Warnings and Precautions

Warnings and precautions include hemorrhage, infections, cytopenias, second primary malignancies, and atrial fibrillation/flutter.1

Hemorrhage: Monitor for bleeding and manage appropriately. Infections: Monitor patients for signs and symptoms of infection and treat as needed. Cytopenias: Monitor complete blood counts monthly during treatment. Second Primary Malignancies: Other malignancies have occurred in patients, including skin cancers and other carcinomas. Advise patients to use sun protection. Atrial Fibrillation and Flutter: Monitor for atrial fibrillation and atrial flutter and manage as appropriate.

Please see Important Safety Information below.

INITIAL DATA ANALYSIS FROM LY-004

Adverse Reactions in LY-004

The most common adverse reactions (≥20%) of any grade were anemia, thrombocytopenia, headache, neutropenia, diarrhea, fatigue, myalgia, and bruising.1

  • Grade 1 severity rates for the most common, non-hematologic events were: headache (25%), diarrhea (16%), fatigue (20%), myalgia (15%), and bruising (19%)

Non-Hematologic Adverse ReactionsNon-Hematologic Adverse Reactions

*Grading per National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03. Bruising: includes all preferred terms (PTs) containing bruise, contusion, petechiae, or ecchymosis; rash: includes all PTs containing rash; hemorrhage/hematoma: includes all PTs containing hemorrhage or hematoma.

In the initial analysis of the LY-004 trial

  • The most common non-hematological adverse reaction was headache,1 which occurred in 39% of patients (47/124)1,2

    • 64% (30/47) of headache events were Grade 1, and 77% of patients (36/47) had only one event; no patients discontinued treatment due to headache2

    • Median time to onset was 5 days; median duration was 11 days2

  • The most common non-hematological Grade 3 or worse adverse reaction was diarrhea in 3.2% of patients2

    • Overall incidence of diarrhea was 31%, all grades (38/124)2

    • 55% (21/38) of diarrhea events were Grade 1, and 74% of patients (28/38) had only one event2

    • Median time to onset of diarrhea was 50 days; median time to resolution was 7 days2

  • No cases of atrial fibrillation or atrial flutter were reported1,2

  • There was 1 Grade 5 event: aortic stenosis in a patient with a medical history of aortic stenosis (not considered treatment-related)2

Select Safety Information

Cytopenias

In the combined safety database of 612 patients with hematologic malignancies, patients treated with CALQUENCE monotherapy experienced Grade 3 or 4 cytopenias, including neutropenia (23%), anemia (11%), and thrombocytopenia (8%), based on laboratory measurements. Monitor complete blood counts monthly during treatment.

Atrial Fibrillation and Flutter

In the combined safety database of 612 patients with hematologic malignancies treated with CALQUENCE monotherapy, atrial fibrillation and atrial flutter of any grade occurred in 3% of patients, and Grade 3 in 1% of patients. Monitor for atrial fibrillation and atrial flutter and manage as appropriate.

Hematological adverse reactions reported in patients with MCL treated with CALQUENCE.Hematological adverse reactions reported in patients with MCL treated with CALQUENCE.

*Grading per National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03.Based on laboratory measurements and adverse reactions.

  • The most common hematological Grade 3 or worse adverse reactions included: neutropenia, 10% (13/124); and anemia, 9% (11/124)2

  • Increases in creatinine 1.5 to 3 times the upper limit of normal occurred in 4.8% of patients1

Dose Reductions & Discontinuations

Most patients completed therapy at the recommended dose1

Rates of dose reduction and discontinuation due to AEs (N=124)1

Rates of dose reduction and discontinuation while taking CALQUENCE.Rates of dose reduction and discontinuation while taking CALQUENCE.

  • Median duration of therapy was 16.6 months (range: 0.1 to 26.6 months)

24-MONTH UPDATE ANALYSIS FROM LY-004

CALQUENCE: Safety Profile Consistent With Initial Analysis

Most common treatment-emergent adverse events (AEs) ≥20%: headache, diarrhea, fatigue, myalgia, and cough3

  • Majority of these events were low-grade and associated with few discontinuations and dose reductions3

Most frequently reported Grade 3 or 4 AEs were anemia and neutropenia3

Treatment-emergent Adverse Events of Clinical InterestTreatment-emergent Adverse Events of Clinical Interest

NSCLC = non-small cell lung cancer. *AEs were coded using the Medical Dictionary for Regulatory Activities (MedDRA) Version 20.1.3

  • Grade 5 events included aortic stenosis, NSCLC, pneumonia, pulmonary embolism, myelodysplastic syndrome, and suicide3

Most patients completed therapy at the recommended dose3

Rates of dose reductions and discontinuation due to adverse events while taking CALQUENCE.Rates of dose reductions and discontinuation due to adverse events while taking CALQUENCE.

  • Median duration of therapy was 17.3 months (range: 0.1 to 35.1 months)

CALQUENCE: Events of Clinical Interest in the 24-Month Update Analysis Were Consistent With Initial Analysis

Most common treatment-emergent adverse events (AEs), Grade 3 or 4Most common treatment-emergent adverse events (AEs), Grade 3 or 4

*Events of clinical interest were coded using the MedDRA Version 20.1.3 Events of clinical interest were identified based on nonclinical findings, emerging data from clinical studies relating to CALQUENCE, and pharmacological effects of an approved BTKi.3 There was 1 Grade 5 AE (NSCLC) reported in the 24-month update.3

  • The most frequently reported infections (≥5% of subjects) were sinusitis (12.1%), upper respiratory tract infection (10.5%), nasopharyngitis (8.1%), bronchitis (7.3%), and pneumonia (6.5%)3

  • The most frequently reported hemorrhage events were contusion (12.9%) and petechiae (8.9%)3

    • Most hemorrhage events were Grade 1 or 23

  • Most cardiac events were Grade 1 or 2; Grade 3 or 4 cardiac events occurred in 4 subjects: acute coronary syndrome, acute myocardial infarction, cardio-respiratory arrest, and coronary artery disease (1 subject each). There was no new onset of atrial fibrillation3

  • 4 secondary malignancies: B-cell lymphoma (large-cell), invasive breast cancer, NSCLC, and metastases to meninges (confirmed by lumbar puncture)3

 

+

IMPORTANT SAFETY INFORMATION ABOUT CALQUENCE® (acalabrutinib) capsules

Serious and Opportunistic Infections

Fatal and serious infections, including opportunistic infections, have occurred in patients with hematologic malignancies treated with CALQUENCE.

Serious or Grade 3 or higher infections (bacterial, viral, or fungal) occurred in 19% of 1029 patients exposed to CALQUENCE in clinical trials, most often due to respiratory tract infections (11% of all patients, including pneumonia in 6%). These infections predominantly occurred in the absence of Grade 3 or 4 neutropenia, with neutropenic infection reported in 1.9% of all patients. Opportunistic infections in recipients of CALQUENCE have included, but are not limited to, hepatitis B virus reactivation, fungal pneumonia, Pneumocystis jiroveci pneumonia, Epstein-Barr virus reactivation, cytomegalovirus, and progressive multifocal leukoencephalopathy (PML). Consider prophylaxis in patients who are at increased risk for opportunistic infections. Monitor patients for signs and symptoms of infection and treat promptly.

Hemorrhage

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

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

Consider the benefit-risk of withholding CALQUENCE for 3-7 days pre- and post-surgery depending upon the type of surgery and the risk of bleeding.

Cytopenias

Grade 3 or 4 cytopenias, including neutropenia (23%), anemia (8%), thrombocytopenia (7%), and lymphopenia (7%), developed in patients with hematologic malignancies treated with CALQUENCE. Grade 4 neutropenia developed in 12% of patients. Monitor complete blood counts regularly during treatment. Interrupt treatment, reduce the dose, or discontinue treatment as warranted.

Second Primary Malignancies

Second primary malignancies, including skin cancers and other solid tumors, occurred in 12% of 1029 patients exposed to CALQUENCE in clinical trials. The most frequent second primary malignancy was skin cancer, reported in 6% of patients. Monitor patients for skin cancers and advise protection from sun exposure.

Atrial Fibrillation and Flutter

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

ADVERSE REACTIONS

The most common adverse reactions (≥20%) of any grade in patients with MCL were anemia,* thrombocytopenia,* headache (39%), neutropenia,* diarrhea (31%), fatigue (28%), myalgia (21%), and bruising (21%). The most common Grade ≥ 3 non-hematological adverse reaction (reported in at least 2% of patients) was diarrhea (3.2%).

*Treatment-emergent decreases (all grades) of hemoglobin (46%), platelets (44%), and neutrophils (36%) were based on laboratory measurements and adverse reactions.

Dosage reductions or discontinuations due to any adverse reaction were reported in 1.6% and 6.5% of patients, respectively.

Increases in creatinine 1.5 to 3 times the upper limit of normal occurred in 4.8% of patients.

DRUG INTERACTIONS

Strong CYP3A Inhibitors: Avoid co-administration with a strong CYP3A inhibitor. If a strong CYP3A inhibitor will be used short-term, interrupt CALQUENCE.

Moderate CYP3A Inhibitors: When CALQUENCE is co-administered with a moderate CYP3A inhibitor, reduce CALQUENCE dose to 100 mg once daily.

Strong CYP3A Inducers: Avoid co-administration with a strong CYP3A inducer. If a strong CYP3A inducer cannot be avoided, increase the CALQUENCE dose to 200 mg approximately every 12 hours.

Gastric Acid Reducing Agents: If treatment with a gastric acid reducing agent is required, consider using an H2-receptor antagonist or an antacid. Take CALQUENCE 2 hours before taking an H2-receptor antagonist. Separate dosing with an antacid by at least 2 hours.

Avoid co-administration with proton pump inhibitors. Due to the long-lasting effect of proton pump inhibitors, separation of doses may not eliminate the interaction with CALQUENCE

SPECIFIC POPULATIONS

Based on findings in animals, CALQUENCE may cause fetal harm and dystocia when administered to a pregnant woman. There are no available data in pregnant women to inform the drug-associated risk. Advise pregnant women of the potential risk to a fetus.

Pregnancy testing is recommended for females of reproductive potential prior to initiating CALQUENCE therapy. Advise female patients of reproductive potential to use effective contraception during treatment with CALQUENCE and for at least 1 week following the last dose of CALQUENCE.

It is not known if CALQUENCE is present in human milk. Advise lactating women not to breastfeed while taking CALQUENCE and for at least 2 weeks after the final dose.

Avoid administration of CALQUENCE in patients with severe hepatic impairment. Dose modifications are not required for patients with mild or moderate hepatic impairment.

INDICATION AND USAGE

CALQUENCE is a Bruton tyrosine kinase (BTK) inhibitor indicated for the treatment of adult patients with mantle cell lymphoma (MCL) who have received at least one prior therapy.

This indication is approved under accelerated approval based on overall response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

Please see complete Prescribing Information including Patient Information.

You may report side effects related to AstraZeneca products by clicking here.

Back to top

Reference:

  1. CALQUENCE [package insert]. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2019.

References:

  1. Dreyling M, Aurer I, Cortelazzo S, et al. Treatment for patients with relapsed/refractory mantle cell lymphoma: European-based recommendations. Leuk Lymphoma. 2018;59(8):1814-1828.
  2. Sandoval-Sus JD, Sotomayor EM, Shah BD. Mantle cell lymphoma: contemporary diagnostic and treatment perspectives in the age of personalized medicine. Hematol Oncol Stem Cell Ther. 2017;10(3):99-115.
  3. Shah BD, Martin P, Sotomayor EM. Mantle cell lymphoma: a clinically heterogeneous disease in need of tailored approaches. Cancer Control. 2012;19(3):227-235.
  4. Parrott M, Rule S, Kelleher M, Wilson J. A systemic review of treatments of relapsed/refractory mantle cell lymphoma. Clin Lymphoma Myeloma Leuk. 2018;18(1):13-25.
  5. Cohen JB, Zain JM, Kahl BS. Current approaches to mantle cell lymphoma: diagnosis, prognosis, and therapies. Am Soc Clin Oncol Educ Book. 2017;37:512-525.
  6. Cheah CY, Seymour JF, Wang ML. Mantle cell lymphoma. J Clin Oncol. 2016;34:1256-1269.
  7. Wang M, Rule S, Zinzani PL, et al. Acalabrutinib in relapsed or refractory mantle cell lymphoma (ACE-LY-004): a single-arm, multicentre, phase 2 trial. Lancet. 2018;391(10121):659-667.
  8. Dreyling M, Ferrero S; on behalf of European Mantle Cell Lymphoma Network. The role of targeted treatment in mantle cell lymphoma: is transplant dead or alive? Haematologica. 2016;101(2):104-114.
  9. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for B-Cell Lymphomas V.4.2018. © National Comprehensive Cancer Network, Inc. 2018. All rights reserved. Accessed May 17, 2018. To view the most recent and complete version of the guideline, go online to NCCN.org.
  10. Pal Singh S, Dammeijer F, Hendriks RW. Role of Bruton’s tyrosine kinase in B cells and malignancies. Mol Cancer. 2018;17(1):57.
  11. Barf T, Covey T, Izumi R, et al. Acalabrutinib (ACP-196): A covalent bruton tyrosine kinase inhibitor with a differentiated selectivity and in vivo potency profile. J Pharmacol Exp Ther. 2017;363(2):240-252.
  12. Barf T, Kaptein A. Irreversible protein kinase inhibitors: balancing the benefits and risks. J Med Chem. 2012;55(14):6243-6262.
  13. Paweletz CP, Andersen JN, Pollock R, et al. Identification of direct target engagement biomarkers for kinase-targeted therapeutics. PLoS One. 2011;6(10):e26459.
  14. CALQUENCE [package insert]. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2019.

Reference:

  1. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for B-Cell Lymphomas V.4.2018. © National Comprehensive Cancer Network, Inc. 2018. All rights reserved. Accessed May 17, 2018. To view the most recent and complete version of the guideline, go online to NCCN.org.

References:

  1. CALQUENCE [package insert]. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2019.
  2. Hendriks RW, Yuvaraj S, Kil LP. Targeting Bruton’s tyrosine kinase in B cell malignancies. Nat Rev Cancer. 2014;14(4):219-232.
  3. Barf T, Covey T, Izumi R, et al. Acalabrutinib (ACP-196): A covalent Bruton tyrosine kinase inhibitor with a differentiated selectivity and in vivo potency profile. J Pharmacol Exp Ther. 2017;363(2):240-252.

References:

  1. CALQUENCE [package insert]. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2019.
  2. Wang M, Rule S, Zinzani PL, et al. Acalabrutinib in relapsed or refractory mantle cell lymphoma (ACE-LY-004): a single-arm, multicentre, phase 2 trial. Lancet. 2018;391(10121):659-667.
  3. Data on File, REF-33702, AstraZeneca Pharmaceuticals LP.

References:

  1. CALQUENCE [package insert]. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2019.
  2. Wang M, Rule S, Zinzani PL, et al. Acalabrutinib in relapsed or refractory mantle cell lymphoma (ACE-LY-004): a single-arm, multicentre, phase 2 trial. Lancet. 2018;391(10121):659-667.
  3. Data on File, REF-43179. AstraZeneca Pharmaceuticals LP.

References:

  1. CALQUENCE [package insert]. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2019.
  2. Wang M, Rule S, Zinzani PL, et al. Acalabrutinib in relapsed or refractory mantle cell lymphoma (ACE-LY-004): a single-arm, multicentre, phase 2 trial. Lancet. 2018;391(10121):659-667.
  3. Data on File, REF-43179. AstraZeneca Pharmaceuticals LP.
  4. Cheson BD, Fisher RI, Barrington SF, et al. Recommendations for initial evaluation, staging, and response assessment of Hodgkin and non-Hodgkin lymphoma: The Lugano Classification. J Clin Oncol. 2014;32:3059-3068.
  5. Data on File, REF-18540. AstraZeneca Pharmaceuticals LP.

References:

  1. CALQUENCE [package insert]. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2019.
  2. Wang M, Rule S, Zinzani PL, et al. Acalabrutinib in relapsed or refractory mantle cell lymphoma (ACE-LY-004): a single-arm, multicentre, phase 2 trial. Lancet. 2018;391(10121):659-667.
  3. Cheson BD, Fisher RI, Barrington SF, et al. Recommendations for initial evaluation, staging, and response assessment of Hodgkin and non-Hodgkin lymphoma: The Lugano Classification. J Clin Oncol. 2014;32:3059-3068.
  4. Data on File, REF-43179. AstraZeneca Pharmaceuticals LP.

References:

  1. Wang M, Rule S, Zinzani PL, et al. Acalabrutinib in relapsed or refractory mantle cell lymphoma (ACE-LY-004): a single-arm, multicentre, phase 2 trial. Lancet. 2018;391(10121):659-667.
  2. CALQUENCE [package insert]. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2019.
  3. Data on File, REF-43179, AstraZeneca Pharmaceuticals LP.

Reference:

  1. CALQUENCE [package insert]. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2019.