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`DEPARTMENT OF HEALTH AND HUMAN SERVICES
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` NDA 021880/S-039, S-040
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`Food and Drug Administration
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`Silver Spring MD 20993
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`SUPPLEMENT APPROVAL
`REMS MODIFICATION
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` Celgene Corporation
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`Attention: Marion Ceruzzi, PhD
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`Senior Director, Regulatory Affairs
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`400 Connell Drive, Suite 7000
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`Connell Corporate Park
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`Berkley Heights, NJ 07922
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`
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`Dear Dr. Ceruzzi:
`
`Please refer to your Supplemental New Drug Applications (sNDAs) dated March 13, 2014,
`received March 13, 2014 for S-039, and your submission dated March 31, 2014, received March
`31, 2014 for S-040, submitted under section 505(b) of the Federal Food, Drug, and Cosmetic Act
`(FDCA) for REVLIMID® (lenalidomide) Capsules 2.5, 5, 10, 15, 20, and 25 mg.
`
`We acknowledge receipt of your amendments dated May 2, 16, June 9, 16, 18, July 10, and
`September 8, 2014.
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`“Prior Approval” supplemental new drug application (S-039) provides for proposed
`modifications to the approved risk evaluation and mitigation strategy (REMS) for REVLIMID®
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`(lenalidomide).
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`“Prior Approval” supplemental new drug application (S-040) provides for updates to the
`REVLIMID® (lenalidomide) package insert, Medication Guide, and REMS documents based
`upon analyses of data regarding the risks of venous thromboembolic events and arterial
`thromboembolic events.
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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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`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
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`Reference ID: 3627118
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`

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`NDA 021880/S-039, S-040
`Page 2
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`http://www.fda.gov/ForIndustry/DataStandards/StructuredProductLabeling/default.htm. Content
`of labeling must be identical to the enclosed labeling (text for the package insert and Medication
`Guide), 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.
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`The SPL will be accessible from publicly available labeling repositories.
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`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).
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`We request that the labeling approved today be available on your website within 10 days of
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` receipt of this letter.
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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 none of these criteria apply to your application, you are exempt from this requirement.
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`RISK EVALUATION AND MITIGATION STRATEGY REQUIREMENTS
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`The REMS for REVLIMID® (lenalidomide) was originally approved on August 3, 2010, REMS
`modifications were approved on May 9, 2012, February 8, 2013, June 5, 2013, and the REMS
`was last modified on November 15, 2013. The REMS consists of elements to assure safe use, an
`implementation system, and a timetable for submission of assessments of the REMS.
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`Your proposed modifications to the REMS consist of the following:
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`1. Removal of the “Rules for Dispensing” section in the Education and Counseling
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`Checklist for Pharmacies.
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`Reference ID: 3627118
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`

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`NDA 021880/S-039, S-040
`Page 3
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`2. Update to the current International Statistical Classification of Diseases and Related
`Health Problems (ICD) classifications in the Patient Prescription Forms.
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`3. Inclusion of new information in REMS materials regarding venous thromboembolic
`events and arterial thromboembolic events.
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`We remind you that section 505-1(f)(8) of FDCA prohibits holders of an approved covered
`application with elements to assure safe use from using any element to block or delay approval
`of an application under section 505(b)(2) or (j). A violation of this provision in 505-1(f) could
`result in enforcement action.
`
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`Your proposed modified REMS, submitted on July 10, 2014, and appended to this letter, is
`approved.
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`We also acknowledge the following changes to the REMS Supporting Document: The
`improvement of the REMS Pharmacy Portal interface and the Prescriber Portal interface and the
`revised pharmacist survey protocol and revised Adult Female of Reproductive Potential (AFRP)
`contraception choice survey protocol.
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`The timetable for submission of assessments of the REMS will remain the same as that approved
`on August 3, 2010.
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`There are no changes to the REMS assessment plan described in our November 15, 2013 letter.
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`In addition to the assessments submitted according to the timetable included in the approved
`REMS, you must submit a REMS assessment when you submit a supplemental application for a
`new indication for use as described in section 505-1(g)(2)(A) of the FDCA.
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`If the assessment instruments and methodology for your REMS assessments are not included in
`the REMS supporting document, or if you propose changes to the submitted assessment
`instruments or methodology, you should update the REMS supporting document to include
`specific assessment instrument and methodology information at least 90 days before the
`assessments will be conducted. Updates to the REMS supporting document may be included in a
`new document that references previous REMS supporting document submission(s) for
`unchanged portions. Alternatively, updates may be made by modifying the complete previous
`REMS supporting document, with all changes marked and highlighted. Prominently identify the
`submission containing the assessment instruments and methodology with the following wording
`in bold capital letters at the top of the first page of the submission:
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`NDA 021880 REMS CORRESPONDENCE
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`(insert concise description of content in bold capital letters, e.g.,
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`UPDATE TO REMS SUPPORTING DOCUMENT - ASSESSMENT
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`METHODOLOGY)
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`An authorized generic drug under this NDA must have an approved REMS prior to marketing.
`Should you decide to market, sell, or distribute an authorized generic drug under this NDA,
`contact us to discuss what will be required in the authorized generic drug REMS submission.
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`Reference ID: 3627118
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`

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`NDA 021880/S-039, S-040
`Page 4
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`Prominently identify the submission containing the REMS assessments or proposed
`modifications of the REMS with the following wording in bold capital letters at the top of the
`first page of the submission as appropriate:
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`NDA 021880 REMS ASSESSMENT
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`NEW SUPPLEMENT FOR NDA 021880
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`PROPOSED REMS MODIFICATION
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` NEW SUPPLEMENT (NEW INDICATION FOR USE)
`FOR NDA 021880
`REMS ASSESSMENT
`PROPOSED REMS MODIFICATION (if included)
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`If you do not submit electronically, please send 5 copies of REMS-related submissions.
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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:
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`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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` You must submit final promotional materials and package insert(s), accompanied by a Form
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` FDA 2253, at the time of initial dissemination or publication [21 CFR 314.81(b)(3)(i)]. Form
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`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.
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`All promotional materials that include representations about your drug product must be promptly
`revised to be consistent with the labeling changes approved in this supplement, including any
`new safety information [21 CFR 314.70(a)(4)]. The revisions in your promotional materials
`should include prominent disclosure of the important new safety information that appears in the
`revised package labeling. Within 7 days of receipt of this letter, submit your statement of intent
`to comply with 21 CFR 314.70(a)(4) to the address above or by fax to 301-847-8444.
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`Reference ID: 3627118
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`

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`Sincerely,
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` {See appended electronic signature page}
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`Robert C. Kane, MD
`Deputy Director of Safety
`Division of Hematology Products Office of
`Hematology and Oncology Products
`Center for Drug Evaluation and Research
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`NDA 021880/S-039, S-040
`Page 5
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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 Theresa Carioti, Regulatory Project Manager, at (301) 796-2848.
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`
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`ENCLOSURES:
`Content of Labeling
`REMS
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`Reference ID: 3627118
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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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`ROBERT C KANE
`09/12/2014
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`Reference ID: 3627118
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`