`
`
`
`
`
`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`Approval Package for:
`
`
`APPLICATION NUMBER:
`021928Orig1s019
`
`
`
`
`CHANTIX
`
`varenicline tartrate
`
`Trade Name:
`
`
`Generic or
`Proper Name:
`
`Sponsor:
`
`Approval Date:
`
`Indication:
`
`Pfizer, Inc.
`
`07/22/2011
`
`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-019
`
`
`
`
`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-019
`NDA 021928/S-019
`
`
`APPLICA TI0N NUMBER:
`
`APPROVAL LETTER
`APPROVAL LETTER
`
`
`
`
`
`
`
`
`
`

`

`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`
`NDA 021928/ S-019/S-020/S-021
`
`Pfizer, Inc.
`235 E. 42nd Street
`New York, NY 10017
`
`Attention: Lilya I. Donohew, Ph.D.
` Director, Worldwide Regulatory Affairs
`
`Dear Dr. Donohew:
`
`Food and Drug Administration
`Silver Spring MD 20993
`
`SUPPLEMENTS APPROVAL
`
`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.
`
`These supplemental new drug applications propose a modification to the approved REMS and
`the following labeling revisions to the Package Insert:
`
`S-019:
`
`the safety and efficacy of Chantix in smokers with cardiovascular disease
`(CVD), and revisions to the Medication Guide that include the possible
`side effects of Chantix
`
`S-020:
`
`the safety and efficacy of Chantix in smokers with chronic obstructive
`pulmonary disease (COPD)
`
`S-021:
`
`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
`include new information on how to take Chantix
`
`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.
`
`Reference ID: 2977906
`
`

`

`NDA 021928/ S-019/S-020/S-021
`Page 2
`
`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 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.
`
`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 in pediatric patients unless this requirement is waived,
`deferred, or inapplicable.
`
`Because none of these criteria apply to your applications, you are exempt from this requirement.
`
`POSTMARKETING REQUIREMENTS UNDER 505(o)
`
`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.
`
`Reference ID: 2977906
`
`

`

`NDA 021928/ S-019/S-020/S-021
`Page 3
`
`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
`consider this information to be “new safety information” as defined in section 505-1(b)(3) of the
`FDCA.
`
`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.
`
`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.
`
`Therefore, based on appropriate scientific data, FDA has determined that you are required to
`conduct the following:
`
`1804
`
`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.
`
`The timetable you submitted on July 18, 2011, states that you will conduct this study according
`to the following schedule:
`
`Draft Protocol Submission: August 15, 2011
`
`Final Protocol Submission: October 1, 2011
`
`Study Completion:
`January 15, 2012
`
`Final Report Submission:
`February 15, 2012
`
`
`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).”
`
`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.
`
`Reference ID: 2977906
`
`

`

`NDA 021928/ S-019/S-020/S-021
`Page 4
`
`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
`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.
`
`RISK EVALUATION AND MITIGATION STRATEGY REQUIREMENTS
`
`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.
`
`Your proposed modified REMS, submitted on June 6, 2011, and appended to this letter, is
`approved.
`
`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 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
`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
`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.
`
`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.
`
`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.
`
`Reference ID: 2977906
`
`

`

`NDA 021928/ S-019/S-020/S-021
`Page 5
`
`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.
`
`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
`PROPOSED REMS MODIFICATION
`REMS ASSESSMENT
`
`NEW SUPPLEMENT (NEW INDICATION FOR USE)
`FOR NDA 021928
`REMS ASSESSMENT
`PROPOSED REMS MODIFICATION (if included)
`
`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:
`
`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
`
`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 Division of Drug Marketing, Advertising, and Communications
`(DDMAC), 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
`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
`
`Reference ID: 2977906
`
`

`

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

`

`---------------------------------------------------------------------------------------------------------
`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
`
`Reference ID: 2977906
`
`

`

`CENTER FOR DRUG EVALUATION AND
`
`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`RESEARCH
`
`APPLICATION NUMBER:
`NDA 021928/S-019
`NDA 021928/S-019
`
`
`APPLICA TI0N NUMBER:
`
`
`LABELING
`LABELING
`
`
`
`
`
`
`
`

`

`-------------------------------CONTRAINDICATIONS------------------------------
`
`History of serious hypersensitivity or skin reactions to CHANTIX (4)
`
`
`-----------------------WARNINGS AND PRECAUTIONS-----------------------­
`• 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. (5.2 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. (5.3 and 6.2)
`• Cardiovascular events: In a trial of patients with stable cardiovascular
`disease (CVD) certain cardiovascular events were reported more
`frequently in patients treated with CHANTIX. Patients with CVD should
`be instructed to notify their health care providers of new or worsening
`cardiovascular symptoms and to seek immediate medical attention if they
`experience signs and symptoms of myocardial infarction. (5.4 and 6.1)
`• 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. (5.5)
`• Nausea: Nausea is the most common adverse reaction (up to 30%
`incidence rate). Dose reduction may be helpful. (5.6)
`
`------------------------------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: Pharmacokinetics or pharmacodynamics of
`certain drugs may be altered due to smoking cessation with CHANTIX,
`necessitating dose adjustment. (7.2)
`
`-----------------------USE IN SPECIFIC POPULATIONS------------------------
`• Pregnancy: CHANTIX should be used during pregnancy only if the
`potential benefit justifies the potential risk to the fetus. (8.1)
`• Nursing Mothers: Discontinue drug or nursing taking into consideration
`importance of drug to mother (8.3)
`• Pediatric Use: Safety and effectiveness not established (8.4)
`• Renal Impairment: Dosage adjustment is required for severe renal
`impairment. (2.2, 8.6)
`
`See 17 for PATIENT COUNSELING INFORMATION and Medication
`Guide
`
`Revised: 07/2011
`
`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
`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
`Alternative Instructions for Setting a Quit Date (2.1)
`Warnings and Precautions
`7/2011
`Cardiovascular Events (5.4)
`----------------------------INDICATIONS AND USAGE---------------------------
`CHANTIX is a nicotinic receptor partial agonist indicated for use as an aid to
`smoking cessation treatment. (1 and 2.1)
`
`7/2011
`
`----------------------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)
`• Renal impairment: Reduce the dose in patients with severe renal
`impairment (estimated creatinine clearance <30 mL/min). (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)
`
`---------------------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
`5.2 Angioedema and Hypersensitivity Reactions
`5.3 Serious Skin Reactions
`5.4 Cardiovascular Events
`5.5 Accidental Injury
`5.6 Nausea
`6 ADVERSE REACTIONS
`6.1 Clinical Trials Experience
`6.2 Postmarketing Experience
`7 DRUG INTERACTIONS
`7.1 Use With Other Drugs for Smoking Cessation
`7.2 Effect of Smoking Cessation on Other Drugs
`8 USE IN SPECIFIC POPULATIONS
`8.1 Pregnancy
`Reference ID: 2977906
`
`8.3 Nursing Mothers
`8.4 Pediatric Use
`8.5 Geriatric Use
`8.6 Renal Impairment
`9 DRUG ABUSE AND DEPENDENCE
`9.1 Controlled Substance
`9.3 Dependence
`10 OVERDOSAGE
`11 DESCRIPTION
`12 CLINICAL PHARMACOLOGY
`12.1 Mechanism of Action
`12.3 Pharmacokinetics
`13 NONCLINICAL TOXICOLOGY
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`14 CLINICAL STUDIES
`14.1 Initiation of Abstinence
`14.2 Urge to Smoke
`14.3 Long-Term Abstinence
` 14.4 Subjects with Cardiovascular and Chronic Obstructive Pulmonary
`Disease
`14.5 Alternative Instructions for Setting a Quit Date
`
`

`

`16 HOW SUPPLIED/STORAGE AND HANDLING
`17 PATIENT COUNSELING INFORMATION
`Medication Guide
`17.1 Initiate Treatment and Continue to Attempt to Quit if Lapse
`17.2 How To Take
`17.3 Starting Week Dosage
`17.4 Continuing Weeks Dosage
`17.5 Dosage Adjustment for CHANTIX or Other Drugs
`17.6 Counseling and Support
`17.7 Neuropsychiatric Symptoms
`17.8 History of Psychiatric Illness
`_______________________________________________________________________________________________________________________________________
`
`17.9 Nicotine Withdrawal
`17.10 Angioedema
`17.11 Serious Skin Reactions
`17.12 Patients with Cardiovascular Disease
`17.13 Driving or Operating Machinery
`17.14 Vivid, Unusual, or Strange Dreams
`17.15 Pregnancy and Lactation
`
`*Sections or subsections omitted from the full prescribing information are not
`listed.
`
`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, and the safety and
`efficacy of CHANTIX in such patients has not been established.
`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) and Adverse Reactions
`6.2)]
`
`INDICATIONS AND USAGE
`1
`CHANTIX is indicated for use as an aid to smoking cessation treatment.
`
`2
`
`DOSAGE AND ADMINISTRATION
`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.
`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 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
`
`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.
`Patients who do not succeed in stopping smoking during 12 weeks of
`initial therapy, or who relapse after treatment, should be encouraged to make
`another attempt 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 <30 mL/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 a day. 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) and 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)].
`
`3
`
`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)
`
`4
`
`CONTRAINDICATIONS
`CHANTIX is contraindicated in patients with a known history of serious
`hypersensitivity reactions or skin reactions to CHANTIX
`
`5 WARNINGS AND PRECAUTIONS
`5.1 Neuropsychiatric Symptoms and Suicidality
`Serious neuropsychiatric symptoms have been reported in patients being
`treated with CHANTIX [see Boxed Warning and Adverse Reactions (6.2)].
`These postmarketing reports have included changes in mood (including
`depression and mania), psychosis, hallucinations, paranoia, delusions, homicidal
`ideation, hostility, agitation, anxiety, and panic, as well as suicidal ideation,
`suicide attempt, and completed suicide. 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. 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; some patients have experienced worsening of their
`psychiatric illnesses. All patients being treated with CHANTIX should be
`observed for neuropsychiatric symptoms or worsening of pre-existing
`psychiatric
`illness.
`Patients with serious psychiatric
`illness such as
`schizophrenia, bipolar disorder, and major depressive disorder did not
`participate in the premarketing studies of CHANTIX, and the safety and
`efficacy of CHANTIX in such patients has not been established.
`Advise patients and caregivers that the patient should stop taking
`CHANTIX and contact a healthcare provider immediately if agitation,
`depressed mood, 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
`
`Reference ID: 2977906
`
`

`

`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
`
`5.2 Angioedema and B ypersensitn>ity Reactions
`There have been postmarketing reports of hypersensitivity reactions
`including angioedema in patients treated with CHANTIX {see Adverse
`Reactions (6.2), and Patitmt Counssling Information (17.10)). Clinical signs
`included swelling of the face, mouth (tongue. lips. and gums). extremities. and
`neck (throat and larynx). There were infrequent reports of life-threatening
`to
`respiratory
`requiring emergent medical attention due
`angioedema
`compromise. Instruct patients to discontinue CHANTIX and immediately seek
`medical care if they experience these symptoms.
`
`5.3 Sei-ious Skin Reactions
`There have been postmarketing reports of rare but serious skin reactions.
`including Stevens-Johnson Syndrome and erythema multiforme. in patients
`using CHANTIX [see Adverss Rsactions (6.2)]. As these skin reactions can be
`life-threatening. instruct patients to stop taking CHANTIX and contact a
`healthcare provider immediately at the first appearance of a skin rash with
`mucosa! lesions or any other signs of hypersensitivity.
`
`5.4 Cudiovascular Events
`In a controlled clinical trial of CHANTIX administered to patients with
`stable cardiovascular disease, with approximately 350 patients per treatment
`arm, certain cardiovascular events were reporte