CALQUENCE

6 ADVERSE REACTIONS The following clinically significant adverse reactions are discussed in greater detail in other sections of the labeling: • Serious and Opportunistic Infections [see Warnings and Precautions (5.1) ] • Hemorrhage [see Warnings and Precautions (5.2) ] • Cytopenias [see Warnings and Precautions (5.3) ] • Second Primary Malignancies [see Warnings and Precautions (5.4) ] • Atrial Fibrillation and Flutter [see Warnings and Precautions (5.5) ] Most common adverse reactions (incidence ≥ 30%) are: anemia, neutropenia, upper respiratory tract infection, thrombocytopenia, headache, diarrhea, and musculoskeletal pain. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact AstraZeneca at 1-800-236-9933 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience As 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 CALQUENCE 100 mg approximately every 12 hours in 1029 patients with hematologic malignancies. Treatment includes CALQUENCE monotherapy in 820 patients in 6 trials, and CALQUENCE with obinutuzumab in 209 patients in 2 trials. Among these recipients of CALQUENCE, 88% were exposed for at least 6 months and 79% were exposed for at least one year. In this pooled safety population, adverse reactions in ≥ 30% of 1029 patients were anemia, neutropenia, upper respiratory tract infection, thrombocytopenia, headache, diarrhea, and musculoskeletal pain. Mantle Cell Lymphoma The safety data described in this section reflect exposure to CALQUENCE (100 mg approximately every 12 hours) in 124 patients with previously treated MCL in Trial LY-004 [see Clinical Studies (14.1) ] . The median duration of treatment with CALQUENCE was 16.6 (range: 0.1 to 26.6) months. A total of 91 (73.4%) patients were treated with CALQUENCE for ≥ 6 months and 74 (59.7%) patients were treated for ≥ 1 year. The most common adverse reactions (≥ 20%) of any grade were anemia, thrombocytopenia, headache, neutropenia, diarrhea, fatigue, myalgia, and bruising. Grade 1 severity for the non-hematologic, most common events were as follows: headache (25%), diarrhea (16%), fatigue (20%), myalgia (15%), and bruising (19%). The most common Grade ≥ 3 non-hematological adverse reaction (reported in at least 2% of patients) was diarrhea. Dose reductions and discontinuation due to any adverse reaction were reported in 1.6% and 6.5% of patients, respectively. Tables 3 and 4 present the frequency category of adverse reactions observed in patients with MCL treated with CALQUENCE. Table 3: Non-Hematologic Adverse Reactions in ≥ 5% (All Grades) of Patients with MCL in Trial LY-004 Body System Adverse Reactions Per NCI CTCAE version 4.03. CALQUENCE Monotherapy N=124 All Grades (%) Grade ≥ 3 (%) Nervous system disorders Headache 39 1.6 Gastrointestinal disorders Diarrhea 31 3.2 Nausea 19 0.8 Abdominal pain 15 1.6 Constipation 15 - Vomiting 13 1.6 General disorders Fatigue 28 0.8 Musculoskeletal and connective tissue disorders Myalgia 21 0.8 Skin and subcutaneous tissue disorders Bruising Bruising: Includes all terms containing ‘bruise,’ ‘contusion,’ ‘petechiae,’ or ‘ecchymosis’ 21 - Rash Rash: Includes all terms containing ‘rash’ 18 0.8 Vascular disorders Hemorrhage Hemorrhage: Includes all terms containing ‘hemorrhage’ or ‘hematoma’ 8 0.8 Respiratory, thoracic and mediastinal disorders Epistaxis 6 - Table 4: Hematologic Adverse Reactions Reported in ≥ 20% of Patients with MCL in Trial LY-004 Hematologic Adverse Reactions Per NCI CTCAE version 4.03; based on laboratory measurements and adverse reactions. CALQUENCE Monotherapy N=124 All Grades (%) Grade ≥ 3 (%) Hemoglobin decreased 46 10 Platelets decreased 44 12 Neutrophils decreased 36 15 Increases in creatinine to 1.5 to 3 times the upper limit of normal (ULN) occurred in 4.8% of patients. Chronic Lymphocytic Leukemia The safety data described below reflect exposure to CALQUENCE (100 mg approximately every 12 hours, with or without obinutuzumab) in 511 patients with CLL from two randomized controlled clinical trials [see Clinical Studies (14.2) ] . The most common adverse reactions (≥ 30%) of any grade in patients with CLL were anemia, neutropenia, thrombocytopenia, headache, upper respiratory tract infection, and diarrhea. ELEVATE-TN The safety of CALQUENCE plus obinutuzumab (CALQUENCE+G), CALQUENCE monotherapy, and obinutuzumab plus chlorambucil (GClb) was evaluated in a randomized, multicenter, open-label, actively controlled trial in 526 patients with previously untreated CLL [see Clinical Studies (14.2) ] . Patients randomized to the CALQUENCE+G arm were treated with CALQUENCE and obinutuzumab in combination for six cycles, then with CALQUENCE as monotherapy until disease progression or unacceptable toxicity. Patients initiated obinutuzumab on Day 1 of Cycle 2, continuing for a total of 6 cycles. Patient randomized to CALQUENCE monotherapy received CALQUENCE approximately every 12 hours until disease progression or unacceptable toxicity. The trial required age ≥ 65 years of age or 18 to < 65 years of age with a total Cumulative Illness Rating Scale (CIRS) > 6 or creatinine clearance of 30 to 69 mL/min, hepatic transaminases ≤ 3 times ULN and total bilirubin ≤ 1.5 times ULN, and allowed patients to receive antithrombotic agents other than warfarin or equivalent vitamin K antagonists. During randomized treatment, the median duration of exposure to CALQUENCE in the CALQUENCE+G and CALQUENCE monotherapy arms was 27.7 months (range 0.3 to 40 months), with 95% and 92% and 89% and 86% of patients with at least 6 months and 12 months of exposure, respectively. In the obinutuzumab and chlorambucil arm the median number of cycles was 6 with 84% of patients receiving at least 6 cycles of obinutuzumab, 70% of patients received at least 6 cycles of chlorambucil. Eighty-five percent of patients in the CALQUENCE+G arm received at least 6 cycles of obinutuzumab. In the CALQUENCE+G and CALQUENCE monotherapy arms, fatal adverse reactions that occurred in the absence of disease progression and with onset within 30 days of the last study treatment were reported in 2% for each treatment arm, most often from infection. Serious adverse reactions were reported in 39% of patients in the CALQUENCE+G arm and 32% in the CALQUENCE monotherapy arm, most often due to events of pneumonia (2.8% to 7%). In the CALQUENCE+G arm, adverse reactions led to treatment discontinuation in 11% of patients and a dose reduction of CALQUENCE in 7% of patients. In the CALQUENCE monotherapy arm, adverse reactions led to discontinuation in 10% and dose reduction in 4% of patients. Tables 5 and 6 present adverse reactions and laboratory abnormalities identified in the ELEVATE-TN trial. Table 5: Common Adverse Reactions (≥ 15% Any Grade) with CALQUENCE in Patients with CLL (ELEVATE-TN) Body System Adverse Reaction Per NCI CTCAE version 4.03 CALQUENCE plus Obinutuzumab N=178 CALQUENCE Monotherapy N=179 Obinutuzumab plus Chlorambucil N=169 All Grades (%) Grade ≥ 3 (%) All Grades (%) Grade ≥ 3 (%) All Grades (%) Grade ≥ 3 (%) Infections Infection Includes any adverse reactions involving infection or febrile neutropenia 69 22 Includes 3 fatal cases in the CALQUENCE plus obinutuzumab arm, 3 fatal cases in the CALQUENCE monotherapy arm and 1 fatal case in the obinutuzumab plus chlorambucil arm 65 14 46 13 Upper respiratory tract infection Includes upper respiratory tract infection, nasopharyngitis and sinusitis 39 2.8 35 0 17 1.2 Lower respiratory tract infection Includes pneumonia, lower respiratory tract infection, bronchitis, bronchiolitis, tracheitis, and lung infection 24 8 18 4.5 7 1.8 Urinary tract infection 15 1.7 15 2.8 5 0.6 Blood and lymphatic system disorders Derived from adverse reaction and laboratory data Neutropenia Includes neutropenia, neutrophil count decreased, and related laboratory data 53 37 23 13 78 50 Anemia Includes anemia, red blood cell count decreased, and related laboratory data 52 12 53 10 54 14 Thrombocytopenia Includes thrombocytopenia, platelet count decreased, and related laboratory data 51 12 32 3.4 61 16 Lymphocytosis Includes lymphocytosis, lymphocyte count increased, and related laboratory data 12 11 16 15 0.6 0.6 Nervous system disorders Headache 40 1.1 39 1.1 12 0 Dizziness 20 0 12 0 7 0 Gastrointestinal disorders Diarrhea 39 4.5 35 0.6 21 1.8 Nausea 20 0 22 0 31 0 Musculoskeletal and connective tissue disorders Musculoskeletal pain Includes back pain, bone pain, musculoskeletal chest pain, musculoskeletal pain, musculoskeletal discomfort, myalgia, neck pain, pain in extremity and spinal pain 37 2.2 32 1.1 16 2.4 Arthralgia 22 1.1 16 0.6 4.7 1.2 General disorders and administration site conditions Fatigue Includes asthenia, fatigue, and lethargy 34 2.2 23 1.1 24 1.2 Skin and subcutaneous tissue disorders Bruising Includes bruise, contusion, and ecchymosis 31 0 21 0 5 0 Rash Includes rash, dermatitis, and other related terms 26 2.2 25 0.6 9 0.6 Vascular disorders Hemorrhage Includes hemorrhage, hematoma, hemoptysis, hematuria, menorrhagia, hemarthrosis, and epistaxis 20 1.7 20 1.7 6 0 Other clinically relevant adverse reactions (all grades incidence < 15%) in recipients of CALQUENCE (CALQUENCE in combination with obinutuzumab and monotherapy) included: • Neoplasms: second primary malignancy (10%), non-melanoma skin cancer (5%) • Cardiac disorders: atrial fibrillation or flutter (3.6%), hypertension (5%) • Infection: herpesvirus infection (6%) Table 6: Select Non-Hematologic Laboratory Abnormalities (≥ 15% Any Grade), New or Worsening from Baseline in Patients Receiving CALQUENCE (ELEVATE-TN) Laboratory Abnormality Per NCI CTCAE version 4.03 Excludes electrolytes CALQUENCE plus Obinutuzumab N=178 CALQUENCE Monotherapy N=179 Obinutuzumab plus Chlorambucil N=169 All Grades (%) Grade ≥ 3 (%) All Grades (%) Grade ≥ 3 (%) All Grades (%) Grade ≥ 3 (%) Uric acid increase 29 29 22 22 37 37 ALT increase 30 7 20 1.1 36 6 AST increase 38 5 17 0.6 60 8 Bilirubin increase 13 0.6 15 0.6 11 0.6 Increases in creatinine to 1.5 to 3 times ULN occurred in 3.9% and 2.8% of patients in the CALQUENCE combination arm and monotherapy arm, respectively. ASCEND The safety of CALQUENCE in patients with relapsed or refractory CLL was evaluated in a randomized, open-label study (ASCEND) [see Clinical Studies (14.2) ] . The trial enrolled patients with relapsed or refractory CLL after at least one prior therapy and required hepatic transaminases ≤ 2 times ULN, total bilirubin ≤ 1.5 times ULN, and an estimated creatinine clearance ≥ 30 mL/min. The trial excluded patients having an absolute neutrophil count < 500/µL, platelet count < 30,000/µL, prothrombin time or activated partial thromboplastin time > 2 times ULN, significant cardiovascular disease, or a requirement for strong CYP3A inhibitors or inducers. Patients were allowed to receive antithrombotic agents other than warfarin or equivalent vitamin K antagonist. In ASCEND, 154 patients received CALQUENCE (100 mg approximately every 12 hours until disease progression or unacceptable toxicity), 118 received idelalisib (150 mg approximately every 12 hours until disease progression or unacceptable toxicity) with up to 8 infusions of a rituximab product, and 35 received up to 6 cycles of bendamustine and a rituximab product. The median age overall was 68 years (range: 32-90); 67% were male; 92% were white; and 88% had an ECOG performance status of 0 or 1. In the CALQUENCE arm, serious adverse reactions occurred in 29% of patients. Serious adverse reactions in > 5% of patients who received CALQUENCE included lower respiratory tract infection (6%). Fatal adverse reactions within 30 days of the last dose of CALQUENCE occurred in 2.6% of patients, including from second primary malignancies and infection. In recipients of CALQUENCE, permanent discontinuation due to an adverse reaction occurred in 10% of patients, most frequently due to second primary malignancies followed by infection. Adverse reactions led to dosage interruptions of CALQUENCE in 34% of patients, most often due to respiratory tract infections followed by neutropenia, and dose reduction in 3.9% of patients. Selected adverse reactions are described in Table 7 and non-hematologic laboratory abnormalities are described in Table 8. These tables reflect exposure to CALQUENCE with median duration of 15.7 months with 94% of patients on treatment for greater than 6 months and 86% of patients on treatment for greater than 12 months. The median duration of exposure to idelalisib was 11.5 months with 72% of patients on treatment for greater than 6 months and 48% of patients on treatment for greater than 12 months. Eighty-three percent of patients completed 6 cycles of bendamustine and rituximab product. Table 7: Common Adverse Reactions (≥ 15% Any Grade) with CALQUENCE in Patients with CLL (ASCEND) Body System Adverse Reaction Per NCI CTCAE version 4.03 CALQUENCE N=154 Idelalisib plus Rituximab Product N=118 Bendamustine plus Rituximab Product N=35 All Grades (%) Grade ≥ 3 (%) All Grades (%) Grade ≥ 3 (%) All Grades (%) Grade ≥ 3 (%) Infections Infection Includes any adverse reactions involving infection or febrile neutropenia 56 15 Includes 1 fatal case in the CALQUENCE monotherapy arm and 1 fatal case in the Idelalisib plus Rituximab arm 65 28 49 11 Upper respiratory tract infection Includes upper respiratory tract infection, rhinitis and nasopharyngitis 29 1.9 26 3.4 17 2.9 Lower respiratory tract infection Includes pneumonia, lower respiratory tract infection, bronchitis, bronchiolitis, tracheitis, and lung infection. 23 6 26 15 14 6 Blood and lymphatic system disorders Derived from adverse reaction and laboratory data Neutropenia Includes neutropenia, neutrophil count decreased, and related laboratory data 48 23 79 53 80 40 Anemia Includes anemia, red blood cell decreased, and related laboratory data 47 15 45 8 57 17 Thrombocytopenia Includes thrombocytopenia, platelet count decreased, and related laboratory data 33 6 41 13 54 6 Lymphocytosis Includes lymphocytosis, lymphocyte count increased and related laboratory data 26 19 23 18 2.9 2.9 Nervous system disorders Headache 22 0.6 6 0 0 0 Gastrointestinal disorders Diarrhea Includes colitis, diarrhea, and enterocolitis 18 1.3 49 25 14 0 Vascular disorders Hemorrhage Includes hemorrhage, hematoma, hemoptysis, hematuria, menorrhagia, hemarthrosis, and epistaxis 16 1.3 5 1.7 6 2.9 General disorders Fatigue Includes asthenia, fatigue, and lethargy 15 1.9 13 0.8 31 6 Musculoskeletal and connective tissue disorders Musculoskeletal pain Includes back pain, musculoskeletal chest pain, musculoskeletal pain, musculoskeletal discomfort, pain in extremity, myalgia, spinal pain and bone pain 15 1.3 15 1.7 2.9 0 Other clinically relevant adverse reactions (all grades incidence < 15%) in recipients of CALQUENCE included: • Skin and subcutaneous disorders: bruising (10%), rash (9%) • Neoplasms: second primary malignancy (12%), non-melanoma skin cancer (6%) • Musculoskeletal and connective tissue disorders: arthralgia (8%) • Cardiac disorders: atrial fibrillation or flutter (5%), hypertension (3.2%) • Infection: herpesvirus infection (4.5%) Table 8: Select Non-Hematologic Laboratory Abnormalities (≥ 10% Any Grade), New or Worsening from Baseline in Patients Receiving CALQUENCE (ASCEND) Laboratory Abnormality Excludes electrolytes CALQUENCE N=154 Idelalisib plus Rituximab Product N=118 Bendamustine plus Rituximab Product N=35 All Grades (%) Grade ≥ 3 (%) All Grades (%) Grade ≥ 3 (%) All Grades (%) Grade ≥ 3 (%) Uric acid increase 15 15 11 11 23 23 ALT increase 15 1.9 59 23 26 2.9 AST increase 13 0.6 48 13 31 2.9 Bilirubin increase 13 1.3 16 1.7 26 11 Per NCI CTCAE version 5 Increases in creatinine to 1.5 to 3 times ULN occurred in 1.3% of patients who received CALQUENCE.

4 CONTRAINDICATIONS None. None. ( 4 )

11 DESCRIPTION CALQUENCE (acalabrutinib) is a kinase inhibitor. The molecular formula for acalabrutinib maleate is C 26 H 23 N 7 O 2 •C 4 H 4 O 4 .H 2 O, and the molecular weight is 599.59. The chemical name is 4-{8-Amino-3-[(2 S )-1-(but-2-ynoyl)pyrrolidin-2-yl]imidazo[1,5- a ]pyrazin-1-yl}- N -(pyridin-2-yl)benzamide (2 Z )-2-butenedioic acid hydrate. The chemical structure of acalabrutinib is shown below: Acalabrutinib maleate is a white to pale brown powder with pH-dependent solubility. It is freely soluble in water at pH values below 3 and practically insoluble at pH values above 6. CALQUENCE tablets are for oral administration. Each tablet contains 100 mg of acalabrutinib (equivalent to 129 mg of acalabrutinib maleate). Inactive ingredients in the tablet core are low-substituted hydroxypropyl cellulose, mannitol, microcrystalline cellulose, and sodium stearyl fumarate. The tablet coating consists of copovidone, ferric oxide yellow, ferric oxide red, hypromellose, medium-chain triglycerides, polyethylene glycol 3350, purified water and titanium dioxide. chemical_structure

2 DOSAGE AND ADMINISTRATION • Recommended dose is 100 mg orally approximately every 12 hours; swallow whole with water and with or without food. ( 2.1 ) • Advise patients not to chew, crush, dissolve, or cut tablets. ( 2.1 ) • Manage toxicities using treatment interruption, dose reduction, or discontinuation. ( 2.2 ) • Avoid CALQUENCE in patients with severe hepatic impairment. ( 8.6 ) 2.1 Recommended Dosage CALQUENCE as Monotherapy For patients with MCL, CLL, or SLL, the recommended dosage of CALQUENCE is 100 mg taken orally approximately every 12 hours until disease progression or unacceptable toxicity. CALQUENCE in Combination with Obinutuzumab For patients with previously untreated CLL or SLL, the recommended dosage of CALQUENCE is 100 mg taken orally approximately every 12 hours until disease progression or unacceptable toxicity. Start CALQUENCE at Cycle 1 (each cycle is 28 days). Start obinutuzumab at Cycle 2 for a total of 6 cycles and refer to the obinutuzumab prescribing information for recommended dosing. Administer CALQUENCE prior to obinutuzumab when given on the same day. Advise patients to swallow tablet whole with water. Advise patients not to chew, crush, dissolve, or cut the tablets. CALQUENCE may be taken with or without food. If a dose of CALQUENCE is missed by more than 3 hours, it should be skipped and the next dose should be taken at its regularly scheduled time. Extra tablets of CALQUENCE should not be taken to make up for a missed dose. 2.2 Recommended Dosage for Drug Interactions Dosage Modifications for Use with CYP3A Inhibitors or Inducers These are described in Table 1 [see Drug Interactions (7) ]. Table 1: Recommended Dosage Modifications for Use with CYP3A Inhibitors or Inducers CYP3A Co-administered Drug Recommended CALQUENCE use Inhibition Strong CYP3A inhibitor Avoid co-administration. If these inhibitors will be used short-term (such as anti‑infectives for up to seven days), interrupt CALQUENCE. After discontinuation of strong CYP3A inhibitor for at least 24 hours, resume previous dosage of CALQUENCE. Moderate CYP3A inhibitor Reduce the CALQUENCE 100 mg every 12 hours dosage to 100 mg once daily. Induction Strong CYP3A inducer Avoid co-administration. If co-administration is unavoidable, increase CALQUENCE dosage to 200 mg approximately every 12 hours. 2.3 Dosage Modifications for Adverse Reactions Recommended dosage modifications of CALQUENCE for Grade 3 or greater adverse reactions are provided in Table 2. Table 2: Recommended Dosage Modifications for Adverse Reactions Event Adverse Reaction Occurrence Dosage Modification (Starting dose = 100 mg approximately every 12 hours) Grade 3 or greater non-hematologic toxicities, Grade 3 thrombocytopenia with bleeding, Grade 4 thrombocytopenia or Grade 4 neutropenia lasting longer than 7 days First and Second Interrupt CALQUENCE. Once toxicity has resolved to Grade 1 or baseline level, CALQUENCE may be resumed at 100 mg approximately every 12 hours. Third Interrupt CALQUENCE. Once toxicity has resolved to Grade 1 or baseline level, CALQUENCE may be resumed at a reduced frequency of 100 mg once daily. Fourth Discontinue CALQUENCE. Adverse reactions graded by the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE). Refer to the obinutuzumab prescribing information for management of obinutuzumab toxicities.

1 INDICATIONS AND USAGE CALQUENCE is a kinase inhibitor indicated for the treatment of adult patients with: • Mantle cell lymphoma (MCL) who have received at least one prior therapy. ( 1.1 ) This indication is approved under accelerated approval based on overall response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials. ( 1.1 , 14.1 ) • Chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). ( 1.2 ) 1.1 Mantle Cell Lymphoma CALQUENCE 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 confirmatory trials. 1.2 Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma CALQUENCE is indicated for the treatment of adult patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL).

7 DRUG INTERACTIONS • Strong CYP3A Inhibitors : Avoid co-administration with CALQUENCE. ( 2.2 , 7 ) • Moderate CYP3A Inhibitors : Reduce the dosage of CALQUENCE. ( 2.2 , 7 ) • Strong CYP3A Inducers : Avoid co-administration with CALQUENCE. If co-administration is unavoidable, increase the dosage of CALQUENCE. ( 2.2 , 7 ) 7.1 Effect of Other Drugs on CALQUENCE Strong CYP3A Inhibitors Clinical Effect Co-administration of CALQUENCE with a strong CYP3A inhibitor increased acalabrutinib plasma concentrations [see Clinical Pharmacology (12.3) ] . Increased acalabrutinib concentrations may result in increased toxicity. Prevention or Management Avoid co-administration of CALQUENCE with strong CYP3A inhibitors. Alternatively, if the inhibitor will be used short-term, interrupt CALQUENCE [see Dosage and Administration (2.2) ]. Moderate CYP3A Inhibitors Clinical Effect Co-administration of CALQUENCE with a moderate CYP3A inhibitor may increase acalabrutinib plasma concentration [see Clinical Pharmacology (12.3) ] . Increased acalabrutinib concentrations may result in increased toxicity. Prevention or Management Reduce the dosage of CALQUENCE when co-administered with a moderate CYP3A inhibitor [see Dosage and Administration (2.2) ]. Strong CYP3A Inducers Clinical Effect Co-administration of CALQUENCE with a strong CYP3A inducer decreased acalabrutinib plasma concentration [see Clinical Pharmacology (12.3) ] . Decreased acalabrutinib concentrations may reduce CALQUENCE activity. Prevention or Management Avoid co-administration of CALQUENCE with strong CYP3A inducers. If co-administration is unavoidable, increase the dosage of CALQUENCE [see Dosage and Administration (2.2) ].

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Acalabrutinib is a small-molecule inhibitor of Bruton tyrosine kinase (BTK). Acalabrutinib and its active metabolite, ACP-5862, form a covalent bond with a cysteine residue in the BTK active site, leading to inhibition of BTK enzymatic 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, acalabrutinib inhibited BTK‑mediated activation of downstream signaling proteins CD86 and CD69 and inhibited malignant B-cell proliferation and tumor growth in mouse xenograft models. 12.2 Pharmacodynamics In patients with B-cell malignancies dosed with acalabrutinib 100 mg approximately every 12 hours, median steady state BTK occupancy of ≥ 95% in peripheral blood was maintained over 12 hours, resulting in inactivation of BTK throughout the recommended dosing interval. Cardiac Electrophysiology At a dose 4 times the approved recommended dosage, CALQUENCE does not prolong the QTc interval to any clinically relevant extent. 12.3 Pharmacokinetics Acalabrutinib and its active metabolite, ACP-5862, exposures increase proportionally with dose across a dose range of 75 to 250 mg (0.75 to 2.5 times the approved recommended single dosage) in patients with B-cell malignancies. At the recommended dose of 100 mg twice daily, the geometric mean (% coefficient of variation [CV]) daily area under the plasma drug concentration over time curve (AUC 24h ) and maximum plasma concentration (C max ) for acalabrutinib were 1843 (38%) ng•h/mL and 563 (29%) ng/mL, respectively, and for ACP-5862 were 3947 (43%) ng•h/mL and 451 (52%) ng/mL, respectively. Absorption The geometric mean absolute bioavailability of acalabrutinib was 25%. Median (min, max) time to peak plasma concentration (T max ) of acalabrutinib and its active metabolite, ACP-5862 were 0.5 (0.2, 3.0) hours and 0.75 (0.5, 4.0) hours, respectively. Effect of Food In healthy subjects, administration of a single 100 mg dose of acalabrutinib with a high-fat, high-calorie meal (approximately 918 calories, 59 grams carbohydrate, 59 grams fat, and 39 grams protein) did not affect the mean AUC as compared to dosing under fasted conditions. Resulting C max decreased by 54% and T max was delayed 1-2 hours. Distribution The geometric mean (% CV) steady-state volume of distribution (V ss ) of acalabrutinib and its active metabolite, ACP-5862 was approximately 101 (52%) L and 67 (32%) L, respectively. Human plasma protein of acalabrutinib and its active metabolite, ACP-5862, were 97.5% and 98.6%, respectively. The mean blood-to-plasma ratio of acalabrutinib and its active metabolite, ACP-5862, was 0.8 and 0.7, respectively. Elimination The geometric mean (% CV) terminal elimination half-life (t 1/2 ) of acalabrutinib and its active metabolite, ACP-5862, were 1.4 (50%) hours and 6.4 (37%) hours, respectively. The geometric mean (%CV) apparent oral clearance (CL/F) of acalabrutinib and its active metabolite, ACP-5862, were 71 (35%) L/hr and 13 (42%) L/hr, respectively. Metabolism Acalabrutinib is predominantly metabolized by CYP3A enzymes, and to a minor extent, by glutathione conjugation and amide hydrolysis, based on in vitro studies. ACP-5862 was identified as the major active metabolite in plasma with a geometric mean exposure (AUC) that was approximately 2- to 3-fold higher than the exposure of acalabrutinib. ACP-5862 is approximately 50% less potent than acalabrutinib with regard to BTK inhibition. Excretion Following administration of a single 100 mg radiolabeled acalabrutinib dose in healthy subjects, 84% of the dose was recovered in the feces (< 2% unchanged) and 12% of the dose was recovered in the urine (< 2% unchanged). Specific Populations There were no clinically significant differences in the pharmacokinetics of acalabrutinib and its active metabolite, ACP‑5862, based on age (32 to 90 years), sex, race (Caucasian, African American), body weight (40 to 149 kg), or mild to moderate renal impairment (eGFR ≥ 30 mL/min/1.73m 2 and eGFR < 89 mL/min/1.73m 2 , as estimated by MDRD (modification of diet in renal disease equation)). The effect of severe renal impairment (eGFR < 29 mL/min/1.73m 2 , MDRD) or renal impairment requiring dialysis on the pharmacokinetics of acalabrutinib is unknown. Patients with Hepatic Impairment The AUC of acalabrutinib increased 1.9-fold in subjects with mild hepatic impairment (Child-Pugh class A), 1.5-fold in subjects with moderate hepatic impairment (Child-Pugh class B) and 5.3-fold in subjects with severe hepatic impairment (Child-Pugh class C) compared to subjects with normal liver function. No clinically relevant PK difference in ACP-5862 was observed in subjects with severe hepatic impairment (Child-Pugh Class C) compared to subjects with normal liver function. No clinically relevant PK differences in acalabrutinib and ACP-5862 were observed in patients with mild or moderate hepatic impairment (total bilirubin less and equal to upper limit of normal [ULN] and AST greater than ULN, or total bilirubin greater than ULN and any AST) relative to patients with normal hepatic function (total bilirubin and AST within ULN). Drug Interaction Studies Clinical Studies and Model-Informed Approaches Strong CYP3A Inhibitors: Co-administration of acalabrutinib with itraconazole (strong CYP3A inhibitor) increase acalabrutinib C max by 3.9-fold and AUC by 5.1-fold in healthy subjects. Moderate CYP3A Inhibitors: Co-administration of acalabrutinib with erythromycin (moderate CYP3A inhibitor), fluconazole (moderate CYP3A inhibitor), diltiazem (moderate CYP3A inhibitor) is predicted to increase acalabrutinib C max and AUC by approximately 2- to 3-fold. Strong CYP3A Inducers: Co-administration of acalabrutinib with rifampin (strong CYP3A inducer) decreased acalabrutinib C max by 68% and AUC by 77% in healthy subjects. Acid-Reducing Agents: No clinically significant differences in the pharmacokinetics of acalabrutinib were observed when co-administered with rabeprazole (proton pump inhibitor). In Vitro Studies Cytochrome P450 (CYP) Enzymes: Acalabrutinib is an inhibitor of CYP3A4/5, CYP2C8 and CYP2C9, but not CYP1A2, CYP2B6, CYP2C19, or CYP2D6. Acalabrutinib’s active metabolite, ACP-5862, is an inhibitor of CYP2C8, CYP2C9 and CYP2C19, but not CYP1A2, CYP2B6, CYP2D6, or CYP3A4/5. Acalabrutinib is an inducer of CYP1A2, CYP2B6, and CYP3A4. Acalabrutinib’s active metabolite, ACP-5862, is an inducer of CYP3A4. Uridine diphosphate (UDP)-glucuronosyl transferase (UGT) Enzymes: Acalabrutinib and its active metabolite, ACP‑5862, are not inhibitors of UGT1A1 or UGT2B7. Transporter System : Acalabrutinib is an inhibitor of breast cancer resistance protein (BCRP), but not multidrug and toxin extrusion protein 1 (MATE1). Acalabrutinib’s active metabolite, ACP-5862, is an inhibitor of MATE1, but not BCRP. Acalabrutinib and its active metabolite, ACP-5862, are not inhibitors of P-glycoprotein (P-gp), organic anion transporter (OAT) 1, OAT3, organic cation transporter 2 (OCT2), organic anion transporting polypeptide (OATP) 1B1, OATP1B3, or MATE2-K. Acalabrutinib and its active metabolite, ACP-5862, are substrates of P-gp and BCRP. Acalabrutinib is not a substrate of OAT1, OAT3, OCT2, OATP1B1, or OATP1B3. Acalabrutinib’s active metabolite, ACP-5862, is not a substrate of OATP1B1 or OATP1B3.

12.1 Mechanism of Action Acalabrutinib is a small-molecule inhibitor of Bruton tyrosine kinase (BTK). Acalabrutinib and its active metabolite, ACP-5862, form a covalent bond with a cysteine residue in the BTK active site, leading to inhibition of BTK enzymatic 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, acalabrutinib inhibited BTK‑mediated activation of downstream signaling proteins CD86 and CD69 and inhibited malignant B-cell proliferation and tumor growth in mouse xenograft models.

12.2 Pharmacodynamics In patients with B-cell malignancies dosed with acalabrutinib 100 mg approximately every 12 hours, median steady state BTK occupancy of ≥ 95% in peripheral blood was maintained over 12 hours, resulting in inactivation of BTK throughout the recommended dosing interval. Cardiac Electrophysiology At a dose 4 times the approved recommended dosage, CALQUENCE does not prolong the QTc interval to any clinically relevant extent.

12.3 Pharmacokinetics Acalabrutinib and its active metabolite, ACP-5862, exposures increase proportionally with dose across a dose range of 75 to 250 mg (0.75 to 2.5 times the approved recommended single dosage) in patients with B-cell malignancies. At the recommended dose of 100 mg twice daily, the geometric mean (% coefficient of variation [CV]) daily area under the plasma drug concentration over time curve (AUC 24h ) and maximum plasma concentration (C max ) for acalabrutinib were 1843 (38%) ng•h/mL and 563 (29%) ng/mL, respectively, and for ACP-5862 were 3947 (43%) ng•h/mL and 451 (52%) ng/mL, respectively. Absorption The geometric mean absolute bioavailability of acalabrutinib was 25%. Median (min, max) time to peak plasma concentration (T max ) of acalabrutinib and its active metabolite, ACP-5862 were 0.5 (0.2, 3.0) hours and 0.75 (0.5, 4.0) hours, respectively. Effect of Food In healthy subjects, administration of a single 100 mg dose of acalabrutinib with a high-fat, high-calorie meal (approximately 918 calories, 59 grams carbohydrate, 59 grams fat, and 39 grams protein) did not affect the mean AUC as compared to dosing under fasted conditions. Resulting C max decreased by 54% and T max was delayed 1-2 hours. Distribution The geometric mean (% CV) steady-state volume of distribution (V ss ) of acalabrutinib and its active metabolite, ACP-5862 was approximately 101 (52%) L and 67 (32%) L, respectively. Human plasma protein of acalabrutinib and its active metabolite, ACP-5862, were 97.5% and 98.6%, respectively. The mean blood-to-plasma ratio of acalabrutinib and its active metabolite, ACP-5862, was 0.8 and 0.7, respectively. Elimination The geometric mean (% CV) terminal elimination half-life (t 1/2 ) of acalabrutinib and its active metabolite, ACP-5862, were 1.4 (50%) hours and 6.4 (37%) hours, respectively. The geometric mean (%CV) apparent oral clearance (CL/F) of acalabrutinib and its active metabolite, ACP-5862, were 71 (35%) L/hr and 13 (42%) L/hr, respectively. Metabolism Acalabrutinib is predominantly metabolized by CYP3A enzymes, and to a minor extent, by glutathione conjugation and amide hydrolysis, based on in vitro studies. ACP-5862 was identified as the major active metabolite in plasma with a geometric mean exposure (AUC) that was approximately 2- to 3-fold higher than the exposure of acalabrutinib. ACP-5862 is approximately 50% less potent than acalabrutinib with regard to BTK inhibition. Excretion Following administration of a single 100 mg radiolabeled acalabrutinib dose in healthy subjects, 84% of the dose was recovered in the feces (< 2% unchanged) and 12% of the dose was recovered in the urine (< 2% unchanged). Specific Populations There were no clinically significant differences in the pharmacokinetics of acalabrutinib and its active metabolite, ACP‑5862, based on age (32 to 90 years), sex, race (Caucasian, African American), body weight (40 to 149 kg), or mild to moderate renal impairment (eGFR ≥ 30 mL/min/1.73m 2 and eGFR < 89 mL/min/1.73m 2 , as estimated by MDRD (modification of diet in renal disease equation)). The effect of severe renal impairment (eGFR < 29 mL/min/1.73m 2 , MDRD) or renal impairment requiring dialysis on the pharmacokinetics of acalabrutinib is unknown. Patients with Hepatic Impairment The AUC of acalabrutinib increased 1.9-fold in subjects with mild hepatic impairment (Child-Pugh class A), 1.5-fold in subjects with moderate hepatic impairment (Child-Pugh class B) and 5.3-fold in subjects with severe hepatic impairment (Child-Pugh class C) compared to subjects with normal liver function. No clinically relevant PK difference in ACP-5862 was observed in subjects with severe hepatic impairment (Child-Pugh Class C) compared to subjects with normal liver function. No clinically relevant PK differences in acalabrutinib and ACP-5862 were observed in patients with mild or moderate hepatic impairment (total bilirubin less and equal to upper limit of normal [ULN] and AST greater than ULN, or total bilirubin greater than ULN and any AST) relative to patients with normal hepatic function (total bilirubin and AST within ULN). Drug Interaction Studies Clinical Studies and Model-Informed Approaches Strong CYP3A Inhibitors: Co-administration of acalabrutinib with itraconazole (strong CYP3A inhibitor) increase acalabrutinib C max by 3.9-fold and AUC by 5.1-fold in healthy subjects. Moderate CYP3A Inhibitors: Co-administration of acalabrutinib with erythromycin (moderate CYP3A inhibitor), fluconazole (moderate CYP3A inhibitor), diltiazem (moderate CYP3A inhibitor) is predicted to increase acalabrutinib C max and AUC by approximately 2- to 3-fold. Strong CYP3A Inducers: Co-administration of acalabrutinib with rifampin (strong CYP3A inducer) decreased acalabrutinib C max by 68% and AUC by 77% in healthy subjects. Acid-Reducing Agents: No clinically significant differences in the pharmacokinetics of acalabrutinib were observed when co-administered with rabeprazole (proton pump inhibitor). In Vitro Studies Cytochrome P450 (CYP) Enzymes: Acalabrutinib is an inhibitor of CYP3A4/5, CYP2C8 and CYP2C9, but not CYP1A2, CYP2B6, CYP2C19, or CYP2D6. Acalabrutinib’s active metabolite, ACP-5862, is an inhibitor of CYP2C8, CYP2C9 and CYP2C19, but not CYP1A2, CYP2B6, CYP2D6, or CYP3A4/5. Acalabrutinib is an inducer of CYP1A2, CYP2B6, and CYP3A4. Acalabrutinib’s active metabolite, ACP-5862, is an inducer of CYP3A4. Uridine diphosphate (UDP)-glucuronosyl transferase (UGT) Enzymes: Acalabrutinib and its active metabolite, ACP‑5862, are not inhibitors of UGT1A1 or UGT2B7. Transporter System : Acalabrutinib is an inhibitor of breast cancer resistance protein (BCRP), but not multidrug and toxin extrusion protein 1 (MATE1). Acalabrutinib’s active metabolite, ACP-5862, is an inhibitor of MATE1, but not BCRP. Acalabrutinib and its active metabolite, ACP-5862, are not inhibitors of P-glycoprotein (P-gp), organic anion transporter (OAT) 1, OAT3, organic cation transporter 2 (OCT2), organic anion transporting polypeptide (OATP) 1B1, OATP1B3, or MATE2-K. Acalabrutinib and its active metabolite, ACP-5862, are substrates of P-gp and BCRP. Acalabrutinib is not a substrate of OAT1, OAT3, OCT2, OATP1B1, or OATP1B3. Acalabrutinib’s active metabolite, ACP-5862, is not a substrate of OATP1B1 or OATP1B3.

20220804

1

3 DOSAGE FORMS AND STRENGTHS Tablets:100 mg acalabrutinib, orange, oval, film-coated, biconvex, debossed with ‘ACA 100’ on one side and plain on the other. Tablets: 100 mg. ( 3 )

CALQUENCE acalabrutinib ACALABRUTINIB ACALABRUTINIB COPOVIDONE K25-31 FERRIC OXIDE RED FERRIC OXIDE YELLOW HYPROMELLOSE, UNSPECIFIED LOW-SUBSTITUTED HYDROXYPROPYL CELLULOSE, UNSPECIFIED MANNITOL MEDIUM-CHAIN TRIGLYCERIDES MICROCRYSTALLINE CELLULOSE POLYETHYLENE GLYCOL 3350 SODIUM STEARYL FUMARATE TITANIUM DIOXIDE WATER biconvex ACA100

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenicity studies have not been conducted with acalabrutinib. Acalabrutinib was not mutagenic in an in vitro bacterial reverse mutation (AMES) assay or clastogenic in an in vitro human lymphocyte chromosomal aberration assay or in an in vivo rat bone marrow micronucleus assay. In a fertility study in rats, there were no effects of acalabrutinib on fertility in male rats at exposures 11 times, or in female rats at exposures 9 times, the AUC observed in patients at the recommended dose of 100 mg twice daily.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenicity studies have not been conducted with acalabrutinib. Acalabrutinib was not mutagenic in an in vitro bacterial reverse mutation (AMES) assay or clastogenic in an in vitro human lymphocyte chromosomal aberration assay or in an in vivo rat bone marrow micronucleus assay. In a fertility study in rats, there were no effects of acalabrutinib on fertility in male rats at exposures 11 times, or in female rats at exposures 9 times, the AUC observed in patients at the recommended dose of 100 mg twice daily.

NDA216387

CALQUENCE

acalabrutinib

0310-3512

HUMAN PRESCRIPTION DRUG

ORAL

PACKAGE/LABEL PRINCIPAL DISPLAY PANEL NDC 0310-3512-60 CALQUENCE ® (acalabrutinib) tablets 100 mg Rx only Do not chew, crush, dissolve, or cut tablets Manufactured for: AstraZeneca Pharmaceuticals LP Wilmington, DE 19850 By: AstraZeneca AB SE-151 85 Södertälje Sweden Product of Switzerland 100mg_60_tablet_bottle

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information). Serious and Opportunistic Infections Inform patients of the possibility of serious infection and to report signs or symptoms suggestive of infection [see Warnings and Precautions (5.1) ] . Hemorrhage Inform patients to report signs or symptoms of bleeding. Inform patients that CALQUENCE may need to be interrupted for major surgeries [see Warnings and Precautions (5.2) ] . Cytopenias Inform patients that they will need periodic blood tests to check blood counts during treatment with CALQUENCE [see Warnings and Precautions (5.3) ] . Second Primary Malignancies Inform patients that other malignancies have been reported in patients who have been treated with CALQUENCE, including skin cancer and other solid tumors. Advise patients to use sun protection [see Warnings and Precautions (5.4) ] . Atrial Fibrillation and Flutter Counsel patients to report any signs of palpitations, dizziness, fainting, chest discomfort, and shortness of breath [see Warnings and Precautions (5.5) ] . Pregnancy Complication CALQUENCE may cause fetal harm and dystocia. Advise women to use effective contraception during treatment and for 1 week after the last dose of CALQUENCE [see Use in Specific Populations (8.3) ] . Lactation Advise females not to breastfeed during treatment with CALQUENCE and for 2 weeks after the last dose [see Use in Specific Populations (8.2) ] . Dosing Instructions Instruct patients to take CALQUENCE orally twice daily, about 12 hours apart. CALQUENCE may be taken with or without food. Advise patients that CALQUENCE tablets should be swallowed whole with a glass of water, without chewing, crushing, dissolving, or cutting [see Dosage and Administration (2.1) ] . Missed Dose Advise patients that if they miss a dose of CALQUENCE, they may still take it up to 3 hours after the time they would normally take it. If more than 3 hours have elapsed, they should be instructed to skip that dose and take their next dose of CALQUENCE at the usual time. Warn patients they should not take extra tablets to make up for the dose that they missed [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) ] . Distributed by: AstraZeneca Pharmaceuticals LP Wilmington, DE 19850 CALQUENCE is a registered trademark of the AstraZeneca group of companies. ©AstraZeneca 2022

14 CLINICAL STUDIES 14.1 Mantle Cell Lymphoma The efficacy of CALQUENCE was based upon Trial LY-004 titled “An Open-label, Phase 2 Study of ACP-196 in Subjects with Mantle Cell Lymphoma” (NCT02213926). Trial LY-004 enrolled a total of 124 patients with MCL who had received at least one prior therapy. The median age was 68 (range 42 to 90) years, 80% were male, and 74% were Caucasian. At baseline, 93% of patients had an ECOG performance status of 0 or 1. The median time since diagnosis was 46.3 months and the median number of prior treatments was 2 (range 1 to 5), including 18% with prior stem cell transplant. Patients who received prior treatment with BTK inhibitors were excluded. The most common prior regimens were CHOP-based (52%) and ARA-C (34%). At baseline, 37% of patients had at least one tumor with a longest diameter ≥ 5 cm, 73% had extra nodal involvement including 51% with bone marrow involvement. The simplified Mantle Cell Lymphoma International Prognostic Index (MIPI) score (which includes age, ECOG score, and baseline lactate dehydrogenase and white cell count) was intermediate in 44% and high in 17% of patients. CALQUENCE was administered orally at 100 mg approximately every 12 hours until disease progression or unacceptable toxicity. The median dose intensity was 98.5%. The major efficacy outcome of Trial LY-004 was overall response rate and the median follow-up was 15.2 months. Table 9: Efficacy Results in Patients with MCL in Trial LY-004 Investigator Assessed N=124 Independent Review Committee (IRC) Assessed N=124 Overall Response Rate (ORR) Per 2014 Lugano Classification. ORR (%) [95% CI] 81 [73, 87] 80 [72, 87] Complete Response (%) [95% CI] 40 [31, 49] 40 [31, 49] Partial Response (%) [95% CI] 41 [32, 50] 40 [32, 50] Duration of Response (DoR) Median DoR in months [range] NE [1+ to 20+] NE [0+ to 20+] CI= Confidence Interval; NE=Not Estimable; + indicates censored observations. The median time to best response was 1.9 months. Lymphocytosis Upon initiation of CALQUENCE, a temporary increase in lymphocyte counts (defined as absolute lymphocyte count increased ≥ 50% from baseline and a post-baseline assessment ≥ 5 x 10 9 /L) in 31.5% of patients in Trial LY-004. The median time to onset of lymphocytosis was 1.1 weeks, and the median duration of lymphocytosis was 6.7 weeks. 14.2 Chronic Lymphocytic Leukemia The efficacy of CALQUENCE in patients with CLL was demonstrated in two randomized, controlled trials. The indication for CALQUENCE includes patients with SLL because it is the same disease. ELEVATE-TN The efficacy of CALQUENCE was evaluated in the ELEVATE-TN trial, a randomized, multicenter, open-label, actively controlled, 3 arm trial of CALQUENCE in combination with obinutuzumab, CALQUENCE monotherapy, and obinutuzumab in combination with chlorambucil in 535 patients with previously untreated chronic lymphocytic leukemia (NCT02475681). Patients 65 years of age or older or between 18 and 65 years of age with a total Cumulative Illness Rating Scale (CIRS) > 6 or creatinine clearance of 30 to 69 mL/min were enrolled. The trial also required hepatic transaminases ≤ 3 times upper limit of normal (ULN) and total bilirubin ≤ 1.5 times ULN, and excluded patients with Richter’s transformation. Patients were randomized in a 1:1:1 ratio into 3 arms to receive: • CALQUENCE plus obinutuzumab (CALQUENCE+G): CALQUENCE 100 mg was administered approximately every 12 hours starting on Cycle 1 Day 1 until disease progression or unacceptable toxicity. Obinutuzumab was administered starting on Cycle 2 Day 1 for a maximum of 6 treatment cycles. Obinutuzumab 1,000 mg was administered on Days 1 and 2 (100 mg on Day 1 and 900 mg on Day 2), 8 and 15 of Cycle 2 followed by 1,000 mg on Day 1 of Cycles 3 up to 7. Each cycle was 28 days. • CALQUENCE monotherapy: CALQUENCE 100 mg was administered approximately every 12 hours until disease progression or unacceptable toxicity. • Obinutuzumab plus chlorambucil (GClb): Obinutuzumab and chlorambucil were administered for a maximum of 6 treatment cycles. Obinutuzumab 1,000 mg was administered intravenously on Days 1 and 2 (100 mg on Day 1 and 900 mg on Day 2), 8 and 15 of Cycle 1 followed by 1,000 mg on Day 1 of Cycles 2 to 6. Chlorambucil 0.5 mg/kg was administered orally on Days 1 and 15 of Cycles 1 to 6. Each cycle was 28 days. Randomization was stratified by 17p deletion mutation status, ECOG performance status (0 or 1 versus 2), and geographic region. A total of 535 patients were randomized, 179 to CALQUENCE+G, 179 to CALQUENCE monotherapy, and 177 to GClb. The overall median age was 70 years (range: 41 to 91 years), 47% had Rai stage III or IV disease, 14% had 17p deletion or TP53 mutation, 63% of patients had an unmutated IGVH, and 18% had 11q deletion. Baseline demographic and disease characteristics were similar between treatment arms. Efficacy was based on progression-free survival (PFS) as assessed by an Independent Review Committee (IRC). The median duration of follow-up was 28.3 months (range: 0.0 to 40.8 months). Efficacy results are presented in Table 10. The Kaplan-Meier curves for PFS are shown in Figure 1. Table 10: Efficacy Results per IRC in Patients with CLL ‒ ITT population (ELEVATE-TN) CALQUENCE plus Obinutuzumab N=179 CALQUENCE Monotherapy N=179 Obinutuzumab plus Chlorambucil N=177 Progression-Free Survival Per 2008 International Workshop on CLL (IWCLL) criteria. Number of events (%) 14 (8) 26 (15) 93 (53) PD, n (%) 9 (5) 20 (11) 82 (46) Death events, n (%) 5 (3) 6 (3) 11 (6) Median (95% CI), months Kaplan-Meier estimate. NE NE (34, NE) 22.6 (20, 28) HR Based on a stratified Cox-Proportional-Hazards model. Both hazard ratios are compared with the obinutuzumab and chlorambucil arm. (95% CI) 0.10 (0.06, 0.17) 0.20 (0.13, 0.30) - p-value Based on a stratified log-rank test, with an alpha level of 0.012 derived from alpha spending function by the O’Brien-Fleming method. < 0.0001 < 0.0001 - Overall Response Rate (CR + CRi + nPR + PR) ORR, n (%) 168 (94) 153 (86) 139 (79) (95% CI) (89, 97) (80, 90) (72, 84) p-value Based on a stratified Cochran–Mantel–Haenszel test, for the comparison with the obinutuzumab and chlorambucil arm. < 0.0001 0.0763 - CR, n (%) 23 (13) 1 (1) 8 (5) CRi, n (%) 1 (1) 0 0 nPR, n (%) 1 (1) 2 (1) 3 (2) PR, n (%) 143 (80) 150 (84) 128 (72) ITT=intent-to-treat; CI=confidence interval; HR=hazard ratio; NE=not estimable; CR=complete response; CRi=complete response with incomplete blood count recovery; nPR=nodular partial response; PR=partial response. Figure 1: Kaplan-Meier Curve of IRC-Assessed PFS in Patients with CLL in ELEVATE-TN With a median follow-up of 28.3 months, median overall survival was not reached in any arm, with fewer than 10% of patients experiencing an event. ASCEND The efficacy of CALQUENCE in patients with relapsed or refractory CLL was based upon a multicenter, randomized, open-label trial (ASCEND; NCT02970318). The trial enrolled 310 patients with relapsed or refractory CLL after at least 1 prior systemic therapy. The trial excluded patients with transformed disease, prolymphocytic leukemia, or previous treatment with venetoclax, a Bruton tyrosine kinase inhibitor, or a phosphoinositide-3 kinase inhibitor. Patients were randomized in a 1:1 ratio to receive either: • CALQUENCE 100 mg approximately every 12 hours until disease progression or unacceptable toxicity, or • Investigator’s choice: ∘ Idelalisib plus a rituximab product (IR): Idelalisib 150 mg orally approximately every 12 hours until disease progression or unacceptable toxicity, in combination with 8 infusions of a rituximab product (375 mg/m2 intravenously on Day 1 of Cycle 1, followed by 500 mg/m2 every 2 weeks for 4 doses and then every 4 weeks for 3 doses), with a 28-day cycle length. ∘ Bendamustine plus a rituximab product (BR): Bendamustine 70 mg/m2 intravenously (Day 1 and 2 of each 28-day cycle), in combination with a rituximab product (375 mg/m2 intravenously on Day 1 of Cycle 1, then 500 mg/m2 on Day 1 of subsequent cycles), for up to 6 cycles. Randomization was stratified by 17p deletion mutation status, ECOG performance status (0 or 1 versus 2), and number of prior therapies (1 to 3 versus ≥ 4). Of 310 patients total, 155 were assigned to CALQUENCE monotherapy, 119 to IR, and 36 to BR. The median age overall was 67 years (range: 32 to 90 years), 42% had Rai stage III or IV disease, 28% had 17p deletion or TP53 mutation, 78% of patients had an unmutated IGVH, and 27% had a 11q deletion. The CALQUENCE arm had a median of 1 prior therapy (range: 1 to 8), with 47% having at least 2 prior therapies. The investigator’s choice arm had a median of 2 prior therapies (range: 1 to 10), with 57% having at least 2 prior therapies. In the CALQUENCE arm, the median treatment duration was 15.7 months, with 94% of patients treated for at least 6 months and 86% of patients treated for at least 1 year. In the investigator’s choice arm, the median treatment duration was 8.4 months, with 59% of patients treated for at least 6 months and 37% treated for at least 1 year. Efficacy was based on PFS as assessed by an IRC, with a median follow-up of 16.1 months (range 0.03 to 22.4 months). Efficacy results are presented in Table 11. The Kaplan-Meier curve for PFS is shown in Figure 2. There was no statistically significant difference in overall response rates between the two treatment arms. Table 11: Efficacy Results per IRC in Patients with Relapsed or Refractory CLL – ITT Population (ASCEND) CALQUENCE Monotherapy N=155 Investigator’s Choice of Idelalisib + Rituximab Product or Bendamustine + Rituximab Product N=155 Progression-Free Survival Per 2008 IWCLL criteria. Number of events, n (%) 27 (17) 68 (44) Disease progression, n 19 59 Death, n 8 9 Median (95% CI), months Kaplan-Meier estimate. NE (NE, NE) 16.5 (14.0, 17.1) HR (95% CI) Based on a stratified Cox-Proportional-Hazards model. 0.31 (0.20, 0.49) P-value Based on a stratified Log-rank test. The pre-specified type I error rate (α) for this interim analysis is 0.012 derived from a Lan-DeMets alpha spending function with O’Brien-Fleming boundary. < 0.0001 Overall Response Rate (CR + CRi + nPR + PR) Through a hierarchical testing procedure, the difference in ORR was not statistically significant, based on a Cochran-Mantel-Haenszel test with adjustment for randomization stratification factors. ORR, n (%) 126 (81) 117 (75) (95% CI) (74, 87) (68, 82) CR, n (%) 0 2 (1) CRi, n (%) 0 0 nPR, n (%) 0 0 PR, n (%) 126 (81) 115 (74) ITT=intent-to-treat; CI=confidence interval; HR=hazard ratio; NE=not estimable; CR=complete response; CRi=complete response with incomplete blood count recovery; nPR=nodular partial response; PR=partial response Figure 2: Kaplan-Meier Curve of IRC-Assessed PFS in Patients with CLL in ASCEND With a median follow-up of 16.1 months, median overall survival was not reached in either arm, with fewer than 11% of patients experiencing an event. figure_1 figure_2

8.5 Geriatric Use Of the 929 patients with CLL or MCL in clinical trials of CALQUENCE, 68% were 65 years of age or older, and 24% were 75 years of age or older. Among patients 65 years of age or older, 59% had Grade 3 or higher adverse reactions and 39% had serious adverse reactions. Among patients younger than age 65, 45% had Grade 3 or higher adverse reactions and 25% had serious adverse reactions. No clinically relevant differences in efficacy were observed between patients ≥ 65 years and younger.

8.4 Pediatric Use The safety and efficacy of CALQUENCE in pediatric patients have not been established.

8.1 Pregnancy Risk Summary Based on findings in animals, CALQUENCE may cause fetal harm and dystocia when administered to a pregnant woman. There are no available data in pregnant women to inform the drug-associated risk. In animal reproduction studies, administration of acalabrutinib to animals during organogenesis resulted in dystocia in rats and reduced fetal growth in rabbits at maternal exposures (AUC) 2 times exposures in patients at the recommended dose of 100 mg approximately every 12 hours ( see Data ) . Advise pregnant women of the potential risk to a fetus. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Data Animal Data In a combined fertility and embryo-fetal development study in female rats, acalabrutinib was administered orally at doses up to 200 mg/kg/day starting 14 days prior to mating through gestational day [GD] 17. No effects on embryo-fetal development and survival were observed. The AUC at 200 mg/kg/day in pregnant rats was approximately 9 times the AUC in patients at the recommended dose of 100 mg approximately every 12 hours. The presence of acalabrutinib and its active metabolite were confirmed in fetal rat plasma. In an embryo-fetal development study in rabbits, pregnant animals were administered acalabrutinib orally at doses up to 200 mg/kg/day during the period of organogenesis (from GD 6-18). Administration of acalabrutinib at doses ≥ 100 mg/kg/day produced maternal toxicity and 100 mg/kg/day resulted in decreased fetal body weights and delayed skeletal ossification. The AUC at 100 mg/kg/day in pregnant rabbits was approximately 2 times the AUC in patients at 100 mg approximately every 12 hours. In a pre- and postnatal development study in rats, acalabrutinib was administered orally to pregnant animals during organogenesis, parturition and lactation, at doses of 50, 100, and 150 mg/kg/day. Dystocia (prolonged or difficult labor) and mortality of offspring were observed at doses ≥ 100 mg/kg/day. The AUC at 100 mg/kg/day in pregnant rats was approximately 2 times the AUC in patients at 100 mg approximately every 12 hours. Underdeveloped renal papilla was also observed in F1 generation offspring at 150 mg/kg/day with an AUC approximately 5 times the AUC in patients at 100 mg approximately every 12 hours.

8 USE IN SPECIFIC POPULATIONS • Pregnancy: May cause fetal harm and dystocia. ( 8.1 ) • Lactation: Advise not to breastfeed. ( 8.2 ) • Severe Hepatic Impairment: Avoid use of CALQUENCE. ( 8.6 ) 8.1 Pregnancy Risk Summary Based on findings in animals, CALQUENCE may cause fetal harm and dystocia when administered to a pregnant woman. There are no available data in pregnant women to inform the drug-associated risk. In animal reproduction studies, administration of acalabrutinib to animals during organogenesis resulted in dystocia in rats and reduced fetal growth in rabbits at maternal exposures (AUC) 2 times exposures in patients at the recommended dose of 100 mg approximately every 12 hours ( see Data ) . Advise pregnant women of the potential risk to a fetus. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Data Animal Data In a combined fertility and embryo-fetal development study in female rats, acalabrutinib was administered orally at doses up to 200 mg/kg/day starting 14 days prior to mating through gestational day [GD] 17. No effects on embryo-fetal development and survival were observed. The AUC at 200 mg/kg/day in pregnant rats was approximately 9 times the AUC in patients at the recommended dose of 100 mg approximately every 12 hours. The presence of acalabrutinib and its active metabolite were confirmed in fetal rat plasma. In an embryo-fetal development study in rabbits, pregnant animals were administered acalabrutinib orally at doses up to 200 mg/kg/day during the period of organogenesis (from GD 6-18). Administration of acalabrutinib at doses ≥ 100 mg/kg/day produced maternal toxicity and 100 mg/kg/day resulted in decreased fetal body weights and delayed skeletal ossification. The AUC at 100 mg/kg/day in pregnant rabbits was approximately 2 times the AUC in patients at 100 mg approximately every 12 hours. In a pre- and postnatal development study in rats, acalabrutinib was administered orally to pregnant animals during organogenesis, parturition and lactation, at doses of 50, 100, and 150 mg/kg/day. Dystocia (prolonged or difficult labor) and mortality of offspring were observed at doses ≥ 100 mg/kg/day. The AUC at 100 mg/kg/day in pregnant rats was approximately 2 times the AUC in patients at 100 mg approximately every 12 hours. Underdeveloped renal papilla was also observed in F1 generation offspring at 150 mg/kg/day with an AUC approximately 5 times the AUC in patients at 100 mg approximately every 12 hours. 8.2 Lactation Risk Summary No data are available regarding the presence of acalabrutinib or its active metabolite in human milk, its effects on the breastfed child, or on milk production. Acalabrutinib and its active metabolite were present in the milk of lactating rats. Due to the potential for adverse reactions in a breastfed child from CALQUENCE, advise lactating women not to breastfeed while taking CALQUENCE and for 2 weeks after the last dose. 8.3 Females and Males of Reproductive Potential CALQUENCE may cause embryo-fetal harm and dystocia when administered to pregnant women [see Use in Specific Populations (8.1) ] . Pregnancy Testing Pregnancy testing is recommended for females of reproductive potential prior to initiating CALQUENCE therapy. Contraception Females Advise female patients of reproductive potential to use effective contraception during treatment with CALQUENCE and for 1 week following the last dose of CALQUENCE. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be informed of the potential hazard to a fetus. 8.4 Pediatric Use The safety and efficacy of CALQUENCE in pediatric patients have not been established. 8.5 Geriatric Use Of the 929 patients with CLL or MCL in clinical trials of CALQUENCE, 68% were 65 years of age or older, and 24% were 75 years of age or older. Among patients 65 years of age or older, 59% had Grade 3 or higher adverse reactions and 39% had serious adverse reactions. Among patients younger than age 65, 45% had Grade 3 or higher adverse reactions and 25% had serious adverse reactions. No clinically relevant differences in efficacy were observed between patients ≥ 65 years and younger. 8.6 Hepatic Impairment Avoid use of CALQUENCE in patients with severe hepatic impairment (Child-Pugh class C). No dosage adjustment of CALQUENCE is recommended in patients with mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment. The safety of CALQUENCE has not been evaluated in patients with moderate or severe hepatic impairment [see Clinical Pharmacology (12.3) ] .

16 HOW SUPPLIED/STORAGE AND HANDLING How Supplied Pack Size Contents NDC Number 60-count bottle Bottle containing 60 tablets with a child-resistant closure 100 mg, orange, oval, biconvex tablet, with debossment ‘ACA100’ on one side and plain on the reverse 0310-3512-60 Storage Store at 20°C-25°C (68°F-77°F); excursions permitted to 15°C-30°C (59°F-86°F) [see USP Controlled Room Temperature].