`
`
`
`
`
`
`
` CENTER FOR DRUG EVALUATION AND RESEARCH
`
`
`Approval Package for:
`
`
`
`
`
`APPLICATION NUMBER:
`
` 021928Orig1s014
`
`
`
`
`
`
` Trade Name:
`
`
`
`
` CHANTIX
`
` varenicline tartrate
`
`
`
`Generic or
`
`
`Proper Name:
`
` Sponsor:
`
` Approval Date: 04/22/2010
`
` 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-014
`
`
`
`
`
`
`
` 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
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`
` x
`
`
`
`
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`
`
`
`
`
`
` x
`
`
`
` x
`
`

`

`CENTER FOR DRUG EVALUATION AND
`
` CENTER FOR DRUG EVALUATION AND
`
`
`
` RESEARCH
`
`RESEARCH
`
`
`APPLICATION NUMBER:
`
`NDA 021928/S-014
`
`NDA 021928/S-014
`
`
`APPLICA TI0N NUMBER:
`
`
`
`
`
` APPROVAL LETTER
`
`APPROVAL LETTER
`
`
`
`
`
`
`
`
`
`

`

`
`
`
`
`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`
`
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`
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`
`
`
`
`Food and Drug Administration
`
`Silver Spring, MD 20993
`
`
`
`SUPPLEMENT APPROVAL
`
`
`
`
`Lilya I. Donohew, Ph.D.
`Director, Worldwide Regulatory Affairs
`
`
`
`NDA 021928/SLR-014, SLR-017
`
`
`Pfizer, Inc.
`235 East 42nd Street
`Mailstop 605 6 31
`New York, NY 10017
`
`Attention:
`
`
`
`Dear Dr. Donohew:
`
`Please refer to your supplemental new drug applications dated July 20, 2009, and January 14,
`2010, received July 20, 2009, and January 14, 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 submissions dated February 17, 2010 (S-017) and February 25,
`2010 (S-014).
`
`Supplement NDA 021928/S-014 proposes conversion of the content of the currently approved
`package insert into the Physicians Labeling Rule (PLR) format as set forth under 21 CFR 201.56
`and 21 CFR 201.57.
`
`We also refer to the email correspondences between FDA and Pfizer dated March 16, 2010, in
`which agreement was reached on content of the package insert in the PLR format.
`
`Supplement NDA 021928/S-017 provides for a proposed modification to the approved risk
`evaluation and mitigation strategy (REMS) and includes your REMS assessment.
`
`We have completed our review of these 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 for the package insert, Medication Guide and modified REMS.
`
`
`CONTENT OF LABELING
`
`As soon as possible, but no later than 14 days from the date of this letter, please submit the
`content of labeling [21 CFR 314.50(l)(1)(i)] in structured product labeling (SPL) format as
`described at http://www.fda.gov/oc/datacouncil/spl.html that is identical to the enclosed
`labeling text for the package insert and Medication Guide). For administrative purposes, please
`designate this submission, “SPL for approved NDA 21928/S-014 and S-017.
`
`

`

`
`
` NDA 21-928/S-014, S-017
`Page 2
`
`
`
`We request that the revised labeling approved today be available on your website within 10 days
`of receipt of this letter.
`
`We are waiving the requirements of 21 CFR 201.57(d)(8) regarding the length of Highlights of
`prescribing information. This waiver applies to all future supplements containing revised
`labeling unless we notify you otherwise.
`
` RISK EVALUATION AND MITIGATION STRATEGY REQUIREMENTS
`
`The REMS for Chantix (varenicline) was originally approved on October 19, 2009. The REMS
`consists of a Medication Guide and a timetable for submission of assessments of the REMS. The
`proposed modified REMS contains a revised Medication Guide that includes a new section
`“Who should not take Chantix".
`
`Your proposed modified REMS, submitted on January 14, 2010, and appended to this letter, is
`
`approved. The REMS consists of the Medication Guide and the timetable for submission of
`assessments.
`
`The timetable for submission of assessments 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.
`
`If you do not submit electronically, please send 5 copies of REMS-related submissions.
`
` PROMOTIONAL MATERIALS
`
`All promotional materials for your drug product that include representations about your drug
`product must be promptly revised to make it consistent with the labeling changes approved in
`this supplement, including any new safety information [21 CFR 314.70(a)(4)]. The revisions to
`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 following address or
`by facsimile at 301-847-8444:
`
`
`
`
`
`
`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
`
`
`In addition, as required under 21 CFR 314.81(b)(3)(i), you must submit your updated final
`
`promotional materials, and the package insert(s), at the time of initial dissemination or
`
`publication, accompanied by a Form FDA-2253, directly to the above address. For instruction
`on completing the Form FDA 2253, see page 2 of the Form. For more information about
`submission of promotional materials to the Division of Drug Marketing, Advertising, and
`
`

`

`
`
` NDA 21-928/S-014, S-017
`Page 3
`
`
`Communications (DDMAC), see
`
`http://www.fda.gov/AboutFDA/CentersOffices/CDER/ucm090142.htm.
`
`LETTERS TO HEALTH CARE PROFESSIONALS
`
`
`If you decide to issue a letter communicating important safety related information about this drug
`product (i.e., a “Dear Health Care Professional” letter), we request that you at least 24 hours
`prior to issuing the letter, an electronic copy of the letter to this NDA, to
`CDERMedWatchSafetyAlerts@fda.hhs.gov, and to the following address:
`
`
`MedWatch
`
`Food and Drug Administration
`
`5600 Fishers Lane, Room 12B05
`
`Rockville, MD 20857
`
`
`
`
`
`
`
`
`
`
`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, contact Ayanna Augustus, Regulatory Project Manager, at
`ayanna.augustus@fda.hhs.gov or (301) 796-3980.
`
`
`
`
`Sincerely,
`
`{See appended electronic signature page}
`
` MD, MHS
`
` Lapteva,
`
`Larissa
`
`
`
`
`Deputy Director for Safety
`Division of Anesthesia and Analgesia
`Products
`Office of Drug Evaluation II
`Center for Drug Evaluation and Research
`
`
`
`
`
`
`
`
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`
`
`
`Enclosures
`
`1. Package Insert
`
`2. Medication Guide
`
`3. REMS
`
`

`

`Application
`Type/Number
`--------------------
`NDA-21928
`NDA-21928
`
`Submission
`Type/Number
`--------------------
`SUPPL-17
`SUPPL-14
`
`Submitter Name
`
`Product Name
`
`--------------------
`PFIZER INC
`PFIZER INC
`
`------------------------------------------
`CHANTIX
`CHANTIX
`
`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`LARISSA LAPTEVA
`04/22/2010
`
`

`

`CENTER FOR DRUG EVALUATION AND
`
` CENTER FOR DRUG EVALUATION AND
`
`
`
` RESEARCH
`
`RESEARCH
`
`
`APPLICATION NUMBER:
`
`NDA 021928/S-014
`
`NDA 021928/S-014
`
`
`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)
`
`
`• 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-----------------------­
`
`
`• 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)
`
`
`• 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)
`
`• Nausea: Nausea is the most common adverse reaction (up to 30%
`
`incidence rate). Dose reduction may be helpful. (5.5)
`
`
`------------------------------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
`
`
`
`----------------------------RECENT MAJOR CHANGES--------------------------
`Boxed Warning
`7/2009
`
`
`
`
`Contraindications
`3/2010
`
`
`Known Hypersensitivity (4)
` 7/2009
`Warnings and Precautions
`
`
`
`
`Neuropsychiatric Symptoms and Suicidality (5.1), Angioedema and
`
`Hypersensitivity Reactions (5.2), Serious Skin Reactions (5.3),
`Accidental Injury (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)
`
`
`
`----------------------DOSAGE AND ADMINISTRATION-----------------------
`
`
`• Begin CHANTIX dosing one week before the date set by the patient to
`
`
`stop smoking. (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)
`
`_______________________________________________________________________________________________________________________________________
`
`
`
`
`
`
`
`
`
`
`Revised: 04/2010
`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`WARNING: SERIOUS NEUROPSYCHIATRIC EVENTS
`
`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 Symptoms and Suicidality
`5.2 Angioedema and Hypersensitivity Reactions
`5.3 Serious Skin Reactions
`5.4 Accidental Injury
`
`5.5 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
`
`16 HOW SUPPLIED/STORAGE AND HANDLING
`
`17 PATIENT COUNSELING INFORMATION
`Medication Guide
`
`17.1 Set Quit Date 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 Driving or Operating Machinery
`17.13 Vivid, Unusual, or Strange Dreams
`_______________________________________________________________________________________________________________________________________
`
`
`17.14 Pregnancy and Lactation
`
`*Sections or subsections omitted from the full prescribing information are not
`listed.
`
`
`FULL PRESCRIBING INFORMATION
`
`
`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)].
`
`DOSAGE FORMS AND STRENGTHS
`Capsular, biconvex tablets: 0.5 mg (white to off-white, debossed with
`
`
`
`"Pfizer" on one side and "CHX 0.5" on the other side) and 1 mg (light blue,
`debossed with "Pfizer" on one side and "CHX 1.0" on the other side)
`
`
`CONTRAINDICATIONS
`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
`
`illness such as
`psychiatric
`illness.
`Patients with serious psychiatric
`
`
`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
`
`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.
`
`
`
`3
`
`
`4
`
`
`
`
`5.2 Angioedema and Hypersensitivity Reactions
`There have been postmarketing reports of hypersensitivity reactions
`
`
`including angioedema in patients treated with CHANTIX [see Adverse
`
`Reactions (6.2), and Patient Counseling 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
`
`requiring emergent medical attention due
`angioedema
`to
`respiratory
`
`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.
`
`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.
`
`
`

`

`compromise. Instruct patients to discontinue CHANTIX and immediately seek
`medical care ifthey experience these symptoms.
`
`5.3 Serious 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 Adverse Reactions (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 ofa skin rash with
`mucosa! lesions or any other signs ofhypersensitivity.
`
`5.4 Accidental Injm-y
`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 ofconsciousness
`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 Nausea
`Nausea was the most common adverse reaction reported with CHANTIX
`treatment. Nausea was generally described as mild or moderate and often
`transient; however, for some patients, it was persistent over several months. Tue
`incidence of nausea was dose-dependent. Initial dose-titration was beneficial in
`reducing the occurrence of nausea. For patients treated to the maximum
`recommended dose of 1 mg twice daily following initial dosage titration, the
`incidence of nausea was 30% compared with 100/o in patients taking a
`comparable placebo regimen. In patients taking CHANTIX 0.5 mg twice daily
`following initial titration, the incidence was 16% compared with 11% for
`placebo. Approximately 3% of patients treated with CHANTIX 1 mg twice
`daily in studies involving 12 weeks of treatment discontinued treatment
`prematurely because of nausea. For patients with intolerable nausea, a dose
`reduction should be considered.
`
`6
`
`ADVERSE REACTIONS
`The following serious adverse reactions were reported in postmarketing
`experience and are discussed in greater detail in other sections ofthe labeling:
`
`•
`
`•
`
`•
`•
`
`Neuropsychiatric symptoms and suicidality [see Boxed Warning and
`Warnings and Precautions (5.1)
`Angioedema and hypersensitivity reactions [see Warnings and
`Precautions (5.2))
`Serious skin reactions [see Warnings and Precautions (5.3))
`Accidental injury [see Warnings and Precautions (5.4))
`
`In the placebo-controlled studies, the most common adverse events
`associated with CHANTIX (>5% and twice the rate seen in placebo-treated
`patients) were nausea, abnormal (vivid, unusual, or strange) dreams,
`constipation, flatulence, and vomiting.
`The treatment discontinuation rate due to adverse events in patients dosed
`\vith 1 mg twice daily was 12% for CHANTIX, compared to 10% for placebo in
`studies ofthree months' treatment. In this group, the discontinuation rates that
`are higher than placebo for the most common adverse events in CHANTIX­
`treated patients were as follows: nausea (3% vs. 0.5% for placebo), insomnia
`(1.2% vs. 1.1% for placebo), and abnormal dreams (03% vs. 0.2% for placebo) .
`Smoking cessation, \vith or without treatment, is associated with nicotine
`withdrawal symptoms and has also been associated with the exacerbation of
`underlying psychiatric illness.
`
`6.1 Clinical Trials Experience
`Because clinical trials are conducted under widely varying conditions, the
`adverse reactions rates observed in the clinical studies of a drug cannot be
`directly compared to rates in the clinical trials of another drug and may not
`reflect the rates observed in clinical practice.
`During the premarketing development of CHANTIX, over 4500 subjects
`were exposed to CHANTIX. with over 450 treated for at least 24 weeks and
`approximately 100 for a year. Most study participants were treated for 12 weeks
`or less.
`Tue most common adverse event associated with CHANTIX treatment is
`nausea, occurring in 30% of patients treated at the recommended dose,
`compared with 10% in patients taking a comparable placebo regimen [see
`Warnings and Precautions (5.5)}.
`Table 1 shows the adverse events for CHANTIX and placebo in the 12­
`week fixed dose studies with titration in the first week [Studies 2 (titrated arm
`only), 4, and 5]. Adverse events were categorized using the Medical Dictionary
`for Regulatory Activities (MedDRA, Version 7.1) .
`
`MedDRA High Level Group Terms (HLGT) reported in 2:: 5% of patients
`in the CHANTIX 1 mg twice daily dose group, and more commonly than in the
`placebo group, are listed, along with subordinate Preferred Terms (PT) reported
`in:::: 1% of CHANTIX patients (and at least 0.5% more frequent than placebo) .
`Closely related Preferred Terms such as 'Insomnia' , 'Initial insomnia' , 'Middle
`insomnia', ·Early morning awakening' were grouped, but individual patients
`reporting two or more grouped events are only counted once.
`
`Table 1: Common T1·eatment Eme1·gent AEs (%)in the Fixed-Dose,
`Placebo-Controlled Studies ~ 1% in the 1 mg BID CHANTIX Group, and
`1 mg BID CHANT IX at least 0.5% mo1·e than Placebo)
`
`SYSTEM ORGAN CLASS
`High Level Group Term
`Preferred T erm
`GASTROINTESTINAL (GI)
`GI Signs and Symptoms
`Nausea
`Abdominal Pain •
`Flatulence
`Dyspepsia
`Vomiting
`GI Motility/Defecation
`Conditions
`Constipation
`Gastroesophageal reflux
`disease
`Salivary Gland Conditions
`Drvmouth
`PSYCHIATRIC
`DISORDERS
`Sleep
`Disorder/Disturbances
`Insomnia 0
`Abnormal dreams
`Sleep disorder
`Ni!!htmare
`NERVOUS SYSTEM
`Headaches
`Headache
`Neurological Disorders
`NEC
`Dysgeusia
`Somnolence
`Letharirv
`GENERAL DISORDERS
`General Disorders NEC
`F ati011,,/Malaise/ Asthenia
`RESPIR!IHORACIC/MEDI
`AST
`Respiratory Disorders NEC
`Rhinorrhea
`Dyspnea
`Upper Respiratory Tract
`Disorder
`SKIN/SUBCUTANEOUS
`TISSUE
`Epidermal and Dermal
`Conditions
`Rash
`Pruritis
`METABOLISM&
`NUTRITION
`Appetite/General Nutrit.
`Disorders
`Increased appetite
`Decreased appetite/
`Anorexia
`
`CHANTIX
`0.5 mgBID
`N=l29
`
`CHANTIX
`1 mg BID
`N=821
`
`Placebo
`
`N=805
`
`16
`5
`9
`5
`1
`
`5
`I
`
`4
`
`19
`9
`2
`2
`
`19
`
`8
`3
`2
`
`4
`
`0
`2
`7
`
`1
`0
`
`4
`1
`
`30
`7
`6
`5
`5
`
`8
`I
`
`6
`
`18
`13
`5
`I
`
`15
`
`5
`3
`I
`
`7
`
`1
`1
`5
`
`3
`1
`
`3
`2
`
`10
`5
`3
`3
`2
`
`3
`0
`
`4
`
`13
`5
`3
`0
`
`13
`
`4
`2
`0
`
`6
`
`0
`1
`4
`
`2
`1
`
`2
`1
`
`* Includes PTs Abdominal (pain, pain upper, pain lower, discomfort,
`tenderness, distension) and Stomach discomfort
`**Includes PTs Insomnia/Initial insomnia/Middle insomnia/Early morning
`awakening
`
`The overall pattern and frequency of adverse events during the longer­
`tenn trials was similar to those described in Table I , though several of the most
`common events were reported by a greater proportion of patients with Jong-term
`
`

`

` use (e.g., nausea was reported in 40% of patients treated with CHANTIX 1 mg
`
`twice daily in a one-year study, compared to 8% of placebo-treated patients).
`
`Following is a list of treatment-emergent adverse events reported by
`
`patients treated with CHANTIX during all clinical trials. The listing does not
`include those events already listed in the previous tables or elsewhere in
`labeling, those events for which a drug cause was remote, those events which
`were so general as to be uninformative, and those events reported only once
`which did not have a substantial probability of being acutely life-threatening.
`
`Infrequent
`
`and Lymphatic System Disorders.
`Blood
`anemia,
`lymphadenopathy. Rare leukocytosis, splenomegaly, thrombocytopenia.
`
`
`
`
`Cardiac Disorders. Infrequent angina pectoris, arrhythmia, bradycardia,
`
`myocardial infarction, palpitations, tachycardia, ventricular extrasystoles. Rare
`
`
`acute coronary syndrome, atrial fibrillation, cardiac flutter, cor pulmonale,
`coronary artery disease.
`
`Ear and Labyrinth Disorders. Infrequent tinnitus, vertigo. Rare deafness,
`
`
`
`
`Meniere’s disease.
`
`Endocrine Disorders. Infrequent thyroid gland disorders.
`
`
`
`Eye Disorders. Infrequent conjunctivitis, dry eye, eye irritation, eye pain,
`
`vision blurred, visual disturbance. Rare acquired night blindness