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`DEPARTMENT OF HEALTH AND HUMAN SERVICES
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`Food and Drug Administration
`Silver Spring MD 20993
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`NDA 205552/S-020
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`SUPPLEMENT APPROVAL
`FULFILLMENT OF POSTMARKETING
`COMMITMMENT
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`Pharmacyclics LLC
`Attention: Usha Ramesh, PhD
`Executive Director, Regulatory Affairs
`995 East Arques Avenue
`Sunnyvale, CA 94085
`
`
`Dear Dr. Ramesh:
`
`Please refer to your Supplemental New Drug Application (sNDA) dated August 2, 2017,
`received August 2, 2017, and your amendments, submitted under section 505(b) of the Federal
`Food, Drug, and Cosmetic Act (FDCA) for Imbruvica® (ibrutnib) capsules, 70 mg and 140 mg.
`
`This Prior Approval supplemental new drug application provides for adding a 70 mg capsule to
`allow for dose reductions in patients with moderate hepatic impairment, updated dose
`modifications for ibrutinib when co-administered with CYP3A inhibitors (Section 2.4 of the
`UPSI) and updates to Section 5.4 in the Warnings and Precautions of the USPI.
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`APPROVAL & LABELING
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`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.
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`WAIVER OF HIGHLIGHTS SECTION
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`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.
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`CONTENT OF LABELING
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`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
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`Reference ID: 4198358
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`

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`NDA 205552/S-020
`Page 2
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`of labeling must be identical to the enclosed labeling (package insert, patient package insert),
`with the addition of any labeling changes in pending “Changes Being Effected” (CBE)
`supplements, as well as annual reportable changes not included in the enclosed labeling.
`Information on submitting SPL files using eList may be found in the guidance for industry 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.
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`Also within 14 days, amend all pending supplemental applications that include labeling changes
`for this NDA, including CBE supplements for which FDA has not yet issued an action letter,
`with the content of labeling [21 CFR 314.50(l)(1)(i)] in 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).
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`CARTON AND IMMEDIATE CONTAINER LABELS
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`Submit final printed carton and immediate container labels that are identical to the carton and
`immediate-container labels submitted on September 27, 2017, and November 20, 2017,
`respectively, 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 205552/S-020.” Approval of this submission by FDA is not
`required before the labeling is used.
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`REQUIRED PEDIATRIC ASSESSMENTS
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`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.
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`Because this drug product for this indication has an orphan drug designation, you are exempt
`from this requirement.
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`FULFILLMENT OF POSTMARKETING COMMITMENT
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`We have received your submission dated August 2, 2017, containing the final report for the
`following postmarketing commitment listed in the January 29, 2015, approval letter.
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`Reference ID: 4198358
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`

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`NDA 205552/S-020
`Page 3
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`PMC 2867-1 Develop and test the stability of a lower (35 to 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.
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`
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`The timetable you submitted on January 23, 2015, states that you will conduct this
`trial according to the following schedule:
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`Final Protocol Submitted:
`Study Completion:
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`Final Report Submission:
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`09/2015
`12/2016
`03/2017
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`We have reviewed your submission and conclude that the above commitment is fulfilled.
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`We remind you that there are postmarketing requirements listed in the November 13, 2013,
`March 4, 2016, and January 18 and August 2, 2017 approval letters and a postmarketing
`commitment listed in the November 13, 2013 approval letter that are still open.
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`PROMOTIONAL MATERIALS
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`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:
`
`
`OPDP Regulatory Project Manager
`Food and Drug Administration
`Center for Drug Evaluation and Research
`Office of Prescription Drug Promotion (OPDP)
`5901-B Ammendale Road
`Beltsville, MD 20705-1266
`
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`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/U
`CM443702.pdf).
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`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
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`Reference ID: 4198358
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`

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`NDA 205552/S-020
`Page 4
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`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.
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`REPORTING REQUIREMENTS
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`We remind you that you must comply with reporting requirements for an approved NDA
`(21 CFR 314.80 and 314.81).
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`If you have any questions, call Suria Yesmin, Regulatory Project Manager, at (301) 348-1725.
`
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`Sincerely,
`
`{See appended electronic signature page}
`
`Albert Deisseroth, MD, PhD
`Supervisory Associate Division Director
`Division of Hematology Products
`Office of Hematology and Oncology Products
`Center for Drug Evaluation and Research
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`
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`ENCLOSURE:
`Content of Labeling
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`Reference ID: 4198358
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`

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`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
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`ALBERT B DEISSEROTH
`12/20/2017
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`Reference ID: 4198358
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`(
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