Adverse reactions
Information about undesirable effects, reasonably associated with use of the drug, that may occur as part of the pharmacological action of the drug or may be unpredictable in its occurrence. Adverse reactions include those that occur with the drug, and if applicable, with drugs in the same pharmacologically active and chemically related class. There is considerable variation in the listing of adverse reactions. They may be categorized by organ system, by severity of reaction, by frequency, by toxicological mechanism, or by a combination of these.
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) ] The most common adverse reactions (≥30%), including laboratory abnormalities, are neutrophil count decreased, platelet count decreased, upper respiratory tract infection, hemorrhage, 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 a 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 nine monotherapy and 2 combination clinical trials, administered at 160 mg twice daily in 1608 patients and at 320 mg once daily in 121 patients. Among these 1729 patients, the median duration of exposure was 27.6 months, 78% of patients were exposed for at least 12 months, and 60% of patients were exposed for at least 24 months. In this pooled safety population, the most common adverse reactions (≥30%), including laboratory abnormalities, were neutrophil count decreased (51%), platelet count decreased (41%), upper respiratory tract infection (38%), hemorrhage (32%), and musculoskeletal pain (31%). 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 0 to 1. Patients had a median of 2 prior lines of therapy (range: 1 to 4). The BGB-3111-206 trial required a platelet count ≥75 × 10 9 /L and an absolute neutrophil count ≥1 × 10 9 /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 a platelet count ≥50 × 10 9 /L and an absolute neutrophil count ≥1 × 10 9 /L independent of growth factor support, hepatic enzymes ≤3 × upper limit of normal, total bilirubin ≤1.5 × ULN. Both trials required a creatinine clearance (CLcr) ≥30 mL/min. Both trials excluded patients with prior allogeneic hematopoietic stem cell transplant, exposure to a BTK inhibitor, known infection with HIV, and serologic evidence of active hepatitis B or hepatitis C 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 6 months or longer, and 68% were exposed for greater than one year. Fatal adverse reactions within 30 days of the last dose of BRUKINSA occurred in 8 (7%) of 118 patients with MCL. Fatal cases included pneumonia in 2 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, 8 (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 3 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 Trials Body System Adverse Reaction Percent of Patients (N=118) All Grades % Grade 3 or Higher % Infections and infestations Upper respiratory tract infection Upper respiratory tract infection includes upper respiratory tract infection, upper respiratory tract infection viral. 39 0 Pneumonia 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. 15 10 Includes fatal adverse reaction. Urinary tract infection 11 0.8 Skin and subcutaneous tissue disorders Rash Rash includes all related terms containing rash. 36 0 Bruising Bruising includes all related terms containing bruise, bruising, contusion, ecchymosis. 14 0 Gastrointestinal disorders Diarrhea 23 0.8 Constipation 13 0 Vascular disorders Hypertension 12 3.4 Hemorrhage Hemorrhage includes all related terms containing hemorrhage, hematoma. 11 3.4 Musculoskeletal and connective tissue disorders Musculoskeletal pain Musculoskeletal pain includes musculoskeletal pain, musculoskeletal discomfort, myalgia, back pain, arthralgia, arthritis. 14 3.4 Respiratory, thoracic, and mediastinal disorders Cough 12 0 Other clinically significant adverse reactions that occurred in <10% of patients with mantle cell lymphoma include major hemorrhage (defined as ≥ Grade 3 hemorrhage or CNS hemorrhage of any grade) (5%) and headache (4.2%). Table 4: Selected Laboratory Abnormalities Based on laboratory measurements. (>20%) in Patients with MCL in Studies BGB-3111-206 and BGB-3111-AU-003 Laboratory Parameter Percent of Patients (N=118) All Grades (%) Grade 3 or 4 (%) Hematologic abnormalities Neutrophils decreased 45 20 Lymphocytosis Asymptomatic lymphocytosis is a known effect of BTK inhibition. 41 16 Platelets decreased 40 7 Hemoglobin decreased 27 6 Chemistry abnormalities Blood uric acid increased 29 2.6 ALT increased 28 0.9 Bilirubin increased 24 0.9 Waldenström's Macroglobulinemia (WM) The safety of BRUKINSA was investigated in two cohorts of Study BGB-3111-302 (ASPEN). Cohort 1 included 199 patients with MYD88 mutation ( MYD88 MUT ) WM, randomized to and treated with either BRUKINSA (101 patients) or ibrutinib (98 patients). The trial also included a non-randomized arm, Cohort 2, with 26 wild type MYD88 ( MYD88 WT ) WM patients and 2 patients with unknown MYD88 status [see Clinical Studies (14.2) ] . Among patients who received BRUKINSA, 93% were exposed for 6 months or longer, and 89% were exposed for greater than 1 year. In Cohort 1 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 2 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 1 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 1 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 2 included pneumonia and pyrexia. Dose reductions of BRUKINSA due to an adverse reaction occurred in 11% of patients in Cohort 1 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 2 patients in Cohort 2 (each with one event: diarrhea and pneumonia). Table 5 summarizes the adverse reactions in Cohort 1 in ASPEN. Table 5: Adverse Reactions (≥10%) Occurring in Patients with WM Who Received BRUKINSA in Cohort 1 Body System Adverse Reaction BRUKINSA (N=101) Ibrutinib (N=98) All Grades (%) Grade 3 or 4 (%) All Grades (%) Grade 3 or 4 (%) Infections and infestations Upper 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. 44 0 40 2 Pneumonia Pneumonia includes lower respiratory tract infection, lung infiltration, pneumonia, pneumonia aspiration, pneumonia viral. 12 4 26 10 Urinary tract infection 11 0 13 2 Gastrointestinal disorders Diarrhea 22 3 34 2 Nausea 18 0 13 1 Constipation 16 0 7 0 Vomiting 12 0 14 1 General disorders Fatigue Fatigue includes asthenia, fatigue, lethargy. 31 1 25 1 Pyrexia 16 4 13 2 Edema peripheral 12 0 20 0 Skin and subcutaneous tissue disorders Bruising Bruising includes all related terms containing bruise, contusion, or ecchymosis. 20 0 34 0 Rash Rash includes all related terms rash, maculo-papular rash, erythema, rash erythematous, drug eruption, dermatitis allergic, dermatitis atopic, rash pruritic, dermatitis, photodermatoses, dermatitis acneiform, stasis dermatitis, vasculitic rash, eyelid rash, urticaria, skin toxicity. 29 0 32 0 Pruritus 11 1 6 0 Musculoskeletal and connective tissue disorders Musculoskeletal 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. 45 9 39 1 Muscle spasms 10 0 28 1 Nervous system disorders Headache 18 1 14 1 Dizziness 13 1 12 0 Respiratory, thoracic, and mediastinal disorders Cough 16 0 18 0 Dyspnea 14 0 7 0 Vascular disorders Hemorrhage 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. 42 4 43 9 Hypertension 14 9 19 14 Clinically relevant adverse reactions in <10% of patients who received BRUKINSA included localized infection, atrial fibrillation or atrial flutter, and hematuria. Table 6 summarizes the laboratory abnormalities in ASPEN. Table 6: Select Laboratory Abnormalities Based on laboratory measurements. (≥20%) that Worsened from Baseline in Patients with WM Who Received BRUKINSA in Cohort 1 Laboratory Abnormality BRUKINSA The denominator used to calculate the rate varied from 86 to 101 based on the number of patients with a baseline value and at least one post-treatment value. Ibrutinib All Grades (%) Grade 3 or 4 (%) All Grades (%) Grade 3 or 4 (%) Hematologic abnormalities Neutrophils decreased 50 24 34 9 Platelets decreased 35 8 39 5 Hemoglobin decreased 20 7 20 7 Chemistry abnormalities Glucose increased 45 2.3 33 2.3 Creatinine increased 31 1 21 1 Calcium decreased 27 2 26 0 Potassium increased 24 2 12 0 Phosphate decreased 20 3.1 18 0 Urate increased 16 3.2 34 6 Bilirubin increased 12 1 33 1 Marginal Zone Lymphoma The 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 ≥1 × 10 9 /L, platelet count ≥50 or ≥75 × 10 9 /L and adequate hepatic function and excluded patients requiring a 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 White, and 19% were Asian. Most patients (92%) had an ECOG performance status of 0 to 1. Eighty percent received BRUKINSA for 6 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 a 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 7 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 BRUKINSA Body System Adverse Reaction BRUKINSA (N=88) All Grades (%) Grade 3 or 4 (%) Infections and infestations Upper respiratory tract infection Upper respiratory tract infection includes upper respiratory tract infection, nasopharyngitis, sinusitis, tonsillitis, rhinitis, viral upper respiratory tract infection. 26 3.4 Urinary tract infection Urinary tract infection includes urinary tract infection, cystitis, Escherichia urinary tract infection, pyelonephritis, cystitis. 11 2.3 Pneumonia Pneumonia includes COVID-19 pneumonia, pneumonia, bronchopulmonary aspergillosis, lower respiratory tract infection, organizing pneumonia. , Includes 2 fatalities from COVID-19 pneumonia. 10 6 Gastrointestinal disorders Diarrhea Diarrhea includes diarrhea and diarrhea hemorrhagic. 25 3.4 Abdominal pain Abdominal pain includes abdominal pain, abdominal pain upper, abdominal discomfort. 14 2.3 Nausea 13 0 Skin and subcutaneous tissue disorders Bruising Bruising includes contusion, ecchymosis, increased tendency to bruise, post procedural contusion. 24 0 Rash 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. 21 0 Musculoskeletal and connective tissue disorders Musculoskeletal pain Musculoskeletal pain includes back pain, arthralgia, musculoskeletal pain, myalgia, pain in extremity, musculoskeletal chest pain, bone pain, musculoskeletal discomfort, neck pain. 27 1.1 Vascular disorders Hemorrhage 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. 23 1.1 General disorders Fatigue Fatigue includes fatigue, lethargy, asthenia. 21 2.3 Respiratory, thoracic, and mediastinal disorders Cough Cough includes cough and productive cough. 10 0 Clinically 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 8 summarizes select laboratory abnormalities. Table 8: Select Laboratory Abnormalities (≥20%) that Worsened from Baseline in Patients with MZL Laboratory Abnormality The denominator used to calculate the rate varied from 87 to 88 based on the number of patients with a baseline value and at least one post-treatment value. BRUKINSA All Grades (%) Grade 3 or 4 (%) Hematologic abnormalities Neutrophils decreased 43 15 Platelets decreased 33 10 Lymphocytes decreased 32 8 Hemoglobin decreased 26 6 Chemistry abnormalities Glucose increased 54 4.6 Creatinine increased 34 1.1 Phosphate decreased 27 2.3 Calcium decreased 23 0 ALT increased 22 1.1 Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma The safety data described below reflect exposure to BRUKINSA (160 mg twice daily) in 675 patients with CLL from two randomized controlled clinical trials [see Clinical Studies (14.4) ] . The trials required patients to be unsuitable for fludarabine, cyclophosphamide, and rituximab (FCR) therapy defined as age ≥65 years, or age 18 to <65 years with either a total Cumulative Illness Rating Scale (CIRS) >6, CLcr 30 to 69 mL/min, or history of serious or frequent infections. The trial excluded patients with AST or ALT ≥2 times the upper limit of normal (ULN) or bilirubin ≥3 times (ULN) and patients requiring a strong CYP3A inhibitor or inducer. SEQUOIA The safety of BRUKINSA monotherapy in patients with previously untreated CLL/SLL was evaluated in a randomized, multicenter, open-label, actively controlled trial [see Clinical Studies (14.4) ] . Patients without deletion of chromosome 17p13.1 (17p deletion) (Cohort 1) received either BRUKINSA 160 mg twice daily until disease progression or unacceptable toxicity (n=240) or bendamustine plus rituximab (BR) for 6 cycles (n=227). Bendamustine was dosed at 90 mg/m 2 /day intravenously on the first 2 days of each cycle, and rituximab was dosed at 375 mg/m 2 on day 1 of Cycle 1 and 500 mg/m 2 on day 1 of Cycles 2 to 6. Additionally, the same BRUKINSA regimen was evaluated in 111 patients with previously untreated CLL/SLL with 17p deletion in a non-randomized single arm (Cohort 2). Randomized Cohort: Previously Untreated CLL/SLL without 17p Deletion In patients with previously untreated CLL/SLL without 17p deletion, the median age was 70, 62% were male, 89% were White, 2% were Asian, and 2% were Black. Most patients (93%) had an ECOG performance status of 0 to 1. The median duration of exposure to BRUKINSA was 26 months, with 71% exposed for more than 2 years. Serious adverse reactions occurred in 36% of patients who received BRUKINSA. Serious adverse reactions that occurred in ≥5% of patients were COVID-19, pneumonia, and second primary malignancy (5% each). Fatal adverse reactions occurred in 11 (4.6%) patients with the leading cause of death being COVID-19 (2.1%). Adverse reactions led to permanent discontinuation of BRUKINSA in 8% of patients, dose reduction in 8%, and dose interruption in 46%. The most common adverse reactions leading to permanent discontinuation were second primary malignancy and COVID-19. The leading causes of dose modification (≥5% of all patients) were respiratory infections (COVID-19, pneumonia) and hemorrhage. Table 9 summarizes select adverse reactions in this randomized cohort. Table 9: Adverse Reactions in ≥10% Patients with Previously Untreated CLL/SLL without 17p Deletion in SEQUOIA CLL/SLL without 17p deletion BRUKINSA (N=240) BR (N=227) System Organ Class Preferred Term All Grades (%) Grade 3 or 4 (%) All Grades (%) Grade 3 or 4 (%) Musculoskeletal and connective tissue disorders Musculoskeletal pain Musculoskeletal pain: musculoskeletal pain, arthralgia, back pain, pain in extremity, myalgia, neck pain, spinal pain, musculoskeletal discomfort, bone pain. 33 1.7 17 0.4 Infections and infestations Upper respiratory tract infection Upper respiratory tract infection: upper respiratory tract infection, nasopharyngitis, sinusitis, rhinitis, pharyngitis, upper respiratory tract congestion, laryngitis, tonsillitis and upper respiratory tract inflammation, and related terms. 28 1.3 15 0.9 Pneumonia Pneumonia: pneumonia, COVID-19 pneumonia, lower respiratory tract infection, lung infiltration, and related terms including specific types of infection. 13 Includes 3 fatal outcomes. 5 8 Includes 2 fatal outcomes. 4 Vascular disorders Hemorrhage Hemorrhage: all terms containing hematoma, hemorrhage, hemorrhagic, and related terms indicative of bleeding. 27 4 4 0.4 Hypertension Includes multiple similar adverse reaction terms. 14 7 5 2.6 Skin and subcutaneous tissue disorders Rash Rash: Rash, dermatitis, drug eruption, and related terms. 24 1.3 30 5 Bruising Bruising: all terms containing bruise, bruising, contusion, or ecchymosis. 24 0 2.6 0 Respiratory, thoracic, and mediastinal disorders Cough 15 0 10 0 Gastrointestinal disorders Diarrhea 14 0.8 12 0.9 Constipation 10 0.4 18 0 Nausea 10 0 33 1.3 General disorders Fatigue Fatigue: fatigue, asthenia, and lethargy. 14 1.3 21 1.8 Neoplasms Second primary malignancy Second primary malignancy: includes non-melanoma skin cancer, malignant solid tumors (including lung, renal, genitourinary, breast, ovarian, and rectal), and chronic myeloid leukemia. 13 6 1.3 0.4 Nervous system disorders Headache 12 0 8 0 Dizziness Dizziness: dizziness and vertigo. 11 0.8 5 0 Other clinically significant adverse reactions occurring in <10% of BRUKINSA recipients in this cohort included COVID-19 (9%), edema (8%), abdominal pain (8%), urinary tract infection (7%), and atrial fibrillation or flutter (3.3%). Table 10 summarizes select laboratory abnormalities in this cohort. Table 10: Select Laboratory Abnormalities (≥20%) that Worsened from Baseline in Patients with Previously Untreated CLL/SLL without 17p Deletion in SEQUOIA Laboratory Abnormality The denominator used to calculate the rate was 239 in the BRUKINSA arm and 227 in the BR arm, based on the number of patients with a baseline value and at least one post-treatment value. Grading is based on NCI CTCAE criteria. BRUKINSA BR All Grades (%) Grade 3 or 4 (%) All Grades (%) Grade 3 or 4 (%) Hematologic abnormalities Neutrophils decreased 37 15 80 53 Hemoglobin decreased 29 2.5 66 8 Platelets decreased 27 1.7 61 11 Leukocytes increased 21 Lymphocytes increased in 15%. 21 0.4 0.4 Chemistry abnormalities Glucose increased Nonfasting conditions. 55 7 67 10 Creatinine increased 22 0.8 18 0.4 Magnesium increased 22 0 14 0.4 Alanine aminotransferase increased 21 2.1 23 2.2 Single-Arm Cohort: Previously Untreated CLL/SLL and 17p Deletion In 111 patients with previously untreated, 17p del CLL/SLL, the median age was 70, 71% were male, 95% were White, and 1% were Asian. Most patients (87%) had an ECOG performance status of 0 to 1. The median duration of exposure to BRUKINSA was 30 months. Fatal adverse reactions occurred in 3 (2.7%) patients, including pneumonia, renal insufficiency, and aortic dissection (1 patient each). Serious adverse reactions occurred in 41% of patients treated with BRUKINSA. Serious adverse reactions reported in ≥5% of patients were pneumonia (8%) and second primary malignancy (7%). Adverse reactions led to treatment discontinuation in 5% of patients, dose reduction in 5%, and dose interruption in 51%. The leading causes of dose modification (≥5% of all patients) were pneumonia, neutropenia, second primary malignancy, and diarrhea. Table 11 summarizes select adverse reactions in this cohort. Table 11: Adverse Reactions in ≥10% of Patients with Previously Untreated CLL/SLL and 17p Deletion in SEQUOIA CLL/SLL with 17p Deletion BRUKINSA (N=111) System Organ Class Preferred Term All Grades (%) Grade 3 or 4 (%) Infections and infestations Upper respiratory tract infection Upper respiratory tract infection: upper respiratory tract infection, nasopharyngitis, sinusitis, rhinitis, pharyngitis, upper respiratory tract congestion, upper respiratory tract inflammation, viral upper respiratory tract infection, and related terms. 38 0 Pneumonia Pneumonia: pneumonia, COVID-19 pneumonia, lower respiratory tract infection, and related terms including specific types of infection. 20 Includes 1 fatal outcome. 8 Musculoskeletal and connective tissue disorders Musculoskeletal pain Musculoskeletal pain: musculoskeletal pain, arthralgia, back pain, pain in extremity, myalgia, neck pain, bone pain. 38 2.7 Skin and subcutaneous tissue disorders Rash Rash: Rash, dermatitis, toxic skin eruption, and related terms. 28 0 Bruising Bruising: all terms containing bruise, bruising, contusion, or ecchymosis. 26 0.9 Vascular disorders Hemorrhage Hemorrhage: all terms containing hematoma, hemorrhage, hemorrhagic, and related terms indicative of bleeding. 28 4.5 Hypertension 11 5.4 Neoplasms Second primary malignancy Second primary malignancy: includes non-melanoma skin cancer, malignant solid tumors (including bladder, lung, renal, breast, prostate, ovarian, pelvis, and ureter), and malignant melanoma. 22 Includes non-melanoma skin cancer in 13%. 6 Gastrointestinal disorders Diarrhea 18 0.9 Nausea 16 0 Constipation 15 0 Abdominal pain 12 1.8 Respiratory, thoracic, and mediastinal disorders Cough Includes multiple similar adverse reaction terms. 18 0 Dyspnea 13 0 General disorders and administration site conditions Fatigue Fatigue: fatigue, asthenia, and lethargy. 14 0.9 Nervous system disorders Headache 11 1.8 Clinically significant adverse reactions occurring in <10% of BRUKINSA recipients in this cohort included urinary tract infection (8%), edema (7%), atrial fibrillation or flutter (4.5%), and COVID-19 (3.6%). Table 12 summarizes select laboratory abnormalities in this cohort. Table 12: Select Laboratory Abnormalities (≥20%) that Worsened from Baseline in Patients with Previously Untreated CLL/SLL and 17p Deletion in SEQUOIA Laboratory Abnormality The denominator used to calculate the rate varied from 110 to 111 based on the number of patients with a baseline value and at least one post-treatment value. Grading is based on NCI CTCAE criteria. BRUKINSA All Grades (%) Grade 3 or 4 (%) Hematologic abnormalities Neutrophils decreased 42 19 Grade 4, 9%. Hemoglobin decreased 26 3.6 Platelets decreased 23 0.9 Chemistry abnormalities Glucose increased Non-fasting conditions. 52 6 Magnesium increased 31 0 Creatinine increased 27 0.9 ALPINE The safety of BRUKINSA monotherapy was evaluated in patients with previously treated CLL/SLL in a randomized, multicenter, open-label, actively controlled trial [see Clinical Studies (14.4) ] . In ALPINE, 324 patients received BRUKINSA monotherapy, 160 mg orally twice daily and 324 patients received ibrutinib monotherapy, 420 mg orally daily until disease progression or unacceptable toxicity. In ALPINE, the median duration of exposure was 24 months for BRUKINSA. Adverse reactions leading to death in the BRUKINSA arm occurred in 24 (7%) patients. Adverse reactions leading to death that occurred in >1% of patients were pneumonia (2.8%) and COVID-19 infection (1.9%). One hundred and four patients in the BRUKINSA arm (32%) reported ≥1 serious adverse reaction. Serious adverse reactions occurring in ≥5% of patients were pneumonia (10%), COVID-19 (7%), and second primary malignancies (5%). Adverse reactions led to treatment discontinuation in 13% of patients, dose reduction in 11%, and dose interruption in 42%. The leading cause of treatment discontinuation was pneumonia. The leading causes of dose modification (≥5% of all patients) were respiratory infections (COVID-19, pneumonia) and neutropenia. Table 13 summarizes select adverse reactions in ALPINE. Table 13: Adverse Reactions in ≥10% of Patients with Relapsed or Refractory CLL/SLL Who Received BRUKINSA in ALPINE System Organ Class Preferred Term BRUKINSA (N=324) Ibrutinib (N=324) All Grades (%) Grade 3 or 4 (%) All Grades (%) Grade 3 or 4 (%) Infections and infestations Upper respiratory tract infection Upper respiratory tract infection: upper respiratory tract infection, sinusitis, pharyngitis, rhinitis, nasopharyngitis, laryngitis, tonsillitis, and related terms. 27 1.2 22 1.2 Pneumonia Pneumonia: Pneumonia, COVID-19 pneumonia, lower respiratory tract infection, lung infiltration, and related terms including specific types of infection. 18 Includes fatal outcomes: pneumonia (9 patients), COVID-19 (8 patients), and hemorrhage (1 patient). 9 19 Includes fatal outcomes: pneumonia (10 patients), COVID-19 (9 patients), and hemorrhage (2 patients). 11 COVID-19 COVID-19: COVID-19, COVID-19 pneumonia, postacute COVID-19 syndrome, SARS-CoV-2 test positive. 14 7 10 4.6 Musculoskeletal and connective tissue disorders Musculoskeletal pain Musculoskeletal pain: musculoskeletal pain, arthralgia, back pain, pain in extremity, myalgia, neck pain, spinal pain, bone pain, and musculoskeletal discomfort. 26 0.6 28 0.6 Vascular disorders Hemorrhage Hemorrhage: all terms containing hematoma, hemorrhage, hemorrhagic, and related terms indicative of bleeding. 24 2.5 26 3.7 Hypertension Includes multiple similar adverse reaction terms. 19 13 20 13 Skin and subcutaneous tissue disorders Rash Rash: Rash, Dermatitis, and related terms. 20 1.2 21 0.9 Bruising Bruising: all terms containing bruise, bruising, contusion, or ecchymosis. 16 0 14 0 Gastrointestinal disorders Diarrhea 14 1.5 22 0.9 General disorders Fatigue Fatigue: asthenia, fatigue, lethargy. 13 0.9 14 0.9 Respiratory, thoracic, and mediastinal disorders Cough 11 0.3 11 0 Nervous system disorders Dizziness 10 0 7 0 Clinically relevant adverse reactions in <10% of patients who received BRUKINSA included urinary tract infection (9%), supraventricular arrhythmias (9%) including atrial fibrillation or flutter (4.6%), abdominal pain (8%), headache (8%), pruritus (6.2%), constipation (5.9%), and edema (4.6%). Table 14 summarizes select laboratory abnormalities in ALPINE. Table 14: Select Laboratory Abnormalities (≥20%) that Worsened from Baseline in Patients Who Received BRUKINSA in ALPINE Laboratory Abnormality The denominator used to calculate the rate was 321 in the BRUKINSA arm, and varied from 320 to 321 in the ibrutinib arm, based on the number of patients with a baseline value and at least one post-treatment value. Grading is based on NCI CTCAE criteria. BRUKINSA Ibrutinib All Grades (%) Grade 3 or 4 (%) All Grades (%) Grade 3 or 4 (%) Hematologic abnormalities Neutrophils decreased 43 15 33 16 Hemoglobin decreased 28 4 32 3.7 Lymphocytes increased 24 19 26 19 Platelets decreased 22 4 24 3.4 Chemistry abnormalities Glucose increased 52 5 29 2.8 Creatinine increased 26 0 23 0 Phosphate decreased 21 2.5 13 2.2 Calcium decreased 21 0.6 29 0 Follicular Lymphoma The safety of BRUKINSA in combination with obinutuzumab was evaluated in 143 adult patients with relapsed or refractory follicular lymphoma (FL) in study BGB-3111-212 (ROSEWOOD), a randomized, multicenter, open-label trial [see Clinical Studies (14.5) ] . The trial required an absolute neutrophil count ≥1 × 10 9 /L, platelet count ≥50 × 10 9 /L, and CLcr ≥30 mL/min and excluded patients requiring a strong CYP3A inhibitor or inducer. Patients were randomized to receive either BRUKINSA 160 mg twice daily until disease progression or unacceptable toxicity plus obinutuzumab (n=143) or obinutuzumab monotherapy (n=71). Obinutuzumab was dosed at 1,000 mg intravenously on Days 1, 8, and 15 of Cycle 1; on Day 1 of Cycles 2 to 6; and then every 8 weeks for up to 20 doses. At the discretion of the investigator, obinutuzumab was administered intravenously on Day 1 (100 mg) and on Day 2 (900 mg) of Cycle 1 instead of 1,000 mg on Day 1 of Cycle 1. In patients who received BRUKINSA in combination with obinutuzumab, the median age was 63, 49% were female, 63% were White, and 21% were Asian. Most patients (97%) had an ECOG performance status of 0 to 1. The median duration of BRUKINSA treatment was 12 months, with 24% of patients treated for at least 2 years. Serious adverse reactions occurred in 35% of patients who received BRUKINSA in combination with obinutuzumab. Serious adverse reactions in ≥5% of patients included pneumonia (11%) and COVID-19 (10%). Fatal adverse reactions occurred in 4.2% of patients, with the leading cause of death being COVID-19 (2.1%). Adverse reactions led to permanent discontinuation of BRUKINSA in 17% of patients, dose reduction in 9%, and dose interruption in 40%. Adverse reactions leading to permanent discontinuation in ≥2% of patients were pneumonia, COVID-19, and second primary malignancy. The leading causes of BRUKINSA dosage modification (42% of all patients) were pneumonia, COVID-19, thrombocytopenia, and neutropenia. Table 15 summarizes adverse reactions in BGB-3111-212. Table 15: Adverse Reactions in ≥10% of Patients with Relapsed or Refractory FL Who Received BRUKINSA in Study BGB-3111-212 System Organ Class Preferred Term BGB-3111-212 BRUKINSA + Obinutuzumab (N=143) Obinutuzumab (N=71) All Grades (%) Grade 3 or 4 (%) All Grades (%) Grade 3 or 4 (%) General disorders and administration site conditions Fatigue Includes multiple related terms. , Fatigue: Fatigue, asthenia, and lethargy. 27 1.4 25 1.4 Pyrexia 13 0 20 0 Musculoskeletal and connective tissue disorders Musculoskeletal pain , Musculoskeletal pain: Back pain, musculoskeletal pain, musculoskeletal discomfort, noncardiac chest pain, neck pain, pain in extremity, myalgia, spinal pain, bone pain, arthralgia, and related terms. 22 3.5 23 1.4 Vascular disorders Hemorrhage , Hemorrhage: All terms containing hematoma, hemorrhage, hemorrhagic, and related terms indicative of bleeding. 20 1.4 10 1.4 Gastrointestinal disorders Diarrhea 18 2.8 17 1.4 Constipation 13 0 9 0 Abdominal pain 11 2.1 11 0 Infections and infestations Upper respiratory tract infection , Upper respiratory tract infection: Upper respiratory tract infection, sinusitis, pharyngitis, laryngitis, rhinitis, nasopharyngitis, laryngopharyngitis, tonsillitis bacterial, and related terms. 17 2.8 10 0 Pneumonia , Pneumonia: Pneumonia, COVID-19 pneumonia, lung infiltration, lung consolidation, and related terms including specific types of infection. , Includes fatal outcomes: COVID-19 (3 patients), pneumonia (2 patients), dyspnea (1 patient). 15 13 11 7 COVID-19 , 13 9 11 4.2 Herpes virus infection Herpes virus infection: Herpes viral infection, herpes zoster, herpes simplex, herpes simplex reactivation, varicella, and Epstein-Barr viremia. 11 2.1 1.4 0 Urinary tract infection Urinary tract infection: Urinary tract infection, cystitis, pyelonephritis, and related terms. 10 1.4 7 0 Respiratory, thoracic, and mediastinal disorders Cough 14 0 14 0 Dyspnea , 11 2.1 13 0 Skin and subcutaneous tissue disorders Rash , Rash: Rash, erythema, dermatitis, drug eruption, skin reaction, and related terms. 11 0 14 0 Clinically relevant adverse reactions in <10% of patients who received BRUKINSA in combination with obinutuzumab included bruising, edema, pruritus, petechiae, vomiting, headache, arthralgia, hypertension, sepsis, cardiac arrhythmias, renal insufficiency, febrile neutropenia, transaminase elevation, and pneumonitis. Table 16: Select Laboratory Abnormalities (≥20%) that Worsened from Baseline in Patients Who Received BRUKINSA in Study BGB-3111-212 Laboratory Abnormality The denominator used to calculate the rate was 122 in the BRUKINSA + obinutuzumab arm, and varied from 56 to 58 in the obinutuzumab arm, based on the number of patients with a baseline value and at least one post-treatment value. Grading is based on NCI CTCAE criteria. BGB-3111-212 BRUKINSA + Obinutuzumab Obinutuzumab All Grades (%) Grade 3 or 4 (%) All Grades (%) Grade 3 or 4 (%) Hematologic abnormalities Platelets decreased 65 11 43 11 Neutrophils decreased 47 17 42 14 Hemoglobin decreased 31 0.8 23 0 Lymphocytes decreased 30 11 51 25 Chemistry Glucose increased Nonfasting conditions. 53 8 41 9 Alanine aminotransferase increased 23 0 28 0 Phosphate decreased 21 0.8 14 0
Table 3: Adverse Reactions (≥10%) in Patients Receiving BRUKINSA in BGB-3111-206 and BGB-3111-AU-003 Trials| Body System | Adverse Reaction | Percent of Patients (N=118) |
|---|
| All Grades % | Grade 3 or Higher % |
|---|
| Infections and infestations | Upper respiratory tract infectionUpper respiratory tract infection includes upper respiratory tract infection, upper respiratory tract infection viral. | 39 | 0 |
| PneumoniaPneumonia 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. | 15 | 10Includes fatal adverse reaction. |
| Urinary tract infection | 11 | 0.8 |
| Skin and subcutaneous tissue disorders | RashRash includes all related terms containing rash. | 36 | 0 |
| BruisingBruising includes all related terms containing bruise, bruising, contusion, ecchymosis. | 14 | 0 |
| Gastrointestinal disorders | Diarrhea | 23 | 0.8 |
| Constipation | 13 | 0 |
| Vascular disorders | Hypertension | 12 | 3.4 |
| HemorrhageHemorrhage includes all related terms containing hemorrhage, hematoma. | 11 | 3.4 |
| Musculoskeletal and connective tissue disorders | Musculoskeletal painMusculoskeletal pain includes musculoskeletal pain, musculoskeletal discomfort, myalgia, back pain, arthralgia, arthritis. | 14 | 3.4 |
| Respiratory, thoracic, and mediastinal disorders | Cough | 12 | 0 |
Table 4: Selected Laboratory AbnormalitiesBased on laboratory measurements. (>20%) in Patients with MCL in Studies BGB-3111-206 and BGB-3111-AU-003| Laboratory Parameter | Percent of Patients (N=118) |
|---|
| All Grades (%) | Grade 3 or 4 (%) |
|---|
| Hematologic abnormalities |
| Neutrophils decreased | 45 | 20 |
| LymphocytosisAsymptomatic lymphocytosis is a known effect of BTK inhibition. | 41 | 16 |
| Platelets decreased | 40 | 7 |
| Hemoglobin decreased | 27 | 6 |
| Chemistry abnormalities |
| Blood uric acid increased | 29 | 2.6 |
| ALT increased | 28 | 0.9 |
| Bilirubin increased | 24 | 0.9 |
Table 5: Adverse Reactions (≥10%) Occurring in Patients with WM Who Received BRUKINSA in Cohort 1| Body System | Adverse Reaction | BRUKINSA (N=101) | Ibrutinib (N=98) |
|---|
| All Grades (%) | Grade 3 or 4 (%) | All Grades (%) | Grade 3 or 4 (%) |
|---|
| Infections and infestations | Upper respiratory tract infectionUpper respiratory tract infection includes upper respiratory tract infection, laryngitis, nasopharyngitis, sinusitis, rhinitis, viral upper respiratory tract infection, pharyngitis, rhinovirus infection, upper respiratory tract congestion. | 44 | 0 | 40 | 2 |
| PneumoniaPneumonia includes lower respiratory tract infection, lung infiltration, pneumonia, pneumonia aspiration, pneumonia viral. | 12 | 4 | 26 | 10 |
| Urinary tract infection | 11 | 0 | 13 | 2 |
| Gastrointestinal disorders | Diarrhea | 22 | 3 | 34 | 2 |
| Nausea | 18 | 0 | 13 | 1 |
| Constipation | 16 | 0 | 7 | 0 |
| Vomiting | 12 | 0 | 14 | 1 |
| General disorders | FatigueFatigue includes asthenia, fatigue, lethargy. | 31 | 1 | 25 | 1 |
| Pyrexia | 16 | 4 | 13 | 2 |
| Edema peripheral | 12 | 0 | 20 | 0 |
| Skin and subcutaneous tissue disorders | BruisingBruising includes all related terms containing bruise, contusion, or ecchymosis. | 20 | 0 | 34 | 0 |
| RashRash includes all related terms rash, maculo-papular rash, erythema, rash erythematous, drug eruption, dermatitis allergic, dermatitis atopic, rash pruritic, dermatitis, photodermatoses, dermatitis acneiform, stasis dermatitis, vasculitic rash, eyelid rash, urticaria, skin toxicity. | 29 | 0 | 32 | 0 |
| Pruritus | 11 | 1 | 6 | 0 |
| Musculoskeletal and connective tissue disorders | Musculoskeletal painMusculoskeletal pain includes back pain, arthralgia, pain in extremity, musculoskeletal pain, myalgia, bone pain, spinal pain, musculoskeletal chest pain, neck pain, arthritis, musculoskeletal discomfort. | 45 | 9 | 39 | 1 |
| Muscle spasms | 10 | 0 | 28 | 1 |
| Nervous system disorders | Headache | 18 | 1 | 14 | 1 |
| Dizziness | 13 | 1 | 12 | 0 |
| Respiratory, thoracic, and mediastinal disorders | Cough | 16 | 0 | 18 | 0 |
| Dyspnea | 14 | 0 | 7 | 0 |
| Vascular disorders | HemorrhageHemorrhage 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. | 42 | 4 | 43 | 9 |
| Hypertension | 14 | 9 | 19 | 14 |
Table 6: Select Laboratory AbnormalitiesBased on laboratory measurements. (≥20%) that Worsened from Baseline in Patients with WM Who Received BRUKINSA in Cohort 1| Laboratory Abnormality | BRUKINSAThe denominator used to calculate the rate varied from 86 to 101 based on the number of patients with a baseline value and at least one post-treatment value. | Ibrutinib |
|---|
| All Grades (%) | Grade 3 or 4 (%) | All Grades (%) | Grade 3 or 4 (%) |
|---|
| Hematologic abnormalities |
| Neutrophils decreased | 50 | 24 | 34 | 9 |
| Platelets decreased | 35 | 8 | 39 | 5 |
| Hemoglobin decreased | 20 | 7 | 20 | 7 |
| Chemistry abnormalities |
| Glucose increased | 45 | 2.3 | 33 | 2.3 |
| Creatinine increased | 31 | 1 | 21 | 1 |
| Calcium decreased | 27 | 2 | 26 | 0 |
| Potassium increased | 24 | 2 | 12 | 0 |
| Phosphate decreased | 20 | 3.1 | 18 | 0 |
| Urate increased | 16 | 3.2 | 34 | 6 |
| Bilirubin increased | 12 | 1 | 33 | 1 |
Table 7: Adverse Reactions Occurring in ≥10% Patients with MZL Who Received BRUKINSA| Body System | Adverse Reaction | BRUKINSA (N=88) |
|---|
| All Grades (%) | Grade 3 or 4 (%) |
|---|
| Infections and infestations | Upper respiratory tract infectionUpper respiratory tract infection includes upper respiratory tract infection, nasopharyngitis, sinusitis, tonsillitis, rhinitis, viral upper respiratory tract infection. | 26 | 3.4 |
| Urinary tract infectionUrinary tract infection includes urinary tract infection, cystitis, Escherichia urinary tract infection, pyelonephritis, cystitis. | 11 | 2.3 |
| PneumoniaPneumonia includes COVID-19 pneumonia, pneumonia, bronchopulmonary aspergillosis, lower respiratory tract infection, organizing pneumonia.,Includes 2 fatalities from COVID-19 pneumonia. | 10 | 6 |
| Gastrointestinal disorders | DiarrheaDiarrhea includes diarrhea and diarrhea hemorrhagic. | 25 | 3.4 |
| Abdominal painAbdominal pain includes abdominal pain, abdominal pain upper, abdominal discomfort. | 14 | 2.3 |
| Nausea | 13 | 0 |
| Skin and subcutaneous tissue disorders | BruisingBruising includes contusion, ecchymosis, increased tendency to bruise, post procedural contusion. | 24 | 0 |
| RashRash 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. | 21 | 0 |
| Musculoskeletal and connective tissue disorders | Musculoskeletal painMusculoskeletal pain includes back pain, arthralgia, musculoskeletal pain, myalgia, pain in extremity, musculoskeletal chest pain, bone pain, musculoskeletal discomfort, neck pain. | 27 | 1.1 |
| Vascular disorders | HemorrhageHemorrhage 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. | 23 | 1.1 |
| General disorders | FatigueFatigue includes fatigue, lethargy, asthenia. | 21 | 2.3 |
| Respiratory, thoracic, and mediastinal disorders | CoughCough includes cough and productive cough. | 10 | 0 |
Table 8: Select Laboratory Abnormalities (≥20%) that Worsened from Baseline in Patients with MZL| Laboratory AbnormalityThe denominator used to calculate the rate varied from 87 to 88 based on the number of patients with a baseline value and at least one post-treatment value. | BRUKINSA |
|---|
| All Grades (%) | Grade 3 or 4 (%) |
|---|
| Hematologic abnormalities |
| Neutrophils decreased | 43 | 15 |
| Platelets decreased | 33 | 10 |
| Lymphocytes decreased | 32 | 8 |
| Hemoglobin decreased | 26 | 6 |
| Chemistry abnormalities |
| Glucose increased | 54 | 4.6 |
| Creatinine increased | 34 | 1.1 |
| Phosphate decreased | 27 | 2.3 |
| Calcium decreased | 23 | 0 |
| ALT increased | 22 | 1.1 |
Table 9: Adverse Reactions in ≥10% Patients with Previously Untreated CLL/SLL without 17p Deletion in SEQUOIA | CLL/SLL without 17p deletion |
|---|
| BRUKINSA (N=240) | BR (N=227) |
|---|
| System Organ Class Preferred Term | All Grades (%) | Grade 3 or 4 (%) | All Grades (%) | Grade 3 or 4 (%) |
|---|
| Musculoskeletal and connective tissue disorders |
| Musculoskeletal painMusculoskeletal pain: musculoskeletal pain, arthralgia, back pain, pain in extremity, myalgia, neck pain, spinal pain, musculoskeletal discomfort, bone pain. | 33 | 1.7 | 17 | 0.4 |
| Infections and infestations |
| Upper respiratory tract infectionUpper respiratory tract infection: upper respiratory tract infection, nasopharyngitis, sinusitis, rhinitis, pharyngitis, upper respiratory tract congestion, laryngitis, tonsillitis and upper respiratory tract inflammation, and related terms. | 28 | 1.3 | 15 | 0.9 |
| PneumoniaPneumonia: pneumonia, COVID-19 pneumonia, lower respiratory tract infection, lung infiltration, and related terms including specific types of infection. | 13Includes 3 fatal outcomes. | 5 | 8Includes 2 fatal outcomes. | 4 |
| Vascular disorders |
| HemorrhageHemorrhage: all terms containing hematoma, hemorrhage, hemorrhagic, and related terms indicative of bleeding. | 27 | 4 | 4 | 0.4 |
| HypertensionIncludes multiple similar adverse reaction terms. | 14 | 7 | 5 | 2.6 |
| Skin and subcutaneous tissue disorders |
| RashRash: Rash, dermatitis, drug eruption, and related terms. | 24 | 1.3 | 30 | 5 |
| Bruising | 24 | 0 | 2.6 | 0 |
| Respiratory, thoracic, and mediastinal disorders |
| Cough | 15 | 0 | 10 | 0 |
| Gastrointestinal disorders |
| Diarrhea | 14 | 0.8 | 12 | 0.9 |
| Constipation | 10 | 0.4 | 18 | 0 |
| Nausea | 10 | 0 | 33 | 1.3 |
| General disorders |
| FatigueFatigue: fatigue, asthenia, and lethargy. | 14 | 1.3 | 21 | 1.8 |
| Neoplasms |
| Second primary malignancySecond primary malignancy: includes non-melanoma skin cancer, malignant solid tumors (including lung, renal, genitourinary, breast, ovarian, and rectal), and chronic myeloid leukemia. | 13 | 6 | 1.3 | 0.4 |
| Nervous system disorders |
| Headache | 12 | 0 | 8 | 0 |
| Dizziness Dizziness: dizziness and vertigo. | 11 | 0.8 | 5 | 0 |
Table 10: Select Laboratory Abnormalities (≥20%) that Worsened from Baseline in Patients with Previously Untreated CLL/SLL without 17p Deletion in SEQUOIA| Laboratory AbnormalityThe denominator used to calculate the rate was 239 in the BRUKINSA arm and 227 in the BR arm, based on the number of patients with a baseline value and at least one post-treatment value. Grading is based on NCI CTCAE criteria. | BRUKINSA | BR |
|---|
| All Grades (%) | Grade 3 or 4 (%) | All Grades (%) | Grade 3 or 4 (%) |
|---|
| Hematologic abnormalities |
| Neutrophils decreased | 37 | 15 | 80 | 53 |
| Hemoglobin decreased | 29 | 2.5 | 66 | 8 |
| Platelets decreased | 27 | 1.7 | 61 | 11 |
| Leukocytes increased | 21Lymphocytes increased in 15%. | 21 | 0.4 | 0.4 |
| Chemistry abnormalities |
| Glucose increasedNonfasting conditions. | 55 | 7 | 67 | 10 |
| Creatinine increased | 22 | 0.8 | 18 | 0.4 |
| Magnesium increased | 22 | 0 | 14 | 0.4 |
| Alanine aminotransferase increased | 21 | 2.1 | 23 | 2.2 |
Table 11: Adverse Reactions in ≥10% of Patients with Previously Untreated CLL/SLL and 17p Deletion in SEQUOIA | CLL/SLL with 17p Deletion |
|---|
| BRUKINSA (N=111) |
|---|
| System Organ Class Preferred Term | All Grades (%) | Grade 3 or 4 (%) |
|---|
| Infections and infestations |
| Upper respiratory tract infectionUpper respiratory tract infection: upper respiratory tract infection, nasopharyngitis, sinusitis, rhinitis, pharyngitis, upper respiratory tract congestion, upper respiratory tract inflammation, viral upper respiratory tract infection, and related terms. | 38 | 0 |
| PneumoniaPneumonia: pneumonia, COVID-19 pneumonia, lower respiratory tract infection, and related terms including specific types of infection. | 20Includes 1 fatal outcome. | 8 |
| Musculoskeletal and connective tissue disorders |
| Musculoskeletal painMusculoskeletal pain: musculoskeletal pain, arthralgia, back pain, pain in extremity, myalgia, neck pain, bone pain. | 38 | 2.7 |
| Skin and subcutaneous tissue disorders |
| RashRash: Rash, dermatitis, toxic skin eruption, and related terms. | 28 | 0 |
| BruisingBruising: all terms containing bruise, bruising, contusion, or ecchymosis. | 26 | 0.9 |
| Vascular disorders |
| HemorrhageHemorrhage: all terms containing hematoma, hemorrhage, hemorrhagic, and related terms indicative of bleeding. | 28 | 4.5 |
| Hypertension | 11 | 5.4 |
| Neoplasms |
| Second primary malignancySecond primary malignancy: includes non-melanoma skin cancer, malignant solid tumors (including bladder, lung, renal, breast, prostate, ovarian, pelvis, and ureter), and malignant melanoma. | 22Includes non-melanoma skin cancer in 13%. | 6 |
| Gastrointestinal disorders |
| Diarrhea | 18 | 0.9 |
| Nausea | 16 | 0 |
| Constipation | 15 | 0 |
| Abdominal pain | 12 | 1.8 |
| Respiratory, thoracic, and mediastinal disorders |
| CoughIncludes multiple similar adverse reaction terms. | 18 | 0 |
| Dyspnea | 13 | 0 |
| General disorders and administration site conditions |
| FatigueFatigue: fatigue, asthenia, and lethargy. | 14 | 0.9 |
| Nervous system disorders |
| Headache | 11 | 1.8 |
Table 12: Select Laboratory Abnormalities (≥20%) that Worsened from Baseline in Patients with Previously Untreated CLL/SLL and 17p Deletion in SEQUOIA| Laboratory AbnormalityThe denominator used to calculate the rate varied from 110 to 111 based on the number of patients with a baseline value and at least one post-treatment value. Grading is based on NCI CTCAE criteria. | BRUKINSA |
|---|
| All Grades (%) | Grade 3 or 4 (%) |
|---|
| Hematologic abnormalities |
| Neutrophils decreased | 42 | 19Grade 4, 9%. |
| Hemoglobin decreased | 26 | 3.6 |
| Platelets decreased | 23 | 0.9 |
| Chemistry abnormalities |
| Glucose increasedNon-fasting conditions. | 52 | 6 |
| Magnesium increased | 31 | 0 |
| Creatinine increased | 27 | 0.9 |
Table 13: Adverse Reactions in ≥10% of Patients with Relapsed or Refractory CLL/SLL Who Received BRUKINSA in ALPINE| System Organ Class Preferred Term | BRUKINSA (N=324) | Ibrutinib (N=324) |
|---|
| All Grades (%) | Grade 3 or 4 (%) | All Grades (%) | Grade 3 or 4 (%) |
|---|
| Infections and infestations |
| Upper respiratory tract infectionUpper respiratory tract infection: upper respiratory tract infection, sinusitis, pharyngitis, rhinitis, nasopharyngitis, laryngitis, tonsillitis, and related terms. | 27 | 1.2 | 22 | 1.2 |
| PneumoniaPneumonia: Pneumonia, COVID-19 pneumonia, lower respiratory tract infection, lung infiltration, and related terms including specific types of infection. | 18Includes fatal outcomes: pneumonia (9 patients), COVID-19 (8 patients), and hemorrhage (1 patient). | 9 | 19Includes fatal outcomes: pneumonia (10 patients), COVID-19 (9 patients), and hemorrhage (2 patients). | 11 |
| COVID-19COVID-19: COVID-19, COVID-19 pneumonia, postacute COVID-19 syndrome, SARS-CoV-2 test positive. | 14 | 7 | 10 | 4.6 |
| Musculoskeletal and connective tissue disorders |
| Musculoskeletal painMusculoskeletal pain: musculoskeletal pain, arthralgia, back pain, pain in extremity, myalgia, neck pain, spinal pain, bone pain, and musculoskeletal discomfort. | 26 | 0.6 | 28 | 0.6 |
| Vascular disorders |
| HemorrhageHemorrhage: all terms containing hematoma, hemorrhage, hemorrhagic, and related terms indicative of bleeding. | 24 | 2.5 | 26 | 3.7 |
| HypertensionIncludes multiple similar adverse reaction terms. | 19 | 13 | 20 | 13 |
| Skin and subcutaneous tissue disorders |
| RashRash: Rash, Dermatitis, and related terms. | 20 | 1.2 | 21 | 0.9 |
| BruisingBruising: all terms containing bruise, bruising, contusion, or ecchymosis. | 16 | 0 | 14 | 0 |
| Gastrointestinal disorders |
| Diarrhea | 14 | 1.5 | 22 | 0.9 |
| General disorders |
| FatigueFatigue: asthenia, fatigue, lethargy. | 13 | 0.9 | 14 | 0.9 |
| Respiratory, thoracic, and mediastinal disorders |
| Cough | 11 | 0.3 | 11 | 0 |
| Nervous system disorders |
| Dizziness | 10 | 0 | 7 | 0 |
Table 14: Select Laboratory Abnormalities (≥20%) that Worsened from Baseline in Patients Who Received BRUKINSA in ALPINE| Laboratory AbnormalityThe denominator used to calculate the rate was 321 in the BRUKINSA arm, and varied from 320 to 321 in the ibrutinib arm, based on the number of patients with a baseline value and at least one post-treatment value. Grading is based on NCI CTCAE criteria. | BRUKINSA | Ibrutinib |
|---|
| All Grades (%) | Grade 3 or 4 (%) | All Grades (%) | Grade 3 or 4 (%) |
|---|
| Hematologic abnormalities |
| Neutrophils decreased | 43 | 15 | 33 | 16 |
| Hemoglobin decreased | 28 | 4 | 32 | 3.7 |
| Lymphocytes increased | 24 | 19 | 26 | 19 |
| Platelets decreased | 22 | 4 | 24 | 3.4 |
| Chemistry abnormalities |
| Glucose increased | 52 | 5 | 29 | 2.8 |
| Creatinine increased | 26 | 0 | 23 | 0 |
| Phosphate decreased | 21 | 2.5 | 13 | 2.2 |
| Calcium decreased | 21 | 0.6 | 29 | 0 |
Table 15: Adverse Reactions in ≥10% of Patients with Relapsed or Refractory FL Who Received BRUKINSA in Study BGB-3111-212| System Organ Class Preferred Term | BGB-3111-212 |
|---|
| BRUKINSA + Obinutuzumab (N=143) | Obinutuzumab (N=71) |
|---|
| All Grades (%) | Grade 3 or 4 (%) | All Grades (%) | Grade 3 or 4 (%) |
|---|
| General disorders and administration site conditions |
| FatigueIncludes multiple related terms.,Fatigue: Fatigue, asthenia, and lethargy. | 27 | 1.4 | 25 | 1.4 |
| Pyrexia | 13 | 0 | 20 | 0 |
| Musculoskeletal and connective tissue disorders |
| Musculoskeletal pain,Musculoskeletal pain: Back pain, musculoskeletal pain, musculoskeletal discomfort, noncardiac chest pain, neck pain, pain in extremity, myalgia, spinal pain, bone pain, arthralgia, and related terms. | 22 | 3.5 | 23 | 1.4 |
| Vascular disorders | | | | |
| Hemorrhage,Hemorrhage: All terms containing hematoma, hemorrhage, hemorrhagic, and related terms indicative of bleeding. | 20 | 1.4 | 10 | 1.4 |
| Gastrointestinal disorders |
| Diarrhea | 18 | 2.8 | 17 | 1.4 |
| Constipation | 13 | 0 | 9 | 0 |
| Abdominal pain | 11 | 2.1 | 11 | 0 |
| Infections and infestations |
| Upper respiratory tract infection,Upper respiratory tract infection: Upper respiratory tract infection, sinusitis, pharyngitis, laryngitis, rhinitis, nasopharyngitis, laryngopharyngitis, tonsillitis bacterial, and related terms. | 17 | 2.8 | 10 | 0 |
| Pneumonia,Pneumonia: Pneumonia, COVID-19 pneumonia, lung infiltration, lung consolidation, and related terms including specific types of infection.,Includes fatal outcomes: COVID-19 (3 patients), pneumonia (2 patients), dyspnea (1 patient). | 15 | 13 | 11 | 7 |
| COVID-19, | 13 | 9 | 11 | 4.2 |
| Herpes virus infectionHerpes virus infection: Herpes viral infection, herpes zoster, herpes simplex, herpes simplex reactivation, varicella, and Epstein-Barr viremia. | 11 | 2.1 | 1.4 | 0 |
| Urinary tract infectionUrinary tract infection: Urinary tract infection, cystitis, pyelonephritis, and related terms. | 10 | 1.4 | 7 | 0 |
| Respiratory, thoracic, and mediastinal disorders | | | |
| Cough | 14 | 0 | 14 | 0 |
| Dyspnea, | 11 | 2.1 | 13 | 0 |
| Skin and subcutaneous tissue disorders |
| Rash,Rash: Rash, erythema, dermatitis, drug eruption, skin reaction, and related terms. | 11 | 0 | 14 | 0 |
Table 16: Select Laboratory Abnormalities (≥20%) that Worsened from Baseline in Patients Who Received BRUKINSA in Study BGB-3111-212| Laboratory AbnormalityThe denominator used to calculate the rate was 122 in the BRUKINSA + obinutuzumab arm, and varied from 56 to 58 in the obinutuzumab arm, based on the number of patients with a baseline value and at least one post-treatment value. Grading is based on NCI CTCAE criteria. | BGB-3111-212 |
|---|
| BRUKINSA + Obinutuzumab | Obinutuzumab |
|---|
| All Grades (%) | Grade 3 or 4 (%) | All Grades (%) | Grade 3 or 4 (%) |
|---|
| Hematologic abnormalities |
| Platelets decreased | 65 | 11 | 43 | 11 |
| Neutrophils decreased | 47 | 17 | 42 | 14 |
| Hemoglobin decreased | 31 | 0.8 | 23 | 0 |
| Lymphocytes decreased | 30 | 11 | 51 | 25 |
| Chemistry | |
| Glucose increasedNonfasting conditions. | 53 | 8 | 41 | 9 |
| Alanine aminotransferase increased | 23 | 0 | 28 | 0 |
| Phosphate decreased | 21 | 0.8 | 14 | 0 |
BRUKINSA Drug Interactions
Information about and practical guidance on preventing clinically significant drug/drug and drug/food interactions that may occur in people taking the drug.
7 DRUG INTERACTIONS CYP3A Inhibitors: Modify BRUKINSA dose with moderate or strong CYP3A inhibitors as described. ( 2.3 , 7.1 ) CYP3A Inducers: Avoid coadministration with strong or moderate CYP3A inducers. Dose adjustment may be recommended with moderate CYP3A inducers. ( 2.3 , 7.1 ) 7.1 Effect of Other Drugs on BRUKINSA Table 17: Drug Interactions that Affect Zanubrutinib Moderate and Strong CYP3A Inhibitors Clinical Impact Coadministration with a moderate or strong CYP3A inhibitor increases zanubrutinib C max and AUC [see Clinical Pharmacology (12.3) ] which may increase the risk of BRUKINSA toxicities. Prevention or management Reduce BRUKINSA dosage when coadministered with moderate or strong CYP3A inhibitors [see Dosage and Administration (2.3) ] . Moderate and Strong CYP3A Inducers Clinical Impact Coadministration with a moderate or strong CYP3A inducer decreases zanubrutinib C max and AUC [see Clinical Pharmacology (12.3) ] which may reduce BRUKINSA efficacy. Prevention or management Avoid coadministration of BRUKINSA with strong CYP3A inducers [see Dosage and Administration (2.3) ] . Avoid coadministration of BRUKINSA with moderate CYP3A inducers [see Dosage and Administration (2.3) ] . If these inducers cannot be avoided, increase BRUKINSA dosage to 320 mg twice daily [see Dosage and Administration (2.3) ] .
Table 17: Drug Interactions that Affect Zanubrutinib| Moderate and Strong CYP3A Inhibitors |
| Clinical Impact | - Coadministration with a 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 management | - Reduce BRUKINSA dosage when coadministered with moderate or strong CYP3A inhibitors [see Dosage and Administration (2.3)].
|
| Moderate and Strong CYP3A Inducers |
| Clinical Impact | - Coadministration with a moderate or strong CYP3A inducer decreases zanubrutinib Cmax and AUC [see Clinical Pharmacology (12.3)] which may reduce BRUKINSA efficacy.
|
| Prevention or management | - Avoid coadministration of BRUKINSA with strong CYP3A inducers [see Dosage and Administration (2.3)].
- Avoid coadministration of BRUKINSA with moderate CYP3A inducers [see Dosage and Administration (2.3)]. If these inducers cannot be avoided, increase BRUKINSA dosage to 320 mg twice daily [see Dosage and Administration (2.3)].
|
Clinical pharmacology
Information about the clinical pharmacology and actions of the drug in humans.
12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Zanubrutinib is a small-molecule inhibitor of Bruton's tyrosine kinase (BTK). Zanubrutinib forms a covalent bond with a cysteine residue in the BTK active site, leading to inhibition of BTK activity. BTK is a 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 Nodes The median steady-state BTK occupancy in peripheral blood mononuclear cells was maintained at 100% over 24 hours at a 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 Electrophysiology At 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 (C max ) and area under the plasma drug concentration over time curve (AUC) increase proportionally over a dosage range from 40 mg to 320 mg (0.13 to 1 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%) ng∙h/mL following 160 mg twice daily and 1,917 (59%) ng∙h/mL following 320 mg once daily. The geometric mean (%CV) zanubrutinib steady-state C max is 295 (55%) ng/mL following 160 mg twice daily and 537 (55%) ng/mL following 320 mg once daily. Absorption The median t max of zanubrutinib is 2 hours. Effect of Food No clinically significant differences in zanubrutinib AUC or C max were observed following administration of a high-fat meal (approximately 1,000 calories with 50% of total caloric content from fat) in healthy subjects. Distribution The 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. Elimination The mean half-life (t ½ ) of zanubrutinib is approximately 2 to 4 hours following a 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. Metabolism Zanubrutinib is primarily metabolized by cytochrome P450(CYP)3A. Excretion Following a 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 Populations No clinically significant differences in the pharmacokinetics of zanubrutinib were observed based on age (19 to 90 years), sex, race (Asian, White, and Other), body weight (36 to 144 kg), or mild, moderate or severe renal impairment (CLcr ≥15 mL/min as estimated by Cockcroft-Gault). The effect of dialysis on zanubrutinib pharmacokinetics is unknown. Hepatic Impairment The 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 : Coadministration of multiple doses of CYP3A inhibitors increases zanubrutinib C max and AUC (Table 18). Table 18: Observed or Predicted Increase in Zanubrutinib Exposure After Coadministration of CYP3A Inhibitors Coadministered CYP3A Inhibitor Increase in Zanubrutinib C max Increase in Zanubrutinib AUC Observed Itraconazole (200 mg once daily) The assessment was conducted in healthy subjects with a single dose of zanubrutinib 20 mg. 157% 278% Fluconazole (400 mg once daily) The assessment was conducted in patients with B-cell lymphoma administered multiple doses of zanubrutinib at the respective recommended zanubrutinib dosages in Table 1. 81% 88% Diltiazem (180 mg once daily) 62% 62% Voriconazole (200 mg twice daily) 229% 230% Clarithromycin (250 mg twice daily) 101% 92% Predicted Posaconazole suspension (100 mg once daily) The predicted values were based on simulations with patients administered multiple doses of zanubrutinib at the respective recommended dosages in Table 1. 169% 180% Posaconazole suspension (100 mg twice daily) 207% 279% Posaconazole delayed-release tablets (300 mg once daily) 232% 407% Posaconazole intravenously (300 mg once daily) 205% 333% Itraconazole (200 mg once daily) 273% 320% CYP3A Inducers : Coadministration of multiple doses of rifampin (strong CYP3A inducer) decreased the zanubrutinib C max by 92% and AUC by 93%. Coadministration of multiple doses of rifabutin (moderate CYP3A inducer) decreased the zanubrutinib C max by 48% and AUC by 44%. Coadministration of multiple doses of efavirenz (moderate CYP3A inducer) is predicted to decrease zanubrutinib C max by 58% and AUC by 60%. CYP3A Substrates : Coadministration of multiple doses of zanubrutinib decreased midazolam (CYP3A substrate) C max by 30% and AUC by 47%. CYP2C19 Substrates : Coadministration of multiple doses of zanubrutinib decreased omeprazole (CYP2C19 substrate) C max by 20% and AUC by 36%. Other CYP Substrates : No clinically significant differences were observed with warfarin (CYP2C9 substrate) pharmacokinetics when coadministered with zanubrutinib. Transporter Systems : Coadministration of multiple doses of zanubrutinib increased digoxin (P-gp substrate) C max by 34% and AUC by 11%. No clinically significant differences in the pharmacokinetics of rosuvastatin (BCRP substrate) were observed when coadministered with zanubrutinib. Gastric Acid Reducing Agents : No clinically significant differences in zanubrutinib pharmacokinetics were observed when coadministered 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 a substrate of P-gp. Zanubrutinib is not a substrate or inhibitor of OAT1, OAT3, OCT2, OATP1B1, or OATP1B3.
Table 18: Observed or Predicted Increase in Zanubrutinib Exposure After Coadministration of CYP3A Inhibitors| Coadministered CYP3A Inhibitor | Increase in Zanubrutinib Cmax | Increase in Zanubrutinib AUC |
|---|
| Observed |
| Itraconazole (200 mg once daily)The assessment was conducted in healthy subjects with a single dose of zanubrutinib 20 mg. | 157% | 278% |
| Fluconazole (400 mg once daily)The assessment was conducted in patients with B-cell lymphoma administered multiple doses of zanubrutinib at the respective recommended zanubrutinib dosages in Table 1. | 81% | 88% |
| Diltiazem (180 mg once daily) | 62% | 62% |
| Voriconazole (200 mg twice daily) | 229% | 230% |
| Clarithromycin (250 mg twice daily) | 101% | 92% |
| Predicted |
| Posaconazole suspension (100 mg once daily)The predicted values were based on simulations with patients administered multiple doses of zanubrutinib at the respective recommended dosages in Table 1. | 169% | 180% |
| Posaconazole suspension (100 mg twice daily) | 207% | 279% |
| Posaconazole delayed-release tablets (300 mg once daily) | 232% | 407% |
| Posaconazole intravenously (300 mg once daily) | 205% | 333% |
| Itraconazole (200 mg once daily) | 273% | 320% |
Mechanism of action
Information about the established mechanism(s) of the drugÕs action in humans at various levels (for example receptor, membrane, tissue, organ, whole body). If the mechanism of action is not known, this field contains a statement about the lack of information.
12.1 Mechanism of Action Zanubrutinib is a small-molecule inhibitor of Bruton's tyrosine kinase (BTK). Zanubrutinib forms a covalent bond with a cysteine residue in the BTK active site, leading to inhibition of BTK activity. BTK is a 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.
Pharmacodynamics
Information about any biochemical or physiologic pharmacologic effects of the drug or active metabolites related to the drugÕs clinical effect in preventing, diagnosing, mitigating, curing, or treating disease, or those related to adverse effects or toxicity.
12.2 Pharmacodynamics BTK Occupancy in PBMCs and Lymph Nodes The median steady-state BTK occupancy in peripheral blood mononuclear cells was maintained at 100% over 24 hours at a 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 Electrophysiology At 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
Information about the clinically significant pharmacokinetics of a drug or active metabolites, for instance pertinent absorption, distribution, metabolism, and excretion parameters.
12.3 Pharmacokinetics Zanubrutinib maximum plasma concentration (C max ) and area under the plasma drug concentration over time curve (AUC) increase proportionally over a dosage range from 40 mg to 320 mg (0.13 to 1 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%) ng∙h/mL following 160 mg twice daily and 1,917 (59%) ng∙h/mL following 320 mg once daily. The geometric mean (%CV) zanubrutinib steady-state C max is 295 (55%) ng/mL following 160 mg twice daily and 537 (55%) ng/mL following 320 mg once daily. Absorption The median t max of zanubrutinib is 2 hours. Effect of Food No clinically significant differences in zanubrutinib AUC or C max were observed following administration of a high-fat meal (approximately 1,000 calories with 50% of total caloric content from fat) in healthy subjects. Distribution The 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. Elimination The mean half-life (t ½ ) of zanubrutinib is approximately 2 to 4 hours following a 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. Metabolism Zanubrutinib is primarily metabolized by cytochrome P450(CYP)3A. Excretion Following a 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 Populations No clinically significant differences in the pharmacokinetics of zanubrutinib were observed based on age (19 to 90 years), sex, race (Asian, White, and Other), body weight (36 to 144 kg), or mild, moderate or severe renal impairment (CLcr ≥15 mL/min as estimated by Cockcroft-Gault). The effect of dialysis on zanubrutinib pharmacokinetics is unknown. Hepatic Impairment The 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 : Coadministration of multiple doses of CYP3A inhibitors increases zanubrutinib C max and AUC (Table 18). Table 18: Observed or Predicted Increase in Zanubrutinib Exposure After Coadministration of CYP3A Inhibitors Coadministered CYP3A Inhibitor Increase in Zanubrutinib C max Increase in Zanubrutinib AUC Observed Itraconazole (200 mg once daily) The assessment was conducted in healthy subjects with a single dose of zanubrutinib 20 mg. 157% 278% Fluconazole (400 mg once daily) The assessment was conducted in patients with B-cell lymphoma administered multiple doses of zanubrutinib at the respective recommended zanubrutinib dosages in Table 1. 81% 88% Diltiazem (180 mg once daily) 62% 62% Voriconazole (200 mg twice daily) 229% 230% Clarithromycin (250 mg twice daily) 101% 92% Predicted Posaconazole suspension (100 mg once daily) The predicted values were based on simulations with patients administered multiple doses of zanubrutinib at the respective recommended dosages in Table 1. 169% 180% Posaconazole suspension (100 mg twice daily) 207% 279% Posaconazole delayed-release tablets (300 mg once daily) 232% 407% Posaconazole intravenously (300 mg once daily) 205% 333% Itraconazole (200 mg once daily) 273% 320% CYP3A Inducers : Coadministration of multiple doses of rifampin (strong CYP3A inducer) decreased the zanubrutinib C max by 92% and AUC by 93%. Coadministration of multiple doses of rifabutin (moderate CYP3A inducer) decreased the zanubrutinib C max by 48% and AUC by 44%. Coadministration of multiple doses of efavirenz (moderate CYP3A inducer) is predicted to decrease zanubrutinib C max by 58% and AUC by 60%. CYP3A Substrates : Coadministration of multiple doses of zanubrutinib decreased midazolam (CYP3A substrate) C max by 30% and AUC by 47%. CYP2C19 Substrates : Coadministration of multiple doses of zanubrutinib decreased omeprazole (CYP2C19 substrate) C max by 20% and AUC by 36%. Other CYP Substrates : No clinically significant differences were observed with warfarin (CYP2C9 substrate) pharmacokinetics when coadministered with zanubrutinib. Transporter Systems : Coadministration of multiple doses of zanubrutinib increased digoxin (P-gp substrate) C max by 34% and AUC by 11%. No clinically significant differences in the pharmacokinetics of rosuvastatin (BCRP substrate) were observed when coadministered with zanubrutinib. Gastric Acid Reducing Agents : No clinically significant differences in zanubrutinib pharmacokinetics were observed when coadministered 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 a substrate of P-gp. Zanubrutinib is not a substrate or inhibitor of OAT1, OAT3, OCT2, OATP1B1, or OATP1B3.
Table 18: Observed or Predicted Increase in Zanubrutinib Exposure After Coadministration of CYP3A Inhibitors| Coadministered CYP3A Inhibitor | Increase in Zanubrutinib Cmax | Increase in Zanubrutinib AUC |
|---|
| Observed |
| Itraconazole (200 mg once daily)The assessment was conducted in healthy subjects with a single dose of zanubrutinib 20 mg. | 157% | 278% |
| Fluconazole (400 mg once daily)The assessment was conducted in patients with B-cell lymphoma administered multiple doses of zanubrutinib at the respective recommended zanubrutinib dosages in Table 1. | 81% | 88% |
| Diltiazem (180 mg once daily) | 62% | 62% |
| Voriconazole (200 mg twice daily) | 229% | 230% |
| Clarithromycin (250 mg twice daily) | 101% | 92% |
| Predicted |
| Posaconazole suspension (100 mg once daily)The predicted values were based on simulations with patients administered multiple doses of zanubrutinib at the respective recommended dosages in Table 1. | 169% | 180% |
| Posaconazole suspension (100 mg twice daily) | 207% | 279% |
| Posaconazole delayed-release tablets (300 mg once daily) | 232% | 407% |
| Posaconazole intravenously (300 mg once daily) | 205% | 333% |
| Itraconazole (200 mg once daily) | 273% | 320% |
Contraindications
Information about situations in which the drug product is contraindicated or should not be used because the risk of use clearly outweighs any possible benefit, including the type and nature of reactions that have been reported.
4 CONTRAINDICATIONS None. None. ( 4 )
Description
General information about the drug product, including the proprietary and established name of the drug, the type of dosage form and route of administration to which the label applies, qualitative and quantitative ingredient information, the pharmacologic or therapeutic class of the drug, and the chemical name and structural formula of the drug.
11 DESCRIPTION BRUKINSA (zanubrutinib) is a kinase inhibitor. The empirical formula of zanubrutinib is C 27 H 29 N 5 O 3 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 a white to off-white powder, with a 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 and administration
Information about the drug product’s dosage and administration recommendations, including starting dose, dose range, titration regimens, and any other clinically sigificant information that affects dosing recommendations.
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 ) 2.1 Recommended Dosage The recommended dosage of BRUKINSA for monotherapy or in combination with obinutuzumab 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 a dose of BRUKINSA is missed, it should be taken as soon as possible on the same day with a return to the normal schedule the following day. 2.2 Dosage 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) ] . 2.3 Dosage Modifications for Drug Interactions Recommended dosage modifications of BRUKINSA for drug interactions are provided in Table 1 [see Drug Interactions (7.1) ] . Table 1: Dosage Modifications for Use with CYP3A Inhibitors or Inducers Coadministered Drug Recommended BRUKINSA Dosage (Starting Dose: 160 mg twice daily or 320 mg once daily) Clarithromycin 250 mg twice daily Since clarithromycin 250 mg twice daily acts as a moderate CYP3A inhibitor, it is recommended that patients be administered clarithromycin 250 mg twice daily with 80 mg BRUKINSA twice daily [see Clinical Pharmacology (12.3) ] . 80 mg twice daily Modify or interrupt zanubrutinib dose as recommended for adverse reactions [see Dosage and Administration (2.4) ] . Clarithromycin 500 mg twice daily 80 mg once daily Posaconazole suspension 100 mg once daily 80 mg twice daily Posaconazole suspension dosage higher than 100 mg once daily Posaconazole delayed-release tablets 300 mg once daily Posaconazole intravenous 300 mg once daily 80 mg once daily Other strong CYP3A inhibitor 80 mg once daily Moderate CYP3A inhibitor 80 mg twice daily Strong CYP3A inducer Avoid concomitant use. Moderate CYP3A inducer Avoid concomitant use. If these inducers cannot be avoided, increase BRUKINSA dose to 320 mg twice daily. After discontinuation of a CYP3A inhibitor or moderate CYP3A inducer, resume previous dose of BRUKINSA [see Dosage and Administration (2.1 , 2.2) and Drug Interactions (7.1) ] . 2.4 Dosage Modifications for Adverse Reactions Recommended dosage modifications of BRUKINSA for Grade 3 or higher adverse reactions are provided in Table 2. Table 2: Recommended Dosage Modifications for Adverse Reaction Adverse Reaction Adverse Reaction Occurrence Dosage Modification (Starting Dose: 160 mg twice daily or 320 mg once daily) Hematological toxicities [see Warnings and Precautions (5.3) ] Grade 3 or Grade 4 febrile neutropenia Platelet count decreased to 25,000-50,000/mm 3 with significant bleeding Neutrophil count decreased to <500/mm 3 (lasting more than 10 consecutive days) Platelet count decreased to <25,000/mm 3 (lasting more than 10 consecutive days) First Interrupt BRUKINSA Once toxicity has resolved to Grade 1 or lower or baseline: Resume at 160 mg twice daily or 320 mg once daily. Second Interrupt BRUKINSA Once toxicity has resolved to Grade 1 or lower or baseline: Resume at 80 mg twice daily or 160 mg once daily. Third Interrupt BRUKINSA Once toxicity has resolved to Grade 1 or lower or baseline: Resume at 80 mg once daily. Fourth Discontinue BRUKINSA Non-hematological toxicities [see Warnings and Precautions (5.5) and Adverse Reactions (6.1) ] Severe or life-threatening non-hematological toxicities Evaluate the benefit-risk before resuming treatment at the same dosage for Grade 4 non-hematological toxicity. First Interrupt BRUKINSA Once toxicity has resolved to Grade 1 or lower or baseline: Resume at 160 mg twice daily or 320 mg once daily. Second Interrupt BRUKINSA Once toxicity has resolved to Grade 1 or lower or baseline: Resume at 80 mg twice daily or 160 mg once daily. Third Interrupt BRUKINSA Once toxicity has resolved to Grade 1 or lower or baseline: Resume at 80 mg once daily. Fourth Discontinue BRUKINSA Asymptomatic lymphocytosis in CLL and MCL should not be regarded as an adverse reaction, and these patients should continue taking BRUKINSA. Refer to the obinutuzumab prescribing information for management of obinutuzumab toxicities.
Table 1: Dosage Modifications for Use with CYP3A Inhibitors or Inducers| Coadministered Drug | Recommended BRUKINSA Dosage (Starting Dose: 160 mg twice daily or 320 mg once daily) |
|---|
| Clarithromycin 250 mg twice dailySince clarithromycin 250 mg twice daily acts as a moderate CYP3A inhibitor, it is recommended that patients be administered clarithromycin 250 mg twice daily with 80 mg BRUKINSA twice daily [see Clinical Pharmacology (12.3)]. | 80 mg twice dailyModify or interrupt zanubrutinib dose as recommended for adverse reactions [see Dosage and Administration (2.4)]. |
| Clarithromycin 500 mg twice daily | 80 mg once daily |
| Posaconazole suspension 100 mg once daily | 80 mg twice daily |
| Posaconazole suspension dosage higher than 100 mg once daily Posaconazole delayed-release tablets 300 mg once daily Posaconazole intravenous 300 mg once daily | 80 mg once daily |
| Other strong CYP3A inhibitor | 80 mg once daily |
| Moderate CYP3A inhibitor | 80 mg twice daily |
| Strong CYP3A inducer | Avoid concomitant use. |
| Moderate CYP3A inducer | Avoid concomitant use. If these inducers cannot be avoided, increase BRUKINSA dose to 320 mg twice daily. |
Table 2: Recommended Dosage Modifications for Adverse Reaction| Adverse Reaction | Adverse Reaction Occurrence | Dosage Modification (Starting Dose: 160 mg twice daily or 320 mg once daily) |
|---|
| Hematological toxicities [see Warnings and Precautions (5.3)] |
| Grade 3 or Grade 4 febrile neutropenia Platelet count decreased to 25,000-50,000/mm3 with significant bleeding Neutrophil count decreased to <500/mm3 (lasting more than 10 consecutive days) Platelet count decreased to <25,000/mm3 (lasting more than 10 consecutive days) | First | Interrupt BRUKINSA Once toxicity has resolved to Grade 1 or lower or baseline: Resume at 160 mg twice daily or 320 mg once daily. |
| Second | Interrupt BRUKINSA Once toxicity has resolved to Grade 1 or lower or baseline: Resume at 80 mg twice daily or 160 mg once daily. |
| Third | Interrupt BRUKINSA Once toxicity has resolved to Grade 1 or lower or baseline: Resume at 80 mg once daily. |
| Fourth | Discontinue BRUKINSA |
| Non-hematological toxicities [see Warnings and Precautions (5.5) and Adverse Reactions (6.1)] |
| Severe or life-threatening non-hematological toxicitiesEvaluate the benefit-risk before resuming treatment at the same dosage for Grade 4 non-hematological toxicity. | First | Interrupt BRUKINSA Once toxicity has resolved to Grade 1 or lower or baseline: Resume at 160 mg twice daily or 320 mg once daily. |
| Second | Interrupt BRUKINSA Once toxicity has resolved to Grade 1 or lower or baseline: Resume at 80 mg twice daily or 160 mg once daily. |
| Third | Interrupt BRUKINSA Once toxicity has resolved to Grade 1 or lower or baseline: Resume at 80 mg once daily. |
| Fourth | Discontinue BRUKINSA |
Information about all available dosage forms and strengths for the drug product to which the labeling applies. This field may contain descriptions of product appearance.
3 DOSAGE FORMS AND STRENGTHS Capsules: Each 80 mg capsule is a size 0, white to off-white opaque capsule marked with "ZANU 80" in black ink. Capsules: 80 mg. ( 3 )
Indications and usage
A statement of each of the drug products indications for use, such as for the treatment, prevention, mitigation, cure, or diagnosis of a disease or condition, or of a manifestation of a recognized disease or condition, or for the relief of symptoms associated with a recognized disease or condition. This field may also describe any relevant limitations of use.
1 INDICATIONS AND USAGE BRUKINSA is a kinase inhibitor indicated for the treatment of adult patients with: Mantle cell lymphoma (MCL) who have received at least one prior therapy. ( 1.1 ) 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 a confirmatory trial. Waldenström's macroglobulinemia (WM). ( 1.2 ) Relapsed or refractory marginal zone lymphoma (MZL) who have received at least one anti–CD20-based regimen. ( 1.3 ) 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 a confirmatory trial. Chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). ( 1.4 ) Relapsed or refractory follicular lymphoma (FL), in combination with obinutuzumab, after two or more lines of systemic therapy. ( 1.5 ) This indication is approved under accelerated approval based on response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial. 1.1 Mantle Cell Lymphoma 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 a confirmatory trial. 1.2 Waldenström's Macroglobulinemia BRUKINSA is indicated for the treatment of adult patients with Waldenström's macroglobulinemia (WM) [see Clinical Studies (14.2) ] . 1.3 Marginal Zone Lymphoma BRUKINSA is indicated for the treatment of adult patients with relapsed or refractory marginal zone lymphoma (MZL) who have received at least one anti–CD20-based regimen. This indication is approved under accelerated approval based on overall response rate [see Clinical Studies (14.3) ] . Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial. 1.4 Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma BRUKINSA is indicated for the treatment of adult patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) [see Clinical Studies (14.4) ] . 1.5 Follicular Lymphoma BRUKINSA is indicated for the treatment of adult patients with relapsed or refractory follicular lymphoma (FL), in combination with obinutuzumab, after two or more lines of systemic therapy. This indication is approved under accelerated approval based on response rate and durability of response [see Clinical Studies (14.5) ] . Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.
Spl product data elements
Usually a list of ingredients in a drug product.
BRUKINSA zanubrutinib SILICON DIOXIDE CROSCARMELLOSE SODIUM MAGNESIUM STEARATE MICROCRYSTALLINE CELLULOSE SODIUM LAURYL SULFATE GELATIN, UNSPECIFIED TITANIUM DIOXIDE FERROSOFERRIC OXIDE ZANUBRUTINIB ZANUBRUTINIB off-white ZANU;80
Carcinogenesis and mutagenesis and impairment of fertility
Information about carcinogenic, mutagenic, or fertility impairment potential revealed by studies in animals. Information from human data about such potential is part of the warnings field.
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenicity studies have not been conducted with zanubrutinib. Zanubrutinib was not mutagenic in a bacterial mutagenicity (Ames) assay, was not clastogenic in a 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 4 weeks prior to mating and through mating and female rats were dosed 2 weeks prior to mating and to gestation day 7. No effect on male or female fertility was noted at lower doses, but at the highest dose tested, morphological abnormalities in sperm and increased postimplantation loss were noted. The high dose of 300 mg/kg/day is approximately 10 times the human recommended dose, based on body surface area.
Nonclinical toxicology
Information about toxicology in non-human subjects.
13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenicity studies have not been conducted with zanubrutinib. Zanubrutinib was not mutagenic in a bacterial mutagenicity (Ames) assay, was not clastogenic in a 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 4 weeks prior to mating and through mating and female rats were dosed 2 weeks prior to mating and to gestation day 7. No effect on male or female fertility was noted at lower doses, but at the highest dose tested, morphological abnormalities in sperm and increased postimplantation 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
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PRINCIPAL DISPLAY PANEL - 80 mg Capsule Carton NDC 72579-011-02 Rx only Brukinsa ® zanubrutinib capsules 80 mg Swallow capsules whole. Do not open, break or chew the capsules. 120 capsules PRINCIPAL DISPLAY PANEL - 80 mg Capsule Carton
Recent major changes
A list of the section(s) that contain substantive changes that have been approved by FDA in the product labeling. The headings and subheadings, if appropriate, affected by the change are listed together with each section’s identifying number and the month and year on which the change was incorporated in the labeling.
Indications and Usage ( 1.5 ) 3/2024
| Indications and Usage (1.5) | 3/2024 |
Spl unclassified section
Information not classified as belonging to one of the other fields. Approximately 40% of labeling with effective_time between June 2009 and August 2014 have information in this field.
Manufactured for: BeiGene USA, Inc. 1840 Gateway Dr., FL 3 San Mateo, CA 94404 BRUKINSA ® is a registered trademark owned by BeiGene, Ltd. © BeiGene, Ltd. 2024
Information necessary for patients to use the drug safely and effectively, such as precautions concerning driving or the concomitant use of other substances that may have harmful additive effects.
17 PATIENT COUNSELING INFORMATION Advise patients to read the FDA-approved patient labeling (Patient Information). Hemorrhage Inform 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) ] . Infections Inform patients to report signs or symptoms suggestive of infection [see Warnings and Precautions (5.2) ] . Cytopenias Inform patients that they will need periodic blood tests to check blood counts during treatment with BRUKINSA [see Warnings and Precautions (5.3) ] . Second Primary Malignancies Inform patients that other malignancies have been reported in patients who have been treated with BRUKINSA, including skin cancer and other solid tumors. Advise patients to use sun protection and have monitoring for development of other cancers [see Warnings and Precautions (5.4) ] . Cardiac Arrhythmias Counsel patients to report any signs of palpitations, lightheadedness, dizziness, fainting, shortness of breath, and chest discomfort [see Warnings and Precautions (5.5) ] . Embryo-Fetal Toxicity Advise pregnant women and females of reproductive potential of the potential hazard to a fetus and to use effective contraception during treatment and for 1 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 1 week after the last dose of BRUKINSA [see Use in Specific Populations (8.3) ] . Lactation Advise females not to breastfeed during treatment with BRUKINSA and for 2 weeks after the last dose [see Use in Specific Populations (8.2) ] . Administration Instructions BRUKINSA may be taken with or without food. Advise patients that BRUKINSA capsules should be swallowed whole with a glass of water, without being opened, broken, or chewed [see Dosage and Administration (2.1) ] . Missed Dose Advise patients that if they miss a dose of BRUKINSA, they may still take it as soon as possible on the same day with a return to the normal schedule the following day [see Dosage and Administration (2.1) ] . Drug Interactions Advise patients to inform their healthcare providers of all concomitant medications, including over-the-counter medications, vitamins, and herbal products [see Drug Interactions (7.1) ] .
Spl patient package insert
Information necessary for patients to use the drug safely and effectively.
PATIENT INFORMATION BRUKINSA ® (BROO-kin-sah) (zanubrutinib) capsules This Patient Information has been approved by the U.S. Food and Drug Administration Revised: 3/2024 What is BRUKINSA? BRUKINSA is a prescription medicine used to treat adults with: Mantle cell lymphoma (MCL) who have received at least one prior treatment for their cancer. Waldenström's 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. Chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). Follicular lymphoma (FL), in combination with the medicine obinutuzumab, when the disease has come back or did not respond to treatment and who have received at least two prior treatments. 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 a history of hepatitis B 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 a pregnancy test before starting treatment with BRUKINSA. Females should avoid getting pregnant during treatment and for 1 week after the last dose of BRUKINSA. You should use effective birth control (contraception) during treatment and for 1 week after the last dose of BRUKINSA. Males should avoid getting female partners pregnant during treatment and for 1 week after the last dose of BRUKINSA. You should use effective birth control (contraception) during treatment and for 1 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 2 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 I take 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 a glass of water. Do not open, break, or chew the capsules. If you miss a 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 BRUKINSA? BRUKINSA may cause serious side effects, including: Bleeding problems (hemorrhage). Bleeding problems are common with BRUKINSA, and can be serious and may lead to death. Your risk of bleeding may increase if you are also taking a 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 a 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 (white blood cells, platelets, and red blood cells). 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, atrial flutter, and ventricular arrhythmias) that can be serious and may lead to death . 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 The most common side effects of BRUKINSA include: decreased white blood cell count decreased platelet count upper respiratory tract infection bleeding muscle, bone, or joint pain These 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 I store BRUKINSA? Store BRUKINSA capsules at room temperature between 68°F to 77°F (20°C to 25°C). BRUKINSA comes in a bottle with a 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 a Patient Information leaflet. Do not use BRUKINSA for a 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 BRUKINSA? Active 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. Manufactured for: BeiGene USA, Inc., 1840 Gateway Dr., FL 3, San Mateo, CA 94404 BRUKINSA ® is a registered trademark owned by BeiGene, Ltd. © BeiGene, Ltd. 2024 For more information, go to www.BRUKINSA.com or call 1-833-969-2463.
| PATIENT INFORMATION BRUKINSA®(BROO-kin-sah) (zanubrutinib) capsules |
|---|
| This Patient Information has been approved by the U.S. Food and Drug Administration | Revised: 3/2024 |
What is BRUKINSA? BRUKINSA is a prescription medicine used to treat adults with:- Mantle cell lymphoma (MCL) who have received at least one prior treatment for their cancer.
- Waldenström's 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.
- Chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL).
- Follicular lymphoma (FL), in combination with the medicine obinutuzumab, when the disease has come back or did not respond to treatment and who have received at least two prior treatments.
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 a history of hepatitis B 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 a pregnancy test before starting treatment with BRUKINSA.
- Females should avoid getting pregnant during treatment and for 1 week after the last dose of BRUKINSA. You should use effective birth control (contraception) during treatment and for 1 week after the last dose of BRUKINSA.
- Males should avoid getting female partners pregnant during treatment and for 1 week after the last dose of BRUKINSA. You should use effective birth control (contraception) during treatment and for 1 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 2 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 I take 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 a glass of water. Do not open, break, or chew the capsules.
- If you miss a 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 BRUKINSA? BRUKINSA may cause serious side effects, including:- Bleeding problems (hemorrhage). Bleeding problems are common with BRUKINSA, and can be serious and may lead to death. Your risk of bleeding may increase if you are also taking a 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 a 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 (white blood cells, platelets, and red blood cells). 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, atrial flutter, and ventricular arrhythmias) that can be serious and may lead to death. 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
|
| The most common side effects of BRUKINSA include: |
- decreased white blood cell count
- decreased platelet count
- upper respiratory tract infection
| - bleeding
- muscle, bone, or joint pain
|
| These 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 I store BRUKINSA?- Store BRUKINSA capsules at room temperature between 68°F to 77°F (20°C to 25°C).
- BRUKINSA comes in a bottle with a 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 a Patient Information leaflet. Do not use BRUKINSA for a 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 BRUKINSA? Active 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. Manufactured for: BeiGene USA, Inc., 1840 Gateway Dr., FL 3, San Mateo, CA 94404 BRUKINSA®is a registered trademark owned by BeiGene, Ltd. © BeiGene, Ltd. 2024 For more information, go to www.BRUKINSA.com or call 1-833-969-2463. |
Clinical studies
This field may contain references to clinical studies in place of detailed discussion in other sections of the labeling.
14 CLINICAL STUDIES 14.1 Mantle Cell Lymphoma The efficacy of BRUKINSA was assessed in BGB-3111-206 [NCT03206970], a 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 a 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: 3 to 102) and the median number of prior therapies was 2 (range: 1 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], a 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 White (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 (IRC). Table 19: Efficacy Results per IRC in Patients with MCL Study 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) CR 59% 22% FDG-PET scans were not required for response assessment. PR 24% 62% Median DOR in months (95% CI) 19.5 (16.6, NE) 18.5 (12.6, NE) 14.2 Waldenström's Macroglobulinemia The efficacy of BRUKINSA was evaluated in ASPEN [NCT03053440], a randomized, active control, open-label trial, comparing BRUKINSA and ibrutinib in patients with MYD88 L265P mutation ( MYD88 MUT ) WM. Patients in Cohort 1 (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 vs 1-3 vs >3) and CXCR4 status (presence or absence of a 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 Waldenström's 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 0 or 1 was present in 93% patients at baseline and 7% had a baseline ECOG performance status of 2. A 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 1 (range: 1 to 8). A total of 91 (45%) patients had International Prognostic Scoring System (IPSS) high WM. The study did not meet statistical significance for the prespecified efficacy outcome of superior CR+VGPR as assessed by IRC, tested first in patients with R/R disease in ASPEN. Table 20 shows the response rates in ASPEN based on IRC assessment. Table 20: Response Rate and Duration of Response Based on IRC Assessment in ASPEN Standard IWWM-6 IWWM-6 criteria (Owen et al, 2013) require complete resolution of extramedullary disease (EMD) if present at baseline for VGPR to be assessed. Modified IWWM-6 Modified IWWM-6 criteria (Treon, 2015) require a reduction in EMD if present at baseline for VGPR to be assessed. Response Category BRUKINSA (N=102) Ibrutinib (N=99) BRUKINSA (N=102) Ibrutinib (N=99) Response rate (CR+VGPR+PR), n (%) 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) 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) 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, 93.8) 94.4% (85.8, 97.9) 87.9% (77, 93.8) ASPEN Cohort 2 Cohort 2 enrolled patients with MYD88 wildtype ( MYD88 WT ) 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). Eighty-six percent of patients had a baseline ECOG performance status 0 or 1 and 14% had a baseline performance status of 2. Twenty-three of the 28 patients in Cohort 2 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). 14.3 Marginal 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 a 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 2 (range: 1 to 6), with 27% having 3 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 2 (range: 1 to 5), with 20% having 3 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 21). Table 21: Efficacy Results per IRC in Patients with MZL Parameter Study 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 estimable. Overall Response Rate (CT-based) Per 2014 CT-based Lugano criteria. FDG-PET scans were not considered for this response assessment. ORR, n 37 (56%) 16 (80%) (95% CI, %) (43, 68) (56, 94) CR, n 13 (20%) 4 (20%) PR, n 24 (36%) 12 (60%) Time to Response Median (range), months 2.9 (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. Median DOR (95% CI), months NE (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 a CR rate of 26%. 14.4 Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma The efficacy of BRUKINSA in patients with CLL/SLL was evaluated in two randomized controlled trials. SEQUOIA The efficacy of BRUKINSA in patients with previously untreated CLL/SLL was evaluated in a multicenter, open-label trial (SEQUOIA; NCT03336333). The trial required patients to be unsuitable for FCR therapy defined as either age ≥65 years or age 18 to <65 with a total Cumulative Illness Rating Scale (CIRS) >6, creatinine clearance 30 to 69 mL/min, or history of serious or recurrent infection. Patients without 17p deletion (17p del) were randomized to receive either BRUKINSA 160 mg twice daily until disease progression or unacceptable toxicity (n=241) or bendamustine plus rituximab (BR) for 6 cycles (n=238). Bendamustine was dosed at 90 mg/m 2 /day intravenously on the first 2 days of each cycle, and rituximab was dosed at 375 mg/m 2 on day 1 of Cycle 1 and 500 mg/m 2 on day 1 of Cycles 2 to 6 with a 28-day cycle length. Randomization was stratified by age, Binet stage, immunoglobulin variable region heavy chain (IGHV) mutational status, and geographic region. Additionally, the same BRUKINSA regimen was evaluated in 110 patients with previously untreated 17p del CLL/SLL in a non-randomized cohort. Efficacy is summarized according to cohort. Randomized Cohort: Previously Untreated CLL/SLL without 17p Deletion In the randomized cohort of patients with previously untreated CLL/SLL without 17p deletion, the median age was 70 years; 62% were male, 89% were White, 3% were Asian, and 1% were Black. Fifty-three percent of patients had an unmutated IGHV gene and 29% had Binet Stage C disease. Baseline characteristics were generally similar between treatment arms. Efficacy in this cohort was based on progression-free survival as assessed by an IRC. Efficacy results are presented in Table 22 and Figure 1. Table 22: Efficacy Results per IRC in Patients with Previously Untreated CLL/SLL without 17p Deletion in SEQUOIA (Randomized Cohort) Parameter Efficacy was assessed using the 2008 International Workshop for Chronic Lymphocytic Leukemia (iwCLL) guidelines and 2014 Lugano criteria for SLL. CLL/SLL without del(17p) BRUKINSA (N=241) Bendamustine + Rituximab (N=238) CI=Confidence interval, CR=complete response, CRi=complete response with incomplete hematopoietic recovery, HR=hazard ratio, NE=not estimable, nPR=nodular partial response, ORR=overall response rate, PFS=progression-free survival, PR=partial response. Progression-free survival Number of Events, n 36 (15%) 71 (30%) Disease Progression 27 (11%) 59 (25%) Death 9 (3.7%) 12 (5%) Median PFS (95% CI), months Based on Kaplan-Meier estimation. Estimated median follow-up for PFS was 25 months. NE (NE, NE) 33.7 (28.1, NE) HR (95% CI) Based on a stratified Cox-regression model with bendamustine + rituximab as the reference group. 0.42 (0.28, 0.63) P-value Based on a stratified log-rank test, with a 2-sided significance level of 0.0372. <0.0001 Overall response rate Defined as CR, CRi, PR, and nPR. No patients had CRi as best response. ORR, n (%) 225 (93) 203 (85) 95% CI, % (89, 96) (80, 90) CR, n (%) 16 (7) 36 (15) nPR, n (%) 3 (1.2) 14 (6) PR, n (%) 206 (85) 153 (64) Figure 1: Kaplan-Meier Plot of IRC-Assessed Progression-Free Survival in Patients with Previously Untreated CLL/SLL without 17p Deletion in SEQUOIA At the time of analysis, overall survival data were immature. With an estimated median follow-up of 25.7 months, median overall survival was not reached in either arm, with fewer than 7% of patients experiencing an event. Figure 1 Single-Arm Cohort: Previously Untreated CLL/SLL with 17p Deletion In this cohort, 110 patients with previously untreated CLL/SLL and centrally confirmed 17p deletion received BRUKINSA 160 mg twice daily until disease progression or unacceptable toxicity. The median age was 70, 71% were male, 95% were White, and 1% were Asian. Sixty percent of patients had an unmutated IGHV gene and 35% had Binet Stage C disease. Efficacy was based on overall response rate and duration of response as assessed by an IRC. Efficacy results are presented in Table 23. Table 23: Efficacy Results per IRC in Patients with Previously Untreated CLL/SLL and 17p Deletion in SEQUOIA Parameter Efficacy was assessed using the 2008 iwCLL guidelines and Lugano criteria for SLL. del(17p) CLL/SLL N=110 DOR=duration of response. A + sign indicates a censored observation. Overall response rate Defined as CR, CRi, PR, and nPR. No patients had CRi as best response. ORR, n (%) 97 (88) (95% CI, %) (81, 94) CR, n (%) 7 (6) nPR, n (%) 2 (1.8) PR, n (%) 88 (80) Time to response Median (range), months 2.9 (1.9 to 13.9) Duration of response Median DOR (95% CI), Kaplan-Meier estimate. Estimated median follow-up for DOR was 25.1 months. months NE (NE, NE) Range, months (5.6 to 35.9+) Rate at 12 months, % (95% CI) 96 (89, 98) Rate at 18 months, % (95% CI) 95 (88, 98) ALPINE The efficacy of BRUKINSA in patients with relapsed or refractory CLL/SLL was evaluated in ALPINE, a randomized, multicenter, open-label, actively controlled trial (NCT03734016). The trial enrolled 652 patients with relapsed or refractory CLL/SLL after at least 1 systemic therapy. The patients were randomized in a 1:1 ratio to receive either BRUKINSA 160 mg orally twice daily (n=327) or ibrutinib 420 mg orally once daily (n=325), each administered until disease progression or unacceptable toxicity. Randomization was stratified by age, geographic region, refractoriness to last therapy, and 17p deletion/ TP53 mutation status. Baseline characteristics were similar between treatment arms. Overall, the median age was 67 years, 68% were male, 81% were White, 14% were Asian, and 1% were Black. Forty-three percent had advanced stage disease, 73% had an unmutated IGHV gene, and 23% had 17p deletion or TP53 mutation. Patients had a median of one prior line of therapy (range: 1-8), 18% of patients had ≥3 prior lines of therapy, 78% had prior chemoimmunotherapy, and 2.3% had prior BCL2 inhibitor. Efficacy was based on overall response rate and duration of response as determined by an IRC. For progression-free survival per IRC, the final analysis occurred with a median follow-up of 31 months. Efficacy results are shown in Table 24 and Figure 2. Table 24: Efficacy Results per IRC in Patients with Relapsed or Refractory CLL/SLL in ALPINE Parameter Efficacy was based on 2008 iwCLL guidelines for CLL and the Lugano criteria for SLL. BRUKINSA (N=327) Ibrutinib (N=325) CI=Confidence interval, CR=complete response, CRi=complete response with incomplete hematopoietic recovery, DOR=duration of response, HR=hazard ratio, NE=not estimable, nPR=nodular partial response, ORR=overall response rate, PR=partial response. A + sign indicates a censored observation. Overall response rate Defined as CR + CRi + nPR + PR. No patients had CRi as best response. ORR, n (%) 263 (80) 237 (73) (95% CI, %) (76, 85) (68, 78) CR, n (%) 13 (4) 8 (2.5) nPR, n (%) 1 (0.3) 0 (0) PR, n (%) 249 (76) 229 (70) Response Rate Ratio (95% CI) Estimate stratified by randomization stratification factors. 1.10 (1.01, 1.20) 2-sided p-value 2-sided significance level of 0.0469 was allocated for ORR superiority testing. 0.0264 Duration of response Median DOR (95% CI) Based on Kaplan-Meier estimate. Estimated median follow-up for DOR was 14.1 months. NE (NE, NE) NE (NE, NE) Range, months (1.4 to 30.4+) (1.9+ to 30.8+) Rate at 12 months, % (95% CI) 92 (87, 95) 86 (80, 91) Progression-free survival Events, n (%) 88 (27) 120 (37) Median PFS (95% CI), months Based on Kaplan-Meier estimation. Estimated median follow-up for PFS was 30.7 months. NE (34.3, NE) 35 (33.2, 44.3) HR (95% CI) Based on a stratified Cox-regression model with ibrutinib as the reference group. 0.65 (0.49, 0.86) 2-sided p-value Based on a stratified log-rank test. 0.0024 The median time to response was 5.5 months for BRUKINSA and 5.6 months for ibrutinib. Figure 2: Kaplan-Meier Plot of Progression-Free Survival by IRC in ALPINE At the time of final analysis, the median overall survival was not reached in either arm. There were a total of 108 deaths: 48 (14.7%) in the zanubrutinib arm and 60 (18.5%) in the ibrutinib arm. Figure 2 14.5 Follicular Lymphoma The efficacy of BRUKINSA, in combination with obinutuzumab, was evaluated in Study BGB-3111-212 (ROSEWOOD; NCT03332017), an open-label, multicenter, randomized trial that enrolled 217 adult patients with relapsed or refractory FL after at least 2 prior systemic treatments. The study required prior receipt of an anti-CD20 antibody and an alkylator-based combination therapy, and excluded patients with FL Grade 3b, transformed lymphoma, and prior exposure to a BTK inhibitor. Patients were randomized in a 2:1 ratio to receive either BRUKINSA 160 mg orally twice daily until disease progression or unacceptable toxicity plus obinutuzumab, or obinutuzumab alone. Obinutuzumab was administered 1,000 mg intravenously on days 1, 8, and 15 of Cycle 1, 1,000 mg on Day 1 of Cycles 2 to 6; and then 1,000 mg every 8 weeks for up to 20 doses. At the discretion of the investigator, obinutuzumab could be administered as 100 mg on Day 1 and 900 mg on Day 2 of Cycle 1. Randomization was stratified by the number of prior lines of therapy (2 to 3 vs ˃3), rituximab-refractory status (yes vs no), and geographic region. Of the 217 patients randomized (145 to BRUKINSA plus obinutuzumab, 72 to obinutuzumab monotherapy), the median age was 64 years (range: 31 to 88), 50% were male, 64% were White, and 22% were Asian. In total, 83% had stage 3 or 4 disease and 57% met Groupe d'Etude des Lymphomes Folliculaires (GELF) criteria at enrollment. Patients had a median of 3 prior lines of therapy (range: 2-11), with 27% of patients having more than 3 prior lines of therapy. In the BRUKINSA in combination with obinutuzumab arm, 5% had received lenalidomide plus rituximab, 21% had received stem cell transplantation, 53% had refractory disease to rituximab, and 37% had progression of disease within 24 months of the first systemic therapy. Efficacy was based on overall response rate and duration of response, as determined by an IRC. Efficacy results are shown in Table 25. The median time to response in the BRUKINSA combination arm was 2.8 months (range 2 to 23 months). Table 25: Efficacy Results per IRC in Patients with Relapsed or Refractory Follicular Lymphoma Parameter BRUKINSA + Obinutuzumab (N=145) Obinutuzumab (N=72) CI=Confidence interval, CR=complete response, DOR=duration of response, NE=not estimable, ORR=overall response rate, PR=partial response. Overall response rate ORR, n (%) 100 (69) 33 (46) (95% CI) Estimated using the Clopper-Pearson method. (61, 76) (34, 58) CR 57 (39) 14 (19) PR 43 (30) 19 (26) Risk difference, % (95% CI) Estimated by stratified Cochran-Mantel-Haenszel method. 22.7 (9, 36.5) 2-sided p-value , Significance level, 0.05. 0.0012 Duration of response Median DOR (95% CI), Estimated by Kaplan-Meier method. Estimated median follow-up for DOR was 19 months overall. months NE (25.3, NE) 14 (9.2, 25.1) The estimated DOR rate at 18 months was 69% (95% CI: 58, 78) in the BRUKINSA combination arm and 42% (95% CI: 23, 60) in the obinutuzumab monotherapy arm.
Table 19: Efficacy Results per IRC in Patients with MCL | Study 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) |
| CR | 59% | 22%FDG-PET scans were not required for response assessment. |
| PR | 24% | 62% |
| Median DOR in months (95% CI) | 19.5 (16.6, NE) | 18.5 (12.6, NE) |
Table 20: Response Rate and Duration of Response Based on IRC Assessment in ASPEN | Standard 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 a reduction in EMD if present at baseline for VGPR to be assessed. |
|---|
| Response Category | BRUKINSA (N=102) | Ibrutinib (N=99) | BRUKINSA (N=102) | Ibrutinib (N=99) |
|---|
| Response rate (CR+VGPR+PR), n (%) | 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) |
| 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) | 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, 93.8) | 94.4% (85.8, 97.9) | 87.9% (77, 93.8) |
Table 21: Efficacy Results per IRC in Patients with MZL| Parameter | Study 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 estimable. |
| Overall Response Rate (CT-based)Per 2014 CT-based Lugano criteria. FDG-PET scans were not considered for this response assessment. | | |
| ORR, n | 37 (56%) | 16 (80%) |
| (95% CI, %) | (43, 68) | (56, 94) |
| CR, n | 13 (20%) | 4 (20%) |
| PR, n | 24 (36%) | 12 (60%) |
| Time to Response | | |
| Median (range), months | 2.9 (1.8, 11.1) | 2.9 (2.6, 23.1) |
| Duration of ResponseBased 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. | | |
| Median DOR (95% CI), months | NE (NE, NE) | NE (8.4, NE) |
| Rate at 12 months (95% CI) | 85% (67, 93) | 72% (40, 88) |
Table 22: Efficacy Results per IRC in Patients with Previously Untreated CLL/SLL without 17p Deletion in SEQUOIA (Randomized Cohort)| ParameterEfficacy was assessed using the 2008 International Workshop for Chronic Lymphocytic Leukemia (iwCLL) guidelines and 2014 Lugano criteria for SLL. | CLL/SLL without del(17p) |
|---|
| BRUKINSA (N=241) | Bendamustine + Rituximab (N=238) |
|---|
| CI=Confidence interval, CR=complete response, CRi=complete response with incomplete hematopoietic recovery, HR=hazard ratio, NE=not estimable, nPR=nodular partial response, ORR=overall response rate, PFS=progression-free survival, PR=partial response. |
| Progression-free survival |
| Number of Events, n | 36 (15%) | 71 (30%) |
| Disease Progression | 27 (11%) | 59 (25%) |
| Death | 9 (3.7%) | 12 (5%) |
| Median PFS (95% CI), monthsBased on Kaplan-Meier estimation. Estimated median follow-up for PFS was 25 months. | NE (NE, NE) | 33.7 (28.1, NE) |
| HR (95% CI)Based on a stratified Cox-regression model with bendamustine + rituximab as the reference group. | 0.42 (0.28, 0.63) |
| P-valueBased on a stratified log-rank test, with a 2-sided significance level of 0.0372. | <0.0001 |
| Overall response rateDefined as CR, CRi, PR, and nPR. No patients had CRi as best response. |
| ORR, n (%) | 225 (93) | 203 (85) |
| 95% CI, % | (89, 96) | (80, 90) |
| CR, n (%) | 16 (7) | 36 (15) |
| nPR, n (%) | 3 (1.2) | 14 (6) |
| PR, n (%) | 206 (85) | 153 (64) |
Table 23: Efficacy Results per IRC in Patients with Previously Untreated CLL/SLL and 17p Deletion in SEQUOIA| ParameterEfficacy was assessed using the 2008 iwCLL guidelines and Lugano criteria for SLL. | del(17p) CLL/SLL N=110 |
|---|
| DOR=duration of response. A + sign indicates a censored observation. |
| Overall response rateDefined as CR, CRi, PR, and nPR. No patients had CRi as best response. |
| ORR, n (%) | 97 (88) |
| (95% CI, %) | (81, 94) |
| CR, n (%) | 7 (6) |
| nPR, n (%) | 2 (1.8) |
| PR, n (%) | 88 (80) |
| Time to response |
| Median (range), months | 2.9 (1.9 to 13.9) |
| Duration of response |
| Median DOR (95% CI),Kaplan-Meier estimate. Estimated median follow-up for DOR was 25.1 months. months | NE (NE, NE) |
| Range, months | (5.6 to 35.9+) |
| Rate at 12 months, % (95% CI) | 96 (89, 98) |
| Rate at 18 months, % (95% CI) | 95 (88, 98) |
Table 24: Efficacy Results per IRC in Patients with Relapsed or Refractory CLL/SLL in ALPINE| ParameterEfficacy was based on 2008 iwCLL guidelines for CLL and the Lugano criteria for SLL. | BRUKINSA (N=327) | Ibrutinib (N=325) |
|---|
| CI=Confidence interval, CR=complete response, CRi=complete response with incomplete hematopoietic recovery, DOR=duration of response, HR=hazard ratio, NE=not estimable, nPR=nodular partial response, ORR=overall response rate, PR=partial response. A + sign indicates a censored observation. |
| Overall response rateDefined as CR + CRi + nPR + PR. No patients had CRi as best response. |
| ORR, n (%) | 263 (80) | 237 (73) |
| (95% CI, %) | (76, 85) | (68, 78) |
| CR, n (%) | 13 (4) | 8 (2.5) |
| nPR, n (%) | 1 (0.3) | 0 (0) |
| PR, n (%) | 249 (76) | 229 (70) |
| Response Rate Ratio (95% CI)Estimate stratified by randomization stratification factors. | 1.10 (1.01, 1.20) |
| 2-sided p-value2-sided significance level of 0.0469 was allocated for ORR superiority testing. | 0.0264 |
| Duration of response |
| Median DOR (95% CI)Based on Kaplan-Meier estimate. Estimated median follow-up for DOR was 14.1 months. | NE (NE, NE) | NE (NE, NE) |
| Range, months | (1.4 to 30.4+) | (1.9+ to 30.8+) |
| Rate at 12 months, % (95% CI) | 92 (87, 95) | 86 (80, 91) |
| Progression-free survival |
| Events, n (%) | 88 (27) | 120 (37) |
| Median PFS (95% CI), monthsBased on Kaplan-Meier estimation. Estimated median follow-up for PFS was 30.7 months. | NE (34.3, NE) | 35 (33.2, 44.3) |
| HR (95% CI)Based on a stratified Cox-regression model with ibrutinib as the reference group. | 0.65 (0.49, 0.86) |
| 2-sided p-valueBased on a stratified log-rank test. | 0.0024 |
Table 25: Efficacy Results per IRC in Patients with Relapsed or Refractory Follicular Lymphoma| Parameter | BRUKINSA + Obinutuzumab (N=145) | Obinutuzumab (N=72) |
|---|
| CI=Confidence interval, CR=complete response, DOR=duration of response, NE=not estimable, ORR=overall response rate, PR=partial response. |
| Overall response rate |
| ORR, n (%) | 100 (69) | 33 (46) |
| (95% CI)Estimated using the Clopper-Pearson method. | (61, 76) | (34, 58) |
| CR | 57 (39) | 14 (19) |
| PR | 43 (30) | 19 (26) |
| Risk difference, % (95% CI)Estimated by stratified Cochran-Mantel-Haenszel method. | 22.7 (9, 36.5) |
| 2-sided p-value,Significance level, 0.05. | 0.0012 |
| Duration of response |
| Median DOR (95% CI),Estimated by Kaplan-Meier method. Estimated median follow-up for DOR was 19 months overall. months | NE (25.3, NE) | 14 (9.2, 25.1) |
Geriatric use
Information about any limitations on any geriatric indications, needs for specific monitoring, hazards associated with use of the drug in the geriatric population.
8.5 Geriatric Use Of the 1729 patients with MCL, MZL, WM, CLL/SLL, and FL in clinical studies with BRUKINSA, 59% were ≥65 years of age, and 21% were ≥75 years of age. Patients ≥65 years of age had numerically higher rates of Grade 3 or higher adverse reactions and serious adverse reactions (57% and 38%, respectively) than patients <65 years of age (51% and 29%, respectively). No overall differences in effectiveness were observed between younger and older patients.
Pediatric use
Information about any limitations on any pediatric indications, needs for specific monitoring, hazards associated with use of the drug in any subsets of the pediatric population (such as neonates, infants, children, or adolescents), differences between pediatric and adult responses to the drug, and other information related to the safe and effective pediatric use of the drug.
8.4 Pediatric Use Safety and effectiveness of BRUKINSA in pediatric patients have not been established.
Pregnancy
Information about effects the drug may have on pregnant women or on a fetus. This field may be ommitted if the drug is not absorbed systemically and the drug is not known to have a potential for indirect harm to the fetus. It may contain information about the established pregnancy category classification for the drug. (That information is nominally listed in the teratogenic_effects field, but may be listed here instead.)
8.1 Pregnancy Risk Summary Based 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 a 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 a 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 Data Embryo-fetal development toxicity studies were conducted in both rats and rabbits. Zanubrutinib was administered orally to pregnant rats during the period of organogenesis at doses of 30, 75, and 150 mg/kg/day. 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 5 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 postimplantation 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 a pre and postnatal 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 5 times the AUC in patients receiving the recommended dose.
Use in specific populations
Information about use of the drug by patients in specific populations, including pregnant women and nursing mothers, pediatric patients, and geriatric patients.
8 USE IN SPECIFIC POPULATIONS Lactation: Advise not to breastfeed. ( 8.2 ) 8.1 Pregnancy Risk Summary Based 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 a 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 a 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 Data Embryo-fetal development toxicity studies were conducted in both rats and rabbits. Zanubrutinib was administered orally to pregnant rats during the period of organogenesis at doses of 30, 75, and 150 mg/kg/day. 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 5 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 postimplantation 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 a pre and postnatal 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 5 times the AUC in patients receiving the recommended dose. 8.2 Lactation Risk Summary There 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 a 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 BRUKINSA can cause embryo-fetal harm when administered to pregnant women [see Use in Specific Populations (8.1) ] . Pregnancy Testing Pregnancy testing is recommended for females of reproductive potential prior to initiating BRUKINSA therapy. Contraception Females Advise female patients of reproductive potential to use effective contraception during treatment with BRUKINSA and for 1 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 a fetus. Males Advise men to avoid fathering a child while receiving BRUKINSA and for 1 week following the last dose of BRUKINSA. 8.4 Pediatric Use Safety and effectiveness of BRUKINSA in pediatric patients have not been established. 8.5 Geriatric Use Of the 1729 patients with MCL, MZL, WM, CLL/SLL, and FL in clinical studies with BRUKINSA, 59% were ≥65 years of age, and 21% were ≥75 years of age. Patients ≥65 years of age had numerically higher rates of Grade 3 or higher adverse reactions and serious adverse reactions (57% and 38%, respectively) than patients <65 years of age (51% and 29%, respectively). No overall differences in 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) ] .
How supplied
Information about the available dosage forms to which the labeling applies, and for which the manufacturer or distributor is responsible. This field ordinarily includes the strength of the dosage form (in metric units), the units in which the dosage form is available for prescribing, appropriate information to facilitate identification of the dosage forms (such as shape, color, coating, scoring, and National Drug Code), and special handling and storage condition information.
16 HOW SUPPLIED/STORAGE AND HANDLING How Supplied Package Size Content NDC Number 120-count Bottle with a child-resistant cap containing 120 capsules 80 mg, white to off-white opaque capsule, marked with "ZANU 80" in black ink 72579-011-02 Storage Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C to 30°C (59°F to 86°F) [See USP Controlled Room Temperature].
| Package Size | Content | NDC Number |
|---|
| 120-count | Bottle with a child-resistant cap containing 120 capsules 80 mg, white to off-white opaque capsule, marked with "ZANU 80" in black ink | 72579-011-02 |
Storage and handling
Information about safe storage and handling of the drug product.
Storage Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C to 30°C (59°F to 86°F) [See USP Controlled Room Temperature].
