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`DEPARTMENT OF HEALTH AND HUMAN SERVICES
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` NDA 021928/S-032, S-036, S-038
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`Food and Drug Administration
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` Silver Spring MD 20993
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`SUPPLEMENT APPROVAL
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` Pfizer, Inc.
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` 235 E. 42nd Street
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` New York, NY 10017
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`Attention:
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`Lilya I. Donohew, PhD
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`Senior Director, Worldwide Regulatory Affairs
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`Dear Dr. Donohew:
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`Please refer to your Supplemental New Drug Applications (sNDAs) dated and received October
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`24, 2013(S-032), April 8, 2014 (S-036), and September 3, 2014 (S-038), submitted under section
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`505(b) of the Federal Food, Drug, and Cosmetic Act (FDCA) for Chantix (varenicline) Tablets;
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`0.5 mg and 1 mg.
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`We acknowledge receipt of your amendments dated November 8, and December 20, 2013, April
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`30, and September 18, 2014 (S-032), April 29, May 2, 5, and 8, August 1, and September 18,
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`2014 (S-036), and September 3, and 18, 2014 (S-038), and your proposed risk evaluation and
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`mitigation strategy (REMS) modification dated November 8, 2013 (S-032) and September 3,
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`2014 (S-038).
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`We also refer to our letter dated August 6, 2014, notifying you, under Section 505(o)(4) of the
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`FDCA, of new safety information that we believe should be included in the labeling for Chantix.
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`This information pertains to the risk of seizures and the potentiation of the intoxicating effects of
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`alcohol.
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`Finally we refer you to our September 4, 2013, and August 6, 2014, letters notifying you, under
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`section 505-1(g)(4)(B) of the FDCA, that your REMS must be modified based on findings from
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`your 18-month REMS assessment and the new safety information described above.
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`Supplement S-032 proposes revisions to the DRUG INTERACTIONS section of the Package
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`Insert regarding a potential interaction between alcohol and varenicline and includes a proposed
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`modification to the approved risk evaluation and mitigation strategy (REMS), including revisions
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`to the Medication Guide and revisions to the Chantix REMS goal.
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`Supplement S-036 proposes changes to the Package Insert based on meta-analyses of varenicline
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`clinical trials and published observational studies pertaining to serious neuropsychiatric events.
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`Supplement S-038 proposes revisions to the labeling for Chantix. The agreed upon changes to
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`the language included in our August 6, 2014, letter are included in the appended labeling text.
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`Reference ID: 3630834
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` NDA 021928/S-032, S-036, S-038
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` Page 2
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`S-038 also includes additional proposed modifications to the approved risk evaluation and
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` mitigation strategy (REMS), comprising further revisions to the Medication Guide as well as
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` revisions to the Chantix REMS goal.
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`APPROVAL & LABELING
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` We have completed our review of these supplemental applications, as amended, and they are
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`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
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` 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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` http://www.fda.gov/ForIndustry/DataStandards/StructuredProductLabeling/default.htm. Content
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`of labeling must be identical to the enclosed labeling(text for the package insert and Medication
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`Guide), with the addition of any labeling changes in pending “Changes Being Effected” (CBE)
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`supplements, as well as annual reportable changes not included in the enclosed 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
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` 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
`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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` RISK EVALUATION AND MITIGATION STRATEGY (REMS)
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`The REMS for Chantix (varenicline) was originally approved on October 19, 2009, and the most
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`recent modification was approved on July 22, 2011. The REMS consists of a Medication Guide
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`and a timetable for submission of assessments of the REMS. Your proposed modifications to the
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`REMS consist of revisions to the Medication Guide to describe the risk of seizures and the
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`potentiation of the intoxicating effects of alcohol, and revise the “What is the most important
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`Reference ID: 3630834
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` NDA 021928/S-032, S-036, S-038
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` Page 3
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` information I should know about CHANTIX” section of the Medication Guide as well as other
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` sections of the Medication Guide so as to furnish adequate information for the safe and effective
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` use of the drug. In addition, the proposed modification includes revisions to the Chantix REMS
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` goal to focus only on neuropsychiatric risks.
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`Your proposed modified REMS, submitted on September 3, 2014, and appended to this letter, is
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`approved.
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`The modified REMS consists of a Medication Guide and a timetable for submission of
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`assessments of the REMS.
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`The timetable for submission of assessments of the REMS will remain the same as that approved
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`on October 19, 2009.
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`There are no changes to the REMS assessment plan described in our October 19, 2009, 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 and may propose a modification to the approved
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`REMS when you submit a supplemental application for a new indication for use as described in
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`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
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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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`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
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`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 021928 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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`Prominently identify the 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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`NDA 021928 REMS ASSESSMENT
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`NEW SUPPLEMENT FOR NDA 021928
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`PROPOSED REMS MODIFICATION
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`Reference ID: 3630834
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` NDA 021928/S-032, S-036, S-038
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` Page 4
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` NEW SUPPLEMENT (NEW INDICATION FOR USE)
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` FOR NDA 021928
` REMS ASSESSMENT
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` 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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`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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`PROMOTIONAL MATERIALS
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`You may request advisory comments on proposed introductory advertising and promotional
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`labeling. To do so, submit the following, in triplicate, (1) a cover letter requesting advisory
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`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
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`Center for Drug Evaluation and Research
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`Office of Prescription Drug Promotion (OPDP)
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`5901-B Ammendale Road
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`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
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`http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM083570.pdf.
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` Information and Instructions for completing the form can be found at
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` http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM375154.pdf. For
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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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` All promotional materials that include representations about your drug product must be promptly
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` 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
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` 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
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` to comply with 21 CFR 314.70(a)(4) to the address above or by fax to 301-847-8444.
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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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`Reference ID: 3630834
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` NDA 021928/S-032, S-036, S-038
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` Page 5
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` If you have any questions, call Ayanna Augustus, PhD, RAC, Sr. Regulatory Project Manager, at
` (301) 796-3980.
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`Sincerely,
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`{See appended electronic signature page}
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`Judith A. Racoosin, MD, MPH
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`Deputy Director for Safety
`Division of Anesthesia, Analgesia and
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`Addiction Products
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`Office of Drug Evaluation II
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`Center for Drug Evaluation and Research
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`ENCLOSURE(S):
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`Content of Labeling
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`REMS
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`Reference ID: 3630834
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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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`JUDITH A RACOOSIN
`09/19/2014
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`Reference ID: 3630834
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