were noted. The high dose of 300 mg/kg/day is approximately 10 times the human recommended dose, based on body surface area.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.


PRINCIPAL DISPLAY PANEL 80 mg Capsule Bottle Label. NDC 72579-011-02 Rx onlyBrukinsa(TM) zanubrutinib capsules80 mgDo not open, break or chew the capsules120 Capsules. PRINCIPAL DISPLAY PANEL 80 mg Capsule Bottle Label.

PEDIATRIC USE SECTION.


8.4 Pediatric Use. Safety and effectiveness in pediatric patients have not been established.

PHARMACODYNULLMICS SECTION.


12.2 Pharmacodynamics. BTK Occupancy in PBMCs and Lymph NodesThe median steady-state BTK occupancy in peripheral blood mononuclear cells was maintained at 100% over 24 hours at total daily dose of 320 mg in patients with B-cell malignancies. The median steady-state BTK occupancy in lymph nodes was 94% to 100% following the approved recommended dosage.. Cardiac ElectrophysiologyAt the approved recommended doses (160 mg twice daily or 320 mg once daily), there were no clinically relevant effects on the QTc interval. The effect of BRUKINSA on the QTc interval above the therapeutic exposure has not been evaluated.

PHARMACOKINETICS SECTION.


12.3 Pharmacokinetics. Zanubrutinib maximum plasma concentration (Cmax) and area under the plasma drug concentration over time curve (AUC) increase proportionally over dosage range from 40 mg to 320 mg (0.13 to time the recommended total daily dose). Limited systemic accumulation of zanubrutinib was observed following repeated administration.The geometric mean (%CV) zanubrutinib steady-state daily AUC is 2,295 (37%) ngh/mL following 160 mg twice daily and 2,180 (41%) ngh/mL following 320 mg once daily. The geometric mean (%CV) zanubrutinib steady-state Cmax is 314 (46%) ng/mL following 160 mg twice daily and 543 (51%) ng/mL following 320 mg once daily.. AbsorptionThe median tmax of zanubrutinib is hours.. Effect of FoodNo clinically significant differences in zanubrutinib AUC or Cmax were observed following administration of high-fat meal (approximately 1,000 calories with 50% of total caloric content from fat) in healthy subjects.. DistributionThe geometric mean (%CV) apparent steady-state volume of distribution of zanubrutinib is 881 (95%) L. The plasma protein binding of zanubrutinib is approximately 94% and the blood-to-plasma ratio is 0.7 to 0.8.. EliminationThe mean half-life (t 1/2 of zanubrutinib is approximately to hours following single oral zanubrutinib dose of 160 mg or 320 mg. The geometric mean (%CV) apparent oral clearance (CL/F) of zanubrutinib is 182 (37%) L/h.. MetabolismZanubrutinib is primarily metabolized by cytochrome P450(CYP)3A.. ExcretionFollowing single radiolabeled zanubrutinib dose of 320 mg to healthy subjects, approximately 87% of the dose was recovered in feces (38% unchanged) and 8% in urine (less than 1% unchanged).. Specific PopulationsNo clinically significant differences in the pharmacokinetics of zanubrutinib were observed based on age (19 to 90 years), sex, race (Asian, Caucasian, and Other), body weight (36 to 140 kg), or mild or moderate renal impairment (creatinine clearance [CLcr] >= 30 mL/min as estimated by Cockcroft-Gault). The effect of severe renal impairment (CLcr 30 mL/min) and dialysis on zanubrutinib pharmacokinetics is unknown.. Hepatic ImpairmentThe total AUC of zanubrutinib increased by 11% in subjects with mild hepatic impairment (Child-Pugh class A), by 21% in subjects with moderate hepatic impairment (Child-Pugh class B), and by 60% in subjects with severe hepatic impairment (Child-Pugh class C) relative to subjects with normal liver function. The unbound AUC of zanubrutinib increased by 23% in subjects with mild hepatic impairment (Child-Pugh class A), by 43% in subjects with moderate hepatic impairment (Child-Pugh class B), and by 194% in subjects with severe hepatic impairment (Child-Pugh class C) relative to subjects with normal liver function. Drug Interaction Studies. Clinical Studies and Model-Informed Approaches. CYP3A Inhibitors: Co-administration of multiple doses of CYP3A inhibitors increases zanubrutinib Cmax and AUC (Table 6).Table 6:Observed or Predicted Increase in Zanubrutinib Exposure After Co-Administration of CYP3A InhibitorsCo-administered CYP3A InhibitorIncrease in Zanubrutinib Cmax Increase in Zanubrutinib AUCObservedItraconazole (200 mg once daily)157%278%PredictedClarithromycin (250 mg twice daily)175%183%Diltiazem (60 mg three times daily)151%157%Erythromycin (500 mg four times daily)284%317%Fluconazole (200 mg once daily)179%177%Fluconazole (400 mg once daily)270%284%. CYP3A Inducers: Co-administration of multiple doses of rifampin (strong CYP3A inducer) decreased the zanubrutinib Cmax by 92% and AUC by 93%.Co-administration of multiple doses of efavirenz (moderate CYP3A inducer) is predicted to decrease zanubrutinib Cmax by 58% and AUC by 60%.. CYP3A Substrates: Co-administration of multiple doses of zanubrutinib decreased midazolam (CYP3A substrate) Cmax by 30% and AUC by 47%.. CYP2C19 Substrates: Co-administration of multiple doses of zanubrutinib decreased omeprazole (CYP2C19 substrate) Cmax by 20% and AUC by 36%.. Other CYP Substrates: No clinically significant differences were observed with warfarin (CYP2C9 substrate) pharmacokinetics or predicted with rosiglitazone (CYP2C8 substrate) pharmacokinetics when co-administered with zanubrutinib.. Transporter Systems: Co-administration of multiple doses of zanubrutinib increased digoxin (P-gp substrate) Cmax by 34% and AUC by 11%. No clinically significant differences in the pharmacokinetics of rosuvastatin (BCRP substrate) were observed when co-administered with zanubrutinib.. Gastric Acid Reducing Agents: No clinically significant differences in zanubrutinib pharmacokinetics were observed when co-administered with gastric acid reducing agents (proton pump inhibitors, H2-receptor antagonists).. In Vitro Studies. CYP Enzymes: Zanubrutinib is an inducer of CYP2B6.. Transporter Systems: Zanubrutinib is likely to be substrate of P-gp. Zanubrutinib is not substrate or inhibitor of OAT1, OAT3, OCT2, OATP1B1, or OATP1B3.

PREGNULLNCY SECTION.


8.1 Pregnancy. Risk SummaryBased 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 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 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 DataEmbryo-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 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 post-implantation 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 pre- and post-natal 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 times the AUC in patients receiving the recommended dose.

RENULLL IMPAIRMENT SUBSECTION.


8.6Renal Impairment. No dosage modification is recommended in patients with mild to moderate renal impairment (CLcr >= 30 mL/min, estimated by Cockcroft-Gault). Monitor for BRUKINSA adverse reactions in patients with severe renal impairment (CLcr 30 mL/min) or on dialysis [see Clinical Pharmacology (12.3)].

SPL PATIENT PACKAGE INSERT SECTION.


PATIENT INFORMATION BRUKINSA(TM) (BROO-kin-sah) (zanubrutinib) capsules This Patient Information has been approved by the U.S. Food and Drug Administration.Issued: 11/2019 What is BRUKINSABRUKINSA is prescription medicine used to treat adults with mantle cell lymphoma (MCL) who have received at least one prior treatment for their cancer.It is not known if BRUKINSA is safe and effective in children.Before taking BRUKINSA, tell your healthcare provider about all of your medical conditions, including if you:have bleeding problems.have had recent surgery or plan to have surgery. Your healthcare provider may stop BRUKINSA for any planned medical, surgical, or dental procedure.have an infection.have or had heart rhythm problems.have high blood pressure.have liver problems, including history of hepatitis virus (HBV) infection.are pregnant or plan to become pregnant. BRUKINSA can harm your unborn baby. If you are able to become pregnant, your healthcare provider may do pregnancy test before starting treatment with BRUKINSA.Females should not become pregnant during treatment and for at least week after the last dose of BRUKINSA. You should use effective birth control (contraception) during treatment and for at least week after the last dose of BRUKINSA.Males should avoid getting female partners pregnant during treatment and for at least week after the last dose of BRUKINSA. You should use effective birth control (contraception) during treatment and for at least week after the last dose of BRUKINSA. are breastfeeding or plan to breastfeed. It is not known if BRUKINSA passes into your breast milk. Do not breastfeed during treatment with BRUKINSA and for at least weeks after your last dose of BRUKINSA.Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Taking BRUKINSA with certain other medications may affect how BRUKINSA works and can cause side effects.How should take BRUKINSATake BRUKINSA exactly as your healthcare provider tells you to take it.Do not change your dose or stop taking BRUKINSA unless your healthcare provider tells you to.Your healthcare provider may tell you to decrease your dose, temporarily stop, or completely stop taking BRUKINSA if you develop certain side effects.Take BRUKINSA with or without food.Swallow BRUKINSA capsules whole with glass of water. Do not open, break, or chew the capsules.If you miss dose of BRUKINSA, take it as soon as you remember on the same day. Return to your normal schedule the next day.What are the possible side effects of BRUKINSABRUKINSA may cause serious side effects, including:Bleeding problems (hemorrhage) that can be serious and may lead to death. Your risk of bleeding may increase if you are also taking blood thinner medicine. Tell your healthcare provider if you have any signs or symptoms of bleeding, including:blood in your stools or black stools (looks like tar)pink or brown urineunexpected bleeding, or bleeding that is severe or you cannot controlvomit blood or vomit that looks like coffee groundscough up blood or blood clotsincreased bruisingdizzinessweaknessconfusionchanges in speechheadache that lasts long timeInfections that can be serious and may lead to death. Tell your healthcare provider right away if you have fever, chills, or flu-like symptoms.Decrease in blood cell counts. Decreased blood counts (white blood cells, platelets, and red blood cells) are common with BRUKINSA, but can also be severe. Your healthcare provider should do blood tests during treatment with BRUKINSA to check your blood counts.Second primary cancers. New cancers have happened in people during treatment with BRUKINSA, including cancers of the skin. Use sun protection when you are outside in sunlight.Heart rhythm problems (atrial fibrillation and atrial flutter). Tell your healthcare provider if you have any of the following signs or symptoms:your heartbeat is fast or irregularfeel lightheaded or dizzypass out (faint)shortness of breathchest discomfortThe most common side effects of BRUKINSA include:decreased white blood cellsdecreased platelet countrashdiarrheaupper respiratory infectiondecreased red blood cells (anemia)bruisingcoughThese are not all the possible side effects of BRUKINSA.Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.How should store BRUKINSAStore BRUKINSA capsules at room temperature between 68F to 77F (20C to 25C).BRUKINSA comes in bottle with child-resistant cap.Keep BRUKINSA and all medicines out of the reach of children.General information about the safe and effective use of BRUKINSA.Medicines are sometimes prescribed for purposes other than those listed in Patient Information leaflet. Do not use BRUKINSA for condition for which it was not prescribed. Do not give BRUKINSA to other people, even if they have the same symptoms you have. It may harm them. You can ask your healthcare provider or pharmacist for more information about BRUKINSA that is written for healthcare professionals.What are the ingredients in BRUKINSAActive ingredient: zanubrutinibInactive ingredients: colloidal silicon dioxide, croscarmellose sodium, magnesium stearate, microcrystalline cellulose, and sodium lauryl sulfate.Capsule shell contains edible black ink, gelatin, and titanium dioxide.Distributed and Marketed by: BeiGene USA, Inc. San Mateo, CA 94403 BRUKINSA(TM) is trademark owned by BeiGene, Ltd. (C) BeiGene, Ltd. 2019 For more information, go to www.BRUKINSA.com or call 1-833-969-2463.. have bleeding problems.. have had recent surgery or plan to have surgery. Your healthcare provider may stop BRUKINSA for any planned medical, surgical, or dental procedure.. have an infection.. have or had heart rhythm problems.. have high blood pressure.. have liver problems, including history of hepatitis virus (HBV) infection.. are pregnant or plan to become pregnant. BRUKINSA can harm your unborn baby. If you are able to become pregnant, your healthcare provider may do pregnancy test before starting treatment with BRUKINSA.Females should not become pregnant during treatment and for at least week after the last dose of BRUKINSA. You should use effective birth control (contraception) during treatment and for at least week after the last dose of BRUKINSA.Males should avoid getting female partners pregnant during treatment and for at least week after the last dose of BRUKINSA. You should use effective birth control (contraception) during treatment and for at least week after the last dose of BRUKINSA. Females should not become pregnant during treatment and for at least week after the last dose of BRUKINSA. You should use effective birth control (contraception) during treatment and for at least week after the last dose of BRUKINSA.. Males should avoid getting female partners pregnant during treatment and for at least week after the last dose of BRUKINSA. You should use effective birth control (contraception) during treatment and for at least week after the last dose of BRUKINSA.. are breastfeeding or plan to breastfeed. It is not known if BRUKINSA passes into your breast milk. Do not breastfeed during treatment with BRUKINSA and for at least weeks after your last dose of BRUKINSA.. Take BRUKINSA exactly as your healthcare provider tells you to take it.. Do not change your dose or stop taking BRUKINSA unless your healthcare provider tells you to.. Your healthcare provider may tell you to decrease your dose, temporarily stop, or completely stop taking BRUKINSA if you develop certain side effects.. Take BRUKINSA with or without food.. Swallow BRUKINSA capsules whole with glass of water. Do not open, break, or chew the capsules.. If you miss dose of BRUKINSA, take it as soon as you remember on the same day. Return to your normal schedule the next day.. Bleeding problems (hemorrhage) that can be serious and may lead to death. Your risk of bleeding may increase if you are also taking blood thinner medicine. Tell your healthcare provider if you have any signs or symptoms of bleeding, including:. blood in your stools or black stools (looks like tar). pink or brown urine. unexpected bleeding, or bleeding that is severe or you cannot control. vomit blood or vomit that looks like coffee grounds. cough up blood or blood clots. increased bruising. dizziness. weakness. confusion. changes in speech. headache that lasts long time. Infections that can be serious and may lead to death. Tell your healthcare provider right away if you have fever, chills, or flu-like symptoms.. Decrease in blood cell counts. Decreased blood counts (white blood cells, platelets, and red blood cells) are common with BRUKINSA, but can also be severe. Your healthcare provider should do blood tests during treatment with BRUKINSA to check your blood counts.. Second primary cancers. New cancers have happened in people during treatment with BRUKINSA, including cancers of the skin. Use sun protection when you are outside in sunlight.. Heart rhythm problems (atrial fibrillation and atrial flutter). Tell your healthcare provider if you have any of the following signs or symptoms:. your heartbeat is fast or irregular. feel lightheaded or dizzy. pass out (faint). shortness of breath. chest discomfort. decreased white blood cells. decreased platelet count. rash. diarrhea. upper respiratory infection. decreased red blood cells (anemia). bruising. cough. Store BRUKINSA capsules at room temperature between 68F to 77F (20C to 25C).. BRUKINSA comes in bottle with child-resistant cap.