`
`
`-------------------------------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 (CV) disease, demonstrated that
`
`
`
`while cardiovascular events were infrequent overall, some were reported
`
`more frequently in patients treated with CHANTIX. These events occurred
`
`
`
`
`
`primarily in patients with known cardiovascular disease. In both the
`
`
`
`
`clinical trial and meta-analysis, all-cause and cardiovascular mortality was
`
`
`
`lower in patients treated with CHANTIX. Instruct patients to notify their
`
`
`
`
`
`
`
`healthcare providers of new or worsening cardiovascular symptoms and to
`
`
`seek immediate medical attention if they experience signs and symptoms
`
`
`
`
`of myocardial infarction (MI) or stroke. (5.5 and 6.1)
`
`
`
`
`
`
`• Somnambulism: Cases of somnambulism have been reported in patients
`
`
`
`
`
`taking CHANTIX. Some cases described harmful behavior to self, others,
`
`
`
`or property. Instruct patients to discontinue CHANTIX and notify their
`
`
`
`
`
`
`healthcare provider if they experience somnambulism. (5.6 and 6.2)
`
`
`
`• Angioedema and Hypersensitivity Reactions: Such reactions, including
`
`
`
`
`angioedema, infrequently life-threatening, have been reported. Instruct
`
`
`
`patients to discontinue CHANTIX and immediately seek medical care if
`
`
`
`symptoms occur. (5.7 and 6.2)
`
`
`• Serious Skin Reactions: Rare, potentially life-threatening skin reactions
`
`
`
`
`
`
`have been reported. Instruct patients to discontinue CHANTIX and contact
`
`
`
`
`a healthcare provider immediately at first appearance of skin rash with
`
`mucosal lesions. (5.8 and 6.2)
`
`
`• Nausea: Nausea is the most common adverse reaction (up to 30%
`
`
`
`
`
`
`incidence rate). Dose reduction may be helpful. (5.9)
`
`
`
`
`
`
`
`
`
`------------------------------ADVERSE REACTIONS------------------------------­
`Most common adverse reactions (>5% and twice the rate seen in
`
`
`
`
`placebo-treated patients) were nausea, abnormal (e.g., vivid, unusual, or
`
`
`
`
`strange) dreams, constipation, flatulence, and vomiting. (6.1)
`
`
`
`To report SUSPECTED ADVERSE REACTIONS, contact Pfizer Inc. at
`
`
`1-800-438-1985 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
`
`
`
`
`
`------------------------------DRUG INTERACTIONS------------------------------­
`• Other Smoking Cessation Therapies: Safety and efficacy in combination
`
`
`
`
`
`
`
`with other smoking cessation therapies has not been established.
`
`
`
`Coadministration of varenicline and transdermal nicotine resulted in a high
`
`
`
`
`
`rate of discontinuation due to adverse events. (7.1)
`
`
`
`• Effect of Smoking Cessation on Other Drugs: Pharmacokinetics or
`
`
`
`
`
`pharmacodynamics of certain drugs (e.g., theophylline, warfarin, insulin)
`
`
`may be altered, necessitating dose adjustment. (7.2)
`
`
`
`
`
`
`See 17 for PATIENT COUNSELING INFORMATION and Medication
`
`
`Guide
`
`
`
`
`
`
`
`
`
`
`Revised: 08/2016
`
`
`
`----------------------DOSAGE AND ADMINISTRATION----------------------­
`• Begin CHANTIX dosing one week before the date set by the patient to
`
`
`
`
`
`stop smoking. Alternatively, the patient can begin CHANTIX dosing and
`
`
`
`
`
`then quit smoking between days 8 and 35 of treatment. (2.1)
`
`
`
`
`• Starting week: 0.5 mg once daily on days 1-3 and 0.5 mg twice daily on
`
`
`
`
`
`
`
`
`
`
`days 4-7. (2.1)
`
`
`• Continuing Weeks: 1 mg twice daily for a total of 12 weeks. (2.1)
`
`
`
`
`
`
`• An additional 12 weeks of treatment is recommended for successful
`
`
`
`
`quitters to increase likelihood of long-term abstinence. (2.1)
`
`• Consider a gradual approach to quitting smoking with CHANTIX for
`
`
`
`patients who are sure that they are not able or willing to quit abruptly.
`
`
`Patients should begin CHANTIX dosing and reduce smoking by 50% from
`
`
`
`baseline within the first four weeks, by an additional 50% in the next four
`
`
`
`
`
`
`
`weeks, and continue reducing with the goal of reaching complete
`
`
`
`
`abstinence by 12 weeks. Continue treatment for an additional 12 weeks,
`
`
`
`
`for a total of 24 weeks. (2.1)
`
`
`• Severe Renal Impairment (estimated creatinine clearance less than
`
`
`
`
`30 mL/min): Begin with 0.5 mg once daily and titrate to 0.5 mg twice
`
`
`
`
`
`
`
`daily. For patients with end-stage renal disease undergoing hemodialysis, a
`
`
`maximum of 0.5 mg daily may be given if tolerated. (2.2)
`
`
`• Consider dose reduction for patients who cannot tolerate adverse effects.
`
`
`
`
`
`(2.1)
`
`• Another attempt at treatment is recommended for those who fail to stop
`
`
`smoking or relapse when factors contributing to the failed attempt have
`
`
`
`
`been addressed. (2.1)
`
`
`• Provide patients with appropriate educational materials and counseling to
`
`
`
`support the quit attempt. (2.1)
`
`
`
`
`
` HIGHLIGHTS OF PRESCRIBING INFORMATION
` These highlights do not include all the information needed to use
`
`
`
` CHANTIX safely and effectively. See full prescribing information for
`
` CHANTIX.
`
`CHANTIX® (varenicline) tablets, for oral use
`
`
`
`
`Initial U.S. Approval: 2006
`
`
`
`
`
`
`WARNING: SERIOUS NEUROPSYCHIATRIC EVENTS
`See full prescribing information for complete boxed warning.
`
`
`
`
`
`• Serious neuropsychiatric events have been reported in patients taking
`
`
`
`
`CHANTIX. (5.1 and 6.2)
`
`
`
`• Advise patients and caregivers that the patient should stop taking
`
`
`
`
`
`CHANTIX and contact a healthcare provider immediately if agitation,
`
`
`
`
`hostility, depressed mood, or changes in behavior or thinking that are
`
`not typical for the patient are observed, or if the patient develops
`
`
`
`suicidal ideation or suicidal behavior while taking CHANTIX or
`
`
`
`shortly after discontinuing CHANTIX. (5.1 and 6.2)
`
`
`
`• Weigh the risks of CHANTIX against benefits of its use. CHANTIX
`
`
`
`has been demonstrated to increase the likelihood of abstinence from
`
`
`
`smoking for as long as one year compared to treatment with placebo.
`
`
`The health benefits of quitting smoking are immediate and
`
`substantial. (5.1 and 6.2)
`
`
`
`
`
`
`
`----------------------------RECENT MAJOR CHANGES-------------------------­
`
`Dosage and Administration, Usual Dosage for Adults (2.1)
`8/2016
`
`
`
`Warnings and Precautions, Somnambulism (5.6)
`8/2016
`
`
`
`
`----------------------------INDICATIONS AND USAGE--------------------------­
`CHANTIX is a nicotinic receptor partial agonist indicated for use as an aid to
`
`
`
`
`
`
`
`smoking cessation treatment. (1 and 2.1)
`
`
`
`
`
`
`
`
`
`---------------------DOSAGE FORMS AND STRENGTHS---------------------­
`
`Tablets: 0.5 mg and 1 mg (3)
`
`
`
`_______________________________________________________________________________________________________________________________________
`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`
`WARNING: SERIOUS NEUROPSYCHIATRIC EVENTS
`
`1
`INDICATIONS AND USAGE
`
`
`2 DOSAGE AND ADMINISTRATION
`
`
`2.1 Usual Dosage for Adults
`
`
`2.2 Dosage in Special Populations
`
`
`3 DOSAGE FORMS AND STRENGTHS
`
`
`4 CONTRAINDICATIONS
`
`
`5 WARNINGS AND PRECAUTIONS
`
`
`5.1 Neuropsychiatric Symptoms and Suicidality
`
`
`
`Reference ID: 3971721
`
`5.2 Seizures
`
`
`5.3
`Interaction with Alcohol
`
`
`
`5.4 Accidental Injury
`
`
`5.5 Cardiovascular Events
`
`
`5.6 Somnambulism
`
`
`5.7 Angioedema and Hypersensitivity Reactions
`
`
`5.8 Serious Skin Reactions
`
`
`
`5.9 Nausea
`
`
`6 ADVERSE REACTIONS
`
`
`6.1 Clinical Trials Experience
`
`
`
`6.2 Postmarketing Experience
`
`
`
`

`

`
`
`
`
`
`
`
`
`
`
`
`
` The patient should set a date to stop smoking. Begin CHANTIX dosing one
`
` week before this date. Alternatively, the patient can begin CHANTIX dosing
`
`
`
`
` and then quit smoking between days 8 and 35 of treatment.
`
`
`
`
`
` CHANTIX should be taken orally after eating and with a full glass of water.
`
`The recommended dose of CHANTIX is 1 mg twice daily following a 1-week
`
`
`
`
`titration as follows:
`
`
`
`
`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
`8.2 Lactation
`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
`_____________________________________________________________
`
`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), Adverse Reactions (6.2)].
`
`
`
`
`
`
`1
`
`
`CHANTIX is indicated for use as an aid to smoking cessation treatment.
`
`
`
`
`
`
`2
`
`
`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.
`
`
`
`
`DOSAGE AND ADMINISTRATION
`
`
`INDICATIONS AND USAGE
`
`
`Reference ID: 3971721
`
`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 Alternative Instructions for Setting a Quit Date
`14.5 Gradual Approach to Quitting Smoking
`14.6 Re-Treatment Study
`14.7 Subjects with Cardiovascular and Chronic Obstructive Pulmonary
`Disease
`14.8 Subjects with Major Depressive Disorder
`16 HOW SUPPLIED/STORAGE AND HANDLING
`17 PATIENT COUNSELING INFORMATION
`
`*Sections or subsections omitted from the full prescribing information are not
`listed.
`__________________________________________________________________________
`
`
`
`
`
`
`
` Days 1 – 3:
`
`
`
` Days 4 – 7:
` Day 8 – end of treatment:
`
`
`
`
`
`
`
` 0.5 mg once daily
` 0.5 mg twice daily
`
`
` 1 mg twice daily
`
`
`
`
`
`
`
`
`Patients should be treated with CHANTIX for 12 weeks. For patients who have
`
`
`
`
`successfully stopped smoking at the end of 12 weeks, an additional course of 12
`
`
`
`weeks treatment with CHANTIX is recommended to further increase the
`
`likelihood of long-term abstinence.
`
`
`
`
`
`
`
`For patients who are sure that they are not able or willing to quit abruptly,
`
`
`
`consider a gradual approach to quitting smoking with CHANTIX. Patients
`should begin CHANTIX dosing and reduce smoking by 50% from baseline
`
`
`
`
`within the first four weeks, by an additional 50% in the next four weeks, and
`
`
`
`
`continue reducing with the goal of reaching complete abstinence by 12 weeks.
`
`
`
`Continue CHANTIX treatment for an additional 12 weeks, for a total of
`
`
`
`
`
`24 weeks of treatment. Encourage patients to attempt quitting sooner if they feel
`
`
`
`
`ready [see Clinical Studies (14.5)].
`
`
`
`
`Patients who are motivated to quit, and who did not succeed in stopping
`
`
`
`
`smoking during prior CHANTIX therapy for reasons other than intolerability
`
`
`
`
`due to adverse events or who relapsed after treatment, should be encouraged to
`
`
`
`
`make another attempt with CHANTIX once factors contributing to the failed
`
`
`
`attempt have been identified and addressed.
`
`
`
`Consider a temporary or permanent dose reduction in patients who cannot
`
`
`
`
`tolerate the adverse effects of CHANTIX.
`
`
`2.2 Dosage in Special Populations
`
`
`
`
`Patients with Impaired Renal Function
`
`
`No dosage adjustment is necessary for patients with mild to moderate renal
`
`
`impairment. For patients with severe renal impairment (estimated creatinine
`
`clearance less than 30 mL per min), the recommended starting dose of
`
`
`
`
`
`CHANTIX is 0.5 mg once daily. The dose may then be titrated as needed to a
`
`
`
`
`maximum dose of 0.5 mg twice daily. For patients with end-stage renal disease
`
`
`
`undergoing hemodialysis, a maximum dose of 0.5 mg once daily may be
`
`
`administered if tolerated [see Use in Specific Populations (8.6), Clinical
`
`
`
`
`
`Pharmacology (12.3)].
`
`
`
`Elderly and Patients with Impaired Hepatic Function
`
`
`No dosage adjustment is necessary for patients with hepatic impairment.
`
`
`
`Because elderly patients are more likely to have decreased renal function, care
`
`should be taken in dose selection, and it may be useful to monitor renal function
`
`
`
`
`[see Use in Specific Populations (8.5)].
`
`
`
`DOSAGE FORMS AND STRENGTHS
`
`
`3
`
`
`
`

`

` 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
`
`
`4
`
`
`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, Adverse Reactions (6.2)]. These
`
`
`
`postmarketing reports have included changes in mood (including depression and
`
`
`
`
`mania), psychosis, hallucinations, paranoia, delusions, homicidal ideation,
`
`
`
`
`hostility, agitation, anxiety, and panic, as well as suicidal ideation, suicide
`
`
`attempt, and completed suicide. Some reported cases may have been
`
`complicated by the symptoms of nicotine withdrawal in patients who stopped
`
`
`smoking. Depressed mood may be a symptom of nicotine withdrawal.
`Depression, rarely including suicidal ideation, has been reported in smokers
`
`
`
`
`undergoing a smoking cessation attempt without medication. However, some of
`
`these symptoms have occurred in patients taking CHANTIX who continued to
`
`
`
`smoke. When symptoms were reported, most were during CHANTIX treatment,
`
`
`
`but some were following discontinuation of CHANTIX therapy.
`
`
`These events have occurred in patients with and without pre-existing psychiatric
`
`
`
`
`disease; some patients have experienced worsening of their psychiatric illnesses.
`
`
`
`All patients being treated with CHANTIX should be observed for
`
`
`
`
`neuropsychiatric symptoms or worsening of pre-existing psychiatric illness.
`
`
`Patients with serious psychiatric illness such as schizophrenia, bipolar disorder,
`
`
`
`and major depressive disorder did not participate in the premarketing studies of
`
`
`
`CHANTIX. Limited safety data are available from postmarketing 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), Clinical Studies (14.8)].
`
`
`
`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 Warnings and Precautions (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).
`
`
`
`Reference ID: 3971721
`
`
`
`
`
`
`
`
`
`
`
`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
`
`
` Placebo
`
` CHANTIX
`
` (N=777)
`
` (N=1130)
` Patients with Suicidal ideation and/or behavior*
`
` 27 (3.5)
`
` 28 (2.5)
`
` [n (%)]**
`
`
` 217
`
` 325
`
`
` 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.
`
`
`
`
`
`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)
`
`
`
` Placebo
`
`
` (N=3449)
`
` 206 (6.0)
`
` 108 (3.1)
` 53 (1.5)
`
`
`
`
`
`
`
` 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
`
`
` Observational Studies
`
`Four observational studies, each including 10,000 to 30,000 users of CHANTIX
`
`
`
`
`in the adjusted analyses, compared the risk of selected serious neuropsychiatric
`
`
`
`
`events (neuropsychiatric hospitalizations, fatal and non-fatal self-harm),
`
`
`between CHANTIX users and prescription NRT or bupropion users. All studies
`
`
`
`
`were retrospective cohort studies and included patients with and without a
`
`
`psychiatric history.
`
`
`Two of the studies found no difference in risk of neuropsychiatric
`
`
`hospitalizations between CHANTIX users and nicotine patch users (Hazard
`
`
`
`
`
`Ratio [HR] 1.14; 95% Confidence Interval [CI]: 0.56–2.34 in the first study, and
`
`
`
`
`
`0.76; 95% CI: 0.40-1.46 in the second study). However, neither study validated
`
`
`
`the diagnostic codes used to identify outcomes against medical records. A third
`
`
`
`
`
`study reported no difference in risk of psychiatric adverse events diagnosed
`
`
`
`during an emergency department visit or inpatient admission between
`
`
`
`CHANTIX users and bupropion users (HR 0.85; 95% CI: 0.55-1.30). Bupropion
`
`
`
`
`
`has also been associated with neuropsychiatric adverse events. A fourth study
`
`
`
`
`examined risk of fatal and non-fatal self-harm in users of CHANTIX compared
`
`
`
`
`to users of NRT. Although the occurrence of detected suicide was rare during
`
`
`the three months after patients initiated any drug treatment (two cases in 31,260
`
`
`
`
`CHANTIX users and six cases in 81,545 NRT users), this study has important
`
`
`
`
`
`limitations. Most importantly, these data were captured following public
`
`
`awareness of reports of neuropsychiatric adverse events in CHANTIX users.
`
`
`CHANTIX users had fewer comorbid conditions that could put them at risk for
`
`
`
`neuropsychiatric adverse events, suggesting that patients with a history of
`
`
`
`
`neuropsychiatric illness were preferentially prescribed NRT, and healthier
`
`
`
`patients were preferentially prescribed CHANTIX.
`
`
`
`Outcomes examined in these studies did not include the full range of
`
`
`
`
`neuropsychiatric adverse events that have been reported.
`
`
`
`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 post-marketing reports of patients experiencing increased
`
`intoxicating effects of alcohol while taking CHANTIX. Some cases described
`
`
`
`
`
`unusual and sometimes aggressive behavior, and were often accompanied by
`
`
`
`
`amnesia for the events. Advise patients to reduce the amount of alcohol they
`
`
`
`
`consume while taking CHANTIX until they know whether CHANTIX affects
`their tolerance for alcohol [see Adverse Reactions (6.2)].
`
`
`
`
`
`
`5.4 Accidental Injury
`
`
`
`There have been postmarketing reports of traffic accidents, near-miss incidents
`
`
`
`
`in traffic, or other accidental injuries in patients taking CHANTIX. In some
`
`cases, the patients reported somnolence, dizziness, loss of consciousness or
`
`
`
`
`difficulty concentrating that resulted in impairment, or concern about potential
`
`
`
`impairment, in driving or operating machinery. Advise patients to use caution
`
`
`
`
`driving or operating machinery or engaging in other potentially hazardous
`
`activities until they know how CHANTIX may affect them.
`
`
`
`5.5 Cardiovascular Events
`
`
`
`
`
`In a placebo-controlled clinical trial of CHANTIX administered to patients with
`
`
`
`
`stable cardiovascular disease, with approximately 350 patients per treatment
`
`
`arm, all-cause and cardiovascular mortality was lower in patients treated with
`
`CHANTIX, but certain nonfatal cardiovascular events occurred more frequently
`
`in patients treated with CHANTIX than in patients treated with placebo [see
`
`
`
`
`
`
`
`Adverse Reactions (6.1)]. Table 3 below shows the incidence of deaths and of
`
`
`
`
`
`
`
`
`
`selected nonfatal serious cardiovascular events occurring more frequently in the
`
`
`CHANTIX arm compared to the placebo arm. These events were adjudicated by
`
`
`
`
`an independent blinded committee. Nonfatal serious cardiovascular events not
`
`
`listed occurred at the same incidence or more commonly in the placebo arm.
`
`
`
`Patients with more than one cardiovascular event of the same type are counted
`
`
`only once per row. Some of the patients requiring coronary revascularization
`
`
`
`underwent the procedure as part of management of nonfatal MI and
`
`hospitalization for angina.
`
`
`
`
`
`Table 3. Mortality and Adjudicated Nonfatal Serious Cardiovascular
`
`
`
`Events in the Placebo-Controlled CHANTIX Trial in Patients with Stable
`
`
`Cardiovascular Disease
`
`
`
` CHANTIX
`
` (N=353)
`
` n (%)
`
`
` Placebo
`
` (N=350)
`
` n (%)
`
`
` 1 (0.3)
`
` 2 (0.6)
`
`
`
` 5 (1.4)
`
`
` 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)
`
`
`
`Mortality and Cardiovascular Events
`
`
` Mortality (Cardiovascular & All-cause up to 52 wks)
` Cardiovascular death
`
`
` All-cause mortality
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` Nonfatal Cardiovascular Events (rate on CHANTIX > Placebo)
`
`
`
` Up to 30 days after treatment
`
`
` Nonfatal myocardial infarction
` 4 (1.1)
`
`
` 2 (0.6)
`
` Nonfatal Stroke
`
` Beyond 30 days after treatment & up
`
`
` to 52 weeks
`
` Nonfatal myocardial infarction
` 3 (0.8)
`
` Need for coronary
`
` 7 (2.0)
`
` revascularization
`
`
` Hospitalization for angina pectoris
`
` 6 (1.7)
`
` Transient ischemia attack
`
` 1 (0.3)
` New diagnosis of peripheral
`
`vascular disease (PVD) or
`
` admission for a PVD procedure
`
`
`
`A meta-analysis of 15 clinical trials of ≥ 12 weeks treatment duration, including
`
`
`
`
`7002 patients (4190 CHANTIX, 2812 placebo), was conducted to
`
`
`
`systematically assess the cardiovascular safety of CHANTIX. The study in
`
`
`patients with stable cardiovascular disease described above was included in the
`
`
`
`
`meta-analysis. There were lower rates of all-cause mortality (CHANTIX 6
`
`
`
`
`
`[0.14%]; placebo 7 [0.25%]) and cardiovascular mortality (CHANTIX 2
`
`
`
`
`
`[0.05%]; placebo 2 [0.07%]) in the CHANTIX arms compared with the placebo
`
`
`
`
`arms in the meta-analysis.
`
`
`
`The key cardiovascular safety analysis included occurrence and timing of a
`
`
`
`
`
`
`composite endpoint of Major Adverse Cardiovascular Events (MACE), defined
`
`
`
`as cardiovascular death, nonfatal MI, and nonfatal stroke. These events included
`
`
`
`
`in the endpoint were adjudicated by a blinded, independent committee. Overall,
`
`
`
`
`a small number of MACE occurred in the trials included in the meta-analysis, as
`
`
`
`
`described in Table 4. These events occurred primarily in patients with known
`
`
`
`
`cardiovascular disease.
`
`
`Reference ID: 3971721
`
`
`Table 4. Number of MACE cases, Hazard Ratio and Rate Difference in a
`
`
`
`
`
`
`
`
`
`
`Meta-Analysis of 15 Clinical Trials Comparing CHANTIX to Placebo*
`
` CHANTIX
`
`
`
` Placebo
`
`
`
` N=2812
`
` N=4190
`
` 13 (0.31%)
`
` 6 (0.21%)
`
`
`
`
`
`
`
`
`
` 1316
`
`
`
`
` 839
`
`
`
`
`
`
` MACE cases, n (%)
`
`
`
`Patient-years of
`
`
` exposure
`
`
` Hazard Ratio (95% CI)
`
` 1.95 (0.79, 4.82)
`
`
`
`
`
` Rate Difference per 1,000 patient-years (95% CI)
`
` 6.30 (-2.40, 15.10)
`
`
`
`*Includes MACE occurring up to 30 days post-treatment.
`
`
`
`
`
`The meta-analysis showed that exposure to CHANTIX resulted in a hazard ratio
`
`for MACE of 1.95 (95% confidence interval from 0.79 to 4.82) for patients up
`
`
`
`
`to 30 days after treatment; this is equivalent to an estimated increase of 6.3
`
`
`
`MACE events per 1,000 patient-years of exposure. The meta-analysis showed
`
`
`
`higher rates of CV endpoints in patients on CHANTIX relative to placebo
`
`
`
`
`across different time frames and pre-specified sensitivity analyses, including
`
`
`
`various study groupings and CV outcomes. Although these findings were not
`
`
`statistically significant they were consistent. Because the number of events was
`
`
`
`
`
`small overall, the power for finding a statistically significant difference in a
`
`
`
`
`signal of this magnitude is low.
`
`
`
`CHANTIX was not studied in patients with unstable cardiovascular disease or
`
`
`
`
`
`cardiovascular events occurring within two months before screening. Patients
`
`
`should be 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 use in smokers with cardiovascular disease. Smoking
`
`
`
`
`
`
`is an independent and major risk factor for cardiovascular disease. CHANTIX
`
`
`has been demonstrated to increase the likelihood of abstinence from smoking
`
`
`
`
`for as long as one year compared to treatment with placebo.
`
`
`
`
`
`5.6 Somnambulism
`
`
`
`
`
`Cases of somnambulism have been reported in patients taking CHANTIX.
`Some cases described harmful behavior to self, others, or property. Instruct
`
`
`
`
`
`patients to discontinue CHANTIX and notify their healthcare provider if they
`
`
`
`
`experience somnambulism [see Adverse Reactions (6.2)].
`
`
`
`5.7 Angioedema and Hypersensitivity Reactions
`
`
`
`
`There have been postmarketing reports of hypersensitivity reactions including
`
`
`angioedema in patients treated with CHANTIX [see Adverse Reactions (6.2),
`
`
`
`
`
`Patient Counseling Information (17)]. Clinical signs included swelling of the
`
`face, mouth (tongue, lips, and gums), extre