`
`
`
`
`
`
`
` CENTER FOR DRUG EVALUATION AND RESEARCH
`
`
`Approval Package for:
`
`
`
`
`
`APPLICATION NUMBER:
`
` 021928Orig1s040
`
`
`
`
`
`
` Trade Name:
`
`
`
`
` CHANTIX
`
` varenicline tartrate
`
`
`
`Generic or
`
`
`Proper Name:
`
` Sponsor:
`
` Approval Date: 12/16/2016
`
` 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-040
`
`
`
`
`
`
`
` 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
`
`

`

`CENTER FOR DRUG EVALUATION AND
`
` CENTER FOR DRUG EVALUATION AND
`
`
`
` RESEARCH
`
`RESEARCH
`
`
`APPLICATION NUMBER:
`
`NDA 021928/S-040
`
`NDA 021928/S-040
`
`
`APPLICA TI0N NUMBER:
`
`
`
`
`
` APPROVAL LETTER
`
`APPROVAL LETTER
`
`
`
`
`
`
`
`
`
`

`

`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`
`Food and Drug Administration
`Silver Spring MD 20993
`
`SUPPLEMENT APPROVAL
`FULFILLMENT OF POSTMARKETING REQUIREMENT
`REMS ASSESSMENT ACKNOWLEDGEMENT
`RELEASE REMS REQUIREMENT
`
`NDA 021928/S-040
`
`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 Application (sNDA) dated and received February
`18, 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 electronic communication dated December 1, 2016; and we acknowledge
`receipt of your risk evaluation and mitigation strategy (REMS) assessment dated October 14,
`2016. After consultation between the Office of Surveillance and Epidemiology and the Office of
`New Drugs, we found the REMS assessment to be complete.
`
`This Prior Approval sNDA proposes changes to the package insert based on clinical trial data
`from the study titled, “A Phase 4, Randomized, Double-Blind, Active and Placebo-Controlled,
`Multicenter Study Evaluating the Neuropsychiatric Safety and Efficacy of 12 Weeks Varenicline
`Tartrate 1 mg BID and Bupropion Hydrochloride 150 mg BID for Smoking Cessation in
`Subjects with and Without a History of Psychiatric Disorders”; the supplement also proposes
`corresponding changes to the Medication Guide, and provides for proposed modification to the
`approved REMS for Chantix (varenicline).
`
`APPROVAL & LABELING
`
`We have completed our review of this supplemental application, as amended. It is approved,
`effective on the date of this letter, for use as recommended in the enclosed, agreed-upon labeling
`text.
`
`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
`
`Reference ID: 4029004
`
`
`

`

`NDA 021928/S-040
`Page 2
`
`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.
`
`FULFILLMENT OF POSTMARKETING REQUIREMENT
`
`We have received your submissions dated November 16, 2015, and February 18, 2016, reporting
`on and containing the final report for the following postmarketing requirement listed in the
`March 12, 2010, post-approval postmarketing requirements letter:
`
`1544-4 A large randomized, double-blind, active- and placebo-controlled trial to compare the
`risk of clinically significant neuropsychiatric events, including but not limited to
`suicidality, in individuals using Chantix (varenicline), bupropion, nicotine replacement
`therapy, or placebo as aids to smoking cessation over 12 weeks of treatment, and to
`determine whether individuals with prior history of psychiatric disorders are at greater
`risk for development of clinically significant neuropsychiatric events compared to
`individuals without prior history of psychiatric disorders while using Chantix
`(varenicline) as an aid to smoking cessation. The trial should be sufficiently powered
`to adequately assess clinically significant neuropsychiatric events with each treatment
`and in both of the two subgroups (i.e., with and without psychiatric disorders).
`
`We have reviewed your submissions and conclude that the above requirement has been fulfilled.
`
`We remind you that there are postmarketing requirements listed in the May 10, 2006, approval
`
`Reference ID: 4029004
`
`
`

`

`NDA 021928/S-040
`
`Page 3
`
`
`letter, and the September 22, 2011, post-approval postmarketing requirement letter that are still
`open.
`
`RISK EVALUATION AND MITIGATION STRATEGY REQUIREMENTS
`
`The REMS for Chantix (varenicline) was originally approved on October 19, 2009, and the most
`recent modification was approved on August 12, 2016. 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 a revised Medication Guide to correspond to changes to the product
`label.
`
`In accordance with section 505-1 of the FDCA, we have determined that the following REMS
`modification is necessary to minimize burden on the healthcare delivery system of complying
`with the REMS:
`
`• Removal of the Medication Guide as an element of the REMS
`
`We have determined that maintaining the Medication Guide as part of the approved labeling is
`adequate to address the serious and significant public health concern and meets the standard in
`21 CFR 208. Therefore, it is no longer necessary to include the Medication Guide as an element
`of the approved REMS to ensure that the benefits of Chantix (varenicline) outweigh its risks. The
`Medication Guide will continue to be part of the approved labeling in accordance with 21 CFR
`208. Like other labeling, Medication Guides are subject to the safety labeling change provisions
`of section 505(o)(4) of the FDCA.
`
`Therefore, because the Medication Guide as part of the REMS is no longer necessary to ensure
`the benefits of the drug outweigh the risks, a REMS is no longer required for Chantix
`(varenicline).
`
`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:
`
`Reference ID: 4029004
`
`

`

`NDA 021928/S-040
`Page 4
`
`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.
`
`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 H. Hertz, MD
`Director
`Division of Anesthesia, Analgesia,
`and Addiction Products
`Office of Drug Evaluation II
`Center for Drug Evaluation and Research
`
`Enclosure:
`
`
`
`Content of Labeling
`
`
`
`
`Reference ID: 4029004
`
`

`

`---------------------------------------------------------------------------------------------------------
`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
`12/16/2016
`
`Reference ID: 4029004
`
`

`

`CENTER FOR DRUG EVALUATION AND
`
` CENTER FOR DRUG EVALUATION AND
`
`
`
` RESEARCH
`
`RESEARCH
`
`
`APPLICATION NUMBER:
`
`NDA 021928/S-040
`
`NDA 021928/S-040
`
`
`APPLICA TI0N NUMBER:
`
`
`
`
` LABELING
`
`LABELING
`
`
`
`
`
`
`
`
`
`

`

`attempt, and completed suicide. Observe patients attempting to quit
`smoking with CHANTIX for the occurrence of such symptoms and
`instruct them to discontinue CHANTIX and contact a healthcare provider
`if they experience such adverse events. (5.1)
`• 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)
`
`-----------------------WARNINGS AND PRECAUTIONS-----------------------­
`• Neuropsychiatric Adverse Events: Postmarketing reports of serious or
`
`clinically significant neuropsychiatric adverse events have included
`changes in mood (including depression and mania), psychosis,
`hallucinations, paranoia, delusions, homicidal ideation, aggression,
`Revised: 12/2016
`hostility, agitation, anxiety, and panic, as well as suicidal ideation, suicide
`_______________________________________________________________________________________________________________________________________
`
`See 17 for PATIENT COUNSELING INFORMATION and Medication
`Guide
`
`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
`
`----------------------------RECENT MAJOR CHANGES-------------------------­
`Boxed Warning-Removed
`12/2016
`Dosage and Administration, Usual Dosage for Adults (2.1)
`8/2016
`Warnings and Precautions,
`Neuropsychiatric Adverse Events including Suicidality (5.1)
`Warnings and Precautions, Somnambulism (5.6)
`
`12/2016
`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 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)
`
`---------------------DOSAGE FORMS AND STRENGTHS---------------------­
`Tablets: 0.5 mg and 1 mg (3)
`
`-------------------------------CONTRAINDICATIONS-----------------------------­
`History of serious hypersensitivity or skin reactions to CHANTIX. (4)
`
`Reference ID: 4029004
`
`

`

`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`INDICATIONS AND USAGE
`1
`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 Adverse Events including Suicidality
`
`
`
`5.2 Seizures
`
`
`
`Interaction with Alcohol
`
`5.3
`
`
`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
`
`
`
`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
`
`
`
`*Sections or subsections omitted from the full prescribing information are not
`8.2 Lactation
`
`
`
`listed.
`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
`Initiation of Abstinence
`
`14.1
`
`
`
`14.2 Urge to Smoke
`
`
`
`
`14.3 Long-Term Abstinence
`
`
`
`
`14.4 Alternative Instructions for Setting a Quit Date
`
`
`
`
`14.5 Gradual Approach to Quitting Smoking
`
`
`
`
`14.6 Re-Treatment Study
`
`
`
`
`14.7 Subjects with Cardiovascular and Chronic Obstructive Pulmonary
`
`
`
`
`Disease
`
`
`
`14.8 Subjects with Major Depressive Disorder
`
`
`
`
`14.9 Postmarketing Neuropsychiatric Safety Outcome Trial
`
`
`
`
`16 HOW SUPPLIED/STORAGE AND HANDLING
`17 PATIENT COUNSELING INFORMATION
`
`Reference ID: 4029004
`
`

`

`FULL PRESCRIBING INFORMATION
`
`1
`
`INDICATIONS AND USAGE
`
`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 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
`
`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)].
`
`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 Adverse Events including Suicidality
`
`Serious neuropsychiatric adverse events have been reported in patients being treated with CHANTIX [see Adverse Reactions (6.2)]. These postmarketing reports have
`included changes in mood (including depression and mania), psychosis, hallucinations, paranoia, delusions, homicidal ideation, aggression, hostility, agitation, anxiety,
`and panic, as well as suicidal ideation, suicide attempt, and completed suicide. Some patients who stopped smoking may have been experiencing symptoms of nicotine
`withdrawal, including depressed mood. Depression, rarely including suicidal ideation, has been reported in smokers undergoing a smoking cessation attempt without
`medication. However, some of these adverse events occurred in patients taking CHANTIX who continued to smoke.
`
`Neuropsychiatric adverse events occurred in patients without and with pre-existing psychiatric disease; some patients experienced worsening of their psychiatric
`illnesses. Some neuropsychiatric adverse events, including unusual and sometimes aggressive behavior directed to oneself or others, may have been worsened by
`concomitant use of alcohol [see Warnings and Precautions (5.3), Adverse Reactions (6.2)]. Observe patients for the occurrence of neuropsychiatric adverse events.
`Advise patients and caregivers that the patient should stop taking CHANTIX and contact a healthcare provider immediately if agitation, 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. The healthcare provider should
`evaluate the severity of the symptoms and the extent to which the patient is benefiting from treatment, and consider options including dose reduction, continued
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`treatment under closer monitoring, or discontinuing treatment. In many postmarketing cases, resolution of symptoms after discontinuation of CHANTIX was reported.
`However, the symptoms persisted in some cases; therefore, ongoing monitoring and supportive care should be provided until symptoms resolve.
`
`The neuropsychiatric safety of CHANTIX was evaluated in a randomized, double-blind, active and placebo-controlled study that included patients without a history of
`psychiatric disorder (non-psychiatric cohort, N=3912) and patients with a history of psychiatric disorder (psychiatric cohort, N=4003). In the non-psychiatric cohort,
`CHANTIX was not associated with an increased incidence of clinically significant neuropsychiatric adverse events in a composite endpoint comprising anxiety,
`depression, feeling abnormal, hostility, agitation, aggression, delusions, hallucinations, homicidal ideation, mania, panic, and irritability. In the psychiatric cohort, there
`were more events reported in each treatment group compared to the non-psychiatric cohort, and the incidence of events in the composite endpoint was higher for each
`of the active treatments compared to placebo: Risk Differences (RDs) (95%CI) vs. placebo were 2.7% (-0.05, 5.4) for CHANTIX, 2.2% (-0.5, 4.9) for bupropion, and
`0.4% (-2.2, 3.0) for transdermal nicotine. In the non-psychiatric cohort, neuropsychiatric adverse events of a serious nature were reported in 0.1% of CHANTIX-treated
`patients and 0.4% of placebo-treated patients. In the psychiatric cohort, neuropsychiatric events of a serious nature were reported in 0.6% of CHANTIX-treated patients,
`with 0.5% involving psychiatric hospitalization. In placebo-treated patients, serious neuropsychiatric events occurred in 0.6%, with 0.2% requiring psychiatric
`hospitalization [see Clinical Studies (14.9)].
`
`5.2 Seizures
`
`During clinical trials and the post marketing experience, there have been reports of seizures in patients treated with CHANTIX. Some patients had no history of
`seizures, whereas others had a history of seizure disorder that was remote or well-controlled. In most cases, the seizure occurred within the first month of therapy.
`Weigh this potential risk against the potential benefits before prescribing CHANTIX in patients with a history of seizures or other factors that can lower the seizure
`threshold. Advise patients to discontinue CHANTIX and contact a healthcare provider immediately if they experience a seizure while on treatment [see Adverse
`Reactions (6.2)].
`
`5.3 Interaction with Alcohol
`
`There have been postmarketing reports of patients experiencing increased intoxicating effects of alcohol while taking CHANTIX. Some cases described unusual and
`sometimes aggressive behavior, and were often accompanied by amnesia for the events. Advise patients to reduce the amount of alcohol they consume while taking
`CHANTIX until they know whether CHANTIX affects their tolerance for alcohol [see Adverse Reactions (6.2)].
`
`5.4 Accidental Injury
`
`There have been postmarketing reports of traffic accidents, near-miss incidents in traffic, or other accidental injuries in patients taking CHANTIX. In some cases, the
`patients reported somnolence, dizziness, loss of consciousness or difficulty concentrating that resulted in impairment, or concern about potential impairment, in driving
`or operating machinery. Advise patients to use caution driving or operating machinery or engaging in other potentially hazardous activities until they know how
`CHANTIX may affect them.
`
`5.5 Cardiovascular Events
`
`In a placebo-controlled clinical trial of CHANTIX administered to patients with stable cardiovascular disease, with approximately 350 patients per treatment arm, all-
`cause and cardiovascular mortality was lower in patients treated with CHANTIX, but certain nonfatal cardiovascular events occurred more frequently in patients treated
`with CHANTIX than in patients treated with placebo [see Adverse Reactions (6.1)]. Table 1 below shows the incidence of deaths and of selected nonfatal serious
`cardiovascular events occurring more frequently in the CHANTIX arm compared to the placebo arm. These events were adjudicated by an independent blinded
`committee. Nonfatal serious cardiovascular events not listed occurred at the same incidence or more commonly in the placebo arm. Patients with more than one
`cardiovascular event of the same type are counted only once per row. Some of the patients requiring coronary revascularization underwent the procedure as part of
`management of nonfatal MI and hospitalization for angina.
`
`Table 1. Mortality and Adjudicated Nonfatal Serious Cardiovascular Events in the Placebo-Controlled CHANTIX Trial in Patients with Stable
`
`
`
`Cardiovascular Disease
`
`
`
`CHANTIX
`(N=353)
`n (%)
`
`Mortality and Cardiovascular Events
`
`Mortality (Cardiovascular & All-cause up to 52 wks)
`Cardiovascular death
`All-cause mortality
`
`Nonfatal Cardiovascular Events (rate on CHANTIX > Placebo)
`Up to 30 days after treatment
`Nonfatal myocardial infarction
`Nonfatal Stroke
`Beyond 30 days after treatment & up
`to 52 weeks
`Nonfatal myocardial infarction
`Need for coronary
`revascularization
`Hospitalization for angina pectoris
`Transient ischemia attack
`New diagnosis of peripheral
`vascular disease (PVD) or
`admission for a PVD procedure
`
`1 (0.3)
`2 (0.6)
`
`4 (1.1)
`2 (0.6)
`
`3 (0.8)
`7 (2.0)
`6 (1.7)
`1 (0.3)
`
`5 (1.4)
`
`Placebo
`(N=350)
`n (%)
`
`2 (0.6)
`5 (1.4)
`
`1 (0.3)
`0 (0)
`
`2 (0.6)
`2 (0.6)
`4 (1.1)
`0 (0)
`
`2 (0.6)
`
`A meta-analysis of 15 clinical trials of ≥ 12 weeks treatment duration, including 7002 patients (4190 CHANTIX, 2812 placebo), was conducted to systematically assess
`the cardiovascular safety of CHANTIX. The study in patients with stable cardiovascular disease described above was included in the meta-analysis. There were lower
`rates of all-cause mortality (CHANTIX 6 [0.14%]; placebo 7 [0.25%]) and cardiovascular mortality (CHANTIX 2 [0.05%]; placebo 2 [0.07%]) in the CHANTIX arms
`compared with the placebo arms in the meta-analysis.
`
`The key cardiovascular safety analysis included occurrence and timing of a composite endpoint of Major Adverse Cardiovascular Events (MACE), defined as
`cardiovascular death, nonfatal MI, and nonfatal stroke. These events included in the endpoint were adjudicated by a blinded, independent committee. Overall, a small
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`number of MACE occurred in the trials included in the meta-analysis, as described in Table 2. These events occurred primarily in patients with known cardiovascular
`disease.
`
`Table 2. Number of MACE cases, Hazard Ratio and Rate Difference in a Meta-Analysis of 15 Clinical Trials Comparing CHANTIX to Placebo*
`
`CHANTIX
`N=4190
`13 (0.31%)
`1316
`
`Placebo
`N=2812
`6 (0.21%)
`839
`
`MACE cases, n (%)
`Patient-years of exposure
`Hazard Ratio (95% CI)
`
`1.95 (0.79, 4.82)
`Rate Difference per 1,000 patient-years (95% CI)
`6.30 (-2.40, 15.10)
`*Includes MACE occurring up to 30 days post-treatment.
`
`The meta-analysis showed that exposure to CHANTIX resulted in a hazard ratio for MACE of 1.95 (95% confidence interval from 0.79 to 4.82) for patients up to 30
`days after treatment; this is equivalent to an estimated increase of 6.3 MACE events per 1,000 patient-years of exposure. The meta-analysis showed higher rates of CV
`endpoints in patients on CHANTIX relative to placebo a