BRUKINSA (zanubrutinib) is a kinase inhibitor. The empirical formula of zanubrutinib is C 27 H 29 N 5 O 3 and the chemical name is ( S )-7-(1-acryloylpiperidin-4-yl)-2-(4-phenoxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5- a ]pyrimidine-3-carboxamide. Zanubrutinib is a white to off-white powder, with a pH of 7.8 in saturated solution. The aqueous solubility of zanubrutinib is pH dependent, from very slightly soluble to practically insoluble. The molecular weight of zanubrutinib is 471.55 Daltons. Zanubrutinib has the following structure: Each BRUKINSA capsule for oral administration contains 80 mg zanubrutinib and the following inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, magnesium stearate, microcrystalline cellulose, and sodium lauryl sulfate. The capsule shell contains edible black ink, gelatin, and titanium dioxide. Each BRUKINSA tablet for oral administration contains 160 mg zanubrutinib and the following inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, lactose monohydrate, magnesium stearate, microcrystalline cellulose, povidone, and sodium lauryl sulfate. The film coating contains FD&C Blue No. 1, FD&C Blue No. 2, hypromellose, titanium dioxide, and triacetin. Chemical Structure

BRUKINSA is a kinase inhibitor indicated for the treatment of adult patients with: Mantle cell lymphoma (MCL) who have received at least one prior therapy. This indication is approved under accelerated approval based on overall response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial. Waldenström's macroglobulinemia (WM). 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. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial. Chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). 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. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial

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 . 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)

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 . 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)

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 . Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.

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. Capsules: 80 mg. Tablets: 160 mg with functional scoring.

Recommended dosage: 160 mg orally twice daily or 320 mg orally once daily with or without food; swallow whole with water. Tablets can be split in half as prescribed by the healthcare provider. Reduce BRUKINSA dose in patients with severe hepatic impairment. Advise patients not to open, break, or chew capsules. Advise patients not to chew or crush tablets. Manage toxicity using treatment interruption, dose reduction, or discontinuation

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 . Clarithromycin 500 mg twice daily 80 mg once daily Posaconazole suspension 100 mg once daily 80 mg twice daily Posaconazole suspension dosage higher than 100 mg once daily Posaconazole delayed-release tablets 300 mg once daily Posaconazole intravenous 300 mg once daily 80 mg once daily Other strong CYP3A inhibitor 80 mg once daily Moderate CYP3A inhibitor 80 mg twice daily Strong CYP3A inducer Avoid concomitant use. Moderate CYP3A inducer Avoid concomitant use. If these inducers cannot be avoided, increase BRUKINSA dose to 320 mg twice daily. After discontinuation of a CYP3A inhibitor or moderate CYP3A inducer, resume previous dose of BRUKINSA

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 Grade 3 or Grade 4 febrile neutropenia Platelet count decreased to 25,000-50,000/mm 3 with significant bleeding Neutrophil count decreased to <500/mm 3 (lasting more than 10 consecutive days) Platelet count decreased to <25,000/mm 3 (lasting more than 10 consecutive days) First Interrupt BRUKINSA Once toxicity has resolved to Grade 1 or lower or baseline: Resume at 160 mg twice daily or 320 mg once daily. Second Interrupt BRUKINSA Once toxicity has resolved to Grade 1 or lower or baseline: Resume at 80 mg twice daily or 160 mg once daily. Third Interrupt BRUKINSA Once toxicity has resolved to Grade 1 or lower or baseline: Resume at 80 mg once daily. Fourth Discontinue BRUKINSA Nonhematological toxicities Severe or life-threatening nonhematological toxicities Evaluate the benefit-risk before resuming treatment at the same dosage for Grade 4 nonhematological toxicity. First Interrupt BRUKINSA Once toxicity has resolved to Grade 1 or lower or baseline: Resume at 160 mg twice daily or 320 mg once daily. Second Interrupt BRUKINSA Once toxicity has resolved to Grade 1 or lower or baseline: Resume at 80 mg twice daily or 160 mg once daily. Third Interrupt BRUKINSA Once toxicity has resolved to Grade 1 or lower or baseline: Resume at 80 mg once daily. Fourth Discontinue BRUKINSA Asymptomatic lymphocytosis in CLL and MCL should not be regarded as an adverse reaction, and these patients should continue taking BRUKINSA. Refer to the obinutuzumab prescribing information for management of obinutuzumab toxicities.

Hemorrhage : Monitor for bleeding and manage appropriately. Infections : Monitor patients for signs and symptoms of infection, including opportunistic infections, and treat as needed. Cytopenias : Monitor complete blood counts during treatment. Second Primary Malignancies : Other malignancies have developed including skin cancers and non-skin carcinomas. Monitor and advise patients to use sun protection. Cardiac Arrhythmias : Monitor for signs and symptoms of arrhythmias and manage appropriately. Hepatotoxicity, Including Drug-Induced Liver Injury : Monitor hepatic function throughout treatment. Embryo-Fetal Toxicity : Can cause fetal harm. Advise women of the potential risk to a fetus and to use effective contraception. 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

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 . 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 . 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 , 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 .

CYP3A Inhibitors: Modify BRUKINSA dose with moderate or strong CYP3A inhibitors as described. CYP3A Inducers: Avoid coadministration with strong or moderate CYP3A inducers. Dose adjustment may be recommended with moderate CYP3A inducers

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 .