1.1 Mantle Cell Lymphoma

BRUKINSA is indicated for the treatment of adult patients with mantle cell lymphoma (MCL) who have received at least one prior therapy.

This indication is approved under accelerated approval based on overall response rate [see Clinical Studies (14.1)]. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.

1.2 Waldenström's Macroglobulinemia

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

1.3 Marginal Zone Lymphoma

BRUKINSA is indicated for the treatment of adult patients with relapsed or refractory marginal zone lymphoma (MZL) who have received at least one anti–CD20-based regimen.

This indication is approved under accelerated approval based on overall response rate [see Clinical Studies (14.3)]. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.

1.4 Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma

BRUKINSA is indicated for the treatment of adult patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) [see Clinical Studies (14.4)].

1.5 Follicular Lymphoma

BRUKINSA is indicated for the treatment of adult patients with relapsed or refractory follicular lymphoma (FL), in combination with obinutuzumab, after two or more lines of systemic therapy.

This indication is approved under accelerated approval based on response rate and durability of response [see Clinical Studies (14.5)]. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.

2.1 Recommended Dosage

The recommended dosage of BRUKINSA for monotherapy or in combination with obinutuzumab is 160 mg taken orally twice daily or 320 mg taken orally once daily until disease progression or unacceptable toxicity.

BRUKINSA can be taken with or without food. Advise patients to swallow capsules whole with water. Advise patients not to open, break, or chew the capsules. If a dose of BRUKINSA is missed, it should be taken as soon as possible on the same day with a return to the normal schedule the following day.

2.2 Dosage Modification for Use in Hepatic Impairment

The recommended dosage of BRUKINSA for patients with severe hepatic impairment is 80 mg orally twice daily [see Use in Specific Populations (8.7) and Clinical Pharmacology (12.3)].

2.3 Dosage Modifications for Drug Interactions

Recommended dosage modifications of BRUKINSA for drug interactions are provided in Table 1 [see Drug Interactions (7.1)].

After discontinuation of a CYP3A inhibitor or moderate CYP3A inducer, resume previous dose of BRUKINSA [see Dosage and Administration (2.1, 2.2) and Drug Interactions (7.1)].

2.4 Dosage Modifications for Adverse Reactions

Recommended dosage modifications of BRUKINSA for Grade 3 or higher adverse reactions are provided in Table 2.

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.

5.1 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.

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. 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.

5.3 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.

5.4 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.

5.5 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.

5.6 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.

5.7 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)].

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The data in the WARNINGS AND PRECAUTIONS reflect exposure to BRUKINSA in nine monotherapy and 2 combination clinical trials, administered at 160 mg twice daily in 1608 patients and at 320 mg once daily in 121 patients. Among these 1729 patients, the median duration of exposure was 27.6 months, 78% of patients were exposed for at least 12 months, and 60% of patients were exposed for at least 24 months.

In this pooled safety population, the most common adverse reactions (≥30%), including laboratory abnormalities, were neutrophil count decreased (51%), platelet count decreased (41%), upper respiratory tract infection (38%), hemorrhage (32%), and musculoskeletal pain (31%).

7.1 Effect of Other Drugs on BRUKINSA

8.1 Pregnancy

8.2 Lactation

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)].

8.4 Pediatric Use

Safety and effectiveness of BRUKINSA in pediatric patients have not been established.

8.5 Geriatric Use

Of the 1729 patients with MCL, MZL, WM, CLL/SLL, and FL in clinical studies with BRUKINSA, 59% were ≥65 years of age, and 21% were ≥75 years of age. Patients ≥65 years of age had numerically higher rates of Grade 3 or higher adverse reactions and serious adverse reactions (57% and 38%, respectively) than patients <65 years of age (51% and 29%, respectively). No overall differences in effectiveness were observed between younger and older patients.

8.6 Renal Impairment

No dosage modification is recommended in patients with mild, moderate, or severe renal impairment (CLcr ≥15 mL/min, estimated by Cockcroft-Gault). Monitor for BRUKINSA adverse reactions in patients on dialysis [see Clinical Pharmacology (12.3)].

8.7 Hepatic Impairment

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

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

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.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity studies have not been conducted with zanubrutinib.

Zanubrutinib was not mutagenic in a bacterial mutagenicity (Ames) assay, was not clastogenic in a chromosome aberration assay in mammalian (CHO) cells, nor was it clastogenic in an in vivo bone marrow micronucleus assay in rats.

A combined male and female fertility and early embryonic development study was conducted in rats at oral zanubrutinib doses of 30 to 300 mg/kg/day. Male rats were dosed 4 weeks prior to mating and through mating and female rats were dosed 2 weeks prior to mating and to gestation day 7. No effect on male or female fertility was noted at lower doses, but at the highest dose tested, morphological abnormalities in sperm and increased postimplantation loss were noted. The high dose of 300 mg/kg/day is approximately 10 times the human recommended dose, based on body surface area.

14.1 Mantle Cell Lymphoma

The efficacy of BRUKINSA was assessed in BGB-3111-206 [NCT03206970], a Phase 2, open-label, multicenter, single-arm trial of 86 previously treated patients with MCL who had received at least one prior therapy. BRUKINSA was given orally at a dose of 160 mg twice daily until disease progression or unacceptable toxicity.

The median age of patients was 60.5 years (range: 34 to 75) and the majority were male (78%). The median time since diagnosis to study entry was 30 months (range: 3 to 102) and the median number of prior therapies was 2 (range: 1 to 4). The most common prior regimens were CHOP-based (91%) followed by rituximab-based (74%). The majority of patients had extranodal involvement (71%) and refractory disease (52%). Blastoid variant of MCL was present in 14% of patients. The MIPI score was low in 58%, intermediate in 29%, and high risk in 13%.

The efficacy of BRUKINSA was also assessed in BGB-3111-AU-003 [NCT02343120], a Phase 1/2, open-label, dose-escalation, global, multicenter, single-arm trial of B cell malignancies including 32 previously treated MCL patients treated with BRUKINSA. BRUKINSA was given orally at doses of 160 mg twice daily or 320 mg daily. The median age of patients with previously treated MCL was 70 years (range: 42 to 86) and 38% of patients were ≥75 years old. Most patients were male (69%) and White (78%). The MIPI score was low in 28%, intermediate in 41%, and high risk in 31%.

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

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 vs 1-3 vs >3) and CXCR4 status (presence or absence of a WHIM-like mutation as measured by Sanger assay).

The major efficacy outcome was the response rate defined as PR or better as assessed by IRC based on standard consensus response criteria from the International Workshop on Waldenström's Macroglobulinemia (IWWM)-6 criteria. An additional efficacy outcome measure was duration of response (DOR).

The median age was 70 years (range: 38 to 90) and 68% were male. Of those enrolled, 2% were Asian, 91% were White, and 7% were of unknown race. ECOG performance status of 0 or 1 was present in 93% patients at baseline and 7% had a baseline ECOG performance status of 2. A total of 82% had relapsed/refractory disease with 85% having received prior alkylating agents and 91% prior anti-CD20 therapy. The median number of prior therapies in those with relapsed/refractory disease was 1 (range: 1 to 8). A total of 91 (45%) patients had International Prognostic Scoring System (IPSS) high WM.

The study did not meet statistical significance for the prespecified efficacy outcome of superior CR+VGPR as assessed by IRC, tested first in patients with R/R disease in ASPEN.

Table 20 shows the response rates in ASPEN based on IRC assessment.

14.3 Marginal Zone Lymphoma

The efficacy of BRUKINSA was assessed in Study BGB-3111-214 [NCT03846427], an open-label, multicenter, single-arm trial that evaluated 66 patients with MZL who received at least one prior anti–CD20-based therapy. BRUKINSA was given orally at a dosage of 160 mg twice daily until disease progression or unacceptable toxicity. The median age was 70 years (range: 37 to 85); 55% were male; 38% had extranodal MZL, 38% nodal, 18% splenic, and 6% had unknown subtype. The median number of prior systemic therapies was 2 (range: 1 to 6), with 27% having 3 or more lines of systemic therapy; 88% had prior rituximab-based chemotherapy; 32% had refractory disease at study entry.

The efficacy of BRUKINSA was also assessed in BGB-3111-AU-003 [NCT02343120], an open-label, multicenter, single-arm trial that included 20 patients with previously treated MZL (45% having extranodal MZL, 25% nodal, 30% splenic). BRUKINSA was given orally at dosages of 160 mg twice daily or 320 mg once daily. The median age was 70 years (range: 52 to 85); 50% were male. The median number of prior systemic therapies was 2 (range: 1 to 5), with 20% having 3 or more lines of systemic therapy; 95% had prior rituximab-based chemotherapy.

Efficacy was based on overall response rate (ORR) and duration of response as assessed by an Independent Review Committee (IRC) using 2014 Lugano criteria (Table 21).

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.

14.5 Follicular Lymphoma

The efficacy of BRUKINSA, in combination with obinutuzumab, was evaluated in Study BGB-3111-212 (ROSEWOOD; NCT03332017), an open-label, multicenter, randomized trial that enrolled 217 adult patients with relapsed or refractory FL after at least 2 prior systemic treatments. The study required prior receipt of an anti-CD20 antibody and an alkylator-based combination therapy, and excluded patients with FL Grade 3b, transformed lymphoma, and prior exposure to a BTK inhibitor.

Patients were randomized in a 2:1 ratio to receive either BRUKINSA 160 mg orally twice daily until disease progression or unacceptable toxicity plus obinutuzumab, or obinutuzumab alone. Obinutuzumab was administered 1,000 mg intravenously on days 1, 8, and 15 of Cycle 1, 1,000 mg on Day 1 of Cycles 2 to 6; and then 1,000 mg every 8 weeks for up to 20 doses. At the discretion of the investigator, obinutuzumab could be administered as 100 mg on Day 1 and 900 mg on Day 2 of Cycle 1.

Randomization was stratified by the number of prior lines of therapy (2 to 3 vs ˃3), rituximab-refractory status (yes vs no), and geographic region.

Of the 217 patients randomized (145 to BRUKINSA plus obinutuzumab, 72 to obinutuzumab monotherapy), the median age was 64 years (range: 31 to 88), 50% were male, 64% were White, and 22% were Asian. In total, 83% had stage 3 or 4 disease and 57% met Groupe d'Etude des Lymphomes Folliculaires (GELF) criteria at enrollment. Patients had a median of 3 prior lines of therapy (range: 2-11), with 27% of patients having more than 3 prior lines of therapy.

In the BRUKINSA in combination with obinutuzumab arm, 5% had received lenalidomide plus rituximab, 21% had received stem cell transplantation, 53% had refractory disease to rituximab, and 37% had progression of disease within 24 months of the first systemic therapy.

Efficacy was based on overall response rate and duration of response, as determined by an IRC. Efficacy results are shown in Table 25. The median time to response in the BRUKINSA combination arm was 2.8 months (range 2 to 23 months).

The estimated DOR rate at 18 months was 69% (95% CI: 58, 78) in the BRUKINSA combination arm and 42% (95% CI: 23, 60) in the obinutuzumab monotherapy arm.

How Supplied

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].

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 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)].