Calquens

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

Composition:

Active substance: acalabrutinib maleate;

One film-coated tablet contains 129 mg of acalabrutinib maleate, equivalent to 100 mg of acalabrutinib;

Excipients: mannitol, microcrystalline cellulose, low-substituted hydroxypropylcellulose, sodium stearyl fumarate; tablet coating: hypromellose, copovidone, titanium dioxide, polyethylene glycol 3350, medium-chain triglycerides, iron oxide yellow (E 172), iron oxide red (E 172).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: film-coated tablet of orange color, with imprint ACA 100 on one side.

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 downstream of B-cell receptors (BCR) and cytokine receptors. In B-cells, signaling through BTK promotes survival and proliferation of B-cells 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, 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, thorough QT study using placebo and a positive control. 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., change not exceeding or equal to 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 received treatments according to the following regimens: Calquence + obinutuzumab, Calquence as monotherapy, or obinutuzumab + chlorambucil. The ELEVATE-TN study included patients aged 65 years or older, or patients aged 18 to 65 years with comorbidities; 27.9% of patients had CrCl < 60 mL/min. Among patients under 65 years of age, the mean CIRS-G score was 8 in 16.1%. 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 occurrence of 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), day 8, and day 15 of cycle 2, then 1000 mg 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 occurrence of unacceptable toxicity.
• Obinutuzumab + chlorambucil (O + CL): 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), day 8, and day 15 of cycle 1, then 1000 mg 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 randomized to receive the O + CL combination 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 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, %	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, %
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 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 as assessed by the 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 in the treatment of patients with CLL as assessed by the IRC
(in the ELEVATE-TN study)

	Calquence + obinutuzumab N = 179	Calquence 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; CRi – complete response with incomplete blood count recovery; nPR – nodular partial response; PR – partial response.

* Assessed by IRC.

†Based on stratified Cox proportional hazards model.

a Median PFS was not reached in either group.

PFS results for regimens containing Calquence with or without obinutuzumab were consistent across all subgroups, including high-risk subgroups. 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 with regimens containing 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 plus chlorambucil.

Table 3. PFS subgroup analysis (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,
patients						0.17)
Deletion 17p Yes	19	0.20	(0.06; 0.64)	21	0.13	(0.04,
No	160	0.20	(0.12, 0.31)	158	0.09	0.46)
						(0.05,
						0.17)
TP53 gene mutation Yes	19	0.15	(0.05, 0.46)	21	0.04	(0.01,
No	160	0.20	(0.12, 0.32)	158	0.11	0.22)
						(0.06,
						0.20)
Deletion 17p and/or TP53 mutation Yes	23	0.23	(0.09, 0.61)	25	0.10	(0.03,
No	156	0.19	(0.11; 0.31)	154	0.10	0.34)
						(0.05,
						0.18)
Immunoglobulin heavy chain variable gene mutation With mutation	58	0.69	(0.31, 1.56)	74	0.15	(0.04,
Without mutation	119	0.11	(0.07, 0.19)	103	0.08	0.52)
						(0.04, 0.16)
Deletion 11q 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)

With 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 investigator-assessed median PFS was not reached for the Calquence + O and Calquence monotherapy groups and was 27.8 months in the O + Chl group. At the time of the final data cutoff, a total of 72 patients (40.7%) initially randomized to receive O + Chl had crossed over 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 (from 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. Investigator-assessed PFS Kaplan-Meier curve 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
Calqueness	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
Calqueness + 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 + XL	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 recurrent 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 to receive:

• Calquence 100 mg twice daily until disease progression or unacceptable toxicity, or
• Investigator’s choice:
  • Idelalisib 150 mg twice daily in combination with rituximab 375 mg/m² intravenously on day 1 of the first cycle, followed by 500 mg/m² intravenously every 2 weeks for 4 doses, then every 4 weeks for 3 additional doses, totaling 8 infusions.
  • Bendamustine 70 mg/m² (on days 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 (present or absent), ECOG performance status (0 or 1 vs. 2), and number of prior lines of therapy received (1–3 vs. ≥4). After confirmed disease progression, 35 patients initially randomized to receive investigator’s choice of idelalisib plus rituximab or bendamustine plus rituximab crossed over to receive Calquence as monotherapy. Table 5 presents the baseline 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
Caucasian 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 therapies received (range)	1 (1–8)	2 (1–10)
Number of prior CLL therapies 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, %
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 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 progression or death in the group of 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 + CRu + PRu + 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.

a Median PFS was not reached in both groups. 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 in the risk group
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 IRC assessment in subgroups (in the ASCEND study)

	Calquence as monotherapy
	N	Risk ratio		95 % CI
All patients	155	0.30		(0.19, 0.48)
17p deletion
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)
17p deletion or TP53 mutation
Yes	45	0.21		(0.09, 0.48)
No	108	0.36		(0.21, 0.61)
Immunoglobulin heavy-chain variable region gene mutation
Mutated	33	0.32		(0.11, 0.94)
Unmutated	118	0.32		(0.19, 0.52)
11q deletion
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 IR/BR combination, 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. The median 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 evaluation are presented in Table 8. Kaplan–Meier curves for investigator-assessed PFS are shown in Figure 3.

Table 8. Results of investigator-assessed efficacy evaluation 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)
PR, 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 choice	155	147	138	118	95	76	66	62	52	42	35	32	28	26	23	12	5	0

Results of PFS for the medicinal product Calquence in the final analysis were consistent 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 Calquence studies 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), geometric mean steady-state area under the concentration-time curve per day (AUC_24h) for acalabrutinib and ACP-5862 was 1679 ng·h/mL and 438 ng·h/mL, respectively, and maximum plasma concentration (C_max) was 4166 ng/mL and 446 ng/mL, respectively, following administration of the recommended dose of 100 mg twice daily.

Calquence tablets and Calquence capsules have been shown to be bioequivalent. Calquence tablets contain acalabrutinib maleate, a salt form of acalabrutinib that demonstrates higher solubility at high pH compared to the base form of acalabrutinib, which is the active substance in Calquence capsules. Thus, Calquence tablets have improved absorption when co-administered with medicinal products that reduce gastric acidity.

Absorption

Time to maximum plasma concentration (T_max) of acalabrutinib and ACP-5862 was 0.2–3.0 hours and 0.5–4.0 hours, respectively. Absolute bioavailability of Calquence was 25%.

Effect of food on acalabrutinib

In healthy subjects, administration of a single 100 mg dose of acalabrutinib in tablet form with a high-fat, high-calorie meal (approximately 918 kcal, 59 g carbohydrates, 59 g fat, and 39 g protein) did not affect mean AUC compared to administration under fasting conditions. However, C_max was reduced by 54%, and T_max was delayed by 1–2 hours.

Distribution

Plasma protein binding in humans 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 (V_ss) 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 primarily 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 than acalabrutinib in inhibiting BTK.

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 use with BCRP inhibitors is unlikely to result in clinically significant interactions with other medicinal products. Concomitant administration with an OATP1B1/1B3 inhibitor (single 600 mg dose of rifampicin) resulted in a 1.2-fold and 1.4-fold increase in C_max and AUC of acalabrutinib, respectively (N = 24, healthy volunteers), which is not considered 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 (t_1/2) was 1.4 hours. The t_1/2 of the active metabolite ACP-5862 was approximately 6.6 hours.

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 dose of 100 mg [14C]-radiolabeled 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 had no 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.

Population pharmacokinetic analysis showed no clinically significant differences in pharmacokinetics among 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). Pharmacokinetics of acalabrutinib have not been studied in patients with severe renal impairment (eGFR <29 mL/min/1.73 m²) or in patients with renal impairment 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 liver 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. Population pharmacokinetic analysis showed no clinically significant differences 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 liver 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 the cytochrome P450 3A4 (CYP3A4) enzyme, and both substances are substrates of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP).

Medicinal products that may increase 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 is recommended 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 "Method of administration and dosage").

Concomitant administration of the medicinal product with moderate CYP3A inhibitors (400 mg fluconazole as a single dose or 200 mg isavuconazole in repeated dosing for 5 days) in healthy volunteers increased Cmax and AUC of acalabrutinib by 1.4 to 2-fold, while Cmax and AUC of its active metabolite ACP-5862 decreased by 0.65 to 0.88-fold 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 "Method of administration and dosage").

Medicinal products that may decrease 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 acidity

No clinically significant differences in acalabrutinib pharmacokinetics were observed when 100 mg acalabrutinib tablets were administered concomitantly with a proton pump inhibitor (20 mg rabeprazole twice daily for 3 days). Acalabrutinib tablets may be administered together with medicinal products that reduce gastric acidity (proton pump inhibitors, H2-receptor antagonists, antacid medicinal products), unlike acalabrutinib capsules, whose absorption is impaired when co-administered with agents that reduce gastric acidity.

Medicinal products whose plasma concentrations may be altered by Calquence

Substrates of CYP3A

Based on in vitro data, it cannot be excluded that acalabrutinib inhibits CYP3A4 in the intestine and may increase exposure to CYP3A4 substrates sensitive to CYP3A metabolism in the gut. 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 transporter systems

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

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"). Close monitoring of patients is required when co-administering medicinal products with MATE1-dependent disposition (e.g., metformin) to detect changes in tolerability due to increased exposure of the concomitant medicinal product during Calquence treatment.

Special precautions for use.

Bleeding

In patients with hematologic malignancies receiving Calquence as monotherapy and in combination with obinutuzumab, severe bleeding events have been observed, including central nervous system and gastrointestinal bleeding, some with fatal outcome. These bleeding events occurred in patients both with and without thrombocytopenia. Less severe bleeding events generally 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 under close medical supervision to detect possible signs of bleeding. Warfarin or other vitamin K antagonists should not be taken concomitantly with 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 Calquence as monotherapy and in combination with obinutuzumab, severe infections (bacterial, viral, or fungal), including fatal cases, have been 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 progressive multifocal leukoencephalopathy (PML) have been reported (see section "Adverse reactions").

Virus reactivation

Cases of hepatitis B virus (HBV) reactivation have been observed in patients receiving Calquence. The hepatitis B virus (HBV) status should be determined before initiating Calquence therapy. Patients with positive serological test results for hepatitis B virus should be referred to hepatologists prior to 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 with fatal outcomes, 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 worsening of such. If PML is suspected, appropriate diagnostic investigations should be performed and treatment with Calquence should be withheld 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), analysis of cerebrospinal fluid (CSF) for JC virus (polyomavirus) DNA, and repeat 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 initiated according to standard medical practice.

Cytopenia

In patients with hematologic malignancies receiving Calquence as monotherapy and in combination with obinutuzumab, grade 3 or 4 treatment-related cytopenias, including neutropenia, anemia, and thrombocytopenia, have been observed. Complete blood counts should be performed as clinically indicated (see section "Adverse reactions").

Other primary malignancies

Other primary malignancies, including skin and non-skin malignancies, have been observed in patients with hematologic malignancies receiving Calquence as monotherapy and in combination with obinutuzumab. 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 "Adive reactions").

Atrial fibrillation

Atrial fibrillation/flutter has been observed in patients with hematologic malignancies receiving Calquence as monotherapy and in combination with obinutuzumab. Patients should be monitored for symptoms of atrial fibrillation or 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 careful assessment of the risk of thromboembolic disease. For patients at high risk of thromboembolic disease, carefully controlled anticoagulant therapy or alternative treatments to Calquence should be considered.

Other medicinal products

Concomitant use of strong CYP3A inhibitors with Calquence leads to increased plasma exposure to acalabrutinib and, consequently, increases the risk of toxicity. Conversely, concomitant use of CYP3A inducers leads to reduced plasma exposure to 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., anti-infective agents for no more than seven days). Patients receiving moderate CYP3A inhibitors 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 reduced treatment efficacy.

Calquence contains sodium

One dose of this medicinal product contains less than 1 mmol of 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 acalabrutinib exposure 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 delayed fetal growth.

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 effects of acalabrutinib on breastfed children or on milk production are lacking. Acalabrutinib and its active metabolite have been detected in rat milk. 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 their reproductive function.

Ability to influence reaction speed when driving or operating machinery.

Calquence has no or negligible influence on the ability to drive and use machines. However, fatigue and dizziness may occur during acalabrutinib therapy; if these symptoms occur, patients should be advised not to drive or operate machinery until symptoms resolve.

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 prescribing information.

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 Calquens 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 Hematologic toxicity Grade 3 or higher	First or second occurrence	Temporarily discontinue therapy with Calqvenc. After toxicity resolves to Grade 1 or baseline, therapy with Calqvenc may be resumed at a dose of 100 mg every 12 hours.
	Third occurrence	Temporarily discontinue therapy with Calqvenc. After toxicity resolves to Grade 1 or baseline, therapy with Calqvenc may be resumed at a reduced dose of 100 mg once daily.
	Fourth occurrence	Permanently discontinue therapy with Calqvenc.

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

Interactions

Recommendations for the use of Calquence with CYP3A inhibitors or inducers 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

	Concomitant medicinal product	Recommendations for the use of Calquence
CYP3A inhibitors	Strong CYP3A inhibitor	Avoid concomitant use. Temporarily discontinue Calquence therapy if short-term use of such medicinal products is anticipated (e.g., anti-infective agents, 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.

Acalabrutinib tablets can be used concomitantly with gastric acid-reducing agents (proton pump inhibitors, H2-receptor antagonists, antacid medications), unlike acalabrutinib capsules, whose absorption is impaired when used with gastric acid-reducing agents (see section "Interaction with other medicinal products and other forms of interaction").

Missed dose

If a patient misses a dose of Calquence by more than 3 hours, the next dose should be taken at the next regularly scheduled time. A supplemental dose 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 Calquence 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. Calquence 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 close monitoring for signs of toxicity. Data are lacking for patients with severe renal impairment or patients on 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 close monitoring for signs of toxicity. Calquence is not recommended for patients with severe hepatic impairment (Child-Pugh class C, or with total bilirubin concentrations more than 3 times the 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 Calquence.

Method of administration

Calquence is intended for oral administration. Tablets should be swallowed whole with water, approximately at the same time each day, and independently of food intake (see section "Interaction with other medicinal products and other forms of interaction"). Tablets should not be chewed, crushed, dissolved in liquid, or split.

Children

The safety and efficacy of Calquence 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 under close medical supervision for possible signs or symptoms of adverse reactions and, if necessary, receive symptomatic treatment.

Adverse Reactions

▼The medicinal product is subject to additional monitoring. This will allow rapid detection 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 studies involving patients treated with Calquence for hematologic malignancies. The median duration of treatment with Calquence in the pooled data set was 26.2 months.

Adverse reactions are listed by system organ class 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 hematologic malignancies receiving acalabrutinib monotherapy (n = 1040)

MedDRA SOC	MedDRA Term	Overall incidence of adverse reactions (all grades according to CTCAE)	Incidence of adverse reactions of grade 3 severity or higher according to 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 test results)	Hemoglobin decreased§	Very common (42.6%)	10.1%
	Neutrophil count absolute decreased§	Very common (41.8%)	20.7%
	Platelet count decreased§	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 many terms describing adverse drug reactions.

± One case of tumor lysis syndrome attributed 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 degrees of deviation from normal according to CTCAE.

Table 12. Adverse reactions* in patients with hematologic malignancies receiving combination therapy with acalabrutinib (n = 223)

MedDRA SOC	MedDRA Term	Overall incidence of adverse reactions (all grades according to CTCAE)	Incidence of adverse reactions Grade 3 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 malignancy† Non-melanoma skin cancer† Second primary malignancy (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	Tumor 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† Ecchymosis Petechiae Haematoma	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	Diarrhea	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 numerous terms describing adverse drug reactions.

± One case of tumor lysis syndrome attributed 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 dosage 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 leading to dose reduction 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 patients aged over 65 years up to 75 years, and 22% were over 75 years of age. No clinically significant differences in 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 aged over 65 years up to 75 years, and 26% were over 75 years of age. No clinically significant differences in safety or efficacy were observed between patients over 65 years of age and younger patients.

Reporting of adverse reactions

Reporting of adverse reactions after medicinal product registration is of great importance. It enables ongoing monitoring of the benefit-risk balance of this 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: https://aisf.dec.gov.ua.

Shelf life.

36 months.

Storage conditions.

No special storage conditions required. Keep out of reach of children.

Packaging.

8 film-coated tablets per blister; 7 blisters per cardboard box, or 10 film-coated tablets per blister; 6 blisters per cardboard box.

Prescription status.

Prescription only.

Manufacturer.

AstraZeneca AB/AstraZeneca AB.

Manufacturer's address and location of its operations.

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