acalabrutinib: prescribing information – dosing, contraindications, interactions, side effects

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

Calquence in combination with venetoclax with or without obinutuzumab is indicated for the treatment of adult patients with previously untreated chronic lymphocytic leukaemia (CLL).

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

Calquence in combination with bendamustine and rituximab (BR) is indicated for the treatment of adult patients with previously untreated mantle cell lymphoma (MCL) who are not eligible for autologous stem cell transplant (ASCT).

Calquence as monotherapy is indicated for the treatment of adult patients with relapsed or refractory mantle cell lymphoma (MCL) not previously treated with a BTK inhibitor.

Treatment with this medicinal product should be initiated and supervised by a physician experienced in the use of anticancer medicinal products.

Posology

The recommended dose of Calquence in monotherapy or in combination with other medicinal products is 100 mg acalabrutinib twice daily (equivalent to a total daily dose of 200 mg).

Calquence dose interval is approximately 12 hours.

For the combination regimens, refer to the prescribing information of each of the medicinal products for their dosing information (for details of the combination regimens, see section 5.1).

Calquence in monotherapy or in combination with obinutuzumab

Treatment with Calquence in monotherapy or in combination with obinutuzumab should be continued until disease progression or unacceptable toxicity.

Calquence in combination with venetoclax with or without obinutuzumab

Treatment with Calquence in combination with venetoclax with or without obinutuzumab, should continue until disease progression, unacceptable toxicity or completion of 14 cycles of treatment (each cycle is 28 days).

Calquence should be administered on Day 1 of Cycle 1 for a total of 14 cycles. Venetoclax should be administered on Day 1 of Cycle 3 for a total of 12 cycles, starting at 20 mg and increasing weekly to 50 mg, 100 mg, 200 mg and finally 400 mg.

If Calquence is given in combination with venetoclax and obinutuzumab, obinutuzumab should be administered at 100 mg on Day 1 of Cycle 2, followed by 900 mg which may be administered on Day 1 or 2. Administer obinutuzumab at 1 000 mg on Day 8 and 15 of Cycle 2, followed by 1 000 mg on Day 1 of Cycles 3 to 7. Obinutuzumab is administered for a total of 6 cycles.

Calquence in combination with bendamustine and rituximab

Calquence should be administered on Day 1 on Cycle 1 (each cycle is 28 days) until disease progression or unacceptable toxicity. Bendamustine should be administered at 90 mg/m2 on Days 1 and 2 of each cycle for a total of 6 cycles. Rituximab should be administered at 375 mg/m2 on Day 1 each cycle for a total of 6 cycles. Patients achieving a response (partial response [PR] or complete response [CR]) after the first 6 cycles, may receive maintenance rituximab at 375 mg/m2 on Day 1 of every other cycle for a maximum of 12 additional doses, starting on Cycle 8 up to Cycle 30.

Dose adjustments

Adverse reactions

Recommended dose modifications of Calquence for Grade ≥ 3 adverse reactions in patients receiving Calquence monotherapy, Calquence in combination with obinutuzumab and Calquence in combination with venetoclax with or without obinutuzumab are provided in Table 1.

Recommended dose modifications for Grade ≥ 3 adverse reactions in patients receiving Calquence in combination with bendamustine and rituximab are provided in Table 2.

Table 1. Recommended dose adjustments for adverse reactions*

Adverse reaction
Adverse reaction occurrence
Dose modification
(Starting dose = 100 mg approximately every
12 hours)
.Grade 3 thrombocytopenia with bleeding

.Grade 4 thrombocytopenia

.Grade 4 neutropenia lasting longer than 7 days

.Grade 3 or greater non-haematological toxicities

First and second
Interrupt Calquence.
Once toxicity has resolved to Grade 1 or baseline, Calquence may be resumed at 100 mg approximately every 12 hours.
Third
Interrupt Calquence.
Once toxicity has resolved to Grade 1 or baseline, Calquence may be resumed at a reduced frequency of 100 mg once daily.
Fourth
Discontinue Calquence.
*Adverse reactions graded by the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0.

Table 2. Recommended dose adjustments for Grade ≥ 3 adverse reactions* in patients receiving Calquence in combination with bendamustine and rituximab

Adverse reaction
Bendamustine dose modification†
Calquence dose modification
Neutropenia

If Grade 3 or Grade 4 neutropenia‡:
Interrupt bendamustine.
Once toxicity has resolved to Grade ≤ 2 or baseline level, bendamustine may be resumed at 70 mg/m2.
Discontinue bendamustine if additional dose reduction is required.
If Grade 4 neutropenia lasting longer than
7 days then interrupt Calquence.
Once toxicity has resolved to Grade ≤ 2 or baseline level, Calquence may be resumed at starting dose (1st adverse reaction occurrence) or at a reduced frequency of 100 mg once daily (2nd and 3rd adverse reaction occurrence).¶ Discontinue Calquence at 4th adverse reaction occurrence.
Thrombocytopenia

If Grade 3 or Grade 4 thrombocytopenia:
Interrupt bendamustine.
Once toxicity has resolved to Grade ≤ 2 or baseline level, bendamustine may be resumed at 70 mg/m2.
Discontinue bendamustine if additional dose reduction is required.
If Grade 3 thrombocytopenia with significant bleeding or Grade 4 then interrupt Calquence.
Once toxicity has resolved to Grade ≤ 2 or baseline level, Calquence may be resumed at starting dose (1st adverse reaction occurrence) or at a reduced frequency of 100 mg once daily (2nd and 3rd occurrence).¶ Discontinue Calquence at 3rd adverse reaction occurrence for thrombocytopenia with significant bleeding.
Discontinue Calquence at 4th adverse reaction occurrence.

Adverse reaction
Bendamustine dose modification†
Calquence dose modification
Other hematologic
Grade 4§ or unmanageable Grade 3 toxicity
Interrupt bendamustine.
Once toxicity has resolved to Grade ≤ 2 or baseline level, bendamustine may be resumed at 70 mg/m2.
Discontinue bendamustine if additional dose reduction is required.
Interrupt Calquence.
Once toxicity has resolved to Grade ≤ 2 or baseline level, Calquence may be resumed at starting dose (1st adverse reaction occurrence) or at a reduced frequency of 100 mg once daily (2nd and 3rd adverse reaction occurrence).¶ Discontinue Calquence at 4th adverse reaction occurrence.
Grade 3 or greater non-hematologic toxicities
Interrupt bendamustine.
Once toxicity has resolved to Grade 1 or baseline level, bendamustine may be resumed at 70 mg/m2.
Discontinue bendamustine if additional dose reduction is required.
Interrupt Calquence.
Once toxicity has resolved to Grade 2 or baseline, Calquence may be resumed at starting dose (1st adverse reaction occurrence) or at a reduced frequency of 100 mg once daily (2nd adverse reaction occurrence).¶ Discontinue Calquence at 3rd adverse reaction occurrence.
*Adverse reactions graded by the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03.
†For any toxicities not listed in this table refer to the bendamustine local prescribing information.
‡Consider use of myeloid growth factors before bendamustine dose modifications.
§Grade 4 lymphopenia is an expected outcome for treatment with bendamustine and rituximab. Dose modification due to lymphopenia is expected only if considered clinically important by investigators e.g. associated recurrent infections.
¶Dose may be re-escalated at the discretion of the physician if patient tolerates a reduced dose for ≥ 4 weeks.

Refer to the prescribing information of each of the medicinal products used in combination with Calquence for additional information for management of toxicities.

Interactions

Recommendations regarding use of Calquence with CYP3A inhibitors or inducers and gastric acid reducing agents are provided in Table 3 (see section 4.5).

Table 3. Use with CYP3A inhibitors or inducers and gastric acid reducing agents

Co-administered medicinal product
Recommended Calquence use
CYP3A inhibitors
Strong CYP3A inhibitor
Avoid concomitant use.
If these inhibitors will be used short-term (such as anti-infectives for up to seven days), interrupt Calquence.
Moderate CYP3A inhibitor
No dose adjustment. Monitor patients closely for adverse reactions if taking moderate CYP3A inhibitors.
Mild CYP3A inhibitor
No dose adjustment.

Co-administered medicinal product
Recommended Calquence use
CYP3A inducers
Strong CYP3A inducer
Avoid concomitant use.
Gastric acid reducing agents
Proton pump inhibitors
Avoid concomitant use.
H2-receptor antagonists
Take Calquence 2 hours before (or 10 hours after) taking a H2-receptor antagonist.
Antacids
The interval between taking the medicinal products should be at least 2 hours.

Missed dose

If a patient misses a dose of Calquence by more than 3 hours, the patient should be instructed to take the next dose at its regularly scheduled time. Double dose of Calquence should not be taken to make up for a missed dose.

Special populations

Elderly

No dose adjustment is required for elderly patients (aged ≥ 65 years) (see section 5.2).

Renal impairment

No specific clinical studies have been conducted in patients with renal impairment. Patients with mild or moderate renal impairment were treated in Calquence clinical studies. No dose adjustment is needed for patients with mild or moderate renal impairment (greater than 30 mL/min creatinine clearance). Hydration should be maintained, and serum creatinine levels monitored periodically. Calquence should be administered to patients with severe renal impairment (< 30mL/min creatinine clearance) only if the benefit outweighs the risk and these patients should be monitored closely for signs of toxicity. There are no data in patients with severe renal impairment or patients on dialysis (see section 5.2).

Hepatic impairment

No dose adjustment is recommended in patients with mild or moderate hepatic impairment (Child-Pugh A, Child-Pugh B, or total bilirubin between 1.5-3 times the upper limit of normal [ULN] and any AST).
However, patients with moderate hepatic impairment should be closely monitored for signs of toxicity. It is not recommended to use Calquence in patients with severe hepatic impairment (Child-Pugh C or total bilirubin >3-times ULN and any AST) (see section 5.2).

Severe cardiac disease

Patients with severe cardiovascular disease were excluded from Calquence clinical studies.

Paediatric population

The safety and efficacy of Calquence in children and adolescents aged 0 to 18 years have not been established. No data are available.

Method of administration

Calquence is for oral use. The capsules should be swallowed whole with water at approximately the same time each day, with or without food (see section 4.5). The capsules should not be chewed, dissolved or opened as this may affect the absorption of the medicinal product into the body.

Treatment with this medicinal product should be initiated and supervised by a physician experienced in the use of anticancer medicinal products.

Posology

The recommended dose of Calquence in monotherapy or in combination with other medicinal products is 100 mg acalabrutinib twice daily (equivalent to a total daily dose of 200 mg).

Calquence dose interval is approximately 12 hours.

For the combination regimens, refer to the prescribing information of each of the medicinal product for their dosing information (for details of the combination regimens, see section 5.1).

Calquence in monotherapy or in combination with obinutuzumab

Treatment with Calquence in monotherapy or in combination with obinutuzumab should be continued until disease progression or unacceptable toxicity.

Calquence in combination with venetoclax with or without obinutuzumab

Treatment with Calquence in combination with venetoclax with or without obinutuzumab, should continue until disease progression, unacceptable toxicity or completion of 14 cycles of treatment (each cycle is 28 days).

Calquence should be administered on Day 1 of Cycle 1 for a total of 14 cycles. Venetoclax should be administered on Day 1 of Cycle 3 for a total of 12 cycles, starting at 20 mg and increasing weekly to 50 mg, 100 mg, 200 mg and finally 400 mg.

If Calquence is given in combination with venetoclax and obinutuzumab, obinutuzumab should be administered at 100 mg on Day 1 of Cycle 2, followed by 900 mg which may be administered on Day 1 or 2. Administer obinutuzumab at 1 000 mg on Day 8 and 15 of Cycle 2, followed by 1 000 mg on Day 1 of Cycles 3 to 7. Obinutuzumab is administered for a total of 6 cycles.

Calquence in combination with bendamustine and rituximab

Calquence should be administered on Day 1 on Cycle 1 (each cycle is 28 days) until disease progression or unacceptable toxicity. Bendamustine should be administered at 90 mg/m2 on Days 1 and 2 of each cycle for a total of 6 cycles. Rituximab should be administered at 375 mg/m2 on Day 1 each cycle for a total of 6 cycles. Patients achieving a response (partial response [PR] or complete response [CR]) after the first 6 cycles, may receive maintenance rituximab at 375 mg/m2 on Day 1 of every other cycle for a maximum of 12 additional doses, starting on Cycle 8 up to Cycle 30.

Dose adjustments

Adverse reactions

Recommended dose modifications of Calquence for Grade ≥ 3 adverse reactions in patients receiving Calquence monotherapy, Calquence in combination with obinutuzumab and Calquence in combination with venetoclax with or without obinutuzumab are provided in Table 1.

Recommended dose modifications for Grade ≥ 3 adverse reactions in patients receiving Calquence in combination with bendamustine and rituximab are provided in Table 2.

Table 1. Recommended dose adjustments for adverse reactions*

Adverse reaction
Adverse reaction occurrence
Dose modification
(Starting dose = 100 mg approximately every
12 hours)
.Grade 3 thrombocytopenia with bleeding

.Grade 4 thrombocytopenia

.Grade 4 neutropenia lasting longer than 7 days

.Grade 3 or greater non-haematological toxicities

First and second
Interrupt Calquence.
Once toxicity has resolved to Grade 1 or baseline, Calquence may be resumed at 100 mg approximately every 12 hours.
Third
Interrupt Calquence.
Once toxicity has resolved to Grade 1 or baseline, Calquence may be resumed at a reduced frequency of 100 mg once daily.
Fourth
Discontinue Calquence.
*Adverse reactions graded by the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0.

Table 2. Recommended dose adjustments for Grade ≥ 3 adverse reactions* in patients receiving Calquence in combination with bendamustine and rituximab

Adverse reaction
Bendamustine dose modification†
Calquence dose modification
Neutropenia

If Grade 3 or Grade 4 neutropenia‡:
Interrupt bendamustine.
Once toxicity has resolved to Grade ≤ 2 or baseline level, bendamustine may be resumed at 70 mg/m2.
Discontinue bendamustine if additional dose reduction is required.
If Grade 4 neutropenia lasting longer than
7 days then interrupt Calquence.
Once toxicity has resolved to Grade ≤ 2 or baseline level, Calquence may be resumed at starting dose (1st adverse reaction occurrence) or at a reduced frequency of 100 mg once daily (2nd and 3rd adverse reaction occurrence).¶ Discontinue Calquence at 4th adverse reaction occurrence.
Thrombocytopenia

If Grade 3 or Grade 4 thrombocytopenia:
Interrupt bendamustine.
Once toxicity has resolved to Grade ≤ 2 or baseline level, bendamustine may be resumed at 70 mg/m2.
Discontinue bendamustine if additional dose reduction is required.
If Grade 3 thrombocytopenia with significant bleeding or Grade 4 then interrupt Calquence.
Once toxicity has resolved to Grade ≤ 2 or baseline level, Calquence may be resumed at starting dose (1st adverse reaction occurrence) or at a reduced frequency of 100 mg once daily (2nd and 3rd occurrence).¶ Discontinue Calquence at 3rd adverse reaction occurrence for thrombocytopenia with significant bleeding.
Discontinue Calquence at 4th adverse reaction occurrence.

Adverse reaction
Bendamustine dose modification†
Calquence dose modification
Other hematologic
Grade 4§ or unmanageable Grade 3 toxicity
Interrupt bendamustine.
Once toxicity has resolved to Grade ≤ 2 or baseline level, bendamustine may be resumed at 70 mg/m2.
Discontinue bendamustine if additional dose reduction is required.
Interrupt Calquence.
Once toxicity has resolved to Grade ≤ 2 or baseline level, Calquence may be resumed at starting dose (1st adverse reaction occurrence) or at a reduced frequency of 100 mg once daily (2nd and 3rd adverse reaction occurrence).¶ Discontinue Calquence at 4th adverse reaction occurrence.
Grade 3 or greater non-hematologic toxicities
Interrupt bendamustine.
Once toxicity has resolved to Grade 1 or baseline level, bendamustine may be resumed at 70 mg/m2.
Discontinue bendamustine if additional dose reduction is required.
Interrupt Calquence.
Once toxicity has resolved to Grade 2 or baseline, Calquence may be resumed at starting dose (1st adverse reaction occurrence) or at a reduced frequency of 100 mg once daily (2nd adverse reaction occurrence).¶ Discontinue Calquence at 3rd adverse reaction occurrence.
*Adverse reactions graded by the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03.
†For any toxicities not listed in this table refer to the bendamustine local prescribing information.
‡Consider use of myeloid growth factors before bendamustine dose modifications.
§Grade 4 lymphopenia is an expected outcome for treatment with bendamustine and rituximab. Dose modification due to lymphopenia is expected only if considered clinically important by investigators e.g. associated recurrent infections.
¶Dose may be re-escalated at the discretion of the physician if patient tolerates a reduced dose for ≥ 4 weeks.

Refer to the prescribing information of each of the medicinal products used in combination with Calquence for additional information for management of toxicities.

Interactions

Recommendations regarding use of Calquence with CYP3A inhibitors or inducers are provided in Table 3 (see section 4.5).

Table 3. Use with CYP3A inhibitors or inducers

Co-administered medicinal product
Recommended Calquence use
CYP3A inhibitors
Strong CYP3A inhibitor
Avoid concomitant use.
If these inhibitors will be used short-term (such as anti-infectives for up to seven days), interrupt Calquence.
Moderate CYP3A inhibitor
No dose adjustment. Monitor patients closely for adverse reactions if taking moderate CYP3A inhibitors.
Mild CYP3A inhibitor
No dose adjustment.

CYP3A inducers
Strong CYP3A inducer
Avoid concomitant use.

Acalabrutinib tablets can be co-administered with gastric acid reducing agents (proton pump inhibitors, H2-receptor antagonists, antacids), unlike acalabrutinib capsules which show impaired uptake when given with acid reducing agents (see section 4.5).

Missed dose

If a patient misses a dose of Calquence by more than 3 hours, the patient should be instructed to take the next dose at its regularly scheduled time. Double dose of Calquence should not be taken to make up for a missed dose.

Special populations

Elderly

No dose adjustment is required for elderly patients (aged ≥ 65 years) (see section 5.2).

Renal impairment

No specific clinical studies have been conducted in patients with renal impairment. Patients with mild or moderate renal impairment were treated in Calquence clinical studies. No dose adjustment is needed for patients with mild or moderate renal impairment (greater than 30 mL/min creatinine clearance). Hydration should be maintained, and serum creatinine levels monitored periodically. Calquence should be administered to patients with severe renal impairment (< 30 mL/min creatinine clearance) only if the benefit outweighs the risk and these patients should be monitored closely for signs of toxicity. There are no data in patients with severe renal impairment or patients on dialysis (see section 5.2).

Hepatic impairment

No dose adjustment is recommended in patients with mild or moderate hepatic impairment (Child-Pugh A, Child-Pugh B, or total bilirubin between 1.5-3 times the upper limit of normal [ULN] and any AST).
However, patients with moderate hepatic impairment should be closely monitored for signs of toxicity. It is not recommended to use Calquence in patients with severe hepatic impairment (Child-Pugh C or total bilirubin > 3-times ULN and any AST) (see section 5.2).

Severe cardiac disease

Patients with severe cardiovascular disease were excluded from Calquence clinical studies.

Paediatric population

The safety and efficacy of Calquence in children and adolescents aged 0 to 18 years have not been established. No data are available.

Method of administration

Calquence is for oral use. The tablets should be swallowed whole with water at approximately the same time each day, with or without food (see section 4.5). The tablets should not be chewed, crushed, dissolved or divided.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Summary of the safety profile

Calquence monotherapy

Of the 1 478 patients treated with Calquence monotherapy, the most common (≥ 20%) adverse drug reactions (ADRs) of any grade were infection, diarrhoea, headache, musculoskeletal pain, bruising, cough, arthralgia, fatigue, nausea and rash. The most commonly reported (≥ 5%) Grade ≥ 3 adverse drug reactions were infection, leukopenia, neutropenia, anaemia, second primary malignancy, and thrombocytopenia.

Calquence in combination with obinutuzumab

Of the 223 patients treated with Calquence in combination with obinutuzumab, the most common (≥ 20%) ADRs of any grade were infection, musculoskeletal pain, diarrhoea, headache, leukopenia, neutropenia, cough, fatigue, arthralgia, nausea, dizziness, and constipation. The most commonly reported (≥ 5%) Grade ≥ 3 adverse drug reactions were leukopenia, neutropenia, infection, thrombocytopenia and anaemia.

Calquence in combination with venetoclax

Of the 291 patients treated with Calquence in combination with venetoclax, the most common (≥ 20%) ADRs of any grade were infections, neutropenia, headache, bruising, diarrhoea and musculoskeletal pain.
The most commonly reported (≥ 5%) Grade ≥ 3 adverse drug reaction was neutropenia.

Calquence in combination with venetoclax and obinutuzumab

Of the 284 patients treated with Calquence in combination with venetoclax and obinutuzumab, the most common (≥ 20%) ADRs of any grade were infections, neutropenia, headache, bruising, diarrhoea, nausea

and musculoskeletal pain. The most commonly reported (≥ 5%) Grade ≥ 3 adverse drug reactions were neutropenia and thrombocytopenia.

Calquence in combination with bendamustine and rituximab

Of the 297 patients treated with Calquence in combination with bendamustine and rituximab, the most common (≥ 20%) ADRs of any grade were neutropenia, nausea, rash, diarrhoea, musculoskeletal pain, headache, fatigue, vomiting, constipation, anaemia and thrombocytopenia. The most commonly reported (≥ 5%) Grade ≥ 3 adverse drug reactions were neutropenia, rash, thrombocytopenia, anaemia, pneumonia, second primary malignancies, hypertension and second primary malignancies excluding non-melanoma skin.

Tabulated list of adverse reactions

The below tables present adverse drug reactions (ADRs) identified in clinical studies with patients receiving Calquence monotherapy or combination therapy for haematological malignancies. The median duration of Calquence monotherapy treatment across the pooled dataset was 38.2 months. The median duration of Calquence treatment in patients treated with Calquence in combination with bendamustine and rituximab was 28.6 months. The median duration of Calquence treatment in patients treated with Calquence in combination with venetoclax with or without obinutuzumab was 12.9 months.

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

Table 4. Adverse drug reactions* of patients with haematological malignancies treated with acalabrutinib monotherapy (N=1 478)

MedDRA SOC
MedDRA Term
All Grades
(%)

Grade ≥ 3*
(%)
Infections and infestations
Upper respiratory tract infection
Very common (25.8)

Haemorrhage

Major haemorrhagic events including central nervous system and gastrointestinal haemorrhage, some with fatal outcome, have occurred in patients with haematologic malignancies treated with Calquence monotherapy and in combination with other medicinal products. These events have occurred in patients both with and without thrombocytopenia. Overall, the bleeding events were less severe events including bruising and petechiae (see section 4.8).

The mechanism for the bleeding events is not well understood.

Patients receiving antithrombotic agents may be at increased risk of haemorrhage. Caution should be used with antithrombotic agents and additional monitoring considered for signs of bleeding when concomitant use is medically necessary. Warfarin or other vitamin K antagonists should not be administered concomitantly with Calquence.

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

Infections

Serious infections (bacterial, viral or fungal), including fatal events, have occurred in patients with haematologic malignancies treated with Calquence monotherapy and in combination with other medicinal products. These infections predominantly occurred in the absence of neutropenia, with neutropenic infection reported in 10.1% of patients receiving monotherapy and 26.8% in patients receiving combination therapy. Infections due to hepatitis B virus (HBV) and herpes zoster virus (HZV) reactivation, aspergillosis and progressive multifocal leukoencephalopathy (PML) have occurred (see section 4.8).

Viral reactivation

Cases of hepatitis B reactivation have been reported in patients receiving Calquence. Hepatitis B virus (HBV) status should be established before initiating treatment with Calquence. If patients have positive hepatitis B serology, a liver disease expert should be consulted before the start of treatment and the patient should be monitored and managed following local medical standards to prevent hepatitis B reactivation.

Cases of progressive multifocal leukoencephalopathy (PML) including fatal ones have been reported following the use of Calquence within the context of a prior or concomitant immunosuppressive therapy.
Physicians should consider PML in the differential diagnosis in patients with new or worsening neurological, cognitive or behavioural signs or symptoms. If PML is suspected, then appropriate

diagnostic evaluations should be undertaken and treatment with Calquence should be suspended until PML is excluded. If any doubt exists, referral to a neurologist and appropriate diagnostic measures for PML including MRI scan preferably with contrast, cerebrospinal fluid (CSF) testing for JC Viral DNA and repeat neurological assessments should be considered.

Consider prophylaxis according to standard of care in patients who are at increased risk for opportunistic infections. Monitor patients for signs and symptoms of infection and treat as medically appropriate.

Cytopenias

Treatment-emergent Grade 3 or 4 cytopenias, including neutropenia, anaemia and thrombocytopenia, occurred in patients with haematologic malignancies treated with Calquence monotherapy and in combination with other medicinal products. Monitor complete blood counts as medically indicated (see section 4.8).

Second primary malignancies

Second primary malignancies, including skin and non-skin cancers, occurred in patients with haematologic malignancies treated with Calquence monotherapy and in combination with other medicinal products. Skin cancers were commonly reported. Monitor patients for the appearance of skin cancers and advise protection from sun exposure (see section 4.8).

Atrial fibrillation

Atrial fibrillation/flutter occurred in patients with haematologic malignancies treated with Calquence monotherapy and in combination with other medicinal products. Monitor for symptoms (e.g., palpitations, dizziness, syncope, chest pain, dyspnoea) of atrial fibrillation and atrial flutter and obtain an ECG as medically indicated (see sections 4.5 and 4.2). In patients who develop atrial fibrillation on therapy with Calquence, a thorough assessment of the risk for thromboembolic disease should be undertaken. In patients at high risk for thromboembolic disease, tightly controlled treatment with anticoagulants and alternative treatment options to Calquence should be considered.

Tumour lysis syndrome

Tumour lysis syndrome (TLS) has been reported with Calquence therapy. Patients considered at risk for TLS (e.g., presence of bulky disease at baseline) should be assessed for possible risk of TLS and closely monitored as clinically indicated.

Interstitial lung disease/pneumonitis

Interstitial lung disease (ILD)/pneumonitis has been reported in patients treated with Calquence in combination with bendamustine and rituximab in MCL. Monitor patients for pulmonary symptoms indicative of ILD/pneumonitis (e.g. cough, dyspnea or hypoxia) and manage ILD/pneumonitis as clinically indicated.

Other medicinal products

Co-administration of strong CYP3A inhibitors with Calquence may lead to increased acalabrutinib exposure and consequently a higher risk for toxicity. On the contrary, co-administration of CYP3A inducers may lead to decreased acalabrutinib exposure and consequently a risk for lack of efficacy.

Concomitant use with strong CYP3A inhibitors should be avoided. If these inhibitors will be used short-term (such as anti-infectives for up to seven days), treatment with Calquence should be interrupted.
Patients should be closely monitored for signs of toxicity if a moderate CYP3A inhibitor is used (see sections 4.2 and 4.5). Concomitant use with strong CYP3A4 inducers should be avoided due to risk for lack of efficacy.

Calquence contains sodium

This medicinal product contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially ‘sodium-free’.

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

Active substances that may increase acalabrutinib plasma concentrations

CYP3A/P-gp inhibitors

Co-administration with a strong CYP3A/P-gp inhibitor (200 mg itraconazole once daily for 5 days) increased acalabrutinib Cmax and AUC by 3.9-fold and 5.0-fold in healthy subjects (N=17), respectively.

Concomitant use with strong CYP3A/P-gp inhibitors should be avoided. If the strong CYP3A/P-gp inhibitors (e.g., ketoconazole, conivaptan, clarithromycin, indinavir, itraconazole, ritonavir, telaprevir, posaconazole, voriconazole) will be used short-term, treatment with Calquence should be interrupted (see section 4.2).

Co-administration with moderate CYP3A inhibitors (400 mg fluconazole as single dose or 200 mg isavuconazole as repeated dose for 5 days) in healthy subjects increased acalabrutinib Cmax and AUC by 1.4-fold to 2-fold while the active metabolite ACP-5862 Cmax and AUC was decreased by 0.65-fold to 0.88-fold relative to when acalabrutinib was dosed alone. No dose adjustment is required in combination with moderate CYP3A inhibitors. Monitor patients closely for adverse reactions (see Section 4.2).

Active substances that may decrease acalabrutinib plasma concentrations

CYP3A inducers

Co--administration of a strong CYP3A inducer (600 mg rifampicin once daily for 9 days) decreased acalabrutinib Cmax and AUC by 68% and 77% in healthy subjects (N=24), respectively.

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

Gastric acid reducing medicinal products

Acalabrutinib solubility decreases with increasing pH. Co-administration of acalabrutinib with an antacid (1 g calcium carbonate) decreased acalabrutinib AUC by 53% in healthy subjects. Co-administration with a proton pump inhibitor (40 mg omeprazole for 5 days) decreased acalabrutinib AUC by 43%.

If treatment with an acid reducing agent is required, consider using an antacid (e.g., calcium carbonate), or an H2-receptor antagonist (e.g., ranitidine or famotidine). For use with antacids, the interval between taking the medicinal products should be at least 2 hours (see section 4.2). For H2-receptor antagonists, Calquence should be taken 2 hours before (or 10 hours after) taking the H2-receptor antagonist.
Due to the long-lasting effect of proton pump inhibitors, separation of doses with proton pump inhibitors may not eliminate the interaction with Calquence and therefore concomitant use should be avoided (see section 4.2).

Active substances whose plasma concentrations may be altered by Calquence

CYP3A substrates

Based on in vitro data, it cannot be excluded that acalabrutinib is an inhibitor of CYP3A4 at the intestinal level and may increase the exposure of CYP3A4 substrates sensitive to gut CYP3A metabolism. Caution should be exercised if co-administering acalabrutinib with CYP3A4 substrates with narrow therapeutic range administered orally (e.g., cyclosporine, ergotamine, pimozide).

Effect of acalabrutinib on CYP1A2 substrates

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

Effects of acalabrutinib and its active metabolite, ACP-5862, on medicinal product transport systems

Acalabrutinib may increase exposure to co-administered BCRP substrates (e.g., methotrexate) by inhibition of intestinal BCRP (see section 5.2). To minimise the potential for an interaction in the Gastrointestinal (GI) tract, oral narrow therapeutic range BCRP substrates such as methotrexate should be taken at least 6 hours before or after acalabrutinib.

ACP-5862 may increase exposure to co-administered MATE1 substrates (e.g., metformin) by inhibition of MATE1 (see section 5.2). Patients taking concomitant medicinal products with disposition dependent upon MATE1 (e.g., metformin) should be monitored for signs of changed tolerability as a result of increased exposure of the concomitant medication whilst receiving Calquence.

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

Active substances that may increase acalabrutinib plasma concentrations

CYP3A/P-gp inhibitors

Co-administration with a strong CYP3A/P-gp inhibitor (200 mg itraconazole once daily for 5 days) increased acalabrutinib Cmax and AUC by 3.9-fold and 5.0-fold in healthy subjects (N=17), respectively.

Concomitant use with strong CYP3A/P-gp inhibitors should be avoided. If the strong CYP3A/P-gp inhibitors (e.g., ketoconazole, conivaptan, clarithromycin, indinavir, itraconazole, ritonavir, telaprevir, posaconazole, voriconazole) will be used short-term, treatment with Calquence should be interrupted (see section 4.2).

Co-administration with moderate CYP3A inhibitors (400 mg fluconazole as single dose or 200 mg isavuconazole as repeated dose for 5 days) in healthy subjects increased acalabrutinib Cmax and AUC by 1.4-fold to 2-fold while the active metabolite ACP-5862 Cmax and AUC was decreased by 0.65-fold to 0.88-fold relative to when acalabrutinib was dosed alone. No dose adjustment is required in combination with moderate CYP3A inhibitors. Monitor patients closely for adverse reactions (see Section 4.2).

Active substances that may decrease acalabrutinib plasma concentrations

CYP3A inducers

Co-administration of a strong CYP3A inducer (600 mg rifampicin once daily for 9 days) decreased acalabrutinib Cmax and AUC by 68% and 77% in healthy subjects (N=24), respectively.

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

Gastric acid reducing medicinal products

No clinically significant differences in acalabrutinib pharmacokinetics were observed when a 100 mg acalabrutinib tablet was used concomitantly with a proton pump inhibitor (rabeprazole 20 mg twice daily for 3 days). Acalabrutinib tablets can be co-administered with gastric acid reducing agents (proton pump

inhibitors, H2-receptor antagonists, antacids), unlike acalabrutinib capsules which show impaired uptake when given with acid reducing agents.

Active substances whose plasma concentrations may be altered by Calquence

CYP3A substrates

Based on in vitro data, it cannot be excluded that acalabrutinib is an inhibitor of CYP3A4 at the intestinal level and may increase the exposure of CYP3A4 substrates sensitive to gut CYP3A metabolism. Caution should be exercised if co-administering acalabrutinib with CYP3A4 substrates with narrow therapeutic range administered orally (e.g., cyclosporine, ergotamine, pimozide).

Effect of acalabrutinib on CYP1A2 substrates

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

Effects of acalabrutinib and its active metabolite, ACP-5862, on medicinal product transport systems

Acalabrutinib may increase exposure to co-administered BCRP substrates (e.g., methotrexate) by inhibition of intestinal BCRP (see section 5.2). To minimise the potential for an interaction in the Gastrointestinal (GI) tract, oral narrow therapeutic range BCRP substrates such as methotrexate should be taken at least 6 hours before or after acalabrutinib.

ACP-5862 may increase exposure to co-administered MATE1 substrates (e.g., metformin) by inhibition of MATE1 (see section 5.2). Patients taking concomitant medicinal products with disposition dependent upon MATE1 (e.g., metformin) should be monitored for signs of changed tolerability as a result of increased exposure of the concomitant medication whilst receiving Calquence.

Women of childbearing potential

Women of childbearing potential should be advised to avoid becoming pregnant while receiving Calquence.

Pregnancy

There are no or limited amount of data from the use of acalabrutinib in pregnant women. Based on findings from animal studies, there may be a risk to the foetus from exposure to acalabrutinib during pregnancy. Dystocia (difficult or prolonged labour) was observed in the rat and administration to pregnant rabbits was associated with reduced foetal growth (see section 5.3).

Calquence should not be used during pregnancy unless the clinical condition of the woman requires treatment with acalabrutinib.

Breast-feeding

It is not known whether acalabrutinib is excreted in human milk. There are no data on the effect of acalabrutinib on the breast-fed child or on milk production. Acalabrutinib and its active metabolite were present in the milk of lactating rats. A risk to the breast-fed child cannot be excluded. Breast-feeding mothers are advised not to breast-feed during treatment with Calquence and for 2 days after receiving the last dose.

Fertility

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

Calquence has no or negligible influence on the ability to drive and use machines. However, during treatment with acalabrutinib, fatigue and dizziness have been reported and patients who experience these symptoms should be advised not to drive or use machines until symptoms abate.

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

5.
PHARMACOLOGICAL PROPERTIES

Pharmacotherapeutic group: Antineoplastic agents, protein kinase inhibitors, ATC code: L01EL02.

Mechanism of action

Acalabrutinib is a selective inhibitor of Bruton tyrosine kinase (BTK). BTK is a signalling molecule of the B-cell antigen receptor (BCR) and cytokine receptor pathways. In B-cells, BTK signalling results in B-cell survival and proliferation, and is required for cellular adhesion, trafficking, and chemotaxis.

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

Pharmacodynamic effects

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

Cardiac electrophysiology

The effect of acalabrutinib on the QTc interval was evaluated in 46 healthy male and female subjects in a randomised, double-blind thorough QT study with placebo and positive controls. At a supratherapeutic dose, 4-times the maximum recommended dose, Calquence did not prolong the QT/QTc interval to any clinically relevant extent (e.g., not greater than or equal to 10 ms) (see sections 4.4, 4.8 and 5.3).

Clinical efficacy and safety

Patients with previously untreated CLL

Calquence monotherapy or in combination with obinutuzumab

The safety and efficacy of Calquence monotherapy or in combination with obinutuzumab in previously untreated CLL were evaluated in a randomised, multi-centre, open-label Phase 3 study (ELEVATE-TN) of 535 patients. Patients received Calquence plus obinutuzumab, Calquence monotherapy, or obinutuzumab plus chlorambucil. Patients 65 years of age or older, or between 18 and 65 years of age with coexisting medical conditions, were included in ELEVATE-TN, 27.9% patients had a CrCl of < 60 mL/min. Of the patients who were < 65 years of age, 16.1% had a median CIRS-G score of 8. The study allowed patients to receive antithrombotic agents. Patients who required anticoagulation with warfarin or equivalent vitamin K antagonists were excluded.

Patients were randomised in a 1:1:1 ratio into 3 arms to receive:
- Calquence plus obinutuzumab (Calquence+G): Calquence 100 mg was administered twice daily starting on Cycle 1 Day 1 until disease progression or unacceptable toxicity. Obinutuzumab was administered starting on Cycle 2 Day 1 for a maximum of 6 treatment cycles. Obinutuzumab 1 000 mg was administered on Days 1 and 2 (100 mg on Day 1 and 900 mg on Day 2), 8 and 15 of Cycle 2 followed by 1 000 mg on Day 1 of Cycles 3 up to 7. Each cycle was 28 days.

• Calquence monotherapy: Calquence 100 mg was administered twice daily until disease progression or unacceptable toxicity.

The pharmacokinetics (PK) of acalabrutinib and its active metabolite, ACP-5862, were studied in healthy subjects and in patients with B-cell malignancies. Acalabrutinib exhibits dose-proportionality, and both acalabrutinib and ACP-5862 exhibit almost linear PK across a dose range of 75 to 250 mg. Population PK modelling suggests that the PK of acalabrutinib and ACP-5862 is similar across patients with different B-cell malignancies. At the recommended dose of 100 mg twice daily in patients with B-cell malignancies (including, CLL), the geometric mean steady state daily area under the plasma concentration over time curve (AUC24h) and maximum plasma concentration (Cmax) for acalabrutinib were 1679 ng•h/mL and 438 ng/mL, respectively, and for ACP-5862 were 4166 ng•h/mL and 446 ng/mL, respectively.

Absorption

The time to peak plasma concentrations (Tmax) was 0.5-1.5 hours for acalabrutinib, and 1.0 hour for ACP-5862. 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 calories, 59 grams carbohydrate, 59 grams fat and 39 grams protein) did not

affect the mean AUC as compared to dosing under fasted conditions. Resulting Cmax decreased by 69% and Tmax was delayed 1-2 hours.

Distribution

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

Biotransformation/Metabolism

The pharmacokinetics (PK) of acalabrutinib and its active metabolite, ACP-5862, were studied in healthy subjects and in patients with B-cell malignancies. Acalabrutinib exhibits dose-proportionality, and both acalabrutinib and ACP-5862 exhibit almost linear PK across a dose range of 75 to 250 mg. Population PK modelling suggests that the PK of acalabrutinib and ACP-5862 is similar across patients with different B-cell malignancies. At the recommended dose of 100 mg twice daily in patients with B-cell malignancies (including, CLL), the geometric mean steady state daily area under the plasma concentration over time curve (AUC24h) and maximum plasma concentration (Cmax) for acalabrutinib were 1679 ng•h/mL and 438 ng/mL, respectively, and for ACP-5862 were 4166 ng•h/mL and 446 ng/mL, respectively.

Calquence tablets and Calquence capsules have been demonstrated to be bioequivalent. Calquence tablets contain acalabrutinib maleate, a salt form of acalabrutinib that shows higher solubility at high pH than the acalabrutinib base, which is the active content of Calquence capsules. Calquence tablets thus have a better absorption when combined with acid reducing agents.

Absorption

The time to peak plasma concentrations (Tmax) was 0.2-3.0 hours for acalabrutinib, and 0.5-4.0 hours for ACP-5862. The absolute bioavailability of Calquence was 25%.

Effect of food on acalabrutinib

In healthy subjects, administration of a single 100 mg dose of acalabrutinib tablet with a high fat, high calorie meal (approximately 918 calories, 59 grams carbohydrate, 59 grams fat and 39 grams protein) did not affect the mean AUC as compared to dosing under fasted conditions. Resulting Cmax decreased by 54% and Tmax was delayed 1-2 hours.

Distribution