LACTATION SECTION.

8.2 Lactation Risk SummaryNo 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.

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 148 (33%) L/hr for acalabrutinib and 19 (23%) 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 (estimated glomerular filtration rate [eGFR] by Modification of Diet in Renal Disease [MDRD] equation: 30 to 90 mL/min). Acalabrutinib PK has not been evaluated in patients with severe renal impairment (eGFR 30 mL/min, 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 <= x ULN and any AST) relative to patients with normal hepatic function (total bilirubin and AST <= 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 Previously Untreated Mantle Cell Lymphoma ECHOThe efficacy of CALQUENCE in patients with previously untreated MCL was evaluated in randomized, double-blind, placebo controlled, multicenter study (ECHO; NCT02972840). The study enrolled 598 patients who were >= 65 years of age and who had no intention for transplant. The study excluded patients with total bilirubin 1.5 upper limit of normal (ULN), AST or ALT 2.5 ULN, or estimated creatinine clearance of <= 50 mL/min. Patients were randomized in 1:1 ratio to receive CALQUENCE plus bendamustine and rituximab (CALQUENCE plus BR) or placebo plus BR. Dosing for both arms was administered in 28-day cycles as follows:oCALQUENCE plus BR was administered for maximum of treatment cycles. CALQUENCE 100 mg orally was administered twice daily starting on Cycle Day 1. Bendamustine was administered at 90 mg/m2 intravenously over 30 minutes on Days and of each of cycles. Rituximab was administered at 375 mg/m2 intravenously on Day of each cycle for cycles.oFor patients achieving response (PR or CR), CALQUENCE 100 mg orally twice daily was administered continuously, in combination with rituximab given at 375 mg/m2 on Day every other cycle for maximum of 12 additional doses up to Cycle 30. After discontinuation of rituximab, patients continued CALQUENCE monotherapy at 100 mg orally twice daily until disease progression or unacceptable toxicity.Patients on the control arm received the same regimen but placebo in lieu of CALQUENCE. Crossover to CALQUENCE monotherapy was permitted for patients in the placebo plus BR arm at disease progression.Of all patients randomized, the median age was 71 years (range: 65-86); 71% were male; 78% were White, 16% Asian, 0.5% were Black or African American. In total, 80% had classic histology of MCL, 7.7% had blastoid MCL, and 5.5% had pleomorphic MCL. The simplified MIPI (Mantle Cell Lymphoma International Prognostic Index) score was low in 33%, intermediate in 43%, and high in 24% of patients. total of 38% of patients had tumor bulk >= cm and 86% had Ann Arbor stage IV disease.The major efficacy outcome was progression-free survival (PFS) as assessed by an Independent Review Committee (IRC) using the Lugano Classification. Efficacy results are presented in Table 15. The Kaplan-Meier curves for PFS are shown in Figure 1. At this prespecified interim analysis, the median follow-up for PFS was 49.8 months in both arms.Table 15. Efficacy Results in Patients with Previously Untreated MCL in ECHOOutcomes per IRCCALQUENCE plus BRN= 299Placebo plus BRN= 299Progression-Free SurvivalStratified by randomization stratification factors: Geographic Regions (North American, Western Europe, Other) and simplified MIPI Score (Low risk [0 to 3], Intermediate risk [4 to 5], High Risk [6 to 11]). Median (95% CI), months66.4 (55.1, NE)49.6 (36.0, 64.1) HREstimated based on stratified Cox Proportional Hazards model for hazard ratio (95% CI). (95% CI)0.73 (0.57, 0.94) P-valueEstimated based on stratified log-rank test for p-value, with an alpha level of 0.039 derived by the OBrien-Fleming method.0.016Overall Response Rate (ORR) (CR PR) ORR (%)272 (91)263 (88) 95% CI87, 9484, 91 CR (%)199 (67)160 (54) PR (%)73 (24)103 (34) p-value0.220HR hazard ratio, CR complete response, PR partial response, NE not evaluableFigure 1. Kaplan-Meier Curve of IRC-Assessed PFS in Patients with Previously Untreated MCL in ECHOAt the time of the PFS analysis, the median overall survival had not been reached in either arm with total of 203 deaths: 97 (32%) patients in the CALQUENCE plus BR arm and 106 (35%) patients in the placebo plus BR arm had died.. oCALQUENCE plus BR was administered for maximum of treatment cycles. CALQUENCE 100 mg orally was administered twice daily starting on Cycle Day 1. Bendamustine was administered at 90 mg/m2 intravenously over 30 minutes on Days and of each of cycles. Rituximab was administered at 375 mg/m2 intravenously on Day of each cycle for cycles.. oFor patients achieving response (PR or CR), CALQUENCE 100 mg orally twice daily was administered continuously, in combination with rituximab given at 375 mg/m2 on Day every other cycle for maximum of 12 additional doses up to Cycle 30. After discontinuation of rituximab, patients continued CALQUENCE monotherapy at 100 mg orally twice daily until disease progression or unacceptable toxicity.. Median (95% CI), months. HREstimated based on stratified Cox Proportional Hazards model for hazard ratio (95% CI). (95% CI). P-valueEstimated based on stratified log-rank test for p-value, with an alpha level of 0.039 derived by the OBrien-Fleming method.. ORR (%). 95% CI. CR (%). PR (%). p-value. Figure1. 14.2 Previously Treated Mantle Cell Lymphoma ACE-LY-004The 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 Mantle Cell Lymphoma International Prognostic Index (MIPI) score (which includes age, ECOG score, and baseline lactate dehydrogenase and white cell count) was intermediate in 44% and high in 17% of patients.CALQUENCE was administered orally at 100 mg approximately every 12 hours until disease progression or unacceptable toxicity. The median dose intensity was 98.5%. The major efficacy outcome of Trial LY-004 was overall response rate and the median follow-up was 15.2 months.Table 16: 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.. 14.3 Chronic Lymphocytic Leukemia The efficacy of CALQUENCE in patients with CLL was demonstrated in three 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 17. The Kaplan-Meier curves for PFS are shown in Figure 2.Table 17. 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 2: Kaplan-Meier Curve of IRC-Assessed PFS in Patients with CLL in ELEVATE-TN With 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 18. The Kaplan-Meier curve for PFS is shown in Figure 3. There was no statistically significant difference in overall response rates between the two treatment arms.Table 18: 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 3: Kaplan-Meier Curve of IRC-Assessed PFS in Patients with CLL in ASCEND With 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.AmplifyThe efficacy of CALQUENCE in combination with venetoclax in previously untreated CLL patients was evaluated in AMPLIFY, randomized, multi-center, open-label study (NCT03836261). The study included patients previously untreated for CLL without del(17p) or TP53 mutation that were 18 years of age and older. Patients were randomized to receive:oCALQUENCE plus venetoclax (AV): CALQUENCE 100 mg was administered twice daily starting on Cycle Day for total of 14 cycles or until disease progression or unacceptable toxicity. On Cycle Day patients started the venetoclax 5-week dose-titration schedule, starting at 20 mg and increasing weekly to 50 mg, 100 mg, 200 mg and finally 400 mg once daily. Venetoclax was administered for total of 12 cycles. Each cycle was 28 days.oInvestigators choice of chemoimmunotherapy (FCR/BR):oFludarabine plus cyclophosphamide plus rituximab (FCR): Fludarabine (25 mg/m2 and cyclophosphamide (250 mg/m2) were administered on Days 1-3 up to maximum of cycles. Rituximab was administered at dose of 375 mg/m2 on Day Cycle and 500 mg/m2 on Day of Cycles up to 6. Each cycle was 28 days.oBendamustine plus rituximab (BR): Bendamustine 90 mg/m2 was administered on Days and up to maximum of cycles. Rituximab was administered at dose of 375 mg/m2 on Day Cycle and 500 mg/m2 on Day of Cycles up to 6. Each cycle was 28 days. oAn additional investigational combination regimen [see Warnings and Precautions (5.1)].Patients were stratified by age (> 65 years or <= 65), IGHV mutational status (mutated versus unmutated), Rai stage (high risk [>= 3] versus non-high risk) and geographic region (North America and Europe versus other). In the efficacy population described in Table 19, overall median age was 61 years (range: 26 to 86 years) and 62% were males; 89% were White, 3.8% Asian, 1.7% were Black or African American, 0.3% American Indian or Alaska Native, 0.3% Native Hawaiian or Other Pacific Islander, and 4.8% not reported; 86% were not Hispanic or Latino, 7% Hispanic or Latino, and 7% not reported. The ECOG performance was 0-1 in 90%, bulky diseases with nodes >= cm was seen in 41%, 45% had Rai stage III or IV disease, 17% had 11q deletion and 58% had unmutated IGHV.The major efficacy outcome was IRC-assessed PFS of AV arm versus Investigators choice arm (FCR/BR). The median duration of PFS follow-up was 42.6 months. Efficacy results are presented in Table 19. The Kaplan-Meier curve for IRC-assessed PFS is shown in Figure 4.Table 19. Efficacy Results per IRC in Patients with previously untreated CLL ITT population (AMPLIFY)CALQUENCE plus venetoclaxN=291FCR/BRb N=290Progression-free survivala Number of events (%)89 (31)95 (33)PD, (%)77 (26)66 (23)Death events (%)12 (4)29 (10)Median (95% CI), monthsNE (51.1, NE)47.6 (43.3, NE)HRc (95% CI)0.65 (0.49, 0.87)P-valued 0.0038Overall Response Rate (CR, CRi, nPR, PR)e ORR (%)270 (93)218 (75)(95% CI)(89, 95)(70, 80)CR26 (9)15 (5)CRi, (%)01 (0.3)nPR, (%)1 (0.3)1 (0.3)PR (%)243 (84)201 (69)NE= Not estimable; CR complete response; CRi=complete response with incomplete blood count recovery; nPR=nodular partial response; PR=partial responsea Per IRC assessment.b Approximately 50% of patients were treated with FCR and 50% were treated with BR per investigators choice.c Based on stratified Cox-Proportional-Hazards model.d Based on stratified Log-rank test. The pre-specified type error rate () for this interim analysis is 0.0469 derived from Lan-DeMets alpha spending function with OBrien-Fleming boundary.e Per iwCLL 2018 criteria.Figure 4: Kaplan-Meier Curve of IRC-Assessed PFS in Patients with previously untreated CLL in AMPLIFYWith median follow-up of 41.0 months, total of 60 death events were reported; 18 (6%) in the AV arm and 42 (14%) in the FCR/BR arm.. 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.. oCALQUENCE plus venetoclax (AV): CALQUENCE 100 mg was administered twice daily starting on Cycle Day for total of 14 cycles or until disease progression or unacceptable toxicity. On Cycle Day patients started the venetoclax 5-week dose-titration schedule, starting at 20 mg and increasing weekly to 50 mg, 100 mg, 200 mg and finally 400 mg once daily. Venetoclax was administered for total of 12 cycles. Each cycle was 28 days.. oInvestigators choice of chemoimmunotherapy (FCR/BR):oFludarabine plus cyclophosphamide plus rituximab (FCR): Fludarabine (25 mg/m2 and cyclophosphamide (250 mg/m2) were administered on Days 1-3 up to maximum of cycles. Rituximab was administered at dose of 375 mg/m2 on Day Cycle and 500 mg/m2 on Day of Cycles up to 6. Each cycle was 28 days.oBendamustine plus rituximab (BR): Bendamustine 90 mg/m2 was administered on Days and up to maximum of cycles. Rituximab was administered at dose of 375 mg/m2 on Day Cycle and 500 mg/m2 on Day of Cycles up to 6. Each cycle was 28 days. oFludarabine plus cyclophosphamide plus rituximab (FCR): Fludarabine (25 mg/m2 and cyclophosphamide (250 mg/m2) were administered on Days 1-3 up to maximum of cycles. Rituximab was administered at dose of 375 mg/m2 on Day Cycle and 500 mg/m2 on Day of Cycles up to 6. Each cycle was 28 days.. oBendamustine plus rituximab (BR): Bendamustine 90 mg/m2 was administered on Days and up to maximum of cycles. Rituximab was administered at dose of 375 mg/m2 on Day Cycle and 500 mg/m2 on Day of Cycles up to 6. Each cycle was 28 days.. oAn additional investigational combination regimen [see Warnings and Precautions (5.1)].. Figure2. Figure3. figure5.

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)]oCardiac Arrhythmias [see Warnings and Precautions (5.5)]oHepatotoxicity, including DILI [see Warnings and Precautions (5.6)]. 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)]. oCardiac Arrhythmias [see Warnings and Precautions (5.5)]. oHepatotoxicity, 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 or laboratory abnormalities (>= 10%) are absolute neutrophil count decreased, uric acid increase, 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 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 1,258 patients in trials, and CALQUENCE combinations in 797 patients in trials. Among these recipients of CALQUENCE, 89% were exposed for at least 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 or 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 LymphomaThe 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)].ECHOThe 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 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. 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 and Table 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 ECHOBody SystemAdverse ReactionsCALQUENCE plus BRN 297Placebo plus BR = 297All Grades (%)Grade or (%)All Grades (%)Grade or (%)Skin and subcutaneous tissue disorders Rasha 4712313Infections Covid-19b 38132711 Upper respiratory tract infectionc 300.7291....Pneumoniad 31172514Gastrointestinal disorders Diarrhea373282.4 Vomiting260.7141 Constipation251250.3General disorders Fatigue373.7324.4 Pyrexia292.4241.3 Edema201.3190Nervous system disorders Headache311.7140.7 Dizziness181170.3Respiratory, thoracic and mediastinal disorders Cough270200.3 Dyspnea171112.7Neoplasms Secondary primary malignancye 197157Musculoskeletal and connective tissue disorders Arthralgia180.7161Vascular disorders Hemorrhagef 201.7113Excludes 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 ECHOLaboratory AbnormalityCALQUENCE plus BRa Placebo plus BRa All grade (%)Grade or (%)All grade (%)Grade or (%)Hematologic AbnormalitiesLymphocytes decreased98879789Hemoglobin decreased80116511Neutrophils decreased76567751Platelets decreased69186016Chemistry AbnormalitiesAST increased535503.4Uric acid increased45454040ALT increased447412.4Potassium increased402382.7Creatinine increased373282.4Phosphate decreased364.4304.7Potassium decreased297236Bilirubin increased192122a The denominator used to calculate the rate varied between 296 and 297 based on the number of patients with baseline value and at least one post-treatment value.Grade 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 LymphomaACE-LY-004The 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. 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 7: Non-Hematologic Adverse Reactions in >= 5% (All Grades) of Patients with MCL in Trial LY-004Body SystemAdverse ReactionsCALQUENCE 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 disordersBruisinga 21-Rashb 180.8Vascular disordersHemorrhagec 80.8Respiratory, thoracic and mediastinal disordersEpistaxis6-Per NCI CTCAE version 4.03.a Bruising: Includes all terms containing bruise, contusion, petechiae, or ecchymosisb Rash: Includes all terms containing rashc Hemorrhage: Includes all terms containing hemorrhage or hematomaTable 8: Hematologic Adverse Reactions Reported in >= 20% of Patients with MCL in Trial LY-004HematologicAdverse Reactions CALQUENCE MonotherapyN=124All Grades (%)Grade >= (%)Hemoglobin decreased4610Platelets decreased4412Neutrophils decreased3615Per NCI CTCAE version 4.03; based on laboratory measurements and adverse reactions.Increases in creatinine to 1.5 to times the upper limit of normal (ULN) 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 (14.3)].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-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 (14.3)].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 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 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 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)All Grades (%)Grade >= (%)All Grades (%)Grade >= (%)All Grades (%)Grade >= (%)InfectionsInfection+ 6922 6514 4613 Upper respiratory tract infectiona 392.8350171.2Lower respiratory tract infectionb 248184.571.8Urinary tract infection151.7152.850.6Blood and lymphatic system disorders Neutropeniac 533723137850Anemiad 521253105414Thrombocytopeniae 5112323.46116Lymphocytosisf 121116150.60.6Nervous system disordersHeadache401.1391.1120Dizziness20012070Gastrointestinal disordersDiarrhea394.5350.6211.8Nausea200220310Musculoskeletal and connective tissue disordersMusculoskeletal paing 372.2321.1162.4Arthralgia221.1160.64.71.2General disorders and administration site conditionsFatigueh 342.2231.1241.2Skin and subcutaneous tissue disordersBruisingi 31021050Rashj 262.2250.690.6Vascular disordersHemorrhagek 201.7201.760Per NCI CTCAE version 4.03+ Includes any adverse reactions involving infection or febrile neutropenia Includes fatal cases in the CALQUENCE plus obinutuzumab arm, fatal cases in the CALQUENCE monotherapy arm and fatal case in the obinutuzumab plus chlorambucil arm Derived from adverse reaction and laboratory data Upper respiratory tract infection, nasopharyngitis and sinusitis Includes pneumonia, lower respiratory tract infection, bronchitis, bronchiolitis, tracheitis, and lung infection Includes neutropenia, neutrophil count decreased, and related laboratory data Includes anemia, red blood cell count decreased, and related laboratory data Includes thrombocytopenia, platelet count decreased, and related laboratory data Includes lymphocytosis, lymphocyte count increased, and related laboratory data Includes back pain, bone pain, musculoskeletal chest pain, musculoskeletal pain, musculoskeletal discomfort, myalgia, neck pain, pain in extremity and spinal pain Includes asthenia, fatigue, and lethargy Includes bruise, contusion, and ecchymosis Includes rash, dermatitis, and other related terms Includes hemorrhage, hematoma, hemoptysis, hematuria, menorrhagia, hemarthrosis, and epistaxisBody SystemAdverse ReactionCALQUENCE plus ObinutuzumabN=178CALQUENCE MonotherapyN=179Obinutuzumab plus Chlorambucil N=169Other 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 10: Select Non-Hematologic Laboratory Abnormalities (>= 15% Any Grade), New or Worsening from Baseline in Patients Receiving CALQUENCE (ELEVATE-TN)Laboratory Abnormality,aCALQUENCE plus ObinutuzumabN=178CALQUENCE MonotherapyN=179Obinutuzumab plus ChlorambucilN=169AllGrades (%)Grade >= (%)AllGrades (%)Grade >= (%)AllGrades (%)Grade >= (%)Uric acid increase292922223737ALT increase307201.1366AST increase385170.6608Bilirubin increase130.6150.6110.6Per NCI CTCAE version 4.03a Excludes electrolytesIncreases in creatinine to 1.5 to times ULN 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 (14.3)]. The trial enrolled patients with relapsed or refractory CLL after at least one prior therapy and required hepatic transaminases <= 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/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 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 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 11: Common Adverse Reactions (>= 15% Any Grade) with CALQUENCE in Patients with CLL (ASCEND)Body SystemAdverse Reaction CALQUENCE N=154Idelalisib plus Rituximab Product N=118Bendamustine plus Rituximab Product N=35 AllGrades (%) Grade >= (%) AllGrades (%) Grade >= (%) AllGrades (%) Grade >= (%) Infections Infection+ 56 15 65 28 49 11 Upper respiratory tract infectiona 29 1.9 26 3.4 17 2.9 Lower respiratory tract infectionb 23 26 15 14 6Blood and lymphatic system disorders Neutropeniac 48 23 79 53 80 40 Anemiad 47 15 45 57 17 Thrombocytopeniae 33 41 13 54 Lymphocytosisf 26 19 23 18 2.9 2.9 Nervous system disorders Headache 22 0.6 0 0 Gastrointestinal disorders Diarrheag 18 1.3 49 25 14 Vascular disorders Hemorrhageh 16 1.3 1.7 2.9 General disorders Fatiguei 15 1.9 13 0.8 31 Musculoskeletal and connective tissue disorders Musculoskeletal painj 15 1.3 15 1.7 2.9 Per NCI CTCAE version 4.03 Includes any adverse reactions involving infection or febrile neutropenia Includes fatal case in the CALQUENCE monotherapy arm and fatal case in the Idelalisib plus Rituximab arm Derived from adverse reaction and laboratory data Upper respiratory tract infection, rhinitis and nasopharyngitis Includes pneumonia, lower respiratory tract infection, bronchitis, bronchiolitis, tracheitis, and lung infection. Includes neutropenia, neutrophil count decreased, and related laboratory data Includes anemia, red blood cell decreased, and related laboratory data Includes thrombocytopenia, platelet count decreased, and related laboratory data Includes lymphocytosis, lymphocyte count increased and related laboratory data Includes colitis, diarrhea, and enterocolitis Includes hemorrhage, hematoma, hemoptysis, hematuria, menorrhagia, hemarthrosis, and epistaxis Includes asthenia, fatigue, and lethargy Includes back pain, musculoskeletal chest pain, musculoskeletal pain, musculoskeletal discomfort, pain in extremity, myalgia, spinal pain and bone painOther 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 12: Select Non-Hematologic Laboratory Abnormalities (>= 10% Any Grade), New or Worsening from Baseline in Patients Receiving CALQUENCE (ASCEND)Laboratory Abnormality CALQUENCEN=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 5a Excludes electrolytesIncreases in creatinine to 1.5 to times ULN occurred in 1.3% of patients who received CALQUENCE.AMPLIFYThe safety of CALQUENCE in patients with previously untreated CLL was evaluated in randomized, multicenter, open-label study (AMPLIFY), in which 291 patients received CALQUENCE plus venetoclax (AV), and 259 patients received Investigators 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 months or longer and 91% were exposed for greater than one year. The median duration of exposure to CALQUENCE was 12.9 months (range: to 18 months) and to venetoclax was 11.1 months (range: 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 AMPLIFYAll Grades (%)Grade or (%)All Grades (%)Grade or (%)Nervous system disordersHeadache351.480.4Gastrointestinal disordersDiarrhea331.7110.4Nausea150360Musculoskeletal and connective tissue disordersMusculoskeletal pain 250.7140.8InfectionsCOVID-192163.91.5General disordersFatigue 180.3171.5Skin and subcutaneous tissue disordersBruising 1701.50Rash 161161.5Excludes 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. Body System Adverse ReactionsCALQUENCE plus Venetoclax = 291Investigators choice of FCR or BR = 259Clinically 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 AMPLIFYLaboratory AbnormalityCALQUENCE plus Venetoclax aInvestigators choice of FCR or BR aAll grade (%)Grade or (%)All grade (%)Grade or (%)Hematologic AbnormalitiesNeutrophils decreased78388053Lymphocytes decreased56129273Platelets decreased4355915Hemoglobin decreased357568Chemistry AbnormalitiesGlucose increased740840Calcium decreased300.7252.3ALT increased263.1281.6Urate increased25252323LDH increased240400Potassium increased222.4123.1AST increased221.4281.6ALP increased200150Glucose decreased200.350Creatinine increased190.3120.8Sodium increased150.390.4a The denominator used to calculate the rate varied between 256 and 290 based on the number of patients with baseline value and at least one post-treatment value.Grade laboratory abnormalities in 15% of patients treated with CALQUENCE plus Venetoclax include absolute neutrophil count decreased (15%).. oNeoplasms: second primary malignancy (10%), non-melanoma skin cancer (5%). oCardiac disorders: atrial fibrillation or flutter (3.6%), hypertension (5%). oInfection: herpesvirus infection (6%). N=154. Product N=118. N=35. AllGrades (%). Grade >= (%). AllGrades (%). Grade >= (%). AllGrades (%). Grade >= (%). Infections Infection+. 56. 15. 65. 28. 49. 11. Upper respiratory tract infectiona. 29. 1.9. 26. 3.4. 17. 2.9. Lower respiratory tract infectionb. 23. 6. 26. 15 14. 6. Neutropeniac. 48. 23. 79. 53. 80. 40. Anemiad. 47. 15. 45. 8. 57. 17. Thrombocytopeniae. 33. 6. 41. 13. 54. 6. Lymphocytosisf. 26. 19. 23. 18. 2.9. 2.9. Nervous system disorders. Headache. 22. 0.6. 6. 0. 0. 0. Gastrointestinal disorders. Diarrheag. 18. 1.3. 49. 25. 14. 0. Vascular disorders. Hemorrhageh 16. 1.3. 5. 1.7. 6. 2.9. General disorders Fatiguei. 15. 1.9. 13. 0.8. 31. 6. Musculoskeletal and connective tissue disorders. Musculoskeletal painj. 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 fatal case in the CALQUENCE monotherapy arm and fatal case in the Idelalisib plus Rituximab arm Derived from adverse reaction and laboratory data. Upper respiratory tract infection, rhinitis and nasopharyngitis. Includes pneumonia, lower respiratory tract infection, bronchitis, bronchiolitis, tracheitis, and lung infection.. 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. 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. 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%). Body System. Adverse Reactions. 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of CALQUENCE. Because these reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure.oCardiac disorders: ventricular arrhythmiasoHepatobiliary disorders: drug-induced liver injury. oCardiac disorders: ventricular arrhythmias. oHepatobiliary disorders: drug-induced liver injury.

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 contain 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 Recommended 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. (2.3)oAvoid CALQUENCE in patients with severe hepatic impairment (8.6). oAdvise patients not to break, open, or chew capsules. (2.1). oManage toxicities using treatment interruption, dose reduction, or discontinuation. (2.3). oAvoid CALQUENCE in patients with severe hepatic impairment (8.6). 2.1 Recommended Dosage CALQUENCE Administration InstructionsAdvise 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.CALQUENCE as MonotherapyFor patients with MCL, CLL, or SLL, the recommended dosage of CALQUENCE is 100 mg taken orally approximately every 12 hours until disease progression or unacceptable toxicity.CALQUENCE in Combination with Bendamustine and Rituximab For patients with previously untreated MCL, the recommended dosage of CALQUENCE is 100 mg taken orally approximately every 12 hours until disease progression or unacceptable toxicity.Start CALQUENCE on Day of Cycle (each cycle is 28 days) and administer until disease progression or unacceptable toxicity. Administer bendamustine 90 mg/m2 on Days and and rituximab 375 mg/m2 on Day of Cycle and continue for total of cycles. Patients achieving response (PR or CR) after the first cycles may receive maintenance rituximab on Day of every other cycle for maximum of 12 additional doses, starting on Cycle up to Cycle 30 [see Clinical Studies (14.1)].CALQUENCE in Combination with ObinutuzumabFor patients with previously untreated CLL or SLL, the recommended dosage of CALQUENCE is 100 mg taken orally approximately every 12 hours until disease progression or unacceptable toxicity. Start CALQUENCE at Cycle (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.CALQUENCE in Combination with VenetoclaxFor patients with previously untreated CLL or SLL, the recommended dosage of CALQUENCE is 100 mg taken orally approximately every 12 hours until disease progression, unacceptable toxicity or completion of 14 cycles of treatment. Start CALQUENCE at Cycle (each cycle is 28 days). Start venetoclax at Cycle for total of 12 cycles. Start venetoclax at 20 mg daily for first week of treatment and increase weekly as per dosing schedule for 5-week ramp up (up to 400 mg daily) as described in the venetoclax USPI. Refer to the venetoclax USPI for additional details.. 2.2 Recommended Dosage for Drug Interactions Dosage Modifications for Use with CYP3A Inhibitors or InducersThese are described in Table [see Drug Interactions (7)].Table 1: Recommended Dosage Modifications for Use with CYP3A Inhibitors or InducersCYP3A Co-administered DrugRecommended CALQUENCE useInhibitionStrong CYP3A inhibitorAvoid co-administration.If these inhibitors will be used short-term (such as anti infectives for up to seven days), interrupt CALQUENCE.After discontinuation of strong CYP3A inhibitor for at least 24 hours, resume previous dosage of CALQUENCE.Moderate CYP3A inhibitorReduce the CALQUENCE 100 mg every 12 hours dosage to 100 mg once daily.InductionStrong CYP3A inducerAvoid co-administration.If co-administration is unavoidable, increase CALQUENCE dosage 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)].. 2.3 Dose Modifications for Adverse Reactions Recommended dosage modifications are provided in Table and 3.Table 2: Recommended Dosage Modifications for Adverse Reactions in Patients Receiving CALQUENCE Monotherapy and CALQUENCE in Combination with ObinutuzumabEventAdverse 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).Table 3: Recommended Dosage Modifications for Adverse Reactions in Patients Receiving CALQUENCE in Combination with BRAdverse Reaction Severitya Dosage Modification (Starting dosage of CALQUENCE 100 mg approximately every 12 hours)Neutropeniab [see Warnings and Precautions (5.3)]Absolute neutrophil count less than 0.5 109/L for greater than daysInterrupt CALQUENCE. Once toxicity has resolved to Grade <= 2, resume CALQUENCE at starting dosage.Upon 2nd or 3rd occurrence, reduce dosage of CALQUENCE to 100 mg once daily.c Discontinue CALQUENCE at 4th occurrence.For bendamustineb:Interrupt bendamustine. Once toxicity has resolved to Grade <= 2, resume bendamustine and consider dosage reduction to 70 mg/m2.d,e Thrombocytopeniaf [see Warnings and Precautions (5.3)]Platelet count 25 to 50 109/L with clinically significant bleeding or platelet count less than 25 109/LInterrupt CALQUENCE. Once toxicity has resolved to Grade <= or baseline, resume CALQUENCE at starting dosage.If recurrence, reduce dosage of CALQUENCE to 100 mg once daily.c Consider discontinuing CALQUENCE at 3rd occurrence.For bendamustinef:Interrupt bendamustine. Once toxicity has resolved to Grade <= or baseline, resume bendamustine and consider dose reduction to 70 mg/m2.e Non hematologic adverse reactions [see Warnings and Precautions (5)]Grade or higherInterrupt CALQUENCE. Once toxicity has resolved to Grade <= or baseline, resume CALQUENCE at starting dosage.If recurrence, reduce dosage of CALQUENCE to 100 mg once daily.c Discontinue CALQUENCE at 3rd occurrence of Grade toxicity. For Grade toxicity, consider the risks and benefits of continuing CALQUENCE.For bendamustine:Interrupt bendamustine. Once toxicity has resolved to Grade <= or baseline, resume bendamustine and consider dose reduction to 70 mg/m2.e Graded per National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03.b For neutropenia with ANC less than x 109/L, consideration for bendamustine dose interruption and dosage reduction to 70 mg/m2 may be appropriate in certain circumstances.c Dose may be re-escalated at the discretion of the physician if patient tolerates reduced dose for >= weeks.d Consider use of myeloid growth factors before bendamustine dosage reduction.e Consider discontinuing bendamustine if additional dosage reduction is required.f For thrombocytopenia, platelet count below 50 109/L should prompt bendamustine dose interruption even in the absence of clinically significant bleeding.Table 4: Recommended Dosage Modifications for Adverse Reactions in Patients Receiving CALQUENCE in Combination with VenetoclaxAdverse Reactiona Adverse Reaction OccurrenceDose ModificationGrade or neutropenia with or without fever and/or infection; Grade neutropenia lasting more than daysFirst occurrence Interrupt CALQUENCE and/or venetoclax.b Once toxicity resolves to Grade <= or baseline, restart CALQUENCE and/or venetoclax at same dose.Second occurrence Interrupt CALQUENCE and/or venetoclax.b Once toxicity resolves to Grade <= or baseline, restart CALQUENCE at same dose and venetoclax at one lower dose levelc. Subsequent occurrence Withhold CALQUENCE and/or venetoclax until toxicity resolves to Grade <= or baseline.b,d Grade or thrombocytopenia and/or bleedingf First occurrence Interrupt CALQUENCE and/or venetoclax. When bleeding resolves and thrombocytopenia is Grade <= or baseline without transfusion support for consecutive days, restart CALQUENCE and/or venetoclax at same dose.Second occurrence Interrupt CALQUENCE and venetoclax until resolution of bleeding and thrombocytopenia resolves to Grade <= or baseline.Restart CALQUENCE at same dose and/or restart venetoclax at one lower dose level.e Subsequent occurrences of severe thrombocytopenia Interrupt CALQUENCE and venetoclax until resolution of bleeding and thrombocytopenia resolves to Grade <= or baseline.Restart CALQUENCE at reduced frequency of 100 mg once daily and/or venetoclax at one lower dose level.c,d,e Grade or tumour lysis syndrome (TLS) First and subsequent episodes If subject experiences blood chemistry changes suggestive of TLS, the following days venetoclax and acalabrutinib dose should be withheld. If resolved within 24-48 hours of last dose, treatment can be resumed at the same dose.For events of clinical TLS or blood chemistry changes requiring more than 48 hours to resolve, venetoclax should be resumed at one lower dose level.c When resuming treatment after interruption due to TLS, monitor for TLS and provide prophylaxis.Grade other non-hematologic eventsg First occurrence Interrupt CALQUENCE and/or venetoclax until toxicity resolves to Grade <= 1.Restart CALQUENCE and/or venetoclax at same dose.Second occurrence Interrupt CALQUENCE and/or venetoclax until toxicity resolves to Grade <= 1d.Grade other non-hematologic eventsg First occurrence Interrupt CALQUENCE and/or venetoclax until toxicity resolves to Grade <= 1. Restart CALQUENCE at reduced frequency of 100 mg once daily and/or venetoclax at one lower dose level.c, Second occurrence Interrupt CALQUENCE and/or venetoclax until toxicity resolves to Grade <= 1d. Adverse reactions graded by the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0.b Growth factor may be used at physician discretion.c See venetoclax USPI for dose level reductions details.d Clinical judgment of the treating physician should guide the management plan of each patient based on the individual benefit/risk assessment for treatment with CALQUENCE in combination with venetoclax.e CALQUENCE dose may be re-escalated at the discretion of the physician if patient tolerates reduced dose for >= weeks.f Platelets may be used at physician discretion.g Certain treatment-emergent non-hematologic AEs (e.g., venous thromboembolic events) may be managed and become clinically stable following medical intervention but may not improve to Grade <= according to the NCI CTCAE definitions. In such cases, if subject is clinically stable, resumption of CALQUENCE may be possible based on clinical judgement of the treating physician.Refer to the prescribing information of each of the products used in combination with CALQUENCE for additional information for management of toxicities.

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS Capsules:100 mg acalabrutinib size hard gelatine capsules, with yellow body and blue cap, marked in black ink with ACA 100 mg.. Capsules: 100 mg. (3).

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS oCYP3A Inhibitors: Avoid co-administration with strong CYP3A inhibitors. Dose adjustments may be recommended. (2.2, 7, 12.3) oCYP3A Inducers: Avoid co-administration with strong CYP3A inducers. Dose adjustments may be recommended. (2.2, 7, 12.3) oGastric Acid Reducing Agents: Avoid co-administration with proton pump inhibitors (PPIs). Stagger dosing with H2-receptor antagonists and antacids. (2.2, 7, 12.3) oCYP3A Inhibitors: Avoid co-administration with strong CYP3A inhibitors. Dose adjustments may be recommended. (2.2, 7, 12.3) oCYP3A Inducers: Avoid co-administration with strong CYP3A inducers. Dose adjustments may be recommended. (2.2, 7, 12.3) oGastric Acid Reducing Agents: Avoid co-administration with proton pump inhibitors (PPIs). Stagger dosing with H2-receptor antagonists and antacids. (2.2, 7, 12.3) 7.1 Effect of Other Drugs on CALQUENCE Strong CYP3A InhibitorsClinical EffectoCo-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 (2.2)].Moderate CYP3A InhibitorsClinical EffectoCo-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 EffectoCo-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 EffectoCo-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 (2.2) ].H2-receptor antagonistsTake CALQUENCE hours before taking the H2-receptor antagonist [see Recommended Dosage for Drug Interactions (2.2) ]. 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 (2.2)].. 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).

GERIATRIC USE SECTION.

8.5 Geriatric Use CLL and Previously Treated MCLOf the 1,758 CALQUENCE-treated patients with B-cell malignancies (excluding previously untreated MCL) in clinical trials, 1,074 (61%) were 65 years of age or older, and 341 (19%) were 75 years of age or older. Among patients 65 years of age or older, 73% had Grade or higher adverse reactions and 55% had serious adverse reactions. Among patients younger than age 65, 58% had Grade or higher adverse reactions and 35% had serious adverse reactions. No clinically relevant differences in efficacy were observed between patients >= 65 years and younger.Of patients that received CALQUENCE in combination with venetoclax in AMPLIFY, 33% (97/291) were >= 65 years of age, and 4.5% (13/291) were >= 75 years of age. In patients 65 years of age or older and younger than age 65, the fatal adverse reactions were 5% and 2.6% respectively. No clinically relevant differences in efficacy were observed between patients >= 65 years of age and younger adults.Previously Untreated MCLOf the 297 CALQUENCE-treated patients with previously untreated MCL, 214 (72%) were 65 to 74 years of age and 83 (28%) were 75 years of age and older. No clinically relevant differences in safety or efficacy were observed between patients ages 65 to 74 years and those who were 75 years of age and older.

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

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 immediately report signs or symptoms suggestive of infection [see Warnings and Precautions (5.1)].HemorrhageInform patients to immediately 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)].Cardiac ArrhythmiasCounsel patients to immediately report any signs of palpitations, dizziness, fainting, chest discomfort, and shortness of breath [see Warnings and Precautions (5.5)].Hepatotoxicity, Including Drug-Induced Liver Injury: Inform patients that liver problems, including drug-induced liver injury and abnormalities in liver tests, may develop during CALQUENCE treatment. Advise patients to contact their healthcare provider immediately if they experience abdominal discomfort, dark urine, or jaundice [see Warnings and Precautions (5.6)]. 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 2026.

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 SwitzerlandAstraZeneca. 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.

PHARMACODYNAMICS 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 148 (33%) L/hr for acalabrutinib and 19 (23%) 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 (estimated glomerular filtration rate [eGFR] by Modification of Diet in Renal Disease [MDRD] equation: 30 to 90 mL/min). Acalabrutinib PK has not been evaluated in patients with severe renal impairment (eGFR 30 mL/min, 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 <= x ULN and any AST) relative to patients with normal hepatic function (total bilirubin and AST <= 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.

PREGNANCY 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.

Dosage and Administration, Recommended Dosage (2.1) 2/2026Dosage and Administration, Dosage Modifications for Adverse Reactions (2.3) 2/2026Warnings and Precautions, Serious and Opportunistic Infections (5.1) 2/2026.

SPL UNCLASSIFIED SECTION.

1.1 Previously Untreated Mantle Cell Lymphoma CALQUENCE in combination with bendamustine and rituximab is indicated for the treatment of adult patients with previously untreated mantle cell lymphoma (MCL) who are ineligible for autologous hematopoietic stem cell transplantation (HSCT).

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)oSevere Hepatic Impairment: Avoid use of CALQUENCE. (8.6). oPregnancy: May cause fetal harm and dystocia. (8.1). oLactation: Advise not to breastfeed (8.2). oSevere Hepatic Impairment: Avoid use of CALQUENCE. (8.6). 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 SummaryNo 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 CALQUENCE may cause embryo-fetal harm and dystocia when administered to pregnant women [see Use in Specific Populations (8.1)].Pregnancy TestingPregnancy testing is recommended for females of reproductive potential prior to initiating CALQUENCE therapy.ContraceptionFemalesAdvise 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 CLL and Previously Treated MCLOf the 1,758 CALQUENCE-treated patients with B-cell malignancies (excluding previously untreated MCL) in clinical trials, 1,074 (61%) were 65 years of age or older, and 341 (19%) were 75 years of age or older. Among patients 65 years of age or older, 73% had Grade or higher adverse reactions and 55% had serious adverse reactions. Among patients younger than age 65, 58% had Grade or higher adverse reactions and 35% had serious adverse reactions. No clinically relevant differences in efficacy were observed between patients >= 65 years and younger.Of patients that received CALQUENCE in combination with venetoclax in AMPLIFY, 33% (97/291) were >= 65 years of age, and 4.5% (13/291) were >= 75 years of age. In patients 65 years of age or older and younger than age 65, the fatal adverse reactions were 5% and 2.6% respectively. No clinically relevant differences in efficacy were observed between patients >= 65 years of age and younger adults.Previously Untreated MCLOf the 297 CALQUENCE-treated patients with previously untreated MCL, 214 (72%) were 65 to 74 years of age and 83 (28%) were 75 years of age and older. No clinically relevant differences in safety or efficacy were observed between patients ages 65 to 74 years and those who were 75 years of age and older.. 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 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)oCardiac Arrhythmias: Monitor for symptoms of arrhythmias and manage. (5.5)oHepatotoxicity, Including Drug-Induced Liver Injury: Monitor hepatic function throughout treatment. (5.6). 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). oCardiac Arrhythmias: Monitor for symptoms of arrhythmias and manage. (5.5). oHepatotoxicity, Including Drug-Induced Liver Injury: Monitor hepatic function throughout treatment. (5.6). 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 29% of 2,055 patients exposed to CALQUENCE in clinical trials, most often due to respiratory tract infections (18% of all patients, including pneumonia in 14%) [see Adverse Reactions (6.1)]. These infections predominantly occurred in the absence of Grade or neutropenia, with neutropenic infection reported in 8% 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.In an additional cohort of patients receiving CALQUENCE in combination with venetoclax with obinutuzumab (AVO) (an unapproved regimen for previously untreated CLL/SLL in AMPLIFY), serious or Grade or higher infections occurred in 25% receiving AVO compared to 14% in patients receiving AV. Fatal infections occurred in 6% receiving AVO compared to 3.1% of patients receiving AV, most commonly due to COVID-19. The safety and effectiveness of AVO has not been established in patients with previously untreated CLL/SLL [see Clinical Studies (14.3)]. 5.2 Hemorrhage Fatal and serious hemorrhagic events have occurred in patients treated with CALQUENCE. Major hemorrhage (serious or Grade or higher bleeding or any central nervous system bleeding) occurred in 4.7% of patients, with fatal hemorrhage occurring in 0.1% of 2,055 patients exposed to CALQUENCE in clinical trials. Bleeding events of any grade, excluding bruising and petechiae, occurred in 39% of patients [see Adverse Reactions (6.1)].Use of antithrombotic agents concomitantly with CALQUENCE may further increase the risk of hemorrhage. In clinical trials, major hemorrhage occurred in 5% of patients taking CALQUENCE without antithrombotic agents and 3.2% 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 to days pre- and post-surgery depending upon the type of surgery and the risk of bleeding.. 5.3 Cytopenias CALQUENCE can cause Grade or cytopenias. Grade or cytopenias included absolute neutrophil count decreased (28%), absolute lymphocyte count decreased (10%), hemoglobin decreased (9%), and platelets decreased (9%) in 1,758 patients treated with CALQUENCE alone and in combination with obinutuzumab or venetoclax; Grade neutropenia developed in 14% [see Adverse Reactions (6.1)].Monitor complete blood counts regularly during treatment. Interrupt treatment, reduce the dose, or discontinue treatment as warranted [see Dosage and Administration (2.3)].. 5.4 Second Primary Malignancies Second primary malignancies, including skin cancers and other solid tumors, occurred in 16% of 2,055 patients exposed to CALQUENCE in clinical trials [see Adverse Reactions (6.1)]. The most frequent second primary malignancy was non-melanoma skin cancer, reported in 9% of patients, followed by other solid tumors in 8% (including melanoma, lung cancer, gastrointestinal cancers, and genitourinary cancers) and hematologic malignancies (1.1%). Fatal second primary malignancies occurred in 0.8% of patients. Monitor patients for the development of second cancers and advise protection from sun exposure.. 5.5 Cardiac Arrhythmias Fatal and serious cardiac arrhythmias have occurred in patients treated with CALQUENCE. Grade or atrial fibrillation or flutter was reported in 2.2% of 2,055 patients treated with CALQUENCE, with all grades of atrial fibrillation or flutter reported in 7% of all patients [see Adverse Reactions (6.1)]. Grade or higher ventricular arrhythmia events were reported in 0.5% of patients, including fatal cases in 0.3% of all patients. The risk of arrhythmias 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.. 5.6 Hepatotoxicity, Including Drug-Induced Liver Injury Hepatotoxicity, including severe, life-threatening, and potentially fatal cases of drug-induced liver injury (DILI), has occurred in patients treated with Bruton tyrosine kinase inhibitors, including CALQUENCE.Evaluate bilirubin and transaminases at baseline and throughout treatment with CALQUENCE. For patients who develop abnormal liver tests after CALQUENCE, monitor more frequently for liver test abnormalities and clinical signs and symptoms of hepatic toxicity. If DILI is suspected, withhold CALQUENCE. Upon confirmation of DILI, discontinue CALQUENCE.