Calquence Drug Information

• 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 upper respiratory tract infection, diarrhea, headache, and musculoskeletal pain. The most common Grade 3 or 4 laboratory abnormalities (≥ 10%) are absolute neutrophil count decreased, uric acid increased, absolute lymphocyte count decreased, and platelets 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 2,055 patients with hematologic malignancies. Treatment includes CALQUENCE monotherapy in 1258 patients in 9 trials, and CALQUENCE combinations in 797 patients in 4 trials. Among these recipients of CALQUENCE, 89% were exposed for at least 6 months and 82% were exposed for at least one year. In this pooled safety population, adverse reactions in ≥ 30% of 2,055 patients, excluding laboratory abnormalities, were upper respiratory tract infection (37%), diarrhea (36%), headache (35%), and musculoskeletal pain (32%). The most common Grade 3 or 4 laboratory abnormalities (≥ 10%) were absolute neutrophil count decreased (32%), uric acid increased (27%), absolute lymphocyte count decreased (21%) and platelets 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 5 and Table 6 summarize select adverse reactions and laboratory abnormalities observed in patients treated in ECHO. Table 5: 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 Pneumoniad 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 6: Select Laboratory Abnormalities (≥ 15%) in Patients with Previously Untreated MCL in ECHO Laboratory Abnormality CALQUENCE plus BR a Placebo plus BR a 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 7 and 8 present the frequency category of adverse reactions observed in patients with MCL treated with CALQUENCE. Table 7: 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 8: 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 9 and 10 present adverse reactions and laboratory abnormalities identified in the ELEVATE-TN trial. Table 9: 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 Hemorrhagek 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 : 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 11 and non-hematologic laboratory abnormalities are described in Table 12. 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 11: 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 12: 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. AMPLIFY The safety of CALQUENCE in patients with previously untreated CLL was evaluated in a randomized, multicenter, open-label study (AMPLIFY), in which 291 patients received CALQUENCE plus venetoclax (AV), and 259 patients received Investigator’s choice of FCR/BR (fludarabine plus cyclophosphamide plus rituximab or bendamustine plus rituximab) [see Clinical Studies (14.3) ]. Among patients who received AV, 96% were exposed for 6 months or longer and 91% were exposed for greater than one year. The median duration of exposure to CALQUENCE was 12.9 months (range: 1 to 18 months) and to venetoclax was 11.1 months (range: 2 to 14 months). Serious adverse reactions occurred in 25% of patients receiving AV. The most common serious adverse reactions (≥ 2%) were COVID-19 including COVID-19 pneumonia (9%), second primary malignancies (2.7%), and neutropenia (2.1%). Fatal adverse events occurred in 3.4% of patients. The most common fatal adverse events included COVID-19 and COVID-19 pneumonia. Treatment discontinuation of CALQUENCE due to adverse reactions occurred in 8% of patients receiving AV. The most common adverse reaction (≥ 2%) leading to treatment discontinuation was COVID-19 pneumonia (2.1%). Dose reduction of CALQUENCE occurred in 6% of patients. Neutropenia was the only adverse reaction leading to dose reduction that occurred in ≥ 1% of patients. Table 13 and Table 14 summarize select adverse reactions and laboratory abnormalities observed in patients treated in AMPLIFY. Table 13: Adverse Reactions* (≥ 15% Any Grade) in Patients with Previously Untreated CLL Who Received CALQUENCE plus Venetoclax in AMPLIFY Body System Adverse Reactions * CALQUENCE plus Venetoclax N = 291 Investigator’s choice of FCR or BR N = 259 All Grades (%) Grade 3 or 4 (%) All Grades (%) Grade 3 or 4 (%) Nervous system disorders Headache 35 1.4 8 0.4 Gastrointestinal disorders Diarrhea 33 1.7 11 0.4 Nausea 15 0 36 0 Musculoskeletal and connective tissue disorders Musculoskeletal pain a 25 0.7 14 0.8 Infections COVID-19 21 6 3.9 1.5 General disorders Fatigue b 18 0.3 17 1.5 Skin and subcutaneous tissue disorders Bruising c 17 0 1.5 0 Rash d 16 1 16 1.5 *Excludes laboratory terms. a Includes back pain, bone pain, musculoskeletal chest pain, musculoskeletal pain, musculoskeletal discomfort, myalgia, neck pain, pain in extremity, spinal pain, non-cardiac chest pain and pain in jaw. b Includes fatigue and asthenia. c Includes increased tendency to bruise, contusion, and ecchymosis. d Includes rash, dermatitis, and other related terms. Clinically relevant adverse reactions in < 15% of patients receiving CALQUENCE plus Venetoclax included upper respiratory tract infections, lower respiratory tract infection, arthralgia, pneumonia, hemorrhage, dizziness, constipation, vomiting, second primary malignancy and hypertension. Table 14: Laboratory Abnormalities (≥ 15% Any Grade), New or Worsening from Baseline in in Patients with Previously Untreated CLL Who Received CALQUENCE plus Venetoclax in AMPLIFY Laboratory Abnormality CALQUENCE plus Venetoclax a Investigator’s choice of FCR or BR a All grade (%) Grade 3 or 4 (%) All grade (%) Grade 3 or 4 (%) Hematologic Abnormalities Neutrophils decreased 78 38 80 53 Lymphocytes decreased 56 12 92 73 Platelets decreased 43 5 59 15 Hemoglobin decreased 35 7 56 8 Chemistry Abnormalities Glucose increased 74 0 84 0 Calcium decreased 30 0.7 25 2.3 ALT increased 26 3.1 28 1.6 Urate increased 25 25 23 23 LDH increased 24 0 40 0 Potassium increased 22 2.4 12 3.1 AST increased 22 1.4 28 1.6 ALP increased 20 0 15 0 Glucose decreased 20 0.3 5 0 Creatinine increased 19 0.3 12 0.8 Sodium increased 15 0.3 9 0.4 a The denominator used to calculate the rate varied between 256 and 290 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 Venetoclax include absolute neutrophil count decreased (15%). 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 disorders: 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) ].

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 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.

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