CENTER FOR DRUG EVALUATION AND RESEARCH
`
`Approval Package for:
`
`APPLICATION NUMBER:
`
` NDA 205552 Orig1s002
`
`Trade Name: IMBRUVICA
`
`Generic or Proper Name: ibrutinib
`
`Sponsor: Pharmacyclics, Inc.
`
`Approval Date: January 29th, 2015
`
`Indication: Imbruvica is indicated for the treatment of paitents with Waldenstromös
`macroglobulinemia (WM)
`
`

`

`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`NDA 205552 Orig1s002
`
`CONTENTS
`
`Reviews / Information Included in this NDA Review.
`
`Approval Letter
`Other Action Letters
`Labeling
`REMS
`Summary Review
`Officer/Employee List
`Office Director Memo
`Cross Discipline Team Leader Review
`Clinical Review(s)
`Product Quality Review(s)
`Non-Clinical Review(s)
`Statistical Review(s)
`Clinical Microbiology / Virology Review(s)
`Clinical Pharmacology Review(s)
`Other Reviews
`Risk Assessment and Risk Mitigation Review(s)
`Proprietary Name Review(s)
`Administrative/Correspondence Document(s)
`
`X
`
`X
`
`X
`X
`
`X
`X
`X
`
`X
`
`X
`
`X
`
`

`

`
`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`APPLICATION NUMBER:
`
`205552Orig1s002
`
`
`APPROVAL LETTER
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`

`

`
`
`
`
`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`
`
`
`
`
`
` NDA 205552/S-002
`
`
`
`
`
`
`
`
`Food and Drug Administration
`
`
` Silver Spring MD 20993
`
`
` SUPPLEMENT APPROVAL
`
`
` POST MARKETING FULFILLMENT
`
`
`
`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 October 17, 2014,
`
`
`
`
`received October 17, 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 October 30; November 3, 7, 20, and 24 (2);
`
`
`December 2, 15, 22, and 23, 2014; and January 7 and 20, 2015.
`
`
`
`
`
`
`This Prior Approval supplemental new drug application provides for a new indication for the
`
`
`treatment of patients with Waldenström’s macroglobulinemia and fulfillment of the
`
`
`postmarketing requirement trial, PMR 2060-5, “An Open-Label, Multicenter, Pharmacokinetic,
`Study of PCI-3265in Subjects with Varying Degrees of Hepatic Impairment”.
`
`
`
`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
`
`
`
`addition of any labeling changes in pending “Changes Being Effected” (CBE) supplements, as
`
`
`
`well as annual reportable changes not included in the enclosed labeling.
`
`
`
`Reference ID: 3694103
`
`

`

`
`
`
`
`
`
` NDA 205552/S-002
`
` Page 2
`
`
` 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).
`
`
`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.
`
`
`POSTMARKETING COMMITMENTS SUBJECT TO REPORTING REQUIREMENTS
`
`UNDER SECTION 506B
`
`
`We remind you of your postmarketing commitment:
`
`
`
`
`2867-1
`
`
`Develop and test the stability of a lower (35 or 70 mg) strength ibrutinib capsule
`
`
`in order to allow dose reductions for patients with moderate hepatic impairment
`
`for whom ibrutinib treatment is currently not recommended. The lower strength
`
`capsule should be sufficiently distinguishable from the 140 mg capsule.
`
`
`
`The timetable you submitted on January 23, 2015, states that you will conduct this study
`
`
`according to the following schedule:
`
`
`
`
`Final Protocol Submission: 09/2015
`
`
`
`12/2016
`
`Study Completion:
`
`
`
`
`Final Report Submission:
`03/2017
`
`
`
`
`Reference ID: 3694103
`
`

`

`
`
`
`
`
`
` NDA 205552/S-002
`
` Page 3
`
`
`
`
`
`
`
` Submit clinical protocols to your IND 102688 for this product. Submit nonclinical and
`
`
` chemistry, manufacturing, and controls protocols and all postmarketing final reports to this
`
`
` NDA. In addition, under 21 CFR 314.81(b)(2)(vii) and 314.81(b)(2)(viii) you should include a
`
` status summary of each commitment in your annual report to this NDA. The status summary
`
`
`
`
`
` should include expected summary completion and final report submission dates, any changes in
`
` plans since the last annual report, and, for clinical studies/trials, number of patients entered into
`
` each study/trial. All submissions, including supplements, relating to these postmarketing
`
`
`commitments should be prominently labeled “Postmarketing Commitment Protocol,”
`“Postmarketing Commitment Final Report,” or “Postmarketing Commitment
`
`Correspondence.”
`
`
` FULFILLMENT OF POSTMARKETING REQUIREMENT UNDER 505(o)
`
`We have received your submission dated September 30, 2014, containing the final report for the
`
`
`
`following postmarketing requirement listed in the November 13, 2013 approval letter.
`
`
`
`
`PMR 2060-5 Evaluate the effect of hepatic impairment on ibrutinib pharmacokinetics. Submit
`
`
`the final report for trial PCI -32765CLL1006 entitled, “An Open-Label,
`
`Multicenter, Pharmacokinetic, Study of PCI-3265in Subjects with Varying
`Degrees of Hepatic Impairment.”
`
`
`
`
`
`The timetable you submitted on November 13, 2013 states that you will conduct this study
`
`
`
`according to the following schedule:
`
`
`
`Final Protocol Submission: Completed 11/2012
`
`
`Trial Completion:
`06/2014
`
`
`
`Final Report Submission:
`12/2014
`
`
`
`We have reviewed your submission and conclude that the above requirement was fulfilled.
`
`
`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
`
`
`Reference ID: 3694103
`
`

`

`
`
` NDA 205552/S-002
`
` Page 4
`
`
`
`
`
`
`
`
` 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}
`
`
`Ann T. Farrell, MD
`
`Director
`
`Division of Hematology Products
`
`
`Office of Hematology and Oncology Products
`
`Center for Drug Evaluation and Research
`
`
`ENCLOSURE(S):
`
`Content of Labeling
`
`
`
`
`Reference ID: 3694103
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`ANN T FARRELL
`01/29/2015
`
`Reference ID: 3694103
`
`

`

`
`
`
`
`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
`
`205552Orig1s002
`
`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 (1.4)
`01/15
`
`
`
`
`
`Dosage and Administration (2.2, 2.3, 2.5)
`01/15
`
`
`
`
`
`01/15
`Warnings and Precautions (5.1, 5.6)
`
`----------------------------INDICATIONS AND USAGE--------------------------­
`
`
`
`IMBRUVICA is a kinase inhibitor indicated for the treatment of patients with:
`
`
`• 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. Continued approval for this indication may be contingent
`
`
`
`upon verification of clinical benefit in confirmatory trials.
`
`
`
`• Chronic lymphocytic leukemia (CLL) who have received at least one
`
`
`prior therapy (1.2).
`
`
`• Chronic lymphocytic leukemia with 17p deletion (1.3).
`
`
`
`
`• Waldenström’s macroglobulinemia (WM) (1.4).
`
`
`-----------------------DOSAGE AND ADMINISTRATION----------------------­
`
`
`
`MCL: 560 mg taken orally once daily (four 140 mg capsules once daily) (2.2).
`
`
`
`
`
`
`
`CLL and WM: 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
`
`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`
`1
`INDICATIONS AND USAGE
`
`
`1.1 Mantle Cell Lymphoma
`
`
`Chronic Lymphocytic Leukemia
`1.2
`
`1.3
`Chronic Lymphocytic Leukemia with 17p deletion
`
`
`
`
`
`1.4 Waldenström's Macroglobulinemia
`
`
`
`2 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 Dose Modifications for Use in Hepatic Impairment
`
`2.6 Missed Dose
`
`
`
`
`3 DOSAGE FORMS AND STRENGTHS
`
`
`4 CONTRAINDICATIONS
`
`
`5 WARNINGS AND PRECAUTIONS
`
`
`5.1 Hemorrhage
`
`
`5.2
`Infections
`
`
`5.3
`Cytopenias
`
`
`5.4 Atrial Fibrillation
`
`
`5.5
`Second Primary Malignancies
`
`5.6
`Tumor Lysis Syndrome
`
`
`
`5.7
`Embryo-Fetal Toxicity
`
`
`
`6 ADVERSE REACTIONS
`
`
`6.1
`Clinical Trials Experiences
`
`
`Postmarketing Experience
`6.2
`
`
`
`
`
`------------------------WARNINGS AND PRECAUTIONS----------------------­
`
`
`• Hemorrhage: Monitor for bleeding (5.1).
`
`
`
`
`
`
`• Infections: Monitor patients for fever and infections and evaluate promptly
`
`
`(5.2).
`
`• Cytopenias: Check complete blood counts monthly (5.3).
`
`
`
`• Atrial Fibrillation: Monitor patients for atrial fibrillation (5.4).
`
`
`
`
`• Second Primary Malignancies: Other malignancies have occurred in
`
`
`patients, including skin cancers, and other carcinomas (5.5).
`
`• Tumor Lysis Syndrome (TLS): Monitor patients at risk for TLS (e.g. high
`
`
`
`tumor burden) (5.6).
`• Embryo-Fetal Toxicity: Can cause fetal harm. Advise women of the
`
`
`
`
`
`
`potential risk to a fetus and to avoid pregnancy while taking the drug (5.7).
`
`------------------------------ADVERSE REACTIONS------------------------------­
`
`
`
`
`The most common adverse reactions (≥25%) in patients with B-cell
`
`malignancies (MCL, CLL, WM) were thrombocytopenia, neutropenia,
`
`
`
`diarrhea, anemia, fatigue, musculoskeletal pain, bruising, nausea, upper
`
`
`
`respiratory tract infection, and rash.
`
`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 moderate or
`
`
`
`severe baseline hepatic impairment. In patients with mild impairment, reduce
`
`
`IMBRUVICA dose (8.7).
`
`See 17 for PATIENT COUNSELING INFORMATION and FDA
`
`approved patient labeling.
`
`
`
`
`Revised: 01/2015
`
`
`
`
`7
`
`DRUG INTERACTIONS
`
`
`
`7.1
`CYP3A Inhibitors
`
`
`7.2
`CYP3A Inducers
`
`
`8 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
`
`
`
`8.9
`Plasmapheresis
`
`
`
`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
`
`
`14.3 Waldenström's Macroglobulinemia
`
`
`
`16 HOW SUPPLIED/STORAGE AND HANDLING
`
`
`
`17 PATIENT COUNSELING INFORMATION
`
`
`* Sections or subsections omitted from the full prescribing information are
`
`
`
`not listed.
`
`
`
`Reference ID: 3694103
`
`
`
` 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. Continued
`approval for this indication may be contingent upon verification of clinical benefit in
`
`confirmatory trials [see Clinical Studies (14.1)].
`
`
`
`Chronic Lymphocytic Leukemia
`1.2
`
`
`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)].
`
`
`
`Chronic Lymphocytic Leukemia with 17p deletion
`1.3
`
`
`
`IMBRUVICA is indicated for the treatment of patients with chronic lymphocytic leukemia
`
`
`(CLL) with 17p deletion [see Clinical Studies (14.2)].
`
`
`1.4 Waldenström’s Macroglobulinemia
`
`
`
`IMBRUVICA is indicated for the treatment of patients with Waldenström’s macroglobulinemia
`
`
`(WM) [see Clinical Studies (14.3)].
`
`
`
`2
`DOSAGE AND ADMINISTRATION
`
`
`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 and Waldenström’s Macroglobulinemia
`
`
`The recommended dose of IMBRUVICA for CLL and WM 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
`
`
`
`
`
`
`
` 2
`
`Reference ID: 3694103
`
`

`

`
` 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:
`
`
`
`
`
` Toxicity Occurrence
`
`First
`
`Second
`Third
`
` Fourth
`
`
`
`
`
`
` MCL Dose Modification After
`
` Recovery
` Starting Dose = 560 mg
`
`
`
`Restart at 560 mg daily
`
`
`
`Restart at 420 mg daily
`Restart at 280 mg daily
`
`
`
` Discontinue IMBRUVICA
`
`
`
`
`
` CLL and WM 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
`
`
`
`
`
`
`
` 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, 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.
`
`
`
` Dose Modifications for Use in Hepatic Impairment
` 2.5
`
`
`
`
`
` For patients with mild liver impairment (Child-Pugh class A), the recommended dose is 140 mg
` daily (one capsule). Avoid the use of IMBRUVICA in patients with moderate or severe hepatic
`
`
`
`
`
`
`
`
`
` impairment (Child-Pugh classes B and C) [see Use in Specific Populations (8.7) and Clinical
`
`
` Pharmacology (12.3)].
`
`
` 2.6 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
`
`Reference ID: 3694103
`
`
`
` 3
`
`

`

`
`4
`
` None
`
`
`
`
`
` CONTRAINDICATIONS
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`5
` WARNINGS AND PRECAUTIONS
`
`
`
` 5.1 Hemorrhage
`
` Fatal bleeding events have occurred in patients treated with IMBRUVICA. 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 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. Grade 3 or greater
`
`
`
` infections occurred in 14% to 26% of patients. [See Adverse Reactions (6.1)]. Cases of
`
`
` progressive multifocal leukoencephalopathy (PML) have occurred in patients treated with
`
`
`
`
`
`
` IMBRUVICA. Monitor patients for fever and infections and evaluate promptly.
` Cytopenias
`
`
` 5.3
`
`
`
`
`
` Treatment-emergent Grade 3 or 4 cytopenias including neutropenia (range, 19 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)].
`
`
` Second Primary Malignancies
`
`
` 5.5
`
`
`
`
`
`
`
` Other malignancies (range, 5 to 14%) including non-skin 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 11 %).
`
`
`
`
`
`
`
`
`
`Reference ID: 3694103
`
`
`
` 4
`
`

`

`
` Tumor Lysis Syndrome
` 5.6
`
`
`
` Tumor lysis syndrome has been reported with IMBRUVICA therapy. Monitor patients closely
` and take appropriate precautions in patients at risk for tumor lysis syndrome (e.g. high tumor
`
`
`
`burden).
`
`
`
` Embryo-Fetal Toxicity
` 5.7
`
`
`
`
` 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 or WM, 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 patient should be apprised of the potential hazard to a fetus [see Use in
`
`
`Specific Populations (8.1)].
`
`
`6
`ADVERSE REACTIONS
`
`
`The following adverse reactions are discussed in more detail in other sections of the labeling:
`
`
`• Hemorrhage [see Warnings and Precautions (5.1)]
`
`
`
`
`
`Infections [see Warnings and Precautions (5.2)]
`
`
`
`
`
`•
`• Cytopenias [see Warnings and Precautions (5.3)]
`
`
`
`
`
`• Atrial Fibrillation [see Warnings and Precautions (5.4)]
`
`
`
`
`• Second Primary Malignancies [see Warnings and Precautions (5.5)]
`
`
`
`
`• Tumor Lysis Syndrome [see Warnings and Precautions (5.6)]
`
`
`
`
`
`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.
`
`
`
`Clinical Trials Experience
`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 occurring adverse reactions (≥ 20%) were thrombocytopenia, diarrhea,
`
`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).
`
`
`
`
`
`Reference ID: 3694103
`
`
`
` 5
`
`

`

`
` The most common Grade 3 or 4 non-hematological adverse reactions (≥ 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
`
`
`occurring at a rate of ≥ 10% are presented in Table 1.
`
`
`
`
`
`
`
`
`
`
`Reference ID: 3694103
`
`
`
` 6
`
`

`

`
`
`
`
` Table 1: Non-Hematologic Adverse Reactions in ≥ 10% of Patients with
`
`
`
` MCL (N=111)
`
`
`
`
` System Organ Class
` Preferred Term
`
`
`Gastrointestinal disorders Diarrhea
`
`
`Nausea
`
`Constipation
`
`Abdominal pain
`
`Vomiting
`
`Stomatitis
`
`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
`
`
`
`
`
`
`
` All Grades (%)
`51
`
`31
`
`25
`
`24
`
`23
`
`17
`
`11
`
`
`34
`
`14
`
`14
`
`14
`
`13
`
`
`41
`
`35
`
`18
`14
`
`30
`
`25
`
`11
`
`
`37
`
`14
`
` 11
`
` 27
`
`19
`11
`
`21
`
`12
`
`
`14
`
`13
`
`
`
`
`
` Grade 3 or 4 (%)
`5
`
`0
`
`0
`
`5
`
`0
`
`1
`
`0
`
`
`0
`
`3
`
`7
`
`5
`
`1
`
`
`5
`
`3
`
`1
`3
`
`0
`
`3
`
`0
`
`
`1
`
`0
`
` 0
`
` 4
`
`0
`0
`
`2
`
`4
`
`
`0
`
`0
`
`
`General disorders and
`
`administrative site
`
`conditions
`
`Skin and subcutaneous
`tissue disorders
`
`
`Musculoskeletal and
`connective tissue disorders
`
`
`
`
` Respiratory, thoracic and
`
` mediastinal disorders
`
`Metabolism and nutrition
`
`disorders
`
`
`Nervous system disorders
`
`Reference ID: 3694103
`
`
`
` 7
`
`

`

` 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)
`
`
`Grade 3 or 4 (%)
`All Grades (%)
`
`
`
`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.
`
` 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.
`
` 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 (≥ 20%) were
`
`
`
`
`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 Study 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
`
`
`
`
`
`IMBRUVICA 420 mg daily occurring at a rate of ≥ 10% are presented in Tables 3 and 4.
`
`
`
`
`
`Reference ID: 3694103
`
`
`
` 8
`
`

`

`
`
`
` Table 3: Non-Hematologic Adverse Reactions in ≥ 10% of Patients with
`
` CLL (N=48) in Study 1
`
`
`
`
`
`
`
` System Organ Class
`
`
`Gastrointestinal disorders
`
`
`Infections and infestations
`
`
`
`General disorders and
`
`
`administrative site conditions
`
`
`
`Skin and subcutaneous tissue
`
`disorders
`
`
`Respiratory, thoracic and
`
`mediastinal disorders
`
`Musculoskeletal and
`
`connective tissue disorders
`
`
`
`Nervous system disorders
`
`
`
` Preferred Term
`Diarrhea
`
`Constipation
`
`Nausea
`
`Stomatitis
`
`Vomiting
`
`Abdominal pain
`
`Dyspepsia
`
`Upper respiratory tract infection
`
`
`Sinusitis
`
`Skin infection
`
`Pneumonia
`
`Urinary tract infection
`
`
`
`Fatigue
`
`Pyrexia
`
`Peripheral edema
`
`Asthenia
`
`Chills
`
`Bruising
`
`Rash
`
`Petechiae
`
`Cough
`
`Oropharyngeal pain
`
`Dyspnea
`
`Musculoskeletal pain
`
`Arthralgia
`
`Muscle spasms
`
`Dizziness
`
`Headache
`
`Peripheral neuropathy
`
`Decreased appetite
`
`
`Second malignancies*
`
`
`Laceration
`
`
`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.
`
`
`
`
`
` All Grades (%)
`63
`
`23
`
`21
`
`21
`
`19
`
`15
`
`13
`
`48
`
`21
`
`17
`
`10
`
`10
`
`
`31
`
`25
`
`23
`
`13
`
`13
`
`54
`
`27
`
`17
`
`19
`
`15
`
`10
`
`27
`
`23
`
`19
`
`21
`
`19
`
`10
`
`17
`
`
`10*
`
`
`10
`
`
`10
`
`10
`
` 17
`
`
`
` Grade 3 or 4
`
` (%)
`4
`
`2
`
`2
`
`0
`
`2
`
`0
`
`0
`
`2
`
`6
`
`6
`
`8
`
`0
`
`
`4
`
`2
`
`0
`
`4
`
`0
`
`2
`
`0
`
`0
`
`0
`
`0
`
`0
`
`6
`
`0
`
`2
`
`0
`
`2
`
`0
`
`2
`
`
`0
`
`
`2
`
`
`0
`
`0
` 8
`
`
`
`
` 9
`
`Reference ID: 3694103
`
`

`

`
`
` Table 4: Treatment-Emergent* Decrease of Hemoglobin, Platelets, or Neutrophils
`
`
`
`
`
`
` in Patients with CLL (N=48) in Study 1
`
`
`
`
`
`
`
`
`Percent of Patients (N=48)
`
`
`Grade 3 or 4 (%)
`All Grades (%)
`
`
`
`
`
`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 ≥ 10% Reported in Study 2
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` System Organ Class
`
`
`ADR Term
`
`Gastrointestinal disorders
`
`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*
`
`IMBRUVICA
`
`
`(N=195)
`Grade 3 or 4
`All Grades
`
`
`
`
`(%)
`(%)
`
`
`
`
`48
`4
`
`
`26
`2
`
`
`17
`1
`
`
`15
`0
`
`
`14
`0
`
`
`
`Ofatumumab
`
`
`(N=191)
`Grade 3 or 4
`All Grades
`
`
`
`
`(%)
`(%)
`
`
`
`
`18
`2
`
`
`18
`0
`
`
`6
`1
`
`
`9
`0
`
`
`6
`1
`
`
`
`
`28
`
`24
`
`
`16
`
`
`15
`
`11