CALQUENCE is indicated for the treatment of adult patients with mantle cell lymphoma (MCL) who have received at least one prior therapy.
CALQUENCE is indicated for the treatment of patients with chronic lymphocytic leukaemia (CLL)/small lymphocytic lymphoma (SLL).

Treatment with CALQUENCE should be initiated and supervised by a physician experienced in the use of anticancer therapies.
 

Posology
MCL
The recommended dose of CALQUENCE for the treatment of MCL is 100 mg (1 capsule) twice daily.

CLL
The recommended dose of CALQUENCE for the treatment of CLL is 100 mg (1 capsule) twice daily, either as monotherapy or in combination with obinutuzumab. Refer to the obinutuzumab prescribing information for recommended obinutuzumab dosing information. (For details of the combination regimen, see section 5.1).

CALQUENCE should be taken orally approximately every twelve hours until disease progression or unacceptable toxicity.

Missed Dose
If a dose of CALQUENCE is missed by more than 3 hours, it should be skipped and the next dose should be taken at its regularly scheduled time. Extra capsules of CALQUENCE should not be taken to make up for a missed dose.

Dose Adjustments
Adverse Reactions
Recommended dose modifications of CALQUENCE for Grade 3 or greater adverse reactions are provided in Table 1.

Table 1: Recommended Dose Modifications for Adverse Reactions

Adverse reactions graded by the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03.

Dose Modifications for Use with CYP3A Inhibitors or Inducers

Recommended dose modifications are described below [see interaction with other medicinal products and other forms of interaction (4.5)].

Concomitant Use with Gastric Acid Reducing Agents
Proton Pump Inhibitors: Avoid concomitant use [see interaction with other medicinal products and other forms of interaction (4.5)].
H2-Receptor Antagonists: Take CALQUENCE 2 hours before taking a H2-receptor antagonist [see interaction with other medicinal products and other forms of interaction (4.5)].Antacids: Separate dosing by at least 2 hours [see interaction with other medicinal products and other forms of interaction (4.5)

Method of Administration
Advise patients to swallow capsule whole with water at approximately the same time each day. Advise patients not to open, break, chew, or dissolve the capsules. CALQUENCE may be taken with or without food.

Special patient populations
Elderly (≥ 65 years)
No dose adjustment is necessary based on age (see section 5.2).

Renal Impairment
No dose adjustment is recommended in patients with mild to moderate renal impairment (eGFR greater than or equal to 30 mL/min/1.73m2 as estimated by MDRD (modification of diet in renal disease equation)). The pharmacokinetics and safety of CALQUENCE in patients with severe renal impairment (eGFR less than 29 mL/min/1.73m2) or end-stage renal disease have not been studied (see section 5.2).

Hepatic Impairment
No dose adjustment is recommended in patients with mild or moderate hepatic impairment (Child-Pugh A, Child-Pugh B, or total bilirubin between 1.5-3 times the upper limit of normal [ULN] and any AST). It is not recommended to administer CALQUENCE in patients with severe hepatic impairment (Child-Pugh C or total bilirubin > 3 times ULN and any AST) (see section 5.2).

Severe Cardiac Disease
Patients with severe cardiovascular disease were excluded from CALQUENCE clinical studies.

Paediatric and adolescents
The safety and efficacy of CALQUENCE in children and adolescents aged less than 18 years have not been established.

Haemorrhage
Fatal and serious hemorrhagic events have occurred in patients with hematologic malignancies treated with CALQUENCE. Major hemorrhage (serious or Grade 3 or higher bleeding or any central nervous system bleeding) occurred in 3.0% of patients, with fatal hemorrhage occurring in 0.1% of 1029 patients exposed to CALQUENCE in clinical trials. Bleeding events of any grade, excluding bruising and petechiae, occurred in 22% of patients.

Use of antithrombotic agents concomitantly with CALQUENCE may further increase the risk of hemorrhage. In clinical trials, major hemorrhage occurred in 2.7% of patients taking CALQUENCE without antithrombotic agents and 3.6% of patients taking CALQUENCE with antithrombotic agents. Consider the risks and benefits of antithrombotic agents when co-administered with CALQUENCE. Monitor patients for signs of bleeding.

Consider the benefit-risk of withholding CALQUENCE for at least 3 days pre- and post-surgery.

Infections
Fatal and serious infections, including opportunistic infections, have occurred in patients with hematologic malignancies treated with CALQUENCE.
Serious or Grade 3 or higher infections (bacterial, viral, or fungal) occurred in 19% of 1029 patients exposed to CALQUENCE in clinical trials, most often due to respiratory tract infections (11% of all patients, including pneumonia in 6%). These infections predominantly occurred in the absence of Grade 3 or 4 neutropenia, with neutropenic infection reported in 1.9% of all patients. Opportunistic infections in recipients of CALQUENCE have included, but are not limited to, hepatitis B 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.

Cytopenias
Grade 3 or 4 cytopenias, including neutropenia (23%), anemia (8%), thrombocytopenia (7%), and lymphopenia (7%), developed in patients with hematologic malignancies treated with CALQUENCE. Grade 4 neutropenia developed in 12% of patients. Monitor complete blood counts regularly during treatment. Interrupt treatment, reduce the dose, or discontinue treatment as warranted [see Posology and method of adminstration (4.2)].
Second Primary Malignancies
Second primary malignancies, including skin cancers and other solid tumors, occurred in 12% of 1029 patients exposed to CALQUENCE in clinical trials. The most frequent second primary malignancy was skin cancer, reported in 6% of patients. Monitor patients for skin cancers and advise protection from sun exposure.

Atrial Fibrillation and Flutter
Grade 3 atrial fibrillation or flutter occurred in 1.1% of 1029 patients treated with CALQUENCE, with all grades of atrial fibrillation or flutter reported in 4.1% of all patients. The risk may be increased in patients with cardiac risk factors, hypertension, previous arrhythmias, and acute infection. Monitor for symptoms of arrhythmia (e.g., palpitations, dizziness, syncope, dyspnea) and manage as appropriate.

Active substances whose plasma concentrations may be altered by CALQUENCE

Active substances whose plasma concentrations may be altered by CALQUENCE

CYP3A Substrates

Based on in vitro data and PBPK modeling, no interaction with CYP substrates is expected at clinically relevant concentrations (see section 5.2).

Effects of Acalabrutinib and its active metabolite, ACP-5862, on Drug Transport Systems

Acalabrutinib may increase exposure to co-administered Breast Cancer Resistance Protein (BCRP) substrates (e.g., methotrexate) by inhibition of intestinal BCRP. (see section 5.2)
ACP-5862 may increase exposure to co-administered MATE1 substrates (e.g., metformin) by inhibition of MATE1 (see section 5.2).

Effect of food on acalabrutinib

In healthy subjects, administration of a single 75 mg dose of acalabrutinib (0.75 times the approved recommended single dose) with a high-fat, high-calorie meal (approximately 918 calories, 59 grams carbohydrate, 59 grams fat, and 39 grams protein) did not affect the mean AUC as compared to dosing under fasted conditions. Resulting Cmax decreased by 73% and Tmax was delayed 1-2 hours.

Pregnancy
Risk Summary

Based on findings in animals, CALQUENCE may cause fetal harm when administered to a pregnant woman. There are no available data in pregnant women to inform the drug-associated risk. In animal reproduction studies, administration of acalabrutinib to pregnant rabbits during organogenesis resulted in reduced fetal growth at maternal exposures (AUC) approximately 4 times exposures in patients at the recommended dose of 100 mg twice daily (see Data). Advise pregnant women of the potential risk to a fetus.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

Data
Animal Data

In a combined fertility and embryo-fetal development study in female rats, acalabrutinib was administered orally at doses up to 200 mg/kg/day starting 14 days prior to mating through gestational day [GD] 17. No effects on embryo-fetal development and survival were observed. The AUC at 200 mg/kg/day in pregnant rats was approximately 16-times the AUC in patients at the recommended dose of 100 mg twice daily. 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 4-times the AUC in patients at 100 mg twice daily. Dystocia was observed in a rat study involving dosing animals from implantation throughout gestation, parturition and lactation at exposures > 2.3-times the human AUC at the recommended dose (see section 5.3)

Lactation
Risk Summary

No data are available regarding the presence of acalabrutinib or its active metabolite in human milk, its effects on the breastfed child, or on milk production. Acalabrutinib and its active metabolite were present in the milk of lactating rats. Due to the potential for adverse reactions in a breastfed child from CALQUENCE, advise lactating women not to breastfeed while taking CALQUENCE and for at least 2 days after the final dose.

Fertility
There are no data on the effect of Calquence on human fertility. In a non-clinical study of acalabrutinib in male and female rats, no adverse effects on fertility parameters were observed (see section 5.3).

CALQUENCE has no or negligible influence on the ability to drive and use machines. However, during treatment with acalabrutinib fatigue and dizziness have been reported and patients who experience these symptoms should observe caution when driving or using machines.

Overall Summary of Adverse Drug Reactions

The overall safety profile of acalabrutinib is based on pooled data from 1040 patients with haematologic malignancies receiving acalabrutinib monotherapy.

The most common (≥ 20%) adverse drug reactions (ADRs) of any grade reported in patients receiving acalabrutinib were infection, headache, diarrhoea, bruising, musculoskeletal pain, nausea, fatigue, and rash.

The most commonly reported (≥ 5%) Grade ≥ 3 adverse drug reactions were infection (17.6%), leuokopenia (16.2%), neutropenia (14.2%) and anaemia (7.8%). Dose reductions due to adverse events were reported in 4.2% of patients. Discontinuation due to adverse events were reported in 9.3% of the patients. The median dose intensity was 98.7%.

Tabulated list of adverse reactions

The following adverse drug reactions (ADRs) have been identified in clinical studies with patients receiving CALQUENCE monotherapy as treatment for haematological malignancies. The median duration of acalabrutinib monotherapy treatment across the pooled dataset was 24.6months.

Adverse drug reactions are listed according to system organ class (SOC) in MedDRA. Within each system organ class, the adverse drug reactions are sorted by frequency, with the most frequent reactions first. In addition, the corresponding frequency category for each ADR is based on the CIOMS III convention and is defined as: very common (≥1/10); common (>1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1000); very rare (<1/10,000); not known (cannot be estimated from available data).

Table 3. Adverse drug reactions* of patients with haematological malignancies treated with acalabrutinib monotherapy (n=1040)

*Per National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03.
†Includes multiple ADR term
±One case of drug-induced Tumour Lysis Syndrome was observed in acalabrutinib arm in the ASCEND Study

Table 4. Treatment-emergent haematological laboratory abnormalities for acalabrutinib monotherapy (n=1040)

Per National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03.

Special populations
Elderly
Of the 1040 patients in clinical trials of CALQUENCE monotherapy, 41% were greater than 65 years of age and less than 75 years of age, and 22% were 75 years of age or older. No clinically relevant differences in safety or efficacy were observed between patients ≥ 65 years and younger.

There is no specific treatment for acalabrutinib overdose and symptoms of overdose have not been established. In the event of an overdose, patients must be closely monitored for signs or symptoms of adverse reactions and appropriate symptomatic treatment instituted.

Pharmacotherapeutic group: acalabrutinib , ATC code (L01EL02)

Mechanism of action

Acalabrutinib is a small-molecule inhibitor of BTK. Acalabrutinib and its active metabolite, ACP-5862, form a covalent bond with a cysteine residue in the BTK active site, leading to inhibition of BTK enzymatic activity. BTK is a signaling molecule of the B cell antigen receptor (BCR) and cytokine receptor pathways. In B cells, BTK signaling results in activation of pathways necessary for B-cell proliferation, trafficking, chemotaxis, and adhesion. In nonclinical
studies, acalabrutinib inhibited BTK-mediated activation of downstream signaling proteins CD86 and CD69 and inhibited malignant B-cell proliferation and. growth in mouse xenograft models.

Pharmacodynamic effects
In patients with B-cell malignancies dosed with 100 mg twice daily, median steady state BTK occupancy of ≥ 95% in peripheral blood was maintained over 12 hours, resulting in inactivation of BTK throughout the recommended dosing interval.

Cardiac Electrophysiology
The effect of acalabrutinib on the QTc interval was evaluated in a randomized, double-blind, double-dummy, placebo- and positive-controlled, 4-way crossover thorough QTc study in 48 healthy adult subjects. Administration of a 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).

Clinical efficacy and safety in patients
MCL
The safety and efficacy of CALQUENCE in MCL were evaluated in an open-label, multi-centre, single-arm Phase 2 study (ACE-LY-004) of 124 previously treated patients. All patients received CALQUENCE 100 mg orally twice daily until disease progression or unacceptable toxicity. The trial did not include patients who received prior treatment with BTK inhibitors. The primary endpoint was investigator-assessed overall response rate (ORR) per the Lugano classification for non-Hodgkin’s lymphoma (NHL). Duration of Response (DoR) was an additional outcome measure. Efficacy results are presented in Table5.

The median age was 68 (range 42 to 90) years, 79.8% were male and 74.2% were Caucasian. At baseline, 92.8% of patients had an ECOG performance status of 0 or 1. The median time since diagnosis was 46.3 months and the median number of prior treatments was 2 (range 1 to 5), including 17.7% with prior stem cell transplant. The most common prior regimens were CHOP- based (51.6%) and ARA-C (33.9%). At baseline, 37.1% of patients had at least one tumour with a longest diameter ≥ 5 cm, 72.6% had extra nodal involvement including 50.8% with bone marrow involvement. The simplified MIPI score (which includes age, ECOG score, and baseline lactate dehydrogenase and white cell count) was intermediate in 43.5% and high in 16.9% of patients.]

Table 5. Overall Response Rate and Duration of Response in (ACE-LY-004) Patients with MCL

CI=Confidence Interval; NR = Not Reached
*95% exact binomial confidence interval.
†Includes subjects without any adequate post-baseline disease assessment.

Based on investigator assessment, 92% of responders achieved a response by cycle 2, with a median time to documented response of 1.9 months. The median DoR had not been reached at
15.2 months median follow-up from treatment initiation. Seventy two percent (72%) of patients had an ongoing response at 12 months per Kaplan-Meier estimate. The ORR was consistent across all pre-specified subgroups including age, performance status, disease stage, and number of prior therapies.

CLL
Patients with Previously Untreated CLL

The safety and efficacy of CALQUENCE in previously untreated CLL were evaluated in a randomised, multi-centre, open-label Phase 3 study (ELEVATE-TN) of 535 patients. Patients received CALQUENCE plus obinutuzumab, CALQUENCE monotherapy, or obinutuzumab plus chlorambucil. Patients 65 years of age or older or between 18 and 65 years of age with coexisting medical conditions were included in ELEVATE-TN. The trial also allowed patients to receive antithrombotic agents other than warfarin or equivalent vitamin K antagonists.

Patients were randomised in a 1:1:1 ratio into 3 arms to receive

• CALQUENCE plus obinutuzumab (CALQUENCE+G): CALQUENCE 100 mg was administered twice daily starting on Cycle 1 Day 1 until disease progression or unacceptable toxicity. Obinutuzumab was administered starting on Cycle 2 Day 1 for a maximum of 6 treatment cycles. Obinutuzumab 1000 mg was administered on Days 1 and 2 (100 mg on Day 1 and 900 mg on Day 2), 8 and 15 of Cycle 2 followed by 1000 mg on Day 1 of Cycles 3 up to 7. Each cycle was 28 days.
• CALQUENCE monotherapy: CALQUENCE 100 mg was administered twice daily until disease progression or unacceptable toxicity.
• Obinutuzumab plus chlorambucil (GClb): Obinutuzumab and chlorambucil were administered for a maximum of 6 treatment cycles. Obinutuzumab 1000 mg was administered on Days 1 and 2 (100 mg on Day 1 and 900 mg on Day 2), 8 and 15 of Cycle 1 followed by 1000 mg on Day 1 of Cycles 2 up to 6. Chlorambucil 0.5 mg/kg was administered on Days 1 and 15 of Cycles 1 up to 6. Each cycle was 28 days.

Patients were stratified by 17p deletion mutation status (presence versus absence), ECOG performance status (0 or 1 versus 2) and geographic region (North America and Western Europe versus Other). After confirmed disease progression, 45 patients randomised on the GClb arm crossed over to CALQUENCE monotherapy.
 

Table 6 summarizes the baseline demographics and disease characteristics of the study population.

Table 6. Baseline Patient Characteristics in (ELEVATE-TN) Patients with Previously Untreated CLL

The primary endpoint was progression-free survival (PFS) as assessed by an Independent Review Committee (IRC) per International Workshop on Chronic Lymphocytic Leukaemia (IWCLL) 2008 criteria with incorporation of the clarification for treatment-related lymphocytosis (Cheson 2012). With a median follow-up of 28.3 months, PFS by IRC indicated a 90% statistically significant reduction in the risk of disease progression or death for previously untreated CLL patients in the CALQUENCE+G arm compared to the GClb arm. At the time of analysis, median overall survival had not been reached in any arm with a total of 37 deaths: 9 (5%) in the CALQUENCE+G arm, 11 (6.1%) in the CALQUENCE monotherapy arm, and 17 (9.6%) in the GClb arm. Efficacy results are presented in Table 7. The Kaplan-Meier curves for PFS are shown in Figure 1.

Table 7. Efficacy Results in (ELEVATE-TN) Patients with CLL

CI=confidence interval; HR=hazard ratio; NR=not reached; CR=complete response; CRi=complete response with incomplete blood count recovery; nPR=nodular partial response; PR=partial response; PRL=PR with lymphocytosis; SD=stable disease; PD=progressive disease
*Per IRC assessment
†Based on stratified Cox-Proportional-Hazards model

PFS results for CALQUENCE with or without obinutuzumab were consistent across subgroups, including high risk features. In the high risk CLL population (17p deletion, 11q deletion, TP53 mutation, and unmutated IGHV), the PFS HRs of CALQUENCE with or without obinutuzumab versus obinutuzumab plus chlorambucil was 0.08 [95% CI (0.04, 0.15)] and 0.13 [95% CI (0.08, 0.21)], respectively.

PFS results for CALQUENCE with or without obinutuzumab were consistent across subgroups, including high risk features. In the high risk CLL population (17p deletion, 11q deletion, TP53 mutation, and unmutated IGHV), the PFS HRs of CALQUENCE with or without obinutuzumab versus obinutuzumab plus chlorambucil was 0.08 [95% CI (0.04, 0.15)] and 0.13 [95% CI (0.08, 0.21)], respectively.

Patients with CLL who received at least one prior therapy
The safety and efficacy of CALQUENCE in relapsed or refractory CLL were evaluated in a randomised, multi-centre, open-label phase 3 study (ASCEND) of 310 patients who received at least one prior therapy. Patients received CALQUENCE monotherapy or investigator’s choice of either idelalisib plus rituximab or bendamustine plus rituximab. The trial allowed patients to receive antithrombotic agents other than warfarin or equivalent vitamin K antagonists.

Patients were randomised 1:1 to receive either:
• CALQUENCE 100 mg twice daily until disease progression or unacceptable toxicity, or
• Investigator’s choice:

o Idelalisib 150 mg twice daily until disease progression or unacceptable toxicity in combination with ≤ 8 infusions of rituximab (375 mg/m2/500 mg/m2) on Day 1 of each 28-day cycle for up to 6 cycles
o Bendamustine 70 mg/m2 (Day 1 and 2 of each 28-day cycle) in combination with rituximab (375 mg/m2/500 mg/m2) on Day 1 of each 28-day cycle for up to 6 cycles.

Patients were stratified by 17p deletion mutation status (presence versus absence), ECOG performance status (0 or 1 versus 2) and number of prior therapies (1 to 3 versus ≥ 4). After confirmed disease progression, 35 patients randomised on investigator’s choice of either idelalisib plus rituximab or bendamustine plus rituximab crossed over to CALQUENCE. Table 8 summarizes the baseline demographics and disease characteristics of the study population.

Table 8. Baseline patient characteristics in (ASCEND) patients with CLL

The primary endpoint was PFS as assessed by IRC IWCLL 2008 criteria with incorporation of the clarification for treatment-related lymphocytosis (Cheson 2012). With a median follow-up of 16.1 months, PFS indicated a 69% statistically significant reduction in the risk of death or progression for patients in the CALQUENCE Arm. At the time of analysis, median overall survival had not been reached in any arm with a total of 33 deaths: 15 (9.7%) in the CALQUENCE monotherapy arm and 18 (11.6%) in the investigator’s choice of either idelalisib plus rituximab or bendamustine plus rituximab arm. Efficacy results are presented in Table 9. The Kaplan-Meier curve for PFS is shown in Figure 2.

Table 9. Efficacy results per IRC Assessments in (ASCEND) patients with CLL

With long term data, the median follow-up was 22.1 months for Calquence and 21.9 months for the IR/BR. The median PFS was not reached in Calquence and was 16.8 months in IR/BR. The hazard ratio of INV-assessed PFS of Calquence compared with IR/BR was 0.27 [95% CI, 0.18 to 0.40] representing a 73% reduction in the risk of death or progression for patients in the Calquence arm. Efficacy results per Investigator Assessments (INV) are presented in Table 10.

Acalabrutinib exhibits dose-proportionality, and both acalabrutinib and its active metabolite, ACP-5862, exposures increase with dose across a 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%) ng•h/mL and 563 (29%) ng/mL, respectively, and for ACP-5862 were 3947 (43%) ng•h/mL and 451 (52%) ng/mL, respectively.

Absorption
The 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.

Distribution
Reversible 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%) L for acalabrutinib and 67 (32%) L for ACP-5862.

Biotransformation/Metabolism
Acalabrutinib is predominantly metabolized by CYP3A enzymes, and to a minor extent, by glutathione conjugation and amide hydrolysis, based on in vitro studies. ACP-5862 was identified as the major active metabolite in plasma with a geometric mean exposure (AUC) that was approximately 2- to 3-fold higher than the exposure of acalabrutinib. ACP-5862 is approximately 50% less potent than acalabrutinib with regard to BTK inhibition.

Elimination
The geometric mean (% CV) terminal elimination half-life (t1/2) was 1 (59%) hour for acalabrutinib and 3.5 (24%) hours for ACP-5862. The geometric mean (%CV) apparent oral clearance (CL/F) was 71 (35%) L/hr for acalabrutinib and 13 (42%) L/hr for ACP-5862. Following administration of a 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.

Pharmacokinetics in Special Populations
Age, Race, and Body Weight
Age (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 Impairment
No clinically relevant PK difference was observed in patients with mild or moderate renal impairment (eGFR ≥ 30 mL/min/1.73m2, as estimated by MDRD (modification of diet in renal disease equation)). Acalabrutinib PK has not been evaluated in patients with severe renal impairment (eGFR < 29 mL/min/1.73m2, MDRD) or renal impairment requiring dialysis.

Hepatic Impairment
The AUC of acalabrutinib increased 1.9-fold in subjects with mild hepatic impairment (Child-Pugh class A), 1.5-fold in subjects with moderate hepatic impairment (Child-Pugh class B) and 5.3-fold in subjects with severe hepatic impairment (Child-Pugh class C) compared to subjects with normal liver function. No clinically relevant PK difference in ACP-5862 was observed in subjects with severe hepatic impairment (Child-Pugh Class C) compared to subjects with normal liver function. No clinically relevant PK differences in acalabrutinib and ACP-5862 were observed in patients with mild or moderate hepatic impairment (total bilirubin less and equal to upper limit of normal [ULN] and AST greater than ULN, or total bilirubin greater than ULN and any AST) relative to patients with normal hepatic function (total bilirubin and AST within ULN).

Drug Interaction Studies
Effect of CYP3A Inhibitors on Acalabrutinib
Co-administration with a strong CYP3A inhibitor (200 mg itraconazole once daily for 5 days) increased acalabrutinib Cmax by 3.7-fold and AUC by 5.1-fold in healthy subjects (N=17).

Effect of CYP3A Inducers on Acalabrutinib
When accounting for both acalabrutinib and its active metabolite, ACP-5862, PBPK simulations with strong CYP3A inducers showed a 21-51% decrease in total AUC of active components. Simulations with a moderate CYP3A inducer (efavirenz) showed a 25% decrease in total AUC of active components.

Gastric Acid Reducing Agents
Acalabrutinib solubility decreases with increasing pH. Co-administration with an antacid (1 g calcium carbonate) decreased acalabrutinib AUC by 53% in healthy subjects. Co-administration with a proton pump inhibitor (40 mg omeprazole for 5 days) decreased acalabrutinib AUC by 43% [see interaction with other medicinal products and other forms of interaction (4.5)].

In Vitro Studies

Metabolic Pathways
Acalabrutinib is a weak inhibitor of CYP3A4/5, CYP2C8 and CYP2C9, but does not inhibit CYP1A2, CYP2B6, CYP2C19, CYP2D6. UGT1A1, and UGT2B7 ACP-5862 is a weak inhibitor of CYP2C8, CYP2C9 and CYP2C19, but does not inhibit CYP1A2, CYP2B6, CYP2D6 ,CYP3A4/5 , UGT1A1, and UGT2B7.

Acalabrutinib is a weak inducer of CYP1A2, CYP2B6 and CYP3A4; ACP-5862 weakly induces CYP3A4.

Drug Transporter Systems
Acalabrutinib and its active metabolite, ACP-5862, are substrates of P-glycoprotein (P-gp) breast cancer resistance protein and BCRP. Acalabrutinib is not a substrate of renal uptake transporters OAT1, OAT3, and OCT2, or hepatic transporters OATP1B1, and OATP1B3. ACP-5862 is not a substrate of OATP1B1 or OATP1B3. ACP-5862 is not a 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 inhibit intestinal BCRP substrates (see section 4.5), while ACP-5862 may inhibit MATE1 (see Section 4.5) at clinically relevant concentrations. Acalabrutinib does not inhibit MATE1, while ACP-5862 does not inhibit BCRP at clinically relevant concentrations.

Carcinogenicity
Carcinogenicity studies have not been conducted with acalabrutinib.

Genotoxicity/Mutagenicity
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.

Repeat-dose toxicity
Daily oral administration of acalabrutinib for up to 6 months duration in rats and 9 months in dogs was tolerated at exposure levels that exceed human therapeutic exposures at the recommended dose ( 2.5-fold in rats, 8.2-fold in dogs, based on AUC).

In rats, renal effects including tubular degeneration were observed at exposures 7 times or greater than that of the recommended human dose. Renal effects were reversible with complete recovery in rats exposed at levels 4.2 times the recommended human dose and partial recovery in rats at the higher exposures ( 6.8-fold or greater).

In rats, dose-responsive reversible liver findings including individual hepatocyte necrosis were observed after exposures 4.2 times or greater than that of the recommended human dose.

Cardiac toxicities (myocardial haemorrhage, inflammation, necrosis) were observed in rats that died during the study and at exposures equivalent to 6.8 times or greater than that of the human recommended dose. Reversibility for the heart findings could not be assessed as these findings were only observed at doses above the maximum tolerated dose (MTD). At exposures representing 4.2 times the human recommended dose, no cardiac toxicities were observed.

Reproductive toxicology
No effects on fertility were observed in male or female rats at exposures 10 or 9 times the human AUC exposure at the recommended dose, respectively.

In a combined fertility and embryofoetal 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 embryofoetal 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 twice daily. The presence of acalabrutinib and its active metabolite were confirmed in foetal rat plasma.

In an embryofoetal study in pregnant rabbits, acalabrutinib was administered orally at doses up to 200 mg/kg/day during the period of organogenesis (from GD 6-18). Acalabrutinib produced no maternal toxicity and no evidence of teratogenicity or foetal development, growth, or survival at doses of 50 mg/kg/day (approximately equivalent to the human AUC exposure at the recommended dose). Decreased foetal body weight and delayed ossification were observed at exposure levels that produced maternal toxicity (doses ≥ 100 mg/kg/day), which were 2.4-times greater than the human exposure levels at the recommended dose.

In a rat reproductive study, dystocia (prolonged /difficult labour) was observed at exposures > 2.3-times the clinical exposure at 100 mg twice daily.

Capsule Content: microcrystalline cellulose, colloidal silicon dioxide, partially pregelatinized starch (maize), magnesium stearate (E572), and sodium starch glycolate (Type A).

Capsule Shell: gelatine, titanium dioxide (E171), yellow iron oxide (E172), and FD&C Blue 2 (Indigotine/Indigo carmine) (E132).

Printing Ink: Shellac, black iron oxide (E172), propylene glycol (E1520), ammonium hydroxide.

Not applicable

Do Not Store Above 30°C.

Aluminium /Aluminium blisters. Cartons of 6 x 10 capsules.
Pack sizes may vary by market.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.