CENTER FOR DRUG EVALUATION AND RESEARCH
`
`Approval Package for:
`
`APPLICATION NUMBER:
`210259Orig1s006
`210259Orig1s007
`CALQUENCE capsules
`
`acalabrutinib
`
`AstraZeneca UK Limited c/o Acerta Pharma
`
`Trade Name:
`
`Generic or Proper
`Name:
`Sponsor:
`
`Approval Date:
`
`November 21, 2019
`
`Indication:
`
`For the treatment of adult patients with chronic
`lymphocytic leukemia (CLL) or small lymphocytic
`lymphoma (SLL).
`
`

`

`CENTER FOR DRUG EVALUATION AND RESEARCH
`210259Orig1s006
`210259Orig1s007
`
`CONTENTS
`
`Reviews / Information Included in this NDA Review.
`
`Approval Letter
`Other Action Letters
`Labeling
`REMS
`Officer/Employee List
`Multidiscipline Review(s)
`(cid:120) Summary Review
`(cid:120) Office Director
`(cid:120) Cross Discipline Team Leader
`(cid:120) Clinical
`(cid:120) Non-Clinical
`(cid:120) Statistical
`(cid:120) Clinical Pharmacology
`Product Quality Review(s)
`Clinical Microbiology / Virology Review(s)
`Other Reviews
`Risk Assessment and Risk Mitigation Review(s)
`Proprietary Name Review(s)
`Administrative/Correspondence Document(s)
`
`X
`
`X
`
`X
`
`X
`
`

`

`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`APPLICATION NUMBER:
`210259Orig1s006
`210259Orig1s007
`
`APPROVAL LETTER
`
`

`

`NDA 210259/S-006
`NDA 210259/S-007
`
`SUPPLEMENT APPROVAL
`FULFILLMENT OF POSTMARKETING REQUIREMENT
`
`AstraZeneca UK Limited
`c/o Acerta Pharma
`Attention: Amanda Roodhouse
`Director, Regulatory Science
`121 Oyster Point Blvd
`South San Francisco, CA 94080
`
`Dear Ms. Roodhouse:
`
`Please refer to your supplemental new drug applications (sNDAs) dated
`September 24, 2019, received September 24, 2019, and your amendments, submitted
`under section 505(b) of the Federal Food, Drug, and Cosmetic Act (FDCA) for
`CALQUENCE (acalabrutinib) capsules.
`
`These Prior Approval supplemental new drug applications provide for the use of
`CALQUENCE for the treatment of adult patients with chronic lymphocytic leukemia
`(CLL) or small lymphocytic lymphoma (SLL).
`
`APPROVAL & LABELING
`
`We have completed our review of this application, as amended. It is approved, effective
`on the date of this letter, for use as recommended in the enclosed agreed-upon
`labeling.
`
`WAIVER OF ½ PAGE LENGTH REQUIREMENT FOR HIGHLIGHTS
`
`We are waiving the requirements of 21 CFR 201.57(d)(8) regarding the length of
`Highlights of Prescribing Information. This waiver applies to all future supplements
`containing revised labeling unless we notify you otherwise.
`
`CONTENT OF LABELING
`
`As soon as possible, but no later than 14 days from the date of this letter, submit the
`content of labeling [21 CFR 314.50(l)] in structured product labeling (SPL) format using
`the FDA automated drug registration and listing system (eLIST), as described at
`FDA.gov.1 Content of labeling must be identical to the enclosed labeling (text for the
`
`1 http://www.fda.gov/ForIndustry/DataStandards/StructuredProductLabeling/default.htm
`
`Reference ID: 4523127
`
`

`

`NDA 210259/S-006
`NDA 210259/S-007
`Page 2
`
`Prescribing Information and Patient Package Insert), with the addition of any labeling
`changes in pending “Changes Being Effected” (CBE) supplements, as well as annual
`reportable changes not included in the enclosed labeling.
`
`Information on submitting SPL files using eList may be found in the guidance for
`industry SPL Standard for Content of Labeling Technical Qs and As.2
`
`The SPL will be accessible from publicly available labeling repositories.
`
`Also, within 14 days, amend all pending supplemental applications that include labeling
`changes for this NDA, including CBE supplements for which FDA has not yet issued an
`action letter, with the content of labeling [21 CFR 314.50(l)(1)(i)] in Microsoft Word
`format, that includes the changes approved in this supplemental application, as well as
`annual reportable changes. To facilitate review of your submission(s), provide a
`highlighted or marked-up copy that shows all changes, as well as a clean Microsoft
`Word version. The marked-up copy should provide appropriate annotations, including
`supplement number(s) and annual report date(s).
`
`REQUIRED PEDIATRIC ASSESSMENTS
`
`Under the Pediatric Research Equity Act (PREA) (21 U.S.C. 355c), all applications for
`new active ingredients (which includes new salts and new fixed combinations), new
`indications, new dosage forms, new dosing regimens, or new routes of administration
`are required to contain an assessment of the safety and effectiveness of the product for
`the claimed indication in pediatric patients unless this requirement is waived, deferred,
`or inapplicable.
`
`Because this drug product for this indication has an orphan drug designation, you are
`exempt from this requirement.
`
`FULFILLMENT OF POSTMARKETING REQUIREMENT
`
`We have received your submission dated September 24, 2019, containing the final
`report for the following postmarketing requirement listed in the October 31, 2017,
`accelerated approval letter for NDA 210259.
`
`PMR 3291-3 Conduct a clinical pharmacokinetic trial to determine an appropriate safe
`dose of acalabrutinib in patients with severe hepatic impairment. This trial
`should be designed and conducted in accordance with the FDA Guidance
`for Industry entitled “Pharmacokinetics in Patients with Impaired Hepatic
`
`2 We update guidances periodically. For the most recent version of a guidance, check the FDA Guidance
`Documents Database https://www.fda.gov/RegulatoryInformation/Guidances/default.htm.
`
`U.S. Food and Drug Administration
`Silver Spring, MD 20993
`www.fda.gov
`
`Reference ID: 4523127
`
`

`

`NDA 210259/S-006
`NDA 210259/S-007
`Page 3
`
`Function: Study Design, Data Analysis, and Impact on Dosing and
`Labeling.”
`
`We have reviewed your submission and conclude that the above requirement was
`fulfilled.
`
`We remind you that there is a postmarketing requirement listed in the October 31, 2017,
`accelerated approval letter that is still open.
`
`PROMOTIONAL MATERIALS
`
`You may request advisory comments on proposed introductory advertising and
`promotional labeling. To do so, submit the following, in triplicate, (1) a cover letter
`requesting advisory comments, (2) the proposed materials in draft or mock-up form with
`annotated references, and (3) the Prescribing Information to:
`
`OPDP Regulatory Project Manager
`Food and Drug Administration
`Center for Drug Evaluation and Research
`Office of Prescription Drug Promotion (OPDP)
`5901-B Ammendale Road
`Beltsville, MD 20705-1266
`
`Alternatively, you may submit a request for advisory comments electronically in eCTD
`format. For more information about submitting promotional materials in eCTD format,
`see the draft guidance for industry Providing Regulatory Submissions in Electronic and
`Non-Electronic Format-Promotional Labeling and Advertising Materials for Human
`Prescription Drugs.3
`
`You must submit final promotional materials and Prescribing Information, accompanied
`by a Form FDA 2253, at the time of initial dissemination or publication
`[21 CFR 314.81(b)(3)(i)]. Form FDA 2253 is available at FDA.gov.4 Information and
`Instructions for completing the form can be found at FDA.gov.5 For more information
`about submission of promotional materials to the Office of Prescription Drug Promotion
`(OPDP), see FDA.gov.6
`
`3 When final, this guidance will represent the FDA’s current thinking on this topic. For the most recent
`version of a guidance, check the FDA guidance web page at
`https://www.fda.gov/RegulatoryInformation/Guidances/default.htm.
`4 http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM083570.pdf
`5 http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM375154.pdf
`6 http://www.fda.gov/AboutFDA/CentersOffices/CDER/ucm090142.htm
`
`U.S. Food and Drug Administration
`Silver Spring, MD 20993
`www.fda.gov
`
`Reference ID: 4523127
`
`

`

`NDA 210259/S-006
`NDA 210259/S-007
`Page 4
`
`REPORTING REQUIREMENTS
`
`We remind you that you must comply with reporting requirements for an approved NDA
`(21 CFR 314.80 and 314.81).
`
`If you have any questions, call Jennifer Lee, Senior Regulatory Health Project Manager,
`at (240) 402-4622.
`
`Sincerely,
`
`{See appended electronic signature page}
`
`Ann T. Farrell, MD
`Director
`Division of Hematology Products
`Office of Drug Evaluation I
`Center for Drug Evaluation and Research
`
`ENCLOSURES:
`(cid:120) Content of Labeling
`o Prescribing Information
`o Patient Package Insert
`
`U.S. Food and Drug Administration
`Silver Spring, MD 20993
`www.fda.gov
`
`Reference ID: 4523127
`
`

`

`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`APPLICATION NUMBER:
`
`210259Orig1s006
`210259Orig1s007
`
`LABELING
`
`

`

`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) capsules, for oral use
`Initial U.S. Approval: 2017
`
`--------------------------- RECENT MAJOR CHANGES --------------------------
`Indications and Usage (1.2)
`11/2019
`Dosage and Administration (2.2)
`11/2019
`
`--------------------------- 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 break, open, or chew capsules. (2.1)
`Manage toxicities using treatment interruption, dose reduction, or
`discontinuation. (2.2)
`Avoid CALQUENCE in patients with severe hepatic impairment (2.2,
`8.6)
`
`!
`!
`
`!
`
`--------------------- DOSAGE FORMS AND STRENGTHS --------------------
`Capsules: 100 mg. (3)
`
`------------------------------ CONTRAINDICATIONS -----------------------------
`None. (4)
`
`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 Hepatic Impairment
`2.3 Recommended Dosage for Drug Interactions
`Concomitant Use with Gastric Acid Reducing Agents
`2.4 Dose 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
`8 USE IN SPECIFIC POPULATIONS
`
`!
`!
`!
`
`----------------------- WARNINGS AND PRECAUTIONS ----------------------
`Serious and Opportunistic Infections: Monitor for signs and symptoms
`!
`of infection and treat promptly. (5.1)
`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%) were: 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 -----------------------------
`CYP3A Inhibitors: Avoid co-administration with strong CYP3A
`!
`inhibitors. Dose adjustments may be recommended. (2.3, 7, 12.3)
`CYP3A Inducers: Avoid co-administration with strong CYP3A
`inducers. Dose adjustments may be recommended. (2.3, 7, 12.3)
`Gastric Acid Reducing Agents: Avoid co-administration with proton
`pump inhibitors (PPIs). Stagger dosing with H2-receptor antagonists and
`antacids. (2.4, 7, 12.3)
`
`!
`
`----------------------- USE IN SPECIFIC POPULATIONS ----------------------
`Pregnancy: May cause fetal harm and dystocia (8.1)
`!
`Lactation: Advise not to breastfeed. (8.2)
`!
`See 17 for PATIENT COUNSELING INFORMATION and
`FDA-approved patient labeling.
`
`Revised: 11/2019
`
`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.
`
`______________________________________________________________________________________________________________________________________
`
`Reference ID: 4523127
`
`

`

`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 dose 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 dose 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 capsule whole with water. Advise patients not to open, break or chew the
`capsules. 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 capsules of CALQUENCE should not be taken to make up for a missed dose.
`
`2.2 Recommended Dosage for Hepatic Impairment
`Avoid administration of CALQUENCE in patients with severe hepatic impairment.
`
`Dose modifications are not required for patients with mild or moderate hepatic impairment [see Use in
`Specific Populations (8.6) and Clinical Pharmacology (12.3)].
`
`Reference ID: 4523127
`
`

`

`2.3 Recommended Dosage for Drug Interactions
`
`Dose Modifications for Use with CYP3A Inhibitors or Inducers
`These are described in Table 1 [see Drug Interactions (7)].
`
`Table 1: Recommended Dose Modifications for Use with CYP3A Inhibitors or Inducers
`
`CYP3A
`
`Co-administered Drug
`
`Strong CYP3A inhibitor
`
`Inhibition
`
`Recommended CALQUENCE use
`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
`
`100 mg once daily.
`
`Induction
`
`Strong CYP3A inducer
`
`Avoid concomitant use.
`If these inducers cannot be avoided, increase
`CALQUENCE dose to 200 mg approximately every 12
`hours.
`
`Concomitant Use with Gastric Acid Reducing Agents
`
`Proton Pump Inhibitors: Avoid concomitant use [see Drug Interactions (7)].
`
`H2-Receptor Antagonists: Take CALQUENCE 2 hours before taking a H2-receptor antagonist [see Drug
`Interactions (7)].
`
`Antacids: Separate dosing by at least 2 hours [see Drug Interactions (7)].
`
`2.4 Dose Modifications for Adverse Reactions
`Recommended dose modifications of CALQUENCE for Grade 3 or greater adverse reactions are
`provided in Table 2.
`
`Table 2: Recommended Dose Modifications for Adverse Reactions
`
`Event
`
`Grade 3 or greater non-
`hematologic toxicities,
`Grade 3 thrombocytopenia
`with bleeding,
`Grade 4 thrombocytopenia
`
`Adverse
`Reaction
`Occurrence
`
`First and Second
`
`Dose 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.
`
`Reference ID: 4523127
`
`

`

`Event
`
`or
`Grade 4 neutropenia lasting
`longer than 7 days
`
`Adverse
`Reaction
`Occurrence
`
`Third
`
`Dose 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 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.
`
`3 DOSAGE FORMS AND STRENGTHS
`
`100 mg capsules.
`
`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%). 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
`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.
`
`Reference ID: 4523127
`
`

`

`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
`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 [see Dose
`Modifications for Adverse Reactions (2.4)].
`
`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. 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. 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.
`
`Reference ID: 4523127
`
`

`

`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
`(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
`
`Grade ≥ 3 (%)
`
`All Grades (%)
`
`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
`
`Reference ID: 4523127
`
`39
`
`31
`19
`15
`15
`13
`
`28
`
`21
`
`21
`
`1.6
`
`3.2
`0.8
`1.6
`-
`1.6
`
`0.8
`
`0.8
`
`-
`
`

`

`Body System
`Adverse Reactions*
`
`CALQUENCE Monotherapy
`N=124
`
`All Grades (%)
`18
`
`Grade ≥ 3 (%)
`0.8
`
`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’
`
`8
`
`6
`
`0.8
`
`-
`
`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 1.5 to 3 times the upper limit of normal 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 upper limit of normal (ULN) and total bilirubin ≤ 1.5
`times ULN, and allowed patients to receive antithrombotic agents other than warfarin or equivalent
`vitamin K antagonists.
`
`Reference ID: 4523127
`
`

`

`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%
`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 presents 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
`(%)
`(%)
`
`Infections
`Infection†
`Upper respiratory tract
`infectiona
`Lower respiratory tract
`infectionb
`15
`Urinary tract infection
`Blood and lymphatic system disorders§
`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
`
`69
`39
`
`24
`
`40
`20
`
`22‡
`2.8
`
`8
`
`1.7
`
`37
`12
`12
`11
`
`1.1
`0
`
`CALQUENCE
`Monotherapy
`N=179
`All Grades
`Grade ≥ 3
`(%)
`(%)
`
`Obinutuzumab plus
`Chlorambucil
`N=169
`All Grades
`Grade ≥ 3
`(%)
`(%)
`
`65
`35
`
`18
`
`15
`
`23
`53
`32
`16
`
`39
`12
`
`35
`22
`
`14‡
`0
`
`4.5
`
`2.8
`
`13
`10
`3.4
`15
`
`1.1
`0
`
`0.6
`0
`
`46
`17
`
`7
`
`5
`
`78
`54
`61
`0.6
`
`12
`7
`
`21
`31
`
`13‡
`1.2
`
`1.8
`
`0.6
`
`50
`14
`16
`0.6
`
`0
`0
`
`1.8
`0
`
`Reference ID: 4523127
`
`

`

`0
`2.2
`
`1.7
`
`20
`
`23
`
`21
`25
`
`20
`
`1.1
`
`0
`0.6
`
`1.7
`
`24
`
`5
`9
`
`6
`
`1.2
`
`0
`0.6
`
`0
`
`Body System
`Adverse Reaction*
`
`CALQUENCE
`Monotherapy
`N=179
`All Grades
`Grade ≥ 3
`(%)
`(%)
`32
`1.1
`16
`0.6
`
`Obinutuzumab plus
`Chlorambucil
`N=169
`All Grades
`Grade ≥ 3
`(%)
`(%)
`16
`2.4
`4.7
`1.2
`
`CALQUENCE plus
`Obinutuzumab
`N=178
`All Grades
`Grade ≥ 3
`(%)
`(%)
`37
`2.2
`Musculoskeletal paing
`22
`1.1
`Arthralgia
`General disorders and administration site conditions
`Fatigueh
`34
`2.2
`Skin and subcutaneous tissue disorders
`Bruisingi
`31
`Rashj
`26
`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
`§ Derived from adverse reaction and laboratory data
`a Upper respiratory tract infection, nasopharyngitis and sinusitis
`b Includes pneumonia, lower respiratory tract infection, bronchitis, bronchiolitis, tracheitis, and lung infection
`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
`gIncludes 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%)
`
`Reference ID: 4523127
`
`

`

`Table 6: Select Non-Hematologic Laboratory Abnormalities (≥ 15% Any Grade), New or
`Worsening from Baseline in Patients Receiving CALQUENCE (ELEVATE-TN)
`
`CALQUENCE plus
`Obinutuzumab
`
`CALQUENCE
`Monotherapy
`
`Obinutuzumab plus
`Chlorambucil
`
`Laboratory
`Abnormality*,a
`
`Uric acid increase
`ALT increase
`AST increase
`Bilirubin increase
`*Per NCI CTCAE version 4.03
`a Excludes electrolytes
`
`All
`Grades (%)
`29
`30
`38
`13
`
`N=178
`Grade ≥ 3
`(%)
`29
`7
`5
`0.6
`
`All
`Grades (%)
`22
`20
`17
`15
`
`N=179
`Grade ≥ 3
`(%)
`22
`1.1
`0.6
`0.6
`
`All
`Grades (%)
`37
`36
`60
`11
`
`N=169
`Grade ≥ 3
`(%)
`37
`6
`8
`0.6
`
`Increases in creatinine 1.5 to 3 times the upper limit of normal occurred in 3.9% and 2.8% of patients in
`the CALQUENCE combination arm and monotherapy arm, respectively.
`
`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 upper limit of
`normal (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