Drug Safety-related Labeling Changes (SrLC)

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CALQUENCE (NDA-210259)

(ACALABRUTINIB)

Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)

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02/19/2026 (SUPPL-12)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.1 Serious and Opportunistic Infections

Additions and/or revisions underlined:

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 29% of 2,055 patients exposed to CALQUENCE in clinical trials, most often due to respiratory tract infections (18% of all patients, including pneumonia in 14%) [see Adverse Reactions (6.1)]. These infections predominantly occurred in the absence of Grade 3 or 4 neutropenia, with neutropenic infection reported in 8% of all patients. Opportunistic infections in recipients of CALQUENCE have included, but are not limited to, hepatitis B virus reactivation, fungal pneumonia, Pneumocystis jirovecii 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.

In an additional cohort of patients receiving CALQUENCE in combination with venetoclax with obinutuzumab (AVO) (an unapproved regimen for previously untreated CLL/SLL in AMPLIFY), serious or Grade 3 or higher infections occurred in 25% receiving AVO compared to 14% in patients receiving AV. Fatal infections occurred in 6% receiving AVO compared to 3.1% of patients receiving AV, most commonly due to COVID-19. The safety and effectiveness of AVO has not been established in patients with previously untreated CLL/SLL [see Clinical Studies (14.3)].

5.2 Hemorrhage

Additions and/or revisions underlined:

Fatal and serious hemorrhagic events have occurred in patients treated with CALQUENCE. Major hemorrhage (serious or Grade 3 or higher bleeding or any central nervous system bleeding) occurred in 4.7% of patients, with fatal hemorrhage occurring in 0.1% of 2,055 patients exposed to CALQUENCE in clinical trials. Bleeding events of any grade, excluding bruising and petechiae, occurred in 39% of patients [see Adverse Reactions (6.1)].

Use of antithrombotic agents concomitantly with CALQUENCE may further increase the risk of hemorrhage. In clinical trials, major hemorrhage occurred in 5% of patients taking CALQUENCE without antithrombotic agents and 3.2% 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 to 7 days pre- and post-surgery depending upon the type of surgery and the risk of bleeding.

5.3 Cytopenias

Additions and/or revisions underlined:

CALQUENCE can cause Grade 3 or 4 cytopenias. Grade 3 or 4 cytopenias included absolute neutrophil count decreased (28%), absolute lymphocyte count decreased (10%), hemoglobin decreased (9%), and platelets decreased (9%) in 1,758 patients treated with CALQUENCE alone and in combination with obinutuzumab or venetoclax; Grade 4 neutropenia developed in 14% [see Adverse Reactions (6.1)].

Monitor complete blood counts regularly during treatment. Interrupt treatment, reduce the dose, or discontinue treatment as warranted [see Dosage and Administration (2.3)].

5.4 Second Primary Malignancies

Additions and/or revisions underlined:

Second primary malignancies, including skin cancers and other solid tumors, occurred in 16% of 2,055 patients exposed to CALQUENCE in clinical trials [see Adverse Reactions (6.1)]. The most frequent second primary malignancy was non-melanoma skin cancer, reported in 9% of patients, followed by other solid tumors in 8% (including melanoma, lung cancer, gastrointestinal cancers, and genitourinary cancers) and hematologic malignancies (1.1%). Fatal second primary malignancies occurred in 0.8% of patients. Monitor patients for the development of second cancers and advise protection from sun exposure.

5.5 Cardiac Arrhythmias

Additions and/or revisions underlined:

Fatal and serious cardiac arrhythmias have occurred in patients treated with CALQUENCE. Grade 3 or 4 atrial fibrillation or flutter was reported in 2.2% of 2,055 patients treated with CALQUENCE, with all grades of atrial fibrillation or flutter reported in 7% of all patients [see Adverse Reactions (6.1)]. Grade 3 or higher ventricular arrhythmia events were reported in 0.5% of patients, including fatal cases in 0.3% of all patients. The risk of arrhythmias 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.

6 Adverse Reactions

6.1 Clinical Trials Experience

Extensive changes; please refer to label for complete information

7 Drug Interactions

7.1 Effect of Other Drugs on CALQUENCE

Changes to table; please refer to label for complete information

8 Use in Specific Populations

8.5 Geriatric Use

Additions and/or revisions underlined:

CLL and Previously Treated MCL

Of the 1,758 CALQUENCE-treated patients with B-cell malignancies (excluding previously untreated MCL) in clinical trials, 1,074 (61%) were 65 years of age or older, and 341 (19%) were 75 years of age or older. Among patients 65 years of age or older, 73% had Grade 3 or higher adverse reactions and 55% had serious adverse reactions. Among patients younger than age 65, 58% had Grade 3 or higher adverse reactions and 35% had serious adverse reactions. No clinically relevant differences in efficacy were observed between patients greater than or equal to 65 years and younger.

Of patients that received CALQUENCE in combination with venetoclax in AMPLIFY, 33% (97/291) were greater than or equal to 65 years of age, and 4.5% (13/291) were greater than or equal to 75 years of age. In patients 65 years of age or older and younger than age 65, the fatal adverse reactions were 5% and 2.6% respectively. No clinically relevant differences in efficacy were observed between patients greater than or equal to 65 years of age and younger adults.

Previously Untreated MCL

Of the 297 CALQUENCE-treated patients with previously untreated MCL, 214 (72%) were 65 to 74 years of age and 83 (28%) were 75 years of age and older. No clinically relevant differences in safety or efficacy were observed between patients ages 65 to 74 years and those who were 75 years of age and older.

8.6 Hepatic Impairment

Additions and/or revisions underlined:

Avoid use of CALQUENCE in patients with severe hepatic impairment (Child-Pugh class C). No dosage adjustment of CALQUENCE is recommended in patients with mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment. The safety of CALQUENCE has not been evaluated in patients with moderate or severe hepatic impairment [see Clinical Pharmacology (12.3)].

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

PATIENT INFORMATION

Additions and/or revisions underlined:

…

How should I take CALQUENCE?

…

• Do not switch (interchange) your CALQUENCE capsules with CALQUENCE tablets.

…

The most common side effects of CALQUENCE include:

• diarrhea

• muscle and joint pain

• upper respiratory infection

• headache

• decreased white blood cell counts

• decreased platelet counts

 …

01/16/2025 (SUPPL-11)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.1 Serious and Opportunistic Infections

Additions and/or revisions underlined:

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 32% of 1,764 patients exposed to CALQUENCE in clinical trials, most often due to respiratory tract infections (19% of all patients, including pneumonia in 9%) [see Adverse Reactions (6.1)]. These infections predominantly occurred in the absence of Grade 3 or 4 neutropenia, with neutropenic infection reported in 2.7% 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.

5.2 Hemorrhage

Additions and/or revisions underlined:

Fatal and serious hemorrhagic events have occurred in patients treated with CALQUENCE. Major hemorrhage (serious or Grade 3 or higher bleeding or any central nervous system bleeding) occurred in 4.4% of patients, with fatal hemorrhage occurring in 0.2% of 1,764 patients exposed to CALQUENCE in clinical trials. Bleeding events of any grade, excluding bruising and petechiae, occurred in 40% of patients [see Adverse Reactions (6.1)].

Use of antithrombotic agents concomitantly with CALQUENCE may further increase the risk of hemorrhage. In clinical trials, major hemorrhage occurred in 7% of patients taking CALQUENCE without antithrombotic agents and 4% 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 to 7 days pre- and post-surgery depending upon the type of surgery and the risk of bleeding.

5.3 Cytopenias

Additions and/or revisions underlined:

CALQUENCE can cause Grade 3 or 4 cytopenias. Grade 3 or 4 cytopenias included absolute neutrophil count decreased (26%), platelets decreased (10%), hemoglobin decreased (10%), and absolute lymphocyte count decreased (10%) in patients treated with CALQUENCE alone or in combination with obinutuzumab; Grade 4 neutropenia developed in 14% [see Adverse Reactions (6.1)].

Monitor complete blood counts regularly during treatment. Interrupt treatment, reduce the dose, or discontinue treatment as warranted [see Dosage and Administration (2.4)].

5.4 Second Primary Malignancies

Additions and/or revisions underlined:

Second primary malignancies, including skin cancers and other solid tumors, occurred in 18% of 1,764 patients exposed to CALQUENCE in clinical trials [see Adverse Reactions (6.1)]. The most frequent second primary malignancy was non-melanoma skin cancer, reported in 10% of patients, followed by other solid tumors in 9% (including melanoma, lung cancer, gastrointestinal cancers, and genitourinary cancers) and hematologic malignancies (1%). Monitor patients for the development of second cancers and advise protection from sun exposure.

5.5 Cardiac Arrhythmias

Additions and/or revisions underlined:

Fatal and serious cardiac arrhythmias have occurred in patients treated with CALQUENCE. Grade 3 or 4 atrial fibrillation or flutter was reported in 2.6% of 1,764 patients treated with CALQUENCE, with all grades of atrial fibrillation or flutter reported in 7% of all patients [see Adverse Reactions (6.1)]. Grade 3 or higher ventricular arrhythmia events were reported in 0.6% of patients, including fatal cases in 0.3% of all patients. The risk of arrhythmias 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.

6 Adverse Reactions

6.1 Clinical Trials Experience

Extensive changes; please refer to label for complete information

8 Use in Specific Populations

8.5 Geriatric Use

Additions and/or revisions underlined:

CLL and Previously Treated MCL

Of the 1,467 CALQUENCE-treated patients with CLL or relapsed or refractory MCL in clinical trials, 977 (67%) were 65 years of age or older, and 328 (22%) were 75 years of age or older. Among patients 65 years of age or older, 74% had Grade 3 or higher adverse reactions and 58% had serious adverse reactions. Among patients younger than age 65, 61% had Grade 3 or higher adverse reactions and 39% had serious adverse reactions. No clinically relevant differences in efficacy were observed between patients greater than or equal to 65 years and younger.

Previously Untreated MCL

Of the 297 CALQUENCE-treated patients with previously untreated MCL, 214 (72%) were 65 to 74 years of age and 83 (28%) were 75 years of age and older. No clinically relevant differences in safety or efficacy were observed between patients ages 65 to 74 years and those who were 75 years of age and older.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

PATIENT INFORMATION

Additions and/or revisions underlined:

What is CALQUENCE?

CALQUENCE is a prescription medicine used to treat adults with:

• Mantle cell lymphoma (MCL) in combination with bendamustine and rituximab in people who have not had prior treatment for MCL and who cannot receive a type of stem cell transplant that uses their own blood stem cells (autologous hematopoietic stem cell transplantation).

• Mantle cell lymphoma (MCL) who have received at least one prior therapy.

• Chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL).

It is not known if CALQUENCE is safe and effective in children.

Before taking CALQUENCE, tell your healthcare provider about all of your medical conditions, including if you:

…

• are pregnant or plan to become pregnant. CALQUENCE may harm your unborn baby and cause problems during childbirth (dystocia).

…

What are the possible side effects of CALQUENCE? CALQUENCE can cause serious side effects, including:

• Serious infections have happened in people treated with CALQUENCE and may lead to death. Your healthcare provider may prescribe certain medicines if you have an increased risk of getting infections. Tell your healthcare provider right away if you have any signs or symptoms of an infection, including fever, chills, or flu-like symptoms.

• Bleeding problems (hemorrhage) have happened in people treated with CALQUENCE and can be serious and may lead to death. Your risk of bleeding may increase if you are also taking a blood thinner medicine. Tell your healthcare provider if you have any signs or symptoms of bleeding, including:

…

• Heart rhythm problems (cardiac arrhythmias) have happened in people treated with CALQUENCE, and can be serious or lead to death. Tell your healthcare provider if you have any of the following signs or symptoms:

  • fast or irregular heartbeat                          

  • chest discomfort

  • dizziness                                                    

  • shortness of breath

  • feeling faint

• Liver problems. Liver problems have happened in people treated with CALQUENCE, and can be severe or life-threatening, or lead to death. Contact your healthcare provider if you experience stomach pain or discomfort, urine of dark color or yellowing of your skin. Your healthcare provider will request tests to monitor your liver function during treatment with CALQUENCE.

The most common side effects of CALQUENCE include:

• diarrhea

• muscle and joint pain

• upper respiratory infection

• headache

• lower respiratory infection

• tiredness

…

06/05/2024 (SUPPL-10)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.5 Cardiac Arrhythmias

Subsection title revision

Additions and/or revisions underlined:

Serious cardiac arrhythmias have occurred in patients treated with CALQUENCE. 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. Grade 3 or higher ventricular arrhythmia events were reported in 0.9% of 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.

5.6 Hepatotoxicity, Including Drug-Induced Liver Injury

Newly added subsection

Hepatotoxicity, including severe, life-threatening, and potentially fatal cases of drug-induced liver injury (DILI), has occurred in patients treated with Bruton tyrosine kinase inhibitors, including CALQUENCE.

Evaluate bilirubin and transaminases at baseline and throughout treatment with CALQUENCE. For patients who develop abnormal liver tests after CALQUENCE, monitor more frequently for liver test abnormalities and clinical signs and symptoms of hepatic toxicity. If DILI is suspected, withhold CALQUENCE. Upon confirmation of DILI, discontinue CALQUENCE.

6 Adverse Reactions

Addition of the following to the bulleted line listing:

• Cardiac Arrhythmias [see Warnings and Precautions (5.5)]

• Hepatotoxicity, including DILI [see Warnings and Precautions (5.6)]

6.2 Postmarketing Experience

Newly added subsection

The following adverse reactions have been identified during postapproval use of CALQUENCE. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

• Cardiac disorders: ventricular arrhythmias
• Hepatobiliary disorders: drug-induced liver injury

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined:

Cardiac Arrhythmias

Counsel patients to report any signs of palpitations, dizziness, fainting, chest discomfort, and shortness of breath [see Warnings and Precautions (5.5)].

Hepatotoxicity, Including Drug-Induced Liver Injury:

Inform patients that liver problems, including drug-induced liver injury and abnormalities in liver tests, may develop during CALQUENCE treatment. Advise patients to contact their healthcare provider immediately if they experience abdominal discomfort, dark urine, or jaundice [see Warnings and Precautions (5.6)].

PATIENT INFORMATION

Additions and/or revisions underlined:

CALQUENCE may cause serious side effects, including:

…

• Heart rhythm problems (cardiac arrhythmias) have happened in people treated with CALQUENCE, which may be serious or lead to death.

  …

• Liver problems. Liver problems can happen during treatment with CALQUENCE, which may be severe or life-threatening, or lead to death. Contact your healthcare provider if you experience stomach pain or discomfort, urine of dark color or yellowing of your skin. Your healthcare provider will request tests to monitor your liver function during treatment with CALQUENCE.

11/21/2019 (SUPPL-6)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.1 Serious and Opportunistic Infections

(Newly Added Subsection)

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.

5.2 Hemorrhage

(Additions and/or revisions underlined)

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.

5.3 Cytopenias

(Additions and/or revisions underlined)

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.

5.4 Second Primary Malignancies

(Additions and/or revisions underlined)

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.

5.5 Atrial Fibrillation and Flutter

(Additions and/or revisions underlined)

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.

6 Adverse Reactions

(Additions and/or revisions underlined) 

The following clinically significant adverse reactions are discussed in greater detail in other sections of the labeling:

• Serious and Opportunistic Infections

6.1 Clinical Trials Experience

(Extensive changes; please refer to labeling)

8 Use in Specific Populations

8.5 Geriatric Use

(Additions and/or revisions underlined)

Of the 929 patients with CLL or MCL in clinical trials of CALQUENCE, 68% were 65 years of age or older, and 24% were 75 years of age or older. Among patients 65 years of age or older, 59% had Grade 3 or higher adverse reactions and 39% had serious adverse reactions. Among patients younger than age 65, 45% had Grade 3 or higher adverse reactions and 25% had serious adverse reactions. No clinically relevant differences in efficacy were observed between patients greater than or equal to 65 years and younger.

8.6 Hepatic Impairment

(Newly Added Subsection)

Avoid administration of CALQUENCE in patients with severe hepatic impairment. The safety of CALQUENCE has not been evaluated in patients with moderate or severe hepatic impairment.

8.1 Pregnancy

(Additions and/or revisions underlined)

Risk Summary

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. In animal reproduction studies, administration of acalabrutinib to animals during organogenesis resulted in dystocia in rats and reduced fetal growth in rabbits at maternal exposures (AUC) 2 times exposures in patients at the recommended dose of 100 mg approximately every 12 hours. Advise pregnant women of the potential risk to a fetus.

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

Data

Animal Data

In a combined fertility and embryo-fetal development study in female rats, acalabrutinib was administered orally at doses up to 200 mg/kg/day starting 14 days prior to mating through gestational day [GD] 17. No effects on embryo-fetal development and survival were observed. The AUC at 200 mg/kg/day in pregnant rats was approximately 9-times the AUC in patients at the recommended dose of 100 mg approximately every 12 hours. The presence of acalabrutinib and its active metabolite were confirmed in fetal rat plasma.

In an embryo-fetal development study in rabbits, pregnant animals were administered acalabrutinib orally at doses up to 200 mg/kg/day during the period of organogenesis (from GD 6-18). Administration of acalabrutinib at doses ? 100 mg/kg/day produced maternal toxicity and 100 mg/kg/day resulted in decreased fetal body weights and delayed skeletal ossification. The AUC at 100 mg/kg/day in pregnant rabbits was approximately 2-times the AUC in patients at 100 mg approximately every 12 hours.

In a pre- and postnatal development study in rats, acalabrutinib was administered orally to pregnant animals during organogenesis, parturition and lactation, at doses of 50, 100, and 150 mg/kg/day. Dystocia (prolonged or difficult labor) and mortality of offspring were observed at doses greater than or equal to 100 mg/kg/day. The AUC at 100 mg/kg/day in pregnant rats was approximately 2-times the AUC in patients at 100 mg approximately every 12 hours. Underdeveloped renal papilla was also observed in F1 generation offspring at 150 mg/kg/day with an AUC approximately 5-times the AUC in patients at 100 mg approximately every 12 hours

8.3 Females and Males of Reproductive Potential

(Newly Added Subsection)

Pregnancy

Pregnancy testing is recommended for females of reproductive potential prior to initiating CALQUENCE therapy.

Contraception

Females

CALQUENCE may cause embryo-fetal harm and dystocia when administered to pregnant women. 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. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be informed of the potential hazard to a fetus.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

17 PATIENT COUNSELING INFORMATION

(Additions and/or revisions underlined)

Advise the patient to read the FDA-approved patient labeling (Patient Information).

Serious and Opportunistic Infections

Inform patients of the possibility of serious infection and to report signs or symptoms suggestive of

infection.

Hemorrhage

Inform patients to report signs or symptoms of bleeding. Inform patients that CALQUENCE may need to be interrupted for major surgeries.

Cytopenias

Inform patients that they will need periodic blood tests to check blood counts during treatment with CALQUENCE.

Second Primary Malignancies

Inform patients that other malignancies have been reported in patients who have been treated with CALQUENCE, including skin cancer and other solid tumors. Advise patients to use sun protection.

Atrial Fibrillation and Flutter

Counsel patients to report any signs of palpitations, dizziness, fainting, chest discomfort, and shortness of breath.

Pregnancy Complication

CALQUENCE may cause fetal harm and dystocia. Advise women to avoid becoming pregnant during treatment and for at least 1 week after the last dose of CALQUENCE.

Lactation

Advise females not to breastfeed during treatment with CALQUENCE and for at least 2 weeks after the final dose.

11/21/2019 (SUPPL-7)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.1 Serious and Opportunistic Infections

(Newly Added Subsection)

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.

5.2 Hemorrhage

(Additions and/or revisions underlined)

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.

5.3 Cytopenias

(Additions and/or revisions underlined)

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.

5.4 Second Primary Malignancies

(Additions and/or revisions underlined)

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.

5.5 Atrial Fibrillation and Flutter

(Additions and/or revisions underlined)

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.

6 Adverse Reactions

(Additions and/or revisions underlined)

The following clinically significant adverse reactions are discussed in greater detail in other sections of the labeling:

• Serious and Opportunistic Infections

6.1 Clinical Trials Experience

(Extensive changes; please refer to labeling)

8 Use in Specific Populations

8.1 Pregnancy

(Additions and/or revisions underlined)

Risk Summary 

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. In animal reproduction studies, administration of acalabrutinib to animals during organogenesis resulted in dystocia in rats and reduced fetal growth in rabbits at maternal exposures (AUC) 2 times exposures in patients at the recommended dose of 100 mg approximately every 12 hours. Advise pregnant women of the potential risk to a fetus.

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

Data

Animal Data

In a combined fertility and embryo-fetal development study in female rats, acalabrutinib was administered orally at doses up to 200 mg/kg/day starting 14 days prior to mating through gestational day [GD] 17. No effects on embryo-fetal development and survival were observed. The AUC at 200 mg/kg/day in pregnant rats was approximately 9-times the AUC in patients at the recommended dose of 100 mg approximately every 12 hours. The presence of acalabrutinib and its active metabolite were confirmed in fetal rat plasma.

In an embryo-fetal development study in rabbits, pregnant animals were administered acalabrutinib orally at doses up to 200 mg/kg/day during the period of organogenesis (from GD 6-18). Administration of acalabrutinib at doses ? 100 mg/kg/day produced maternal toxicity and 100 mg/kg/day resulted in decreased fetal body weights and delayed skeletal ossification. The AUC at 100 mg/kg/day in pregnant rabbits was approximately 2-times the AUC in patients at 100 mg approximately every 12 hours.

In a pre- and postnatal development study in rats, acalabrutinib was administered orally to pregnant animals during organogenesis, parturition and lactation, at doses of 50, 100, and 150 mg/kg/day. Dystocia (prolonged or difficult labor) and mortality of offspring were observed at doses greater than or equal to 100 mg/kg/day. The AUC at 100 mg/kg/day in pregnant rats was approximately 2-times the AUC in patients at 100 mg approximately every 12 hours. Underdeveloped renal papilla was also observed in F1 generation offspring at 150 mg/kg/day with an AUC approximately 5-times the AUC in patients at 100 mg approximately every 12 hours.

8.3 Females and Males of Reproductive Potential

(Newly Added Subsection)

Pregnancy

Pregnancy testing is recommended for females of reproductive potential prior to initiating CALQUENCE therapy.

Contraception 

Females

CALQUENCE may cause embryo-fetal harm and dystocia when administered to pregnant women. 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. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be informed of the potential hazard to a fetus.

8.5 Geriatric Use

(Additions and/or revisions underlined)

Of the 929 patients with CLL or MCL in clinical trials of CALQUENCE, 68% were 65 years of age or older, and 24% were 75 years of age or older. Among patients 65 years of age or older, 59% had Grade 3 or higher adverse reactions and 39% had serious adverse reactions. Among patients younger than age 65, 45% had Grade 3 or higher adverse reactions and 25% had serious adverse reactions. No clinically relevant differences in efficacy were observed between patients greater than or equal to 65 years and younger.

8.6 Hepatic Impairment

(Newly Added Subsection)

Avoid administration of CALQUENCE in patients with severe hepatic impairment. The safety of CALQUENCE has not been evaluated in patients with moderate or severe hepatic impairment.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

17 PATIENT COUNSELING INFORMATION

(Additions and/or revisions underlined)

Advise the patient to read the FDA-approved patient labeling (Patient Information).

Serious and Opportunistic Infections

Inform patients of the possibility of serious infection and to report signs or symptoms suggestive of

infection.

Hemorrhage

Inform patients to report signs or symptoms of bleeding. Inform patients that CALQUENCE may need to be interrupted for major surgeries.

Cytopenias

Inform patients that they will need periodic blood tests to check blood counts during treatment with CALQUENCE.

Second Primary Malignancies

Inform patients that other malignancies have been reported in patients who have been treated with CALQUENCE, including skin cancer and other solid tumors. Advise patients to use sun protection.

Atrial Fibrillation and Flutter

Counsel patients to report any signs of palpitations, dizziness, fainting, chest discomfort, and shortness of breath.

Pregnancy Complication

CALQUENCE may cause fetal harm and dystocia. Advise women to avoid becoming pregnant during treatment and for at least 1 week after the last dose of CALQUENCE.

Lactation

Advise females not to breastfeed during treatment with CALQUENCE and for at least 2 weeks after the final dose.