CENTER FOR DRUG EVALUATION AND RESEARCH
`
`Approval Package for:
`
`APPLICATION NUMBER:
`
`210563Orig1s000
`210563Orig2s000
`
` Imbruvica® tablets, 140 mg, 280 mg, 420 mg,
`and 560 mg.
`
`ibrutinib
`
`Trade Name:
`
`Generic or
`Established:
`
`Sponsor:
`
`
`
`Approval Date:
`
`
`Indication:
`
`
`Pharmacyclics LLC
`
`February 16, 2018
`
`NDA 210563/Original 1 – Treatment of adult patients
`with chronic lymphocytic leukemia (CLL)/small
`lymphocytic lymphoma (SLL), chronic lymphocytic
`leukemia (CLL)/small lymphocytic lymphoma (SLL)
`with 17p deletion, Waldenström’s
`macroglobulinemia (WM), and chronic graft versus host
`disease (cGVHD) after failure of
`one or more lines of systemic therapy.
`
` NDA 210563/Original 2 – Treatment of adult patients
`with mantle cell lymphoma (MCL) who have received at
`least one prior therapy, and marginal zone lymphoma
`(MZL) who require systemic therapy and have received
`at least one prior anti-CD20-based therapy.
`
`

`

`
`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`210563Orig1s000
`210563Orig2s000
`
`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
`
`X
`X
`
`

`

`
`
`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`APPLICATION NUMBER:
`210563Orig1s000
`210563Orig2s000
`
`APPROVAL LETTER
`
`
`
`
`
`
`
`

`

`
`
`
`
`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`
`
`
`
`
`
`NDA 210563/Original 1
`
`
`
`
`
`Food and Drug Administration
`Silver Spring MD 20993
`
`NDA APPROVAL
`
`
`Pharmacyclics LLC
`Attention: Usha Ramesh, PhD
`Executive Director, Regulatory Affairs
`995 East Arques Avenue
`Sunnyvale, CA 94085-4521
`
`
`Dear Dr. Ramesh:
`
`Please refer to your New Drug Application (NDA) dated August 31, 2017, received
`August 31, 2017, and your amendments, submitted under section 505(b) of the Federal Food,
`Drug, and Cosmetic Act (FDCA) for Imbruvica® (ibrutinib) tablets, 140 mg, 280 mg, 420 mg,
`and 560 mg.
`
`NDA 210563 provides for the use of Imbruvica® for the following indications which, for
`administrative purposes, we have designated as follows:
`
`
` NDA 210563/Original 1 – Treatment of adult patients with chronic lymphocytic
`leukemia (CLL)/small lymphocytic lymphoma (SLL), chronic lymphocytic leukemia
`(CLL)/small lymphocytic lymphoma (SLL) with 17p deletion, Waldenström’s
`macroglobulinemia (WM), and chronic graft versus host disease (cGVHD) after failure of
`one or more lines of systemic therapy.
`
` NDA 210563/Original 2 – Treatment of adult patients with mantle cell lymphoma (MCL)
`who have received at least one prior therapy, and marginal zone lymphoma (MZL) who
`require systemic therapy and have received at least one prior anti-CD20-based therapy.
`
`
`The subject of this action letter is NDA 210563/Original 1. A separate action letter will be
`issued for NDA 210563/Original 2.
`
`APPROVAL & LABELING
`
`We have completed our review of this application, as amended. It is approved, effective on the
`date of this letter, for use as recommended in the enclosed agreed-upon labeling text.
`
`EXPIRATION DATING PERIOD
`
`We grant a 24-month expiration period for the drug product when stored at controlled room
`temperature 20°C to 25°C (68°F to 77°F) with excursions permitted between 15°C and 30°C
`(between 59°F and 86°F).
`
`
`Reference ID: 4223095
`
`

`

`NDA 210563/Original 1
`Page 2
`
`
`WAIVER OF HIGHLIGHTS SECTION
`
`We are waiving the requirements of 21 CFR 201.57(d)(8) regarding the length of Highlights of
`prescribing information. This waiver applies to all future supplements containing revised
`labeling unless we notify you otherwise.
`
`CONTENT OF LABELING
`
`As soon as possible, but no later than 14 days from the date of this letter, submit the content of
`labeling [21 CFR 314.50(l)] in structured product labeling (SPL) format using the FDA
`automated drug registration and listing system (eLIST), as described at
`http://www.fda.gov/ForIndustry/DataStandards/StructuredProductLabeling/default.htm. Content
`of labeling must be identical to the enclosed labeling (package insert and patient package insert).
`Information on submitting SPL files using eLIST may be found in the guidance for industry SPL
`Standard for Content of Labeling Technical Qs and As, available at
`http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/
`UCM072392.pdf.
`
`The SPL will be accessible via publicly available labeling repositories.
`
`CARTON AND IMMEDIATE CONTAINER LABELS
`
`Submit final printed carton and container labels that are identical to the carton and immediate
`container labels submitted on February 14, 2018, as soon as they are available, but no more than
`30 days after they are printed. Please submit these labels electronically according to the
`guidance for industry titled Providing Regulatory Submissions in Electronic Format — Certain
`Human Pharmaceutical Product Applications and Related Submissions Using the eCTD
`Specifications (May 2015, Revision 3). For administrative purposes, designate this submission
`“Final Printed Carton and Container Labels for approved NDA 210563.” Approval of this
`submission by FDA is not required before the labeling is used.
`
`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.
`
`PROMOTIONAL MATERIALS
`
`You may request advisory comments on proposed introductory advertising and promotional
`labeling. To do so, submit, in triplicate, a cover letter requesting advisory comments, the
`proposed materials in draft or mock-up form with annotated references, and the prescribing
`information to:
`
`Reference ID: 4223095
`
`

`

`NDA 210563/Original 1
`Page 3
`
`
`
`
`OPDP Regulatory Project Manager
`Food and Drug Administration
`Center for Drug Evaluation and Research
`Office of Prescription Drug Promotion
`5901-B Ammendale Road
`Beltsville, MD 20705-1266
`
`
`Alternatively, you may submit a request for advisory comments electronically in eCTD format.
`For more information about submitting promotional materials in eCTD format, see the draft
`Guidance for Industry (available at:
`http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/
`UCM443702.pdf).
`
`As required under 21 CFR 314.81(b)(3)(i), you must submit final promotional materials, and the
`prescribing information, at the time of initial dissemination or publication, accompanied by a
`Form FDA 2253. 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, please contact Jennifer Lee, Regulatory Project Manager, at
`(240) 402-4622.
`
`
`Sincerely,
`
`{See appended electronic signature page}
`
`R. Angelo de Claro, MD
`Deputy Division Director (Acting)
`Division of Hematology Products
`Office of Hematology and Oncology Products
`Center for Drug Evaluation and Research
`
`
`
`ENCLOSURE:
`Content of Labeling
`
`Reference ID: 4223095
`
`

`

`
`
`
`
`
`
`
`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`
`
`
`
`
`
`
`
`Food and Drug Administration
`Silver Spring MD 20993
`
`NDA 210563/Original 2
`
`ACCELERATED APPROVAL
`
`
`Pharmacyclics LLC
`Attention: Usha Ramesh, PhD
`Executive Director, Regulatory Affairs
`995 East Arques Avenue
`Sunnyvale, CA 94085-4521
`
`
`Dear Dr. Ramesh:
`
`Please refer to your New Drug Application (NDA) dated August 31, 2017, received
`August 31, 2017, and your amendments, submitted under section 505(b) of the Federal Food,
`Drug, and Cosmetic Act (FDCA) for Imbruvica® (ibrutinib) tablets, 140 mg, 280 mg, 420 mg,
`and 560 mg.
`
`NDA 210563 provides for the use of Imbruvica® for the following indications which, for
`administrative purposes, we have designated as follows:
`
`
` NDA 210563/Original 1 – Treatment of adult patients with chronic lymphocytic
`leukemia/small lymphocytic lymphoma (CLL), chronic lymphocytic leukemia
`(CLL)/small lymphocytic lymphoma (SLL) with 17p deletion, Waldenström’s
`macroglobulinemia (WM), and chronic graft versus host disease (cGVHD) after failure of
`one or more lines of systemic therapy.
`
` NDA 210563/Original 2 – Treatment of adult patients with mantle cell lymphoma (MCL)
`who have received at least one prior therapy, and marginal zone lymphoma (MZL) who
`require systemic therapy and have received at least one prior anti-CD20-based therapy.
`
`
`The subject of this action letter is NDA 210563/Original 2. A separate action letter will be
`issued for NDA 210563/Original 1.
`
`APPROVAL & LABELING
`
`We have completed our review of this application, as amended. It is approved under the
`provisions of accelerated approval regulations (21 CFR 314.500), effective on the date of this
`letter, for use as recommended in the enclosed agreed-upon labeling text. Marketing of this drug
`product and related activities must adhere to the substance and procedures of the referenced
`accelerated approval regulations.
`
`
`
`Reference ID: 4223111
`
`

`

`NDA 210563/Original 2
`Page 2
`
`
`EXPIRATION DATING PERIOD
`
`We grant a 24-month expiration period for the drug product when stored at controlled room
`temperature 20°C to 25°C (68°F to 77°F) with excursions permitted between 15°C and 30°C
`(between 59°F and 86°F).
`
`WAIVER OF HIGHLIGHTS SECTION
`
`We are waiving the requirements of 21 CFR 201.57(d)(8) regarding the length of Highlights of
`prescribing information. This waiver applies to all future supplements containing revised
`labeling unless we notify you otherwise.
`
`CONTENT OF LABELING
`
`As soon as possible, but no later than 14 days from the date of this letter, submit the content of
`labeling [21 CFR 314.50(l)] in structured product labeling (SPL) format using the FDA
`automated drug registration and listing system (eLIST), as described at
`http://www.fda.gov/ForIndustry/DataStandards/StructuredProductLabeling/default.htm. Content
`of labeling must be identical to the enclosed labeling (package insert and patient package insert).
`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/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/U
`CM072392.pdf.
`
`The SPL will be accessible via publicly available labeling repositories.
`
`CARTON AND IMMEDIATE CONTAINER LABELS
`
`Submit final printed carton and container labels that are identical to the carton and immediate
`container labels submitted on February 14, 2018, as soon as they are available, but no more than
`30 days after they are printed. Please submit these labels electronically according to the
`guidance for industry titled Providing Regulatory Submissions in Electronic Format — Certain
`Human Pharmaceutical Product Applications and Related Submissions Using the eCTD
`Specifications (May 2015, Revision 3). For administrative purposes, designate this submission
`“Final Printed Carton and Container Labels for approved NDA 210563.” Approval of this
`submission by FDA is not required before the labeling is used.
`
`ACCELERATED APPROVAL REQUIREMENTS
`
`Products approved under the accelerated approval regulations, 21 CFR 314.510, require further
`adequate and well-controlled clinical trials to verify and describe clinical benefit. You are
`required to conduct such clinical trials with due diligence. If postmarketing clinical trials fail to
`verify clinical benefit or are not conducted with due diligence, we may, following a hearing in
`accordance with 21 CFR 314.530, withdraw this approval. We remind you of your
`postmarketing requirement for treatment of patients with mantle cell lymphoma who have
`received at least one prior therapy, specified in your submission dated February 6, 2018. This
`requirement, along with required completion dates, is listed below.
`
`Reference ID: 4223111
`
`

`

`NDA 210563/Original 2
`Page 3
`
`
`
`PMR 3343-1 Complete and submit the final results of the ongoing randomized, double-blind,
`placebo controlled Phase 3 clinical trial (PCI-32765MCL3002) of ibrutinib in
`combination with bendamustine and rituximab in patients with newly diagnosed
`mantle cell lymphoma. Enrollment of approximately 520 patients is expected.
`The primary endpoint is progression-free survival as assessed by investigators.
`Overall survival is a key secondary endpoint.
`
`
`Trial Completion:
`Final Report Submission:
`
`
`
`
`
`We remind you of your postmarketing requirement for treatment of patients with marginal zone
`lymphoma who require systemic therapy specified in your submission dated February 6, 2018.
`This requirement, along with required completion dates, is listed below.
`
`PMR 3343-2 Submit the complete final report and data from a randomized, Phase 3 trial,
`comparing ibrutinib in combination with bendamustine and rituximab or
`rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone versus
`bendamustine and rituximab or rituximab, cyclophosphamide, doxorubicin,
`vincristine, and prednisone in subjects with previously treated follicular
`lymphoma or marginal zone lymphoma. At least 50 enrolled subjects need to
`have a diagnosis of marginal zone lymphoma. The primary endpoint is
`progression-free survival in the overall intent-to-treat population.
`
`12/2018
`03/2019
`
`
`Trial Completion:
`Final Report Submission:
`
`05/2019
`08/2019
`
`
`
`
`
`Under 21 CFR 314.81(b)(2)(vii) and 314.81(b)(2)(viii) you should include a status summary of
`each requirement 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 trial.
`
`Submit final reports to this NDA as a supplemental application. For administrative purposes, all
`submissions relating to this postmarketing requirement must be clearly designated “Subpart H
`Postmarketing Requirement(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.
`
`
`Reference ID: 4223111
`
`

`

`NDA 210563/Original 2
`Page 4
`
`
`PROMOTIONAL MATERIALS
`
`Under 21 CFR 314.550, you are required to submit, during the application pre-approval review
`period, all promotional materials, including promotional labeling and advertisements, that you
`intend to use in the first 120 days following marketing approval (i.e., your launch campaign). If
`you have not already met this requirement, you must immediately contact the Office of
`Prescription Drug Promotion (OPDP) at (301) 796-1200. Please ask to speak to a regulatory
`project manager or the appropriate reviewer to discuss this issue.
`
`As further required by 21 CFR 314.550, submit all promotional materials that you intend to use
`after the 120 days following marketing approval (i.e., your post-launch materials) at least 30
`days before the intended time of initial dissemination of labeling or initial publication of the
`advertisement. We ask that each submission include a detailed cover letter together with three
`copies each of the promotional materials, annotated references, and approved package insert
`(PI)/Medication Guide/patient PI (as applicable).
`
`Send each submission directly to:
`
`OPDP Regulatory Project Manager
`Food and Drug Administration
`Center for Drug Evaluation and Research
`Office of Prescription Drug Promotions (OPDP)
`5901-B Ammendale Road
`Beltsville, MD 20705-1266
`
`
`REPORTING REQUIREMENTS
`
`We remind you that you must comply with the reporting requirements for an approved NDA
`(21 CFR 314.80 and 314.81).
`
`If you have any questions, please contact Jennifer Lee, Regulatory Project Manager, at
`(240) 402-4622.
`
`
`Sincerely,
`
`{See appended electronic signature page}
`
`R. Angelo de Claro, MD
`Deputy Division Director (Acting)
`Division of Hematology Products
`Office of Hematology and Oncology Products
`Center for Drug Evaluation and Research
`
`
`
`ENCLOSURE:
`Content of Labeling
`
`Reference ID: 4223111
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`ROMEO A DE CLARO
`02/16/2018
`
`Reference ID: 4223095
`
`(
`
`
`
`