HIGHLIGHTS OF PRESCRIBING INFORMATION
`These highlights do not include all the information needed to use
`CALQUENCE safely and effectively. See full prescribing information for
`CALQUENCE.
`
`CALQUENCE® (acalabrutinib) tablets, for oral use
`Initial U.S. Approval: 2017
`
` --------------------------- INDICATIONS AND USAGE --------------------------
`CALQUENCE is a kinase inhibitor indicated for the treatment of adult
`patients with:
`• Mantle cell lymphoma (MCL) who have received at least one prior
`therapy. (1.1)
`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. (1.1, 14.1)
`Chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma
`(SLL). (1.2)
`
`•
`
` ---------------------- DOSAGE AND ADMINISTRATION ----------------------
`Recommended dose is 100 mg orally approximately every 12 hours;
`•
`swallow whole with water and with or without food. (2.1)
`Advise patients not to chew, crush, dissolve, or cut tablets. (2.1)
`•
`• Manage toxicities using treatment interruption, dose reduction, or
`discontinuation. (2.2)
`Avoid CALQUENCE in patients with severe hepatic impairment. (8.6)
`
`•
`
` --------------------- DOSAGE FORMS AND STRENGTHS --------------------
`Tablets: 100 mg. (3)
`
` ------------------------------ CONTRAINDICATIONS -----------------------------
`None. (4)
`
` ----------------------- WARNINGS AND PRECAUTIONS ----------------------
`Serious and Opportunistic Infections: Monitor for signs and symptoms
`•
`of infection and treat promptly. (5.1)
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`1 INDICATIONS AND USAGE
`1.1 Mantle Cell Lymphoma
`1.2 Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma
`2 DOSAGE AND ADMINISTRATION
`2.1 Recommended Dosage
`2.2 Recommended Dosage for Drug Interactions
`2.3 Dosage Modifications for Adverse Reactions
`3 DOSAGE FORMS AND STRENGTHS
`4 CONTRAINDICATIONS
`5 WARNINGS AND PRECAUTIONS
`5.1 Serious and Opportunistic Infections
`5.2 Hemorrhage
`5.3 Cytopenias
`5.4 Second Primary Malignancies
`5.5 Atrial Fibrillation and Flutter
`6 ADVERSE REACTIONS
`6.1 Clinical Trials Experience
`7 DRUG INTERACTIONS
`7.1 Effect of Other Drugs on CALQUENCE
`8 USE IN SPECIFIC POPULATIONS
`
`•
`•
`•
`
`•
`
`Hemorrhage: Monitor for bleeding and manage appropriately. (5.2)
`Cytopenias: Monitor complete blood counts regularly. (5.3)
`Second Primary Malignancies: Other malignancies have occurred,
`including skin cancers and other solid tumors. Advise patients to use sun
`protection. (5.4)
`Atrial Fibrillation and Flutter: Monitor for symptoms of arrhythmias and
`manage. (5 5)
`
` ------------------------------ ADVERSE REACTIONS -----------------------------
`Most common adverse reactions (incidence ≥ 30%) are: anemia, neutropenia,
`upper respiratory tract infection, thrombocytopenia, headache, diarrhea, and
`musculoskeletal pain. (6.1)
`To report SUSPECTED ADVERSE REACTIONS, contact AstraZeneca
`at 1-800-236-9933 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
`
`•
`
` ------------------------------ DRUG INTERACTIONS -----------------------------
`Strong CYP3A Inhibitors: Avoid co-administration with CALQUENCE.
`•
`(2.2, 7)
`• Moderate CYP3A Inhibitors: Reduce the dosage of CALQUENCE. (2.2,
`7)
`Strong CYP3A Inducers: Avoid co-administration with CALQUENCE.
`If co-administration is unavoidable, increase the dosage of
`CALQUENCE. (2.2, 7)
` ----------------------- USE IN SPECIFIC POPULATIONS ----------------------
`Pregnancy: May cause fetal harm and dystocia. (8.1)
`•
`•
`Lactation: Advise not to breastfeed. (8.2)
`Severe Hepatic Impairment: Avoid use of CALQUENCE. (8.6)
`•
`See 17 for PATIENT COUNSELING INFORMATION and
`FDA-approved patient labeling.
`
`Revised: 8/2022
`
`
`
`8.1 Pregnancy
`8.2 Lactation
`8.3 Females and Males of Reproductive Potential
`8.4 Pediatric Use
`8.5 Geriatric Use
`8.6 Hepatic Impairment
`11 DESCRIPTION
`12 CLINICAL PHARMACOLOGY
`12.1 Mechanism of Action
`12.2 Pharmacodynamics
`12.3 Pharmacokinetics
`13 NONCLINICAL TOXICOLOGY
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`14 CLINICAL STUDIES
`14.1 Mantle Cell Lymphoma
`14.2 Chronic Lymphocytic Leukemia
`16 HOW SUPPLIED/STORAGE AND HANDLING
`17 PATIENT COUNSELING INFORMATION
`
`
`*Sections or subsections omitted from the full prescribing information are not listed.
`
`______________________________________________________________________________________________________________________________________
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`FULL PRESCRIBING INFORMATION
`
`1 INDICATIONS AND USAGE
`
`1.1 Mantle Cell Lymphoma
`CALQUENCE is 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 [see Clinical
`Studies (14.1)]. Continued approval for this indication may be contingent upon verification and
`description of clinical benefit in confirmatory trials.
`
`1.2 Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma
`CALQUENCE is indicated for the treatment of adult patients with chronic lymphocytic leukemia (CLL)
`or small lymphocytic lymphoma (SLL).
`
`2 DOSAGE AND ADMINISTRATION
`
`2.1 Recommended Dosage
`CALQUENCE as Monotherapy
`
`For patients with MCL, CLL, or SLL, the recommended dosage of CALQUENCE is 100 mg taken orally
`approximately every 12 hours until disease progression or unacceptable toxicity.
`
`CALQUENCE in Combination with Obinutuzumab
`
`For patients with previously untreated CLL or SLL, the recommended dosage of CALQUENCE is
`100 mg taken orally approximately every 12 hours until disease progression or unacceptable toxicity.
`Start CALQUENCE at Cycle 1 (each cycle is 28 days). Start obinutuzumab at Cycle 2 for a total of 6
`cycles and refer to the obinutuzumab prescribing information for recommended dosing. Administer
`CALQUENCE prior to obinutuzumab when given on the same day.
`
`Advise patients to swallow tablet whole with water. Advise patients not to chew, crush, dissolve, or cut
`the tablets. CALQUENCE may be taken with or without food. If a dose of CALQUENCE is missed by
`more than 3 hours, it should be skipped and the next dose should be taken at its regularly scheduled time.
`Extra tablets of CALQUENCE should not be taken to make up for a missed dose.
`
`2.2 Recommended Dosage for Drug Interactions
`Dosage Modifications for Use with CYP3A Inhibitors or Inducers
`
`These are described in Table 1 [see Drug Interactions (7)].
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`Table 1: Recommended Dosage Modifications for Use with CYP3A Inhibitors or Inducers
`
`CYP3A
`
`Co-administered Drug
`
`Strong CYP3A inhibitor
`
`Inhibition
`
`Recommended CALQUENCE use
`Avoid co-administration.
`If these inhibitors will be used short-term (such as
`anti-infectives for up to seven days), interrupt
`CALQUENCE.
`After discontinuation of strong CYP3A inhibitor for at
`least 24 hours, resume previous dosage of
`CALQUENCE.
`
`Moderate CYP3A inhibitor
`
`Reduce the CALQUENCE 100 mg every 12 hours
`dosage to 100 mg once daily.
`
`Induction
`
`Strong CYP3A inducer
`
`Avoid co-administration.
` If co-administration is unavoidable, increase
`CALQUENCE dosage to 200 mg approximately every
`12 hours.
`
`2.3 Dosage Modifications for Adverse Reactions
`Recommended dosage modifications of CALQUENCE for Grade 3 or greater adverse reactions are
`provided in Table 2.
`
`Table 2: Recommended Dosage Modifications for Adverse Reactions
`
`Event
`
`Grade 3 or greater non-
`hematologic toxicities,
`Grade 3 thrombocytopenia
`with bleeding,
`Grade 4 thrombocytopenia or
`Grade 4 neutropenia lasting
`longer than 7 days
`
`Adverse
`Reaction
`Occurrence
`
`First and Second
`
`Third
`
`Dosage Modification
`(Starting dose = 100 mg approximately every 12
`hours)
`Interrupt CALQUENCE.
`Once toxicity has resolved to Grade 1 or baseline
`level, CALQUENCE may be resumed at 100 mg
`approximately every 12 hours.
`
`Interrupt CALQUENCE.
`Once toxicity has resolved to Grade 1 or baseline
`level, CALQUENCE may be resumed at a
`reduced frequency of 100 mg once daily.
`
`Discontinue CALQUENCE.
`Fourth
`Adverse reactions graded by the National Cancer Institute Common Terminology Criteria for Adverse Events
`(NCI CTCAE).
`
`
`Refer to the obinutuzumab prescribing information for management of obinutuzumab toxicities.
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`3 DOSAGE FORMS AND STRENGTHS
`
`Tablets:100 mg acalabrutinib, orange, oval, film-coated, biconvex, debossed with ‘ACA 100’ on one side
`and plain on the other.
`
`4 CONTRAINDICATIONS
`
`None.
`
`5 WARNINGS AND PRECAUTIONS
`
`5.1 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%) [see Adverse Reactions (6.1)]. 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 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.
`
`5.2 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 [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 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 to 7 days pre- and post-surgery depending
`upon the type of surgery and the risk of bleeding.
`
`5.3 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 [see Adverse Reactions (6.1)]. Monitor complete blood
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`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
`Second primary malignancies, including skin cancers and other solid tumors, occurred in 12% of 1029
`patients exposed to CALQUENCE in clinical trials [see Adverse Reactions (6.1)]. 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
`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 [see Adverse Reactions (6.1)]. 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
`
`The following clinically significant adverse reactions are discussed in greater detail in other sections of
`the labeling:
`
`• Serious and Opportunistic Infections [see Warnings and Precautions (5.1)]
`• Hemorrhage [see Warnings and Precautions (5.2)]
`• Cytopenias [see Warnings and Precautions (5.3)]
`• Second Primary Malignancies [see Warnings and Precautions (5.4)]
`• Atrial Fibrillation and Flutter [see Warnings and Precautions (5.5)]
`
`6.1 Clinical Trials Experience
`As clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the
`clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may
`not reflect the rates observed in practice.
`
`The data in the Warnings and Precautions reflect exposure to CALQUENCE 100 mg approximately every
`12 hours in 1029 patients with hematologic malignancies. Treatment includes CALQUENCE
`monotherapy in 820 patients in 6 trials, and CALQUENCE with obinutuzumab in 209 patients in 2 trials.
`Among these recipients of CALQUENCE, 88% were exposed for at least 6 months and 79% were
`exposed for at least one year. In this pooled safety population, adverse reactions in ≥ 30% of 1029
`patients were anemia, neutropenia, upper respiratory tract infection, thrombocytopenia, headache,
`diarrhea, and musculoskeletal pain.
`
`Mantle Cell Lymphoma
`
`The safety data described in this section reflect exposure to CALQUENCE (100 mg approximately every
`12 hours) in 124 patients with previously treated MCL in Trial LY-004 [see Clinical Studies (14.1)]. The
`median duration of treatment with CALQUENCE was 16.6 (range: 0.1 to 26.6) months. A total of 91
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`(73.4%) patients were treated with CALQUENCE for ≥ 6 months and 74 (59.7%) patients were treated
`for ≥ 1 year.
`
`The most common adverse reactions (≥ 20%) of any grade were anemia, thrombocytopenia, headache,
`neutropenia, diarrhea, fatigue, myalgia, and bruising. Grade 1 severity for the non-hematologic, most
`common events were as follows: headache (25%), diarrhea (16%), fatigue (20%), myalgia (15%), and
`bruising (19%). The most common Grade ≥ 3 non-hematological adverse reaction (reported in at least
`2% of patients) was diarrhea.
`
`Dose reductions and discontinuation due to any adverse reaction were reported in 1.6% and 6.5% of
`patients, respectively.
`
`Tables 3 and 4 present the frequency category of adverse reactions observed in patients with MCL treated
`with CALQUENCE.
`
`Table 3: Non-Hematologic Adverse Reactions in ≥ 5% (All Grades) of Patients with MCL in Trial
`LY-004
`
`CALQUENCE Monotherapy
`N=124
`
`All Grades (%)
`
`Grade ≥ 3 (%)
`
`Body System
`Adverse Reactions*
`Nervous system disorders
`Headache
`Gastrointestinal disorders
`Diarrhea
`Nausea
`Abdominal pain
`Constipation
`Vomiting
`General disorders
`Fatigue
`Musculoskeletal and connective tissue disorders
`Myalgia
`Skin and subcutaneous tissue disorders
`Bruisinga
`Rashb
`Vascular disorders
`Hemorrhagec
`Respiratory, thoracic and mediastinal disorders
`Epistaxis
`*Per NCI CTCAE version 4.03.
`a Bruising: Includes all terms containing ‘bruise,’ ‘contusion,’ ‘petechiae,’ or ‘ecchymosis’
`b Rash: Includes all terms containing ‘rash’
`c Hemorrhage: Includes all terms containing ‘hemorrhage’ or ‘hematoma’
`
`1.6
`
`3.2
`0.8
`1.6
`-
`1.6
`
`0.8
`
`0.8
`
`-
`0.8
`
`0.8
`
`-
`
`39
`
`31
`19
`15
`15
`13
`
`28
`
`21
`
`21
`18
`
`8
`
`6
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`Table 4: Hematologic Adverse Reactions Reported in ≥ 20% of Patients with MCL in Trial LY-004
`
`Hematologic
`Adverse Reactions*
`
`All Grades (%)
`46
`Hemoglobin decreased
`44
`Platelets decreased
`36
`Neutrophils decreased
`*Per NCI CTCAE version 4.03; based on laboratory measurements and adverse reactions.
`
`CALQUENCE Monotherapy
`N=124
`
`Grade ≥ 3 (%)
`10
`12
`15
`
`Increases in creatinine to 1.5 to 3 times the upper limit of normal (ULN) occurred in 4.8% of patients.
`
`Chronic Lymphocytic Leukemia
`
`The safety data described below reflect exposure to CALQUENCE (100 mg approximately every 12
`hours, with or without obinutuzumab) in 511 patients with CLL from two randomized controlled clinical
`trials [see Clinical Studies (14.2)].
`
`The most common adverse reactions (≥ 30%) of any grade in patients with CLL were anemia,
`neutropenia, thrombocytopenia, headache, upper respiratory tract infection, and diarrhea.
`
`ELEVATE-TN
`
`The safety of CALQUENCE plus obinutuzumab (CALQUENCE+G), CALQUENCE monotherapy, and
`obinutuzumab plus chlorambucil (GClb) was evaluated in a randomized, multicenter, open-label, actively
`controlled trial in 526 patients with previously untreated CLL [see Clinical Studies (14.2)].
`
`Patients randomized to the CALQUENCE+G arm were treated with CALQUENCE and obinutuzumab in
`combination for six cycles, then with CALQUENCE as monotherapy until disease progression or
`unacceptable toxicity. Patients initiated obinutuzumab on Day 1 of Cycle 2, continuing for a total of 6
`cycles. Patient randomized to CALQUENCE monotherapy received CALQUENCE approximately every
`12 hours until disease progression or unacceptable toxicity. The trial required age ≥ 65 years of age or 18
`to < 65 years of age with a total Cumulative Illness Rating Scale (CIRS) > 6 or creatinine clearance of 30
`to 69 mL/min, hepatic transaminases ≤ 3 times ULN and total bilirubin ≤ 1.5 times ULN, and allowed
`patients to receive antithrombotic agents other than warfarin or equivalent vitamin K antagonists.
`
`During randomized treatment, the median duration of exposure to CALQUENCE in the
`CALQUENCE+G and CALQUENCE monotherapy arms was 27.7 months (range 0.3 to 40 months), with
`95% and 92% and 89% and 86% of patients with at least 6 months and 12 months of exposure,
`respectively. In the obinutuzumab and chlorambucil arm the median number of cycles was 6 with 84% of
`patients receiving at least 6 cycles of obinutuzumab, 70% of patients received at least 6 cycles of
`chlorambucil. Eighty-five percent of patients in the CALQUENCE+G arm received at least 6 cycles of
`obinutuzumab.
`
`In the CALQUENCE+G and CALQUENCE monotherapy arms, fatal adverse reactions that occurred in
`the absence of disease progression and with onset within 30 days of the last study treatment were reported
`in 2% for each treatment arm, most often from infection. Serious adverse reactions were reported in 39%
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`of patients in the CALQUENCE+G arm and 32% in the CALQUENCE monotherapy arm, most often due
`to events of pneumonia (2.8% to 7%).
`
`In the CALQUENCE+G arm, adverse reactions led to treatment discontinuation in 11% of patients and a
`dose reduction of CALQUENCE in 7% of patients. In the CALQUENCE monotherapy arm, adverse
`reactions led to discontinuation in 10% and dose reduction in 4% of patients.
`
`Tables 5 and 6 present adverse reactions and laboratory abnormalities identified in the ELEVATE-TN
`trial.
`
`Table 5: Common Adverse Reactions (≥ 15% Any Grade) with CALQUENCE in Patients with
`CLL (ELEVATE-TN)
`
`Body System
`Adverse Reaction*
`
`
`
`CALQUENCE plus
`Obinutuzumab
`N=178
`All Grades
`Grade ≥ 3
`(%)
`(%)
`
`CALQUENCE
`Monotherapy
`N=179
`All Grades
`Grade ≥ 3
`(%)
`(%)
`
`Obinutuzumab plus
`Chlorambucil
`N=169
`All Grades
`Grade ≥ 3
`(%)
`(%)
`
`Infections
`Infection†
`Upper respiratory tract
`infection§
`Lower respiratory tract
`infectiona
`15
`Urinary tract infection
`Blood and lymphatic system disordersb
`Neutropeniac
`53
`Anemiad
`52
`Thrombocytopeniae
`51
`Lymphocytosisf
`12
`Nervous system disorders
`Headache
`Dizziness
`Gastrointestinal disorders
`4.5
`39
`Diarrhea
`0
`20
`Nausea
`Musculoskeletal and connective tissue disorders
`37
`2.2
`Musculoskeletal paing
`Arthralgia
`22
`1.1
`General disorders and administration site conditions
`Fatigueh
`34
`2.2
`Skin and subcutaneous tissue disorders
`Bruisingi
`31
`Rashj
`26
`
`69
`39
`
`24
`
`40
`20
`
`22‡
`2.8
`
`8
`
`1.7
`
`37
`12
`12
`11
`
`1.1
`0
`
`0
`2.2
`
`65
`35
`
`18
`
`15
`
`23
`53
`32
`16
`
`39
`12
`
`35
`22
`
`32
`16
`
`23
`
`21
`25
`
`14‡
`0
`
`4.5
`
`2.8
`
`13
`10
`3.4
`15
`
`1.1
`0
`
`0.6
`0
`
`1.1
`0.6
`
`1.1
`
`0
`0.6
`
`46
`17
`
`7
`
`5
`
`78
`54
`61
`0.6
`
`12
`7
`
`21
`31
`
`16
`4.7
`
`24
`
`5
`9
`
`13‡
`1.2
`
`1.8
`
`0.6
`
`50
`14
`16
`0.6
`
`0
`0
`
`1.8
`0
`
`2.4
`1.2
`
`1.2
`
`0
`0.6
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`Body System
`Adverse Reaction*
`
`
`
`CALQUENCE plus
`Obinutuzumab
`N=178
`All Grades
`Grade ≥ 3
`(%)
`(%)
`
`CALQUENCE
`Monotherapy
`N=179
`All Grades
`Grade ≥ 3
`(%)
`(%)
`
`Obinutuzumab plus
`Chlorambucil
`N=169
`All Grades
`Grade ≥ 3
`(%)
`(%)
`
`20
`
`1.7
`
`20
`
`1.7
`
`6
`
`0
`
`Vascular disorders
`Hemorrhagek
`*Per NCI CTCAE version 4.03
`† Includes any adverse reactions involving infection or febrile neutropenia
`‡ Includes 3 fatal cases in the CALQUENCE plus obinutuzumab arm, 3 fatal cases in the CALQUENCE
`monotherapy arm and 1 fatal case in the obinutuzumab plus chlorambucil arm
`§ Includes upper respiratory tract infection, nasopharyngitis and sinusitis
`a Includes pneumonia, lower respiratory tract infection, bronchitis, bronchiolitis, tracheitis, and lung infection
`b Derived from adverse reaction and laboratory data
`c Includes neutropenia, neutrophil count decreased, and related laboratory data
`d Includes anemia, red blood cell count decreased, and related laboratory data
`e Includes thrombocytopenia, platelet count decreased, and related laboratory data
`f Includes lymphocytosis, lymphocyte count increased, and related laboratory data
`g Includes back pain, bone pain, musculoskeletal chest pain, musculoskeletal pain, musculoskeletal discomfort,
`myalgia, neck pain, pain in extremity and spinal pain
`h Includes asthenia, fatigue, and lethargy
`i Includes bruise, contusion, and ecchymosis
`j Includes rash, dermatitis, and other related terms
`k Includes hemorrhage, hematoma, hemoptysis, hematuria, menorrhagia, hemarthrosis, and epistaxis
`
`Other clinically relevant adverse reactions (all grades incidence < 15%) in recipients of CALQUENCE
`(CALQUENCE in combination with obinutuzumab and monotherapy) included:
`
`• Neoplasms: second primary malignancy (10%), non-melanoma skin cancer (5%)
`• Cardiac disorders: atrial fibrillation or flutter (3.6%), hypertension (5%)
`Infection: herpesvirus infection (6%)
`•
`
`Table 6: Select Non-Hematologic Laboratory Abnormalities (≥ 15% Any Grade), New or
`Worsening from Baseline in Patients Receiving CALQUENCE (ELEVATE-TN)
`
`Laboratory
`Abnormality*,a
`
`CALQUENCE plus
`Obinutuzumab
`N=178
`All Grades
`Grade ≥ 3
`(%)
`(%)
`29
`29
`30
`7
`38
`5
`13
`0.6
`
`CALQUENCE
`Monotherapy
`N=179
`All Grades
`Grade ≥ 3
`(%)
`(%)
`22
`22
`20
`1.1
`17
`0.6
`15
`0.6
`
`Obinutuzumab plus
`Chlorambucil
`N=169
`All Grades
`Grade ≥ 3
`(%)
`(%)
`37
`37
`36
`6
`60
`8
`11
`0.6
`
`Uric acid increase
`ALT increase
`AST increase
`Bilirubin increase
`*Per NCI CTCAE version 4.03
`a Excludes electrolytes
`Increases in creatinine to 1.5 to 3 times ULN occurred in 3.9% and 2.8% of patients in the CALQUENCE
`combination arm and monotherapy arm, respectively.
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`ASCEND
`
`The safety of CALQUENCE in patients with relapsed or refractory CLL was evaluated in a randomized,
`open-label study (ASCEND) [see Clinical Studies (14.2)]. The trial enrolled patients with relapsed or
`refractory CLL after at least one prior therapy and required hepatic transaminases ≤ 2 times ULN, total
`bilirubin ≤ 1.5 times ULN, and an estimated creatinine clearance ≥ 30 mL/min. The trial excluded
`patients having an absolute neutrophil count < 500/µL, platelet count < 30,000/µL, prothrombin time or
`activated partial thromboplastin time > 2 times ULN, significant cardiovascular disease, or a requirement
`for strong CYP3A inhibitors or inducers. Patients were allowed to receive antithrombotic agents other
`than warfarin or equivalent vitamin K antagonist.
`
`In ASCEND, 154 patients received CALQUENCE (100 mg approximately every 12 hours until disease
`progression or unacceptable toxicity), 118 received idelalisib (150 mg approximately every 12 hours until
`disease progression or unacceptable toxicity) with up to 8 infusions of a rituximab product, and 35
`received up to 6 cycles of bendamustine and a rituximab product. The median age overall was 68 years
`(range: 32-90); 67% were male; 92% were white; and 88% had an ECOG performance status of 0 or 1.
`
`In the CALQUENCE arm, serious adverse reactions occurred in 29% of patients. Serious adverse
`reactions in > 5% of patients who received CALQUENCE included lower respiratory tract infection (6%).
`Fatal adverse reactions within 30 days of the last dose of CALQUENCE occurred in 2.6% of patients,
`including from second primary malignancies and infection.
`
`In recipients of CALQUENCE, permanent discontinuation due to an adverse reaction occurred in 10% of
`patients, most frequently due to second primary malignancies followed by infection. Adverse reactions
`led to dosage interruptions of CALQUENCE in 34% of patients, most often due to respiratory tract
`infections followed by neutropenia, and dose reduction in 3.9% of patients.
`
`Selected adverse reactions are described in Table 7 and non-hematologic laboratory abnormalities are
`described in Table 8. These tables reflect exposure to CALQUENCE with median duration of 15.7
`months with 94% of patients on treatment for greater than 6 months and 86% of patients on treatment for
`greater than 12 months. The median duration of exposure to idelalisib was 11.5 months with 72% of
`patients on treatment for greater than 6 months and 48% of patients on treatment for greater than 12
`months. Eighty-three percent of patients completed 6 cycles of bendamustine and rituximab product.
`
`Reference ID: 5024985
`
`10
`
`

`

`56
`29
`
`23
`
`22
`
`18
`
`16
`
`15‡
`1.9
`
`6
`
`23
`15
`6
`19
`
`0.6
`
`1.3
`
`1.3
`
`65
`26
`
`26
`
`79
`45
`41
`23
`
`6
`
`49
`
`5
`
`13
`
`15
`
`28‡
`3.4
`
`15
`
`53
`8
`13
`18
`
`0
`
`25
`
`1.7
`
`0.8
`
`1.7
`
`49
`17
`
`14
`
`80
`57
`54
`2.9
`
`0
`
`14
`
`6
`
`31
`
`2.9
`
`11
`2.9
`
`6
`
`40
`17
`6
`2.9
`
`0
`
`0
`
`2.9
`
`6
`
`0
`
`Table 7: Common Adverse Reactions (≥ 15% Any Grade) with CALQUENCE in Patients with
`CLL (ASCEND)
`
`CALQUENCE
`N=154
`All Grades
`Grade ≥ 3
`(%)
`(%)
`
`Idelalisib plus
`Rituximab
`Product N=118
`All Grades
`Grade ≥ 3
`(%)
`(%)
`
`Bendamustine plus
`Rituximab Product
`N=35
`All Grades
`Grade ≥ 3
`(%)
`(%)
`
`
`
`Body System
`Adverse Reaction*
`Infections
`Infection†
`Upper respiratory tract
`infection§
`Lower respiratory tract
`infection a
`Blood and lymphatic system disordersb
`Neutropeniac
`48
`Anemiad
`47
`33
`Thrombocytopeniae
`Lymphocytosisf
`26
`Nervous system disorders
`Headache
`Gastrointestinal disorders
`Diarrheag
`Vascular disorders
`Hemorrhageh
`General disorders
`Fatiguei
`1.9
`15
`Musculoskeletal and connective tissue disorders
`Musculoskeletal painj
`15
`1.3
`* Per NCI CTCAE version 4.03
`† Includes any adverse reactions involving infection or febrile neutropenia
`‡ Includes 1 fatal case in the CALQUENCE monotherapy arm and 1 fatal case in the Idelalisib plus Rituximab arm
`§ Includes upper respiratory tract infection, rhinitis and nasopharyngitis
`a Includes pneumonia, lower respiratory tract infection, bronchitis, bronchiolitis, tracheitis, and lung infection.
`b Derived from adverse reaction and laboratory data
`c Includes neutropenia, neutrophil count decreased, and related laboratory data
`d Includes anemia, red blood cell decreased, and related laboratory data
`e Includes thrombocytopenia, platelet count decreased, and related laboratory data
`f Includes lymphocytosis, lymphocyte count increased and related laboratory data
`g Includes colitis, diarrhea, and enterocolitis
`h Includes hemorrhage, hematoma, hemoptysis, hematuria, menorrhagia, hemarthrosis, and epistaxis
`i Includes asthenia, fatigue, and lethargy
`j Includes back pain, musculoskeletal chest pain, musculoskeletal pain, musculoskeletal discomfort, pain in
`extremity, myalgia, spinal pain and bone pain
`
`Other clinically relevant adverse reactions (all grades incidence < 15%) in recipients of CALQUENCE
`included:
`
`• Skin and subcutaneous disorders: bruising (10%), rash (9%)
`
`Reference ID: 5024985
`
`11
`
`

`

`• Neoplasms: second primary malignancy (12%), non-melanoma skin cancer (6%)
`• Musculoskeletal and connective tissue disorders: arthralgia (8%)
`• Cardiac disorders: atrial fibrillation or flutter (5%), hypertension (3.2%)
`Infection: herpesvirus infection (4.5%)
`•
`
`Table 8: Select Non-Hematologic Laboratory Abnormalities (≥ 10% Any Grade), New or
`Worsening from Baseline in Patients Receiving CALQUENCE (ASCEND)
`
`Laboratory
`Abnormality a
`
`CALQUENCE
`
`N=154
`
`All Grades
`(%)
`15
`15
`13
`13
`
`Grade ≥ 3
`(%)
`15
`1.9
`0.6
`1.3
`
`Idelalisib plus
`Rituximab Product
`
`Bendamustine plus
`Rituximab Product
`
`N=118
`All Grades
`Grade ≥ 3
`(%)
`(%)
`11
`11
`59
`23
`48
`13
`16
`1.7
`
`N=35
`All Grades
`Grade ≥ 3
`(%)
`(%)
`23
`23
`26
`2.9
`31
`2.9
`26
`11
`
`Uric acid increase
`ALT increase
`AST increase
`Bilirubin increase
`Per NCI CTCAE version 5
`a Excludes electrolytes
`
`Increases in creatinine to 1.5 to 3 times ULN occurred in 1.3% of patients who received CALQUENCE.
`
`7 DRUG INTERACTIONS
`
`Prevention or
`Management
`
`7.1 Effect of Other Drugs on CALQUENCE
`Strong CYP3A Inhibitors
`Clinical Effect Co-administration of CALQUENCE with a strong CYP3A inhibitor increased
`acalabrutinib plasma concentrations [see Clinical Pharmacology (12.3)]. Increased
`acalabrutinib concentrations may result in increased toxicity.
`Avoid co-administration of CALQUENCE with strong CYP3A inhibitors.
`Alternatively, if the inhibitor will be used short-term, interrupt CALQUENCE [see
`Dosage and Administration (2.2)].
`Moderate CYP3A Inhibitors
`Clinical Effect Co-administration of CALQUENCE with a moderate CYP3A inhibitor may increase
`acalabrutinib plasma concentration [see Clinical Pharmacology (12.3)]. Increased
`acalabrutinib concentrations may result in increased toxicity.
`Reduce the dosage of CALQUENCE when co-administered with a moderate CYP3A
`inhibitor [see Dosage and Administration (2.2)].
`
`Prevention or
`Management
`
`Strong CYP3A Inducers
`Clinical Effect Co-administration of CALQUENCE with a strong CYP3A inducer decreased
`acalabrutinib plasma concentration [see Clinical Pharmacology (12.3)]. Decreased
`acalabrutinib concentrations may reduce CALQUENCE activity.
`
`Reference ID: 5024985
`
`12
`
`

`

`Prevention or
`Management
`
`Avoid co-administration of CALQUENCE with strong CYP3A inducers. If co-
`administration is unavoidable, increase the dosage of CALQUENCE [see Dosage and
`Administration (2.2)].
`
`8 USE IN SPECIFIC POPULATIONS
`
`8.1 Pregnancy
`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 (see Data). 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 to 4% and 15 to 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 appro