LACTATION SECTION.


8.2 Lactation Risk Summary. No data are available regarding the presence of acalabrutinib or its active metabolite in human milk, its effects on the breastfed child, or on milk production. Acalabrutinib and its active metabolite were present in the milk of lactating rats. Due to the potential for adverse reactions in breastfed child from CALQUENCE, advise lactating women not to breastfeed while taking CALQUENCE and for at least weeks after the final dose.

ADVERSE REACTIONS SECTION.


6 ADVERSE REACTIONS The following clinically significant adverse reactions are discussed in greater detail in other sections of the labeling:oSerious and Opportunistic Infections [see Warnings and Precautions (5.1)]oHemorrhage [see Warnings and Precautions (5.2)]oCytopenias [see Warnings and Precautions (5.3)]oSecond Primary Malignancies [see Warnings and Precautions (5.4)]oAtrial Fibrillation and Flutter [see Warnings and Precautions (5.5)]. oSerious and Opportunistic Infections [see Warnings and Precautions (5.1)]. oHemorrhage [see Warnings and Precautions (5.2)]. oCytopenias [see Warnings and Precautions (5.3)]. oSecond Primary Malignancies [see Warnings and Precautions (5.4)]. oAtrial Fibrillation and Flutter [see Warnings and Precautions (5.5)]. Most common adverse reactions (incidence >= 30%) were: anemia, neutropenia, upper respiratory tract infection, thrombocytopenia, headache, diarrhea, and musculoskeletal pain. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact AstraZeneca at 1-800-236-9933 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience As clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.The data in the Warnings and Precautions reflect exposure to CALQUENCE 100 mg approximately every 12 hours in 1029 patients with hematologic malignancies. Treatment includes CALQUENCE monotherapy in 820 patients in trials, and CALQUENCE with obinutuzumab in 209 patients in trials. Among these recipients of CALQUENCE, 88% were exposed for at least months and 79% were exposed for at least one year. In this pooled safety population, adverse reactions in >= 30% of 1029 patients were anemia, neutropenia, upper respiratory tract infection, thrombocytopenia, headache, diarrhea, and musculoskeletal pain.Mantle Cell LymphomaThe safety data described in this section reflect exposure to CALQUENCE (100 mg approximately every 12 hours) in 124 patients with previously treated MCL in Trial LY-004 [see Clinical Studies (14.1)]. The median duration of treatment with CALQUENCE was 16.6 (range: 0.1 to 26.6) months. total of 91 (73.4%) patients were treated with CALQUENCE for >= months and 74 (59.7%) patients were treated for >= year.The most common adverse reactions (>= 20%) of any grade were anemia, thrombocytopenia, headache, neutropenia, diarrhea, fatigue, myalgia, and bruising. Grade 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 >= 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 and present the frequency category of adverse reactions observed in patients with MCL treated with CALQUENCE.Table 3: Non-Hematologic Adverse Reactions in >= 5% (All Grades) of Patients with MCL in Trial LY-004Body SystemAdverse ReactionsPer NCI CTCAE version 4.03.CALQUENCE MonotherapyN=124All Grades (%)Grade >= (%)Nervous system disordersHeadache391.6Gastrointestinal disordersDiarrhea313.2Nausea190.8Abdominal pain151.6Constipation15-Vomiting131.6General disordersFatigue280.8Musculoskeletal and connective tissue disordersMyalgia210.8Skin and subcutaneous tissue disordersBruisingBruising: Includes all terms containing bruise, contusion, petechiae, or ecchymosis 21-RashRash: Includes all terms containing rash 180.8Vascular disordersHemorrhageHemorrhage: Includes all terms containing hemorrhage or hematoma 80.8Respiratory, thoracic and mediastinal disordersEpistaxis6-Table 4: Hematologic Adverse Reactions Reported in >= 20% of Patients with MCL in Trial LY-004HematologicAdverse ReactionsPer NCI CTCAE version 4.03; based on laboratory measurements and adverse reactions.CALQUENCE MonotherapyN=124All Grades (%)Grade >= (%)Hemoglobin decreased4610Platelets decreased4412Neutrophils decreased3615Increases in creatinine 1.5 to times the upper limit of normal occurred in 4.8% of patients.Chronic Lymphocytic LeukemiaThe safety data described below reflect exposure to CALQUENCE (100 mg approximately every 12 hours, with or without obinutuzumab) in 511 patients with CLL from two randomized controlled clinical trials [see Clinical Studies (14.2)].The most common adverse reactions (>= 30%) of any grade in patients with CLL were anemia, neutropenia, thrombocytopenia, headache, upper respiratory tract infection, and diarrhea.ELEVATE-TNThe safety of CALQUENCE plus obinutuzumab (CALQUENCE+G), CALQUENCE monotherapy, and obinutuzumab plus chlorambucil (GClb) was evaluated in randomized, multicenter, open-label, actively controlled trial in 526 patients with previously untreated CLL [see Clinical Studies (14.2)].Patients randomized to the CALQUENCE+G arm were treated with CALQUENCE and obinutuzumab in combination for six cycles, then with CALQUENCE as monotherapy until disease progression or unacceptable toxicity. Patients initiated obinutuzumab on Day of Cycle 2, continuing for total of 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 total Cumulative Illness Rating Scale (CIRS) 6 or creatinine clearance of 30 to 69 mL/min, hepatic transaminases <= times upper limit of normal (ULN) and total bilirubin <= 1.5 times ULN, and allowed patients to receive antithrombotic agents other than warfarin or equivalent vitamin 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 months and 12 months of exposure, respectively. In the obinutuzumab and chlorambucil arm the median number of cycles was with 84% of patients receiving at least cycles of obinutuzumab, 70% of patients received at least cycles of chlorambucil. Eighty-five percent of patients in the CALQUENCE+G arm received at least 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 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 and presents adverse reactions and laboratory abnormalities identified in the ELEVATE-TN trial.Table 5: Common Adverse Reactions (>= 15% Any Grade) with CALQUENCE in Patients with CLL (ELEVATE-TN)Body SystemAdverse ReactionPer NCI CTCAE version 4.03 CALQUENCE plus ObinutuzumabN=178CALQUENCE MonotherapyN=179Obinutuzumab plus Chlorambucil N=169All Grades (%)Grade >= (%)All Grades (%)Grade >= (%)All Grades (%)Grade >= (%) Infections InfectionIncludes any adverse reactions involving infection or febrile neutropenia6922Includes fatal cases in the CALQUENCE plus obinutuzumab arm, fatal cases in the CALQUENCE monotherapy arm and fatal case in the obinutuzumab plus chlorambucil arm 6514 4613 Upper respiratory tract infectionUpper respiratory tract infection, nasopharyngitis and sinusitis392.8350171.2 Lower respiratory tract infectionIncludes pneumonia, lower respiratory tract infection, bronchitis, bronchiolitis, tracheitis, and lung infection248184.571.8 Urinary tract infection151.7152.850.6 Blood and lymphatic system disordersDerived from adverse reactions and laboratory data NeutropeniaIncludes neutropenia, neutrophil count decreased, and related laboratory data533723137850 AnemiaIncludes anemia, red blood cell count decreased, and related laboratory data521253105414 ThrombocytopeniaIncludes thrombocytopenia, platelet count decreased, and related laboratory data5112323.46116 LymphocytosisIncludes lymphocytosis, lymphocyte count increased, and related laboratory data121116150.60.6 Nervous system disorders Headache401.1391.1120 Dizziness20012070 Gastrointestinal disorders Diarrhea394.5350.6211.8 Nausea200220310 Musculoskeletal and connective tissue disorders Musculoskeletal painIncludes back pain, bone pain, musculoskeletal chest pain, musculoskeletal pain, musculoskeletal discomfort, myalgia, neck pain, pain in extremity and spinal pain372.2321.1162.4 Arthralgia221.1160.64.71.2 General disorders and administration site conditions FatigueIncludes asthenia, fatigue, and lethargy342.2231.1241.2 Skin and subcutaneous tissue disorders BruisingIncludes bruise, contusion, and ecchymosis 31 21 5 RashIncludes rash, dermatitis, and other related terms 26 2.2 25 0.6 0.6 Vascular disorders HemorrhageIncludes hemorrhage, hematoma, hemoptysis, hematuria, menorrhagia, hemarthrosis, and epistaxis201.7201.760Other clinically relevant adverse reactions (all grades incidence 15%) in recipients of CALQUENCE (CALQUENCE in combination with obinutuzumab and monotherapy) included:oNeoplasms: second primary malignancy (10%), non-melanoma skin cancer (5%)oCardiac disorders: atrial fibrillation or flutter (3.6%), hypertension (5%)oInfection: herpesvirus infection (6%)Table 6: Select Non-Hematologic Laboratory Abnormalities (>= 15% Any Grade), New or Worsening from Baseline in Patients Receiving CALQUENCE (ELEVATE-TN)Laboratory AbnormalityPer NCI CTCAE version 4.03Excludes electrolytesCALQUENCE plus ObinutuzumabN=178CALQUENCE MonotherapyN=179Obinutuzumab plus ChlorambucilN=169AllGrades (%)Grade >= (%)AllGrades (%)Grade >= (%)AllGrades (%)Grade >= (%)Uric acid increase292922223737ALT increase307201.1366AST increase385170.6608Bilirubin increase130.6150.6110.6Increases in creatinine 1.5 to times the upper limit of normal occurred in 3.9% and 2.8% of patients in the CALQUENCE combination arm and monotherapy arm, respectively.ASCENDThe safety of CALQUENCE in patients with relapsed or refractory CLL was evaluated in randomized, open-label study (ASCEND) [see Clinical Studies (14.2)]. The trial enrolled patients with relapsed or refractory CLL after at least one prior therapy and required hepatic transaminases <= times upper limit of normal (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/uL, platelet count 30,000/uL, prothrombin time or activated partial thromboplastin time 2 times ULN, significant cardiovascular disease, or requirement for strong CYP3A inhibitors or inducers. Patients were allowed to receive antithrombotic agents other than warfarin or equivalent vitamin 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 infusions of rituximab product, and 35 received up to cycles of bendamustine and 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 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 and non-hematologic laboratory abnormalities are described in Table 8. These tables reflect exposure to CALQUENCE with median duration of 15.7 months with 94% of patients on treatment for greater than 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 months and 48% of patients on treatment for greater than 12 months. Eighty-three percent of patients completed cycles of bendamustine and rituximab product.Table 7: Common Adverse Reactions (>= 15% Any Grade) with CALQUENCE in Patients with CLL (ASCEND)Body SystemAdverse ReactionPer NCI CTCAE version 4.03 CALQUENCEN=154Idelalisib plus RituximabProduct N=118Bendamustine plus Rituximab ProductN=35AllGrades (%)Grade >= (%)AllGrades (%)Grade >= (%)AllGrades (%)Grade >= (%) Infections InfectionIncludes any adverse reactions involving infection or febrile neutropenia 56 15Includes fatal case in the CALQUENCE monotherapy arm and fatal case in the Idelalisib plus Rituximab arm 65 28 49 11 Upper respiratory tract infectionUpper respiratory tract infection, rhinitis and nasopharyngitis 29 1.9 26 3.4 17 2.9 Lower respiratory tract infectionIncludes pneumonia, lower respiratory tract infection, bronchitis, bronchiolitis, tracheitis, and lung infection 23 26 15 14 Blood and lymphatic system disordersDerived from adverse reaction and laboratory data NeutropeniaIncludes neutropenia, neutrophil count decreased, and related laboratory data 48 23 79 53 80 40 AnemiaIncludes anemia, red blood cell decreased, and related laboratory data 47 15 45 57 17 ThrombocytopeniaIncludes thrombocytopenia, platelet count decreased, and related laboratory data 33 41 13 54 LymphocytosisIncludes lymphocytosis, lymphocyte count increased and related laboratory data 26 19 23 18 2.9 2.9 Nervous system disorders Headache 22 0.6 0 0 Gastrointestinal disorders DiarrheaIncludes colitis, diarrhea, and enterocolitis 18 1.3 49 25 14 Vascular disorders HemorrhageIncludes hemorrhage, hematoma, hemoptysis, hematuria, menorrhagia, hemarthrosis, and epistaxis 16 1.3 1.7 2.9 General disorders FatigueIncludes asthenia, fatigue, and lethargy 15 1.9 13 0.8 31 Musculoskeletal and connective tissue disorders Musculoskeletal PainIncludes back pain, musculoskeletal chest pain, musculoskeletal pain, musculoskeletal discomfort, pain in extremity, myalgia, spinal pain and bone pain 15 1.3 15 1.7 2.9 0Other clinically relevant adverse reactions (all grades incidence 15%) in recipients of CALQUENCE included:oSkin and subcutaneous disorders: bruising (10%), rash (9%)oNeoplasms: second primary malignancy (12%), non-melanoma skin cancer (6%)oMusculoskeletal and connective tissue disorders: arthralgia (8%)oCardiac disorders: atrial fibrillation or flutter (5%), hypertension (3.2%)oInfection: herpesvirus infection (4.5%)Table 8: Select Non-Hematologic Laboratory Abnormalities (>= 10% Any Grade), New or Worsening from Baseline in Patients Receiving CALQUENCE (ASCEND)Laboratory AbnormalityExcludes electrolytesCALQUENCE N=154Idelalisib plus Rituximab ProductN=118Bendamustine plus Rituximab ProductN=35AllGrades (%)Grade >= (%)AllGrades (%)Grade >= (%)AllGrades (%)Grade >= (%)Uric acid increase151511112323ALT increase151.95923262.9AST increase130.64813312.9Bilirubin increase131.3161.72611Per NCI CTCAE version 5. Infections. InfectionIncludes any adverse reactions involving infection or febrile neutropenia. Upper respiratory tract infectionUpper respiratory tract infection, nasopharyngitis and sinusitis. Lower respiratory tract infectionIncludes pneumonia, lower respiratory tract infection, bronchitis, bronchiolitis, tracheitis, and lung infection. Urinary tract infection. Blood and lymphatic system disordersDerived from adverse reactions and laboratory data. NeutropeniaIncludes neutropenia, neutrophil count decreased, and related laboratory data. AnemiaIncludes anemia, red blood cell count decreased, and related laboratory data. ThrombocytopeniaIncludes thrombocytopenia, platelet count decreased, and related laboratory data. LymphocytosisIncludes lymphocytosis, lymphocyte count increased, and related laboratory data. Nervous system disorders. Headache. Dizziness. Gastrointestinal disorders. Diarrhea. Nausea. Musculoskeletal and connective tissue disorders. Musculoskeletal painIncludes back pain, bone pain, musculoskeletal chest pain, musculoskeletal pain, musculoskeletal discomfort, myalgia, neck pain, pain in extremity and spinal pain. Arthralgia. General disorders and administration site conditions. FatigueIncludes asthenia, fatigue, and lethargy. Skin and subcutaneous tissue disorders. BruisingIncludes bruise, contusion, and ecchymosis. 31. 0. 21. 0. 5. 0. RashIncludes rash, dermatitis, and other related terms. 26. 2.2. 25. 0.6. 9. 0.6. Vascular disorders. HemorrhageIncludes hemorrhage, hematoma, hemoptysis, hematuria, menorrhagia, hemarthrosis, and epistaxis. oNeoplasms: second primary malignancy (10%), non-melanoma skin cancer (5%). oCardiac disorders: atrial fibrillation or flutter (3.6%), hypertension (5%). oInfection: herpesvirus infection (6%). Infections. InfectionIncludes any adverse reactions involving infection or febrile neutropenia. 56. 15Includes fatal case in the CALQUENCE monotherapy arm and fatal case in the Idelalisib plus Rituximab arm. 65. 28. 49. 11. Upper respiratory tract infectionUpper respiratory tract infection, rhinitis and nasopharyngitis. 29. 1.9. 26. 3.4. 17. 2.9. Lower respiratory tract infectionIncludes pneumonia, lower respiratory tract infection, bronchitis, bronchiolitis, tracheitis, and lung infection. 23. 6. 26. 15. 14. 6. Blood and lymphatic system disordersDerived from adverse reaction and laboratory data. NeutropeniaIncludes neutropenia, neutrophil count decreased, and related laboratory data. 48. 23. 79. 53. 80. 40. AnemiaIncludes anemia, red blood cell decreased, and related laboratory data. 47. 15. 45. 8. 57. 17. ThrombocytopeniaIncludes thrombocytopenia, platelet count decreased, and related laboratory data. 33. 6. 41. 13. 54. 6. LymphocytosisIncludes lymphocytosis, lymphocyte count increased and related laboratory data. 26. 19. 23. 18. 2.9. 2.9. Nervous system disorders. Headache. 22. 0.6. 6. 0. 0. 0. Gastrointestinal disorders. DiarrheaIncludes colitis, diarrhea, and enterocolitis. 18. 1.3. 49. 25. 14. 0. Vascular disorders. HemorrhageIncludes hemorrhage, hematoma, hemoptysis, hematuria, menorrhagia, hemarthrosis, and epistaxis. 16. 1.3. 5. 1.7. 6. 2.9. General disorders. FatigueIncludes asthenia, fatigue, and lethargy. 15. 1.9. 13. 0.8. 31. 6. Musculoskeletal and connective tissue disorders. Musculoskeletal PainIncludes back pain, musculoskeletal chest pain, musculoskeletal pain, musculoskeletal discomfort, pain in extremity, myalgia, spinal pain and bone pain. 15. 1.3. 15. 1.7. 2.9. 0. oSkin and subcutaneous disorders: bruising (10%), rash (9%). oNeoplasms: second primary malignancy (12%), non-melanoma skin cancer (6%). oMusculoskeletal and connective tissue disorders: arthralgia (8%). oCardiac disorders: atrial fibrillation or flutter (5%), hypertension (3.2%). oInfection: herpesvirus infection (4.5%).

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.


13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenicity studies have not been conducted with acalabrutinib.Acalabrutinib was not mutagenic in an in vitro bacterial reverse mutation (AMES) assay or clastogenic in an in vitro human lymphocyte chromosomal aberration assay or in an in vivo rat bone marrow micronucleus assay.In 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 PHARMACOLOGY SECTION.


12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Acalabrutinib is small-molecule inhibitor of BTK. Acalabrutinib and its active metabolite, ACP-5862, form covalent bond with cysteine residue in the BTK active site, leading to inhibition of BTK enzymatic activity. BTK is signaling molecule of the cell antigen receptor (BCR) and cytokine receptor pathways. In cells, BTK signaling results in activation of pathways necessary for B-cell proliferation, trafficking, chemotaxis, and adhesion. In nonclinical studies, acalabrutinib inhibited BTK-mediated activation of downstream signaling proteins CD86 and CD69 and inhibited malignant B-cell proliferation and tumor growth in mouse xenograft models.. 12.2 Pharmacodynamics In patients with B-cell malignancies dosed with 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 ElectrophysiologyThe effect of acalabrutinib on the QTc interval was evaluated in randomized, double-blind, double-dummy, placebo- and positive-controlled, 4-way crossover thorough QTc study in 48 healthy adult subjects. Administration of single dose of acalabrutinib that is the 4-fold maximum recommended single dose did not prolong the QTc interval to any clinically relevant extent (i.e., >= 10 ms).. 12.3 Pharmacokinetics Acalabrutinib exhibits dose-proportionality, and both acalabrutinib and its active metabolite, ACP-5862, exposures increase with dose across dose range of 75 to 250 mg (0.75 to 2.5 times the approved recommended single dose) 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 (AUC24h) and maximum plasma concentration (Cmax) for acalabrutinib were 1843 (38%) ngoh/mL and 563 (29%) ng/mL, respectively, and for ACP-5862 were 3947 (43%) ngoh/mL and 451 (52%) ng/mL, respectively.AbsorptionThe geometric mean absolute bioavailability of acalabrutinib was 25%. Median [min, max] time to peak acalabrutinib plasma concentrations (Tmax) was 0.9 [0.5, 1.9] hours, and 1.6 [0.9, 2.7] hour for ACP-5862.Effect of FoodIn healthy subjects, administration of single 75 mg dose of acalabrutinib (0.75 times the approved recommended single dose) with 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 Cmax decreased by 73% and Tmax was delayed 1-2 hours.DistributionReversible binding to human plasma protein was 97.5% for acalabrutinib and 98.6% for ACP-5862. The in vitro mean blood-to-plasma ratio was 0.8 for acalabrutinib and 0.7 for ACP-5862. The geometric mean (% CV) steady-state volume of distribution (Vss) was approximately 101 (52%) for acalabrutinib and 67 (32%) for ACP-5862.EliminationThe geometric mean (% CV) terminal elimination half-life (t1/2) was (59%) hour for acalabrutinib and 3.5 (24%) hours for ACP-5862. The geometric mean (%CV) apparent oral clearance (CL/F) was 71 (35%) L/hr for acalabrutinib and 13 (42%) L/hr for ACP-5862.MetabolismAcalabrutinib is predominantly metabolized by CYP3A enzymes, and to 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 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.ExcretionFollowing administration of single 100 mg radiolabeled acalabrutinib dose in healthy subjects, 84% of the dose was recovered in the feces and 12% of the dose was recovered in the urine, with less than 2% of the dose excreted as unchanged acalabrutinib in urine and feces.Specific PopulationsAge, Race, and Body WeightAge (32 to 90 years), sex, race (Caucasian, African American), and body weight (40 to 149 kg) did not have clinically meaningful effects on the PK of acalabrutinib and its active metabolite, ACP-5862.Renal ImpairmentNo clinically relevant PK difference was observed in patients with mild or moderate renal impairment (eGFR >= 30 mL/min/1.73m2, as estimated by MDRD (modification of diet in renal disease equation)). Acalabrutinib PK has not been evaluated in patients with severe renal impairment (eGFR 29 mL/min/1.73m2, MDRD) or renal impairment requiring dialysis.Hepatic ImpairmentThe 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 StudiesEffect of CYP3A Inhibitors on AcalabrutinibCo-administration with strong CYP3A inhibitor (200 mg itraconazole once daily for days) increased the acalabrutinib Cmax by 3.9-fold and AUC by 5.1-fold in healthy subjects.Physiologically based pharmacokinetic (PBPK) simulations with acalabrutinib and moderate CYP3A inhibitors (erythromycin, fluconazole, diltiazem) showed that co-administration increased acalabrutinib Cmax and AUC approximately 2- to 3-fold.Effect of CYP3A Inducers on AcalabrutinibCo-administration with strong CYP3A inducer (600 mg rifampin once daily for days) decreased acalabrutinib Cmax by 68% and AUC by 77% in healthy subjects.Gastric Acid Reducing AgentsAcalabrutinib solubility decreases with increasing pH. Co-administration with an antacid (1 calcium carbonate) decreased acalabrutinib AUC by 53% in healthy subjects. Co-administration with proton pump inhibitor (40 mg omeprazole for days) decreased acalabrutinib AUC by 43%.In Vitro StudiesMetabolic PathwaysAcalabrutinib is weak inhibitor of CYP3A4/5, CYP2C8 and CYP2C9, but does not inhibit CYP1A2, CYP2B6, CYP2C19, CYP2D6, UGT1A1, and UGT2B7. ACP-5862 is weak inhibitor of CYP2C8, CYP2C9 and CYP2C19, but does not inhibit CYP1A2, CYP2B6, CYP2D6, CYP3A4/5, UGT1A1, and UGT2B7.Acalabrutinib is weak inducer of CYP1A2, CYP2B6 and CYP3A4; ACP-5862 weakly induces CYP3A4.Based on in vitro data and PBPK modeling, no interaction with CYP substrates is expected at clinically relevant concentrations.Drug Transporter SystemsAcalabrutinib and its active metabolite, ACP-5862, are substrates of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP). Acalabrutinib is not substrate of renal uptake transporters OAT1, OAT3, and OCT2, or hepatic transporters OATP1B1, and OATP1B3. ACP-5862 is not substrate of OATP1B1 or OATP1B3.Acalabrutinib and ACP-5862 do not inhibit P-gp, OAT1, OAT3, OCT2, OATP1B1, OATP1B3, and MATE2-K at clinically relevant concentrations.Acalabrutinib may increase exposure to co-administered BCRP substrates (e.g., methotrexate) by inhibition of intestinal BCRP. ACP-5862 does not inhibit BCRP at clinically relevant concentrations. Acalabrutinib does not inhibit MATE1, while ACP-5862 may increase exposure to co-administered MATE1 substrates (e.g., metformin) by inhibition of MATE1.

CLINICAL STUDIES SECTION.


14 CLINICAL STUDIES 14.1 Mantle Cell Lymphoma The efficacy of CALQUENCE was based upon Trial LY-004 textd An Open-label, Phase Study of ACP-196 in Subjects with Mantle Cell Lymphoma (NCT02213926). Trial LY-004 enrolled 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 or 1. The median time since diagnosis was 46.3 months and the median number of prior treatments was (range 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 longest diameter >= cm, 73% had extra nodal involvement including 51% with bone marrow involvement. The simplified MIPI score (which includes age, ECOG score, and baseline lactate dehydrogenase and white cell count) was intermediate in 44% and high in 17% of patients.CALQUENCE was administered orally at 100 mg approximately every 12 hours until disease progression or unacceptable toxicity. The median dose intensity was 98.5%. The major efficacy outcome of Trial LY-004 was overall response rate and the median follow-up was 15.2 months.Table 9: Efficacy Results in Patients with MCL in Trial LY-004Investigator AssessedN=124Independent Review Committee (IRC) AssessedN=124Overall 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 observationsThe median time to best response was 1.9 months.LymphocytosisUpon initiation of CALQUENCE, temporary increase in lymphocyte counts (defined as absolute lymphocyte count (ALC) increased >= 50% from baseline and post baseline assessment >= x 109) in 31.5% of patients in Trial LY-004. The median time to onset of lymphocytosis was 1.1 weeks and the median duration of lymphocytosis was 6.7 weeks.. 14.2 Chronic Lymphocytic Leukemia The efficacy of CALQUENCE in patients with CLL was demonstrated in two randomized, controlled trials. The indication for CALQUENCE includes patients with SLL because it is the same disease.ELEVATE-TNThe efficacy of CALQUENCE was evaluated in the ELEVATE-TN trial, randomized, multicenter, open-label, actively controlled, 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 total Cumulative Illness Rating Scale (CIRS) 6 or creatinine clearance of 30 to 69 mL/min were enrolled. The trial also required hepatic transaminases <= times upper limit of normal (ULN) and total bilirubin <= 1.5 times ULN, and excluded patients with Richters transformation.Patients were randomized in 1:1:1 ratio into arms to receive:oCALQUENCE plus obinutuzumab (CALQUENCE+G): CALQUENCE 100 mg was administered approximately every 12 hours starting on Cycle Day until disease progression or unacceptable toxicity. Obinutuzumab was administered starting on Cycle Day for maximum of treatment cycles. Obinutuzumab 1000 mg was administered on Days and (100 mg on Day and 900 mg on Day 2), and 15 of Cycle followed by 1000 mg on Day of Cycles up to 7. Each cycle was 28 days.oCALQUENCE monotherapy: CALQUENCE 100 mg was administered approximately every 12 hours until disease progression or unacceptable toxicity.oObinutuzumab plus chlorambucil (GClb): Obinutuzumab and chlorambucil were administered for maximum of treatment cycles. Obinutuzumab 1000 mg was administered intravenously on Days and (100 mg on Day and 900 mg on Day 2), and 15 of Cycle followed by 1000 mg on Day of Cycles to 6. Chlorambucil 0.5 mg/kg was administered orally on Days and 15 of Cycles to 6. Each cycle was 28 days.Randomization was stratified by 17p deletion mutation status, ECOG performance status (0 or versus 2), and geographic region. total of 535 patients were randomized, 179 to CALQUENCE+G, 179 to CALQUENCE monotherapy, and 177 to GClb. The overall median age was 70 years (range: 41 to 91 years), 47% had Rai stage III or IV disease, 14% had 17p deletion or TP53 mutation, 63% of patients had an unmutated IGVH, and 18% had 11q deletion. Baseline demographic and disease characteristics were similar between treatment arms.Efficacy was based on progression-free survival (PFS) as assessed by an Independent Review Committee (IRC). The median duration of follow-up was 28.3 months (range: 0.0 to 40.8 months). Efficacy results are presented in Table 10. The Kaplan-Meier curves for PFS are shown in Figure 1.Table 10: Efficacy Results per IRC in Patients with CLL -- ITT population (ELEVATE-TN)CALQUENCE plus ObinutuzumabN=179CALQUENCE MonotherapyN=179Obinutuzumab plus ChlorambucilN=177Progression-Free SurvivalPer 2008 International Workshop on CLL (IWCLL) criteria. Number of events (%)14 (8)26 (15)93 (53) PD, (%)9 (5)20 (11)82 (46) Death events, (%)5 (3)6 (3)11 (6) Median (95% CI), monthsKaplan-Meier estimate. NENE (34, NE)22.6 (20, 28) HRBased on stratified Cox-Proportional-Hazards model. Both hazard ratios are compared with the obinutuzumab and chlorambucil arm.(95% CI)0.10 (0.06, 0.17)0.20 (0.13, 0.30)- p-valueBased on stratified log-rank test, with an alpha level of 0.012 derived from alpha spending function by the OBrien-Fleming method. 0.0001< 0.0001-Overall Response Rate (CR CRi nPR PR) ORR, (%)168 (94)153 (86)139 (79) (95% CI)(89, 97)(80, 90)(72, 84) p-valueBased on stratified Cochran-Mantel-Haenszel test, for the comparison with the obinutuzumab and chlorambucil arm. 0.00010.0763- CR, (%)23 (13)1 (1)8 (5) CRi, (%)1 (1)00 nPR, (%)1 (1)2 (1)3 (2) PR, (%)143 (80)150 (84)128 (72)ITT=intent-to-treat; CI=confidence interval; HR=hazard ratio; NE=not estimable; CR=complete response; CRi=complete response with incomplete blood count recovery; nPR=nodular partial response; PR=partial response.Figure 1: Kaplan-Meier Curve of IRC-Assessed PFS in Patients with CLL in ELEVATE-TNWith 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.ASCENDThe efficacy of CALQUENCE in patients with relapsed or refractory CLL was based upon multicenter, randomized, open-label trial (ASCEND; NCT02970318). The trial enrolled 310 patients with relapsed or refractory CLL after at least prior systemic therapy. The trial excluded patients with transformed disease, prolymphocytic leukemia, or previous treatment with venetoclax, Bruton tyrosine kinase inhibitor, or phosphoinositide-3 kinase inhibitor.Patients were randomized in 1:1 ratio to receive either:oCALQUENCE 100 mg approximately every 12 hours until disease progression or unacceptable toxicity, oroInvestigators choice:oIdelalisib plus rituximab product (IR): Idelalisib 150 mg orally approximately every 12 hours until disease progression or unacceptable toxicity, in combination with infusions of rituximab product (375 mg/m2 intravenously on Day of Cycle 1, followed by 500 mg/m2 every weeks for doses and then every weeks for doses), with 28-day cycle length.oBendamustine plus rituximab product (BR): Bendamustine 70 mg/m2 intravenously (Day and of each 28-day cycle), in combination with rituximab product (375 mg/m2 intravenously on Day of Cycle 1, then 500 mg/m2 on Day of subsequent cycles), for up to cycles. Randomization was stratified by 17p deletion mutation status, ECOG performance status (0 or versus 2), and number of prior therapies (1 to 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 11q deletion. The CALQUENCE arm had median of prior therapy (range 1-8), with 47% having at least prior therapies. The investigators choice arm had median of prior therapies (range 1-10), with 57% having at least prior therapies.In the CALQUENCE arm, the median treatment duration was 15.7 months, with 94% of patients treated for at least months and 86% of patients treated for at least year. In the investigators choice arm, the median treatment duration was 8.4 months, with 59% of patients treated for at least months and 37% treated for at least year.Efficacy was based on PFS as assessed by an IRC, with median follow-up of 16.1 months (range 0.03 to 22.4 months). Efficacy results are presented in Table 11. The Kaplan-Meier curve for PFS is shown in Figure 2. There was no statistically significant difference in overall response rates between the two treatment arms.Table 11: Efficacy Results per IRC in Patients with Relapsed or Refractory CLL ITT Population (ASCEND)CALQUENCE MonotherapyN=155Investigators Choice of Idelalisib Rituximab Product or Bendamustine Rituximab ProductN=155Progression-Free SurvivalPer 2008 IWCLL criteria. Number of events, (%)27 (17)68 (44) Disease progression, 19 59 Death, 8 Median (95% CI), monthsKaplan-Meier estimate NE (NE, NE)16.5 (14.0, 17.1) HR (95% CI)Based on stratified Cox-Proportional-Hazards model 0.31 (0.20, 0.49) P-valueBased on stratified Log-rank test. The pre-specified type error rate () for this interim analysis is 0.012 derived from Lan-DeMets alpha spending function with OBrien-Fleming boundary 0.0001Overall Response Rate (CR CRi nPR PR)Through hierarchical testing procedure, the difference in ORR was not statistically significant, based on Cochran-Mantel Haenzel test with adjustment for randomization stratification factors. ORR, (%) 126 (81)117 (75) (95% CI) (74, 87) (68, 82) CR, (%)02 (1) CRi, (%)00 nPR, (%)00 PR, (%)126 (81)115 (74)ITT=intent-to-treat; CI=confidence interval; HR=hazard ratio; NE=not estimable; CR=complete response; CRi=complete response with incomplete blood count recovery; nPR=nodular partial response; PR=partial response Figure 2: Kaplan-Meier Curve of IRC-Assessed PFS in Patients with CLL in ASCENDWith 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.. oCALQUENCE plus obinutuzumab (CALQUENCE+G): CALQUENCE 100 mg was administered approximately every 12 hours starting on Cycle Day until disease progression or unacceptable toxicity. Obinutuzumab was administered starting on Cycle Day for maximum of treatment cycles. Obinutuzumab 1000 mg was administered on Days and (100 mg on Day and 900 mg on Day 2), and 15 of Cycle followed by 1000 mg on Day of Cycles up to 7. Each cycle was 28 days.. oCALQUENCE monotherapy: CALQUENCE 100 mg was administered approximately every 12 hours until disease progression or unacceptable toxicity.. oObinutuzumab plus chlorambucil (GClb): Obinutuzumab and chlorambucil were administered for maximum of treatment cycles. Obinutuzumab 1000 mg was administered intravenously on Days and (100 mg on Day and 900 mg on Day 2), and 15 of Cycle followed by 1000 mg on Day of Cycles to 6. Chlorambucil 0.5 mg/kg was administered orally on Days and 15 of Cycles to 6. Each cycle was 28 days.. oCALQUENCE 100 mg approximately every 12 hours until disease progression or unacceptable toxicity, or. oInvestigators choice:oIdelalisib plus rituximab product (IR): Idelalisib 150 mg orally approximately every 12 hours until disease progression or unacceptable toxicity, in combination with infusions of rituximab product (375 mg/m2 intravenously on Day of Cycle 1, followed by 500 mg/m2 every weeks for doses and then every weeks for doses), with 28-day cycle length.oBendamustine plus rituximab product (BR): Bendamustine 70 mg/m2 intravenously (Day and of each 28-day cycle), in combination with rituximab product (375 mg/m2 intravenously on Day of Cycle 1, then 500 mg/m2 on Day of subsequent cycles), for up to cycles. oIdelalisib plus rituximab product (IR): Idelalisib 150 mg orally approximately every 12 hours until disease progression or unacceptable toxicity, in combination with infusions of rituximab product (375 mg/m2 intravenously on Day of Cycle 1, followed by 500 mg/m2 every weeks for doses and then every weeks for doses), with 28-day cycle length.. oBendamustine plus rituximab product (BR): Bendamustine 70 mg/m2 intravenously (Day and of each 28-day cycle), in combination with rituximab product (375 mg/m2 intravenously on Day of Cycle 1, then 500 mg/m2 on Day of subsequent cycles), for up to cycles.. Figure 1. Figure 2.

CONTRAINDICATIONS SECTION.


4 CONTRAINDICATIONS None.. None. (4).

DESCRIPTION SECTION.


11 DESCRIPTION CALQUENCE (acalabrutinib) is an inhibitor of Bruton tyrosine kinase (BTK). The molecular formula for acalabrutinib is C26H23N7O2, and the molecular weight is 465.51. The chemical name is 4-8-amino-3-[(2S)-1-(but-2-ynoyl)pyrrolidin-2-yl]imidazo[1,5-a]pyrazin-1-yl)-N-(pyridine-2-yl)benzamide.The chemical structure of acalabrutinib is shown below:Acalabrutinib is white to yellow powder with pH-dependent solubility. It is freely soluble in water at pH values below and practically insoluble at pH values above 6.CALQUENCE capsules for oral administration contains 100 mg acalabrutinib and the following inactive ingredients: silicified microcrystalline cellulose, partially pregelatinized starch, magnesium stearate, and sodium starch glycolate. The capsule shell contains gelatin, titanium dioxide, yellow iron oxide, FD&C Blue and is imprinted with edible black ink.. ChemicalStructure.

DOSAGE & ADMINISTRATION SECTION.


2 DOSAGE AND ADMINISTRATION oRecommended dose is 100 mg orally approximately every 12 hours; swallow whole with water and with or without food. (2.1)oAdvise patients not to break, open, or chew capsules. (2.1)oManage toxicities using treatment interruption, dose reduction, or discontinuation. (2.2)oAvoid CALQUENCE in patients with severe hepatic impairment (2.2,8.6). oRecommended dose is 100 mg orally approximately every 12 hours; swallow whole with water and with or without food. (2.1). oAdvise patients not to break, open, or chew capsules. (2.1). oManage toxicities using treatment interruption, dose reduction, or discontinuation. (2.2). oAvoid CALQUENCE in patients with severe hepatic impairment (2.2,8.6). 2.1 Recommended Dosage CALQUENCE as MonotherapyFor patients with MCL, CLL, or SLL, the recommended dose of CALQUENCE is 100 mg taken orally approximately every 12 hours until disease progression or unacceptable toxicity.CALQUENCE in Combination with ObinutuzumabFor patients with previously untreated CLL or SLL, the recommended dose of CALQUENCE is 100 mg taken orally approximately every 12 hours until disease progression or unacceptable toxicity. Start CALQUENCE at Cycle (each cycle is 28 days). Start obinutuzumab at Cycle for total of cycles and refer to the obinutuzumab prescribing information for recommended dosing. Administer CALQUENCE prior to obinutuzumab when given on the same day.Advise patients to swallow capsule whole with water. Advise patients not to open, break or chew the capsules. CALQUENCE may be taken with or without food. If dose of CALQUENCE is missed by more than hours, it should be skipped and the next dose should be taken at its regularly scheduled time. Extra capsules of CALQUENCE should not be taken to make up for missed dose.. 2.2 Recommended Dosage for Hepatic Impairment. Avoid administration of CALQUENCE in patients with severe hepatic impairment.Dose modifications are not required for patients with mild or moderate hepatic impairment [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)].. 2.3 Recommended Dosage for Drug Interactions Dose Modifications for Use with CYP3A Inhibitors or InducersThese are described in Table [see Drug Interactions (7)].Table 1: Recommended Dose Modifications for Use with CYP3A Inhibitors or InducersCYP3A Co-administered DrugRecommended CALQUENCE useInhibitionStrong CYP3A inhibitorAvoid concomitant use.If these inhibitors will be used short-term (such as anti-infectives for up to seven days), interrupt CALQUENCE.Moderate CYP3A inhibitor100 mg once daily.InductionStrong CYP3A inducerAvoid concomitant use.If these inducers cannot be avoided, increase CALQUENCE dose to 200 mg approximately every 12 hours.Concomitant Use with Gastric Acid Reducing AgentsProton Pump Inhibitors: Avoid concomitant use [see Drug Interactions (7)].H2-Receptor Antagonists: Take CALQUENCE hours before taking H2-receptor antagonist [see Drug Interactions (7)].Antacids: Separate dosing by at least hours [see Drug Interactions (7)].. 2.4 Dose Modifications for Adverse Reactions Recommended dose modifications of CALQUENCE for Grade or greater adverse reactions are provided in Table 2.Table 2: Recommended Dose Modifications for Adverse ReactionsEventAdverse Reaction OccurrenceDose Modification(Starting dose 100 mg approximately every 12 hours)Grade or greater non-hematologic toxicities,Grade thrombocytopenia with bleeding,First and SecondInterrupt CALQUENCE.Once toxicity has resolved to Grade or baseline level, CALQUENCE may be resumed at 100 mg approximately every 12 hours.Grade thrombocytopenia orGrade neutropenia lasting longer than daysThirdInterrupt CALQUENCE.Once toxicity has resolved to Grade or baseline level, CALQUENCE may be resumed at reduced frequency of 100 mg once daily.FourthDiscontinue CALQUENCE.Adverse reactions graded by the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE).Refer to the obinutuzumab prescribing information for management of obinutuzumab toxicities.

DOSAGE FORMS & STRENGTHS SECTION.


3 DOSAGE FORMS AND STRENGTHS 100 mg capsules.. Capsules: 100 mg. (3).

DRUG INTERACTIONS SECTION.


7 DRUG INTERACTIONS Strong CYP3A InhibitorsClinical ImpactoCo-administration of CALQUENCE with strong CYP3A inhibitor (itraconazole) increased acalabrutinib plasma concentrations [see Clinical Pharmacology (12.3)].oIncreased acalabrutinib concentrations may result in increased toxicity.Prevention or ManagementoAvoid co-administration of strong CYP3A inhibitors with CALQUENCE.oAlternatively, if the inhibitor will be used short-term, interrupt CALQUENCE [see Recommended Dosage for Drug Interactions (2.3)].Moderate CYP3A InhibitorsClinical ImpactoCo-administration of CALQUENCE with moderate CYP3A inhibitor may increase acalabrutinib plasma concentrations [see Clinical Pharmacology (12.3)].oIncreased acalabrutinib concentrations may result in increased toxicity.Prevention or ManagementoWhen CALQUENCE is co-administered with moderate CYP3A inhibitors, reduce acalabrutinib dose to 100 mg once daily.Strong CYP3A InducersClinical ImpactoCo-administration of CALQUENCE with strong CYP3A inducer (rifampin) decreased acalabrutinib plasma concentrations [see Clinical Pharmacology (12.3)].oDecreased acalabrutinib concentrations may reduce CALQUENCE activity.Prevention or ManagementoAvoid co-administration of strong CYP3A inducers with CALQUENCE.oIf strong CYP3A inducer cannot be avoided, increase the acalabrutinib dose to 200 mg approximately every 12 hours.Gastric Acid Reducing AgentsClinical ImpactoCo-administration of CALQUENCE with proton pump inhibitor, H2-receptor antagonist, or antacid may decrease acalabrutinib plasma concentrations [see Clinical Pharmacology (12.3)].oDecreased acalabrutinib concentrations may reduce CALQUENCE activity.oIf treatment with gastric acid reducing agent is required, consider using H2-receptor antagonist (e.g., ranitidine or famotidine) or an antacid (e.g., calcium carbonate).Prevention or ManagementAntacidsSeparate dosing by at least hours [see Recommended Dosage for Drug Interactions (2.3)].H2-receptor antagonistsTake CALQUENCE hours before taking the H2-receptor antagonist [see Recommended Dosage for Drug Interactions (2.3)]. Proton pump inhibitorsAvoid co-administration. Due to the long-lasting effect of proton pump inhibitors, separation of doses may not eliminate the interaction with CALQUENCE.. oCo-administration of CALQUENCE with strong CYP3A inhibitor (itraconazole) increased acalabrutinib plasma concentrations [see Clinical Pharmacology (12.3)].. oIncreased acalabrutinib concentrations may result in increased toxicity.. oAvoid co-administration of strong CYP3A inhibitors with CALQUENCE.. oAlternatively, if the inhibitor will be used short-term, interrupt CALQUENCE [see Recommended Dosage for Drug Interactions (2.3)].. oCo-administration of CALQUENCE with moderate CYP3A inhibitor may increase acalabrutinib plasma concentrations [see Clinical Pharmacology (12.3)].. oIncreased acalabrutinib concentrations may result in increased toxicity.. oWhen CALQUENCE is co-administered with moderate CYP3A inhibitors, reduce acalabrutinib dose to 100 mg once daily.. oCo-administration of CALQUENCE with strong CYP3A inducer (rifampin) decreased acalabrutinib plasma concentrations [see Clinical Pharmacology (12.3)].. oDecreased acalabrutinib concentrations may reduce CALQUENCE activity.. oAvoid co-administration of strong CYP3A inducers with CALQUENCE.. oIf strong CYP3A inducer cannot be avoided, increase the acalabrutinib dose to 200 mg approximately every 12 hours.. oCo-administration of CALQUENCE with proton pump inhibitor, H2-receptor antagonist, or antacid may decrease acalabrutinib plasma concentrations [see Clinical Pharmacology (12.3)].. oDecreased acalabrutinib concentrations may reduce CALQUENCE activity.. oIf treatment with gastric acid reducing agent is required, consider using H2-receptor antagonist (e.g., ranitidine or famotidine) or an antacid (e.g., calcium carbonate).. oCYP3A Inhibitors: Avoid co-administration with strong CYP3A inhibitors. Dose adjustments may be recommended. (2.3, 7, 12.3) oCYP3A Inducers: Avoid co-administration with strong CYP3A inducers. Dose adjustments may be recommended. (2.3, 7, 12.3) oGastric Acid Reducing Agents: Avoid co-administration with proton pump inhibitors (PPIs). Stagger dosing with H2-receptor antagonists and antacids. (2.4, 7, 12.3) oCYP3A Inhibitors: Avoid co-administration with strong CYP3A inhibitors. Dose adjustments may be recommended. (2.3, 7, 12.3) oCYP3A Inducers: Avoid co-administration with strong CYP3A inducers. Dose adjustments may be recommended. (2.3, 7, 12.3) oGastric Acid Reducing Agents: Avoid co-administration with proton pump inhibitors (PPIs). Stagger dosing with H2-receptor antagonists and antacids. (2.4, 7, 12.3).

GERIATRIC USE SECTION.


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

HOW SUPPLIED SECTION.


16 HOW SUPPLIED/STORAGE AND HANDLING How SuppliedPack SizeContentsNDC Number60-count bottleBottle containing 60 capsules100 mg, hard gelatin capsules with yellow body and blue cap, marked in black ink with ACA 100 mg0310-0512-60StorageStore at 20C-25C (68F-77F); excursions permitted to 15C-30C (59F-86F) [see USP Controlled Room Temperature].

INDICATIONS & USAGE SECTION.


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

INFORMATION FOR PATIENTS SECTION.


17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information).Serious and Opportunistic InfectionsInform patients of the possibility of serious infection and to report signs or symptoms suggestive of infection [see Warnings and Precautions (5.1)].HemorrhageInform patients to report signs or symptoms of bleeding. Inform patients that CALQUENCE may need to be interrupted for major surgeries [see Warnings and Precautions (5.2)].CytopeniasInform patients that they will need periodic blood tests to check blood counts during treatment with CALQUENCE [see Warnings and Precautions (5.3)].Second Primary MalignanciesInform patients that other malignancies have been reported in patients who have been treated with CALQUENCE, including skin cancer and other solid tumors. Advise patients to use sun protection [see Warnings and Precautions (5.4)].Atrial Fibrillation and FlutterCounsel patients to report any signs of palpitations, dizziness, fainting, chest discomfort, and shortness of breath [see Warnings and Precautions (5.5)].Pregnancy ComplicationCALQUENCE may cause fetal harm and dystocia. Advise women to avoid becoming pregnant during treatment and for at least week after the last dose of CALQUENCE [see Use in Specific Populations (8.3)].LactationAdvise females not to breastfeed during treatment with CALQUENCE and for at least weeks after the final dose [see Use in Specific Populations (8.2)].Dosing InstructionsInstruct patients to take CALQUENCE orally twice daily, about 12 hours apart. CALQUENCE may be taken with or without food. Advise patients that CALQUENCE capsules should be swallowed whole with glass of water, without being opened, broken, or chewed [see Dosage and Administration (2.1)].Missed DoseAdvise patients that if they miss dose of CALQUENCE, they may still take it up to hours after the time they would normally take it. If more than hours have elapsed, they should be instructed to skip that dose and take their next dose of CALQUENCE at the usual time. Warn patients they should not take extra capsules to make up for the dose that they missed [see Dosage and Administration (2.1)].Drug InteractionsAdvise patients to inform their healthcare providers of all concomitant medications, including over-the-counter medications, vitamins and herbal products [see Drug Interactions (7)].Distributed by:AstraZeneca Pharmaceuticals LPWilmington, DE 19850CALQUENCE is registered trademark of the AstraZeneca group of companies.(C)AstraZeneca 2019.

MECHANISM OF ACTION SECTION.


12.1 Mechanism of Action Acalabrutinib is small-molecule inhibitor of BTK. Acalabrutinib and its active metabolite, ACP-5862, form covalent bond with cysteine residue in the BTK active site, leading to inhibition of BTK enzymatic activity. BTK is signaling molecule of the cell antigen receptor (BCR) and cytokine receptor pathways. In 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.

NONCLINICAL TOXICOLOGY SECTION.


13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenicity studies have not been conducted with acalabrutinib.Acalabrutinib was not mutagenic in an in vitro bacterial reverse mutation (AMES) assay or clastogenic in an in vitro human lymphocyte chromosomal aberration assay or in an in vivo rat bone marrow micronucleus assay.In 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.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.


PACKAGE/LABEL PRINCIPAL DISPLAY PANEL NDC 0310-0512-60 60 capsulesCALQUENCE(R) (acalabrutinib) capsules100 mgRx onlyManufactured for:AstraZeneca Pharmaceuticals LPWilmington, DE 19850By: AstraZeneca ABSE-151 85 Sodertalje, SwedenProduct of SwitzerlandAstra Zeneca. Calquence 100 mg bottle label.

PEDIATRIC USE SECTION.


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

PHARMACODYNULLMICS SECTION.


12.2 Pharmacodynamics In patients with B-cell malignancies dosed with 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 ElectrophysiologyThe effect of acalabrutinib on the QTc interval was evaluated in randomized, double-blind, double-dummy, placebo- and positive-controlled, 4-way crossover thorough QTc study in 48 healthy adult subjects. Administration of single dose of acalabrutinib that is the 4-fold maximum recommended single dose did not prolong the QTc interval to any clinically relevant extent (i.e., >= 10 ms).

PHARMACOKINETICS SECTION.


12.3 Pharmacokinetics Acalabrutinib exhibits dose-proportionality, and both acalabrutinib and its active metabolite, ACP-5862, exposures increase with dose across dose range of 75 to 250 mg (0.75 to 2.5 times the approved recommended single dose) 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 (AUC24h) and maximum plasma concentration (Cmax) for acalabrutinib were 1843 (38%) ngoh/mL and 563 (29%) ng/mL, respectively, and for ACP-5862 were 3947 (43%) ngoh/mL and 451 (52%) ng/mL, respectively.AbsorptionThe geometric mean absolute bioavailability of acalabrutinib was 25%. Median [min, max] time to peak acalabrutinib plasma concentrations (Tmax) was 0.9 [0.5, 1.9] hours, and 1.6 [0.9, 2.7] hour for ACP-5862.Effect of FoodIn healthy subjects, administration of single 75 mg dose of acalabrutinib (0.75 times the approved recommended single dose) with 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 Cmax decreased by 73% and Tmax was delayed 1-2 hours.DistributionReversible binding to human plasma protein was 97.5% for acalabrutinib and 98.6% for ACP-5862. The in vitro mean blood-to-plasma ratio was 0.8 for acalabrutinib and 0.7 for ACP-5862. The geometric mean (% CV) steady-state volume of distribution (Vss) was approximately 101 (52%) for acalabrutinib and 67 (32%) for ACP-5862.EliminationThe geometric mean (% CV) terminal elimination half-life (t1/2) was (59%) hour for acalabrutinib and 3.5 (24%) hours for ACP-5862. The geometric mean (%CV) apparent oral clearance (CL/F) was 71 (35%) L/hr for acalabrutinib and 13 (42%) L/hr for ACP-5862.MetabolismAcalabrutinib is predominantly metabolized by CYP3A enzymes, and to 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 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.ExcretionFollowing administration of single 100 mg radiolabeled acalabrutinib dose in healthy subjects, 84% of the dose was recovered in the feces and 12% of the dose was recovered in the urine, with less than 2% of the dose excreted as unchanged acalabrutinib in urine and feces.Specific PopulationsAge, Race, and Body WeightAge (32 to 90 years), sex, race (Caucasian, African American), and body weight (40 to 149 kg) did not have clinically meaningful effects on the PK of acalabrutinib and its active metabolite, ACP-5862.Renal ImpairmentNo clinically relevant PK difference was observed in patients with mild or moderate renal impairment (eGFR >= 30 mL/min/1.73m2, as estimated by MDRD (modification of diet in renal disease equation)). Acalabrutinib PK has not been evaluated in patients with severe renal impairment (eGFR 29 mL/min/1.73m2, MDRD) or renal impairment requiring dialysis.Hepatic ImpairmentThe 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 StudiesEffect of CYP3A Inhibitors on AcalabrutinibCo-administration with strong CYP3A inhibitor (200 mg itraconazole once daily for days) increased the acalabrutinib Cmax by 3.9-fold and AUC by 5.1-fold in healthy subjects.Physiologically based pharmacokinetic (PBPK) simulations with acalabrutinib and moderate CYP3A inhibitors (erythromycin, fluconazole, diltiazem) showed that co-administration increased acalabrutinib Cmax and AUC approximately 2- to 3-fold.Effect of CYP3A Inducers on AcalabrutinibCo-administration with strong CYP3A inducer (600 mg rifampin once daily for days) decreased acalabrutinib Cmax by 68% and AUC by 77% in healthy subjects.Gastric Acid Reducing AgentsAcalabrutinib solubility decreases with increasing pH. Co-administration with an antacid (1 calcium carbonate) decreased acalabrutinib AUC by 53% in healthy subjects. Co-administration with proton pump inhibitor (40 mg omeprazole for days) decreased acalabrutinib AUC by 43%.In Vitro StudiesMetabolic PathwaysAcalabrutinib is weak inhibitor of CYP3A4/5, CYP2C8 and CYP2C9, but does not inhibit CYP1A2, CYP2B6, CYP2C19, CYP2D6, UGT1A1, and UGT2B7. ACP-5862 is weak inhibitor of CYP2C8, CYP2C9 and CYP2C19, but does not inhibit CYP1A2, CYP2B6, CYP2D6, CYP3A4/5, UGT1A1, and UGT2B7.Acalabrutinib is weak inducer of CYP1A2, CYP2B6 and CYP3A4; ACP-5862 weakly induces CYP3A4.Based on in vitro data and PBPK modeling, no interaction with CYP substrates is expected at clinically relevant concentrations.Drug Transporter SystemsAcalabrutinib and its active metabolite, ACP-5862, are substrates of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP). Acalabrutinib is not substrate of renal uptake transporters OAT1, OAT3, and OCT2, or hepatic transporters OATP1B1, and OATP1B3. ACP-5862 is not substrate of OATP1B1 or OATP1B3.Acalabrutinib and ACP-5862 do not inhibit P-gp, OAT1, OAT3, OCT2, OATP1B1, OATP1B3, and MATE2-K at clinically relevant concentrations.Acalabrutinib may increase exposure to co-administered BCRP substrates (e.g., methotrexate) by inhibition of intestinal BCRP. ACP-5862 does not inhibit BCRP at clinically relevant concentrations. Acalabrutinib does not inhibit MATE1, while ACP-5862 may increase exposure to co-administered MATE1 substrates (e.g., metformin) by inhibition of MATE1.

PREGNULLNCY SECTION.


8.1 Pregnancy Risk SummaryBased on findings in animals, CALQUENCE may cause fetal harm and dystocia when administered to 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) 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 fetus.The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have 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 2-4% and 15-20%, respectively.DataAnimal DataIn 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 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.

RECENT MAJOR CHANGES SECTION.


Indications and Usage (1.2) 11/2019Dosage and Administration (2.2) 11/2019.

RISKS.


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 breastfed child from CALQUENCE, advise lactating women not to breastfeed while taking CALQUENCE and for at least weeks after the final dose.

SPL PATIENT PACKAGE INSERT SECTION.


PATIENT INFORMATIONCALQUENCE(R) (KAL-kwens)(acalabrutinib)CapsulesWhat is CALQUENCECALQUENCE is prescription medicine used to treat adults with:oMantle cell lymphoma (MCL) who have received at least one prior treatment for their cancer.oChronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL).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:ohave had recent surgery or plan to have surgery. Your healthcare provider may stop CALQUENCE for any planned medical, surgical, or dental procedure.ohave bleeding problems.ohave or had heart rhythm problems.ohave an infection.ohave or had liver problems, including hepatitis virus (HBV) infection.oare pregnant or plan to become pregnant. CALQUENCE may harm your unborn baby and problems during childbirth (dystocia).oIf you are able to become pregnant, your healthcare provider may do pregnancy test before you start treatment with CALQUENCEoFemales who are able to become pregnant should use effective birth control (contraception) during treatment with CALQUENCE and for at least week after the last dose of CALQUENCE.oare breastfeeding or plan to breastfeed. It is not known if CALQUENCE passes into your breast milk. Do not breastfeed during treatment with CALQUENCE and for at least weeks after your final dose of CALQUENCE.Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Taking CALQUENCE with certain other medications may affect how CALQUENCE works and can cause side effects. Especially tell your healthcare provider if you take blood thinner medicine.How should take CALQUENCEoTake CALQUENCE exactly as your healthcare provider tells you to take it.oDo not change your dose or stop taking CALQUENCE unless your healthcare provider tells you to.oYour healthcare provider may tell you to decrease your dose, temporarily stop, or completely stop taking CALQUENCE if you develop certain side effects.oTake CALQUENCE times day (about 12 hours apart).oTake CALQUENCE with or without food.oSwallow CALQUENCE capsules whole with glass of water. Do not open, break, or chew capsules.oIf you need to take an antacid medicine, take it either hours before or hours after you take CALQUENCE.oIf you need to take certain other medicines called acid reducers (H-2 receptor blockers), take CALQUENCE hours before the acid reducer medicine.oIf you miss dose of CALQUENCE, take it as soon as you remember. If it is more than hours past your usual dosing time, skip the missed dose and take your next dose of CALQUENCE at your regularly scheduled time. Do not take an extra dose to make up for missed dose.What are the possible side effects of CALQUENCECALQUENCE may cause serious side effects, including:oSerious infections can happen during treatment with CALQUENCE and may lead to death. Your healthcare provider may prescribe certain medicines if you have an increased risk of getting infections. Tell your healthcare provider right away if you have any signs or symptoms of an infection, including fever, chills, or flu-like symptoms.oBleeding problems (hemorrhage) can happen during treatment with CALQUENCE and can be serious and may lead to death. Your risk of bleeding may increase if you are also taking blood thinner medicine. Tell your healthcare provider if you have any signs or symptoms of bleeding, including:oblood in your stools or black stools (looks like tar)opink or brown urineounexpected bleeding, or bleeding that is severe or you cannot controlovomit blood or vomit that looks like coffee groundsocough up blood or blood clotsodizzinessoweaknessoconfusionochanges in your speechoheadache that lasts long timeobruising or red or purple skin marksoDecrease in blood cell counts. Decreased blood counts (white blood cells, platelets, and red blood cells) are common with CALQUENCE, but can also be severe. Your healthcare provider should do blood tests to check your blood counts regularly during treatment with CALQUENCE.oSecond primary cancers. New cancers have happened in people during treatment with CALQUENCE, including cancers of the skin or other organs. Your healthcare provider will check you for skin cancers during treatment with CALQUENCE. Use sun protection when you are outside in sunlight.oHeart rhythm problems (atrial fibrillation and atrial flutter) have happened in people treated with CALQUENCE. Tell your healthcare provider if you have any of the following signs or symptoms: ofast or irregular heartbeatodizzinessofeeling faintochest discomfortoshortness of breathThe most common side effects of CALQUENCE include:oheadacheodiarrheaomuscle and joint painoupper respiratory tract infectionobruisingThese 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 store CALQUENCEoStore CALQUENCE at room temperature between 68F to 77F (20C to 25C). 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 Patient Information leaflet. Do not use CALQUENCE for 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 CALQUENCEActive ingredient: acalabrutinibInactive ingredients: silicified microcrystalline cellulose, pregelatinized starch, magnesium stearate, and sodium starch glycolate. Capsule shell contains: gelatin, titanium dioxide, yellow iron oxide, FD&C Blue 2, and black ink.Distributed by: AstraZeneca Pharmaceuticals LP, Wilmington, DE 19850CALQUENCE is registered trademark of the AstraZeneca group of companies.(C)AstraZeneca XXXXFor more information, go to www.CALQUENCE.com or call 1-800-236-9933.This Patient Information has been approved by the U.S. Food and Drug Administration. Revised: 11/2019. oMantle cell lymphoma (MCL) who have received at least one prior treatment for their cancer.. oChronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL).. ohave had recent surgery or plan to have surgery. Your healthcare provider may stop CALQUENCE for any planned medical, surgical, or dental procedure.. ohave bleeding problems.. ohave or had heart rhythm problems.. ohave an infection.. ohave or had liver problems, including hepatitis virus (HBV) infection.. oare pregnant or plan to become pregnant. CALQUENCE may harm your unborn baby and problems during childbirth (dystocia).oIf you are able to become pregnant, your healthcare provider may do pregnancy test before you start treatment with CALQUENCEoFemales who are able to become pregnant should use effective birth control (contraception) during treatment with CALQUENCE and for at least week after the last dose of CALQUENCE.. oIf you are able to become pregnant, your healthcare provider may do pregnancy test before you start treatment with CALQUENCE. oFemales who are able to become pregnant should use effective birth control (contraception) during treatment with CALQUENCE and for at least week after the last dose of CALQUENCE.. oare breastfeeding or plan to breastfeed. It is not known if CALQUENCE passes into your breast milk. Do not breastfeed during treatment with CALQUENCE and for at least weeks after your final dose of CALQUENCE.. oTake CALQUENCE exactly as your healthcare provider tells you to take it.. oDo not change your dose or stop taking CALQUENCE unless your healthcare provider tells you to.. oYour healthcare provider may tell you to decrease your dose, temporarily stop, or completely stop taking CALQUENCE if you develop certain side effects.. oTake CALQUENCE times day (about 12 hours apart).. oTake CALQUENCE with or without food.. oSwallow CALQUENCE capsules whole with glass of water. Do not open, break, or chew capsules.. oIf you need to take an antacid medicine, take it either hours before or hours after you take CALQUENCE.. oIf you need to take certain other medicines called acid reducers (H-2 receptor blockers), take CALQUENCE hours before the acid reducer medicine.. oIf you miss dose of CALQUENCE, take it as soon as you remember. If it is more than hours past your usual dosing time, skip the missed dose and take your next dose of CALQUENCE at your regularly scheduled time. Do not take an extra dose to make up for missed dose.. oSerious infections can happen during treatment with CALQUENCE and may lead to death. Your healthcare provider may prescribe certain medicines if you have an increased risk of getting infections. Tell your healthcare provider right away if you have any signs or symptoms of an infection, including fever, chills, or flu-like symptoms.. oBleeding problems (hemorrhage) can happen during treatment with CALQUENCE and can be serious and may lead to death. Your risk of bleeding may increase if you are also taking blood thinner medicine. Tell your healthcare provider if you have any signs or symptoms of bleeding, including:. oblood in your stools or black stools (looks like tar). opink or brown urine. ounexpected bleeding, or bleeding that is severe or you cannot control. ovomit blood or vomit that looks like coffee grounds. ocough up blood or blood clots. odizziness. oweakness. oconfusion. ochanges in your speech. oheadache that lasts long time. obruising or red or purple skin marks. oDecrease in blood cell counts. Decreased blood counts (white blood cells, platelets, and red blood cells) are common with CALQUENCE, but can also be severe. Your healthcare provider should do blood tests to check your blood counts regularly during treatment with CALQUENCE.. oSecond primary cancers. New cancers have happened in people during treatment with CALQUENCE, including cancers of the skin or other organs. Your healthcare provider will check you for skin cancers during treatment with CALQUENCE. Use sun protection when you are outside in sunlight.. oHeart rhythm problems (atrial fibrillation and atrial flutter) have happened in people treated with CALQUENCE. Tell your healthcare provider if you have any of the following signs or symptoms: ofast or irregular heartbeat. odizziness. ofeeling faint. ochest discomfort. oshortness of breath. oheadache. odiarrhea. omuscle and joint pain. oupper respiratory tract infection. obruising. oStore CALQUENCE at room temperature between 68F to 77F (20C to 25C).. Keep CALQUENCE and all medicines out of the reach of children.

SPL UNCLASSIFIED SECTION.


1.1 Mantle Cell Lymphoma CALQUENCE is indicated for the treatment of adult patients with mantle cell lymphoma (MCL) who have received at least one prior therapy.This indication is approved under accelerated approval based on overall response rate [see Clinical Studies (14.1)]. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

USE IN SPECIFIC POPULATIONS SECTION.


8 USE IN SPECIFIC POPULATIONS oPregnancy: May cause fetal harm and dystocia. (8.1)oLactation: Advise not to breastfeed (8.2). oPregnancy: May cause fetal harm and dystocia. (8.1). oLactation: Advise not to breastfeed (8.2). 8.1 Pregnancy Risk SummaryBased on findings in animals, CALQUENCE may cause fetal harm and dystocia when administered to 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) 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 fetus.The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have 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 2-4% and 15-20%, respectively.DataAnimal DataIn 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 pre- and postnatal development study in rats, acalabrutinib was administered orally to pregnant animals during organogenesis, parturition and lactation, at doses of 50, 100, and 150 mg/kg/day. Dystocia (prolonged or difficult labor) and mortality of offspring were observed at doses >= 100 mg/kg/day. The AUC at 100 mg/kg/day in pregnant rats was approximately 2-times the AUC in patients at 100 mg approximately every 12 hours. Underdeveloped renal papilla was also observed in F1 generation offspring at 150 mg/kg/day with an AUC approximately 5-times the AUC in patients at 100 mg approximately every 12 hours.. 8.2 Lactation Risk Summary. No data are available regarding the presence of acalabrutinib or its active metabolite in human milk, its effects on the breastfed child, or on milk production. Acalabrutinib and its active metabolite were present in the milk of lactating rats. Due to the potential for adverse reactions in breastfed child from CALQUENCE, advise lactating women not to breastfeed while taking CALQUENCE and for at least weeks after the final dose.. 8.3 Females and Males of Reproductive Potential PregnancyPregnancy testing is recommended for females of reproductive potential prior to initiating CALQUENCE therapy.Contraception FemalesCALQUENCE may cause embryo-fetal harm and dystocia when administered to pregnant women [see Use in Specific Populations (8.1)]. Advise female patients of reproductive potential to use effective contraception during treatment with CALQUENCE and for at least 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 fetus.. 8.4 Pediatric Use The safety and efficacy of CALQUENCE in pediatric patients have not been established.. 8.5 Geriatric Use Of the 929 patients with CLL or MCL in clinical trials of CALQUENCE, 68% were 65 years of age or older, and 24% were 75 years of age or older. Among patients 65 years of age or older, 59% had Grade or higher adverse reactions and 39% had serious adverse reactions. Among patients younger than age 65, 45% had Grade or higher adverse reactions and 25% had serious adverse reactions. No clinically relevant differences in efficacy were observed between patients >= 65 years and younger.. 8.6 Hepatic Impairment Avoid administration of CALQUENCE in patients with severe hepatic impairment. The safety of CALQUENCE has not been evaluated in patients with moderate or severe hepatic impairment [see Recommended Dosage for Hepatic Impairment (2.2) and Clinical Pharmacology (12.3)].

WARNINGS AND PRECAUTIONS SECTION.


5 WARNINGS AND PRECAUTIONS oSerious and Opportunistic Infections: Monitor for signs and symptoms of infection and treat promptly. (5.1)oHemorrhage: Monitor for bleeding and manage appropriately. (5.2)oCytopenias: Monitor complete blood counts regularly. (5.3)oSecond Primary Malignancies: Other malignancies have occurred, including skin cancers and other solid tumors. Advise patients to use sun protection. (5.4)oAtrial Fibrillation and Flutter: Monitor for symptoms of arrhythmias and manage. (5.5). oSerious and Opportunistic Infections: Monitor for signs and symptoms of infection and treat promptly. (5.1). oHemorrhage: Monitor for bleeding and manage appropriately. (5.2). oCytopenias: Monitor complete blood counts regularly. (5.3). oSecond Primary Malignancies: Other malignancies have occurred, including skin cancers and other solid tumors. Advise patients to use sun protection. (5.4). oAtrial Fibrillation and Flutter: Monitor for symptoms of arrhythmias and manage. (5.5). 5.1 Serious and Opportunistic Infections Fatal and serious infections, including opportunistic infections, have occurred in patients with hematologic malignancies treated with CALQUENCE. Serious or Grade or higher infections (bacterial, viral, or fungal) occurred in 19% of 1029 patients exposed to CALQUENCE in clinical trials, most often due to respiratory tract infections (11% of all patients, including pneumonia in 6%). These infections predominantly occurred in the absence of Grade or neutropenia, with neutropenic infection reported in 1.9% of all patients. Opportunistic infections in recipients of CALQUENCE have included, but are not limited to, hepatitis virus reactivation, fungal pneumonia, Pneumocystis jiroveci pneumonia, Epstein-Barr virus reactivation, cytomegalovirus, and progressive multifocal leukoencephalopathy (PML). Consider prophylaxis in patients who are at increased risk for opportunistic infections. Monitor patients for signs and symptoms of infection and treat promptly.. 5.2 Hemorrhage Fatal and serious hemorrhagic events have occurred in patients with hematologic malignancies treated with CALQUENCE. Major hemorrhage (serious or Grade or higher bleeding or any central nervous system bleeding) occurred in 3.0% of patients, with fatal hemorrhage occurring in 0.1% of 1029 patients exposed to CALQUENCE in clinical trials. Bleeding events of any grade, excluding bruising and petechiae, occurred in 22% of patients.Use of antithrombotic agents concomitantly with CALQUENCE may further increase the risk of hemorrhage. In clinical trials, major hemorrhage occurred in 2.7% of patients taking CALQUENCE without antithrombotic agents and 3.6% of patients taking CALQUENCE with antithrombotic agents. Consider the risks and benefits of antithrombotic agents when co-administered with CALQUENCE. Monitor patients for signs of bleeding.Consider the benefit-risk of withholding CALQUENCE for 3-7 days pre- and post-surgery depending upon the type of surgery and the risk of bleeding.. 5.3 Cytopenias Grade or cytopenias, including neutropenia (23%), anemia (8%), thrombocytopenia (7%), and lymphopenia (7%), developed in patients with hematologic malignancies treated with CALQUENCE. Grade neutropenia developed in 12% of patients. Monitor complete blood counts regularly during treatment. Interrupt treatment, reduce the dose, or discontinue treatment as warranted [see Dose Modifications for Adverse Reactions (2.4)].. 5.4 Second Primary Malignancies Second primary malignancies, including skin cancers and other solid tumors, occurred in 12% of 1029 patients exposed to CALQUENCE in clinical trials. The most frequent second primary malignancy was skin cancer, reported in 6% of patients. Monitor patients for skin cancers and advise protection from sun exposure.. 5.5 Atrial Fibrillation and Flutter Grade atrial fibrillation or flutter occurred in 1.1% of 1029 patients treated with CALQUENCE, with all grades of atrial fibrillation or flutter reported in 4.1% of all patients. The risk may be increased in patients with cardiac risk factors, hypertension, previous arrhythmias, and acute infection. Monitor for symptoms of arrhythmia (e.g., palpitations, dizziness, syncope, dyspnea) and manage as appropriate.