CENTER FOR DRUG EVALUATION AND RESEARCH
`
`Approval Package for:
`
`
`APPLICATION NUMBER:
`
`205552Orig1s01
`
`Imbruvica
`
`Ibrutinib
`
`Pharmacyclics, Inc.
`
`7/28/2014
`
`Imbruvica is a kinase inhibitor indicated for the treatment of
`patients with:
`
`1. Mantle cell lymphoma (MCL) who have received at least
`one prior therapy
`
`
`2. Chronic lymphocytic leukemia (CLL) who have received
`at least one prior therapy
`
`3. Chronic lymphocytic leukemia with 17p deletion
`
`
`
`
`
`Trade Name:
`
`Generic Name:
`
`Sponsor:
`
`Approval Date:
`
`Indications:
`
`
`
`
`
`
`

`

`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`APPLICATION NUMBER:
`205552Orig1s01
`CONTENTS
`
`
`Reviews / Information Included in this NDA Review.
`
`
`X
`
`X
`
`X
`X
`X
`X
`X
`
`
`X
`
`X
`
`
`X
`X
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`
`
`
`Approval Letter
`Other Action Letters
`Labeling
`Summary Review
`Officer/Employee List
`Office Director Memo
`Cross Discipline Team Leader Review
`Medical Review(s)
`Chemistry Review(s)
`Environmental Assessment
`Pharmacology Review(s)
`Statistical Review(s)
`Microbiology Review(s)
`Clinical Pharmacology/Biopharmaceutics Review(s)
`Risk Assessment and Risk Mitigation Review(s)
`Proprietary Name Review(s)
`Other Review(s)
`Administrative/Correspondence Document(s)
`
`
`
`
`
`

`

`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`
`
`APPLICATION NUMBER:
`205552Orig1s01
`
`APPROVAL LETTER
`
`
`
`
`
`

`

`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`
`Food and Drug Administration
`Silver Spring MD 20993
`
`SUPPLEMENT APPROVAL
`FULFILLMENT OF POSTMARKETING
`REQUIREMENTS
`RELEASE FROM
`POSTMARKETING REQUIREMENT
`
`NDA 205552/S-001
`
`Pharmacyclics, Inc.
`Attention: Christine Salido
`Executive Director, Regulatory Affairs
`995 East Arques Avenue
`Sunnyvale, CA 94085-4521
`
`Dear Ms. Salido:
`
`Please refer to your Supplemental New Drug Application (sNDA) dated April 7, 2014, received
`April 7, 2014, submitted under section 505(b) of the Federal Food, Drug, and Cosmetic Act
`(FDCA) for Imbruvica (ibrutinib) capsules,140mg.
`
`We acknowledge receipt of your amendments dated December 17, 2013; April 14 and 23, 2014;
`May 23, 27, 29, and 30, 2014; June 3, 9, and 16, 2014; and July 24, 2014.
`
`This Prior Approval supplemental new drug application proposes the indication: Imbruvica is a
`kinase inhibitor indicated for the treatment of patients with:
`• Chronic lymphocytic leukemia (CLL) who have received at least one prior therapy
`• Chronic lymphocytic leukemia with 17p deletion.
`
`APPROVAL & LABELING
`
`We have completed our review of this supplemental application, as amended. It is approved,
`effective on the date of this letter, for use as recommended in the enclosed, agreed-upon labeling
`text.
`
`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
`http://www.fda.gov/ForIndustry/DataStandards/StructuredProductLabeling/default.htm. Content
`of labeling must be identical to the enclosed labeling (text for the package insert), with the
`
`Reference ID: 3600356
`
`

`

`NDA 205552/S-001
`Page 2
`
`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 titled
`“SPL Standard for Content of Labeling Technical Qs and As” at
`http://www.fda.gov/downloads/DrugsGuidanceComplianceRegulatoryInformation/Guidances/U
`CM072392.pdf.
`
`The SPL will be accessible from publicly available labeling repositories.
`
`Also within 14 days, amend all pending supplemental applications that includes 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 MS Word format, that includes the
`changes approved in this supplemental application, as well as annual reportable changes and
`annotate each change. To facilitate review of your submission, 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).
`
`SUBPART H FULFILLED
`
`We approved this NDA under the regulations at 21 CFR 314 Subpart H for accelerated approval
`of new drugs for serious or life-threatening illnesses. As we advised in the accelerated approval
`letter of February 12, 2014, approval of this supplement fulfills your accelerated approval
`requirements, listed below, made under 21 CFR 314.510 for the following indication: chronic
`lymphocytic leukemia (CLL) who have received at least one prior therapy.
`
`PMR 2122-1 Complete and submit the results of the ongoing randomized, open-label Phase 3
`clinical trial (PCYC-1112-CA) of ibrutinib versus ofatumumab in patients with
`relapsed or refractory chronic lymphocytic leukemia or relapsed or refractory
`small lymphocytic lymphoma. Enrollment of approximately 350 patients is
`expected. The primary endpoint is progression-free survival as assessed by an
`Independent Review Committee.
`
`Final Protocol Submission: Completed
`Trial Completion:
`01/2014
`Final Report Submission:
`06/2014
`
`We have reviewed your submission and conclude that the above requirement was fulfilled.
`
`RELEASE OF ACCELERATED APPROVAL POSTMARKETING REQUIREMENT
`
`We refer to the following postmarketing requirement listed in the February 12, 2014 approval
`letter.
`
`Reference ID: 3600356
`
`

`

`NDA 205552/S-001
`Page 3
`
`PMR 2122-2 Complete and submit the results of the ongoing randomized, double-blind,
`placebo-controlled Phase 3 clinical trial (PCI-32765CLL3001) of ibrutinib in
`combination with bendamustine and rituximab in patients with relapsed or
`refractory chronic lymphocytic leukemia or relapsed or refractory small
`lymphocytic lymphoma. Enrollment of at approximately 580 patients is expected.
`The primary endpoint is progression-free survival as assessed by an Independent
`Review Committee.
`
`Final Protocol Submission: Completed
`Trial Completion:
`07/2016
`Final Report Submission:
`11/2016
`
`We have determined that you are released from the above requirement because PMR 2122-1
`fulfilled the accelerated approval requirement. Therefore, while this trial is not required under
`Subpart H, we encourage you to complete this trial.
`
`REQUIRED PEDIATRIC ASSESSMENTS
`
`Under the Pediatric Research Equity Act (PREA) (21 U.S.C. 355c), all applications for new
`active ingredients, 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(s) 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 UNDER 505(o)
`
`We have received your submission dated December 17, 2013, containing the final report for the
`following postmarketing requirement listed in the November 13, 2013 approval letter.
`
`PMR 2060-6 Determine effect of a strong CYP3A Inducer on ibrutinib pharmacokinetics.
`Submit the final report for trial PCI-32765CLL1010 entitled, “An Open-Label,
`Sequential Design Study to Assess the Effect of Rifampin on the
`Pharmacokinetics of PCI-32765 in Healthy Subjects.”
`
`The timetable you submitted on November 13, 2013, states that you will conduct
`this trial according to the following schedule:
`
`Final Protocol Submission: Completed 01/2013
`Trial Completion:
`Completed 01/2013
`Final Report Submission:
`04/2014
`
`We have reviewed your submission and conclude that the above requirement was fulfilled.
`
`Reference ID: 3600356
`
`

`

`NDA 205552/S-001
`Page 4
`
`We remind you that there are postmarketing requirements and a postmarketing commitment
`listed in the November 13, 2013 approval letter that are 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 package insert(s) to:
`
`Food and Drug Administration
`Center for Drug Evaluation and Research
`Office of Prescription Drug Promotion (OPDP)
`5901-B Ammendale Road
`Beltsville, MD 20705-1266
`
`You must submit final promotional materials and package insert(s), 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
`http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM083570.pdf.
`Information and Instructions for completing the form can be found at
`http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM375154.pdf. For
`more information about submission of promotional materials to the Office of Prescription Drug
`Promotion (OPDP), see http://www.fda.gov/AboutFDA/CentersOffices/CDER/ucm090142.htm.
`
`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 Alycia Anderson, Regulatory Project Manager, at
`(240) 402-4270.
`
`Sincerely,
`
`{See appended electronic signature page}
`
`Edvardas Kaminskas, MD
`Deputy Director
`Division of Hematology Products
`Office of Hematology and Oncology Products
`Center for Drug Evaluation and Research
`
`ENCLOSURE(S):
`Content of Labeling
`
`Reference ID: 3600356
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`EDVARDAS KAMINSKAS
`07/28/2014
`
`Reference ID: 3600356
`
`

`

` CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`
`
`APPLICATION NUMBER:
`205552Orig1s01
`
`LABELING
`
`
`
`
`
`

`

`HIGHLIGHTS OF PRESCRIBING INFORMATION
`These highlights do not include all the information needed to use
`IMBRUVICA safely and effectively. See full prescribing information for
`IMBRUVICA.
`IMBRUVICA® (ibrutinib) capsules, for oral use
`Initial U.S. Approval: 2013
`----------------------------RECENT MAJOR CHANGES--------------------------
`Indications and Usage (1.2, 1.3)
`07/14
`Dosage and Administration (2.2, 2.3)
`1/14
`Warnings and Precautions (5)
`07/14
`----------------------------INDICATIONS AND USAGE---------------------------
`IMBRUVICA is a kinase inhibitor indicated for the treatment of patients with:
`(cid:120) Mantle cell lymphoma (MCL) who have received at least one prior
`therapy (1.1).
`Accelerated approval was granted for this indication based on overall
`response rate. Improvements in survival or disease-related symptoms have
`not been established. Continued approval for this indication may be
`contingent upon verification of clinical benefit in confirmatory trials.
`(cid:120) Chronic lymphocytic leukemia (CLL) who have received at least one
`prior therapy (1.2).
`(cid:120) Chronic lymphocytic leukemia with 17p deletion (1.3).
`-----------------------DOSAGE AND ADMINISTRATION-----------------------
`MCL: 560 mg taken orally once daily (four 140 mg capsules once daily) (2.2).
`CLL: 420 mg taken orally once daily (three 140 mg capsules once daily) (2.2).
`Capsules should be taken orally with a glass of water. Do not open, break, or
`chew the capsules (2.1).
`----------------------DOSAGE FORMS AND STRENGTHS---------------------
`Capsule: 140 mg (3)
`-------------------------------CONTRAINDICATIONS------------------------------
`None
`------------------------WARNINGS AND PRECAUTIONS-----------------------
`(cid:120) Hemorrhage: Monitor for bleeding (5.1).
`
`2
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`1
`INDICATIONS AND USAGE
`1.1 Mantle Cell Lymphoma
`1.2
`Chronic Lymphocytic Leukemia
`1.3
`Chronic Lymphocytic Leukemia with 17p deletion
`DOSAGE AND ADMINISTRATION
`2.1 Dosing Guidelines
`2.2 Dosage
`2.3 Dose Modifications for Adverse Reactions
`2.4 Dose Modifications for Use with CYP3A Inhibitors
`2.5 Missed Dose
`DOSAGE FORMS AND STRENGTHS
`3
`CONTRAINDICATIONS
`4
`5 WARNINGS AND PRECAUTIONS
`5.1 Hemorrhage
`5.2
`Infections
`5.3
`Cytopenias
`5.4 Atrial Fibrillation
`5.5
`Second Primary Malignancies
`5.6
`Embryo-Fetal Toxicity
`ADVERSE REACTIONS
`6.1 Mantle Cell Lymphoma
`6.2
`Chronic Lymphocytic Leukemia
`DRUG INTERACTIONS
`
`6
`
`7
`
`(cid:120) Infections: Monitor patients for fever and infections and evaluate promptly
`(5.2).
`(cid:120) Cytopenias: Check complete blood counts monthly (5.3).
`(cid:120) Atrial Fibrillation: Monitor patients for atrial fibrillation (5.4).
`(cid:120) Second Primary Malignancies: Other malignancies have occurred in
`patients, including skin cancers, and other carcinomas (5.5).
`(cid:120) Embryo-Fetal Toxicity: Can cause fetal harm. Advise women of the
`potential risk to a fetus and to avoid pregnancy while taking the drug (5.6).
`------------------------------ADVERSE REACTIONS-------------------------------
`The most common adverse (cid:85)(cid:72)(cid:68)(cid:70)(cid:87)(cid:76)(cid:82)(cid:81)(cid:86) (cid:11)(cid:149)(cid:21)(cid:19)(cid:8)(cid:12) (cid:76)(cid:81) (cid:83)(cid:68)(cid:87)(cid:76)(cid:72)(cid:81)(cid:87)(cid:86) (cid:90)(cid:76)(cid:87)(cid:75) (cid:48)(cid:38)(cid:47) (cid:90)(cid:72)(cid:85)(cid:72)
`thrombocytopenia, diarrhea, neutropenia, anemia, fatigue, musculoskeletal
`pain, peripheral edema, upper respiratory tract infection, nausea, bruising,
`dyspnea, constipation, rash, abdominal pain, vomiting and decreased appetite
`(6.1).
`(cid:55)(cid:75)(cid:72) (cid:80)(cid:82)(cid:86)(cid:87) (cid:70)(cid:82)(cid:80)(cid:80)(cid:82)(cid:81) (cid:68)(cid:71)(cid:89)(cid:72)(cid:85)(cid:86)(cid:72) (cid:85)(cid:72)(cid:68)(cid:70)(cid:87)(cid:76)(cid:82)(cid:81)(cid:86) (cid:11)(cid:149)(cid:21)(cid:19)(cid:8)(cid:12) (cid:76)(cid:81) (cid:83)(cid:68)(cid:87)(cid:76)(cid:72)(cid:81)(cid:87)(cid:86) (cid:90)(cid:76)(cid:87)(cid:75) (cid:38)(cid:47)(cid:47) were
`thrombocytopenia, neutropenia, diarrhea, anemia, fatigue, musculoskeletal
`pain, upper respiratory tract infection, rash, nausea, and pyrexia (6.2).
`To report SUSPECTED ADVERSE REACTIONS, contact
`Pharmacyclics at 1-877-877-3536 or FDA at 1-800-FDA-1088
`or www.fda.gov/medwatch
`-------------------------------DRUG INTERACTIONS------------------------------
`CYP3A Inhibitors: Avoid co-administration with strong and moderate CYP3A
`inhibitors. If a moderate CYP3A inhibitor must be used, reduce IMBRUVICA
`dose (2.4, 7 1).
`CYP3A Inducers: Avoid co-administration with strong CYP3A inducers (7.2).
`-----------------------USE IN SPECIFIC POPULATIONS------------------------
`Hepatic Impairment: Avoid use of IMBRUVICA in patients with baseline
`hepatic impairment (8.7).
`See 17 for PATIENT COUNSELING INFORMATION and FDA
`approved patient labeling.
`
`Revised: 07/2014
`
`8
`
`CYP3A Inhibitors
`7.1
`CYP3A Inducers
`7.2
`USE IN SPECIFIC POPULATIONS
`8.1
`Pregnancy
`8.3 Nursing Mothers
`8.4
`Pediatric Use
`8.5 Geriatric Use
`8.6
`Renal Impairment
`8.7 Hepatic Impairment
`8.8
`Females and Males of Reproductive Potential
`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: 3600356
`
`1
`
`

`

`FULL PRESCRIBING INFORMATION
`1
`INDICATIONS AND USAGE
`1.1 Mantle Cell Lymphoma
`IMBRUVICA is indicated for the treatment of patients with mantle cell lymphoma (MCL) who
`have received at least one prior therapy.
`Accelerated approval was granted for this indication based on overall response rate.
`Improvements in survival or disease-related symptoms have not been established. Continued
`approval for this indication may be contingent upon verification of clinical benefit in
`confirmatory trials [see Clinical Studies (14.1)].
`1.2
`Chronic Lymphocytic Leukemia
`IMBRUVICA is indicated for the treatment of patients with chronic lymphocytic leukemia
`(CLL) who have received at least one prior therapy [see Clinical Studies (14.2)].
`1.3
`Chronic Lymphocytic Leukemia with 17p deletion
`IMBRUVICA is indicated for the treatment of patients with chronic lymphocytic leukemia
`(CLL) with 17p deletion [see Clinical Studies (14.2)].
`
`DOSAGE AND ADMINISTRATION
`2
`Dosing Guidelines
`2.1
`Administer IMBRUVICA orally once daily at approximately the same time each day. Swallow
`the capsules whole with water. Do not open, break, or chew the capsules.
`2.2
`Dosage
`Mantle Cell Lymphoma
`The recommended dose of IMBRUVICA for MCL is 560 mg (four 140 mg capsules) orally once
`daily.
`Chronic Lymphocytic Leukemia
`The recommended dose of IMBRUVICA for CLL is 420 mg (three 140 mg capsules) orally once
`daily.
`Dose Modifications for Adverse Reactions
`2.3
`Interrupt IMBRUVICA therapy for any Grade 3 or greater non-hematological, Grade 3 or greater
`neutropenia with infection or fever, or Grade 4 hematological toxicities. Once the symptoms of
`the toxicity have resolved to Grade 1 or baseline (recovery), IMBRUVICA therapy may be
`reinitiated at the starting dose. If the toxicity reoccurs, reduce dose by one capsule (140 mg per
`day). A second reduction of dose by 140 mg may be considered as needed. If these toxicities
`persist or recur following two dose reductions, discontinue IMBRUVICA.
`Recommended dose modifications are described below:
`
`2
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`Reference ID: 3600356
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`Toxicity Occurrence
`
`CLL Dose Modification
`After Recovery
`Starting Dose = 420 mg
`Restart at 420 mg daily
`Restart at 280 mg daily
`Restart at 140 mg daily
`Discontinue IMBRUVICA
`
`MCL Dose Modification
`After Recovery
`Starting Dose = 560 mg
`Restart at 560 mg daily
`First
`Restart at 420 mg daily
`Second
`Restart at 280 mg daily
`Third
`Discontinue IMBRUVICA
`Fourth
`Dose Modifications for Use with CYP3A Inhibitors
`2.4
`Avoid co-administration with strong or moderate CYP3A inhibitors and consider alternative
`agents with less CYP3A inhibition.
`Concomitant use of strong CYP3A inhibitors which would be taken chronically (e.g., ritonavir,
`indinavir, nelfinavir, saquinavir, boceprevir, telaprevir, nefazodone) is not recommended. For
`short-term use (treatment for 7 days or less) of strong CYP3A inhibitors (e.g., antifungals and
`antibiotics) consider interrupting IMBRUVICA therapy until the CYP3A inhibitor is no longer
`needed [see Drug Interactions (7.1)].
`Reduce IMBRUVICA dose to 140 mg if a moderate CYP3A inhibitor must be used (e.g.,
`fluconazole, darunavir, erythromycin, diltiazem, atazanavir, aprepitant, amprenavir, fosamprevir,
`crizotinib, imatinib, verapamil, grapefruit products and ciprofloxacin) [see Drug Interactions
`(7.1)].
`Patients taking concomitant strong or moderate CYP3A inhibitors should be monitored more
`closely for signs of IMBRUVICA toxicity.
`2.5 Missed Dose
`If a dose of IMBRUVICA is not taken at the scheduled time, it can be taken as soon as possible
`on the same day with a return to the normal schedule the following day. Extra capsules of
`IMBRUVICA should not be taken to make up for the missed dose.
`
`DOSAGE FORMS AND STRENGTHS
`3
`140 mg capsules
`
`CONTRAINDICATIONS
`
`4
`None
`
`WARNINGS AND PRECAUTIONS
`5
`Hemorrhage
`5.1
`Grade 3 or higher bleeding events (subdural hematoma, gastrointestinal bleeding, hematuria and
`post procedural hemorrhage) have occurred in up to 6% of patients. Bleeding events of any
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`3
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`

`

`grade, including bruising and petechiae, occurred in approximately half of patients treated with
`IMBRUVICA.
`The mechanism for the bleeding events is not well understood.
`IMBRUVICA may increase the risk of hemorrhage in patients receiving antiplatelet or
`anticoagulant therapies.
`Consider the benefit-risk of withholding IMBRUVICA for at least 3 to 7 days pre and post-
`surgery depending upon the type of surgery and the risk of bleeding [see Clinical Studies (14)].
`5.2
`Infections
`Fatal and non-fatal infections have occurred with IMBRUVICA therapy. Twenty-five percent of
`patients with MCL and 26% of patients with CLL had infections Grade 3 or greater NCI
`Common Terminology Criteria for Adverse Events (CTCAE) [See Adverse Reactions (6.1) and
`(6.2)]. Monitor patients for fever and infections and evaluate promptly.
`5.3
`Cytopenias
`Treatment-emergent Grade 3 or 4 cytopenias including neutropenia (range, 23 to 29%),
`thrombocytopenia (range, 5 to 17%), and anemia (range, 0 to 9%) occurred in patients treated
`with IMBRUVICA.
`Monitor complete blood counts monthly.
`5.4
`Atrial Fibrillation
`Atrial fibrillation and atrial flutter (range, 6 to 9%) have occurred in patients treated with
`IMBRUVICA, particularly in patients with cardiac risk factors, acute infections, and a previous
`history of atrial fibrillation. Periodically monitor patients clinically for atrial fibrillation. Patients
`who develop arrhythmic symptoms (e.g., palpitations, lightheadedness) or new onset dyspnea
`should have an ECG performed. If atrial fibrillation persists, consider the risks and benefits of
`IMBRUVICA treatment and dose modification [see Dosage and Administration (2.3)].
`5.5
`Second Primary Malignancies
`Other malignancies (range, 5 to 10%) including carcinomas (range, 1 to 3%) have occurred in
`patients treated with IMBRUVICA. The most frequent second primary malignancy was non-
`melanoma skin cancer (range, 4 to 8%).
`5.6
`Embryo-Fetal Toxicity
`Based on findings in animals, IMBRUVICA can cause fetal harm when administered to a
`pregnant woman. Ibrutinib caused malformations in rats at exposures 14 times those reported in
`patients with MCL and 20 times those reported in patients with CLL, receiving the ibrutinib dose
`of 560 mg per day and 420 mg per day, respectively. Reduced fetal weights were observed at
`lower exposures. Advise women to avoid becoming pregnant while taking IMBRUVICA. If this
`drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the
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`patient should be apprised of the potential hazard to a fetus [see Use in Specific Populations
`(8.1)].
`
`ADVERSE REACTIONS
`6
`The following adverse reactions are discussed in more detail in other sections of the labeling:
`(cid:120) Hemorrhage [see Warnings and Precautions (5.1)]
`Infections [see Warnings and Precautions (5.2)]
`(cid:120)
`(cid:120) Cytopenias [see Warnings and Precautions (5.3)]
`(cid:120) Atrial Fibrillation [see Warnings and Precautions (5.4)]
`(cid:120) Second Primary Malignancies [see Warnings and Precautions (5.5)]
`Because clinical trials are conducted under widely variable conditions, adverse event rates
`observed in clinical trials of a drug cannot be directly compared with rates of clinical trials of
`another drug and may not reflect the rates observed in practice.
`6.1 Mantle Cell Lymphoma
`The data described below reflect exposure to IMBRUVICA in a clinical trial that included
`111 patients with previously treated MCL treated with 560 mg daily with a median treatment
`duration of 8.3 months.
`The most commonly (cid:82)(cid:70)(cid:70)(cid:88)(cid:85)(cid:85)(cid:76)(cid:81)(cid:74) (cid:68)(cid:71)(cid:89)(cid:72)(cid:85)(cid:86)(cid:72) (cid:85)(cid:72)(cid:68)(cid:70)(cid:87)(cid:76)(cid:82)(cid:81)(cid:86) (cid:11)(cid:149) (cid:21)(cid:19)(cid:8)(cid:12) (cid:90)(cid:72)(cid:85)(cid:72) (cid:87)(cid:75)(cid:85)(cid:82)(cid:80)(cid:69)(cid:82)(cid:70)(cid:92)(cid:87)(cid:82)(cid:83)(cid:72)(cid:81)(cid:76)(cid:68)(cid:15) (cid:71)(cid:76)(cid:68)(cid:85)(cid:85)(cid:75)(cid:72)(cid:68)(cid:15)
`neutropenia, anemia, fatigue, musculoskeletal pain, peripheral edema, upper respiratory tract
`infection, nausea, bruising, dyspnea, constipation, rash, abdominal pain, vomiting and decreased
`appetite (See Tables 1 and 2).
`The most common Grade 3 or 4 non-(cid:75)(cid:72)(cid:80)(cid:68)(cid:87)(cid:82)(cid:79)(cid:82)(cid:74)(cid:76)(cid:70)(cid:68)(cid:79) (cid:68)(cid:71)(cid:89)(cid:72)(cid:85)(cid:86)(cid:72) (cid:85)(cid:72)(cid:68)(cid:70)(cid:87)(cid:76)(cid:82)(cid:81)(cid:86) (cid:11)(cid:149) 5%) were pneumonia,
`abdominal pain, atrial fibrillation, diarrhea, fatigue, and skin infections.
`Fatal and serious cases of renal failure have occurred with IMBRUVICA therapy. Increases in
`creatinine 1.5 to 3 times the upper limit of normal occurred in 9% of patients.
`Adverse reactions from the MCL trial (N=111) using single agent IMBRUVICA 560 mg daily
`(cid:82)(cid:70)(cid:70)(cid:88)(cid:85)(cid:85)(cid:76)(cid:81)(cid:74) (cid:68)(cid:87) (cid:68) (cid:85)(cid:68)(cid:87)(cid:72) (cid:82)(cid:73) (cid:149) (cid:20)(cid:19)(cid:8) (cid:68)(cid:85)(cid:72) (cid:83)(cid:85)(cid:72)(cid:86)(cid:72)(cid:81)(cid:87)(cid:72)(cid:71) (cid:76)(cid:81) (cid:55)(cid:68)(cid:69)(cid:79)(cid:72) 1.
`Table 1: Non-(cid:43)(cid:72)(cid:80)(cid:68)(cid:87)(cid:82)(cid:79)(cid:82)(cid:74)(cid:76)(cid:70) (cid:36)(cid:71)(cid:89)(cid:72)(cid:85)(cid:86)(cid:72) (cid:53)(cid:72)(cid:68)(cid:70)(cid:87)(cid:76)(cid:82)(cid:81)(cid:86) (cid:76)(cid:81) (cid:149) (cid:20)(cid:19)(cid:8) (cid:82)(cid:73) (cid:51)(cid:68)(cid:87)(cid:76)(cid:72)(cid:81)(cid:87)(cid:86) (cid:90)(cid:76)(cid:87)(cid:75)
`MCL (N=111)
`
`Grade 3 or 4 (%)
`
`5
`
`500501
`
`All Grades (%)
`51
`31
`25
`24
`23
`17
`
`Preferred Term
`System Organ Class
`Gastrointestinal disorders Diarrhea
`Nausea
`Constipation
`Abdominal pain
`Vomiting
`Stomatitis
`
`Reference ID: 3600356
`
`

`

`All Grades (%)
`11
`
`Grade 3 or 4 (%)
`0
`
`03751
`
`5 3 1 3
`
`030
`
`10 0
`
`4 0 0
`
`24
`
`00
`
`34
`14
`14
`14
`13
`41
`35
`18
`14
`30
`25
`11
`37
`14
`11
`27
`19
`11
`21
`12
`14
`13
`
`System Organ Class
`
`General disorders and
`administrative site
`conditions
`
`Skin and subcutaneous
`tissue disorders
`
`Preferred Term
`Dyspepsia
`Infections and infestations Upper respiratory tract
`infection
`Urinary tract infection
`Pneumonia
`Skin infections
`Sinusitis
`Fatigue
`Peripheral edema
`Pyrexia
`Asthenia
`Bruising
`Rash
`Petechiae
`Musculoskeletal pain
`Muscle spasms
`Arthralgia
`Dyspnea
`Cough
`Epistaxis
`Decreased appetite
`Dehydration
`Dizziness
`Headache
`
`Musculoskeletal and
`connective tissue disorders
`
`Respiratory, thoracic and
`mediastinal disorders
`
`Metabolism and nutrition
`disorders
`Nervous system disorders
`
`Table 2: Treatment-Emergent* Decrease of Hemoglobin, Platelets, or Neutrophils
`in Patients with MCL (N=111)
`
`Platelets Decreased
`Neutrophils Decreased
`Hemoglobin Decreased
`* Based on laboratory measurements and adverse reactions
`
`Percent of Patients (N=111)
`All Grades (%)
`Grade 3 or 4 (%)
`57
`17
`47
`29
`41
`9
`
`Ten patients (9%) discontinued treatment due to adverse reactions in the trial (N=111). The most
`frequent adverse reaction leading to treatment discontinuation was subdural hematoma (1.8%).
`Adverse reactions leading to dose reduction occurred in 14% of patients.
`Patients with MCL who develop lymphocytosis greater than 400,000/mcL have developed
`intracranial hemorrhage, lethargy, gait instability, and headache. However, some of these cases
`were in the setting of disease progression.
`
`6
`
`Reference ID: 3600356
`
`

`

`Forty percent of patients had elevated uric acid levels on study including 13% with values above
`10 mg/dL. Adverse reaction of hyperuricemia was reported for 15% of patients.
`6.2
`Chronic Lymphocytic Leukemia
`The data described below reflect exposure to IMBRUVICA in an open label clinical trial (Study
`1) that included 48 patients with previously treated CLL and a randomized clinical trial (Study 2)
`that included 391 randomized patients with previously treated CLL or SLL.
`The most commonly occurring adverse reactions in Study 1 and Study 2 (cid:11)(cid:149) (cid:21)(cid:19)(cid:8)(cid:12) (cid:90)(cid:72)(cid:85)(cid:72)
`thrombocytopenia, neutropenia, diarrhea, anemia, fatigue, musculoskeletal pain, upper
`respiratory tract infection, rash, nausea, and pyrexia.
`
`Approximately five percent of patients receiving IMBRUVICA in Study 1 and 2 discontinued
`treatment due to adverse events. These included infections, subdural hematomas and diarrhea.
`Adverse events leading to dose reduction occurred in approximately 6% of patients.
`Study 1
`Adverse reactions and laboratory abnormalities from the CLL trial (N=48) using single agent
`(cid:44)(cid:48)(cid:37)(cid:53)(cid:56)(cid:57)(cid:44)(cid:38)(cid:36) (cid:23)(cid:21)(cid:19) (cid:80)(cid:74) (cid:71)(cid:68)(cid:76)(cid:79)(cid:92) (cid:82)(cid:70)(cid:70)(cid:88)(cid:85)(cid:85)(cid:76)(cid:81)(cid:74) (cid:68)(cid:87) (cid:68) (cid:85)(cid:68)(cid:87)(cid:72) (cid:82)(cid:73) (cid:149) (cid:20)(cid:19)(cid:8) (cid:68)(cid:85)(cid:72) (cid:83)(cid:85)(cid:72)(cid:86)(cid:72)(cid:81)(cid:87)(cid:72)(cid:71) (cid:76)(cid:81) (cid:55)(cid:68)(cid:69)(cid:79)(cid:72)s 3 and 4.
`Table 3: Non-(cid:43)(cid:72)(cid:80)(cid:68)(cid:87)(cid:82)(cid:79)(cid:82)(cid:74)(cid:76)(cid:70) (cid:36)(cid:71)(cid:89)(cid:72)(cid:85)(cid:86)(cid:72) (cid:53)(cid:72)(cid:68)(cid:70)(cid:87)(cid:76)(cid:82)(cid:81)(cid:86) (cid:76)(cid:81) (cid:149) (cid:20)(cid:19)(cid:8) (cid:82)(cid:73) (cid:51)(cid:68)(cid:87)(cid:76)(cid:72)(cid:81)(cid:87)(cid:86) (cid:90)(cid:76)(cid:87)(cid:75)
`CLL (N=48) in Study 1
`
`System Organ Class
`
`Preferred Term
`
`All Grades (%)
`
`Grade 3 or 4
`(%)
`4
`2
`2
`0
`2
`0
`0
`2
`6
`6
`8
`0
`4
`2
`0
`4
`0
`
`200
`
`7
`
`Gastrointestinal disorders
`
`Infections and infestations
`
`Diarrhea
`Constipation
`Nausea
`Stomatitis
`Vomiting
`Abdominal pain
`Dyspepsia
`Upper respiratory tract infection
`Sinusitis
`Skin infection
`Pneumonia
`Urinary tract infection
`Fatigue
`General disorders and
`administrative site conditions Pyrexia
`Peripheral edema
`Asthenia
`Chills
`Bruising
`Rash
`Petechiae
`
`Skin and subcutaneous tissue
`disorders
`
`63
`23
`21
`21
`19
`15
`13
`48
`21
`17
`10
`10
`31
`25
`23
`13
`13
`54
`27
`17
`
`Reference ID: 3600356
`
`

`

`System Organ Class
`
`Preferred Term
`
`All Grades (%)
`
`Grade 3 or 4
`(%)
`
`000
`
`602
`
`020
`
`2
`
`0
`
`2
`
`00
`
`8
`
`19
`15
`10
`27
`23
`19
`21
`19
`10
`17
`
`10*
`
`10
`
`10
`10
`17
`
`Cough
`Oropharyngeal pain
`Dyspnea
`Musculoskeletal pain
`Arthralgia
`Muscle spasms
`Dizziness
`Headache
`Peripheral neuropathy
`Decreased appetite
`
`Second malignancies*
`
`Laceration
`
`Respiratory, thoracic and
`mediastinal disorders
`
`Musculoskeletal and
`connective tissue disorders
`
`Nervous system disorders
`
`Metabolism and nutrition
`disorders
`Neoplasms benign,
`malignant, unspecified
`Injury, poisoning and
`procedural complications
`Psychiatric disorders
`
`Anxiety
`Insomnia
`Hypertension
`Vascular disorders
`*One patient death due to histiocytic sarcoma.
`
`Table 4: Treatment-Emergent* Decrease of Hemoglobin, Platelets, or Neutrophils
`in Patients with CLL (N=48) in Study 1
`
`Percent of Patients (N=48)
`All Grades (%)
`Grade 3 or 4 (%)
`71
`10
`Platelets Decreased
`54
`27
`Neutrophils Decreased
`44
`0
`Hemoglobin Decreased
`* Based on laboratory measurements per IWCLL criteria and adverse reactions
`
`Study 2
`Adverse reactions and laboratory abnormalities described below in Tables 5 and 6 reflect
`exposure to IMBRUVICA with a median duration of 8.6 months and exposure to ofatumumab
`with a median of 5.3 months in Study 2.
`Table 5: Non-Hematologic Adverse Reactions (cid:149) 10% Reported in Study 2
`
`System Organ Class ADR
`Term
`Gastrointestinal disorders
`
`Reference ID: 3600356
`
`IMBRUVICA
`(N=195)
`All Grades
`Grade 3 or 4
`(%)
`(%)
`
`Ofatumumab
`(N=191)
`All Grades
`Grade 3 or 4
`(%)
`(%)
`
`8
`
`

`

`IMBRUVICA
`(N=195)
`
`Ofatumumab
`(N=191)
`
`48
`26
`17
`15
`14
`
`28
`24
`
`16
`
`15
`11
`10
`
`24
`14
`12
`
`28
`17
`
`14
`11
`
`11
`
`4
`2
`1
`0
`0
`
`2
`2
`
`1
`
`10
`1
`4
`
`3
`0
`0
`
`2
`1
`
`1
`0
`
`0
`
`Diarrhea
`Nausea
`Stomatitis*
`Constipation
`Vomiting
`General disorders and
`administration site conditions
`Fatigue
`Pyrexia
`Infections and infestations
`Upper respiratory tract
`infection
`Pneumonia*
`Sinusitis*
`Urinary tract infection
`Skin and subcutaneous tissue
`disorders
`Rash*
`Petechiae
`Bruising*
`Musculoskeletal and
`connective tissue disorders
`Musculoskeletal Pain*
`Arthralgia
`Nervous system disorders
`Headache
`Dizziness
`Injury, poisoning and
`procedural complications
`Contusion
`Eye disorders
`3
`0
`10
`Vision blurred
`Subjects with multiple events for a given ADR te