Brukinsa Drug Information

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. Advise patients to swallow capsules whole with water and not to open, break, or chew capsules.

Tablet Administration Instructions Administer BRUKINSA tablets with or without food. Advise patients to swallow tablets whole with water and not to chew or crush the tablets. 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).

Dosage Modifications for Drug Interactions

Recommended dosage modifications of BRUKINSA for drug interactions are provided in Table 1. Table 1: Dosage Modifications for Use with CYP3A Inhibitors or Inducers Coadministered Drug Recommended BRUKINSA Dosage (Starting Dose: 160 mg twice daily or 320 mg once daily) Clarithromycin 250 mg twice daily Since clarithromycin 250 mg twice daily acts as a moderate CYP3A inhibitor, it is recommended that patients be administered clarithromycin 250 mg twice daily with 80 mg BRUKINSA twice daily. 80 mg twice daily Modify or interrupt zanubrutinib dose as recommended for adverse reactions. After discontinuation of a CYP3A inhibitor or moderate CYP3A inducer, resume previous dose of BRUKINSA.

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 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.

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. 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 and BGB-3111-AU-003. The median age of patients who received % 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). 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 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 4: Selected Laboratory Abnormalities Based on laboratory measurements. > Waldenström's Macroglobulinemia (WM) The safety of BRUKINSA was investigated in two cohorts of Study BGB-3111-302 (ASPEN).

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. In Cohort 1, serious adverse reactions occurred in 44% of patients who received BRUKINSA. In Cohort 2, serious adverse reactions occurred in 39% of patients.

Serious adverse reactions in >2 patients included pneumonia (14%). 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.

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 Clinically relevant adverse reactions in <10% of patients who received BRUKINSA included localized infection, atrial fibrillation or atrial flutter, and hematuria. Table 6 summarizes the laboratory abnormalities in ASPEN. Table 6: Select Laboratory Abnormalities Based on laboratory measurements. (≥20%) that Worsened from Baseline in Patients with WM Who Received was evaluated in 88 patients with previously treated MZL in two single-arm clinical studies, BGB-3111-214 and BGB-3111-AU-003.

The trials required an absolute neutrophil count ≥1 × 10 9 /L, platelet count /L and adequate hepatic function and excluded patients requiring a strong CYP3A inhibitor or inducer. 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- 0 Clinically relevant adverse reactions in <10% of patients who received BRUKINSA included peripheral neuropathy, second primary malignancies, dizziness, edema, headache, petechiae, purpura, and atrial fibrillation or flutter.

Table 8 summarizes select laboratory abnormalities. Table 8: Select Laboratory Abnormalities (≥20%) that Worsened from Baseline in Patients with MZL 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. 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. 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). 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).

The median duration of exposure to BRUKINSA was 26 months, with 71% exposed for more than 2 years. 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 10 summarizes select laboratory abnormalities in this cohort. 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 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 monotherapy was evaluated in patients with previously treated CLL/SLL in a randomized, multicenter, open-label, actively controlled trial. 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. 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. Table 13 summarizes select adverse reactions in ALPINE. Table 14 summarizes select laboratory abnormalities in ALPINE.

Table 14: Select Laboratory Abnormalities (≥20%) that Worsened from Baseline in Patients Who Received 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. 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). 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%). 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 0 Clinically relevant adverse reactions in <10% of patients who received BRUKINSA in combination with obinutuzumab included bruising, edema, pruritus, petechiae, vomiting, headache, arthralgia, hypertension, sepsis, cardiac arrhythmias, renal insufficiency, febrile neutropenia, transaminase elevation, and pneumonitis. 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

Effect of Other Drugs on BRUKINSA Table 17: Drug Interactions that Affect Zanubrutinib Moderate and Strong CYP3A Inhibitors Clinical Impact Coadministration with a moderate or strong CYP3A inhibitor increases zanubrutinib C max and AUC which may increase the risk of BRUKINSA toxicities. Prevention or management Reduce BRUKINSA dosage when coadministered with moderate or strong CYP3A inhibitors. Moderate and Strong CYP3A Inducers Clinical Impact Coadministration with a moderate or strong CYP3A inducer decreases zanubrutinib C max and AUC which may reduce BRUKINSA efficacy.

Prevention or management Avoid coadministration of BRUKINSA with strong CYP3A inducers. Avoid coadministration of BRUKINSA with moderate CYP3A inducers. If these inducers cannot be avoided, increase BRUKINSA dosage to 320 mg twice daily.

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 respectively. Data Animal Data Embryo-fetal development toxicity studies were conducted in both rats and rabbits.

Zanubrutinib was administered orally to pregnant rats during the period of organogenesis at doses of 30, 75, and 150 mg/kg/day. Malformations in the heart (2 or 3-chambered hearts) were noted at all dose levels in the absence of maternal toxicity. The dose of 30 mg/kg/day is approximately 5 times the exposure (AUC) in patients receiving the recommended dose of 160 mg twice daily.

Administration of zanubrutinib to pregnant rabbits during the period of organogenesis at 30, 70, and 150 mg/kg/day resulted in postimplantation loss at the highest dose. The dose of 150 mg/kg is approximately 32 times the exposure (AUC) in patients at the recommended dose and was associated with maternal toxicity. In a pre and postnatal developmental toxicity study, zanubrutinib was administered orally to rats at doses of 30, 75, and 150 mg/kg/day from implantation through weaning.

The offspring from the middle and high dose groups had decreased body weights preweaning, and all dose groups had adverse ocular findings (e.g., cataract, protruding eye).

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