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`DEPARTMENT OF HEALTH AND HUMAN SERVICES
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`Food and Drug Administration
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` Silver Spring MD 20993
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` NDA 203214/S-010
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` SUPPLEMENT APPROVAL
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`REMS MODIFICATION APPROVAL
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`PF Prism C.V.
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`c/o Pfizer Inc.
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`500 Arcola Road
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`Collegeville, PA 19426
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`Attention: Alicia Holsey, MS, RAC
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`Senior Manager, Worldwide Safety and Regulatory
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`Dear Ms. Holsey:
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`Please refer to your Supplemental New Drug Application (sNDA) dated December 19, 2014,
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`received December 19, 2014, submitted under section 505(b) of the Federal Food, Drug, and
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`Cosmetic Act (FDCA) for Xeljanz (tofacitinib) 5 mg Tablets.
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`We acknowledge receipt of your amendments dated April 16, and 24, May 18, June 16, and 19,
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`2015.
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`This Prior Approval supplemental new drug application provides for revisions to the
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`WARNINGS and PRECAUTIONS, USE IN SPECIFIC POPULATIONS, and CLINICAL
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`PHARMACOLOGY, sections of the package insert as well as revisions to the Medication Guide
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`to include information regarding the risk of herpes zoster (HZ) in patients in Japan. This
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`supplemental new drug application also provides for proposed modifications to the approved risk
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`evaluation and mitigation strategy (REMS).
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`APPROVAL & LABELING
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`We have completed our review of this supplemental application, as amended. It is approved,
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`effective on the date of this letter, for use as recommended in the enclosed, agreed-upon labeling
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`text.
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`WAIVER OF HIGHLIGHTS SECTION
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`Please note that we have previously granted a waiver of the requirements of 21 CFR
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`201.57(d)(8) regarding the length of Highlights of prescribing information.
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`Reference ID: 3782156
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` NDA 203214/S-010
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` Page 2
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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
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`labeling [21 CFR 314.50(l)] in structured product labeling (SPL) format using the FDA
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`automated drug registration and listing system (eLIST), as described at
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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 the
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`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
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`labeling.
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`Information on submitting SPL files using eList may be found in the guidance for industry titled
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`“SPL Standard for Content of Labeling Technical Qs and As at
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`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
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`for this NDA, including CBE supplements for which FDA has not yet issued an action letter,
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`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
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`annotate each change. To facilitate review of your submission, provide a highlighted or marked-
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`up copy that shows all changes, as well as a clean Microsoft Word version. The marked-up copy
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`should provide appropriate annotations, including supplement number(s) and annual report
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`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
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`active ingredients, new indications, new dosage forms, new dosing regimens, or new routes of
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`administration are required to contain an assessment of the safety and effectiveness of the
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`product for the claimed indication(s) in pediatric patients unless this requirement is waived,
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`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 Xeljanz (tofacitinib) was originally approved on November 6, 2012, and the most
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`recent modification was approved on February 11, 2015. The REMS consists of a
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`communication plan and a timetable for submission of assessments of the REMS. Your
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`proposed modifications to the REMS consists of revised communication plan materials to
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`Reference ID: 3782156
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` NDA 203214/S-010
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` Page 3
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` include information regarding the increased risk of herpes zoster in Japanese patients treated
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` with Xeljanz (tofacitinib).
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`Your proposed modified REMS, submitted on June 19, 2015, and appended to this letter, is
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`approved.
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`The modified REMS consists of a communication plan and a timetable for submission of
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`assessments of the REMS. The timetable for submission of assessments of the REMS may
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`remain the same as that approved on November 6, 2012.
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`We remind you that in addition to the REMS assessments submitted according to the timetable in
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`the approved REMS, you must include an adequate rationale to support a proposed REMS
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`modification for the addition, modification, or removal of any of goal or element of the REMS,
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`as described in section 505-1(g)(4) of the FDCA.
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`We also remind you that you must submit a REMS assessment when you submit a supplemental
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`application for a new indication for use as described in section 505-1(g)(2)(A). This assessment
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`should include:
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`a) An evaluation of how the benefit-risk profile will or will not change with the new
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`indication;
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`b) A determination of the implications of a change in the benefit-risk profile for the current
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`REMS;
`c) If the new indication for use introduces unexpected risks: A description of those risks
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`and an evaluation of whether those risks can be appropriately managed with the currently
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`approved REMS.
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`d) If a REMS assessment was submitted in the 18 months prior to submission of the
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`supplemental application for a new indication for use: A statement about whether the
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`REMS was meeting its goals at the time of that the last assessment and if any
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`modifications of the REMS have been proposed since that assessment.
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`e) If a REMS assessment has not been submitted in the 18 months prior to submission of the
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`supplemental application for a new indication for use: Provision of as many of the
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`currently listed assessment plan items as is feasible.
`f) If you propose a REMS modification based on a change in the benefit-risk profile or
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`because of the new indication of use, submit an adequate rationale to support the
`modification, including: Provision of the reason(s) why the proposed REMS
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`modification is necessary, the potential effect on the serious risk(s) for which the REMS
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`was required, on patient access to the drug, and/or on the burden on the health care
`delivery system; and other appropriate evidence or data to support the proposed change.
`Additionally, include any changes to the assessment plan necessary to assess the
`proposed modified REMS. If you are not proposing REMS modifications, provide a
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`rationale for why the REMS does not need to be modified.
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`If the assessment instruments and methodology for your REMS assessments are not included in
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`the REMS supporting document, or if you propose changes to the submitted assessment
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`instruments or methodology, you should update the REMS supporting document to include
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`Reference ID: 3782156
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` NDA 203214/S-010
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` Page 4
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` specific assessment instrument and methodology information at least 90 days before the
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` assessments will be conducted. Updates to the REMS supporting document may be included in a
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` new document that references previous REMS supporting document submission(s) for
` unchanged portions. Alternatively, updates may be made by modifying the complete previous
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` REMS supporting document, with all changes marked and highlighted. Prominently identify the
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` submission containing the assessment instruments and methodology with the following wording
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` in bold capital letters at the top of the first page of the submission:
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`NDA 203214 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.
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`Should you decide to market, sell, or distribute an authorized generic drug under this NDA,
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`contact us to discuss what will be required in the authorized generic drug REMS submission.
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`Prominently identify any submission containing the REMS assessments or proposed
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`modifications of the REMS with the following wording in bold capital letters at the top of the
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`first page of the submission as appropriate:
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`NDA203214 REMS ASSESSMENT
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`NEW SUPPLEMENT FOR NDA 203214/S-000 CHANGES BEING EFFECTED IN
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`30 DAYS
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`PROPOSED MINOR REMS MODIFICATION
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`Or
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`NEW SUPPLEMENT FOR NDA 203214/S-000 PRIOR APPROVAL
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`SUPPLEMENT
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`PROPOSED MAJOR REMS MODIFICATION
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`or
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`NEW SUPPLEMENT FOR NDA 203214/S-000 PRIOR APPROVA SUPPLEMENT
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`PROPOSED REMS MODIFICATIONS DUE TO SAFETY LABEL CHANGES
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`SUBMITTED IN SUPPLEMENT XXX
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`NEW SUPPLEMENT (NEW INDICATION FOR USE) FOR NDA 203214/S-000
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`REMS ASSESSMENT
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`PROPOSED REMS MODIFICATION (if included)
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`Should you choose to submit a REMS revision, prominently identify the submission containing
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`the REMS revisions with the following wording in bold capital letters at the top of the first page
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`of the submission:
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`Reference ID: 3782156
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` REMS REVISIONS FOR NDA203214
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` NDA 203214/S-010
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` Page 5
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`To facilitate review of your submission, we request that you submit your proposed modified
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`REMS and other REMS-related materials in Microsoft Word format. If certain documents, such
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`as enrollment forms, are only in PDF format, they may be submitted as such, but the preference
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`is to include as many as possible in Word format.
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`If you do not submit electronically, please send 5 copies of REMS-related submissions
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`REPORTING REQUIREMENTS
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` We remind you that you must comply with reporting requirements for an approved NDA
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` (21 CFR 314.80 and 314.81).
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` If you have any questions, call Sadaf Nabavian, Senior Regulatory Project Manager, at (301)
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` 796-2777.
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` Sincerely,
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` {See appended electronic signature page}
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` Sally Seymour, MD
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` Deputy Director for Safety
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` Division of Pulmonary, Allergy, and Rheumatology
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` Office of Drug Evaluation II
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` Center for Drug Evaluation and Research
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`ENCLOSURES:
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`Content of Labeling
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`REMS
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`Reference ID: 3782156
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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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`SALLY M SEYMOUR
`06/19/2015
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`Reference ID: 3782156
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