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 (>=30%) include neutrophil count decreased, upper respiratory tract infection, platelet count decreased, hemorrhage, lymphocyte count decreased, rash and musculoskeletal pain. (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.. 6.1 Clinical 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 in seven clinical trials, administered as single agent at 160 mg twice daily in 730 patients, at 320 mg once daily in 105 patients, and at 40 mg to 160 mg once daily (0.125 to 0.5 times the recommended dosage) in 12 patients. Among 847 patients receiving BRUKINSA, 73% were exposed for at least year, 57% were exposed for at least years and 26% were exposed for at least years.In this pooled safety population, the most common adverse reactions, including laboratory abnormalities, in >= 30% of patients included neutrophil count decreased (54%), upper respiratory tract infection (47%), platelet count decreased (41%), hemorrhage (35%), lymphocyte count decreased (31%), rash (31%) and musculoskeletal pain (30%).. 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 (%)Hematologic abnormalities 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. Waldenstroms Macroglobulinemia (WM)The safety of BRUKINSA was investigated in two cohorts of Study BGB-3111-302 (ASPEN). Cohort included 199 patients with MYD88 mutation (MYD88MUT WM, randomized to and treated with either BRUKINSA (101 patients) or ibrutinib (98 patients). The trial also included non-randomized arm, Cohort 2, with 26 wild type MYD88 (MYD88WT WM patients and patients with unknown MYD88 status [see Clinical Studies (14.2)]. Among patients who received BRUKINSA, 93% were exposed for months or longer, and 89% were exposed for greater than year.In Cohort of the ASPEN study safety population (N=101), the median age of patients who received BRUKINSA was 70 years (45-87 years old); 67% were male, 86% were White, 4% were Asian and 10% were not reported (unknown race). In Cohort of the ASPEN study safety population (N=28), the median age of patients who received BRUKINSA was 72 (39-87 years old); 50% were male, 96% were White and 4% were not reported (unknown race).In Cohort 1, serious adverse reactions occurred in 44% of patients who received BRUKINSA. Serious adverse reactions in 2% of patients included influenza (3%), pneumonia (4%), neutropenia and neutrophil count decreased (3%), hemorrhage (4%), pyrexia (3%) and febrile neutropenia (3%). In Cohort 2, serious adverse reactions occurred in 39% of patients. Serious adverse reactions in 2 patients included pneumonia (14%).Permanent discontinuation of BRUKINSA due to an adverse reaction occurred in 2% of patients in Cohort and included hemorrhage (1 patient), neutropenia and neutrophil count decreased (1 patient); in Cohort 2, permanent discontinuation of BRUKINSA due to an adverse reaction occurred in 7% of patients and included subdural hemorrhage (1 patient) and diarrhea (1 patient).Dosage interruptions of BRUKINSA due to an adverse reaction occurred in 32% of patients in Cohort and in 29% in Cohort 2. Adverse reactions which required dosage interruption in 2% of patients included neutropenia, vomiting, hemorrhage, thrombocytopenia and pneumonia in Cohort 1. Adverse reactions leading to dosage interruption in 2 patients in Cohort included pneumonia and pyrexia.Dose reductions of BRUKINSA due to an adverse reaction occurred in 11% of patients in Cohort and in 7% in Cohort 2. Adverse reactions which required dose reductions in 2% of patients included neutropenia in Cohort 1. Adverse reaction leading to dose reduction occurred in patients in Cohort (each with one event: diarrhea and pneumonia).Table summarizes the adverse reactions in Cohort in ASPEN.Table 5: Adverse Reactions (>= 10%) Occurring in Patients with WM Who Received BRUKINSA in Cohort 1Body SystemAdverse ReactionBRUKINSA (N=101)Ibrutinib (N=98)All GradesGrade or (%)All GradesGrade or (%)(%)(%)Infections and infestationsUpper respiratory tract infection Upper respiratory tract infection includes upper respiratory tract infection, laryngitis, nasopharyngitis, sinusitis, rhinitis, viral upper respiratory tract infection, pharyngitis, rhinovirus infection, upper respiratory tract congestion. 440402Pneumonia Pneumonia includes lower respiratory tract infection, lung infiltration, pneumonia, pneumonia aspiration, pneumonia viral. 1242610Urinary tract infection110132Gastrointestinal disordersDiarrhea223342Nausea180131Constipation16070Vomiting120141General disorders and administration site conditionsFatigue Fatigue includes asthenia, fatigue, lethargy. 311251Pyrexia164132Edema peripheral120200Skin and subcutaneous tissue disordersBruising Bruising includes all related terms containing bruise, contusion, or ecchymosis. 200340 RashRash includes all related terms rash, maculo-papular rash, erythema, rash erythematous, drug eruption, dermatitis allergic, dermatitis atopic, rash pruritic, dermatitis, photodermatosis, dermatitis acneiform, stasis dermatitis, vasculitic rash, eyelid rash, urticaria, skin toxicity. 290320Pruritus11160Musculoskeletal and connective tissue disordersMusculoskeletal pain Musculoskeletal pain includes back pain, arthralgia, pain in extremity, musculoskeletal pain, myalgia, bone pain, spinal pain, musculoskeletal chest pain, neck pain, arthritis, musculoskeletal discomfort. 459391Muscle spasms100281Nervous system disordersHeadache181141Dizziness131120Respiratory, thoracic and mediastinal disordersCough160180Dyspnea14070Vascular disordersHemorrhage Hemorrhage includes epistaxis, hematuria, conjunctival hemorrhage, hematoma, rectal hemorrhage, periorbital hemorrhage, mouth hemorrhage, post procedural hemorrhage, hemoptysis, skin hemorrhage, hemorrhoidal hemorrhage, ear hemorrhage, eye hemorrhage, hemorrhagic diathesis, periorbital hematoma, subdural hemorrhage, wound hemorrhage, gastric hemorrhage, lower gastrointestinal hemorrhage, spontaneous hematoma, traumatic hematoma, traumatic intracranial hemorrhage, tumor hemorrhage, retinal hemorrhage, hematochezia, diarrhea hemorrhagic, hemorrhage, melena, post procedural hematoma, subdural hematoma, anal hemorrhage, hemorrhagic disorder, pericardial hemorrhage, postmenopausal hemorrhage, stoma site hemorrhage, subarachnoid hemorrhage. 424439Hypertension1491914Clinically relevant adverse reactions in 10% of patients who received BRUKINSA included localized infection, atrial fibrillation or atrial flutter and hematuria.Table summarizes the laboratory abnormalities in ASPEN.Table 6: Select Laboratory AbnormalitiesBased on laboratory measurements. (>= 20%) That Worsened from Baseline in Patients with WM Who Received BRUKINSA in Cohort 1Laboratory AbnormalityBRUKINSAThe denominator used to calculate the rate varied from 86 to 101 based on the number of patients with baseline value and at least one post-treatment value. Ibrutinib All Grades (%)Grade or (%)All Grades (%)Grade or (%)Hematologic AbnormalitiesNeutrophils decreased5024349Platelets decreased358395Hemoglobin decreased207207Chemistry AbnormalitiesBilirubin increased121.0331.0Calcium decreased272.0260Creatinine increased311.0211.0Glucose increased452.3332.3Potassium increased242.0120Urate increased163.2346Phosphate decreased203.1180. Marginal Zone LymphomaThe safety of BRUKINSA was evaluated in 88 patients with previously treated MZL in two single-arm clinical studies, BGB-3111-214 and BGB-3111-AU-003 [see Clinical Studies (14.3)]. The trials required an absolute neutrophil count >= x 109/L, platelet count >= 50 or >= 75 109/L and adequate hepatic function and excluded patients requiring strong CYP3A inhibitor or inducer. Patients received BRUKINSA 160 mg twice daily (97%) or 320 mg once daily (3%). The median age in both studies combined was 70 years (range: 37 to 95), 52% were male, 64% were Caucasian and 19% were Asian. Most patients (92%) had an ECOG performance status of to 1. Eighty percent received BRUKINSA for months or longer, and 67% received treatment for more than one year.Two fatal adverse reactions (2.3%) occurred within 30 days of the last dose of BRUKINSA, including myocardial infarction and Covid-19 related death.Serious adverse reactions occurred in 40% of patients. The most frequent serious adverse reactions were pyrexia (8%) and pneumonia (7%).Adverse reactions lead to treatment discontinuation in 6% of patients, dose reduction in 2.3%, and dose interruption in 34%. The leading cause of dose modification was respiratory tract infections (13%).Table summarizes selected adverse reactions in BGB-3111-214 and BGB-3111-AU-003. Table 7: Adverse Reactions Occurring in >= 10% Patients with MZL Who Received BRUKINSABody SystemAdverse ReactionBRUKINSA (N=88)All Grades (%)Grade or (%)Infections and infestationsUpper respiratory tract infections Upper respiratory tract infections includes upper respiratory tract infection, nasopharyngitis, sinusitis, tonsillitis, rhinitis, viral upper respiratory tract infection. 263.4Urinary tract infection Urinary tract infection includes urinary tract infection, cystitis, Escherichia urinary tract infection, pyelonephritis, cystitis. 112.3Pneumonia Pneumonia includes COVID-19 pneumonia, pneumonia, bronchopulmonary aspergillosis, lower respiratory tract infection, organizing pneumonia. Includes fatal events of COVID-19 pneumonia. 106Gastrointestinal disordersDiarrhea Diarrhea includes diarrhea and diarrhea hemorrhagic. 253.4Abdominal pain Abdominal pain includes abdominal pain, abdominal pain upper, abdominal discomfort. 142.3Nausea130Skin and subcutaneous tissue disordersBruising Bruising includes contusion, ecchymosis, increased tendency to bruise, post procedural contusion. 240Rash Rash includes rash, rash maculo-papular, rash pruritic, dermatitis, dermatitis allergic, dermatitis atopic, dermatitis contact, drug reaction with eosinophilia and systemic symptoms, erythema, photosensitivity reaction, rash erythematous, rash papular, seborrheic dermatitis. 210Musculoskeletal and connective tissue disordersMusculoskeletal pain Musculoskeletal pain includes back pain, arthralgia, musculoskeletal pain, myalgia, pain in extremity, musculoskeletal chest pain, bone pain, musculoskeletal discomfort, neck pain. 271.1Vascular disordersHemorrhage Hemorrhage includes epistaxis, hematuria, hemorrhoidal hemorrhage, hematoma, hemoptysis, conjunctival hemorrhage, diarrhea hemorrhagic, hemorrhage urinary tract, mouth hemorrhage, pulmonary hematoma, subcutaneous hematoma, gingival bleeding, melena, upper gastrointestinal hemorrhage. 231.1General disordersFatigue Fatigue includes fatigue, lethargy, asthenia. 212.3Respiratory, thoracic and mediastinal disordersCough Cough includes cough and productive cough. 100Clinically relevant adverse reactions in 10% of patients who received BRUKINSA included peripheral neuropathy, second primary malignancies, dizziness, edema, headache, petechiae, purpura and atrial fibrillation or flutter.Table summarizes selected laboratory abnormalities.Table 8: Select Laboratory Abnormalities (>= 20%) That Worsened from Baseline in Patients with MZLLaboratory AbnormalityThe denominator used to calculate the rate varied from 87 to 88 based on the number of patients with baseline value and at least one post-treatment value. BRUKINSAAll Grades (%)Grade or (%)Hematologic abnormalitiesNeutrophils decreased4315Platelets decreased3310Lymphocytes decreased328Hemoglobin decreased266Chemistry abnormalitiesGlucose increased544.6Creatinine increased341.1Phosphate decreased272.3Calcium decreased230ALT increased221.1.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Zanubrutinib is small-molecule inhibitor of Brutons tyrosine kinase (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 2,099 (42%) ngh/mL following 160 mg twice daily and 1,917 (59%) ngh/mL following 320 mg once daily. The geometric mean (%CV) zanubrutinib steady-state Cmax is 295 (55%) ng/mL following 160 mg twice daily and 537 (55%) 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 volume of distribution (Vz/F) of zanubrutinib is 537 (73%) 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 128 (58%) 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 144 kg) or mild, moderate or severe renal impairment (creatinine clearance [CLcr] >= 15 mL/min as estimated by Cockcroft-Gault). The effect of 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 10).Table 10: 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 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 and CYP2C8.. 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 11: 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 estimable.ORR (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). 14.2Waldenstroms Macroglobulinemia. The efficacy of BRUKINSA was evaluated in ASPEN [NCT03053440], randomized, active control, open-label trial, comparing BRUKINSA and ibrutinib in patients with MYD88 L265P mutation (MYD88MUT WM. Patients in Cohort (n=201) were randomized 1:1 to receive BRUKINSA 160 mg twice daily or ibrutinib 420 mg once daily until disease progression or unacceptable toxicity. Randomization was stratified by number of prior therapies (0 versus 1-3 versus 3) and CXCR4 status (presence or absence of WHIM-like mutation as measured by Sanger assay).The major efficacy outcome was the response rate defined as PR or better as assessed by IRC based on standard consensus response criteria from the International Workshop on Waldenstroms Macroglobulinemia (IWWM)-6 criteria. An additional efficacy outcome measure was duration of response (DOR).The median age was 70 years (range: 38 to 90) and 68% were male. Of those enrolled, 2% were Asian, 91% were White and 7% were of unknown race. ECOG performance status of or was present in 93% patients at baseline and 7% had baseline ECOG performance status of 2. total of 82% had relapsed/refractory disease with 85% having received prior alkylating agents and 91% prior anti-CD20 therapy. The median number of prior therapies in those with relapsed/refractory disease was (range: to 8). total of 91 (45%) patients had International Prognostic Scoring System (IPSS) high WM.The study did not meet statistical significance for the pre-specified efficacy outcome of superior CR+VGPR as assessed by IRC, tested first in patients with R/R disease in ASPEN.Table 12 shows the response rates in ASPEN based on IRC assessment.Table 12: Response Rate and Duration of Response Based on IRC Assessment in ASPENStandard IWWM-6IWWM-6 criteria (Owen et al, 2013) require complete resolution of extramedullary disease (EMD) if present at baseline for VGPR to be assessed. Modified IWWM-6Modified IWWM-6 criteria (Treon, 2015) require reduction in EMD if present at baseline for VGPR to be assessed. Response CategoryBRUKINSA (N=102)Ibrutinib (N=99)BRUKINSA (N=102)Ibrutinib (N=99)Response rate (CR+VGPR+PR), (%)79 (77.5)77 (77.8)79 (77.5)77 (77.8) 95% CI (%)2-sided Clopper-Pearson 95% confidence interval. (68.1, 85.1)(68.3, 85.5)(68.1, 85.1)(68.3, 85.5) Complete Response (CR)0 (0.0)0 (0.0)0 (0.0)0 (0.0) Very Good Partial Response (VGPR)16 (15.7)7 (7.1)29 (28.4)19 (19.2) Partial Response (PR), (%)63 (61.8)70 (70.7)50 (49.0)58 (58.6)Duration of response (DOR), Event-free at 12 months (95% CI)Estimated by Kaplan-Meier method with 95% CIs estimated using the method of Brookmeyer and Crowley. 94.4%(85.8, 97.9)87.9%(77.0, 93.8)94.4%(85.8, 97.9)87.9%(77.0, 93.8). ASPEN Cohort 2Cohort enrolled patients with MYD88 wildtype (MYD88WT or MYD88 mutation unknown WM (N 26 and 2, respectively) and received BRUKINSA 160 mg twice daily. The median age was 72 years (range: 39 to 87) with 43% 75 years, 50% were male, 96% were White and 4% were not reported (unknown race). 86% patients had baseline ECOG performance status or and 14% had baseline performance status of 2. Twenty-three of the 28 patients in Cohort had relapsed or refractory disease.In Cohort 2, response (CR+VGPR+PR) as assessed by IRC using IWWM-6 or modified IWWM-6 was seen in 50% (13 out of 26 response evaluable patients; 95% CI: 29.9, 70.1).. 14.3Marginal Zone Lymphoma. The efficacy of BRUKINSA was assessed in Study BGB-3111-214 [NCT03846427], an open-label, multicenter, single-arm trial that evaluated 66 patients with MZL who received at least one prior anti-CD20-based therapy. BRUKINSA was given orally at dosage of 160 mg twice daily until disease progression or unacceptable toxicity. The median age was 70 years (range: 37 to 85); 55% were male; 38% had extranodal MZL, 38% nodal, 18% splenic and 6% had unknown subtype. The median number of prior systemic therapies was (range: to 6), with 27% having or more lines of systemic therapy; 88% had prior rituximab-based chemotherapy; 32% had refractory disease at study entry.The efficacy of BRUKINSA was also assessed in BGB-3111-AU-003 [NCT02343120], an open-label, multicenter, single-arm trial that included 20 patients with previously treated MZL (45% having extranodal MZL, 25% nodal, 30% splenic). BRUKINSA was given orally at dosages of 160 mg twice daily or 320 mg once daily. The median age was 70 years (range: 52 to 85); 50% were male. The median number of prior systemic therapies was (range: to 5), with 20% having or more lines of systemic therapy; 95% had prior rituximab-based chemotherapy.Efficacy was based on overall response rate (ORR) and duration of response as assessed by an Independent Review Committee (IRC) using 2014 Lugano criteria (Table 13).Table 13: Efficacy Results per IRC in Patients with MZLParameterStudy BGB-3111-214(N=66)Study BGB-3111-AU-003 (N=20)ORR: overall response rate, CR: complete response, PR: partial response, DoR: duration of response, CI: confidence interval, NE: not estimableOverall Response Rate (CT-based) Per 2014 CT-based Lugano criteria. FDG-PET scans were not considered for this response assessment. ORR, n37 (56%)16 (80%) (95% CI, %)(43, 68)(56, 94) CR, n13 (20%)4 (20%) PR, n24 (36%)12 (60%)Time to Response Median (range), months2.9 (1.8, 11.1)2.9 (2.6, 23.1)Duration of Response Based on Kaplan-Meier estimation. Estimated median follow-up for DoR was 8.3 months for Study BGB-3111-214 and 31.4 months for Study BGB-3111-AU-003. c Median DoR (95% CI), monthsNE (NE, NE)NE (8.4, NE) Rate at 12 months (95% CI)85% (67, 93)72% (40, 88)In study BGB-3111-214, ORR prioritizing PET-CT when available (55 patients, with the remainder assessed by CT scan) was 67% (95% CI: 54, 78) with CR rate of 26%.

CLINICAL TRIALS EXPERIENCE SECTION.

6.1 Clinical 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 in seven clinical trials, administered as single agent at 160 mg twice daily in 730 patients, at 320 mg once daily in 105 patients, and at 40 mg to 160 mg once daily (0.125 to 0.5 times the recommended dosage) in 12 patients. Among 847 patients receiving BRUKINSA, 73% were exposed for at least year, 57% were exposed for at least years and 26% were exposed for at least years.In this pooled safety population, the most common adverse reactions, including laboratory abnormalities, in >= 30% of patients included neutrophil count decreased (54%), upper respiratory tract infection (47%), platelet count decreased (41%), hemorrhage (35%), lymphocyte count decreased (31%), rash (31%) and musculoskeletal pain (30%).. 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 (%)Hematologic abnormalities 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. Waldenstroms Macroglobulinemia (WM)The safety of BRUKINSA was investigated in two cohorts of Study BGB-3111-302 (ASPEN). Cohort included 199 patients with MYD88 mutation (MYD88MUT WM, randomized to and treated with either BRUKINSA (101 patients) or ibrutinib (98 patients). The trial also included non-randomized arm, Cohort 2, with 26 wild type MYD88 (MYD88WT WM patients and patients with unknown MYD88 status [see Clinical Studies (14.2)]. Among patients who received BRUKINSA, 93% were exposed for months or longer, and 89% were exposed for greater than year.In Cohort of the ASPEN study safety population (N=101), the median age of patients who received BRUKINSA was 70 years (45-87 years old); 67% were male, 86% were White, 4% were Asian and 10% were not reported (unknown race). In Cohort of the ASPEN study safety population (N=28), the median age of patients who received BRUKINSA was 72 (39-87 years old); 50% were male, 96% were White and 4% were not reported (unknown race).In Cohort 1, serious adverse reactions occurred in 44% of patients who received BRUKINSA. Serious adverse reactions in 2% of patients included influenza (3%), pneumonia (4%), neutropenia and neutrophil count decreased (3%), hemorrhage (4%), pyrexia (3%) and febrile neutropenia (3%). In Cohort 2, serious adverse reactions occurred in 39% of patients. Serious adverse reactions in 2 patients included pneumonia (14%).Permanent discontinuation of BRUKINSA due to an adverse reaction occurred in 2% of patients in Cohort and included hemorrhage (1 patient), neutropenia and neutrophil count decreased (1 patient); in Cohort 2, permanent discontinuation of BRUKINSA due to an adverse reaction occurred in 7% of patients and included subdural hemorrhage (1 patient) and diarrhea (1 patient).Dosage interruptions of BRUKINSA due to an adverse reaction occurred in 32% of patients in Cohort and in 29% in Cohort 2. Adverse reactions which required dosage interruption in 2% of patients included neutropenia, vomiting, hemorrhage, thrombocytopenia and pneumonia in Cohort 1. Adverse reactions leading to dosage interruption in 2 patients in Cohort included pneumonia and pyrexia.Dose reductions of BRUKINSA due to an adverse reaction occurred in 11% of patients in Cohort and in 7% in Cohort 2. Adverse reactions which required dose reductions in 2% of patients included neutropenia in Cohort 1. Adverse reaction leading to dose reduction occurred in patients in Cohort (each with one event: diarrhea and pneumonia).Table summarizes the adverse reactions in Cohort in ASPEN.Table 5: Adverse Reactions (>= 10%) Occurring in Patients with WM Who Received BRUKINSA in Cohort 1Body SystemAdverse ReactionBRUKINSA (N=101)Ibrutinib (N=98)All GradesGrade or (%)All GradesGrade or (%)(%)(%)Infections and infestationsUpper respiratory tract infection Upper respiratory tract infection includes upper respiratory tract infection, laryngitis, nasopharyngitis, sinusitis, rhinitis, viral upper respiratory tract infection, pharyngitis, rhinovirus infection, upper respiratory tract congestion. 440402Pneumonia Pneumonia includes lower respiratory tract infection, lung infiltration, pneumonia, pneumonia aspiration, pneumonia viral. 1242610Urinary tract infection110132Gastrointestinal disordersDiarrhea223342Nausea180131Constipation16070Vomiting120141General disorders and administration site conditionsFatigue Fatigue includes asthenia, fatigue, lethargy. 311251Pyrexia164132Edema peripheral120200Skin and subcutaneous tissue disordersBruising Bruising includes all related terms containing bruise, contusion, or ecchymosis. 200340 RashRash includes all related terms rash, maculo-papular rash, erythema, rash erythematous, drug eruption, dermatitis allergic, dermatitis atopic, rash pruritic, dermatitis, photodermatosis, dermatitis acneiform, stasis dermatitis, vasculitic rash, eyelid rash, urticaria, skin toxicity. 290320Pruritus11160Musculoskeletal and connective tissue disordersMusculoskeletal pain Musculoskeletal pain includes back pain, arthralgia, pain in extremity, musculoskeletal pain, myalgia, bone pain, spinal pain, musculoskeletal chest pain, neck pain, arthritis, musculoskeletal discomfort. 459391Muscle spasms100281Nervous system disordersHeadache181141Dizziness131120Respiratory, thoracic and mediastinal disordersCough160180Dyspnea14070Vascular disordersHemorrhage Hemorrhage includes epistaxis, hematuria, conjunctival hemorrhage, hematoma, rectal hemorrhage, periorbital hemorrhage, mouth hemorrhage, post procedural hemorrhage, hemoptysis, skin hemorrhage, hemorrhoidal hemorrhage, ear hemorrhage, eye hemorrhage, hemorrhagic diathesis, periorbital hematoma, subdural hemorrhage, wound hemorrhage, gastric hemorrhage, lower gastrointestinal hemorrhage, spontaneous hematoma, traumatic hematoma, traumatic intracranial hemorrhage, tumor hemorrhage, retinal hemorrhage, hematochezia, diarrhea hemorrhagic, hemorrhage, melena, post procedural hematoma, subdural hematoma, anal hemorrhage, hemorrhagic disorder, pericardial hemorrhage, postmenopausal hemorrhage, stoma site hemorrhage, subarachnoid hemorrhage. 424439Hypertension1491914Clinically relevant adverse reactions in 10% of patients who received BRUKINSA included localized infection, atrial fibrillation or atrial flutter and hematuria.Table summarizes the laboratory abnormalities in ASPEN.Table 6: Select Laboratory AbnormalitiesBased on laboratory measurements. (>= 20%) That Worsened from Baseline in Patients with WM Who Received BRUKINSA in Cohort 1Laboratory AbnormalityBRUKINSAThe denominator used to calculate the rate varied from 86 to 101 based on the number of patients with baseline value and at least one post-treatment value. Ibrutinib All Grades (%)Grade or (%)All Grades (%)Grade or (%)Hematologic AbnormalitiesNeutrophils decreased5024349Platelets decreased358395Hemoglobin decreased207207Chemistry AbnormalitiesBilirubin increased121.0331.0Calcium decreased272.0260Creatinine increased311.0211.0Glucose increased452.3332.3Potassium increased242.0120Urate increased163.2346Phosphate decreased203.1180. Marginal Zone LymphomaThe safety of BRUKINSA was evaluated in 88 patients with previously treated MZL in two single-arm clinical studies, BGB-3111-214 and BGB-3111-AU-003 [see Clinical Studies (14.3)]. The trials required an absolute neutrophil count >= x 109/L, platelet count >= 50 or >= 75 109/L and adequate hepatic function and excluded patients requiring strong CYP3A inhibitor or inducer. Patients received BRUKINSA 160 mg twice daily (97%) or 320 mg once daily (3%). The median age in both studies combined was 70 years (range: 37 to 95), 52% were male, 64% were Caucasian and 19% were Asian. Most patients (92%) had an ECOG performance status of to 1. Eighty percent received BRUKINSA for months or longer, and 67% received treatment for more than one year.Two fatal adverse reactions (2.3%) occurred within 30 days of the last dose of BRUKINSA, including myocardial infarction and Covid-19 related death.Serious adverse reactions occurred in 40% of patients. The most frequent serious adverse reactions were pyrexia (8%) and pneumonia (7%).Adverse reactions lead to treatment discontinuation in 6% of patients, dose reduction in 2.3%, and dose interruption in 34%. The leading cause of dose modification was respiratory tract infections (13%).Table summarizes selected adverse reactions in BGB-3111-214 and BGB-3111-AU-003. Table 7: Adverse Reactions Occurring in >= 10% Patients with MZL Who Received BRUKINSABody SystemAdverse ReactionBRUKINSA (N=88)All Grades (%)Grade or (%)Infections and infestationsUpper respiratory tract infections Upper respiratory tract infections includes upper respiratory tract infection, nasopharyngitis, sinusitis, tonsillitis, rhinitis, viral upper respiratory tract infection. 263.4Urinary tract infection Urinary tract infection includes urinary tract infection, cystitis, Escherichia urinary tract infection, pyelonephritis, cystitis. 112.3Pneumonia Pneumonia includes COVID-19 pneumonia, pneumonia, bronchopulmonary aspergillosis, lower respiratory tract infection, organizing pneumonia. Includes fatal events of COVID-19 pneumonia. 106Gastrointestinal disordersDiarrhea Diarrhea includes diarrhea and diarrhea hemorrhagic. 253.4Abdominal pain Abdominal pain includes abdominal pain, abdominal pain upper, abdominal discomfort. 142.3Nausea130Skin and subcutaneous tissue disordersBruising Bruising includes contusion, ecchymosis, increased tendency to bruise, post procedural contusion. 240Rash Rash includes rash, rash maculo-papular, rash pruritic, dermatitis, dermatitis allergic, dermatitis atopic, dermatitis contact, drug reaction with eosinophilia and systemic symptoms, erythema, photosensitivity reaction, rash erythematous, rash papular, seborrheic dermatitis. 210Musculoskeletal and connective tissue disordersMusculoskeletal pain Musculoskeletal pain includes back pain, arthralgia, musculoskeletal pain, myalgia, pain in extremity, musculoskeletal chest pain, bone pain, musculoskeletal discomfort, neck pain. 271.1Vascular disordersHemorrhage Hemorrhage includes epistaxis, hematuria, hemorrhoidal hemorrhage, hematoma, hemoptysis, conjunctival hemorrhage, diarrhea hemorrhagic, hemorrhage urinary tract, mouth hemorrhage, pulmonary hematoma, subcutaneous hematoma, gingival bleeding, melena, upper gastrointestinal hemorrhage. 231.1General disordersFatigue Fatigue includes fatigue, lethargy, asthenia. 212.3Respiratory, thoracic and mediastinal disordersCough Cough includes cough and productive cough. 100Clinically relevant adverse reactions in 10% of patients who received BRUKINSA included peripheral neuropathy, second primary malignancies, dizziness, edema, headache, petechiae, purpura and atrial fibrillation or flutter.Table summarizes selected laboratory abnormalities.Table 8: Select Laboratory Abnormalities (>= 20%) That Worsened from Baseline in Patients with MZLLaboratory AbnormalityThe denominator used to calculate the rate varied from 87 to 88 based on the number of patients with baseline value and at least one post-treatment value. BRUKINSAAll Grades (%)Grade or (%)Hematologic abnormalitiesNeutrophils decreased4315Platelets decreased3310Lymphocytes decreased328Hemoglobin decreased266Chemistry abnormalitiesGlucose increased544.6Creatinine increased341.1Phosphate decreased272.3Calcium decreased230ALT increased221.1.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. Recommended dosage: 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 dosage: 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 dosage 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 dosage 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 dosage modifications of BRUKINSA for drug interactions are provided in Table [see Drug Interactions (7.1)]. Table 1: Dosage Modifications for Use With CYP3A Inhibitors or InducersCo-administered DrugRecommended BRUKINSA DoseStrong CYP3A inhibitor80 mg once dailyInterrupt dose as recommended for adverse reactions [see Dosage and Administration (2.4)]. Moderate CYP3A inhibitor80 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 dosage modifications of BRUKINSA for Grade or higher adverse reactions are provided in Table 2:Table 2: Recommended Dosage Modification for Adverse ReactionEventAdverse Reaction OccurrenceDosage Modification(Starting Dose: 160 mg twice daily or 320 mg once daily)Hematological toxicities [see Warnings and Precautions (5.3)]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 Grade or lower or baseline: Resume at 160 mg twice daily or 320 mg once daily.SecondInterrupt BRUKINSAOnce toxicity has resolved to Grade or lower or baseline: Resume at 80 mg twice daily or 160 mg once daily.ThirdInterrupt BRUKINSAOnce toxicity has resolved to Grade or lower or baseline: Resume at 80 mg once daily.FourthDiscontinue BRUKINSANon-hematological toxicities [see Warnings and Precautions (5.5) and Adverse Reactions (6.1)]Grade or non-hematological toxicities Evaluate the benefit-risk before resuming treatment at the same dose for Grade non-hematological toxicity. FirstInterrupt BRUKINSAOnce toxicity has resolved to Grade or lower or baseline: Resume at 160 mg twice daily or 320 mg once dailyEvaluate the benefit-risk before resuming treatment at the same dose for Grade non-hematological toxicity..SecondInterrupt BRUKINSAOnce toxicity has resolved to Grade or lower or baseline: Resume at 80 mg twice daily or 160 mg once daily.ThirdInterrupt BRUKINSAOnce toxicity has resolved to Grade or lower or baseline: Resume at 80 mg once daily.FourthDiscontinue BRUKINSAAsymptomatic lymphocytosis should not be regarded as an adverse reaction, and these patients should continue taking BRUKINSA.

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 2,099 (42%) ngh/mL following 160 mg twice daily and 1,917 (59%) ngh/mL following 320 mg once daily. The geometric mean (%CV) zanubrutinib steady-state Cmax is 295 (55%) ng/mL following 160 mg twice daily and 537 (55%) 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 volume of distribution (Vz/F) of zanubrutinib is 537 (73%) 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 128 (58%) 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 144 kg) or mild, moderate or severe renal impairment (creatinine clearance [CLcr] >= 15 mL/min as estimated by Cockcroft-Gault). The effect of 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 10).Table 10: 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 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 and CYP2C8.. Transporter Systems: Zanubrutinib is likely to be substrate of P-gp. Zanubrutinib is not substrate or inhibitor of OAT1, OAT3, OCT2, OATP1B1 or OATP1B3.

SPL PATIENT PACKAGE INSERT SECTION.

PATIENT INFORMATION BRUKINSA(R) (BROO-kin-sah) (zanubrutinib) capsules This Patient Information has been approved by the U.S. Food and Drug Administration.Revised: 9/2021 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.Waldenstroms macroglobulinemia (WM).Marginal zone lymphoma (MZL) when the disease has come back or did not respond to treatment and who have received at least one certain type of treatment.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 avoid getting pregnant during treatment and for week after the last dose of BRUKINSA. You should use effective birth control (contraception) during treatment and for week after the last dose of BRUKINSA.Males should avoid getting female partners pregnant during treatment and for week after the last dose of BRUKINSA. You should use effective birth control (contraception) during treatment and for 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 weeks after the 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 bruisingdizzinessweaknessconfusionchange 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 or other organs. Your healthcare provider will check you for other cancers during treatment with BRUKINSA. 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 cellsupper respiratory tract infectiondecreased platelet countbleedingrashmuscle or joint painThese 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: zanubrutinib Inactive 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., 2955 Campus Drive, Suite 200, San Mateo, CA 94403 BRUKINSA(R) is registered trademark owned by BeiGene, Ltd. (C) BeiGene, Ltd. 2021 For more information, go to www.BRUKINSA.com or call 1-833-969-2463.. Mantle cell lymphoma (MCL) who have received at least one prior treatment for their cancer.. Waldenstroms macroglobulinemia (WM).. Marginal zone lymphoma (MZL) when the disease has come back or did not respond to treatment and who have received at least one certain type of treatment.. 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 avoid getting pregnant during treatment and for week after the last dose of BRUKINSA. You should use effective birth control (contraception) during treatment and for week after the last dose of BRUKINSA.Males should avoid getting female partners pregnant during treatment and for week after the last dose of BRUKINSA. You should use effective birth control (contraception) during treatment and for week after the last dose of BRUKINSA. Females should avoid getting pregnant during treatment and for week after the last dose of BRUKINSA. You should use effective birth control (contraception) during treatment and for week after the last dose of BRUKINSA.. Males should avoid getting female partners pregnant during treatment and for week after the last dose of BRUKINSA. You should use effective birth control (contraception) during treatment and for 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 weeks after the 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. change 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 or other organs. Your healthcare provider will check you for other cancers during treatment with BRUKINSA. 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. upper respiratory tract infection. decreased platelet count. bleeding. rash. muscle or joint pain. Store BRUKINSA capsules at room temperature between 68F to 77F (20C to 25C).. BRUKINSA comes in bottle with child-resistant cap.

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 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 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 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 847 patients in clinical studies with BRUKINSA, 53% were >= 65 years of age, and 20% were >= 75 years of age. No overall differences in safety or effectiveness were observed between younger and older patients.. 8.6 Renal Impairment. No 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 patients on dialysis [see Clinical Pharmacology (12.3)]. 8.7 Hepatic 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)].

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). 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 hemorrhage including intracranial and gastrointestinal hemorrhage, hematuria and hemothorax have been reported in 3.4% of patients treated with BRUKINSA monotherapy. Hemorrhage events of any grade, excluding purpura and petechiae, occurred in 35% of patients.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 27% of patients, most commonly 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 (26%), thrombocytopenia (11%) and anemia (8%) based on laboratory measurements, developed in patients treated with BRUKINSA monotherapy [see Adverse Reactions (6.1)]. Grade neutropenia occurred in 13% of patients, and Grade thrombocytopenia occurred in 3.6% of patients.Monitor complete blood counts regularly during treatment and interrupt treatment, reduce the dose, or discontinue treatment as warranted [see Dosage and Administration (2.4)]. Treat using growth factor or transfusions, as needed.. 5.4Second Primary Malignancies. Second primary malignancies, including non-skin carcinoma, have occurred in 14% of patients treated with BRUKINSA monotherapy. The most frequent second primary malignancy was non-melanoma skin cancer reported in 8% of patients. Other second primary malignancies included malignant solid tumors (4.0%), melanoma (1.7%) and hematologic malignancies (1.2%). Advise patients to use sun protection and monitor patients for the development of second primary malignancies.. 5.5 Cardiac Arrhythmias. Atrial fibrillation and atrial flutter were reported in 3.2% 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 1.1% of patients treated with BRUKINSA monotherapy. Monitor signs and symptoms for atrial fibrillation and atrial flutter and manage as appropriate [see Dosage and Administration (2.4)].. 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 week after the last dose. Advise men to avoid fathering child during treatment and for 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)].