CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
`
`210563Orig1s000
`210563Orig2s000
`
`
`OTHER REVIEW(S)
`
`

`

`MEMORANDUM
`REVIEW OF REVISED LABEL AND LABELING
`Division of Medication Error Prevention and Analysis (DMEPA)
`Office of Medication Error Prevention and Risk Management (OMEPRM)
`Office of Surveillance and Epidemiology (OSE)
`Center for Drug Evaluation and Research (CDER)
`
`Date of This Memorandum:
`February 15, 2018
`Requesting Office or Division:
`Division of Hematology Products (DHP)
`Application Type and Number: NDA 210563
`Product Name and Strength:
`Imbruvica (ibrutinib) tablets, 140 mg, 280 mg, 420 mg, and
`560 mg
`Pharmacyclics LLC
`February 14, 2018
`2017-1815-2
`Nicole Garrison, PharmD, BCPS
`Hina Mehta, PharmD
`
`Applicant/Sponsor Name:
`FDA Received Date:
`OSE RCM #:
`DMEPA Safety Evaluator:
`DMEPA Team Leader:
`
`PURPOSE OF MEMO
`1
`The Division of Hematology Products (DHP) requested that we review the revised carton
`labeling and blister pack labeling for Imbruvica tablets (Appendix A) to determine if it is
`acceptable from a medication error perspective. The revisions are in response to
`recommendations that we made during a previous label and labeling review.a
`
` CONCLUSION
`2
`The revised carton labeling and blister pack labeling for Imbruvica tablets is acceptable from a
`medication error perspective. We have no further recommendations at this time.
`
`a Garrison N. Label and Labeling Review Memo for IMBRUVICA (NDA 210563). Silver Spring (MD): FDA, CDER, OSE,
`DMEPA (US); 2018 FEB 07. RCM No.: 2017-1815-1.
`
`1
`
`Reference ID: 4222519
`
`8 Page(s) of Draft Labeling have been Withheld in Full as b4 (CCI/TS) immediately following this page
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`NICOLE B GARRISON
`02/15/2018
`
`HINA S MEHTA
`02/15/2018
`
`Reference ID: 4222519
`
`

`

`MEMORANDUM
`REVIEW OF REVISED LABEL AND LABELING
`Division of Medication Error Prevention and Analysis (DMEPA)
`Office of Medication Error Prevention and Risk Management (OMEPRM)
`Office of Surveillance and Epidemiology (OSE)
`Center for Drug Evaluation and Research (CDER)
`
`Date of This Memorandum:
`February 7, 2018
`Requesting Office or Division:
`Division of Hematology Products (DHP)
`Application Type and Number: NDA 210563
`Product Name and Strength:
`Imbruvica (ibrutinib) tablets, 140 mg, 280 mg, 420 mg, and
`560 mg
`Pharmacyclics LLC
`January 22, 2018
`2017-1815-1
`Nicole Garrison, PharmD, BCPS
`Hina Mehta, PharmD
`
`Applicant/Sponsor Name:
`FDA Received Date:
`OSE RCM #:
`DMEPA Safety Evaluator:
`DMEPA Team Leader:
`
`PURPOSE OF MEMO
`1
`The Division of Hematology Products (DHP) requested that we review the revised carton
`labeling and blister pack labeling for Imbruvica tablets (Appendix A) to determine if it is
`acceptable from a medication error perspective. The revisions are in response to
`recommendations that we made during a previous label and labeling review.a
`
` CONCLUSION
`2
`The revised carton labeling and blister pack labeling is unacceptable from a medication error
`perspective. For the carton labeling, there is inadequate differentiation between the 140 mg
`capsule strength
` and the 420 mg tablet strength
`.
`In our previous label and labeling review for Imbruvica tablets, we recommended deletion of
` on the blister pack labeling
`
`. The Sponsor
`acknowledged our concern, however; based upon several market research studies they
`conducted with patients, nurses, pharmacists, and distributors,
`labeling was
`
`a Garrison N. Label and Labeling Review for Imbruvica (NDA 210563). Silver Spring (MD): FDA, CDER, OSE, DMEPA
`(US); 2018 JAN 11. RCM No.: 2017-1815.
`
`1
`
`Reference ID: 4216695
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`the preferred package configuration
`
`. We acknowledge the
`Sponsor’s response to our information request, but provide additional revisions to the blister
`pack labeling. As currently presented, the blister pack labeling may potentially confuse the
`intended users and differs from other available dose packs.
`
`
`
`RECOMMENDATIONS FOR PHARMACYCLICS LLC
`3
`We recommend the following be implemented prior to approval of this NDA:
`A. Carton labeling
`There is inadequate differentiation between the 140 mg capsule strength
` and the 420 mg tablet strength
`). Revise the color scheme of
`the 420 mg tablet strength
`, so that it appears in its own unique
`color and the color does not overlap with any other colors utilized in highlighting
`the strengths. The use of the same
` scheme for the product’s 140 mg
`capsule and 420 mg tablet strengths minimizes the difference between the
`strengths, which may lead to wrong strength selection errors.
`B. Blister pack labeling
`1. We recommend deleting
`
`
`
`
` in the blister pack as this may confuse the intended
`
`user.
`2. For increased clarity, we recommend
`
`
`
`
`
`3. We also recommend deleting
`
`.
`4. Add the proprietary name, established name, and product strength from the
`back of the blister pack labeling to the front of the blister pack labeling. In
`addition, revise the product strength to display the strength per tablet (e.g. 560
`mg per tablet).
`
`b Response to Information Request received on January 22, 2018.
`2
`
`Reference ID: 4216695
`
`7 Page(s) of Draft Labeling have been Withheld in Full as b4 (CCI/TS) immediately following this page
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`NICOLE B GARRISON
`02/07/2018
`
`HINA S MEHTA
`02/07/2018
`
`Reference ID: 4216695
`
`

`

`Department of Health and Human Services
`Public Health Service
`Food and Drug Administration
`Center for Drug Evaluation and Research
`Office of Medical Policy
`
`PATIENT LABELING REVIEW
`
`January 19, 2018
`
`Ann Farrell, MD
`Director
`Division of Hematology Products (DHP)
`
`LaShawn Griffiths, MSHS-PH, BSN, RN
`Associate Director for Patient Labeling
`Division of Medical Policy Programs (DMPP)
`
`Barbara Fuller, RN, MSN, CWOCN
`Team Leader, Patient Labeling
`Division of Medical Policy Programs (DMPP)
`
`Susan Redwood, MPH, BSN, RN
`Patient Labeling Reviewer
`Division of Medical Policy Programs (DMPP)
`
`Nisha Patel, PharmD
`Regulatory Review Officer
`Office of Prescription Drug Promotion (OPDP)
`Review of Patient Labeling: Patient Package Insert (PPI)
`
`IMBRUVICA (ibrutinib)
`
`tablets, for oral use
`
`
`Date:
`
`To:
`
`
`Through:
`
`
`From:
`
`Subject:
`
`Drug Name (established
`name):
`Dosage Form and
`Route:
`Application
`Type/Number:
`Applicant:
`
`NDA 210563
`
`Pharmacyclics LLC
`
`
`
`
`
`
`
`
`
`
`Reference ID: 4209235
`
`

`

` 1
`
`
`
` 2
`
`INTRODUCTION
`On August 31, 2017, Pharmacyclics LLC., submitted for the Agency’s review a 505
`(b) (1) New Drug Application (NDA) 210563 for IMBRUVICA (ibrutinib) tablets,
`for oral use. IMBRUVICA (ibrutinib) capsules, for oral use, 140 mg was approved
`by the Agency in November 2013. To reduce the patient pill burden, and improve
`patient’s compliance, a new tablet formulation of ibrutinib in four strengths was
`developed by Pharmacyclics. The purpose of this submission is to seek the approval
`of IMBRUVICA (ibrutinib) tablets for the same approved indications as the
`approved capsule formulation (NDA 205552), for the treatment of adult patients
`with:
` Mantle cell lymphoma (MCL) who have received at least one prior therapy
`•
`• Chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL)
`• Chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) with
`17p deletion
`• Waldenström’s macroglobulinemia (WM)
`• Marginal zone lymphoma (MZL) who require systemic therapy and have
`received at least one prior anti-CD20-based therapy
`• Chronic graft versus host disease (cGVHD) after failure of one or more lines of
`systemic therapy.
`This collaborative review is written by the Division of Medical Policy Programs
`(DMPP) and the Office of Prescription Drug Promotion (OPDP) in response to a
`request by the Division of Hematology Products (DHP) on November 1, 2017 for
`DMPP to review the Applicant’s proposed Patient Package Insert (PPI) for
`IMBRUVICA (ibrutinib) capsules, for oral use and IMBRUVICA (ibrutinib) tablets,
`for oral use.
`
` MATERIAL REVIEWED
`• Draft IMBRUVICA (ibrutinib) capsules and IMBRUVICA (ibrutinib) tablets PPI
`received on August 31, 2017, revised by the Review Division throughout the
`review cycle, and received by DMPP and OPDP on January 16, 2018 and
`January 18, 2018.
`• Draft IMBRUVICA (ibrutinib) capsules and IMBRUVICA (ibrutinib) tablets
`Prescribing Information (PI) received on August 31, 2017, revised by the Review
`Division throughout the review cycle, and received by DMPP and OPDP on
`January 16, 2018 and January 18, 2018.
`• Approved IMBRUVICA (ibrutinib) capsules NDA 205552 labeling dated
`December 20, 2017.
`
`
`3 REVIEW METHODS
`
`
`
`
`
`Reference ID: 4209235
`
`
`
`

`

`To enhance patient comprehension, materials should be written at a 6th to 8th grade
`reading level, and have a reading ease score of at least 60%. A reading ease score of
`60% corresponds to an 8th grade reading level.
`Additionally, in 2008 the American Society of Consultant Pharmacists Foundation
`(ASCP) in collaboration with the American Foundation for the Blind (AFB)
`published Guidelines for Prescription Labeling and Consumer Medication
`Information for People with Vision Loss. The ASCP and AFB recommended using
`fonts such as Verdana, Arial or APHont to make medical information more
`accessible for patients with vision loss.
`In collaborative review of the PPI we:
`simplified wording and clarified concepts where possible
`•
`ensured that the PPI is consistent with the Prescribing Information (PI)
`•
`removed unnecessary or redundant information
`•
`ensured that the PPI is free of promotional language or suggested revisions to
`•
`ensure that it is free of promotional language
`ensured that the PPI meets the criteria as specified in FDA’s Guidance for
`Useful Written Consumer Medication Information (published July 2006)
`ensured that the PPI is consistent with the approved labeling where applicable.
`
`•
`
`•
`
` 4
`
` 5
`
` CONCLUSIONS
`The PPI is acceptable with our recommended changes.
`
` RECOMMENDATIONS
`• Please send these comments to the Applicant and copy DMPP and OPDP on the
`correspondence.
`• Our collaborative review of the PPI is appended to this memorandum. Consult
`DMPP and OPDP regarding any additional revisions made to the PI to determine
`if corresponding revisions need to be made to the PPI.
` Please let us know if you have any questions.
`
`
`
`
`
`Reference ID: 4209235
`
`
`
`6 Page(s) of Draft Labeling have been Withheld in Full as b4 (CCI/TS) immediately following this page
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`SUSAN W REDWOOD
`01/19/2018
`
`NISHA PATEL
`01/19/2018
`
`BARBARA A FULLER
`01/19/2018
`
`Reference ID: 4209235
`
`

`

`FOOD AND DRUG ADMINISTRATION
`Center for Drug Evaluation and Research
`Office of Prescription Drug Promotion
`****Pre-decisional Agency Information****
`
`
`
`
`Memorandum
`
`Date:
`January 19, 2018
`
`
`To:
`
`
`Kelly Miller, Regulatory Project Manager
`Division of Hematology Products (DHP)
`
`Virginia Kwitkowski, Associate Director for Labeling, DHP
`
`Nisha Patel, Regulatory Review Officer
`Office of Prescription Drug Promotion (OPDP)
`
`Mathilda Fienkeng, Team Leader, OPDP
`
`
`
`
`From:
`
`
`
`CC:
`
`Subject:
`
`OPDP Labeling Comments for IMBRUVICA® (ibrutinib) capsules, for oral
`use, IMBRUVICA® (ibrutinib) tablets, for oral use
`
`210563
`
`
`NDA:
`
`
`
`In response to DHP’s consult request dated September 15, 2017, OPDP has reviewed the
`proposed product labeling (PI) and patient package insert (PPI) for the original NDA
`submission for IMBRUVICA® (ibrutinib) capsules, for oral use and IMBRUVICA® (ibrutinib)
`tablets, for oral use (Imbruvica).
`
`PI and PPI: OPDP’s comments on the proposed labeling are based on the draft PI emailed to
`OPDP on January 16, 2018, and are provided below.
`
` A
`
` combined OPDP and Division of Medical Policy Programs (DMPP) review was completed,
`and comments on the proposed PPI were sent under separate cover on January 19, 2018.
`
`Thank you for your consult. If you have any questions, please contact Nisha Patel at (301)
`796-3715 or nisha.patel@fda.hhs.gov.
`
`
`
`
`
`
`
`
`
`
`Reference ID: 4209411
`
`1
`
`

`

`Statement from draft
`Inform patients to take IMBRUVICA orally
`once daily according to their physician’s
`instructions and that the oral dosage (capsules
`or tablets) should be swallowed whole with a
`glass of water without
`
`approximately the same
`time each day (emphasis added).
`
`
`Comment
`We note that the Dosage and Administration
`section of the full PI states, “Do not open,
`break, or chew the capsules. Do not cut,
`crush, or chew the tablets (emphasis
`added).” OPDP recommends revising the
`Patient Counseling Information section of the
`full PI to include the information above
`regarding tablets.
`
`
`Package Insert
`
`Section
`17 Patient Counseling
`Information
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 4209411
`
`2
`
`39 Page(s) of Draft Labeling have been Withheld in Full as b4 (CCI/TS) immediately following this page
`
`(b) (4)
`
`(b) (4)
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`NISHA PATEL
`01/19/2018
`
`Reference ID: 4209411
`
`

`

`LABEL AND LABELING REVIEW
`Division of Medication Error Prevention and Analysis (DMEPA)
`Office of Medication Error Prevention and Risk Management (OMEPRM)
`Office of Surveillance and Epidemiology (OSE)
`Center for Drug Evaluation and Research (CDER)
`
`*** This document contains proprietary information that cannot be released to the public***
`
`Date of This Review:
`January 12, 2018
`Requesting Office or Division:
`Division of Hematology Products (DHP)
`Application Type and Number: NDA 210563
`Product Name and Strength:
`Imbruvica (ibrutinib) tablets, 140 mg, 280 mg, 420 mg, and
`560 mg
`Single-Ingredient Product
`Rx
`Pharmacyclics LLC
`August 31, 2017, September 21, 2017 and December 28,
`2017
`2017-1815
`Nicole Garrison, PharmD, BCPS
`Hina Mehta, PharmD
`
`Product Type:
`Rx or OTC:
`Applicant/Sponsor Name:
`Submission Date:
`
`OSE RCM #:
`DMEPA Safety Evaluator:
`DMEPA Team Leader:
`
`Reference ID: 4206614
`
`1
`
`

`

`REASON FOR REVIEW
`1
`This review evaluates the proposed container label, carton labeling, and Prescribing
`Information (PI) for Imbruvica (ibrutinib) tablets, 140 mg, 280 mg, 420 mg, and 560 mg (NDA
`210563) for areas of vulnerability that could lead to medication errors. The Division of
`Hematology Products (DHP) requested this review as a part of their evaluation to the 505(b)(1)
`NDA submission for Imbruvica (ibrutinib) tablets.
`
`1.1 BACKGROUND INFORMATION
`Imbruvica (ibrutinib) capsules NDA 205552 was approved on November 13, 2013 for the
`treatment of patients with Mantle Cell Lymphoma (MCL). Since its original approval, Imbruvica
`has received additional indications for the treatment of patients with Chronic Lymphocytic
`Leukemia (CLL), Waldenstrom’s Macroglobulinemia (WM), CLL/Small lymphocytic lymphoma
`(SLL), CLL/SLL with 17p deletion, Marginal Zone Lymphoma (MZL), and Chronic graft versus host
`disease (cGVHD).
`
`Imbruvica capsule 140 mg is currently marketed in the United States. On December 20, 2017,
`the 70 mg capsule was approved to allow for dose reductions in patients with moderate hepatic
`impairment. Depending on the treatment indication, patients may be required to take 3
`capsules (420 mg) or 4 capsules (560 mg) per dose. To reduce the patient pill burden, and
`improve patient’s compliance, the Applicant has proposed a new tablet formulation of
`Imbruvica in four strengths (140 mg, 280 mg, 420 mg, and 560 mg). The tablet formulation is
`intended for the treatment of the same approved indications and the same dose as the
`approved capsule formulation (NDA 205552).
`
`2 MATERIALS REVIEWED
`We considered the materials listed in Table 1 for this review. The Appendices provide the
`methods and results for each material reviewed.
`Table 1. Materials Considered for this Label and Labeling Review
`Appendix Section
`Material Reviewed
`(for Methods and Results)
`A
`B
`C- N/A
`D- N/A
`E- N/A
`F- N/A
`G
`
`Product Information/Prescribing Information
`Previous DMEPA Reviews
`Human Factors Study
`ISMP Newsletters
`FDA Adverse Event Reporting System (FAERS)*
`Other
`Labels and Labeling
`N/A=not applicable for this review
`
`Reference ID: 4206614
`
`2
`
`

`

`Table 1. Materials Considered for this Label and Labeling Review
`Appendix Section
`Material Reviewed
`(for Methods and Results)
`*We do not typically search FAERS for our label and labeling reviews unless we are aware of
`medication errors through our routine postmarket safety surveillance
`
`3 OVERALL ASSESSMENT OF THE MATERIALS REVIEWED
`Pharmcyclics submitted a 505 (b)(1) application to obtain marketing approval of Imbruvica
`tablets to reduce patient pill burden and increase patient compliance with therapy. Imbruvica
`tablets will have the same indication and dosing as the currently marketed Imbruvica capsules.
`Imbruvica tablets will be supplied in cartons with blister cards containing 28 tablets.
`
`We performed a risk assessment of the proposed container labels, carton labeling, and PI for
`Imbruvica (ibrutinib) tablets to determine whether there are significant concerns in terms of
`safety, related to preventable medication errors. We identified areas of the proposed labels
`and labeling that could be revised to improve clarity and readability of important information.
`For the proposed labels and labeling, we recommend revising the color scheme of the 280 mg,
`420 mg, and 560 mg strengths, including the package type on the principal display panel (PDP),
`revising the usual dose statement and the product strength statement. For the blister pack
`labeling we recommend deleting
` and revising the cautionary statement.
`For the proposed PI, we recommend revising statements in Section 2 Dosage and
`Administration to provide clarity on administration of the dose.
`
`CONCLUSION & RECOMMENDATIONS
`4
`DMEPA concludes that the proposed PI, labels and labeling can be improved to increase clarity
`of important information on the labels to promote the safe use of the product. We provide
`recommendations in Section 4.1 and Section 4.2 below and advise that they are implemented
`prior to the approval of this NDA.
`
`4.1 RECOMMENDATIONS FOR THE DIVISION
`A. Highlights of Prescribing Information
`1. Dosage and Administration
`a.Revise the statement,
` To “Dose should be taken orally with a glass of water.”
`b.Revise the statement,
` To “Do not
`cut, crush, or chew the tablets.”
`B. Full Prescribing Information
`1. Dosage and Administration
`a.Section 2.1, Dosing Guidelines
`
`
`
`Reference ID: 4206614
`
`3
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`i.
`
`ii.
`
`
`Revise the statement,
` to “The dose should be taken orally
`with a glass of water.”
`See A.1.b and revise the full prescribing information
`accordingly.
`
`4.2 RECOMMENDATIONS FOR PHARMCYCLICS
`We recommend the following be implemented prior to approval of this NDA:
`A. Carton labeling
`1. There is inadequate differentiation between the font color of the proprietary
`name
` and the color scheme of the 280 mg and 560 mg strengths
`
`. Revise the color scheme of the 280 mg and 560 mg strengths
`, so that either strength appears in its own unique color and the color does
`not overlap with any other colors utilized in highlighting the strengths. The use
`of the same
` color font for the proprietary name and one for the product’s
`strength minimizes the difference between the strengths, which may lead to
`wrong strength selection errors.
`2. There is inadequate differentiation between the 140 mg capsule strength
`and the 420 mg tablet strength
`). Revise the color scheme of
`the 420 mg tablet strength
` so that it appears in its own unique
`color and the color does not overlap with any other colors utilized in highlighting
`the strengths. The use of the same
` color scheme for the product’s 140 mg
`capsule and 420 mg tablet strengths minimizes the difference between the
`strengths, which may lead to wrong strength selection errors.
`3. The package type (wallet card) is omitted from Principal Display Panel (PDP).
`Revise the PDP to include the net quantity with the package type as follows:
`
`
`
`“Wallet card contains 28 tablets”
`
`4. Revise the usual dose statement from
`“Dosage: See prescribing information” in accordance with 21 CFR 201.55.
`5. Revise the product strength on the PDP to state the total product strength (e.g.
`560 mg per tablet).
`6. Revise the statement,
`or chew the tablets.” to prevent confusion.
`
` To “Do not cut, crush,
`
` to
`
`A. Blister pack labeling
`1. We recommend deleting
`
`. We recommend this revision to prevent delays in dosing.
`2. For each strength of Imbruvica tablets, revise the cautionary statement,
`
`
`
`
`
`
` to
`
`4
`
`Reference ID: 4206614
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`“Every tablet is identical and contains (include the total amount [e.g. 560 mg]) of
`Imbruvica per tablet”
`
`Reference ID: 4206614
`
`5
`
`

`

`APPENDICES: METHODS & RESULTS FOR EACH MATERIALS REVIEWED
`
`Imbruvica tablets
`N/A
`
`APPENDIX A. PRODUCT INFORMATION/PRESCRIBING INFORMATION
`Table 2 presents relevant product information for Imbruvica that Pharmacyclics submitted on
`August 31, 2017 and December 28, 2017.
`Table 2. Relevant Product Information for Imbruvica
`Imbruvica capsules
`Product Name
`November 13, 2013
`Initial Approval Date
`Ibrutinib
`Active Ingredient
`Imbruvica is indicated for the treatment of patients with:
`Indication
` Mantle cell lymphoma (MCL) who have received at least one
`prior therapy
` Chronic lymphocytic leukemia (CLL)/Small lymphocytic
`lymphoma (SLL)
` Chronic lymphocytic leukemia (CLL)/Small lymphocytic
`lymphoma (SLL) with 17p deletion
` Waldenstrom’s macroglobulinemia (WM)
` Marginal zone lymphoma (MZL) for patients who require
`systemic therapy and have received at least one prior anti-
`CD20-based therapy.
` Chronic graft versus host disease (cGVHD) after failure of
`one or more lines of systemic therapy.
`
`Oral
`
`Capsules
`Capsules: 70 mg and 140 mg
`
`Tablets
`Tablets: 140 mg, 280 mg, 420
`mg, and 560 mg
`Dose and Frequency MCL and LZL: 560 mg taken orally once daily
`CLL/SLL, WM, and cGVHD: 420 mg taken orally once daily
`
`
`70 mg capsules (28
`140 mg tablets (28
`capsules per bottle)
`tablets per carton)
`140 mg capsules (90 and
`280 mg tablets (28
`120 capsules per bottle)
`tablets per carton)
`420 mg tablets (28
`tablets per carton)
`560 mg tablets (28
`tablets per carton)
`Store tablets in original
`packaging at room
`temperature 20°C to
`
`Route of
`Administration
`Dosage Form
`Strength
`
`How Supplied
`
`Storage
`
`
`
`
`
`Store bottles at room
`temperature 20°C to
`25°C (68°F to 77°F).
`
`
`
`
`
`
`
`
`
`Reference ID: 4206614
`
`6
`
`

`

`Container Closure
`
`Excursions are permitted
`between 15°C and 30°C
`(59°F to 86°F). Retain in
`original package until
`dispensing.
` White HDPE bottles with
`a child-resistant closure
`
`25°C (68°F to 77°F).
`Excursions are permitted
`between 15°C and 30°C
`(59°F to 86°F).
`
` Carton of one folded
`blister card containing
`two 14-count blister
`strips for a total of 28
`tablets
`
`Reference ID: 4206614
`
`7
`
`

`

`APPENDIX B. PREVIOUS DMEPA REVIEWS
`On December 29, 2017, we searched DMEPA’s previous reviews using the terms, Imbruvica.
`Our search identified four labeling reviewsa,b,c,d and one post marketing reviewe, and we
`confirmed that our previous recommendations were implemented.
`
`a Rahimi, L. Label and Labeling Review for Imbruvica NDA 205552/S-002. Silver Spring (MD): FDA, CDER, OSE,
`DMEPA (US); 2014 JAN 12. RCM No.: 2014-2236.
`b Garrison, N. Label and Labeling Review for Imbruvica NDA 205552/S-016. Silver Spring (MD): FDA, CDER, OSE,
`DMEPA (US); 2016 NOV 02. RCM No.: 2016-2187.
`c Garrison, N. Label and Labeling Review for Imbruvica NDA 205552/S-20. Silver Spring (MD): FDA, CDER, OSE,
`DMEPA (US); 2017 NOV 08. RCM No.: 2017-1565.
`d Garrison, N. Label and Labeling Review Memorandum for Imbruvica NDA 205552/S-20. Silver Spring (MD): FDA,
`CDER, OSE, DMEPA (US); 2017 DEC 01. RCM No.: 2017-1565-1.
`e Ayres, E. Postmarket Signal Work for Imbruvica NDA 205552. Silver Spring (MD): FDA, CDER, OSE, DMEPA (US);
`22015 DEC 18. RCM No.: 2015-2548.
`
`8
`
`Reference ID: 4206614
`
`

`

`APPENDIX G. LABELS AND LABELING
`G.1
`List of Labels and Labeling Reviewed
`Using the principles of human factors and Failure Mode and Effects Analysis,f along with
`postmarket medication error data, we reviewed the following Imbruvica labels and labeling
`submitted by Pharmacyclics on August 31, 2017, September 21, 2017 and December 28, 2017.
`
` Container labels and Carton labeling
`
`Prescribing Information
`
`G.2
`
`Label and Labeling Images
`
`Container labels and Carton labeling
`
`f Institute for Healthcare Improvement (IHI). Failure Modes and Effects Analysis. Boston. IHI:2004.
`
`Reference ID: 4206614
`
`9
`
`8 Page(s) of Draft Labeling have been Withheld in Full as b4 (CCI/TS) immediately following this page
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`NICOLE B GARRISON
`01/12/2018
`
`HINA S MEHTA
`01/12/2018
`
`Reference ID: 4206614
`
`

`

`M E M O R A N D U M
`
`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`PUBLIC HEALTH SERVICE
`FOOD AND DRUG ADMINISTRATION
`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`DATE:
`
`TO:
`
`
`
`
`
`FROM:
`
`
`
`12/1/2017
`
`Division of Hematology Products
`Office of Hermatology and Oncology Products
`
`Division of New Drug Bioequivalence Evaluation (DNDBE)
`Office of Study Integrity and Surveillance (OSIS)
`
`SUBJECT: Recommendation to accept data without an on-site inspection
`
`RE:
`
`NDA 210563
`
`The Division of New Drug Bioequivalence Evaluation (DNDBE) within the Office of Study Integrity
`and Surveillance (OSIS) recommends accepting data without an on-site inspection. The rationale for
`this decision is noted below.
`
`
`
`Rationale
`
`OSIS recently inspected the sites listed below. The inspectional outcomes of the inspections were
`classified as No Action Indicated (NAI). Although the bioanalytical study reports were not provided
`, the clinical portions of the current studies concluded between January and
`November 2016. Therefore, OSIS infers that the bioanalytical portions of the current studies were
`conducted around that time (Jan – Nov 2016) and that the previously inspected studies were conducted
`within approximately one to two years of the bioanalytical portion of the current studies.
`
`
`
`
`
`
`
`Inspection Sites
`
`
`
`Facility Type
`
`Facility Name
`
`Facility Address
`
`Analytical
`
`Clinical
`
`Celerion
`
`2420 West Baseline Road, Tempe, AZ
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 4189398
`
`Page 1 of 2
`
`(b) (4)
`
`(b) (4)
`
`

`

`
`
`
`
`
`
`
`
`
`
`
`
`
`
`M E M O R A N D U M
`
`
`
`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`PUBLIC HEALTH SERVICE
`FOOD AND DRUG ADMINISTRATION
`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`DATE:
`
`TO:
`
`
`
`
`
`FROM:
`
`
`
`11/29/2017
`
`Division of Hematology Products
`Office of Hermatology and Oncology Products
`
`Division of New Drug Bioequivalence Evaluation (DNDBE)
`Office of Study Integrity and Surveillance (OSIS)
`
`SUBJECT: Decline to Inspect Mamo
`
`RE:
`
`NDA 210563
`
`The Division of New Drug Bioequivalence Evaluation (DNDBE) within the Office of Study Integrity
`and Surveillance (OSIS) recommends accepting data without an on-site inspection. The rationale for
`this decision is noted below.
`
`
`
`Rationale
`
`OSIS has no inspection history for Janssen-Cilag International, however, an inspection of the site can
`not be conducted because the requested review goal date of February 28, 2018 provides insufficient
`time for the inspection to be completed to meet that goal date.
`
`
`
`Inspection Site
`
`
`
`Facility Type
`
`Facility Name
`
`Facility Address
`
`Clinical
`
`Janssen-Cilag International N.V.
`
`Janssen Research and Development
`Pharmacology Unit, Merksem, Lange
`Bremstraat 70, B-2170 Antwerpen,
`Belgium.
`
`Reference ID: 4189398
`
`
`Page 2 of 2
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`SHILA S NKAH
`12/01/2017
`
`Reference ID: 4189398
`
`