Brukinsa

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Description for Brukinsa

BRUKINSA (zanubrutinib) is a Bruton’s tyrosine kinase (BTK) inhibitor. The empirical formula of zanubrutinib is C₂₇H₂₉N₅O₃ and the chemical name is (S)-7-(1-acryloylpiperidin-4-yl)-2-(4phenoxyphenyl)-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.

Uses for Brukinsa

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.

Waldenström’s Macroglobulinemia

BRUKINSA is indicated for the treatment of adult patients with Waldenström’s macroglobulinemia (WM) [see Clinical Studies (14.2)].

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.

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)].

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.

Dosage for Brukinsa

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.

Capsule Administration Instructions

• Administer BRUKINSA capsules with or without food [see Clinical Pharmacology (12.3)]. Advise patients to swallow capsules whole with water and not to open, break, or chew

Tablet Administration Instructions

• Administer BRUKINSA tablets with or without food [see Clinical Pharmacology (12.3)]. Advise patients to swallow tablets whole with water and not to chew or crush the The tablets can be split in half as prescribed by the healthcare provider.

Missed Dose

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.

Dosage Modification for Use in Hepatic Impairment

The recommended dosage of BRUKINSA for patients with severe hepatic impairment (Child- Pugh class C) is 80 mg orally twice daily; no dosage modification is recommended for patients with mild or moderate hepatic impairment (Child-Pugh class A or B) [see Use in Specific Populations (8.7) and Clinical Pharmacology (12.3)].

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 dailya	80 mg twice dailyb
Clarithromycin 500 mg twice daily	80 mg once dailyb
Posaconazole suspension 100 mg once daily	80 mg twice dailyb
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 dailyb
Other strong CYP3A inhibitor	80 mg once dailyb
Moderate CYP3A inhibitor	80 mg twice dailyb
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.
a 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)]. b Modify or interrupt zanubrutinib dose as recommended for adverse reactions [see Dosage and Administration (2.4)].

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)].

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/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
Nonhematological toxicities [see Warnings and Precautions (5.5) and Adverse Reactions (6.1)]
Severe or life-threatening nonhematological toxicitiesa	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.a
	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
a Evaluate the benefit-risk before resuming treatment at the same dosage for Grade 4 nonhematological toxicity.

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.

HOW SUPPLIED

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.

Tablets: 160 mg, blue, oval, film-coated tablets debossed with “zanu” on one side and functional scoring on the other side.

How Supplied

Strength	Description	Package Size	NDC Number
80 mg	white to off-white opaque capsule, marked with “ZANU 80” in black ink	120-count capsules in a bottle with a child- resistant cap	72579-011-02
160 mg	blue, oval, film-coated tablets debossed with “zanu” on one side and functional scoring on the other side	60-count tablets in a bottle with a child- resistant cap	72579-122-01

Storage

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

BRUKINSA Capsules: Manufactured for: BeOne Medicines USA, Inc. Pennington, NJ 08534

BRUKINSA Tablets: Manufactured for: BeOne Medicines USA, Inc. Pennington, NJ 08534

Manufactured by: Catalent Pharma Solutions, LLC Winchester, KY 40391

BRUKINSA^® is a registered trademark owned by BeOne Medicines I GmbH or its affiliates.

© BeOne Medicines I GmbH, 2025. All Rights Reserved.

Side Effects for Brukinsa

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)]
• Hepatotoxicity, including DILI [see Warnings and Precautions (5.6)]

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 × 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 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 infectiona	39	0
	Pneumoniab	15	10c
	Urinary tract infection	11	0.8
Skin and subcutaneous tissue disorders	Rashd	36	0
	Bruisinge	14	0
Gastrointestinal disorders	Diarrhea	23	0.8
	Constipation	13	0
Vascular disorders	Hypertension	12	3.4
	Hemorrhagef	11	3.4c
Musculoskeletal and connective tissue disorders	Musculoskeletal paing	14	3.4
Respiratory, thoracic, and mediastinal disorders	Cough	12	0
a Upper respiratory tract infection includes upper respiratory tract infection, upper respiratory tract infection viral. b 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. c Includes fatal adverse reaction. d Rash includes all related terms containing rash. e Bruising includes all related terms containing bruise, bruising, contusion, ecchymosis. f Hemorrhage includes all related terms containing hemorrhage, hematoma. g Musculoskeletal pain includes musculoskeletal pain, musculoskeletal discomfort, myalgia, back pain, arthralgia, arthritis.

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 Abnormalitiesa (>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
Lymphocytosisb	41	16
Platelets decreased	40	7
Hemoglobin decreased	27	6
Chemistry abnormalities
Blood uric acid increased	29	2.6
ALT increased	28	0.9

Laboratory Parameter	Percent of Patients (N=118)
	All Grades (%)	Grade 3 or 4 (%)
Bilirubin increased	24	0.9
a Based on laboratory measurements. b Asymptomatic lymphocytosis is a known effect of BTK inhibition.

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 infectiona	44	0	40	2
	Pneumoniab	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	Fatiguec	31	1	25	1
	Pyrexia	16	4	13	2
	Edema peripheral	12	0	20	0
Skin and subcutaneous tissue disorders	Bruisingd	20	0	34	0
	Rashe	29	0	32	0
	Pruritus	11	1	6	0
Musculoskeletal and connective tissue disorders	Musculoskeletal painf	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	Hemorrhageg	42	4	43	9
	Hypertension	14	9	19	14
a 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. b Pneumonia includes lower respiratory tract infection, lung infiltration, pneumonia, pneumonia aspiration, pneumonia viral. c Fatigue includes asthenia, fatigue, lethargy. d Bruising includes all related terms containing bruise, contusion, or ecchymosis. e 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. f Musculoskeletal pain includes back pain, arthralgia, pain in extremity, musculoskeletal pain, myalgia, bone pain, spinal pain, musculoskeletal chest pain, neck pain, arthritis, musculoskeletal discomfort. g 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

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^a (≥20%) that Worsened from Baseline in Patients with WM Who Received BRUKINSA in Cohort 1

Laboratory Abnormality	BRUKINSAb		Ibrutinibb
	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
a Based on laboratory measurements. b 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.

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 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 infectiona	26	3.4
	Urinary tract infectionb	11	2.3
	Pneumoniac,d	10	6
Gastrointestinal disorders	Diarrheae	25	3.4
	Abdominal painf	14	2.3
	Nausea	13	0
Skin and subcutaneous tissue disorders	Bruisingg	24	0
	Rashh	21	0
Musculoskeletal and connective tissue disorders	Musculoskeletal paini	27	1.1
Vascular disorders	Hemorrhagej	23	1.1
General disorders	Fatiguek	21	2.3
Respiratory, thoracic, and mediastinal disorders	Coughl	10	0
a Upper respiratory tract infection includes upper respiratory tract infection, nasopharyngitis, sinusitis, tonsillitis, rhinitis, viral upper respiratory tract infection. b Urinary tract infection includes urinary tract infection, cystitis, Escherichia urinary tract infection, pyelonephritis, cystitis. c Pneumonia includes COVID-19 pneumonia, pneumonia, bronchopulmonary aspergillosis, lower respiratory tract infection, organizing pneumonia. d Includes 2 fatalities from COVID-19 pneumonia. e Diarrhea includes diarrhea and diarrhea hemorrhagic. f Abdominal pain includes abdominal pain, abdominal pain upper, abdominal discomfort. g Bruising includes contusion, ecchymosis, increased tendency to bruise, post procedural contusion. h 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. i Musculoskeletal pain includes back pain, arthralgia, musculoskeletal pain, myalgia, pain in extremity, musculoskeletal chest pain, bone pain, musculoskeletal discomfort, neck pain. j 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. k Fatigue includes fatigue, lethargy, asthenia. l Cough includes cough and productive cough.

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 Abnormalitya	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
a 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.

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/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		BR
	(N=240)		(N=227)
System Organ Class	All Grades	Grade 3	All Grades	Grade 3 or
Preferred Term	(%)	or 4	(%)	4
		(%)		(%)
Musculoskeletal and connective tissue disorders
Musculoskeletal paina	33	1.7	17	0.4
Infections and infestations
Upper respiratory tract infectionb	28	1.3	15	0.9
Pneumoniac	13*	5	8†	4
Vascular disorders
Hemorrhaged	27*	4	4	0.4
Hypertensione	14	7	5	2.6
Skin and subcutaneous tissue disorders
Rashf	24	1.3	30	5
Bruisingg	24	0	2.6	0
Respiratory, thoracic, and mediastinal disorders
Coughe	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
Fatigueh	14	1.3	21	1.8
Neoplasms

	CLL/SLL without 17p deletion
	BRUKINSA		BR
	(N=240)		(N=227)
System Organ Class	All Grades	Grade 3	All Grades	Grade 3 or
Preferred Term	(%)	or 4	(%)	4
		(%)		(%)
Second primary malignancyi	13*	6	1.3	0.4
Nervous system disorders
Headachee	12	0	8	0
Dizzinessj	11	0.8	5	0
* Includes 3 fatal outcomes. † Includes 2 fatal outcomes. a Musculoskeletal pain: musculoskeletal pain, arthralgia, back pain, pain in extremity, myalgia, neck pain, spinal pain, musculoskeletal discomfort, bone pain. b 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. c Pneumonia: pneumonia, COVID-19 pneumonia, lower respiratory tract infection, lung infiltration, and related terms including specific types of infection. d Hemorrhage: all terms containing hematoma, hemorrhage, hemorrhagic, and related terms indicative of bleeding. e Includes multiple similar adverse reaction terms. f Rash: Rash, dermatitis, drug eruption, and related terms. g Bruising: all terms containing bruise, bruising, contusion, or ecchymosis. h Fatigue: fatigue, asthenia, and lethargy. i Second primary malignancy: includes non-melanoma skin cancer, malignant solid tumors (including lung, renal, genitourinary, breast, ovarian, and rectal), and chronic myeloid leukemia. j Dizziness: dizziness and vertigo.

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 Abnormalitya	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	21b	21	0.4	0.4
Chemistry abnormalities
Glucose increasedc	55	7	67	10
Creatinine increased	22	0.8	18	0.4
Magnesium increased	22	0	14	0.4

Laboratory Abnormalitya	BRUKINSA		BR
	All Grades (%)	Grade 3 or 4 (%)	All Grades (%)	Grade 3 or 4 (%)
Alanine aminotransferase increased	21	2.1	23	2.2
a 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. b Lymphocytes increased in 15%. c Nonfasting conditions.

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

System Organ Class Preferred Term	CLL/SLL with 17p Deletion
	BRUKINSA (N=111)
	All Grades (%)	Grade 3 or 4 (%)
Infections and infestations
Upper respiratory tract infectiona	38	0
Pneumoniab	20*	8
Musculoskeletal and connective tissue disorders
Musculoskeletal painc	38	2.7
Skin and subcutaneous tissue disorders
Rashd	28	0
Bruisinge	26	0.9
Vascular disorders
Hemorrhagef	28	4.5
Hypertensiong	11	5.4

System Organ Class Preferred Term	CLL/SLL with 17p Deletion
	BRUKINSA (N=111)
	All Grades (%)	Grade 3 or 4 (%)
Neoplasms
Second primary malignancyh	22†	6
Gastrointestinal disorders
Diarrhea	18	0.9
Nausea	16	0
Constipation	15	0
Abdominal paing	12	1.8
Respiratory, thoracic, and mediastinal disorders
Coughg	18	0
Dyspneag	13	0
General disorders and administration site conditions
Fatiguei	14	0.9
Nervous system disorders
Headache	11	1.8
* Includes 1 fatal outcome. † Includes non-melanoma skin cancer in 13%. a 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. b Pneumonia: pneumonia, COVID-19 pneumonia, lower respiratory tract infection, and related terms including specific types of infection. c Musculoskeletal pain: musculoskeletal pain, arthralgia, back pain, pain in extremity, myalgia, neck pain, bone pain. d Rash: Rash, dermatitis, toxic skin eruption, and related terms. e Bruising: all terms containing bruise, bruising, contusion, or ecchymosis. f Hemorrhage: all terms containing hematoma, hemorrhage, hemorrhagic, and related terms indicative of bleeding. g Includes multiple similar adverse reaction terms. h Second primary malignancy: includes non-melanoma skin cancer, malignant solid tumors (including bladder, lung, renal, breast, prostate, ovarian, pelvis, and ureter), and malignant melanoma. i Fatigue: fatigue, asthenia, and lethargy.

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 Abnormalitya	BRUKINSA
	All Grades (%)	Grade 3 or 4 (%)
Hematologic abnormalities
Neutrophils decreased	42	19b
Hemoglobin decreased	26	3.6
Platelets decreased	23	0.9
Chemistry abnormalities
Glucose increasedc	52	6
Magnesium increased	31	0
Creatinine increased	27	0.9
a 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. b Grade 4, 9%. c Nonfasting conditions.

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 infectiona	27	1.2	22	1.2
Pneumoniab	18*	9	19†	11
COVID-19c	14*	7	10†	4.6
Musculoskeletal and connective tissue disorders
Musculoskeletal paind	26	0.6	28	0.6
Vascular disorders
Hemorrhagee	24*	2.5	26†	3.7
Hypertensionf	19	13	20	13
Skin and subcutaneous tissue disorders
Rashg	20	1.2	21	0.9
Bruisingh	16	0	14	0
Gastrointestinal disorders
Diarrhea	14	1.5	22	0.9
General disorders
Fatiguei	13	0.9	14	0.9
Respiratory, thoracic, and mediastinal disorders
Coughf	11	0.3	11	0
Nervous system disorders
Dizzinessf	10	0	7	0
* 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). a Upper respiratory tract infection: upper respiratory tract infection, sinusitis, pharyngitis, rhinitis, nasopharyngitis, laryngitis, tonsillitis, and related terms. b Pneumonia: Pneumonia, COVID-19 pneumonia, lower respiratory tract infection, lung infiltration, and related terms including specific types of infection. c COVID-19: COVID-19, COVID-19 pneumonia, postacute COVID-19 syndrome, SARS-CoV-2 test positive. d Musculoskeletal pain: musculoskeletal pain, arthralgia, back pain, pain in extremity, myalgia, neck pain, spinal pain, bone pain, and musculoskeletal discomfort. e Hemorrhage: all terms containing hematoma, hemorrhage, hemorrhagic, and related terms indicative of bleeding. f Includes multiple similar adverse reaction terms. g Rash: Rash, Dermatitis, and related terms. h Bruising: all terms containing bruise, bruising, contusion, or ecchymosis. i Fatigue: asthenia, fatigue, lethargy.

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 Abnormalitya	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
a 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.

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 × 10⁹/L, platelet count ≥50 × 10⁹/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
Fatiguea,b	27	1.4	25	1.4
Pyrexia	13	0	20	0
Musculoskeletal and connective tissue disorders
Musculoskeletal paina,c	22	3.5	23	1.4
Vascular disorders
Hemorrhagea,d	20	1.4	10	1.4
Gastrointestinal disorders
Diarrhea	18	2.8	17	1.4
Constipation	13	0	9	0
Abdominal paina	11	2.1	11	0
Infections and infestations
Upper respiratory tract infectiona,e	17	2.8	10	0
Pneumoniaa,f,*	15	13	11	7
COVID-19a,*	13	9	11	4.2
Herpes virus infectiong	11	2.1	1.4	0
Urinary tract infectionh	10	1.4	7	0
Respiratory, thoracic, and mediastinal disorders
Cougha	14	0	14	0
Dyspneaa,*	11	2.1	13	0
Skin and subcutaneous tissue disorders
Rasha,i	11	0	14	0
* Includes fatal outcomes: COVID-19 (3 patients), pneumonia (2 patients), dyspnea (1 patient). a Includes multiple related terms. b Fatigue: Fatigue, asthenia, and lethargy. c 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. d Hemorrhage: All terms containing hematoma, hemorrhage, hemorrhagic, and related terms indicative of bleeding. e Upper respiratory tract infection: Upper respiratory tract infection, sinusitis, pharyngitis, laryngitis, rhinitis, nasopharyngitis, laryngopharyngitis, tonsillitis bacterial, and related terms. f Pneumonia: Pneumonia, COVID-19 pneumonia, lung infiltration, lung consolidation, and related terms including specific types of infection. g Herpes virus infection: Herpes viral infection, herpes zoster, herpes simplex, herpes simplex reactivation, varicella, and Epstein-Barr viremia. h Urinary tract infection: Urinary tract infection, cystitis, pyelonephritis, and related terms. i Rash: Rash, erythema, dermatitis, drug eruption, skin reaction, and related terms.

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 Abnormalitya	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 increasedb	53	8	41	9
Alanine aminotransferase increased	23	0	28	0
Phosphate decreased	21	0.8	14	0
a 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. b Nonfasting conditions.

Postmarketing Experience

The following adverse reactions have been identified during postapproval use of BRUKINSA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

• Hepatobiliary disorder: drug-induced liver injury

Drug Interactions for Brukinsa

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 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)].

Warnings for Brukinsa

Included as part of the PRECAUTIONS section.

Precautions for Brukinsa

Hemorrhage

Fatal and serious hemorrhage has occurred in patients with hematological malignancies treated with BRUKINSA. Grade 3 or higher hemorrhage including intracranial and gastrointestinal hemorrhage, hematuria, and hemothorax was reported in 3.8% of patients treated with BRUKINSA in clinical trials, with fatalities occurring in 0.2% of patients. Bleeding of any grade, excluding purpura and petechiae, occurred in 32% 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 before and after surgery depending upon the type of surgery and the risk of bleeding.

Infections

Fatal and serious infections (including bacterial, viral, or fungal infections) and opportunistic infections have occurred in patients with hematological malignancies treated with BRUKINSA. Grade 3 or higher infections occurred in 26% of patients, most commonly pneumonia (7.9%), with fatal infections occurring in 3.2% 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.

Cytopenias

Grade 3 or 4 cytopenias, including neutropenia (21%), thrombocytopenia (8%), and anemia (8%) based on laboratory measurements, developed in patients treated with BRUKINSA [see Adverse Reactions (6.1)]. Grade 4 neutropenia occurred in 10% of patients, and Grade 4 thrombocytopenia occurred in 2.5% 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.

Second Primary Malignancies

Second primary malignancies, including non-skin carcinoma, have occurred in 14% of patients treated with BRUKINSA. The most frequent second primary malignancy was non-melanoma skin cancers (8%), followed by other solid tumors in 7% of the patients (including melanoma in 1% of patients) and hematologic malignancies (0.7%). Advise patients to use sun protection and monitor patients for the development of second primary malignancies.

Cardiac Arrhythmias

Serious cardiac arrhythmias have occurred in patients treated with BRUKINSA. Atrial fibrillation and atrial flutter were reported in 4.4% of patients treated with BRUKINSA, including Grade 3 or higher cases in 1.9% 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 0.3% 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.

Hepatotoxicity, Including Drug-Induced Liver Injury

Hepatotoxicity, including severe, life-threatening, and potentially fatal cases of drug-induced liver injury (DILI), has occurred in patients treated with Bruton tyrosine kinase inhibitors, including BRUKINSA.

Evaluate bilirubin and transaminases at baseline and throughout treatment with BRUKINSA. For patients who develop abnormal liver tests after BRUKINSA, monitor more frequently for liver test abnormalities and clinical signs and symptoms of hepatic toxicity. If DILI is suspected, withhold BRUKINSA. Upon confirmation of DILI, discontinue BRUKINSA.

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)].

NONCLINICAL TOXICOLOGY

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.

Overdose Information for Brukinsa

No Information Provided

Contraindications for Brukinsa

None.

Clinical Pharmacology for Brukinsa

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

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.

In Vitro Platelet Aggregation

In blood samples from healthy donors, patients on anticoagulant or antiplatelet therapy, and those with severe renal dysfunction, zanubrutinib demonstrated inhibition of platelet aggregation mediated by collagen, CRP-XL, or rhodocytin. Zanubrutinib did not show meaningful inhibition of platelet aggregation for ADP and PAR4-AP.

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

BRUKINSA Capsules

Zanubrutinib AUC decreased 7% and Cmax increased 3% following administration of BRUKINSA capsules with a high-fat meal (1,000 calories, 50% fat) in healthy subjects.

BRUKINSA Tablets

Zanubrutinib AUC increased up to 17% and Cmax up to 79% following administration of BRUKINSA tablets with a high-fat meal (1,000 calories, 50% 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, 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 Cmax and AUC (Table 18).

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)a	157%	278%
Fluconazole (400 mg once daily)b	81%	88%
Diltiazem (180 mg once daily)b	62%	62%
Voriconazole (200 mg twice daily)b	229%	230%

Coadministered CYP3A Inhibitor	Increase in Zanubrutinib Cmax	Increase in Zanubrutinib AUC
Clarithromycin (250 mg twice daily)b	101%	92%
	Predicted
Posaconazole suspension (100 mg once daily)c	169%	180%
Posaconazole suspension (100 mg twice daily)c	207%	279%
Posaconazole delayed-release tablets (300 mg once daily)c	232%	407%
Posaconazole intravenously (300 mg once daily)c	205%	333%
Itraconazole (200 mg once daily)c	273%	320%
a The assessment was conducted in healthy subjects with a single dose of zanubrutinib 20 mg. b The assessment was conducted in patients with B-cell lymphoma administered multiple doses of zanubrutinib at the respective recommended zanubrutinib dosages in Table 1. c The predicted values were based on simulations with patients administered multiple doses of zanubrutinib at the respective recommended dosages in Table 1.

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.

Patient Information for Brukinsa

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)].

Hepatotoxicity, Including Drug-Induced Liver Injury

Inform patients that liver problems, including drug-induced liver injury and abnormalities in liver tests, may develop during BRUKINSA treatment. Advise patients to contact their healthcare provider immediately if they experience abdominal discomfort, dark urine, or jaundice [see Warnings and Precautions (5.6)].

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 (5.7)]. 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 capsules may be taken with or without Advise patients that BRUKINSA capsules should be swallowed whole with a glass of water and not to open, break, or chew the capsules [see Dosage and Administration (2.1)].
• BRUKINSA tablets may be taken with or without food. Advise patients that BRUKINSA tablets should be swallowed whole with a glass of water and not to chew or crush the Tablets can be split in half as prescribed by the healthcare provider [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)].