Calquens

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT KALQVENZ (CALQUENCE®)

Composition:

Active substance: acalabrutinib;

1 hard capsule contains: acalabrutinib 100 mg;

Excipients: siliconized microcrystalline cellulose; partially pregelatinized starch; sodium starch glycolate, type A; magnesium stearate;

composition of the hard gelatin capsule shell: shell (gelatin, iron oxide yellow (E 172), indigotine – FD&C Blue 2 (E 132), titanium dioxide (E 171)); printing ink (shellac glaze – 45% (20% esterified) in ethanol, iron oxide black (E 172), propylene glycol, ammonium hydroxide 28%).

Pharmaceutical form. Hard capsules.

Main physicochemical characteristics: hard capsule size №1 with an opaque blue cap and an opaque yellow body, with black print “ACA100mg”.

Pharmacotherapeutic group.

Antineoplastic agents, protein kinase inhibitors. Acalabrutinib. ATC code L01EL02.

Pharmacological Properties

Pharmacodynamics

Mechanism of action

Acalabrutinib is a selective, low-molecular-weight inhibitor of Bruton's tyrosine kinase (BTK). BTK is a signaling molecule for B-cell antigen receptors (BCR) and cytokine receptors. In B-cells, BTK-mediated signaling promotes B-cell survival and proliferation and is essential for cellular adhesion, migration, and chemotaxis.

Acalabrutinib and its active metabolite, ACP-5862, form a covalent bond with the cysteine residue in the active site of BTK, resulting in irreversible inactivation of BTK with minimal off-target interactions.

Pharmacodynamic effect

In patients with B-cell lymphoproliferative disorders receiving acalabrutinib at a dose of 100 mg twice daily, the median BTK occupancy in peripheral blood at steady state was ≥ 95%, maintained for over 12 hours, resulting in sustained BTK inactivation throughout the recommended dosing interval.

Cardiac electrophysiology

The effect of acalabrutinib on the QTc interval was evaluated in 46 healthy men and women in a randomized, double-blind, placebo- and positive-controlled thorough QT study. At a supratherapeutic dose four times higher than the maximum recommended dose, Calquence did not result in a clinically meaningful increase in QT/QTc interval (e.g., exceeding or equaling 10 ms) (see sections "Special precautions for use" and "Adverse reactions").

Clinical efficacy and safety

Patients with previously untreated chronic lymphocytic leukemia (CLL)

The safety and efficacy of Calquence for the treatment of previously untreated CLL were evaluated in a randomized, multicenter, open-label Phase 3 study (ELEVATE-TN) involving 535 patients. Patients were assigned to one of the following treatment regimens: Calquence + obinutuzumab, Calquence monotherapy, or obinutuzumab + chlorambucil. The ELEVATE-TN study included patients aged 65 years or older, or patients aged 18 to 65 years with comorbid conditions; 27.9% of patients had a creatinine clearance (CrCl) < 60 mL/min. Among patients aged 18 to 65 years (16.1% of total), the mean CIRS-G score was 8. Study participants were permitted to take antithrombotic medications. Patients requiring anticoagulation therapy with warfarin or similar vitamin K antagonists were excluded from the study.

Patients were randomized in a 1:1:1 ratio into three groups and received:

• Calquence + obinutuzumab (Calquence + O): Calquence was administered at a dose of 100 mg twice daily starting on day 1 of cycle 1 until disease progression or unacceptable toxicity. Obinutuzumab was administered starting on day 1 of cycle 2 for up to 6 cycles of therapy. Obinutuzumab was given at 1000 mg on days 1 and 2 (100 mg on day 1 and 900 mg on day 2), days 8 and 15 of cycle 2, and then on day 1 of cycles 3–7. Each cycle lasted 28 days.
• Calquence monotherapy: Calquence was administered at a dose of 100 mg twice daily until disease progression or unacceptable toxicity.
• Obinutuzumab + chlorambucil (O + C): obinutuzumab and chlorambucil were administered for up to 6 cycles of therapy. Obinutuzumab was given at 1000 mg on days 1 and 2 (100 mg on day 1 and 900 mg on day 2), days 8 and 15 of cycle 1, and then on day 1 of cycles 2–6. Chlorambucil was administered at 0.5 mg/kg on days 1 and 15 of cycles 1–6. Each cycle lasted 28 days.

Patients were stratified by 17p deletion mutation status (presence or absence), ECOG performance status (0 or 1 vs. 2), and geographic region (North America and Western Europe vs. other regions). After confirmed disease progression, 45 patients originally randomized to the O + C group crossed over to Calquence monotherapy. Table 1 presents the key demographic and disease characteristics of the study population.

Table 1

Baseline characteristics of patients with previously untreated CLL (in the ELEVATE-TN study)

Characteristic	Calquence + obinutuzumab N = 179	Calquence as monotherapy N = 179	Obinutuzumab + chlorambucil N = 177
Median age in years (range)	70 (41–88)	70 (44–87)	71 (46–91)
Male, %	62	62	59.9
Caucasian race, %	91.6	95	93.2
ECOG performance status 0-1, %	94.4	92.2	94.4
Median time since diagnosis (months)	30.5	24.4	30.7
Generalized lymphadenopathy with nodes ≥ 5 cm, %	25.7	38	31.1
Cytogenetic profile/ chromosomal abnormality assessed by fluorescence in situ hybridization (FISH), %
Chromosome 17p deletion	9.5	8.9	9
Chromosome 11q deletion	17.3	17.3	18.6
TP53 gene mutation	11.7	10.6	11.9
Unmutated immunoglobulin heavy-chain variable region gene	57.5	66.5	65.5
Complex karyotype (≥ 3 abnormalities)	16.2	17.3	18.1
Rai stage of CLL, %
0	1.7	0	0.6
I	30.2	26.8	28.2
II	20.1	24.6	27.1
III	26.8	27.9	22.6
IV	21.2	20.7	21.5

The primary endpoint was progression-free survival (PFS) of patients receiving Calquence + O compared to patients receiving O + Chl, as assessed by an Independent Review Committee (IRC) according to the 2008 International Workshop on Chronic Lymphocytic Leukemia (IWCLL) criteria, including clarification regarding treatment-related lymphocytosis (Cheson 2012). With a median follow-up of 28.3 months, PFS of previously untreated CLL patients assessed by IRC in the Calquence + O group demonstrated a statistically significant 90% reduction in the risk of disease progression or death compared to the O + Chl combination group. Efficacy results are presented in Table 2.

Table 2

Efficacy of treatment in patients with CLL as assessed by IRC (in the ELEVATE-TN study)

	Calquence + obinutuzumab N = 179	Calquence as monotherapy N = 179	Obinutuzumab + chlorambucil N = 177
Progression-free survival *
Number of events (%)	14 (7.8)	26 (14.5)	93 (52.5)
PD, n (%)	9 (5)	20 (11.2)	82 (46.3)
Deaths (%)	5 (2.8)	6 (3.4)	11 (6.2)
Median (95% CI), months	NR	NR (34.2, NR)	22.6 (20.2, 27.6)
HR† (95% CI)	0.10 (0.06, 0.17)	0.20 (0.13, 0.30)	-
P-value	< 0.0001	< 0.0001	-
Estimated at 24 months, % (95% CI)	92.7 (87.4, 95.8)	87.3 (80.9, 91.7)	46.7 (38.5, 54.6)
Overall survivala
Deaths (%)	9 (5)	11 (6.1)	17 (9.6)
Hazard ratio (95% CI)†	0.47 (0.21, 1.06)	0.60 (0.28, 1.27)	-
Best overall response rate * (CR + CRi + PR + PRi)
ORR, n (%)	168 (93.9)	153 (85.5)	139 (78.5)
(95% CI)	(89.3, 96.5)	(79.6, 89.9)	(71.9, 83.9)
P-value	< 0.0001	0.0763	-
CR, n (%)	23 (12.8)	1 (0.6)	8 (4.5)
CRi, n (%)	1 (0.6)	0	0
PRi, n (%)	1 (0.6)	2 (1.1)	3 (1.7)
PR, n (%)	143 (79.9)	150 (83.8)	128 (72.3)

CI – confidence interval; HR – hazard ratio; NR – not reached; PR with incomplete blood count recovery – partial response with incomplete blood count recovery; nPR – nodular partial response; PR – partial response.

*Assessed by IRC.

†Based on stratified Cox proportional hazards model.

aMedian PFS was not reached in either group.

PFS results for regimens including Calquence with or without obinutuzumab were consistent across all subgroups, including subgroups with high-risk features. In the high-risk CLL population (with 17p deletion, 11q deletion, TP53 gene mutation, and unmutated immunoglobulin heavy-chain variable gene), HR for PFS for regimens including Calquence with or without obinutuzumab was 0.08 [95% CI (0.04, 0.15)] compared to 0.13 [95% CI (0.08, 0.21)] for obinutuzumab + chlorambucil regimen.

Table 3

PFS analysis in subgroups (in the ELEVATE-TN study)

	Calquence as monotherapy			Calquence+O
	N	Risk ratio	95% CI	N	Risk ratio	95% CI
All	179	0.20	(0.13; 0.30)	179	0.10	(0.06, 0.17)
patients
17p deletion Yes	19	0.20	(0.06; 0.64)	21	0.13	(0.04, 0.46)
No	160	0.20	(0.12, 0.31)	158	0.09	(0.05, 0.17)
TP53 gene mutation Yes	19	0.15	(0.05, 0.46)	21	0.04	(0.01, 0.22)
No	160	0.20	(0.12, 0.32)	158	0.11	(0.06, 0.20)
17p deletion and/or TP53 mutation Yes	23	0.23	(0.09, 0.61)	25	0.10	(0.03, 0.34)
No	156	0.19	(0.11; 0.31)	154	0.10	(0.05, 0.18)
Immunoglobulin heavy chain variable gene mutation	58	0.69	(0.31, 1.56)	74	0.15	(0.04, 0.52)
Without mutation	119	0.11	(0.07, 0.19)	103	0.08	(0.04, 0.16)
11q deletion Yes No	31 148	0.07 0.26	(0.02, 0.22) (0.16, 0.41)	31 148	0.09 0.10	(0.03, 0.26) (0.05, 0.20)
Complex karyotype Yes No	31 117	0.10 0.27	(0.03, 0.33) (0.16, 0.46)	29 126	0.09 0.11	(0.03, 0.29) (0.05, 0.21)

In the long-term data, the median follow-up was 58.2 months for the Calquence + O group, 58.1 months for the Calquence monotherapy group, and 58.2 months for the O + ChL group. The median PFS assessed by the investigator was not reached for the Calquence + O group and the Calquence monotherapy group, and was 27.8 months in the O + ChL group. At the time of the last data cutoff, a total of 72 patients (40.7%) initially randomized to receive O + ChL had switched to Calquence monotherapy. The median overall survival was not reached in any group; the total number of deaths was 76: 18 (10.1%) in the Calquence + O group, 30 (16.8%) in the Calquence monotherapy group, and 28 (15.8%) in the O + ChL group.

Table 4

Investigator-assessed efficacy results in patients with CLL
(in the ELEVATE-TN study)

	Calquence + obinutuzumab N=179	Calquence as monotherapy N=179	Obinutuzumab + chlorambucil N=177
Progression-free survival
Number of events (%)	27 (15.1)	50 (27.9)	124 (70.1)
PD, n (%)	14 (7.8)	30 (16.8)	112 (63.3)
Deaths (%)	13 (7.3)	20 (11.2)	12 (6.8)
Median (95% CI), months*	NR	NR (66.5, NR)	27.8 (22.6, 33.2)
HR† (95% CI)	0.11 (0.07, 0.16)	0.21 (0.15, 0.30)	-
Overall survival
Deaths (%)	18 (10.1)	30 (16.8)	28 (15.8)
Hazard ratio (95% CI)	0.55 (0.30, 0.99)	0.98 (0.58, 1.64)	-

CI – confidence interval; HR – hazard ratio; NR – not reached; PD – progressive disease.

* 95% confidence interval based on Kaplan-Meier estimate.

† Estimate based on stratified Cox proportional hazards model for hazard ratio (95% CI), stratified by 17p deletion status (yes or no).

Figure 1. Kaplan-Meier curve for PFS by investigator assessment in patients with CLL (ITT population) (in the ELEVATE-TN study)

Time from randomization (months)

Month	0	3	6	9	12	15	18	21	24	27	30	33	36	39	42	45	48	51	54	57	60	63	66	69	70
Calquens	179	167	163	158	156	155	153	150	149	146	142	141	137	135	133	130	129	124	120	93	63	39	22	6	1
Calquens+O	179	175	170	168	164	163	160	157	156	156	153	152	151	146	144	141	140	138	133	99	65	39	27	7	1
O+CHL	177	163	156	153	139	125	110	100	86	82	67	66	56	49	44	40	38	31	30	20	13	8	7	2	0

Patients with CLL who received at least one prior line of therapy

The safety and efficacy of Calquence for the treatment of relapsed or refractory CLL were evaluated in a randomized, multicenter, open-label, phase 3 study (ASCEND) involving 310 patients who had received at least one prior line of therapy that did not include BCL-2 inhibitors or B-cell receptor inhibitors. Patients were randomized to receive one of the following treatment regimens: Calquence as monotherapy or investigator’s choice of idelalisib plus rituximab or bendamustine plus rituximab. Participants in the study were permitted to take antithrombotic agents. Patients requiring anticoagulation therapy with warfarin or similar vitamin K antagonists were excluded from the study.

Patients were randomized in a 1:1 ratio and received:

• Calquence 100 mg twice daily until disease progression or unacceptable toxicity, or
• Investigator’s choice of:
  • Idelalisib 150 mg twice daily in combination with rituximab 375 mg/m² intravenously on day 1 of cycle 1, followed by 500 mg/m² intravenously every 2 weeks for 4 doses, then every 4 weeks for 3 additional doses, for a total of 8 infusions, or
  • Bendamustine 70 mg/m² (on days 1 and 2 of each 28-day cycle) in combination with rituximab (375 mg/m² or 500 mg/m²) on day 1 of each 28-day cycle for up to 6 cycles.

Patients were stratified by 17p deletion mutation status (present or absent), ECOG performance status (0 or 1 vs. 2), and number of prior lines of therapy (1–3 vs. ≥4). After confirmed disease progression, 35 patients randomized to investigator’s choice of idelalisib plus rituximab or bendamustine plus rituximab crossed over to Calquence monotherapy. Table 5 presents the key demographic and disease characteristics of the study population.

Table 5

Baseline characteristics of patients with CLL (in the ASCEND study)

Characteristic	Calquence as monotherapy N = 155	Idelalisib + rituximab or bendamustine + rituximab at investigator's choice N = 155
Median age in years (range)	68 (32–89)	67 (34–90)
Male, %	69.7	64.5
White race, %	93.5	91.0
ECOG performance status, %
0	37.4	35.5
1	50.3	51.0
2	12.3	13.5
Median time since diagnosis (months)	85.3	79.0
Generalized lymphadenopathy with nodes ≥ 5 cm, %	49.0	48.4
Median number of prior CLL treatment regimens received (range)	1 (1–8)	2 (1–10)
Number of prior CLL treatment regimens received, %
1	52.9	43.2
2	25.8	29.7
3	11.0	15.5
≥ 4	10.3	11.6
Cytogenetic profile/chromosomal abnormality assessed by fluorescence in situ hybridization (FISH), %
Chromosome 17p deletion	18.1	13.5
Chromosome 11q deletion	25.2	28.4
TP53 gene mutation	25.2	21.9
Unmutated immunoglobulin heavy-chain variable region gene	76.1	80.6
Complex karyotype (≥ 3 abnormalities)	32.3	29.7
Rai stage of CLL, %
0	1.3	2.6
I	25.2	20.6
II	31.6	34.8
III	13.5	11.6
IV	28.4	29.7

The primary endpoint was PFS assessed by IRC according to the criteria of the International Workshop on Chronic Lymphocytic Leukemia (IWCLL) held in 2008, including clarification regarding treatment-related lymphocytosis (Cheson 2012). With a median follow-up of 16.1 months, PFS demonstrated a statistically significant 69% reduction in the risk of death or disease progression in patients receiving Calquence. Efficacy results are presented in Table 6. Kaplan–Meier curves for PFS are shown in Figure 2.

Table 6

Efficacy of treatment in patients with CLL as assessed by IRC (in the ASCEND study)

	Calquence as monotherapy N = 155	Idelalisib + rituximab or bendamustine + rituximab at investigator's choice N = 155
Progression-free survival*
Number of events (%)	27 (17.4)	68 (43.9)
PD, n (%)	19 (12.3)	59 (38.1)
Deaths (%)	8 (5.2)	9 (5.8)
Median (95% CI), months	NR	16.5 (14.0, 17.1)
HR† (95% CI)	0.31 (0.20, 0.49)
P-value	< 0.0001
Estimated at 15 months, % (95% CI)	82.6 (75.0, 88.1)	54.9 (45.4, 63.5)
Overall survivala
Deaths (%)	15 (9.7)	18 (11.6)
Hazard ratio (95% CI)†	0.84 (0.42, 1.66)	-
Best overall response rate* (CR + CRi + PRi + PR)**
ORR, n (%)	126 (81.3)	117 (75.5)
(95% CI)	(74.4, 86.6)	(68.1, 81.6)
P-value	0.2248	-
CR, n (%)	0	2 (1.3)
PR, n (%)	126 (81.3)	115 (74.2)
Duration of response (DOR)
Median (95% CI), months	NR	13.6 (11.9, NR)

CI – confidence interval; HR – hazard ratio; NR – not reached; PR with incomplete blood count recovery – partial response with incomplete blood count recovery; nPR – nodular partial response; PR – partial response; PD – progressive disease.

*According to IRC assessment.

aMedian PFS was not reached in either group. The P-value for PFS was < 0.6089.

**PR with incomplete blood count recovery and nPR account for 0.

†Based on stratified Cox proportional hazards model.

Figure 2. Kaplan–Meier curve for PFS in patients with CLL (ITT population) according to IRC assessment (in the ASCEND study)

Time from randomization (months)

			Number of patients at risk
Month	0	1	2	3	4	5	6	7	8	9	10	11	12	13	14	15	16	17	18	19	20	21	22	23
Calquense	155	153	153	149	147	146	145	143	143	139	139	137	118	116	73	61	60	25	21	21	1	1	1	0
Investigator's choice	155	150	150	146	144	142	136	130	129	112	105	101	82	77	56	44	39	18	10	8	0

The PFS results for the medicinal product Calquence were similar across all subgroups, including subgroups with features of high risk. In the high-risk CLL population (with 17p deletion, 11q deletion, TP53 gene mutation, and unmutated immunoglobulin heavy-chain variable gene), the HR for PFS was 0.27 [95 % CI (0.17, 0.44)].

Table 7

PFS analysis by investigator assessment in subgroups (in the ASCEND study)

	Calquence as monotherapy
	N	Risk ratio		95% CI
All patients	155	0.30		(0.19, 0.48)
Deletion 17p
Yes	28	0.21		(0.07, 0.68)
No	127	0.33		(0.21, 0.54)
TP53 gene mutation
Yes	39	0.24		(0.11, 0.56)
No	113	0.33		(0.20, 0.57)
Deletion 17p or TP53 mutation
Yes	45	0.21		(0.09, 0.48)
No	108	0.36		(0.21, 0.61)
Mutation of immunoglobulin heavy chain variable region gene
With mutation	33	0.32		(0.11, 0.94)
Without mutation	118	0.32		(0.19, 0.52)
Deletion 11q
Yes	39	0.28		(0.11, 0.70)
No	116	0.31		(0.19, 0.53)
Complex karyotype Yes	50		0.32		(0.16, 0.63)
No	97		0.23		(0.12, 0.44)

At the final analysis with a median follow-up of 46.5 months for Calquence and 45.3 months for the investigator’s choice of rituximab plus bendamustine (IR/BR), a 72% reduction in the risk of disease progression or death, as assessed by the investigator, was observed in the group of patients receiving Calquence. Median progression-free survival (PFS) as assessed by the investigator was not reached in the Calquence group and was 16.8 months in the IR/BR group. Results of the investigator-assessed efficacy outcomes at the final analysis are presented in Table 8. Kaplan–Meier curves for investigator-assessed PFS are shown in Figure 3.

Table 8

Results of investigator-assessed efficacy outcomes at final analysis in patients with CLL (in the ASCEND study)

	Calquence as monotherapy N=155	Idelalisib + rituximab or bendamustine + rituximab at investigator's choice N=155
Progression-free survival*
Number of events (%)	62 (40.0)	119 (76.8)
PD, n (%)	43 (27.7)	102 (65.8)
Deaths (%)	19 (12.3)	17 (11.0)
Median (95% CI), months	NR	16.8 (14.1, 22.5)
HR† (95% CI)	0.28 (0.20, 0.38)
Overall survivala
Deaths (%)	41 (26.5)	54 (34.8)
Hazard ratio (95% CI)†	0.69 (0.46, 1.04)	-

CI – confidence interval; HR – hazard ratio; NR – not reached; PD – progressive disease.

*Investigator-assessed.

a Median PFS was not reached in either group. P-value for PFS was 0.0783.

†Based on stratified Cox proportional hazards model.

Figure 3. Kaplan–Meier curve for PFS by investigator assessment in patients with CLL (in the ASCEND study)

Time from randomization (months)

Month	0	3	6	9	12	15	18	21	24	27	30	33	36	39	42	45	48	51	54
Calquens	155	151	143	139	133	128	121	117	111	110	100	94	85	80	79	52	21	4	0
Investigator's choice	155	147	138	118	95	76	66	62	52	42	35	32	28	26	23	12	5	0

The results of PFS for the medicinal product Calquence in the final analysis were similar across all subgroups, including subgroups with features of high risk, and were consistent with the results of the primary analysis.

Pediatric population

The European Medicines Agency has waived the obligation to submit results of studies with Calquence in all subgroups of the pediatric population with CLL (information on use in children is provided in section "Posology and method of administration").

Pharmacokinetics

The pharmacokinetics of acalabrutinib and its active metabolite ACP-5862 were studied in trials involving healthy subjects and patients with B-cell lymphoproliferative disorders. Acalabrutinib exhibits dose proportionality, with pharmacokinetic parameters of both acalabrutinib and ACP-5862 being nearly linear over the dose range of 75 to 250 mg. According to population pharmacokinetic modeling, the pharmacokinetics of acalabrutinib and ACP-5862 are similar in patients with various B-cell lymphoproliferative disorders. In patients with B-cell lymphoproliferative disorders (including patients with CLL), the geometric mean steady-state area under the concentration-time curve over 24 hours (AUC24h) for acalabrutinib and ACP-5862 was 1679 ng × h/mL and 438 ng × h/mL, respectively, and the maximum plasma concentration (Cmax) was 4166 ng/mL and 446 ng/mL, respectively, following administration of the recommended dose of 100 mg twice daily.

Absorption

The time to reach maximum plasma concentration (Tmax) of acalabrutinib and ACP-5862 was 0.5–1.5 hours and 1 hour, respectively. The absolute bioavailability of Calquence was 25%.

Effect of food on acalabrutinib

In healthy subjects, administration of a single 75 mg dose of acalabrutinib with a high-fat, high-calorie meal (approximately 918 kcal, 59 g carbohydrates, 59 g fat, and 39 g protein) did not affect the mean AUC compared to administration under fasting conditions. However, Cmax decreased by 69%, and Tmax was prolonged by 1–2 hours.

Distribution

Plasma protein binding was 99.4% for acalabrutinib and 98.8% for ACP-5862. The mean blood-to-plasma concentration ratio in vitro was 0.8 for acalabrutinib and 0.7 for ACP-5862. The mean steady-state volume of distribution (Vss) of acalabrutinib was approximately 34 L.

Biotransformation/metabolism

In vitro, acalabrutinib is primarily metabolized by CYP3A enzymes and to a lesser extent via glutathione conjugation and amide hydrolysis. ACP-5862 is the major metabolite in plasma, which is further metabolized predominantly via CYP3A-mediated oxidation, and its geometric mean exposure (AUC) is approximately 2–3 times higher than that of acalabrutinib. ACP-5862 is approximately 50% less potent in inhibiting BTK than acalabrutinib.

In vitro studies indicate that acalabrutinib does not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, UGT1A1, or UGT2B7 at clinically relevant concentrations and is unlikely to affect the clearance of substrates of these CYP enzymes.

In vitro studies indicate that ACP-5862 does not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A4/5, UGT1A1, or UGT2B7 at clinically relevant concentrations, and its effect on the clearance of substrates of these CYP enzymes is unlikely.

Interaction with transporter proteins

In vitro studies indicate that acalabrutinib and ACP-5862 are substrates of P-gp and BCRP. However, concomitant administration with BCRP inhibitors is unlikely to result in clinically significant interactions with other medicinal products. Concomitant administration with an OATP1B1/1B3 inhibitor (a single 600 mg dose of rifampicin) resulted in a 1.2- and 1.4-fold increase in Cmax and AUC of acalabrutinib, respectively (N = 24, healthy volunteers), which is not clinically significant.

Acalabrutinib and ACP-5862 do not inhibit P-gp, OAT1, OAT3, OCT2, OATP1B1, OATP1B3, or MATE2-K at clinically relevant concentrations. At clinically relevant concentrations, acalabrutinib may inhibit BCRP in the intestine, while ACP-5862 may inhibit MATE1 (see section "Interaction with other medicinal products and other forms of interaction"). Acalabrutinib does not inhibit MATE1, and ACP-5862 does not inhibit BCRP at clinically relevant concentrations.

Elimination

After a single 100 mg oral dose of acalabrutinib, the elimination half-life (t1/2) was 1–2 hours. The t1/2 of the active metabolite ACP-5862 was approximately 7 hours.

The mean apparent oral clearance (CL/F) in patients with B-cell lymphoproliferative disorders was 134 L/h and 22 L/h for acalabrutinib and ACP-5862, respectively.

After a single 100 mg dose of radiolabeled [14C]-acalabrutinib administered to healthy volunteers, 84% of the administered dose was excreted in feces and 12% in urine; less than 2% was excreted unchanged.

Special patient populations

According to population pharmacokinetic analysis, age (>18 years), sex, race (Caucasian, African American), and patient body weight did not have a clinically significant effect on the pharmacokinetics of acalabrutinib and its active metabolite ACP-5862.

Pediatric population

Pharmacokinetic studies of Calquence in patients under 18 years of age have not been conducted.

Patients with renal impairment

Acalabrutinib is minimally excreted in urine. Pharmacokinetic studies in patients with renal impairment have not been conducted.

According to population pharmacokinetic analysis, no clinically significant differences in pharmacokinetics were observed between 408 patients with mild renal impairment (estimated glomerular filtration rate [eGFR] 60–89 mL/min/1.73 m²), 109 patients with moderate renal impairment (eGFR 30–59 mL/min/1.73 m²), and 192 patients with normal renal function (eGFR ≥90 mL/min/1.73 m²). The pharmacokinetics of acalabrutinib have not been studied in patients with severe renal impairment (eGFR <29 mL/min/1.73 m²) or in patients requiring dialysis. Patients with creatinine levels more than 2.5 times the upper limit of normal (ULN) were excluded from clinical trials (see section "Posology and method of administration").

Patients with hepatic impairment

Acalabrutinib is metabolized in the liver. In dedicated pharmacokinetic studies of acalabrutinib in patients with mild (n = 6, Child-Pugh class A), moderate (n = 6, Child-Pugh class B), and severe (n = 8, Child-Pugh class C) hepatic impairment (HI), AUC was increased by 1.9-, 1.5-, and 5.3-fold, respectively, compared to patients with normal hepatic function (n = 6). However, no significant changes in drug elimination were observed in patients with moderate HI, suggesting that the impact of moderate HI may have been underestimated in this study. According to population pharmacokinetic analysis, no clinically significant differences were observed between patients with mild (n = 79) or moderate hepatic impairment (n = 6) (total bilirubin 1.5–3 times ULN at any AST level) and patients with normal hepatic function (n = 613) (total bilirubin and AST within ULN) (see section "Posology and method of administration").

Clinical Characteristics

Indications

Calquence is indicated as monotherapy or in combination with obinutuzumab for the treatment of adult patients with previously untreated chronic lymphocytic leukemia (CLL).

Calquence is indicated as monotherapy for the treatment of adult patients with chronic lymphocytic leukemia (CLL) who have received at least one prior therapy.

Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in the section "Composition".

Interaction with other medicinal products and other forms of interaction

Acalabrutinib and its active metabolite are primarily metabolized by cytochrome P450 enzyme 3A4 (CYP3A4), and both substances are substrates of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP).

Medicinal products that may lead to increased plasma concentrations of acalabrutinib

Inhibitors of CYP3A/P-gp

Concomitant administration of acalabrutinib with a strong CYP3A/P-gp inhibitor (200 mg itraconazole once daily for 5 days) in healthy volunteers (n = 17) resulted in a 3.9-fold increase in Cmax and a 5-fold increase in AUC of acalabrutinib.

Concomitant use with strong CYP3A/P-gp inhibitors should be avoided. Temporary discontinuation of Calquence therapy is required if short-term use of strong CYP3A/P-gp inhibitors (e.g., ketoconazole, conivaptan, clarithromycin, indinavir, itraconazole, ritonavir, telaprevir, posaconazole, voriconazole) is anticipated (see section "Dosage and administration").

Concomitant administration of the medicinal product with moderate CYP3A inhibitors (400 mg fluconazole as a single dose or 200 mg isavuconazole under repeated dosing for 5 days) in healthy volunteers increased Cmax and AUC of acalabrutinib by 1.4 to 2 times, while Cmax and AUC of its active metabolite ACP-5862 decreased by 0.65 to 0.88 times compared to acalabrutinib administered alone. Dose adjustment is not required when used in combination with moderate CYP3A inhibitors. Patients should be closely monitored for adverse reactions (see section "Dosage and administration").

Medicinal products that may lead to decreased plasma concentrations of acalabrutinib

Inducers of CYP3A

Concomitant administration of acalabrutinib with a strong CYP3A inducer (600 mg rifampicin once daily for 9 days) in healthy volunteers (n = 24) resulted in a 68% reduction in Cmax and a 77% reduction in AUC of acalabrutinib.

Concomitant use with strong inducers of CYP3A activity (e.g., phenytoin, rifampicin, carbamazepine) should be avoided. Concomitant use of St. John’s wort should also be avoided, as it may unpredictably reduce plasma concentrations of acalabrutinib.

Medicinal products that reduce gastric acid secretion

The solubility of acalabrutinib decreases with increasing pH. Concomitant administration of acalabrutinib with an antacid (1 g calcium carbonate) in healthy volunteers resulted in a 53% reduction in AUC of acalabrutinib. Concomitant administration with a proton pump inhibitor (40 mg omeprazole for 5 days) reduced AUC of acalabrutinib by 43%.

If use of a medicinal product that reduces gastric acid secretion is necessary, consider administration of an antacid (e.g., calcium carbonate) or an H2-receptor antagonist (e.g., ranitidine or famotidine). When co-administered with antacids, the interval between doses should be at least 2 hours (see section "Dosage and administration"). Calquence should be taken 2 hours before or 10 hours after H2-receptor antagonists.

Separate administration of proton pump inhibitors and Calquence may not eliminate their interaction due to the prolonged effect of proton pump inhibitors; therefore, concomitant use should be avoided (see section "Dosage and administration").

Medicinal products whose plasma concentrations may be altered by Calquence

Substrates of CYP3A

Based on in vitro study data, inhibition of intestinal CYP3A4 by acalabrutinib cannot be excluded, which may increase exposure to orally administered CYP3A substrates sensitive to CYP3A metabolism in the intestine. Caution should be exercised when co-administering acalabrutinib with oral CYP3A4 substrates that have a narrow therapeutic index (e.g., cyclosporine, ergotamine, pimozide).

Effect of acalabrutinib on CYP1A2 substrates

In vitro studies indicate that acalabrutinib induces CYP1A2. Concomitant administration of acalabrutinib with CYP1A2 substrates (e.g., theophylline, caffeine) may reduce their exposure.

Effect of acalabrutinib and its active metabolite ACP-5862 on drug transport systems

When co-administered with substrates of breast cancer resistance protein (BCRP) (e.g., methotrexate), acalabrutinib may increase their exposure due to inhibition of BCRP in the intestine (see section "Pharmacokinetics"). To minimize the potential for interaction in the gastrointestinal tract, oral BCRP substrates with a narrow therapeutic index, such as methotrexate, should be administered at least 6 hours before or after acalabrutinib.

ACP-5862 may increase exposure to substrates of multidrug and toxin extrusion protein 1 (MATE1) (e.g., metformin) when co-administered due to inhibition of MATE1 (see section "Pharmacokinetics"). When co-administering medicinal products with MATE1-dependent disposition (e.g., metformin), careful monitoring of the patient is required to detect changes in tolerability due to increased exposure to the co-administered medicinal product during Calquence therapy.

Special precautions for use

Bleeding

In patients with hematologic malignancies receiving the medicinal product Calquence as monotherapy and in combination with obinutuzumab, major bleeding events were observed, including central nervous system and gastrointestinal bleeding, some of which were fatal. These bleeding events occurred both in patients with and without thrombocytopenia. Overall, less severe bleeding included bruising and petechiae (see section "Adverse reactions").

The mechanism of bleeding is not fully understood.

Patients taking antithrombotic medicinal products may have an increased risk of bleeding. If concomitant use of acalabrutinib and antithrombotic agents is necessary, it should be done with caution, and patients should be closely monitored for possible signs of bleeding. Warfarin or other vitamin K antagonists should not be taken concomitantly with the medicinal product Calquence.

The benefit and risks of temporarily discontinuing Calquence should be considered for at least 3 days before and after surgical procedures.

Infections

In patients with hematologic malignancies receiving the medicinal product Calquence as monotherapy and in combination with obinutuzumab, severe infections (bacterial, viral, or fungal), including fatal cases, were observed. These infections mostly occurred in the absence of grade 3 or 4 neutropenia, while neutropenic infection was observed in 1.9% of patients. Cases of infections due to reactivation of hepatitis B virus (HBV), herpes zoster, aspergillosis, and cases of progressive multifocal leukoencephalopathy (PML) were observed (see section "Adverse reactions").

Viral reactivation

Cases of hepatitis B virus (HBV) reactivation have been observed in patients receiving Calquence. The hepatitis B virus (HBV) status should be determined prior to initiating treatment with Calquence. Patients with positive serological test results for hepatitis B virus should be referred to hepatologists before starting treatment. These patients should be monitored and managed according to local medical standards to prevent hepatitis B virus reactivation.

Cases of progressive multifocal leukoencephalopathy (PML), some of which were fatal, have been observed in patients receiving Calquence in the context of prior or concomitant immunosuppressive therapy. Physicians should consider the risk of PML when differentially diagnosing patients presenting with new neurological, cognitive, or behavioral signs or symptoms or with worsening of such symptoms. In case of suspected PML, appropriate diagnostic investigations should be performed and treatment with Calquence should be suspended until PML is ruled out. In case of any suspicion, referral to a neurologist and appropriate diagnostic testing for PML, including MRI preferably with contrast, cerebrospinal fluid (CSF) analysis for JC virus (polyomavirus) DNA, and repeated neurological evaluations, should be considered.

For patients at increased risk of opportunistic infections, prophylactic measures should be considered. Patients should be monitored for signs and symptoms of infection and appropriate therapy should be administered according to standard medical practice.

Cytopenia

In patients with hematologic malignancies receiving the medicinal product Calquence as monotherapy and in combination with obinutuzumab, cases of grade 3 or 4 cytopenia, including neutropenia, anemia, and thrombocytopenia, related to treatment were observed. Complete blood counts should be performed as clinically indicated (see section "Adverse reactions").

Other primary malignancies

In patients with hematologic malignancies receiving the medicinal product Calquence as monotherapy and in combination with obinutuzumab, other primary malignancies, including skin and non-skin malignancies, were observed. Skin cancer was frequently reported. Patients should be monitored for the development of skin cancer, and patients should be advised to avoid prolonged sun exposure (see section "Adverse reactions").

Atrial fibrillation

Atrial fibrillation/flutter was observed in patients with hematologic malignancies receiving the medicinal product Calquence as monotherapy and in combination with obinutuzumab. Patients should be monitored for symptoms of atrial fibrillation and flutter (such as palpitations, dizziness, syncope, chest pain, dyspnea), and ECG should be performed as clinically indicated (see sections "Interaction with other medicinal products and other forms of interaction" and "Posology and method of administration"). Patients who develop atrial fibrillation during treatment with Calquence should undergo a thorough assessment of the risk of thromboembolic disease. For patients at high risk of thromboembolic disease, carefully controlled anticoagulant therapy and alternative treatment options to Calquence should be considered.

Other medicinal products

Concomitant use of strong CYP3A inhibitors with Calquence leads to increased plasma exposure of acalabrutinib and, consequently, increases the risk of toxicity. Conversely, concomitant use of CYP3A inducers leads to decreased plasma exposure of Calquence, thus increasing the risk of inadequate treatment efficacy. Concomitant use with strong CYP3A inhibitors should be avoided. Temporary discontinuation of Calquence therapy should be considered if short-term use of such inhibitors is anticipated (e.g., antimicrobial agents for no more than seven days). Patients receiving a moderate CYP3A inhibitor should be closely monitored for signs of toxicity (see sections "Posology and method of administration" and "Interaction with other medicinal products and other forms of interaction"). Concomitant use with strong CYP3A4 inducers should be avoided due to the risk of inadequate treatment efficacy.

Calquence contains sodium

One dose of this medicinal product contains less than 1 mmol sodium (23 mg), i.e., it is considered essentially "sodium-free".

Use during pregnancy or breastfeeding

Females of reproductive potential

Females of reproductive potential are advised to avoid pregnancy during treatment with Calquence.

Use during pregnancy

Data on the use of acalabrutinib in pregnant women are lacking or limited. Animal studies indicate that exposure to acalabrutinib during pregnancy may pose a risk to the fetus. Dystocia (difficult or prolonged labor) was observed in rats, and administration to pregnant rabbits resulted in fetal growth retardation.

Calquence should not be used during pregnancy, except when the woman's clinical condition requires treatment with acalabrutinib.

Use during breastfeeding

It is unknown whether acalabrutinib is excreted in human breast milk. Data on the effect of acalabrutinib on breastfed children or on milk production are lacking. Acalabrutinib and its active metabolite were detected in the milk of rats. Risk to the breastfed infant cannot be excluded. Women are advised to avoid breastfeeding during treatment with Calquence and for 2 days after the last dose.

Fertility

Data on the effect of Calquence on human reproductive function are lacking. Preclinical studies of acalabrutinib in male and female rats did not show adverse effects on reproductive function.

Ability to influence the speed of reaction while driving or operating machinery

The medicinal product Calquence has no effect or has a negligible effect on the ability to drive vehicles or operate machinery. However, fatigue and dizziness may occur during treatment with acalabrutinib, and patients experiencing these symptoms should be advised not to drive or operate machinery until symptoms resolve.

Method of Administration and Dosage

This medicinal product should be prescribed and administered only under the supervision of a physician experienced in the use of anticancer medicinal products.

Dosage

The recommended dose is 100 mg of acalabrutinib twice daily (corresponding to a total daily dose of 200 mg). See dosing information for obinutuzumab in the obinutuzumab medical instructions.

The interval between doses should be approximately 12 hours.

Treatment with Kalkvens should be continued until disease progression or occurrence of unacceptable toxicity.

Dose Adjustment

Adverse reactions

Dose modification recommendations for Calquence in the event of adverse reactions of grade 3 and higher are provided in Table 9.

Table 9

Dose modification recommendations in the event of adverse reactions*

Adverse reaction	Frequency of occurrence of adverse reaction	Dose modification (Initial dose = 100 mg approximately every 12 hours).
Grade 3 thrombocytopenia with bleeding Grade 4 thrombocytopenia or Grade 4 neutropenia lasting more than 7 days Grade 3 or higher non-hematologic toxicity	First or second occurrence	Temporarily discontinue treatment with Calquens. After toxicity decreases to grade 1 or baseline level, treatment with Calquens may be resumed at a dose of 100 mg every 12 hours.
	Third occurrence	Temporarily discontinue treatment with Calquens. After toxicity decreases to grade 1 or baseline level, treatment with Calquens may be resumed with dose reduction to 100 mg once daily.
	Fourth occurrence	Permanently discontinue treatment with Calquens.

*Classification of adverse reactions according to version 4.03 of the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE).

Interactions

Recommendations for the use of Calquence with CYP3A inhibitors or inducers and with medicinal products that reduce gastric acid secretion are provided in Table 10 (see section "Interaction with other medicinal products and other forms of interactions").

Table 10

Use with CYP3A inhibitors or inducers and medicinal products that reduce gastric acid secretion

Concomitant medicinal product		Recommendations for use of Calquens medicinal product
CYP3A inhibitors	Strong CYP3A inhibitor	Avoid concomitant use. Temporarily discontinue therapy with Calquens medicinal product if short-term use of such medicinal products is anticipated (e.g. anti-infectives, for no more than seven days).
	Moderate CYP3A inhibitor	No dose adjustment required. Monitor patients for adverse reactions when moderate CYP3A inhibitors are administered.
	Weak CYP3A inhibitor	No dose adjustment required.
CYP3A inducers	Strong CYP3A inducer	Avoid concomitant use.
Medicinal products that reduce gastric acid secretion	Proton pump inhibitors	Avoid concomitant use.
	H2-histamine receptor antagonists	Take Calquens medicinal product 2 hours before or 10 hours after administration of H2-histamine receptor antagonist.
	Antacid medicinal products	The interval between administration of these medicinal products should be at least 2 hours.

Missed Dose of the Medicinal Product

If a patient misses a dose of Calquens by more than 3 hours, the next dose should be taken at the next regularly scheduled time. An additional dose of the medicinal product should not be taken to compensate for the missed dose.

Special Patient Categories

Elderly Patients

Dose adjustment is not required for elderly patients (over 65 years of age) (see section "Pharmacokinetics").

Patients with Renal Impairment

Specific studies on the use of the medicinal product in patients with renal impairment have not been conducted. Clinical trials of Calquens included patients with mild or moderate renal impairment. Dose adjustment is not required for patients with mild or moderate renal impairment (creatinine clearance >30 mL/min). Adequate hydration should be maintained, and serum creatinine levels should be monitored periodically. Calquens should be administered to patients with severe renal impairment (creatinine clearance <30 mL/min) only if the potential benefit outweighs the risk, and such patients require careful monitoring for signs of toxicity. Data are lacking in patients with severe renal impairment or in patients undergoing dialysis (see section "Pharmacokinetics").

Patients with Hepatic Impairment

Dose adjustment is not required for patients with mild or moderate hepatic impairment (Child-Pugh class A or B, or with total bilirubin concentrations 1.5 to 3 times the upper limit of normal [ULN], at any AST activity). However, patients with moderate hepatic impairment require careful monitoring for signs of toxicity. Calquens is not recommended for use in patients with severe hepatic impairment (Child-Pugh class C or with total bilirubin concentrations more than 3 times ULN, at any AST activity) (see section "Pharmacokinetics").

Patients with Severe Cardiac Disease

Patients with severe cardiac disease were not included in clinical trials of Calquens.

Method of Administration

Calquens is intended for oral administration. Capsules should be swallowed whole with water, approximately at the same time each day, and can be taken independently of food (see section "Interaction with Other Medicinal Products and Other Forms of Interaction"). Capsules should not be chewed, dissolved in liquid, or opened, as this may affect drug absorption.

Children

The safety and efficacy of Calquens in children (under 18 years of age) have not been established. Data are lacking.

Overdose.

Symptoms and specific treatment for acalabrutinib overdose have not been defined. In case of overdose, patients should be closely monitored medically for possible signs or symptoms of adverse reactions and should receive symptomatic treatment as necessary.

Adverse Reactions

▼The medicinal product is subject to additional monitoring. This will enable rapid identification of new safety information. Healthcare professionals are requested to report any suspected adverse reactions.

Summary of safety profile

The most common (≥ 20%) adverse reactions (ARs) of any grade reported in 1,040 patients receiving Calquence as monotherapy were infection (66.7%), headache (37.8%), diarrhea (36.7%), bruising (34.1%), musculoskeletal pain (33.1%), nausea (21.7%), fatigue (21.3%), cough (21%), and rash (20.3%). The most common (≥ 5%) adverse reactions of grade 3 or higher were infection (17.6%), leukopenia (14.3%), neutropenia (14.2%), and anemia (7.8%).

The most common (≥ 20%) ARs of any grade reported in 223 patients receiving Calquence in combination therapy were infection (74%), musculoskeletal pain (44.8%), diarrhea (43.9%), headache (43%), leukopenia (31.8%), neutropenia (31.8%), cough (30.5%), fatigue (30.5%), arthralgia (26.9%), nausea (26.9%), dizziness (23.8%), and constipation (20.2%). The most common (≥ 5%) adverse reactions of grade 3 or higher were leukopenia (30%), neutropenia (30%), infection (21.5%), thrombocytopenia (9%), and anemia (5.8%).

Summary table of adverse reactions

Listed below are adverse reactions (ARs) reported in clinical trials involving patients treated with Calquence for hematological malignancies. The median duration of treatment with Calquence in the pooled dataset was 26.2 months.

Adverse reactions are listed by system organ classes according to the Medical Dictionary for Regulatory Activities (MedDRA). Within each system organ class, adverse reactions are presented in order of decreasing frequency. Adverse reaction frequency categories are defined as follows: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000), and not known (cannot be estimated from available data). Within each frequency category, adverse reactions are listed in order of decreasing severity.

Table 11

Adverse reactions* in patients with hematological malignancies receiving acalabrutinib monotherapy (n = 1040)

MedDRA SOC	MedDRA Term	Overall incidence of adverse reactions (all grades by CTCAE)	Incidence of adverse reactions of grade 3 severity and higher by CTCAE†
Infections and infestations	Upper respiratory tract infection	Very common (22%)	0.8%
	Sinusitis	Very common (10.7%)	0.3%
	Pneumonia	Common (8.7%)	5.1%
	Urinary tract infections	Common (8.5%)	1.5%
	Nasopharyngitis	Common (7.4%)	0%
	Bronchitis	Common (7.6%)	0.3%
	Herpesvirus infections†	Common (5.9%)	0.7%
	Aspergillosis†	Uncommon (0.5%)	0.4%
	Hepatitis B reactivation	Uncommon (0.1%)	0.1%
Benign, malignant and unspecified neoplasms	Other primary malignancy† Non-melanoma skin cancer† Other primary malignancy (excluding non-melanoma skin cancer)†	Very common (12.2%) Common (6.6%) Common (6.5%)	4.1% 0.5% 3.8%
Blood and lymphatic system disorders	Neutropenia†	Very common (15.7%)	14.2%
	Anemia†	Very common (13.8%)	7.8%
	Thrombocytopenia†	Common (8.9%)	4.8%
	Lymphocytosis	Uncommon (0.3%)	0.2%
Metabolism and nutrition disorders	Tumor lysis syndrome±	Uncommon (0.5%)	0.4%
Nervous system disorders	Headache	Very common (37.8%)	1.1%
	Dizziness	Very common (13.4%)	0.2%
Cardiac disorders	Atrial fibrillation/flutter†	Common (4.4%)	1.3%
Vascular disorders	Contusion† Ecchymosis Petechiae Ecchymoses	Very common (34.1%) Very common (21.7%) Very common (10.7%) Common (6.3%)	0% 0% 0% 0%
	Bleeding/hematoma† Gastrointestinal hemorrhage Intracranial hemorrhage	Very common (12.6%) Common (2.3%) Common (1%)	1.8% 0.6% 0.5%
	Hypertension†	Common (7.6%)	3.5%
	Nosebleed	Common (7%)	0.3%
Gastrointestinal disorders	Diarrhea	Very common (36.7%)	2.6%
	Nausea	Very common (21.7%)	1.2%
	Constipation	Very common (14.5%)	0.1%
	Vomiting	Very common (13.3%)	0.9%
	Abdominal pain†	Very common (12.5%)	1%
Skin and subcutaneous tissue disorders	Rash†	Very common (20.3%)	0.6%
Musculoskeletal and connective tissue disorders	Musculoskeletal pain†	Very common (33.1%)	1.5%
	Arthralgia	Very common (19.1%)	0.7%
General disorders and administration site conditions	Fatigue	Very common (21.3%)	1.7%
	Asthenia	Common (5.3%)	0.8%
Investigations¶ (identified by laboratory tests)	Decreased hemoglobin level§	Very common (42.6%)	10.1%
	Decreased absolute neutrophil count§	Very common (41.8%)	20.7%
	Decreased platelet count§	Very common (31.1%)	6.9%

*According to the classification of adverse reactions based on version 4.03 of the National Cancer Institute's Common Terminology Criteria for Adverse Events (NCI CTCAE).

†Includes multiple terms indicating adverse drug reactions.

±One case of tumor lysis syndrome related to the study drug was reported in the acalabrutinib group in the ASCEND study.

§Represents the frequency of laboratory parameter abnormalities, not the frequency of reported adverse reactions.

¶Presented as grades of deviation from normal according to CTCAE.

Table 12

Adverse reactions* in patients with hematologic malignancies who received combination therapy with acalabrutinib (n = 223)

MedDRA SOC	MedDRA Term	Overall frequency of adverse reactions (all grades according to CTCAE)	Frequency of adverse reactions of grade 3 severity and higher according to CTCAE†
Infections and infestations	Upper respiratory tract infection	Very common (31.4%)	1.8%
	Sinusitis	Very common (15.2%)	0.4%
	Nasopharyngitis	Very common (13.5%)	0.4%
	Urinary tract infections	Very common (13%)	0.9%
	Pneumonia	Very common (10.8%)	5.4%
	Bronchitis	Common (9.9%)	0%
	Herpesvirus infections†	Common (6.7%)	1.3%
	Progressive multifocal leukoencephalopathy	Uncommon (0.4%)	0.4%
	Hepatitis B reactivation	Uncommon (0.9%)	0.1%
	Aspergillosis†	Very rare (0%)	0%
Benign, malignant and unspecified neoplasms	Other primary malignant neoplasm† Non-melanoma skin cancer† Second primary malignant neoplasm (excluding non-melanoma skin cancer)†	Very common (13%) Common (7.6%) Common (6.3%)	4.0% 0.4% 3.6%
Blood and lymphatic system disorders	Neutropenia†	Very common (31.8%)	30%
	Thrombocytopenia†	Very common (13.9%)	9%
	Anemia†	Very common (11.7%)	5.8%
	Lymphocytosis	Uncommon (0.4%)	0.4%
Metabolism and nutrition disorders	Tumour lysis syndrome±	Uncommon (1.8%)	1.3%
Nervous system disorders	Headache	Very common (43%)	0.9%
	Dizziness	Very common (23.8%)	0%
Cardiac disorders	Atrial fibrillation/flutter†	Common (3.1%)	0.9%
Vascular disorders	Contusion† Haematoma Petechiae Ecchymoses	Very common (38.6%) Very common (27.4%) Very common (11.2%) Common (3.1%)	0% 0% 0% 0%
	Bleeding/hematoma† Gastrointestinal haemorrhage Intracranial haemorrhage	Very common (17.5%) Common (3.6%) Uncommon (0.9%)	1.3% 0.9% 0%
	Hypertension†	Very common (13.5%)	3.6%
	Nosebleed	Common (8.5%)	0%
Gastrointestinal disorders	Diarrhoea	Very common (43.9%)	4.5%
	Nausea	Very common (26.9%)	0%
	Constipation	Very common (20.2%)	0%
	Vomiting	Very common (19.3%)	0.9%
	Abdominal pain†	Very common (14.8%)	1.3%
Skin and subcutaneous tissue disorders	Rash†	Very common (30.9%)	1.8%
Musculoskeletal and connective tissue disorders	Musculoskeletal pain†	Very common (44.8%)	2.2%
	Arthralgia	Very common (26.9%)	1.3%
General disorders and administration site conditions	Fatigue	Very common (30.5%)	1.8%
	Asthenia	Common (7.6%)	0.4%
Investigations¶ (identified by laboratory tests)	Decreased absolute neutrophil count§	Very common (57.4%)	35%
	Decreased platelet count§	Very common (46.2%)	10.8%
	Decreased hemoglobin level§	Very common (43.9%)	9%

*According to the classification of adverse reactions based on version 4.03 of the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE).

† Includes multiple terms describing adverse drug reactions.

± One case of tumor lysis syndrome related to the medicinal product was reported in the acalabrutinib arm of the ASCEND study.

§ Represents the frequency of laboratory parameter abnormalities, not the frequency of reported adverse reactions.

¶ Presented as grades of deviation from normal according to CTCAE.

Description of selected adverse reactions

Reduction or discontinuation of therapy due to adverse reactions

Among 1040 patients who received Calquence as monotherapy, 9.3% discontinued treatment due to adverse reactions. The main adverse reactions included pneumonia, thrombocytopenia, and diarrhea. Dose reduction was required in 4.2% of patients due to adverse reactions. The main adverse reactions included hepatitis B virus reactivation, sepsis, and diarrhea.

Among 223 patients who received Calquence in combination therapy, 10.8% discontinued treatment due to adverse reactions. The main adverse reactions included pneumonia, thrombocytopenia, and diarrhea. Dose reduction was required in 6.7% of patients due to adverse reactions. The main adverse reactions included neutropenia, diarrhea, and vomiting.

Elderly patients

Among 1040 participants in clinical trials receiving Calquence as monotherapy, 41% were aged over 65 years and up to 75 years, and 22% were over 75 years of age. No clinically significant differences in terms of safety or efficacy were observed between patients over 65 years of age and younger patients.

Among 223 patients who participated in clinical trials of Calquence in combination with obinutuzumab, 47% were over 65 years and up to 75 years of age, and 26% were over 75 years of age. No clinically significant differences in terms of safety or efficacy were observed between patients over 65 years of age and younger patients.

Reporting of adverse reactions

Reporting of adverse reactions following marketing authorization is important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare and pharmaceutical professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

Shelf life.

36 months.

Storage conditions.

Store at a temperature not exceeding 30 °C. Keep out of reach of children.

Packaging.

6 hard capsules in a blister; 10 blisters in a cardboard box, or 8 hard capsules in a blister; 7 blisters in a cardboard box.

Prescription status.

Prescription only.

Manufacturer.

AstraZeneca AB / AstraZeneca AB.

Manufacturer's address and location of operations.

Gertunavägen, Södertälje, 152 57, Sweden / Gartunavagen, Sodertalje, 152 57, Sweden.