CALQUENCE- acalabrutinib_tablet, film coated

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. 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. Acalabrutinib and its active metabolite, ACP-5862, exposures increase proportionally with dose across a dose range of 75 to 250 mg (0. 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 max Absorption The geometric mean absolute bioavailability of acalabrutinib was 25%. Median (min, max) time to peak plasma concentration (T max 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 max Distribution The geometric mean (% CV) steady-state volume of distribution (V ss Elimination The geometric mean (% CV) terminal elimination half-life (t 1/2 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 2 2 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: max Moderate CYP3A Inhibitors: max Strong CYP3A Inducers: max Acid-Reducing Agents: In Vitro Studies Cytochrome P450 (CYP) Enzymes: Uridine diphosphate (UDP)-glucuronosyl transferase (UGT) Enzymes: Transporter System 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.

CALQUENCE is a kinase inhibitor indicated: 1. 3 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). CALQUENCE is indicated for the treatment of adult patients with MCL who have received at least one prior therapy. CALQUENCE is indicated for the treatment of adult patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL).

6 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 2 [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 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. 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 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 rd c Discontinue CALQUENCE at 4 th 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 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. c Discontinue CALQUENCE at 3 rd 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. 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.

The following clinically significant adverse reactions are discussed in greater detail in other sections of the labeling: [see Warnings and Precautions (5. 1) [see Warnings and Precautions (5. 2) [see Warnings and Precautions (5. 3) [see Warnings and Precautions (5. 4) [see Warnings and Precautions (5. 5) [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. 1 To report SUSPECTED ADVERSE REACTIONS, contact AstraZeneca at 1-800-236-9933 or FDA at 1-800-FDA-1088 or www. gov/medwatch. 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 median duration of treatment with CALQUENCE was 28. 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. 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. 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. 4 Pyrexia 29 2. 3 Edema 20 1. 3 19 0 Nervous system disorders Headache 31 1. 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 b c d e f 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. 7 Potassium decreased 29 7 23 6 Bilirubin increased 19 2 12 2 a 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 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. 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 - * a b c 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 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. 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 CALQUENCE Monotherapy N=179 Obinutuzumab plus Chlorambucil All Grades (%) Grade >= 3 (%) All Grades (%) Grade >= 3 (%) All Grades (%) Grade >= 3 (%) Infections Infection dagger 69 22 double dagger 65 14 double dagger 46 13 double dagger Upper respiratory tract infection section 39 2. 8 35 0 17 1. 2 Lower respiratory tract infection a 24 8 18 4. 8 Urinary tract infection 15 1. 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 Nervous system disorders Headache 40 1. 1 12 0 Dizziness 20 0 12 0 7 0 Gastrointestinal disorders Diarrhea 39 4. 8 Nausea 20 0 22 0 31 0 Musculoskeletal and connective tissue disorders Musculoskeletal pain g 37 2. 4 Arthralgia 22 1. 2 General disorders and administration site conditions Fatigue h 34 2. 2 Skin and subcutaneous tissue disorders Bruising i 31 0 21 0 5 0 Rash j 26 2. 6 Vascular disorders Hemorrhage k 20 1. 7 6 0 *Per NCI CTCAE version 4. dagger double dagger section a b c d e f g h i j k Other clinically relevant adverse reactions (all grades incidence < 15%) in recipients of CALQUENCE (CALQUENCE in combination with obinutuzumab and monotherapy) included: Neoplasms: Cardiac disorders: Infection: 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 Grade >= 3 (%) All Grade >= 3 (%) All 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 Increases in creatinine to 1. 5 to 3 times ULN occurred in 3. 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) ] 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 dagger 56 15 double dagger 65 28 double dagger 49 11 Upper respiratory tract infection section 29 1. 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 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. 9 General disorders Fatigue i 15 1. 8 31 6 Musculoskeletal and connective tissue disorders Musculoskeletal pain j 15 1. 9 0 * dagger double dagger section a b c d e f g h i j Other clinically relevant adverse reactions (all grades incidence < 15%) in recipients of CALQUENCE included: Skin and subcutaneous disorders: Neoplasms: Musculoskeletal and connective tissue disorders: Cardiac disorders: Infection: 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 (%) Grade >= 3 (%) All (%) Grade >= 3 (%) All 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. 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. 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. .

6 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. 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. 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. 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. 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. The safety and efficacy of CALQUENCE in pediatric patients have not been established. CLL and Previously Treated MCL Of the 1,467 CALQUENCE-treated patients with CLL or relapsed or refractory MCL in clinical trials, 977 (67%) were 65 years of age or older, and 328 (22%) were 75 years of age or older. Among patients 65 years of age or older, 74% had Grade 3 or higher adverse reactions and 58% had serious adverse reactions. Among patients younger than age 65, 61% had Grade 3 or higher adverse reactions and 39% had serious adverse reactions. No clinically relevant differences in efficacy were observed between patients >= 65 years and younger. Previously Untreated MCL Of the 297 CALQUENCE-treated patients with previously untreated MCL, 214 (72%) were 65 to 74 years of age and 83 (28%) were 75 years of age and older. No clinically relevant differences in safety or efficacy were observed between patients ages 65 to 74 years and those who were 75 years of age and older. 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.

Strong CYP3A Inhibitors 2. 2 7 Moderate CYP3A Inhibitors 2. 2 7 Strong CYP3A Inducers 2. 2 7 Strong CYP3A Inhibitors Clinical Effect Co-administration of CALQUENCE with a strong CYP3A inhibitor increased acalabrutinib plasma concentrations [see Clinical Pharmacology (12. 3) 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) 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) 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.

NONCLINICAL TOXICOLOGY
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.
CLINICAL STUDIES
ECHO The efficacy of CALQUENCE in patients with previously untreated MCL was evaluated in a randomized, double blind, placebo controlled, multicenter study (ECHO; NCT02972840). The study enrolled 598 patients who were >= 65 years of age and who had no intention for transplant. The study excluded patients with total bilirubin > 1. 5 × upper limit of normal (ULN), AST or ALT > 2. 5 × ULN, or estimated creatinine clearance of <= 50 mL/min. Patients were randomized in a 1:1 ratio to receive CALQUENCE plus bendamustine and rituximab (CALQUENCE plus BR) or placebo plus BR. Dosing for both arms was administered in 28-day cycles as follows: 2 2 2 Patients on the control arm received the same regimen but placebo in lieu of CALQUENCE. Crossover to CALQUENCE monotherapy was permitted for patients in the placebo plus BR arm at disease progression. Of all patients randomized, the median age was 71 years (range: 65-86); 71% were male; 78% were White, 16% Asian, 0. 5% were Black or African American. In total, 80% had classic histology of MCL, 7. 7% had blastoid MCL, and 5. 5% had pleomorphic MCL. The simplified MIPI (Mantle Cell Lymphoma International Prognostic Index) score was low in 33%, intermediate in 43%, and high in 24% of patients. A total of 38% of patients had tumor bulk >= 5 cm and 86% had Ann Arbor stage IV disease. The major efficacy outcome was progression-free survival (PFS) as assessed by an Independent Review Committee (IRC) using the Lugano Classification. Efficacy results are presented in Table 12. The Kaplan-Meier curves for PFS are shown in Figure 1. At this prespecified interim analysis, the median follow-up for PFS was 49. 8 months in both arms. Efficacy Results in Patients with Previously Untreated MCL in ECHO Outcomes per IRC CALQUENCE plus BR N= 299 Placebo plus BR N= 299 Progression-Free Survival a 66. 016 Overall Response Rate (ORR) (CR + PR) 272 (91) 263 (88) 87, 94 84, 91 199 (67) 160 (54) 73 (24) 103 (34) 0. 220 HR = hazard ratio, CR = complete response, PR = partial response, NE en dash not evaluable a b c Figure 1. Kaplan-Meier Curve of IRC-Assessed PFS in Patients with Previously Untreated MCL in ECHO At the time of the PFS analysis, the median overall survival had not been reached in either arm with a total of 203 deaths: 97 (32%) patients in the CALQUENCE plus BR arm and 106 (35%) patients in the placebo plus BR arm had died. Figure_1 ACE-LY-004 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. The major efficacy outcome of Trial LY-004 was overall response rate and the median follow-up was 15. Table 13: 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. 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 109/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. 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: 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. Efficacy results are presented in Table 14. The Kaplan-Meier curves for PFS are shown in Figure 2. Table 14: Efficacy Results per IRC in Patients with CLL figure dash 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. 14 (8) 26 (15) 93 (53) 9 (5) 20 (11) 82 (46) 5 (3) 6 (3) 11 (6) Kaplan-Meier estimate. NE NE (34, NE) 22. 6 (20, 28) Based on a stratified Cox-Proportional-Hazards model. Both hazard ratios are compared with the obinutuzumab and chlorambucil arm. 30) - 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. 0001 - Overall Response Rate (CR + CRi + nPR + PR) 168 (94) 153 (86) 139 (79) (89, 97) (80, 90) (72, 84) Based on a stratified Cochranen dashMantelen dashHaenszel test, for the comparison with the obinutuzumab and chlorambucil arm. 0763 - 23 (13) 1 (1) 8 (5) 1 (1) 0 0 1 (1) 2 (1) 3 (2) 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 2: 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: ∘ 2 2 ∘ 2 2 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. Efficacy results are presented in Table 15. The Kaplan-Meier curve for PFS is shown in Figure 3. There was no statistically significant difference in overall response rates between the two treatment arms. Table 15: Efficacy Results per IRC in Patients with Relapsed or Refractory CLL en dash 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. 27 (17) 68 (44) 19 59 8 9 Kaplan-Meier estimate. NE (NE, NE) 16. 1) Based on a stratified Cox-Proportional-Hazards model. 49) Based on a stratified Log-rank test. The pre-specified type I error rate (alpha) for this interim analysis is 0. 012 derived from a Lan-DeMets alpha spending function with O’Brien-Fleming boundary. 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. 126 (81) 117 (75) (74, 87) (68, 82) 0 2 (1) 0 0 0 0 126 (81) 115 (74) 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_2 figure_3.
PATIENT INFORMATION
PATIENT INFORMATION CALQUENCE registered (acalabrutinib) tablets What is CALQUENCE? CALQUENCE is a prescription medicine used to treat adults with: It is not known if CALQUENCE is safe and effective in children. Before taking CALQUENCE, tell your healthcare provider about all of your medical conditions, including if you: o o Tell your healthcare provider about all the medicines you take How should I take CALQUENCE? What are the possible side effects of CALQUENCE? CALQUENCE can cause serious side effects, including: Serious infections Bleeding problems (hemorrhage) ∘ ∘ ∘ ∘ ∘ ∘ ∘ ∘ ∘ ∘ ∘ Decrease in blood cell counts. Second primary cancers. Heart rhythm problems (cardiac arrhythmias) ∘ ∘ ∘ ∘ ∘ Liver problems. The most common side effects of CALQUENCE include: These are not all of the possible side effects of CALQUENCE. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1‑800‑FDA‑1088. How should I store CALQUENCE? Keep CALQUENCE and all medicines out of the reach of children. General information about the safe and effective use of CALQUENCE. Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use CALQUENCE for a condition for which it was not prescribed. Do not give CALQUENCE to other people, even if they have the same symptoms you have. It may harm them. You can ask your healthcare provider or pharmacist for more information about CALQUENCE that is written for health professionals. What are the ingredients in CALQUENCE? Active ingredient: Inactive ingredients: Tablet core: Tablet coating: Distributed by: AstraZeneca Pharmaceuticals LP, Wilmington, DE 19850 CALQUENCE is a registered trademark of the AstraZeneca group of companies. copyrightAstraZeneca 2025 For more information, go to www.CALQUENCE.com This Patient Information has been approved by the U.S. Food and Drug Administration Revised: 1/2025

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