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`DEPARTMENT OF HEALTH AND HUMAN SERVICES
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`NDA 021928/ S-019/S-020/S-021
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`Food and Drug Administration
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`Silver Spring MD 20993
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`SUPPLEMENTS APPROVAL
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`S-019:
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`the safety and efficacy of Chantix in smokers with cardiovascular disease
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`(CVD), and revisions to the Medication Guide that include the possible
`side effects of Chantix
`
`Pfizer, Inc.
`235 E. 42nd Street
`New York, NY 10017
`
`Attention: Lilya I. Donohew, Ph.D.
` Director, Worldwide Regulatory Affairs
`
`
`Dear Dr. Donohew:
`
`Please refer to your Supplemental New Drug Applications (sNDAs) dated September 22, 2010,
`received September 23, 2010, submitted under section 505(b) of the Federal Food, Drug, and
`Cosmetic Act (FDCA) for Chantix (varenicline) Tablets; 0.5 mg and 1 mg.
`
`We acknowledge receipt of your amendments dated October 7, November 10 and 12, and
`December 6, 2010, January 6, February 2 and 25, March 4 (2), May, 6, 17, 20, and 24, June 6, 8,
`and 20, July 18 and 22, 2011, and your risk evaluation and mitigation strategy (REMS)
`assessment dated November 3, 2010.
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`These supplemental new drug applications propose a modification to the approved REMS and
`the following labeling revisions to the Package Insert:
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`S-020:
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`the safety and efficacy of Chantix in smokers with chronic obstructive
`pulmonary disease (COPD)
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`S-021:
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`the safety and efficacy of Chantix when used according to an alternative set of
`directions for setting a quit date, and revisions to the Medication Guide that
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`include new information on how to take Chantix
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`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.
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`Reference ID: 2977906
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`

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` NDA 021928/ S-019/S-020/S-021
`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
`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
`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.
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`Information on submitting SPL files using eLIST may be found in the guidance for industry
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`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 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 numbers and annual report dates.
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`We request that the labeling approved today be available on your website within 10 days of
`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 in pediatric patients unless this requirement is waived,
`deferred, or inapplicable.
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`Because none of these criteria apply to your applications, you are exempt from this requirement.
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`POSTMARKETING REQUIREMENTS UNDER 505(o)
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`Section 505(o)(3) of the FDCA authorizes FDA to require holders of approved drug and
`biological product applications to conduct postmarketing studies and clinical trials for certain
`purposes, if FDA makes certain findings required by the statute.
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`Reference ID: 2977906
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`

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` NDA 021928/ S-019/S-020/S-021
`Page 3
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`Since Chantix was approved on May 10, 2006, we have become aware of the possibility of an
`increased risk of certain cardiovascular adverse events in patients taking Chantix (varenicline)
`based on the review of the randomized, double-blind, placebo-controlled clinical trial designed to
`assess the efficacy and safety of Chantix for smoking cessation in patients with stable,
`documented cardiovascular disease, and a review of the Integrated Summary of Safety. We
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`consider this information to be “new safety information” as defined in section 505-1(b)(3) of the
`FDCA.
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`We have determined that an analysis of spontaneous postmarketing adverse events reported
`under subsection 505(k)(1) of the FDCA will not be sufficient to assess the signal of a serious
`risk of cardiovascular events.
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`Furthermore, the new pharmacovigilance system that FDA is required to establish under section
`505(k)(3) of the FDCA will not be sufficient to assess this serious risk.
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`Therefore, based on appropriate scientific data, FDA has determined that you are required to
`conduct the following:
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`1804
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`Conduct a meta-analysis evaluating the incidence of cardiovascular adverse
`events in Chantix-treated patients compared to control patients in Pfizer-
`sponsored randomized clinical trials. The study must include an analysis of all
`serious adverse events with adjudication and an analysis of all adverse events
`without adjudication.
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`The timetable you submitted on July 18, 2011, states that you will conduct this study according
`to the following schedule:
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`Draft Protocol Submission: August 15, 2011
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`Final Protocol Submission: October 1, 2011
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`Study Completion:
`January 15, 2012
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`Final Report Submission:
`February 15, 2012
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`Submit the protocol to your IND 058994, with a cross-reference letter to this NDA. Submit the
`final report to your NDA. Prominently identify the submission with the following wording in
`bold, capital letters at the top of the first page of each submission, as appropriate: “Required
`Postmarketing Protocol Under 505(o)”, “Required Postmarketing Final Report Under
`505(o)”, “Required Postmarketing Correspondence Under 505(o).”
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`Section 505(o)(3)(E)(ii) of the FDCA requires you to report periodically on the status of any
`study or clinical trial required under this section. This section also requires you to periodically
`report to FDA on the status of any study or clinical trial otherwise undertaken to investigate a
`safety issue. Section 506B of the FDCA, as well as 21 CFR 314.81(b)(2)(vii) requires you to
`report annually on the status of any postmarketing commitments or required studies or clinical
`trials.
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`Reference ID: 2977906
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`

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` NDA 021928/ S-019/S-020/S-021
`Page 4
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`FDA will consider the submission of your annual report under section 506B and 21 CFR
`314.81(b)(2)(vii) to satisfy the periodic reporting requirement under section 505(o)(3)(E)(ii)
`provided that you include the elements listed in 505(o) and 21 CFR 314.81(b)(2)(vii). We
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`remind you that to comply with 505(o), your annual report must also include a report on the
`status of any study or clinical trial otherwise undertaken to investigate a safety issue. Failure to
`submit an annual report for studies or clinical trials required under 505(o) on the date required
`will be considered a violation of FDCA section 505(o)(3)(E)(ii) and could result in enforcement
`action.
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`RISK EVALUATION AND MITIGATION STRATEGY REQUIREMENTS
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`The REMS for Chantix was originally approved on October 19, 2009, and a REMS modification
`was approved on April 22, 2010. The REMS consists of a Medication Guide and a timetable for
`submission of assessments of the REMS. Your proposed modification to the REMS consists of
`revisions to the Medication Guide that include new information on how to take Chantix and the
`possible side effects of Chantix.
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`Your proposed modified REMS, submitted on June 6, 2011, and appended to this letter, is
`approved.
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`The timetable for submission of assessments of the REMS will remain the same as that approved
`on October 19, 2009. There are no changes to the REMS assessment plan described in our
`October 19, 2009 letter.
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`We remind you that assessments of an approved REMS must also include, under section 505-
`1(g)(3)(B) and (C), information on the status of any postapproval study or clinical trial required
`under section 505(o) or otherwise undertaken to investigate a safety issue. With respect to any
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`such postapproval study, you must include the status of such study, including whether any
`difficulties completing the study have been encountered. With respect to any such postapproval
`clinical trial, you must include the status of such clinical trial, including whether enrollment has
`begun, the number of participants enrolled, the expected completion date, whether any
`difficulties completing the clinical trial have been encountered, and registration information with
`respect to requirements under subsections (i) and (j) of section 402 of the Public Health Service
`Act. You can satisfy these requirements in your REMS assessments by referring to relevant
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`information included in the most recent annual report required under section 506B and 21 CFR
`314.81(b)(2)(vii) and including any material or significant updates to the status information since
`the annual report was prepared. Failure to comply with the REMS assessments provisions in
`section 505-1(g) could result in enforcement action.
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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
`REMS when you submit a supplemental application for a new indication for use as described in
`section 505-1(g)(2)(A) of FDCA.
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`If you currently distribute or plan to distribute an authorized generic product under this NDA,
`you must submit a complete proposed REMS that relates only to the authorized generic product.
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`Reference ID: 2977906
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`

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` NDA 021928/ S-019/S-020/S-021
`Page 5
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`Submit a proposed REMS, REMS supporting document, and any required appended documents
`as a prior approval supplement. Approval of the proposed REMS is required before you may
`market your authorized generic product.
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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 021928 REMS ASSESSMENT
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`NEW SUPPLEMENT FOR NDA 021928
`PROPOSED REMS MODIFICATION
`REMS ASSESSMENT
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`NEW SUPPLEMENT (NEW INDICATION FOR USE)
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`FOR NDA 021928
`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
`Division of Drug Marketing, Advertising, and Communications
`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/opacom/morechoices/fdaforms/cder.html;
`instructions are provided on page 2 of the form. For more information about submission of
`promotional materials to the Division of Drug Marketing, Advertising, and Communications
`(DDMAC), 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
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`Reference ID: 2977906
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`

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` NDA 021928/ S-019/S-020/S-021
`Page 6
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`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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`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 Ayanna Augustus, Regulatory Health Project Manager, at (301)
`796-3980.
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`Sincerely,
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`
`{See appended electronic signature page}
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`Bob A. Rappaport, M.D.
`
`Director
`Division of Anesthesia, Analgesia,
`and Addiction Products
`Office of Drug Evaluation II
`Center for Drug Evaluation and Research
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`ENCLOSURE(S):
`Content of Labeling
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`Package Insert
` Medication Guide
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`REMS
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`Reference ID: 2977906
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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/
`----------------------------------------------------
`
`BOB A RAPPAPORT
`07/22/2011
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`Reference ID: 2977906
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`