` 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
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`
`
`
`Initial U.S. Approval: 2006
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`
`----------------------------RECENT MAJOR CHANGES-------------------------­
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`
`Boxed Warning-Removed
`12/2016
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`
`
`Dosage and Administration, Usual Dosage for Adults (2.1)
`8/2016
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`
`Warnings and Precautions,
`
`
`
`Neuropsychiatric Adverse Events including Suicidality (5.1)
`
`
`
`Warnings and Precautions, Somnambulism (5.6)
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`----------------------------INDICATIONS AND USAGE--------------------------­
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`CHANTIX is a nicotinic receptor partial agonist indicated for use as an aid to
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`smoking cessation treatment. (1 and 2.1)
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`12/2016
`
`8/2016
`
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`attempt, and completed suicide. Observe patients attempting to quit
`
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`smoking with CHANTIX for the occurrence of such symptoms and
`
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`instruct them to discontinue CHANTIX and contact a healthcare provider
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`if they experience such adverse events. (5.1)
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`• Seizures: New or worsening seizures have been observed in patients taking
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`CHANTIX. CHANTIX should be used cautiously in patients with a
`
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`history of seizures or other factors that can lower the seizure threshold.
`
`(5.2)
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`• Interaction with Alcohol: Increased effects of alcohol have been reported.
`
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`Instruct patients to reduce the amount of alcohol they consume until they
`
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`know whether CHANTIX affects them. (5.3)
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`• Accidental Injury: Accidental injuries (e.g., traffic accidents) have been
`
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`reported. Instruct patients to use caution driving or operating machinery
`
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`
`until they know how CHANTIX may affect them. (5.4)
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`
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`• Cardiovascular Events: A meta-analysis of 15 clinical trials, including a
`
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`
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`trial in patients with stable cardiovascular (CV) disease, demonstrated that
`
`
`
`while cardiovascular events were infrequent overall, some were reported
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`more frequently in patients treated with CHANTIX. These events occurred
`
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`primarily in patients with known cardiovascular disease. In both the
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`clinical trial and meta-analysis, all-cause and cardiovascular mortality was
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`lower in patients treated with CHANTIX. Instruct patients to notify their
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`healthcare providers of new or worsening cardiovascular symptoms and to
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`seek immediate medical attention if they experience signs and symptoms
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`of myocardial infarction (MI) or stroke. (5.5 and 6.1)
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`
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`• Somnambulism: Cases of somnambulism have been reported in patients
`
`
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`
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`taking CHANTIX. Some cases described harmful behavior to self, others,
`
`
`
`or property. Instruct patients to discontinue CHANTIX and notify their
`
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`healthcare provider if they experience somnambulism. (5.6 and 6.2)
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`
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`• 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
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`
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`symptoms occur. (5.7 and 6.2)
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`• Serious Skin Reactions: Rare, potentially life-threatening skin reactions
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`
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`have been reported. Instruct patients to discontinue CHANTIX and contact
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`a healthcare provider immediately at first appearance of skin rash with
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`mucosal lesions. (5.8 and 6.2)
`
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`• Nausea: Nausea is the most common adverse reaction (up to 30%
`
`
`
`
`
`
`incidence rate). Dose reduction may be helpful. (5.9)
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`
`
`
`
`
`
`------------------------------ADVERSE REACTIONS------------------------------­
`Most common adverse reactions (>5% and twice the rate seen in
`
`
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`placebo-treated patients) were nausea, abnormal (e.g., vivid, unusual, or
`
`
`
`
`strange) dreams, constipation, flatulence, and vomiting. (6.1)
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`
`
`To report SUSPECTED ADVERSE REACTIONS, contact Pfizer Inc. at
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`
`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
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`with other smoking cessation therapies has not been established.
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`Coadministration of varenicline and transdermal nicotine resulted in a high
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`rate of discontinuation due to adverse events. (7.1)
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`
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`• Effect of Smoking Cessation on Other Drugs: Pharmacokinetics or
`
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`
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`pharmacodynamics of certain drugs (e.g., theophylline, warfarin, insulin)
`
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`may be altered, necessitating dose adjustment. (7.2)
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`
`----------------------DOSAGE AND ADMINISTRATION----------------------­
`
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`
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`• Begin CHANTIX dosing one week before the date set by the patient to
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`stop smoking. Alternatively, the patient can begin CHANTIX dosing and
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`then quit smoking between days 8 and 35 of treatment. (2.1)
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`• Starting week: 0.5 mg once daily on days 1-3 and 0.5 mg twice daily on
`
`
`
`days 4-7. (2.1)
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`• Continuing Weeks: 1 mg twice daily for a total of 12 weeks. (2.1)
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`• An additional 12 weeks of treatment is recommended for successful
`
`
`
`
`quitters to increase likelihood of long-term abstinence. (2.1)
`
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`• Consider a gradual approach to quitting smoking with CHANTIX for
`
`
`
`patients who are sure that they are not able or willing to quit abruptly.
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`Patients should begin CHANTIX dosing and reduce smoking by 50% from
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`baseline within the first four weeks, by an additional 50% in the next four
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`weeks, and continue reducing with the goal of reaching complete
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`abstinence by 12 weeks. Continue treatment for an additional 12 weeks,
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`for a total of 24 weeks. (2.1)
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`• Severe Renal Impairment (estimated creatinine clearance less than
`
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`30 mL/min): Begin with 0.5 mg once daily and titrate to 0.5 mg twice
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`daily. For patients with end-stage renal disease undergoing hemodialysis, a
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`maximum of 0.5 mg daily may be given if tolerated. (2.2)
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`• Consider dose reduction for patients who cannot tolerate adverse effects.
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`(2.1)
`
`• Another attempt at treatment is recommended for those who fail to stop
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`smoking or relapse when factors contributing to the failed attempt have
`
`
`been addressed. (2.1)
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`• Provide patients with appropriate educational materials and counseling to
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`support the quit attempt. (2.1)
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`
`
`Reference ID: 4029004
`
`
`
`---------------------DOSAGE FORMS AND STRENGTHS---------------------­
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`Tablets: 0.5 mg and 1 mg (3)
`
`-------------------------------CONTRAINDICATIONS-----------------------------­
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`History of serious hypersensitivity or skin reactions to CHANTIX. (4)
`
`-----------------------WARNINGS AND PRECAUTIONS-----------------------­
`
`
`
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`• Neuropsychiatric Adverse Events: Postmarketing reports of serious or
`
`clinically significant neuropsychiatric adverse events have included
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`
`
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`changes in mood (including depression and mania), psychosis,
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`hallucinations, paranoia, delusions, homicidal ideation, aggression,
`
`Revised: 12/2016
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`hostility, agitation, anxiety, and panic, as well as suicidal ideation, suicide
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`_______________________________________________________________________________________________________________________________________
`
`
`See 17 for PATIENT COUNSELING INFORMATION and Medication
`
`
`
`
`Guide
`
`
`

`

`
`
`8.5 Geriatric Use
`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`
`8.6 Renal Impairment
`
`
`
`9 DRUG ABUSE AND DEPENDENCE
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`
`INDICATIONS AND USAGE
`1
`
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`9.1 Controlled Substance
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`2 DOSAGE AND ADMINISTRATION
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`9.3 Dependence
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`2.1 Usual Dosage for Adults
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`10 OVERDOSAGE
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`2.2 Dosage in Special Populations
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`
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`11 DESCRIPTION
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`3 DOSAGE FORMS AND STRENGTHS
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`
`
`12 CLINICAL PHARMACOLOGY
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`4 CONTRAINDICATIONS
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`
`12.1 Mechanism of Action
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`5 WARNINGS AND PRECAUTIONS
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`12.3 Pharmacokinetics
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`5.1 Neuropsychiatric Adverse Events including Suicidality
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`13 NONCLINICAL TOXICOLOGY
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`5.2 Seizures
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`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
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`5.3
`Interaction with Alcohol
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`
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`14 CLINICAL STUDIES
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`
`5.4 Accidental Injury
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`
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`Initiation of Abstinence
`
`14.1
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`5.5 Cardiovascular Events
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`14.2 Urge to Smoke
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`5.6 Somnambulism
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`14.3 Long-Term Abstinence
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`5.7 Angioedema and Hypersensitivity Reactions
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`14.4 Alternative Instructions for Setting a Quit Date
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`5.8 Serious Skin Reactions
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`14.5 Gradual Approach to Quitting Smoking
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`5.9 Nausea
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`14.6 Re-Treatment Study
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`6 ADVERSE REACTIONS
`
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`14.7 Subjects with Cardiovascular and Chronic Obstructive Pulmonary
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`6.1 Clinical Trials Experience
`
`
`Disease
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`6.2 Postmarketing Experience
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`14.8 Subjects with Major Depressive Disorder
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`7 DRUG INTERACTIONS
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`14.9 Postmarketing Neuropsychiatric Safety Outcome Trial
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`7.1 Use with Other Drugs for Smoking Cessation
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`16 HOW SUPPLIED/STORAGE AND HANDLING
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`7.2 Effect of Smoking Cessation on Other Drugs
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`17 PATIENT COUNSELING INFORMATION
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`8 USE IN SPECIFIC POPULATIONS
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`8.1 Pregnancy
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`*Sections or subsections omitted from the full prescribing information are not
`
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`8.2 Lactation
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`listed.
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`8.4 Pediatric Use
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`_______________________________________________________________________________________________________________________________________
`
`Reference ID: 4029004
`
`

`

`
`
`
`
` INDICATIONS AND USAGE
`
`
`DOSAGE AND ADMINISTRATION
`
` FULL PRESCRIBING INFORMATION
`
`1
`
`
`
`
`
`
`
`CHANTIX is indicated for use as an aid to smoking cessation treatment.
`
`2
`
`
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`2.1 Usual Dosage for Adults
`
`
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`
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`
`
`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.
`
`
`
`
`
`
`
`
`
`
`
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`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
`
`
`
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`smoking between days 8 and 35 of treatment.
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`
`CHANTIX should be taken orally after eating and with a full glass of water.
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`The recommended dose of CHANTIX is 1 mg twice daily following a 1-week titration as follows:
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`
` Days 1 – 3:
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`
` Days 4 – 7:
` Day 8 – end of treatment:
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` 0.5 mg once daily
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`
` 0.5 mg twice daily
` 1 mg twice daily
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`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
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`
`
`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
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`to attempt quitting sooner if they feel ready [see Clinical Studies (14.5)].
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`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
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`events or who relapsed after treatment, should be encouraged to make another attempt with CHANTIX once factors contributing to the failed attempt have been
`
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`
`
`identified and addressed.
`
`
`Consider a temporary or permanent dose reduction in patients who cannot tolerate the adverse effects of CHANTIX.
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`2.2 Dosage in Special Populations
`
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`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
`
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`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
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`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
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`Populations (8.6), Clinical Pharmacology (12.3)].
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`Elderly and Patients with Impaired Hepatic Function
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`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
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`in dose selection, and it may be useful to monitor renal function [see Use in Specific Populations (8.5)].
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`DOSAGE FORMS AND STRENGTHS
`
`
`3
`
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`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
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`"Pfizer" on one side and "CHX 1.0" on the other side).
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`
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`CONTRAINDICATIONS
`
`
`4
`
`
`CHANTIX is contraindicated in patients with a known history of serious hypersensitivity reactions or skin reactions to CHANTIX.
`
`
`
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`
`
`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
`
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`withdrawal, including depressed mood. Depression, rarely including suicidal ideation, has been reported in smokers undergoing a smoking cessation attempt without
`
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`medication. However, some of these adverse events occurred in patients taking CHANTIX who continued to smoke.
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`Neuropsychiatric adverse events occurred in patients without and with pre-existing psychiatric disease; some patients experienced worsening of their psychiatric
`
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`illnesses. Some neuropsychiatric adverse events, including unusual and sometimes aggressive behavior directed to oneself or others, may have been worsened by
`
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`
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`concomitant use of alcohol [see Warnings and Precautions (5.3), Adverse Reactions (6.2)]. Observe patients for the occurrence of neuropsychiatric adverse events.
`
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`Advise patients and caregivers that the patient should stop taking CHANTIX and contact a healthcare provider immediately if agitation, depressed mood, or changes in
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`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
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`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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`
`
`Reference ID: 4029004
`
`

`

`
`
`
` 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.
`
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`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,
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`CHANTIX was not associated with an increased incidence of clinically significant neuropsychiatric adverse events in a composite endpoint comprising anxiety,
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`depression, feeling abnormal, hostility, agitation, aggression, delusions, hallucinations, homicidal ideation, mania, panic, and irritability. In the psychiatric cohort, there
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`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
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`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
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`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
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`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,
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`with 0.5% involving psychiatric hospitalization. In placebo-treated patients, serious neuropsychiatric events occurred in 0.6%, with 0.2% requiring psychiatric
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`hospitalization [see Clinical Studies (14.9)].
`
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`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
`
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`
`
`
`
`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
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`
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`patients reported somnolence, dizziness, loss of consciousness or difficulty concentrating that resulted in impairment, or concern about potential impairment, in driving
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`or operating machinery. Advise patients to use caution driving or operating machinery or engaging in other potentially hazardous activities until they know how
`
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`
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`
`
`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
`
`
`
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`
`
`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
`
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`
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`cardiovascular events occurring more frequently in the CHANTIX arm compared to the placebo arm. These events were adjudicated by an independent blinded
`
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`committee. Nonfatal serious cardiovascular events not listed occurred at the same incidence or more commonly in the placebo arm. Patients with more than one
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`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
`
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`
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`management of nonfatal MI and hospitalization for angina.
`
`
`
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`
`
` 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
`
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`A meta-analysis of 15 clinical trials of ≥ 12 weeks treatment duration, including 7002 patients (4190 CHANTIX, 2812 placebo), was conducted to systematically assess
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`
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`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.
`
`
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`
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`The key cardiovascular safety analysis included occurrence and timing of a composite endpoint of Major Adverse Cardiovascular Events (MACE), defined as
`
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`
`
`
`
`
`
`
`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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`Reference ID: 4029004
`
`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
`
`
`
`
`
`
`
`
` 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)
`
`
` 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)
`
`

`

`
` 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.
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`
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`
` 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
`
`
`
`
`
` MACE cases, n (%)
`
` Patient-years of exposure
` Hazard Ratio (95% CI)
`
`
`
`
`
` Placebo
`
` N=2812
`
` 6 (0.21%)
`
` 839
`
`
`
`
`
`
`
`
`
` 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.
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` 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
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`
`
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` endpoints in patients on CHANTIX relative to placebo across different time frames and pre-specified sensitivity analyses, including various study groupings and CV
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`
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` outcomes. Although these findings were not statistically significant they were consistent. Because the number of events was small overall, the power for finding a
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` statistically significant difference in a signal of this magnitude is low.
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`CHANTIX was not studied in patients with unstable cardiovascular disease or cardiovascular events occurring within two months before screening. Patients should be
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`advised to notify a healthcare provider of new or worsening symptoms of cardiovascular disease. The risks of CHANTIX should be weighed against the benefits of its
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`
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`use in smokers with cardiovascular disease. Smoking is an independent and major risk factor for cardiovascular disease. CHANTIX has been demonstrated to increase
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`the likelihood of abstinence from smoking for as long as one year compared to treatment with placebo.
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`5.6 Somnambulism
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`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 [see Adverse Reactions (6.2)].
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`5.7 Angioedema and Hypersensitivity Reactions
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`
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`There have been postmarketing reports of hypersensitivity reactions including angioedema in patients treated with CHANTIX [see Adverse Reactions (6.2), Patient
`
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`Counseling Information (17)]. Clinical signs included swelling of the face, mouth (tongue, lips, and gums), extremities, and neck (throat and larynx). There were
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`
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`infrequent reports of life-threatening angioedema requiring emergent medical attention due to respiratory compromise. Instruct patients to discontinue CHANTIX and
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`immediately seek medical care if they experience these symptoms.
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`5.8 Serious Skin Reactions
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`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
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`at the first appearance of a skin rash with mucosal lesions or any other signs of hypersensitivity.
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`5.9 Nausea
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`Nausea was the most common adverse reaction reported with CHANTIX treatment. Nausea was generally described as mild or moderate and often transient; however,
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`for some patients, it was persistent over several months. The incidence of nausea was dose-dependent. Initial dose-titration was beneficial in reducing the occurrence of
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`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
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`10% 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
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`11% for placebo. Approximately 3% of patients treated with CHANTIX 1 mg twice daily in studies involving 12 weeks of treatment discontinued treatment
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`
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`prematurely because of nausea. For patients with intolerable nausea, a dose reduction should be considered.
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`
`ADVERSE REACTIONS
`
`
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`Neuropsychiatric Adverse Events including Suicidality [see Warnings and Precautions (5.1)]
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`
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`Seizures [see Warnings and Precautions (5.2)]
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`
`Interaction with alcohol [see Warnings and Precautions (5.3)]
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`Accidental injury [see Warnings and Precautions (5.4)]
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`Cardiovascular events [see Warnings and Precautions (5.5)]
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`Somnambulism [see Warnings and Precautions (5.6)]
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`Angioedema and hypersensitivity reactions [see Warnings and Precautions (5.7)]
`
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`Serious skin reactions [see Warnings and Precautions (5.8)]
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`6
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`The following serious adverse reactions were reported in postmarketing experience and are discussed in greater detail in other sections of the labeling:
`
`
`•
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`•
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`•
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`•
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`•
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`•
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`•
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`•
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`In the placebo-controlled premarketing studies, the most common adverse events associated with CHANTIX (>5% and twice the rate seen in placebo-treated patients)
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`were nausea, abnormal (vivid, unusual, or strange) dreams, constipation, flatulence, and vomiting.
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`The treatment discontinuation rate due to adverse events in patients dosed with 1 mg twice daily was 12% for CHANTIX, compared to 10% for placebo in studies of
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`three 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
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`
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`follows: nausea (3% vs. 0.5% for placebo), insomnia (1.2% vs. 1.1% for placebo), and abnormal dreams (0.3% vs. 0.2% for placebo).
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`
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`Smoking cessation, with or without treatment, is associated with nicotine withdrawal symptoms and has also been associated with the exacerbation of underlying
`
`psychiatric illness.
`
`
`Reference ID: 4029004
`
`

`

`
`
` 6.1 Clinical Trials Experience
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`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
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`to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.
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`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.
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`The 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 (5.9)].
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`Table 3 shows the adverse events for CHANTIX and placebo in the 12- week fixed dose premarketing studies with titration in the first week [Studies 2 (titrated arm
`
`
`
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`only), 4, and 5]. Adverse events were categorized using the Medical Dictionary for Regulatory Activities (MedDRA, Version 7.1).
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`MedDRA High Level Group Terms (HLGT) reported in ≥ 5% of patients in the CHANTIX 1 mg twice daily dose group, and more commonly than in the placebo
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`
`
`
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`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
`
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`
`
`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.
`
`
`
`
`
` 5
`
` 1
`
`
`
` 4
`
`
`
`
` 19
` 9
`
`
` 2
`
` 2
`
`
`
` 19
`
`
`
` 8
`
` 3
`
` 2
`
`
`
` 4
`
`
`
` 0
`
` 2
`
` 7
`
`
`
`
`
` 1
`
` 0
`
`
`
`
` 4
`
` 1
`
`
` 8
`
` 1
`
`
`
` 6
`
`
`
`
` 18
`
` 13
` 5
`
`
` 1
`
`
`
` 15
`
`
`
` 5
`
` 3
`
` 1
`
`
`
` 7
`
`
`
` 1
`
` 1
`
` 5
`
`
`
`
`
` 3
`
` 1
`
`
`
`
` 3
`
` 2
`
`
` 3
`
` 0
`
`
`
` 4
`
`
`
`
` 13
` 5
`
`
` 3
`
` 0
`
`
`
` 13
`
`
`
` 4
`
` 2
`
` 0
`
`
`
` 6
`
`
`
` 0
`
` 1
`
` 4
`
`
`
`
`
` 2
`
` 1
`
`
`
`
` 2
`
` 1
`
`
`
`
`
`
`
`
` Table 3: Common Treatment Emergent AEs (%) in the Fixed-Dose, Placebo-Controlled Studies (HLGTs >5% of patients in the 1 mg BID CHANTIX
`Group and more commonly than Placebo and PT ≥ 1% in the 1 mg BID CHANTIX Group, and 1 mg BID CHANTIX at least 0.5% more than Placebo)
`
`
`
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`
`
`
`
`
`
` SYSTEM ORGAN CLASS
` CHANTIX
`
`
` CHANTIX
`
`
` Placebo
`
`
` 0.5 mg BID
`
` 1 mg BID
`
` High Level Group Term
`
`
`
` N=805
` N=129
` N=821
`
` Preferred Term
`
`
`
`
`
` GASTROINTESTINAL (GI)
`
`
`
` GI Signs and Symptoms
`
`
`
`
`
` 16
` 30
` 10
`
`
` Nausea
` 5
` 7
` 5
`
`
`
`
`
` Abdominal Pain *
`
` 9
`
` 6
`
` 3
`
`
` Flatulence
`
` 5
`
` 5
`
` 3
`
`
` Dyspepsia
`
` 1
`
` 5
`
` 2
`
`
` Vomiting
`
`
`
`
` GI Motility/Defecation
`
` Conditions
`
`
`
` Constipation
` Gastroesophageal reflux
`
`
`
` disease
`
` Salivary Gland Conditions
`
`
` Dry mouth
` PSYCHIATRIC DISORDERS
`
`
` Sleep
`
`
` Disorder/Disturbances
`
`
` Insomnia **
`
`
` Abnormal dreams
`
`
` Sleep disorder
`
`
` Nightmare
`
` NERVOUS SYSTEM
`
`
` Headaches
`
`
` Headache
`
` Neurological Disorders
`
`
` NEC
`
`
` Dysgeusia
`
` Somnolence
`
`
`
` Lethargy
`
` GENERAL DISORDERS
`
` General Disorders NEC
`
`
`
` Fatigue/Malaise/Asthenia
`
` RESPIR/THORACIC/MEDIAST
`
`
` Respiratory Disorders NEC
`