Label: BRUKINSA- zanubrutinib capsule

  • NDC Code(s): 72579-011-01, 72579-011-02
  • Packager: BEIGENE USA, INC.
  • Category: HUMAN PRESCRIPTION DRUG LABEL
  • DEA Schedule: None
  • Marketing Status: New Drug Application

Drug Label Information

Updated January 12, 2023

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  • HIGHLIGHTS OF PRESCRIBING INFORMATION
    These highlights do not include all the information needed to use BRUKINSA safely and effectively. See full prescribing information for BRUKINSA.

    BRUKINSA® (zanubrutinib) capsules, for oral use
    Initial U.S. Approval: 2019

    RECENT MAJOR CHANGES

    Indications and Usage (1.4)1/2023
    Dosage and Administration (2.3)1/2023
    Warnings and Precautions (5.4, 5.5)1/2023

    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)

    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)

    DOSAGE FORMS AND STRENGTHS

    Capsules: 80 mg. (3)

    CONTRAINDICATIONS

    None. (4)

    WARNINGS AND PRECAUTIONS

    • Hemorrhage: Monitor for bleeding and manage appropriately. (5.1)
    • Infections: Monitor patients for signs and symptoms of infection, including opportunistic infections, and treat as needed. (5.2)
    • Cytopenias: Monitor complete blood counts during treatment. (5.3)
    • Second Primary Malignancies: Other malignancies have developed including skin cancers and non-skin carcinomas. Monitor and advise patients to use sun protection. (5.4)
    • Cardiac Arrhythmias: Monitor for signs and symptoms of arrhythmias and manage appropriately. (5.5)
    • Embryo-Fetal Toxicity: Can cause fetal harm. Advise women of the potential risk to a fetus and to use effective contraception. (5.6)

    ADVERSE REACTIONS

    The most common adverse reactions (≥30%), including laboratory abnormalities, are neutrophil count decreased, upper respiratory tract infection, platelet count decreased, 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.

    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)

    USE IN SPECIFIC POPULATIONS

    Lactation: Advise not to breastfeed. (8.2)

    See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling.

    Revised: 1/2023

  • Table of Contents
  • 1 INDICATIONS AND USAGE

    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)].

  • 2 DOSAGE AND ADMINISTRATION

    2.1 Recommended Dosage

    The recommended dosage of BRUKINSA is 160 mg taken orally twice daily or 320 mg taken orally once daily until disease progression or unacceptable toxicity.

    BRUKINSA can be taken with or without food. Advise patients to swallow capsules whole with water. Advise patients not to open, break, or chew the capsules. If 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 DrugRecommended BRUKINSA Dosage
    (Starting Dose: 160 mg twice daily or 320 mg once daily)
    Strong CYP3A inhibitor80 mg once daily.
    Interrupt dose as recommended for adverse reactions [see Dosage and Administration (2.4)].
    Moderate CYP3A inhibitor80 mg twice daily.
    Modify dose as recommended for adverse reactions [see Dosage and Administration (2.4)].
    Strong CYP3A inducerAvoid concomitant use.
    Moderate CYP3A inducerAvoid concomitant use.
    If these inducers cannot be avoided, increase BRUKINSA dose to 320 mg twice daily.

    After discontinuation of a CYP3A inhibitor or moderate CYP3A4 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 Modification for Adverse Reaction
    Adverse ReactionAdverse Reaction OccurrenceDosage Modification
    (Starting Dose: 160 mg twice daily or 320 mg once daily)
    *
    Evaluate the benefit-risk before resuming treatment at the same dosage for Grade 4 non-hematological toxicity.
    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)
    FirstInterrupt BRUKINSA
    Once toxicity has resolved to Grade 1 or lower or baseline: Resume at 160 mg twice daily or 320 mg once daily.
    SecondInterrupt BRUKINSA
    Once toxicity has resolved to Grade 1 or lower or baseline: Resume at 80 mg twice daily or 160 mg once daily.
    ThirdInterrupt BRUKINSA
    Once toxicity has resolved to Grade 1 or lower or baseline: Resume at 80 mg once daily.
    FourthDiscontinue BRUKINSA
    Non-hematological toxicities [see Warnings and Precautions (5.5) and Adverse Reactions (6.1)]
    Severe or life-threatening non-hematological toxicities*FirstInterrupt BRUKINSA
    Once toxicity has resolved to Grade 1 or lower or baseline: Resume at 160 mg twice daily or 320 mg once daily.*
    SecondInterrupt BRUKINSA
    Once toxicity has resolved to Grade 1 or lower or baseline: Resume at 80 mg twice daily or 160 mg once daily.
    ThirdInterrupt BRUKINSA
    Once toxicity has resolved to Grade 1 or lower or baseline: Resume at 80 mg once daily.
    FourthDiscontinue BRUKINSA

    Asymptomatic lymphocytosis should not be regarded as an adverse reaction, and these patients should continue taking BRUKINSA.

  • 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.

  • 4 CONTRAINDICATIONS

    None.

  • 5 WARNINGS AND PRECAUTIONS

    5.1 Hemorrhage

    Fatal and serious hemorrhage has occurred in patients with hematological malignancies treated with BRUKINSA monotherapy. Grade 3 or higher hemorrhage including intracranial and gastrointestinal hemorrhage, hematuria, and hemothorax was reported in 3.6% of patients treated with BRUKINSA monotherapy in clinical trials, with fatalities occurring in 0.3% of patients. Bleeding of any grade, excluding purpura and petechiae, occurred in 30% of patients.

    Bleeding has occurred in patients with and without concomitant antiplatelet or anticoagulation therapy. Coadministration of BRUKINSA with antiplatelet or anticoagulant medications may further increase the risk of hemorrhage.

    Monitor for signs and symptoms of bleeding. Discontinue BRUKINSA if intracranial hemorrhage of any grade occurs. Consider the benefit-risk of withholding BRUKINSA for 3-7 days pre and post surgery depending upon the type of surgery and the risk of bleeding.

    5.2 Infections

    Fatal and serious infections (including bacterial, viral, or fungal infections) and opportunistic infections have occurred in patients with hematological malignancies treated with BRUKINSA monotherapy. Grade 3 or higher infections occurred in 24% of patients, most commonly pneumonia (11%), with fatal infections occurring in 2.9% of patients. Infections due to hepatitis B virus (HBV) reactivation have occurred.

    Consider prophylaxis for herpes simplex virus, pneumocystis jirovecii pneumonia, and other infections according to standard of care in patients who are at increased risk for infections. Monitor and evaluate patients for fever or other signs and symptoms of infection and treat appropriately.

    5.3 Cytopenias

    Grade 3 or 4 cytopenias, including neutropenia (22%), thrombocytopenia (8%), and anemia (7%) based on laboratory measurements, developed in patients treated with BRUKINSA monotherapy [see Adverse Reactions (6.1)]. Grade 4 neutropenia occurred in 11% of patients, and Grade 4 thrombocytopenia occurred in 2.8% of patients.

    Monitor complete blood counts regularly during treatment and interrupt treatment, reduce the dose, or discontinue treatment as warranted [see Dosage and Administration (2.4)]. Treat using growth factor or transfusions, as needed.

    5.4 Second Primary Malignancies

    Second primary malignancies, including non-skin carcinoma, have occurred in 13% of patients treated with BRUKINSA monotherapy. The most frequent second primary malignancy was non-melanoma skin cancer, reported in 7% of patients. Other second primary malignancies included malignant solid tumors (5%), melanoma (1.2%), and hematologic malignancies (0.5%). Advise patients to use sun protection and monitor patients for the development of second primary malignancies.

    5.5 Cardiac Arrhythmias

    Serious cardiac arrhythmias have occurred in patients treated with BRUKINSA. Atrial fibrillation and atrial flutter were reported in 3.7% of 1550 patients treated with BRUKINSA monotherapy, including Grade 3 or higher cases in 1.7% of patients. Patients with cardiac risk factors, hypertension, and acute infections may be at increased risk. Grade 3 or higher ventricular arrhythmias were reported in 0.2% of patients.

    Monitor for signs and symptoms of cardiac arrhythmias (e.g., palpitations, dizziness, syncope, dyspnea, chest discomfort), manage appropriately [see Dosage and Administration (2.4)], and consider the risks and benefits of continued BRUKINSA treatment.

    5.6 Embryo-Fetal Toxicity

    Based on findings in animals, BRUKINSA can cause fetal harm when administered to a pregnant woman. Administration of zanubrutinib to pregnant rats during the period of organogenesis caused embryo-fetal toxicity, including malformations at exposures that were 5 times higher than those reported in patients at the recommended dose of 160 mg twice daily. Advise women to avoid becoming pregnant while taking BRUKINSA and for 1 week after the last dose. Advise men to avoid fathering a child during treatment and for 1 week after the last dose. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus [see Use in Specific Populations (8.1)].

  • 6 ADVERSE REACTIONS

    The following clinically significant adverse reactions are discussed in more detail in other sections of the labeling:

    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 as a single-agent in nine clinical trials, administered at 160 mg twice daily in 1445 patients and at 320 mg once daily in 105 patients. Among these 1550 patients, the median duration of exposure was 26 months, 80% of patients were exposed for at least 12 months, and 58% of patients were exposed for at least 24 months.

    In this pooled safety population, the most common adverse reactions (≥30%), including laboratory abnormalities, included neutrophil count decreased (42%), upper respiratory tract infection (39%), platelet count decreased (34%), hemorrhage (30%), and musculoskeletal pain (30%).

    Mantle Cell Lymphoma (MCL)

    The safety of BRUKINSA was evaluated in 118 patients with MCL who received at least one prior therapy in two single-arm clinical trials, BGB-3111-206 [NCT03206970] and BGB-3111-AU-003 [NCT02343120] [see Clinical Studies (14.1)]. The median age of patients who received BRUKINSA in studies BGB-3111-206 and BGB-3111-AU-003 was 62 years (range: 34 to 86), 75% were male, 75% were Asian, 21% were White, and 94% had an ECOG performance status of 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 × 109/L and an absolute neutrophil count ≥1 × 109/L independent of growth factor support, hepatic enzymes ≤2.5 × upper limit of normal, total bilirubin ≤1.5 × ULN. The BGB-3111-AU-003 trial required a platelet count ≥50 × 109/L and an absolute neutrophil count ≥1 × 109/L independent of growth factor support, hepatic enzymes ≤3 × upper limit of normal, total bilirubin ≤1.5 × ULN. Both trials required a 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 events 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 SystemAdverse ReactionPercent of Patients (N=118)
    All Grades %Grade 3 or Higher %
    *
    Upper respiratory tract infection includes upper respiratory tract infection, upper respiratory tract infection viral.
    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.
    Includes fatal adverse reaction.
    §
    Rash includes all related terms containing rash.
    Bruising includes all related terms containing bruise, bruising, contusion, ecchymosis.
    #
    Hemorrhage includes all related terms containing hemorrhage, hematoma.
    Þ
    Musculoskeletal pain includes musculoskeletal pain, musculoskeletal discomfort, myalgia, back pain, arthralgia, arthritis.
    Infections and infestationsUpper respiratory tract infection*390
    Pneumonia1510
    Urinary tract infection110.8
    Skin and subcutaneous tissue disordersRash§360
    Bruising140
    Gastrointestinal disordersDiarrhea230.8
    Constipation130
    Vascular disordersHypertension123.4
    Hemorrhage#113.4
    Musculoskeletal and connective tissue disordersMusculoskeletal painÞ143.4
    Respiratory, thoracic and mediastinal disordersCough120

    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* (>20%) in Patients with MCL in Studies BGB-3111-206 and BGB-3111-AU-003
    Laboratory ParameterPercent of Patients (N=118)
    All Grades (%)Grade 3 or 4 (%)
    *
    Based on laboratory measurements.
    Asymptomatic lymphocytosis is a known effect of BTK inhibition.
    Hematologic abnormalities
      Neutrophils decreased4520
      Lymphocytosis4116
      Platelets decreased407
      Hemoglobin decreased276
    Chemistry abnormalities
      Blood uric acid increased292.6
      ALT increased280.9
      Bilirubin increased240.9

    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 (MYD88MUT) 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 (MYD88WT) 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 SystemAdverse ReactionBRUKINSA (N=101)Ibrutinib (N=98)
    All Grades
    (%)
    Grade 3 or 4
    (%)
    All Grades
    (%)
    Grade 3 or 4
    (%)
    *
    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.
    Pneumonia includes lower respiratory tract infection, lung infiltration, pneumonia, pneumonia aspiration, pneumonia viral.
    Fatigue includes asthenia, fatigue, lethargy.
    §
    Bruising includes all related terms containing bruise, contusion, or ecchymosis.
    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.
    #
    Musculoskeletal pain includes back pain, arthralgia, pain in extremity, musculoskeletal pain, myalgia, bone pain, spinal pain, musculoskeletal chest pain, neck pain, arthritis, musculoskeletal discomfort.
    Þ
    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.
    Infections and infestationsUpper respiratory tract infection*440402
    Pneumonia1242610
    Urinary tract infection110132
    Gastrointestinal disordersDiarrhea223342
    Nausea180131
    Constipation16070
    Vomiting120141
    General disordersFatigue311251
    Pyrexia164132
    Edema peripheral120200
    Skin and subcutaneous tissue disordersBruising§200340
    Rash290320
    Pruritus11160
    Musculoskeletal and connective tissue disordersMusculoskeletal pain#459391
    Muscle spasms100281
    Nervous system disordersHeadache181141
    Dizziness131120
    Respiratory, thoracic and mediastinal disordersCough160180
    Dyspnea14070
    Vascular disordersHemorrhageÞ424439
    Hypertension1491914

    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* (≥20%) that Worsened from Baseline in Patients with WM Who Received BRUKINSA in Cohort 1
    Laboratory AbnormalityBRUKINSAIbrutinib
    All Grades
    (%)
    Grade 3 or 4
    (%)
    All Grades
    (%)
    Grade 3 or 4
    (%)
    *
    Based on laboratory measurements.
    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.
    Hematologic abnormalities
    Neutrophils decreased5024349
    Platelets decreased358395
    Hemoglobin decreased207207
    Chemistry abnormalities
    Glucose increased452.3332.3
    Creatinine increased311211
    Calcium decreased272260
    Potassium increased242120
    Phosphate decreased203.1180
    Urate increased163.2346
    Bilirubin increased121331

    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 × 109/L, platelet count ≥50 or ≥75 × 109/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 Caucasian 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 SystemAdverse ReactionBRUKINSA (N=88)
    All Grades
    (%)
    Grade 3 or 4
    (%)
    *
    Upper respiratory tract infection includes upper respiratory tract infection, nasopharyngitis, sinusitis, tonsillitis, rhinitis, viral upper respiratory tract infection.
    Urinary tract infection includes urinary tract infection, cystitis, Escherichia urinary tract infection, pyelonephritis, cystitis.
    Pneumonia includes COVID-19 pneumonia, pneumonia, bronchopulmonary aspergillosis, lower respiratory tract infection, organizing pneumonia.
    §
    Includes 2 fatalities from COVID-19 pneumonia.
    Diarrhea includes diarrhea and diarrhea hemorrhagic.
    #
    Abdominal pain includes abdominal pain, abdominal pain upper, abdominal discomfort.
    Þ
    Bruising includes contusion, ecchymosis, increased tendency to bruise, post procedural contusion.
    ß
    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.
    à
    Musculoskeletal pain includes back pain, arthralgia, musculoskeletal pain, myalgia, pain in extremity, musculoskeletal chest pain, bone pain, musculoskeletal discomfort, neck pain.
    è
    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.
    ð
    Fatigue includes fatigue, lethargy, asthenia.
    ø
    Cough includes cough and productive cough.
    Infections and infestationsUpper respiratory tract infection*263.4
    Urinary tract infection112.3
    Pneumonia,§106
    Gastrointestinal disordersDiarrhea253.4
    Abdominal pain#142.3
    Nausea130
    Skin and subcutaneous tissue disordersBruisingÞ240
    Rashß210
    Musculoskeletal and connective tissue disordersMusculoskeletal painà271.1
    Vascular disordersHemorrhageè231.1
    General disordersFatigueð212.3
    Respiratory, thoracic and mediastinal disordersCoughø100

    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*BRUKINSA
    All Grades (%)Grade 3 or 4 (%)
    *
    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.
    Hematologic abnormalities
    Neutrophils decreased4315
    Platelets decreased3310
    Lymphocytes decreased328
    Hemoglobin decreased266
    Chemistry abnormalities
    Glucose increased544.6
    Creatinine increased341.1
    Phosphate decreased272.3
    Calcium decreased230
    ALT increased221.1

    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 trial 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, creatinine clearance 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/m2/day intravenously on the first 2 days of each cycle, and rituximab was dosed at 375 mg/m2 on day 1 of Cycle 1 and 500 mg/m2 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 pain: musculoskeletal pain, arthralgia, back pain, pain in extremity, myalgia, neck pain, spinal pain, musculoskeletal discomfort, bone pain.
    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.
    Pneumonia: pneumonia, COVID-19 pneumonia, lower respiratory tract infection, lung infiltration, and related terms including specific types of infection.
    §
    Includes 3 fatal outcomes.
    Includes 2 fatal outcomes.
    #
    Hemorrhage: all terms containing hematoma, hemorrhage, hemorrhagic, and related terms indicative of bleeding.
    Þ
    Includes multiple similar adverse reaction terms.
    ß
    Rash: Rash, dermatitis, drug eruption, and related terms.
    à
    Bruising: all terms containing bruise, bruising, contusion, or ecchymosis.
    è
    Fatigue: fatigue, asthenia, and lethargy.
    ð
    Second primary malignancy: includes non-melanoma skin cancer, malignant solid tumors (including lung, renal, genitourinary, breast, ovarian, and rectal), and chronic myeloid leukemia.
    ø
    Dizziness: dizziness and vertigo.
    Musculoskeletal and connective tissue disorders
      Musculoskeletal pain*331.7170.4
    Infections and infestations
      Upper respiratory tract infection281.3150.9
      Pneumonia13§584
    Vascular disorders
      Hemorrhage#27§440.4
      HypertensionÞ14752.6
    Skin and subcutaneous tissue disorders
      Rashß241.3305
      Bruisingà2402.60
    Respiratory, thoracic and mediastinal disorders
      CoughÞ150100
    Gastrointestinal disorders
      Diarrhea140.8120.9
      Constipation100.4180
      Nausea100331.3
    General disorders
      Fatigueè141.3211.8
    Neoplasms
      Second primary malignancyð13§61.30.4
    Nervous system disorders
      HeadacheÞ12080
      Dizzinessø110.850

    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*BRUKINSABR
    All Grades
    (%)
    Grade 3 or 4
    (%)
    All Grades
    (%)
    Grade 3 or 4
    (%)
    *
    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.
    Lymphocytes increased in 15%.
    Non-fasting conditions.
    Hematologic abnormalities
    Neutrophils decreased37158053
    Hemoglobin decreased292.5668
    Platelets decreased271.76111
    Leukocytes increased21210.40.4
    Chemistry abnormalities
    Glucose increased5576710
    Creatinine increased220.8180.4
    Magnesium increased220140.4
    Alanine aminotransferase increased212.1232.2

    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
    (%)
    *
    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.
    Pneumonia: pneumonia, COVID-19 pneumonia, lower respiratory tract infection, and related terms including specific types of infection.
    Includes 1 fatal outcome.
    §
    Musculoskeletal pain: musculoskeletal pain, arthralgia, back pain, pain in extremity, myalgia, neck pain, bone pain.
    Rash: Rash, dermatitis, toxic skin eruption, and related terms.
    #
    Bruising: all terms containing bruise, bruising, contusion, or ecchymosis.
    Þ
    Hemorrhage: all terms containing hematoma, hemorrhage, hemorrhagic, and related terms indicative of bleeding.
    ß
    Second primary malignancy: includes non-melanoma skin cancer, malignant solid tumors (including bladder, lung, renal, breast, prostate, ovarian, pelvis, and ureter), and malignant melanoma.
    à
    Includes non-melanoma skin cancer in 13%.
    è
    Includes multiple similar adverse reaction terms.
    ð
    Fatigue: fatigue, asthenia, and lethargy.
    Infections and infestations
      Upper respiratory tract infection*380.0
      Pneumonia208
    Musculoskeletal and connective tissue disorders
      Musculoskeletal pain§382.7
    Skin and subcutaneous tissue disorders
      Rash280.0
      Bruising#260.9
    Vascular disorders
      HemorrhageÞ284.5
      Hypertensionè115.4
    Neoplasms
      Second primary malignancyß22à6
    Gastrointestinal disorders
      Diarrhea180.9
      Nausea160.0
      Constipation150.0
      Abdominal painè121.8
    Respiratory, thoracic and mediastinal disorders
      Coughè180.0
      Dyspneaè130.0
    General disorders and administration site conditions
      Fatigueð140.9
    Nervous system disorders
      Headache111.8

    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*BRUKINSA
    All Grades (%)Grade 3 or 4 (%)
    *
    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.
    Grade 4, 9%.
    Non-fasting conditions.
    Hematologic abnormalities
    Neutrophils decreased4219
    Hemoglobin decreased263.6
    Platelets decreased230.9
    Chemistry abnormalities
    Glucose increased526
    Magnesium increased310
    Creatinine increased270.9

    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
    (%)
    *
    Upper respiratory tract infection: upper respiratory tract infection, sinusitis, pharyngitis, rhinitis, nasopharyngitis, laryngitis, tonsillitis, and related terms.
    Pneumonia: Pneumonia, COVID-19 pneumonia, lower respiratory tract infection, lung infiltration, and related terms including specific types of infection.
    Includes fatal outcomes: pneumonia (9 patients), COVID-19 (8 patients), and hemorrhage (1 patient).
    §
    Includes fatal outcomes: pneumonia (10 patients), COVID-19 (9 patients), and hemorrhage (2 patients).
    COVID-19: COVID-19, COVID-19 pneumonia, post-acute COVID-19 syndrome, SARS-CoV-2 test positive.
    #
    Musculoskeletal pain: musculoskeletal pain, arthralgia, back pain, pain in extremity, myalgia, neck pain, spinal pain, bone pain, and musculoskeletal discomfort.
    Þ
    Hemorrhage: all terms containing hematoma, hemorrhage, hemorrhagic, and related terms indicative of bleeding.
    ß
    Includes multiple similar adverse reaction terms.
    à
    Rash: Rash, Dermatitis, and related terms.
    è
    Bruising: all terms containing bruise, bruising, contusion, or ecchymosis.
    ð
    Fatigue: asthenia, fatigue, lethargy.
    Infections and infestations
      Upper respiratory tract infection*271.2221.2
      Pneumonia18919§11
      COVID-1914710§4.6
    Musculoskeletal and connective tissue disorders
      Musculoskeletal pain#260.6280.6
    Vascular disorders
      HemorrhageÞ242.526§3.7
      Hypertensionß19132013
    Skin and subcutaneous tissue disorders
      Rashà201.2210.9
      Bruisingè160.0140.0
    Gastrointestinal disorders
      Diarrhea 141.5220.9
    General disorders
      Fatigueð130.9140.9
    Respiratory, thoracic and mediastinal disorders
      Coughß110.3110.0
    Nervous system disorders
      Dizzinessß100.070.0

    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*BRUKINSAIbrutinib
    All Grades
    (%)
    Grade 3 or 4
    (%)
    All Grades
    (%)
    Grade 3 or 4
    (%)
    *
    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.
    Hematologic abnormalities
    Neutrophils decreased43153316
    Hemoglobin decreased284323.7
    Lymphocytes increased24192619
    Platelets decreased224243.4
    Chemistry abnormalities
    Glucose increased525292.8
    Creatinine increased260230
    Phosphate decreased212.5132.2
    Calcium decreased210.6290
  • 7 DRUG INTERACTIONS

    7.1 Effect of Other Drugs on BRUKINSA

    Table 15: 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
    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
  • 8 USE IN SPECIFIC POPULATIONS

    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 post-implantation loss at the highest dose. The dose of 150 mg/kg is approximately 32 times the exposure (AUC) in patients at the recommended dose and was associated with maternal toxicity.

    In 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 in pediatric patients have not been established.

    8.5 Geriatric Use

    Of the 1550 patients with MCL, MZL, WM, and CLL/SLL in clinical studies with BRUKINSA, 61% were ≥65 years of age, and 22% 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 (63% and 47%, respectively) than patients <65 years of age (57% and 36%, 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)].

  • 11 DESCRIPTION

    BRUKINSA (zanubrutinib) is a kinase inhibitor. The empirical formula of zanubrutinib is C27H29N5O3 and the chemical name is (S)-7-(1-acryloylpiperidin-4-yl)-2-(4-phenoxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide. Zanubrutinib is 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:

    Chemical 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.

  • 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 (Cmax) 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 Cmax is 295 (55%) ng/mL following 160 mg twice daily and 537 (55%) ng/mL following 320 mg once daily.

    Absorption

    The median tmax of zanubrutinib is 2 hours.

    Effect of Food

    No clinically significant differences in zanubrutinib AUC or Cmax 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 (t½) 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, Caucasian, and Other), body weight (36 to 144 kg) or mild, moderate or severe renal impairment (creatinine clearance [CLcr] ≥15 mL/min as estimated by Cockcroft-Gault). The effect of dialysis on zanubrutinib pharmacokinetics is unknown.

    Hepatic 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 Cmax and AUC (Table 16).

    Table 16: Observed or Predicted Increase in Zanubrutinib Exposure After Coadministration of CYP3A Inhibitors
    Coadministered CYP3A InhibitorIncrease in Zanubrutinib CmaxIncrease in Zanubrutinib AUC
    Observed
    Itraconazole (200 mg once daily)157%278%
    Predicted
    Clarithromycin (250 mg twice daily)175%183%
    Diltiazem (60 mg three times daily)151%157%
    Erythromycin (500 mg four times daily)284%317%
    Fluconazole (200 mg once daily)179%177%
    Fluconazole (400 mg once daily)270%284%

    CYP3A Inducers: Coadministration of multiple doses of rifampin (strong CYP3A inducer) decreased the zanubrutinib Cmax by 92% and AUC by 93%. Coadministration of multiple doses of rifabutin (moderate CYP3A inducer) decreased the zanubrutinib Cmax by 48% and AUC by 44%.

    Coadministration of multiple doses of efavirenz (moderate CYP3A inducer) is predicted to decrease zanubrutinib Cmax by 58% and AUC by 60%.

    CYP3A Substrates: Coadministration of multiple doses of zanubrutinib decreased midazolam (CYP3A substrate) Cmax by 30% and AUC by 47%.

    CYP2C19 Substrates: Coadministration of multiple doses of zanubrutinib decreased omeprazole (CYP2C19 substrate) Cmax by 20% and AUC by 36%.

    Other CYP Substrates: No clinically significant differences were observed with warfarin (CYP2C9 substrate) pharmacokinetics when coadministered with zanubrutinib.

    Transporter Systems: Coadministration of multiple doses of zanubrutinib increased digoxin (P-gp substrate) Cmax by 34% and AUC by 11%. No clinically significant differences in the pharmacokinetics of rosuvastatin (BCRP substrate) were observed when 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.

  • 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 but at the highest dose tested, morphological abnormalities in sperm and increased post-implantation loss were noted. The high dose of 300 mg/kg/day is approximately 10 times the human recommended dose, based on body surface area.

  • 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 Caucasian (78%). The MIPI score was low in 28%, intermediate in 41%, and high risk in 31%.

    Tumor response was according to the 2014 Lugano Classification for both studies, and the primary efficacy endpoint was overall response rate as assessed by an Independent Review Committee.

    Table 17: Efficacy Results in Patients with MCL by Independent Review Committee
    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.
    *
    FDG-PET scans were not required for response assessment.
    ORR (95% CI)84% (74, 91)84% (67, 95)
    CR      59%22%*
    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 (MYD88MUT) 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 versus 1-3 versus >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 18 shows the response rates in ASPEN based on IRC assessment.

    Table 18: Response Rate and Duration of Response Based on IRC Assessment in ASPEN
    Standard IWWM-6*Modified IWWM-6
    Response CategoryBRUKINSA
    (N=102)
    Ibrutinib
    (N=99)
    BRUKINSA
    (N=102)
    Ibrutinib
    (N=99)
    *
    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 criteria (Treon, 2015) require a reduction in EMD if present at baseline for VGPR to be assessed.
    2-sided Clopper-Pearson 95% confidence interval.
    §
    Estimated by Kaplan-Meier method with 95% CIs estimated using the method of Brookmeyer and Crowley.
    Response rate (CR+VGPR+PR), (%)79 (77.5)77 (77.8)79 (77.5)77 (77.8)
      95% CI (%)(68.1, 85.1)(68.3, 85.5)(68.1, 85.1)(68.3, 85.5)
      Complete Response (CR)0 (0.0)0 (0.0)0 (0.0)0 (0.0)
      Very Good Partial Response (VGPR)16 (15.7)7 (7.1)29 (28.4)19 (19.2)
      Partial Response (PR), (%)63 (61.8)70 (70.7)50 (49.0)58 (58.6)
    Duration of response (DOR), Event-free at 12 months (95% CI)§94.4%
    (85.8, 97.9)
    87.9%
    (77.0, 93.8)
    94.4%
    (85.8, 97.9)
    87.9%
    (77.0, 93.8)

    ASPEN Cohort 2

    Cohort 2 enrolled patients with MYD88 wildtype (MYD88WT) or MYD88 mutation unknown WM (N=26 and 2, respectively) and received BRUKINSA 160 mg twice daily. The median age was 72 years (range: 39 to 87) with 43% >75 years, 50% were male, 96% were White, and 4% were not reported (unknown race). 86% patients had 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 19).

    Table 19: Efficacy Results per IRC in Patients with MZL
    ParameterStudy 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.
    *
    Per 2014 CT-based Lugano criteria. FDG-PET scans were not considered for this response assessment.
    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.
    Overall Response Rate (CT-based)*
      ORR, n37 (56%) 16 (80%)
        (95% CI, %)(43, 68)(56, 94)
      CR, n13 (20%)4 (20%)
      PR, n24 (36%)12 (60%)
    Time to Response
      Median (range), months2.9 (1.8, 11.1)2.9 (2.6, 23.1)
    Duration of Response
      Median DoR (95% CI), monthsNE (NE, NE)NE (8.4, NE)
      Rate at 12 months (95% CI)85% (67, 93)72% (40, 88)

    In study BGB-3111-214, ORR prioritizing PET-CT when available (55 patients, with the remainder assessed by CT scan) was 67% (95% CI: 54, 78) with 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; NCT0333633). 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/m2/day intravenously on the first 2 days of each cycle, and rituximab was dosed at 375 mg/m2 on day 1 of Cycle 1 and 500 mg/m2 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, 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 20 and Figure 1.

    Table 20: Efficacy Results per IRC in Patients with Previously Untreated CLL/SLL without 17p Deletion in SEQUOIA (Randomized Cohort)
    Parameter*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.
    *
    Efficacy was assessed using the 2008 International Workshop for Chronic Lymphocytic Leukemia (iwCLL) guidelines and 2014 Lugano criteria for SLL.
    Based on Kaplan-Meier estimation. Estimated median follow-up for PFS was 25.0 months.
    Based on a stratified Cox-regression model with bendamustine + rituximab as the reference group.
    §
    Based on a stratified log-rank test, with a 2-sided significance level of 0.0372.
    Defined as CR, CRi, PR and nPR. No patients had CRi as best response.
    Progression-free survival
    Number of Events, n36 (15%)71 (30%)
      Disease Progression27 (11%)59 (25%)
      Death9 (3.7%)12 (5%)
    Median PFS (95% CI), monthsNE (NE, NE)33.7 (28.1, NE)
    HR (95% CI)0.42 (0.28, 0.63)
    P-value§<0.0001
    Overall response rate
    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

    Figure 1

    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.

    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 21.

    Table 21: Efficacy Results Per IRC in Patients with Previously Untreated CLL/SLL and 17p Deletion in SEQUOIA
    Parameter*del(17p) CLL/SLL
    N=110
    DOR=duration of response. A + sign indicates a censored observation.
    *
    Efficacy was assessed using the 2008 iwCLL guidelines and Lugano criteria for SLL.
    Defined as CR, CRi, PR and nPR. No patients had CRi as best response.
    Kaplan-Meier estimate. Estimated median follow-up for DOR was 25.1 months.
    Overall response rate
    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), months2.9 (1.9 to 13.9)
    Duration of response
    Median DOR (95% CI), monthsNE (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, 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. Efficacy results are shown in Table 22.

    Table 22: Efficacy Results per IRC in Patients with Relapsed or Refractory CLL/SLL in ALPINE
    Outcome*Zanubrutinib
    (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.
    *
    Efficacy was based on 2008 iwCLL guidelines for CLL and the Lugano criteria for SLL.
    Defined as CR + CRi + nPR + PR. No patients had CRi as best response.
    Estimate stratified by randomization stratification factors.
    §
    2-sided significance level of 0.0469 was allocated for ORR superiority testing.
    Based on Kaplan-Meier estimate. Estimated median follow-up for DOR was 14.1 months.
    Overall response rate
        ORR, n (%)263 (80)237 (73)
        (95% CI, %)(76, 85)(68, 78)
    CR, n (%)13 (4.0)8 (2.5)
    nPR, n (%)1 (0.3)0 (0)
    PR, n (%)249 (76)229 (70)
    Response Rate Ratio (95% CI)1.10 (1.01, 1.20)
    2-sided p-value§0.0264
    Time to response
    Median (range), months5.5 (2.6 to 22.1)5.6 (2.3 to 19.8)
    Duration of response
    Median DOR (95% CI)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)

    At the time of analysis, overall survival data were immature. With an estimated median follow-up of 24.7 months, median overall survival was not reached in either arm with 11% of patients experiencing an event.

  • 16 HOW SUPPLIED/STORAGE AND HANDLING

    How Supplied

    Package SizeContentNDC Number
    120-countBottle 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].

  • 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 women 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 UNCLASSIFIED SECTION

    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. 2023

  • PATIENT PACKAGE INSERT

    PATIENT INFORMATION
    BRUKINSA® (BROO-kin-sah)
    (zanubrutinib)
    capsules
    This Patient Information has been approved by the U.S. Food and Drug Administration.Revised: 1/2023
    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).
    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
    • upper respiratory tract infection
    • decreased platelet count
    • 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. 2023
    For more information, go to www.BRUKINSA.com or call 1-833-969-2463.
  • PRINCIPAL DISPLAY PANEL - 80 mg Capsule Carton

    NDC 72579-011-02
    Rx only

    Brukinsa®
    zanubrutinib
    capsules

    80 mg

    Do not open, break or
    chew the capsules

    120 Capsules

    PRINCIPAL DISPLAY PANEL - 80 mg Capsule Carton
  • INGREDIENTS AND APPEARANCE
    BRUKINSA 
    zanubrutinib capsule
    Product Information
    Product TypeHUMAN PRESCRIPTION DRUGItem Code (Source)NDC:72579-011
    Route of AdministrationORAL
    Active Ingredient/Active Moiety
    Ingredient NameBasis of StrengthStrength
    ZANUBRUTINIB (UNII: AG9MHG098Z) (ZANUBRUTINIB - UNII:AG9MHG098Z) ZANUBRUTINIB80 mg
    Inactive Ingredients
    Ingredient NameStrength
    SILICON DIOXIDE (UNII: ETJ7Z6XBU4)  
    CROSCARMELLOSE SODIUM (UNII: M28OL1HH48)  
    MAGNESIUM STEARATE (UNII: 70097M6I30)  
    MICROCRYSTALLINE CELLULOSE (UNII: OP1R32D61U)  
    SODIUM LAURYL SULFATE (UNII: 368GB5141J)  
    GELATIN, UNSPECIFIED (UNII: 2G86QN327L)  
    TITANIUM DIOXIDE (UNII: 15FIX9V2JP)  
    FERROSOFERRIC OXIDE (UNII: XM0M87F357)  
    Product Characteristics
    ColorWHITE (off-white) Scoreno score
    ShapeCAPSULESize22mm
    FlavorImprint Code ZANU;80
    Contains    
    Packaging
    #Item CodePackage DescriptionMarketing Start DateMarketing End Date
    1NDC:72579-011-021 in 1 CARTON11/14/2019
    1120 in 1 BOTTLE, PLASTIC; Type 0: Not a Combination Product
    2NDC:72579-011-011 in 1 CARTON11/14/201909/30/2021
    260 in 1 BOTTLE, PLASTIC; Type 0: Not a Combination Product
    Marketing Information
    Marketing CategoryApplication Number or Monograph CitationMarketing Start DateMarketing End Date
    NDANDA21321711/14/2019
    Labeler - BEIGENE USA, INC. (081210042)
    Establishment
    NameAddressID/FEIBusiness Operations
    AndersonBrecon Inc.053217022PACK(72579-011) , LABEL(72579-011)
    Establishment
    NameAddressID/FEIBusiness Operations
    Changzhou SynTheAll Pharmaceutical Co., Ltd544385021ANALYSIS(72579-011) , API MANUFACTURE(72579-011)
    Establishment
    NameAddressID/FEIBusiness Operations
    Catalent CTS, LLC962674474ANALYSIS(72579-011) , MANUFACTURE(72579-011)
    Establishment
    NameAddressID/FEIBusiness Operations
    Beigene (Suzhou) Co.,Ltd543941083ANALYSIS(72579-011)