CALQUENCE

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

CALQUENCE is a kinase inhibitor indicated: • In combination with bendamustine and rituximab for the treatment of adult patients with previously untreated mantle cell lymphoma (MCL) who are ineligible for autologous hematopoietic stem cell transplantation (HSCT). ( 1.1 ) • For the treatment of adult patients with MCL who have received at least one prior therapy. ( 1.2 ) • For the treatment of adult patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). ( 1.3 ) 1.1 Previously Untreated Mantle Cell Lymphoma CALQUENCE in combination with bendamustine and rituximab is indicated for the treatment of adult patients with previously untreated mantle cell lymphoma (MCL) who are ineligible for autologous hematopoietic stem cell transplantation (HSCT). 1.2 Previously Treated Mantle Cell Lymphoma CALQUENCE is indicated for the treatment of adult patients with MCL who have received at least one prior therapy. 1.3 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).

• 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 Administration Instructions 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. 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 Bendamustine and Rituximab For patients with previously untreated MCL, the recommended dosage of CALQUENCE is 100 mg taken orally approximately every 12 hours until disease progression or unacceptable toxicity. Start CALQUENCE on Day 1 of Cycle 1 (each cycle is 28 days) and administer until disease progression or unacceptable toxicity. Administer bendamustine 90 mg/m 2 on Days 1 and 2 and rituximab 375 mg/m 2 on Day 1 of Cycle 1 and continue for a total of 6 cycles. Patients achieving a response (PR or CR) after the first 6 cycles may receive maintenance rituximab on Day 1 of every other cycle for a maximum of 12 additional doses, starting on Cycle 8 up to Cycle 30 [see Clinical Studies (14.1) ] . 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 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 are provided in Table 2 and 3. Table 2: Recommended Dosage Modifications for Adverse Reactions in Patients Receiving CALQUENCE Monotherapy and CALQUENCE in Combination with Obinutuzumab 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). Table 3: Recommended Dosage Modifications for Adverse Reactions in Patients Receiving CALQUENCE in Combination with BR Adverse Reaction Severitya Dosage Modification (Starting dosage of CALQUENCE = 100 mg approximately every 12 hours) Neutropenia b [see Warnings and Precautions (5.4)] Absolute neutrophil count less than 0.5 x 109/L for greater than 7 days Interrupt CALQUENCE. Once toxicity has resolved to Grade ≤ 2, resume CALQUENCE at starting dosage. Upon 2 nd or 3 rd occurrence, reduce dosage of CALQUENCE to 100 mg once daily. c Discontinue CALQUENCE at 4 th occurrence. For bendamustine b : Interrupt bendamustine. Once toxicity has resolved to Grade ≤ 2, resume bendamustine and consider dosage reduction to 70 mg/m 2 . d,e Thrombocytopenia f [see Warnings and Precautions (5.4)] Platelet count 25 to 50 x 109/L with clinically significant bleeding or platelet count less than 25 x 109/L Interrupt CALQUENCE. Once toxicity has resolved to Grade ≤ 2 or baseline, resume CALQUENCE at starting dosage. If recurrence, reduce dosage of CALQUENCE to 100 mg once daily. c Consider discontinuing CALQUENCE at 3 rd occurrence. For bendamustine f : Interrupt bendamustine. Once toxicity has resolved to Grade ≤ 2 or baseline, resume bendamustine and consider dose reduction to 70 mg/m 2 . e Non‑hematologic adverse reactions [see Warnings and Precautions (5)] Grade 3 or higher Interrupt CALQUENCE. Once toxicity has resolved to Grade ≤ 2 or baseline, resume CALQUENCE at starting dosage. If recurrence, reduce dosage of CALQUENCE to 100 mg once daily. c Discontinue CALQUENCE at 3 rd occurrence of Grade 4 toxicity. For Grade 3 toxicity, consider the risks and benefits of continuing CALQUENCE. For bendamustine : Interrupt bendamustine. Once toxicity has resolved to Grade ≤ 2 or baseline, resume bendamustine and consider dose reduction to 70 mg/m 2 . e a Graded per National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03. b For neutropenia with ANC less than 1 x 109/L, consideration for bendamustine dose interruption and dosage reduction to 70 mg/m2 may be appropriate in certain circumstances. c Dose may be re-escalated at the discretion of the physician if patient tolerates a reduced dose for ≥4 weeks. d Consider use of myeloid growth factors before bendamustine dosage reduction. e Consider discontinuing bendamustine if additional dosage reduction is required. f For thrombocytopenia, a platelet count below 50 x 109/L should prompt bendamustine dose interruption even in the absence of clinically significant bleeding . Refer to the prescribing information of each of the products used in combination with CALQUENCE for additional information for management of toxicities.

None. None. ( 4 )

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) ] • Cardiac Arrhythmias [see Warnings and Precautions (5.5) ] • Hepatotoxicity, including DILI [see Warnings and Precautions (5.6) ] The most common adverse reactions (≥ 30%), excluding laboratory abnormalities, are diarrhea, upper respiratory tract infection, headache, musculoskeletal pain, lower respiratory tract infection, and fatigue. The most common Grade 3 or 4 laboratory abnormalities (≥ 10%) are absolute neutrophil count decreased, absolute lymphocyte count decreased, platelets decreased, and hemoglobin decreased. ( 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 Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The data in the Warnings and Precautions reflect exposure to CALQUENCE 100 mg approximately every 12 hours in 1,764 patients with hematologic malignancies. Treatment includes CALQUENCE monotherapy in 1,256 patients in 9 trials, and CALQUENCE combinations in 508 patients in 3 trials. Among these recipients of CALQUENCE, 88% were exposed for at least 6 months and 80% were exposed for at least one year. In this pooled safety population, adverse reactions in ≥ 30% of 1,764 patients, excluding laboratory abnormalities, were diarrhea (37%), upper respiratory tract infection (36%), headache (35%), musculoskeletal pain (33%), lower respiratory tract infection (32%), and fatigue (32%). The most common grade 3 or 4 laboratory abnormalities (≥10%) were absolute neutrophil count decreased (31%), absolute lymphocyte count decreased (23%), platelets decreased (11%), and hemoglobin decreased (10%). Previously Untreated Mantle Cell Lymphoma The safety data described below reflect exposure to CALQUENCE (100 mg approximately every 12 hours, with or without BR) in patients with MCL [see Clinical Studies (14.1) ] . ECHO The safety of CALQUENCE in combination with bendamustine and rituximab (CALQUENCE plus BR) was evaluated in 297 patients with previously untreated MCL in ECHO [see Clinical Studies (14.1) ] . The trial enrolled patients with previously untreated MCL, ≥ 65 years of age with no intention for transplant, total bilirubin ≤ 1.5 × ULN, AST or ALT ≤ 2.5 × ULN, and estimated creatinine clearance of > 50 mL/min. Patients received 6 cycles (as 28-day cycles) of CALQUENCE 100 mg orally twice daily (n = 297) or placebo (n = 297) in combination with bendamustine and rituximab. Patients then received CALQUENCE 100 mg orally twice daily or placebo continuously until progressive disease or unacceptable toxicity, with 12 additional dosages of rituximab every other cycle up to Cycle 30. The median duration of treatment with CALQUENCE was 28.6 months. A total of 171 (57.6%) patients were treated with CALQUENCE for ˃ 24 months and 122 (41.1%) patients were treated for ˃ 36 months. Serious adverse reactions occurred in 69% of patients who received CALQUENCE plus BR. Serious adverse reactions reported in ≥ 2% of patients were pneumonia (23%; includes COVID-19 pneumonia), COVID-19 (20%; includes COVID-19 pneumonia), pyrexia (6%), second primary malignancy (7%), rash (3.4%), febrile neutropenia (3.4%), atrial fibrillation (3%), sepsis (2.7%), and anemia (2.4%). Fatal adverse reactions that occurred within 30 days of the last study treatment were reported in 12% who received CALQUENCE plus BR including COVID-19 (6%; includes COVID-19 pneumonia), pneumonia (1%), sepsis (0.3%), second primary malignancy (0.7%), and pneumonitis (0.3%). Adverse reactions led to permanent discontinuation of CALQUENCE in 43%, dosage interruptions in 74%, and dosage reductions in 10% of patients. Adverse reactions that resulted in dosage modification in > 10% included infections, cytopenias, rashes, and gastrointestinal toxicity. Adverse reactions which resulted in permanent discontinuation of CALQUENCE in ≥ 4% of patients included COVID-19 (includes COVID-19 pneumonia) and neutropenia. Table 4 and Table 5 summarize select adverse reactions and laboratory abnormalities observed in patients treated in ECHO. Table 4: Adverse Reactions* (≥ 15%) in Patients with Previously Untreated MCL Who Received CALQUENCE plus BR in ECHO Body System Adverse Reactions* CALQUENCE plus BR N = 297 Placebo plus BR N = 297 All Grades (%) Grade 3 or 4 (%) All Grades (%) Grade 3 or 4 (%) Skin and subcutaneous tissue disorders Rash a 47 12 31 3 Infections COVID-19 b 38 13 27 11 Upper respiratory tract infection c 30 0.7 29 1 Pneumonia d 31 17 25 14 Gastrointestinal disorders Diarrhea 37 3 28 2.4 Vomiting 26 0.7 14 1 Constipation 25 1 25 0.3 General disorders Fatigue 37 3.7 32 4.4 Pyrexia 29 2.4 24 1.3 Edema 20 1.3 19 0 Nervous system disorders Headache 31 1.7 14 0.7 Dizziness 18 1 17 0.3 Respiratory, thoracic and mediastinal disorders Cough 27 0 20 0.3 Dyspnea 17 1 11 2.7 Neoplasms Secondary primary malignancy e 19 7 15 7 Musculoskeletal and connective tissue disorders Arthralgia 18 0.7 16 1 Vascular disorders Hemorrhage f 20 1.7 11 3 *Excludes laboratory terms. a Includes rash, dermatitis, and other related terms. b Includes the following fatal adverse reactions: n=24 for COVID-19. c Includes upper respiratory tract infection, sinusitis, pharyngitis, and related terms. d Includes pneumonia, terms containing pneumonia, and related infections. COVID-19 pneumonia is represented under both Pneumonia and COVID-19. e Includes terms related to malignant neoplasms including cutaneous neoplasms. f Includes all terms containing hematoma or hemorrhage and related terms indicative of bleeding. Clinically relevant adverse reactions in < 15% of patients receiving CALQUENCE plus BR included bruising, abdominal pain, atrial fibrillation or flutter, and tumor lysis syndrome. Table 5: Select Laboratory Abnormalities (≥ 15%) in Patients with Previously Untreated MCL in ECHO Laboratory Abnormality CALQUENCE plus BR Placebo plus BR All grade (%) Grade 3 or 4 (%) All grade (%) Grade 3 or 4 (%) Hematologic Abnormalities Lymphocytes decreased 98 87 97 89 Hemoglobin decreased 80 11 65 11 Neutrophils decreased 76 56 77 51 Platelets decreased 69 18 60 16 Chemistry Abnormalities AST increased 53 5 50 3.4 Uric acid increased 45 45 40 40 ALT increased 44 7 41 2.4 Potassium increased 40 2 38 2.7 Creatinine increased 37 3 28 2.4 Phosphate decreased 36 4.4 30 4.7 Potassium decreased 29 7 23 6 Bilirubin increased 19 2 12 2 a The denominator used to calculate the rate varied between 296 and 297 based on the number of patients with a baseline value and at least one post-treatment value. Grade 4 laboratory abnormalities in > 15% of patients treated with CALQUENCE plus BR include absolute lymphocyte count decreased (26%), absolute neutrophil count decreased (36%), and uric acid increased (17%). Previously Treated Mantle Cell Lymphoma ACE-LY-004 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 (14.2) ] . 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 6 and 7 present the frequency category of adverse reactions observed in patients with MCL treated with CALQUENCE. Table 6: Non-Hematologic Adverse Reactions in ≥ 5% (All Grades) of Patients with MCL in Trial LY-004 Body System Adverse Reactions * 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 a 21 - Rash b 18 0.8 Vascular disorders Hemorrhage c 8 0.8 Respiratory, thoracic and mediastinal disorders Epistaxis 6 - * Per NCI CTCAE version 4.03. a Bruising: Includes all terms containing ‘bruise,’ ‘contusion,’ ‘petechiae,’ or ‘ecchymosis’. b Rash: Includes all terms containing ‘rash’. c Hemorrhage: Includes all terms containing ‘hemorrhage’ or ‘hematoma’. Table 7: Hematologic Adverse Reactions Reported in ≥ 20% of Patients with MCL in Trial LY 004 Hematologic Adverse Reactions * CALQUENCE Monotherapy N=124 All Grades (%) Grade ≥ 3 (%) Hemoglobin decreased 46 10 Platelets decreased 44 12 Neutrophils decreased 36 15 *Per NCI CTCAE version 4.03; based on laboratory measurements and adverse reactions. 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 (14.3) ] . 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 (14.3)] . 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 8 and 9 present adverse reactions and laboratory abnormalities identified in the ELEVATE-TN trial. Table 8: Common Adverse Reactions (≥ 15% Any Grade) with CALQUENCE in Patients with CLL (ELEVATE-TN) Body System Adverse Reaction * 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 † 69 22 ‡ 65 14 ‡ 46 13 ‡ Upper respiratory tract infection § 39 2.8 35 0 17 1.2 Lower respiratory tract infection a 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 b Neutropenia c 53 37 23 13 78 50 Anemia d 52 12 53 10 54 14 Thrombocytopenia e 51 12 32 3.4 61 16 Lymphocytosis f 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 g 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 h 34 2.2 23 1.1 24 1.2 Skin and subcutaneous tissue disorders Bruising i 31 0 21 0 5 0 Rash j 26 2.2 25 0.6 9 0.6 Vascular disorders Hemorrhage k 20 1.7 20 1.7 6 0 *Per NCI CTCAE version 4.03. † Includes any adverse reactions involving infection or febrile neutropenia. ‡ 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. § Includes upper respiratory tract infection, nasopharyngitis and sinusitis. a Includes pneumonia, lower respiratory tract infection, bronchitis, bronchiolitis, tracheitis, and lung infection. b Derived from adverse reaction and laboratory data. c Includes neutropenia, neutrophil count decreased, and related laboratory data. d Includes anemia, red blood cell count decreased, and related laboratory data. e Includes thrombocytopenia, platelet count decreased, and related laboratory data. f Includes lymphocytosis, lymphocyte count increased, and related laboratory data. g Includes back pain, bone pain, musculoskeletal chest pain, musculoskeletal pain, musculoskeletal discomfort, myalgia, neck pain, pain in extremity and spinal pain. h Includes asthenia, fatigue, and lethargy. i Includes bruise, contusion, and ecchymosis. j Includes rash, dermatitis, and other related terms. k Includes hemorrhage, hematoma, hemoptysis, hematuria, menorrhagia, hemarthrosis, and epistaxis. 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 9: 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 (14.3) ] . 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 10 and non-hematologic laboratory abnormalities are described in Table 11. 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 10: Common Adverse Reactions (≥ 15% Any Grade) with CALQUENCE in Patients with CLL (ASCEND) Body System Adverse Reaction * 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 † 56 15 ‡ 65 28 ‡ 49 11 Upper respiratory tract infection § 29 1.9 26 3.4 17 2.9 Lower respiratory tract infection a 23 6 26 15 14 6 Blood and lymphatic system disorders b Neutropenia c 48 23 79 53 80 40 Anemia d 47 15 45 8 57 17 Thrombocytopenia e 33 6 41 13 54 6 Lymphocytosis f 26 19 23 18 2.9 2.9 Nervous system disorders Headache 22 0.6 6 0 0 0 Gastrointestinal disorders Diarrhea g 18 1.3 49 25 14 0 Vascular disorders Hemorrhage h 16 1.3 5 1.7 6 2.9 General disorders Fatigue i 15 1.9 13 0.8 31 6 Musculoskeletal and connective tissue disorders Musculoskeletal pain j 15 1.3 15 1.7 2.9 0 * Per NCI CTCAE version 4.03. † Includes any adverse reactions involving infection or febrile neutropenia. ‡ Includes 1 fatal case in the CALQUENCE monotherapy arm and 1 fatal case in the Idelalisib plus Rituximab arm. § Includes upper respiratory tract infection, rhinitis and nasopharyngitis. a Includes pneumonia, lower respiratory tract infection, bronchitis, bronchiolitis, tracheitis, and lung infection. b Derived from adverse reaction and laboratory data. c Includes neutropenia, neutrophil count decreased, and related laboratory data. d Includes anemia, red blood cell decreased, and related laboratory data. e Includes thrombocytopenia, platelet count decreased, and related laboratory data. f Includes lymphocytosis, lymphocyte count increased and related laboratory data. g Includes colitis, diarrhea, and enterocolitis. h Includes hemorrhage, hematoma, hemoptysis, hematuria, menorrhagia, hemarthrosis, and epistaxis. i Includes asthenia, fatigue, and lethargy. j Includes back pain, musculoskeletal chest pain, musculoskeletal pain, musculoskeletal discomfort, pain in extremity, myalgia, spinal pain and bone pain. 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 11: 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. 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of CALQUENCE. 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. • Cardiac disorders: ventricular arrhythmias • Hepatobiliary disorder: Drug induced liver injury

• 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) ].