`
`
`
`
`
`
`
` CENTER FOR DRUG EVALUATION AND RESEARCH
`
`
`Approval Package for:
`
`
`
`
`
`APPLICATION NUMBER:
`
` 021928Orig1s039
`
`
`
`
`
`
` Trade Name:
`
`
`
`
` CHANTIX
`
` varenicline tartrate
`
`
`
`Generic or
`
`
`Proper Name:
`
` Sponsor:
`
` Approval Date: 08/12/2016
`
` Indication:
`
`
`
`
`
` Pfizer, Inc.
`
`
`
`
`
`
`
` CHANTIX is a nicotinic receptor partial agonist indicated for
`
`
` use as an aid to smoking cessation treatment.
`
`
`
`
`
`
`
`

`

` CENTER FOR DRUG EVALUATION AND
`
`
`
` RESEARCH
`
`
`
`APPLICATION NUMBER:
`
`NDA 021928/S-039
`
`
`
`
`
`
`
` CONTENTS
`
`
` Reviews / Information Included in this NDA Review.
`
`
`
`
`
`
` Approval Letter
`
` Other Action Letters
`
` Labeling
`
` REMS
` Summary Review
`
`
` Officer/Employee List
`
` Office Director Memo
` Cross Discipline Team Leader Review
`
` Medical Review(s)
` Chemistry Review(s)
`
` Environmental Assessment
`
` Pharmacology Review(s)
`
` Statistical Review(s)
` Microbiology Review(s)
`
` Clinical Pharmacology/Biopharmaceutics Review(s)
`
` Other Reviews
` Risk Assessment and Risk Mitigation Review(s)
`
`
` Proprietary Name Review(s)
` Administrative/Correspondence Document(s)
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` x
`
`
` x
`
` x
`
` x
`
`
`
` x
`
` x
`
`
`
` x
`
` x
`
`
`
` x
`
` x
`
`
` x
`
`

`

`CENTER FOR DRUG EVALUATION AND
`
` CENTER FOR DRUG EVALUATION AND
`
`
`
` RESEARCH
`
`RESEARCH
`
`
`APPLICATION NUMBER:
`
`NDA 021928/S-039
`
`NDA 021928/S-039
`
`
`APPLICA TI0N NUMBER:
`
`
`
`
`
` APPROVAL LETTER
`
`APPROVAL LETTER
`
`
`
`
`
`
`
`
`
`

`

`
`
`
`
`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`
`
`
`
`
`
`
` NDA 021928/S-039, S-041
`
`
`
`
`
`
`
`
`Food and Drug Administration
`
`Silver Spring MD 20993
`
`
`SUPPLEMENT APPROVAL
`
`
` Pfizer, Inc.
`
` 235 E. 42nd Street
`
` New York, NY 10017
`
`
`
`Attention:
`
`
`
`Lilya I. Donohew, PhD
`
`Senior Director, Worldwide Regulatory Affairs
`
`
`
`
`Dear Dr. Donohew:
`
`
`
`
`
`
`
`
`Please refer to your Supplemental New Drug Applications (sNDAs) dated and received October
`
`
`13, 2015, and July 21, 2016, and your amendments, 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 also refer to our Safety Labeling Change notification letter dated July 15, 2016, notifying
`
`
`
`you, under Section 505(o)(4) of the FDCA, of new safety information that we believe should be
`
`
`
`
`included in the labeling for Chantix (varenicline). This information pertains to the risk of
`
`somnambulism.
`
`
`
`
`
`
`
`These Prior Approval supplemental new drug applications propose the following revisions to the
`
`package insert:
`
`
`
`S-039: Changes to the DOSAGE AND ADMINISTRATION, and CLINICAL
`
`
`STUDIES sections of the Package Insert, and modification to the approved risk
`
`
`
`
`
`evaluation and mitigation strategy (REMS) for Chantix, comprising of revisions
`to the MEDICATION GUIDE, to support the reduce-to-quit paradigm.
`
`
`
`
`
`
`
`
`
`
`
`
`S-041: Consistent with our July 15, 2016, Safety Labeling Change notification letter,
`
`changes to the WARNINGS AND PRECAUTIONS, ADVERSE
`
`
`REACTIONS, PATIENT COUNSELING INFORMATION sections of the
`
`
`
`
`labeling. S-041 also includes additional modification to the approved REMS,
`
`
`
`comprising further revisions to the MEDICATION GUIDE regarding the new
`
`
`
`
`
`safety information pertaining to risk of somnambulism.
`
`
`
`APPROVAL & LABELING
`
`
`
`
`
`
`We have completed our review of these supplemental applications, as amended and they are
`
`approved, effective on the date of this letter, for use as recommended in the enclosed, agreed-
`
`upon labeling text.
`
`Reference ID: 3971721
`
`

`

`
`
`
`
`
`
`
`
` NDA 021928/S-039 & S-041
`
` Page 2
`
`
`
` WAIVER OF HIGHLIGHTS SECTION
`
` Please note that we have previously granted a waiver of the requirements of 21 CFR
`
`
`
`
`
`
` 201.57(d)(8) regarding the length of Highlights of prescribing information.
`
`
`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
`
` 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 include 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.
`
`
`
`RISK EVALUATION AND MITIGATION STRATEGY (REMS)
`
`The REMS for Chantix (varenicline) was originally approved on October 19, 2009, and the most
`
`
`
`recent modification was approved on October 15, 2014. The REMS consists of a Medication
`
`
`Guide and a timetable for submission of assessments of the REMS. Your proposed
`
`modifications to the REMS consist of revisions to the Medication Guide to add new language
`
`describing a reduce-to-quit regimen and to provide information about the risk of somnambulism
`
`
`
`
`
`
`so as to furnish adequate information for the safe and effective use of the drug.
`
`
`
`
`
`
`
`
`Reference ID: 3971721
`
`

`

`
`
`
`
`
`
` NDA 021928/S-039 & S-041
`
`
` Page 3
`
`
`
` Your proposed modified REMS, submitted on October 13, 2015, and appended to this letter, is
`
` approved.
`
`
`
`
`
`
`The modified REMS consist of a Medication Guide and a timetable for submission of
`
`assessments of the REMS.
`
`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.
`
`
`We remind you that in addition to the REMS assessments submitted according to the timetable in
`
`
`the approved REMS, you must include an adequate rationale to support a proposed REMS
`
`
`
`modification for the addition, modification, or removal of any of goal or element of the REMS,
`
`
`as described in section 505-1(g)(4) of the FDCA.
`
`
`
`
`We also remind you that 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). This assessment
`
`should include:
`
`
`
`
`a) An evaluation of how the benefit-risk profile will or will not change with the new
`
`
`indication;
`
`
`b) A determination of the implications of a change in the benefit-risk profile for the current
`
`
`REMS;
`
`c) If the new, proposed indication for use introduces unexpected risks: A description of
`
`
`those risks and an evaluation of whether those risks can be appropriately managed with
`
`
`the currently approved REMS.
`d) If a REMS assessment was submitted in the 18 months prior to submission of the
`
`
`
`supplemental application for a new indication for use: A statement about whether the
`
`
`
`
`
`REMS was meeting its goals at the time of the last assessment and if any modifications
`
`of the REMS have been proposed since that assessment.
`e) If a REMS assessment has not been submitted in the 18 months prior to submission of the
`
`
`
`
`
`supplemental application for a new indication for use: Provision of as many of the
`
`
`
`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
`
`
`
`
`because of the new indication of use, submit an adequate rational to support the
`
`
`modification, including: Provision of the reason(s) why the proposed REMS
`
`
`modification is necessary, the potential effect on the serious risk(s) for which the REMS
`
`
`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 a REMS modification, provide a
`
`
`
`rationale for why the REMS does not need to be modified.
`
`
`
`
`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
`
`Reference ID: 3971721
`
`

`

`
`
`
`
`
`
`
`
` NDA 021928/S-039 & S-041
`
`
` Page 4
`
`
`
` 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 021928 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 021928 REMS ASSESSMENT
`
`
`
`
`NEW SUPPLEMENT FOR NDA 021928/S-000/
`
`
`
`
`
`CHANGES BEING EFFECTED IN 30 DAYS
`
`
`
`
`PROPOSED MINOR REMS MODIFICATION
`
`
`
`
`or
`
`
`
`
`
`
`
`
`NEW SUPPLEMENT FOR NDA 021928/S-000/
`
`
`
`PRIOR APPROVAL SUPPLEMENT
`
`
`
`
`PROPOSED MAJOR REMS MODIFICATION
`
`
`
`or
`
`
`
`
`NEW SUPPLEMENT FOR NDA 021928/S-000/
`
`
`PRIOR APPROVAL SUPPLEMENT
`
`
`
`PROPOSED REMS MODIFICATIONS DUE TO SAFETY LABEL CHANGES
`
`SUBMITTED IN SUPPLEMENT XXX
`
`
`
`NEW SUPPLEMENT (NEW INDICATION FOR USE)
`
`
`
`FOR NDA 021928/S-000/
`
`
`
`
`REMS ASSESSMENT
`
`
`PROPOSED REMS MODIFICATION (if included)
`
`
`
`
`
`
`
`Reference ID: 3971721
`
`
`
`

`

`
`
`
`
`
`
`
`REMS REVISION FOR NDA 021928
`
` NDA 021928/S-039 & S-041
`
` Page 5
`
`
`
` Should you choose to submit a REMS revision, prominently identify the submission containing
`
`
` the REMS revisions with the following wording in bold capital letters at the top of the first page
`
` of the submission:
`
`
`
`
`
`
`To facilitate review of your submission, we request that you submit your proposed modified
`REMS and other REMS-related materials in Microsoft Word format. If certain documents, such
`
`
`as enrollment forms, are only in PDF format, they may be submitted as such, but the preference
`
`
`
`is to include as many as possible in Word format.
`
`
`
`If you do not submit electronically, please send 5 copies of REMS-related submissions.
`
`
`
`
`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:
`
`
`
`OPDP Regulatory Project Manager
`
`Food and Drug Administration
`
`Center for Drug Evaluation and Research
`
`Office of Prescription Drug Promotion (OPDP)
`
`5901-B Ammendale Road
`
`Beltsville, MD 20705-1266
`
`
`
`Alternatively, you may submit a request for advisory comments electronically in eCTD format.
`
`
`For more information about submitting promotional materials in eCTD format, see the draft
`Guidance for Industry (available at:
`
`
`http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/U
`CM443702.pdf ).
`
`
`
`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/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.
`
`
`
`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
`
`Reference ID: 3971721
`
`

`

`
`
`
`
`
`
` NDA 021928/S-039 & S-041
`
` Page 6
`
`
` 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, by fax to 301-847-8444, or
` electronically in eCTD format. For more information about submitting promotional materials in
`
`
` eCTD format, see the draft Guidance for Industry (available at:
`
`
`
`
`http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/U
`CM443702.pdf ).
`
`
`
`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 Ayanna Augustus, PhD, RAC, Sr. Regulatory Project Manager, at
`
`
`
`
`
`(301) 796-3980.
`
`
`
`
`Sincerely,
`
`
`{See appended electronic signature page}
`
`
`Sharon Hertz, MD
`
`
`Director
`
`Division of Anesthesia, Analgesia, and
`Addiction Products
`
`
`Office of Drug Evaluation II
`
`
`Center for Drug Evaluation and Research
`
`
`
`
`
`ENCLOSURE(S):
`
`Content of Labeling
`
`
`REMS
`
`
`
`
`Reference ID: 3971721
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`SHARON H HERTZ
`08/12/2016
`
`Reference ID: 3971721
`
`

`

`CENTER FOR DRUG EVALUATION AND
`
` CENTER FOR DRUG EVALUATION AND
`
`
`
` RESEARCH
`
`RESEARCH
`
`
`APPLICATION NUMBER:
`
`NDA 021928/S-039
`
`NDA 021928/S-039
`
`
`APPLICA TI0N NUMBER:
`
`
`
`
` LABELING
`
`LABELING
`
`
`
`
`
`
`
`
`
`

`

`
`
`
`-------------------------------CONTRAINDICATIONS-----------------------------­
`History of serious hypersensitivity or skin reactions to CHANTIX. (4)
`
`
`
`
`
`
`
`-----------------------WARNINGS AND PRECAUTIONS-----------------------­
`
`
`
`
`
`
`• Seizures: New or worsening seizures have been observed in patients taking
`
`
`CHANTIX. CHANTIX should be used cautiously in patients with a
`
`
`
`history of seizures or other factors that can lower the seizure threshold.
`
`(5.2)
`
`
`• Interaction with Alcohol: Increased effects of alcohol have been reported.
`
`
`
`
`Instruct patients to reduce the amount of alcohol they consume until they
`
`
`
`
`know whether CHANTIX affects them. (5.3)
`
`
`
`
`
`• Accidental Injury: Accidental injuries (e.g., traffic accidents) have been
`
`
`
`
`
`
`reported. Instruct patients to use caution driving or operating machinery
`
`
`
`
`
`until they know how CHANTIX may affect them. (5.4)
`
`
`
`
`• Cardiovascular Events: A meta-analysis of 15 clinical trials, including a
`
`
`
`
`
`
`trial in patients with stable cardiovascular (CV) disease, demonstrated that
`
`
`
`while cardiovascular events were infrequent overall, some were reported
`
`more frequently in patients treated with CHANTIX. These events occurred
`
`
`
`
`
`primarily in patients with known cardiovascular disease. In both the
`
`
`
`
`clinical trial and meta-analysis, all-cause and cardiovascular mortality was
`
`
`
`lower in patients treated with CHANTIX. Instruct patients to notify their
`
`
`
`
`
`
`
`healthcare providers of new or worsening cardiovascular symptoms and to
`
`
`seek immediate medical attention if they experience signs and symptoms
`
`
`
`
`of myocardial infarction (MI) or stroke. (5.5 and 6.1)
`
`
`
`
`
`
`• Somnambulism: Cases of somnambulism have been reported in patients
`
`
`
`
`
`
`taking CHANTIX. Some cases described harmful behavior to self, others,
`
`
`
`or property. Instruct patients to discontinue CHANTIX and notify their
`
`
`
`
`
`
`healthcare provider if they experience somnambulism. (5.6 and 6.2)
`
`
`
`• Angioedema and Hypersensitivity Reactions: Such reactions, including
`
`
`
`
`
`angioedema, infrequently life-threatening, have been reported. Instruct
`
`
`
`patients to discontinue CHANTIX and immediately seek medical care if
`
`
`
`symptoms occur. (5.7 and 6.2)
`
`
`• Serious Skin Reactions: Rare, potentially life-threatening skin reactions
`
`
`
`
`
`
`
`have been reported. Instruct patients to discontinue CHANTIX and contact
`
`
`
`
`a healthcare provider immediately at first appearance of skin rash with
`
`mucosal lesions. (5.8 and 6.2)
`
`
`• Nausea: Nausea is the most common adverse reaction (up to 30%
`
`
`
`
`
`
`
`incidence rate). Dose reduction may be helpful. (5.9)
`
`
`
`
`
`
`
`
`
`------------------------------ADVERSE REACTIONS------------------------------­
`Most common adverse reactions (>5% and twice the rate seen in
`
`
`
`
`placebo-treated patients) were nausea, abnormal (e.g., vivid, unusual, or
`
`
`
`strange) dreams, constipation, flatulence, and vomiting. (6.1)
`
`
`
`
`To report SUSPECTED ADVERSE REACTIONS, contact Pfizer Inc. at
`
`
`1-800-438-1985 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
`
`
`
`
`
`------------------------------DRUG INTERACTIONS------------------------------­
`• Other Smoking Cessation Therapies: Safety and efficacy in combination
`
`
`
`
`
`
`
`
`with other smoking cessation therapies has not been established.
`
`
`
`Coadministration of varenicline and transdermal nicotine resulted in a high
`
`
`
`
`
`rate of discontinuation due to adverse events. (7.1)
`
`
`
`• Effect of Smoking Cessation on Other Drugs: Pharmacokinetics or
`
`
`
`
`
`
`pharmacodynamics of certain drugs (e.g., theophylline, warfarin, insulin)
`
`
`may be altered, necessitating dose adjustment. (7.2)
`
`
`
`
`
`
`See 17 for PATIENT COUNSELING INFORMATION and Medication
`
`
`Guide
`
`
`
`
`
`
`
`
`
`
`Revised: 08/2016
`
`
`
`----------------------DOSAGE AND ADMINISTRATION----------------------­
`• Begin CHANTIX dosing one week before the date set by the patient to
`
`
`
`
`
`
`stop smoking. Alternatively, the patient can begin CHANTIX dosing and
`
`
`
`
`
`then quit smoking between days 8 and 35 of treatment. (2.1)
`
`
`
`
`• Starting week: 0.5 mg once daily on days 1-3 and 0 5 mg twice daily on
`
`
`
`
`
`
`
`
`
`
`days 4-7. (2.1)
`
`
`• Continuing Weeks: 1 mg twice daily for a total of 12 weeks. (2.1)
`
`
`
`
`
`
`
`
`• An additional 12 weeks of treatment is recommended for successful
`
`
`
`
`quitters to increase likelihood of long-term abstinence. (2.1)
`
`
`• Consider a gradual approach to quitting smoking with CHANTIX for
`
`
`
`
`patients who are sure that they are not able or willing to quit abruptly.
`
`
`Patients should begin CHANTIX dosing and reduce smoking by 50% from
`
`
`
`baseline within the first four weeks, by an additional 50% in the next four
`
`
`
`
`
`
`
`weeks, and continue reducing with the goal of reaching complete
`
`
`
`
`abstinence by 12 weeks. Continue treatment for an additional 12 weeks,
`
`
`
`
`for a total of 24 weeks. (2.1)
`
`
`• Severe Renal Impairment (estimated creatinine clearance less than
`
`
`
`
`
`30 mL/min): Begin with 0.5 mg once daily and titrate to 0.5 mg twice
`
`
`
`
`
`
`
`daily. For patients with end-stage renal disease undergoing hemodialysis, a
`
`
`maximum of 0.5 mg daily may be given if tolerated. (2.2)
`
`
`• Consider dose reduction for patients who cannot tolerate adverse effects.
`
`
`
`
`
`
`(2.1)
`
`• Another attempt at treatment is recommended for those who fail to stop
`
`
`
`smoking or relapse when factors contributing to the failed attempt have
`
`
`
`
`been addressed. (2.1)
`
`
`• Provide patients with appropriate educational materials and counseling to
`
`
`
`
`support the quit attempt. (2.1)
`
`
`
`
`
` HIGHLIGHTS OF PRESCRIBING INFORMATION
` These highlights do not include all the information needed to use
`
`
`
` CHANTIX safely and effectively. See full prescribing information for
`
` CHANTIX.
`
`CHANTIX® (varenicline) tablets, for oral use
`
`
`
`
`Initial U.S. Approval: 2006
`
`
`
`
`
`
`WARNING: SERIOUS NEUROPSYCHIATRIC EVENTS
`See full prescribing information for complete boxed warning.
`
`
`
`
`
`• Serious neuropsychiatric events have been reported in patients taking
`
`
`
`
`
`CHANTIX. (5.1 and 6.2)
`
`
`
`• Advise patients and caregivers that the patient should stop taking
`
`
`
`
`
`
`CHANTIX and contact a healthcare provider immediately if agitation,
`
`
`
`
`hostility, depressed mood, or changes in behavior or thinking that are
`
`not typical for the patient are observed, or if the patient develops
`
`
`
`suicidal ideation or suicidal behavior while taking CHANTIX or
`
`
`
`shortly after discontinuing CHANTIX. (5.1 and 6.2)
`
`
`
`• Weigh the risks of CHANTIX against benefits of its use. CHANTIX
`
`
`
`
`has been demonstrated to increase the likelihood of abstinence from
`
`
`
`smoking for as long as one year compared to treatment with placebo.
`
`
`The health benefits of quitting smoking are immediate and
`
`substantial. (5.1 and 6.2)
`
`
`
`
`
`
`
`----------------------------RECENT MAJOR CHANGES-------------------------­
`
`Dosage and Administration, Usual Dosage for Adults (2.1)
`8/2016
`
`
`
`Warnings and Precautions, Somnambulism (5.6)
`8/2016
`
`
`
`
`----------------------------INDICATIONS AND USAGE--------------------------­
`CHANTIX is a nicotinic receptor partial agonist indicated for use as an aid to
`
`
`
`
`
`
`
`smoking cessation treatment. (1 and 2.1)
`
`
`
`
`
`
`
`
`
`---------------------DOSAGE FORMS AND STRENGTHS---------------------­
`
`Tablets: 0.5 mg and 1 mg (3)
`
`
`
`_______________________________________________________________________________________________________________________________________
`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`
`WARNING: SERIOUS NEUROPSYCHIATRIC EVENTS
`
`1
`INDICATIONS AND USAGE
`
`
`2 DOSAGE AND ADMINISTRATION
`
`
`2.1 Usual Dosage for Adults
`
`
`2.2 Dosage in Special Populations
`
`
`3 DOSAGE FORMS AND STRENGTHS
`
`
`4 CONTRAINDICATIONS
`
`
`5 WARNINGS AND PRECAUTIONS
`
`
`5.1 Neuropsychiatric Symptoms and Suicidality
`
`
`
`Reference ID: 3971721
`
`5.2 Seizures
`
`
`5.3
`Interaction with Alcohol
`
`
`
`5.4 Accidental Injury
`
`
`5.5 Cardiovascular Events
`
`
`5.6 Somnambulism
`
`
`5.7 Angioedema and Hypersensitivity Reactions
`
`
`5.8 Serious Skin Reactions
`
`
`
`5.9 Nausea
`
`
`6 ADVERSE REACTIONS
`
`
`6.1 Clinical Trials Experience
`
`
`
`6.2 Postmarketing Experience
`
`
`
`

`

`
`
`
`
`The patient should set a date to stop smoking. Begin CHANTIX dosing one
`
`
`
`
`
`week before this date. Alternatively, the patient can begin CHANTIX dosing
`
`
`
`
`
`and then quit smoking between days 8 and 35 of treatment.
`
`CHANTIX should be taken orally after eating and with a full glass of water.
`
`
`
`
`
`The recommended dose of CHANTIX is 1 mg twice daily following a 1-week
`
`
`
`
`titration as follows:
`
`
`
`
`
`
`
` Days 1 – 3:
`
`
`
` Days 4 – 7:
` Day 8 – end of treatment:
`
`
`
`
`
`
`
` 0.5 mg once daily
` 0.5 mg twice daily
`
`
` 1 mg twice daily
`
`
`
`
`
`13 NONCLINICAL TOXICOLOGY
`
`7 DRUG INTERACTIONS
`
`
`
`
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`
`
`
`
`
`7.1 Use with Other Drugs for Smoking Cessation
`
`
`14 CLINICAL STUDIES
`
`
`
`7.2 Effect of Smoking Cessation on Other Drugs
`
`
`Initiation of Abstinence
`14.1
`
`8 USE IN SPECIFIC POPULATIONS
`
`
`
`14.2 Urge to Smoke
`
`
`8.1 Pregnancy
`
`
`14.3 Long-Term Abstinence
`
`
`8.2 Lactation
`
`
`
`14.4 Alternative Instructions for Setting a Quit Date
`
`
`8.4 Pediatric Use
`
`
`
`14.5 Gradual Approach to Quitting Smoking
`
`
`8.5 Geriatric Use
`
`
`14.6 Re-Treatment Study
`
`
`8.6 Renal Impairment
`
`
`
`
`14.7 Subjects with Cardiovascular and Chronic Obstructive Pulmonary
`
`
`9 DRUG ABUSE AND DEPENDENCE
`
`
`Disease
`
`
`9.1 Controlled Substance
`
`
`
`14.8 Subjects with Major Depressive Disorder
`
`
`9.3 Dependence
`
`
`16 HOW SUPPLIED/STORAGE AND HANDLING
`
`
`10 OVERDOSAGE
`
`
`17 PATIENT COUNSELING INFORMATION
`
`
`11 DESCRIPTION
`
`
`
`12 CLINICAL PHARMACOLOGY
`
`
`
`*Sections or subsections omitted from the full prescribing information are not
`
`12.1 Mechanism of Action
`
`
`listed.
`
`
`12.3 Pharmacokinetics
`__________________________________________________________________________
`_____________________________________________________________
`
`
`FULL PRESCRIBING INFORMATION
`
`
`
`WARNING: SERIOUS NEUROPSYCHIATRIC EVENTS
`
`
`
`
`
`
`Serious neuropsychiatric events including, but not limited to, depression,
`suicidal ideation, suicide attempt, and completed suicide have been
`
`reported in patients taking CHANTIX. Some reported cases may have been
`
`
`
`complicated by the symptoms of nicotine withdrawal in patients who
`
`
`stopped smoking. Depressed mood may be a symptom of nicotine
`
`withdrawal. Depression, rarely including suicidal ideation, has been
`reported in smokers undergoing a smoking cessation attempt without
`
`medication. However, some of these symptoms have occurred in patients
`
`taking CHANTIX who continued to smoke.
`
`
`All patients being treated with CHANTIX should be observed for
`
`
`neuropsychiatric symptoms including changes in behavior, hostility,
`
`
`agitation, depressed mood, and suicide-related events, including ideation,
`
`
`behavior, and attempted suicide. These symptoms, as well as worsening of
`
`
`
`pre-existing psychiatric illness and completed suicide, have been reported
`
`
`
`
`in some patients attempting to quit smoking while taking CHANTIX in the
`
`
`
`postmarketing experience. When symptoms were reported, most were
`during CHANTIX treatment, but some were following discontinuation of
`
`
`
`CHANTIX therapy.
`
`
`These events have occurred in patients with and without pre-existing
`
`
`psychiatric disease. Patients with serious psychiatric illness such as
`
`
`
`schizophrenia, bipolar disorder, and major depressive disorder did not
`
`participate in the premarketing studies of CHANTIX.
`
`
`
`Advise patients and caregivers that the patient should stop taking
`
`
`
`CHANTIX and contact a healthcare provider immediately if agitation,
`
`
`
`
`hostility, depressed mood, or changes in behavior or thinking that are not
`
`
`
`
`typical for the patient are observed, or if the patient develops suicidal
`
`
`ideation or suicidal behavior. In many postmarketing cases, resolution of
`
`
`
`symptoms after discontinuation of CHANTIX was reported, although in
`
`
`
`
`some cases the symptoms persisted; therefore, ongoing monitoring and
`
`
`
`supportive care should be provided until symptoms resolve.
`
`
`The risks of CHANTIX should be weighed against the benefits of its use.
`
`
`
`
`CHANTIX has been demonstrated to increase the likelihood of abstinence
`
`
`
`
`from smoking for as long as one year compared to treatment with placebo.
`
`
`
`
`
`The health benefits of quitting smoking are immediate and substantial [see
`
`
`
`Warnings and Precautions (5.1), Adverse Reactions (6.2)].
`
`
`
`
`
`1
`
`
`CHANTIX is indicated for use as an aid to smoking cessation treatment.
`
`
`
`
`
`
`2
`
`
`2.1 Usual Dosage for Adults
`
`
`
`
`Smoking cessation therapies are more likely to succeed for patients who are
`
`
`motivated to stop smoking and who are provided additional advice and support.
`
`
`Provide patients with appropriate educational materials and counseling to
`
`
`
`support the quit attempt.
`
`
`
`
`DOSAGE AND ADMINISTRATION
`
`
`INDICATIONS AND USAGE
`
`
`Reference ID: 3971721
`
`3
`
`
`
`
`
`
`
`
`Patients should be treated with CHANTIX for 12 weeks. For patients who have
`
`
`
`
`successfully stopped smoking at the end of 12 weeks, an additional course of 12
`
`
`
`weeks treatment with CHANTIX is recommended to further increase the
`
`likelihood of long-term abstinence.
`
`
`
`
`
`
`
`For patients who are sure that they are not able or willing to quit abruptly,
`
`
`
`consider a gradual approach to quitting smoking with CHANTIX. Patients
`should begin CHANTIX dosing and reduce smoking by 50% from baseline
`
`
`
`
`within the first four weeks, by an additional 50% in the next four weeks, and
`
`
`
`
`continue reducing with the goal of reaching complete abstinence by 12 weeks.
`
`
`
`Continue CHANTIX treatment for an additional 12 weeks, for a total of
`
`
`
`
`
`24 weeks of treatment. Encourage patients to attempt quitting sooner if they feel
`
`
`
`
`ready [see Clinical Studies (14.5)].
`
`
`
`
`Patients who are motivated to quit, and who did not succeed in stopping
`
`
`
`
`smoking during prior CHANTIX therapy for reasons other than intolerability
`
`
`
`
`due to adverse events or who relapsed after treatment, should be encouraged to
`
`
`
`
`make another attempt with CHANTIX once factors contributing to the failed
`
`
`
`attempt have been identified and addressed.
`
`
`
`Consider a temporary or permanent dose reduction in patients who cannot
`
`
`
`
`tolerate the adverse effects of CHANTIX.
`
`
`2.2 Dosage in Special Populations
`
`
`
`
`Patients with Impaired Renal Function
`
`
`No dosage adjustment is necessary for patients with mild to moderate renal
`
`
`impairment. For patients with severe renal impairment (estimated creatinine
`
`clearance less than 30 mL per min), the recommended starting dose of
`
`
`
`
`
`CHANTIX is 0.5 mg once daily. The dose may then be titrated as needed to a
`
`
`
`
`maximum dose of 0.5 mg twice daily. For patients with end-stage renal disease
`
`
`
`undergoing hemodialysis, a maximum dose of 0.5 mg once daily may be
`
`
`administered if tolerated [see Use in Specific Populations (8.6), Clinical
`
`
`
`
`
`Pharmacology (12.3)].
`
`
`
`Elderly and Patients with Impaired Hepatic Function
`
`
`No dosage adjustment is necessary for patients with hepatic impairment.
`
`
`
`Because elderly patients are more likely to have decreased renal function, care
`
`should be taken in dose selection, and it may be useful to monitor renal function
`
`
`
`
`[see Use in Specific Populations (8.5)].
`
`
`
`DOSAGE FORMS AND STRENGTHS
`
`
`

`

` Capsular, biconvex tablets: 0.5 mg (white to off-white, debossed with "Pfizer"
`
`
`
`
`
`
` on one side and "CHX 0.5" on the other side) and 1 mg (light blue, debossed
` with "Pfizer" on one side and "CHX 1.0" on the other side).
`
`
`
`CONTRAINDICATIONS
`
`
`4
`
`
`CHANTIX is contraindicated in patients with a known history of serious
`
`
`
`
`hypersensitivity reactions or skin reactions to CHANTIX.
`
`
`
`5 WARNINGS A