`
`
`
`
`
`
`
` CENTER FOR DRUG EVALUATION AND RESEARCH
`
`
`Approval Package for:
`
`
`
`
`
`APPLICATION NUMBER:
`
` 021928Orig1s036
`
`
`
`
`
`
` Trade Name:
`
`
`
`
` CHANTIX
`
` varenicline tartrate
`
`
`
`Generic or
`
`
`Proper Name:
`
` Sponsor:
`
` Approval Date: 09/19/2014
`
` 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-036
`
`
`
`
`
`
`
` 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
`
`

`

`CENTER FOR DRUG EVALUATION AND
`
` CENTER FOR DRUG EVALUATION AND
`
`
`
` RESEARCH
`
`RESEARCH
`
`
`APPLICATION NUMBER:
`
`NDA 021928/S-036
`
`NDA 021928/S-036
`
`
`APPLICA TI0N NUMBER:
`
`
`
`
`
` APPROVAL LETTER
`
`APPROVAL LETTER
`
`
`
`
`
`
`
`
`
`

`

`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`
`NDA 021928/S-032, S-036, S-038
`
`Pfizer, Inc.
`235 E. 42nd Street
`New York, NY 10017
`
`Attention:
`
`
`Lilya I. Donohew, PhD
`Senior Director, Worldwide Regulatory Affairs
`
`Dear Dr. Donohew:
`
`Food and Drug Administration
`Silver Spring MD 20993
`
`SUPPLEMENT APPROVAL
`
`Please refer to your Supplemental New Drug Applications (sNDAs) dated and received October
`24, 2013(S-032), April 8, 2014 (S-036), and September 3, 2014 (S-038), 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 November 8, and December 20, 2013, April
`30, and September 18, 2014 (S-032), April 29, May 2, 5, and 8, August 1, and September 18,
`2014 (S-036), and September 3, and 18, 2014 (S-038), and your proposed risk evaluation and
`mitigation strategy (REMS) modification dated November 8, 2013 (S-032) and September 3,
`2014 (S-038).
`
`We also refer to our letter dated August 6, 2014, 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.
`This information pertains to the risk of seizures and the potentiation of the intoxicating effects of
`alcohol.
`
`Finally we refer you to our September 4, 2013, and August 6, 2014, letters notifying you, under
`section 505-1(g)(4)(B) of the FDCA, that your REMS must be modified based on findings from
`your 18-month REMS assessment and the new safety information described above.
`
`Supplement S-032 proposes revisions to the DRUG INTERACTIONS section of the Package
`Insert regarding a potential interaction between alcohol and varenicline and includes a proposed
`modification to the approved risk evaluation and mitigation strategy (REMS), including revisions
`to the Medication Guide and revisions to the Chantix REMS goal.
`
`Supplement S-036 proposes changes to the Package Insert based on meta-analyses of varenicline
`clinical trials and published observational studies pertaining to serious neuropsychiatric events.
`
`Supplement S-038 proposes revisions to the labeling for Chantix. The agreed upon changes to
`the language included in our August 6, 2014, letter are included in the appended labeling text.
`
`Reference ID: 3630834
`
`

`

`NDA 021928/S-032, S-036, S-038
`Page 2
`
`S-038 also includes additional proposed modifications to the approved risk evaluation and
`mitigation strategy (REMS), comprising further revisions to the Medication Guide as well as
`revisions to the Chantix REMS goal.
`
`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.
`
`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 includes 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 July 22, 2011. 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 describe the risk of seizures and the
`potentiation of the intoxicating effects of alcohol, and revise the “What is the most important
`
`Reference ID: 3630834
`
`

`

`NDA 021928/S-032, S-036, S-038
`
`Page 3
`
`
`information I should know about CHANTIX” section of the Medication Guide as well as other
`sections of the Medication Guide so as to furnish adequate information for the safe and effective
`use of the drug. In addition, the proposed modification includes revisions to the Chantix REMS
`goal to focus only on neuropsychiatric risks.
`
`Your proposed modified REMS, submitted on September 3, 2014, and appended to this letter, is
`approved.
`
`The modified REMS consists 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.
`
`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 the FDCA.
`
`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
`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)
`
`
`
`
`
`
`
`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
`
`
`
`
`Reference ID: 3630834
`
`

`

`NDA 021928/S-032, S-036, S-038
`
`Page 4
`
`
`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.
`
`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.
`
`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
`
`Office of Prescription Drug Promotion (OPDP)
`
`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/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
`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 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).
`
`Reference ID: 3630834
`
`

`

`NDA 021928/S-032, S-036, S-038
`Page 5
`
`If you have any questions, call Ayanna Augustus, PhD, RAC, Sr. Regulatory Project Manager, at
`(301) 796-3980.
`
`Sincerely,
`
`{See appended electronic signature page}
`
`Judith A. Racoosin, MD, MPH
`Deputy Director for Safety
`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: 3630834
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`JUDITH A RACOOSIN
`09/19/2014
`
`Reference ID: 3630834
`
`

`

`CENTER FOR DRUG EVALUATION AND
`
` CENTER FOR DRUG EVALUATION AND
`
`
`
` RESEARCH
`
`RESEARCH
`
`
`APPLICATION NUMBER:
`
`NDA 021928/S-036
`
`NDA 021928/S-036
`
`
`APPLICA TI0N NUMBER:
`
`
`
`
` LABELING
`
`LABELING
`
`
`
`
`
`
`
`
`
`

`

`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-------------------------­
`Warnings and Precautions
`Neuropsychiatric Symptoms and Suicidality (5.1)
`Seizures (5.2)
`Interaction with Alcohol (5.3)
`
`09/2014
`09/2014
`09/2014
`
`----------------------------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)
`• 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)
`
`-------------------------------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 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
`health care providers of new or worsening cardiovascular symptoms and to
`seek immediate medical attention if they experience signs and symptoms
`of myocardial infarction or stroke. (5 5 and 6.1)
`• 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. (5.6 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. (5.7 and 6.2)
`• Nausea: Nausea is the most common adverse reaction (up to 30%
`
`incidence rate). Dose reduction may be helpful. (5.8)
`------------------------------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: 09/2014
`_______________________________________________________________________________________________________________________________________
`
`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 Seizures
`5.3
`Interaction with Alcohol
`5.4 Accidental Injury
`5.5 Cardiovascular Events
`
`Reference ID: 3630834
`
`5.6 Angioedema and Hypersensitivity Reactions
`5.7 Serious Skin Reactions
`5.8 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
`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
`*Sections or subsections omitted from the full prescribing information are not
`Medication Guide
`listed.
`_______________________________________________________________________________________________________________________________________
`
`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 Seizures
`17.11 Interaction with Alcohol
`17.12 Driving or Operating Machinery
`17.13 Cardiovascular Events
`17.14 Angioedema
`
`17.15 Serious Skin Reactions
`17.16 Vivid, Unusual, or Strange Dreams
`17.17 Pregnancy and Lactation
`
`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) and Adverse Reactions
`6.2)]
`
`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 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
`
`Reference ID: 3630834
`
`

`

`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. Limited safety data are
`available from post-marketing smoking cessation studies in two patient groups:
`1) patients with major depressive disorder, and 2) patients with stable
`schizophrenia or schizoaffective disorder [see Adverse Reactions (6.1)].
`Some reported neuropsychiatric events, including unusual and sometimes
`aggressive behavior directed to oneself or others, may have been worsened by
`concomitant use of alcohol [see Interaction with Alcohol (5.3), Adverse
`Reactions (6.2)].
`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
`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.
`Since the initial signal of neuropsychiatric symptoms and suicidality
`emerged, additional analyses and studies have been conducted to further
`evaluate this association.
`
`Analyses of clinical trials
`A meta-analysis of 5 randomized, double blind, placebo controlled trials,
`including 1907 patients (1130 CHANTIX, 777 placebo) was conducted to
`assess suicidal ideation and behavior as reported on the Columbia-Suicide
`Severity Rating Scale (C SSRS). This meta-analysis included one trial (N=127)
`in patients with a history of schizophrenia or schizoaffective disorder and
`another trial (N=525) in patients with a history of depression. The results
`showed no increase in the incidence of suicidal ideation and/or behavior in
`patients treated with CHANTIX compared to patients treated with placebo, with
`a Risk Ratio (RR) of 0.79 (95% Confidence Interval [CI]: 0.46 , 1.36), as shown
`in Table 1. Forty-eight (48) of the 55 patients who reported suicidal ideation or
`behavior (24 CHANTIX, 24 placebo) were observed in the two trials that
`enrolled patients with a history of schizophrenia, schizoaffective disorder, or
`depression. Few events were observed in the other three trials (4 CHANTIX, 3
`placebo).
`
`Table 1. Number of patients and Risk Ratio for Suicidal Ideation and/or
`
`
`
`Behavior Reported on C-SSRS from a Meta-Analysis of 5 Clinical Trials
`
`
`
`Comparing CHANTIX to Placebo
`
`
`
`CHANTIX Placebo
`(N=1130)
`(N=777)
`Patients with Suicidal ideation and/or behavior*
`28 (2.5)
`27 (3.5)
`[n (%)]**
`325
`217
`Patient-years of exposure
`Risk Ratio # (RR; 95% CI)
`0.79 (0.46, 1.36)
`
` * Of the events, one patient in each treatment arm reported suicidal behavior
`** Patients with events up to 30 days after treatment; % are not weighted by
`study
`# RR of incidence rates per 100 patient years
`
`A pooled analysis of 18 double-blind, randomized, placebo-controlled
`clinical trials, which includes the 5 trials that collected C-SSRS described in
`Table 1, was conducted to assess the psychiatric safety of CHANTIX. This
`pooled analysis included 8521 patients (5072 CHANTIX, 3449 placebo), some
`of whom had psychiatric conditions at baseline. Table 2 describes the most
`frequently (≥ 1%) reported adverse events related to psychiatric safety. The
`results showed a similar incidence of common psychiatric events in patients
`treated with CHANTIX compared to patients treated with placebo.
`
`Reference ID: 3630834
`
`Table 2. Psychiatric Adverse Events Occurring in ≥ 1% of Patients from
`Pooled Analysis of 18 Clinical Trials
`CHANTIX
`(N=5072)
`253 (5.0)
`179 (3.5)
`116 (2.3)
`
`Anxiety disorders and symptoms
`Depressed mood disorders and disturbances
`Mood disorders and disturbances NEC*
`* NEC = Not Elsewhere Classified
`Counts (percentages) corresponds to the number of patients reporting the event
`
`Placebo
`(N=3449)
`206 (6.0)
`108 (3.1)
`53 (1.5)
`
`Observational Studies
`Four observational studies, each incl