`
`
`
`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`
`
`
`
`
` NDA 021880/S-029/S-033
`
`
`
`
`
`
`
`
`
`Food and Drug Administration
`
`Silver Spring MD 20993
`
`
`SUPPLEMENT APPROVAL
`REMOVE REMS ELEMENT
`
`
`Celgene Corporation
`
`Marion Ceruzzi, PhD
`
`Director of Regulatory Affairs
`
`400 Connell Drive
`
`Building 400, Suite 7000
`
`Berkeley Heights, NJ 07922
`
`
`
`Dear Dr. Ceruzzi:
`
`Please refer to your Supplemental New Drug Applications (sNDA) dated December 29, 2011,
`received December 29, 2011, and November 7, 2012, received November 8, 2012, submitted
`under section 505(b) of the Federal Food, Drug, and Cosmetic Act (FDCA) for Revlimid®
`
`(lenalidomide) Capsules 2.5, 5, 10, 15, and 25 mg.
`
`We acknowledge receipt of your amendments dated January 12, 2012; February 1, 2012; August
`6, 2012; November 21 and 27, 2012; December 6 and 19, 2012; February 6 and 7, 2013; and
`your risk evaluation and mitigation strategy (REMS) assessment dated August 3, 2012.
`
`This “Prior Approval” sNDA S-029 provides for proposed modifications to the approved risk
`evaluation and mitigation strategy (REMS) that harmonizes the REMS programs for Revlimid®
`
`(lenalidomide) Capsules, Thalomid® (thalidomide) capsules, and Pomalyst (pomalidomide)
`capsules. Additionally, this sNDA proposes to eliminate the requirement for the approved
` Revlimid® (lenalidomide) Capsules Medication Guide as an element of the approved Revlimid®
`
`(lenalidomide) Capsules REMS.
`
`The “Changes Being Effected” (CBE) sNDA, S-033, provides for the addition of new QTc
`information to the Pharmacodynamics Section 12.2 of the Revlimid® (lenalidomide) Capsules
`US Package Insert.
`
`We have completed our review of these supplemental applications, as amended. They are
`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
`
`Reference ID: 3258475
`
`

`

`
`
` NDA 21880/S-029/S-033
`
`Page 2
`
`
`
`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
`
`
`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).
`
`We request that the labeling approved today be available on your website within 10 days of
`receipt of this letter.
`
`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 none of these criteria apply to your application, you are exempt from this requirement.
`
`POSTMARKETING COMMITMENT SUBJECT TO REPORTING REQUIREMENTS
`
`UNDER SECTION 506B
`
`We remind you that there is a postmarketing commitment that is subject to reporting
`requirements under section 506B listed in the June 29, 2006 approval letter that is still open.
`
`
`RISK EVALUATION AND MITIGATION STRATEGY REQUIREMENTS
`
`The REMS for Revlimid® (lenalidomide) Capsules was originally approved on August 3, 2010,
`and the most recent REMS modification was approved on May 9, 2012. The REMS consists of a
`Medication Guide, elements to assure safe use, implementation system, and a timetable for
`submission of assessments of the REMS.
`
`
`
`Reference ID: 3258475
`
`

`

`
`
` NDA 21880/S-029/S-033
`Page 3
`
`
`
`Your proposed modifications to the REMS consist of eliminating the requirement for the
`Medication Guide as an element of the REMSand harmonizing the REMS programs for
`Revlimid® (lenalidomide) Capsules and Thalomid® (thalidomide).
`
`We have determined that maintaining the Medication Guide as part of the approved labeling is
`adequate to address the serious and significant public health concern and meets the standard in
`21 CFR 208.1. Therefore, it is no longer necessary to include the Medication Guide as an
`element of the approved REMS to ensure that the benefits of Revlimid® (lenalidomide) Capsules
`outweigh the risks. Therefore, we agree with your proposal, and a Medication Guide is no
`longer required as part of the REMS for Revlimid® (lenalidomide) Capsules.
`
`Your proposed modified REMS, submitted on February 7, 2013, and appended to this letter, is
`approved.
`
`The modified REMS consists of elements to assure safe use, implementation system, and a
`timetable for submission of assessments of the REMS. We remind you that the Medication
`Guide will continue to be part of the approved labeling for Revlimid® (lenalidomide) Capsules
`
`in accordance with 21 CFR 208.
`
`The timetable for submission of assessments of the REMS will remain the same as that approved
`on August 3, 2010.
`
`
`
`The revised REMS assessment plan eliminates information regarding distribution and dispensing
`of the Medication Guide and the periodic surveys of prescribers and patients. The revised REMS
`assessment plan should include, but is not limited to, the following:
`
`
`1. Pregnancies:
`
`
`
`a. Number of pregnancies reported during the current REMS assessment reporting
`period and during each previous REMS assessment reporting period;
`
`
`
`b. Outcome of each pregnancy;
`
`
`
`
`
`
`c. Follow-up of outstanding pregnancy reports from previous assessment reporting
`period;
`
`
`
`d. Root cause analysis of each reported pregnancy; and
`
`
`e. Discussion of any new information provided in the most recent Periodic Safety
`Update Report (PSUR) regarding pregnancy. In the electronic REMS assessment
`submission, include a hyperlink to the most recent PSUR that provides information
`on worldwide pregnancies.
`
`
`2. Reporting on the restricted distribution program:
`
`
`Reference ID: 3258475
`
`

`

`
`
` NDA 21880/S-029/S-033
`Page 4
`
`
`
`
`a.
`
` Number of pharmacies and physicians certified, and patients enrolled during the
`current REMS assessment reporting period and during each previous REMS
`assessment reporting period;
`
`
`
`b. Patient demographics for the current REMS assessment reporting period and for
`previous REMS assessment reporting periods to include gender, age, diagnosis,
`females of reproductive potential (FRP); and
`
`
`
` c. Number of female patients for whom pregnancy testing can be discontinued
`
`because menopause has been documented by follicle-stimulating
`hormone/luteinizing hormone (FSH/LH) levels during this REMS assessment
`reporting period and for previous REMS assessment reporting periods.
`
`
`
`3. Documentation of safe use conditions
`
`Based on information collected through patient enrollment and mandatory surveys that are
`used to document safe use conditions, provide information on:
`
`
`
`a. Flagged prescriptions/documentations of safe use of particular interest include
`those that have the potential of allowing pregnant patients access to the drug, and
`those that result in a delay or interruption of treatment. Provide the following,
`relative to flagged prescriptions/documentation of safe use:
`
`
`
`
`
`
`i. A list of identified flags, the reasons for the flags, and the actions taken to
`correct. Provide for the reporting period (by month); and summarize
`findings from each previous assessment report.
`
`
`
`
`ii. Provide the number and proportion of flagged prescriptions intended for
`an FRP due to lack of documentation of a negative pregnancy test,
`positive pregnancy test, and/or a delay in obtaining a pregnancy test.
`
`
`iii. Provide the number and proportion of flags that caused a delay in
`treatment initiation or a gap in therapy for patients. Provide the time to
`resolution of flags (mean, minimum, maximum) and include a graph of
`time to resolution versus numbers of prescriptions (or number of
`mandatory surveys conducted to document safe use conditions) for the
`reporting period and for each previous reporting period
`
`
`We remind you that each REMS assessment report must be submitted with the title of the report
`stating that this is a REMS assessment report, and each report must address all items in the
`REMS assessment plan outlined in this approval letter.
`
`The requirements for assessments of an approved REMS under section 505-1(g)(3) include with
`respect to each goal included in the strategy, an assessment of the extent to which the approved
`strategy, including each element of the strategy, is meeting the goal or whether one or more such
`goals or such elements should be modified.
`
`Reference ID: 3258475
`
`

`

`NDA 21880/S-029/S-033
`
`Page 5
`
`
`
`In addition to the assessments submitted according to the timetable included in the approved
`REMS, you must submit a REMS assessment and may propose a modification to the approved
`REMS when you submit a supplemental application for a new indication for use as described in
`section 505-1(g)(2)(A) of the FDCA.
`
`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:
`
`
`NDA 21880 REMS CORRESPONDENCE
`
`(insert concise description of content in bold capital letters, e.g.,
`
`UPDATE TO REMS SUPPORTING DOCUMENT - ASSESSMENT
`
`METHODOLOGY
`
`
`
`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.
`
`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:
`
`
`NDA 21880 REMS ASSESSMENT
`
`NEW SUPPLEMENT FOR NDA 21880
`
`PROPOSED REMS MODIFICATION
`
`
`NEW SUPPLEMENT (NEW INDICATION FOR USE)
`
`FOR NDA 21880
`REMS ASSESSMENT
`PROPOSED REMS MODIFICATION (if included)
`
`
`If you do not submit electronically, please send 5 copies of REMS-related submissions.
`
`
`Reference ID: 3258475
`
`

`

`
`
`
`
` NDA 21880/S-029/S-033
`Page 6
`
`
` 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
`
`
`
`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/opacom/morechoices/fdaforms/cder.html;
`instructions are provided on page 2 of the form. 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 Theresa Carioti, Regulatory Project Manager, at (301) 796-2848.
`
`
`Sincerely,
`
`{See appended electronic signature page}
`
`
`Robert C. Kane, MD
`Deputy Director for Safety
`Division of Hematology Products
`Office of Hematology and Oncology Products
`Center for Drug Evaluation and Research
`
`
`ENCLOSURE(S):
`Content of Labeling
`REMS
`
`
`
`Reference ID: 3258475
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`ROBERT C KANE
`02/08/2013
`
`Reference ID: 3258475
`
`