attempt, and completed suicide. Observe patients attempting to quit
`smoking with CHANTIX for the occurrence of such symptoms and
`instruct them to discontinue CHANTIX and contact a healthcare provider
`if they experience such adverse events. (5.1)
` Seizures: New or worsening seizures have been observed in patients taking
`CHANTIX. CHANTIX should be used cautiously in patients with a
`history of seizures or other factors that can lower the seizure threshold.
`(5.2)
` Interaction with Alcohol: Increased effects of alcohol have been reported.
`Instruct patients to reduce the amount of alcohol they consume until they
`know whether CHANTIX affects them. (5.3)
` Accidental Injury: Accidental injuries (e.g., traffic accidents) have been
`reported. Instruct patients to use caution driving or operating machinery
`until they know how CHANTIX may affect them. (5.4)
` Cardiovascular Events: Patients with underlying cardiovascular (CV)
`disease may be at increased risk of CV events; however, these concerns
`must be balanced with the health benefits of smoking cessation. Instruct
`patients to notify their healthcare providers of new or worsening CV
`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)
`
`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)
`
`
`HIGHLIGHTS OF PRESCRIBING INFORMATION
`These highlights do not include all the information needed to use
`CHANTIX safely and effectively. See full prescribing information for
`CHANTIX.
`
`CHANTIX® (varenicline) tablets, for oral use
`Initial U.S. Approval: 2006
`
`----------------------------RECENT MAJOR CHANGES--------------------------
`Warnings and Precautions, Cardiovascular Events (5.5)
`6/2018
`
`----------------------------INDICATIONS AND USAGE---------------------------
`CHANTIX is a nicotinic receptor partial agonist indicated for use as an aid to
`smoking cessation treatment. (1 and 2.1)
`
`
`----------------------DOSAGE AND ADMINISTRATION-----------------------
` Begin CHANTIX dosing one week before the date set by the patient to
`stop smoking. Alternatively, the patient can begin CHANTIX dosing and
`then quit smoking between days 8 and 35 of treatment. (2.1)
` Starting Week: 0.5 mg once daily on days 1-3 and 0.5 mg twice daily on
`days 4-7. (2.1)
` Continuing Weeks: 1 mg twice daily for a total of 12 weeks. (2.1)
` An additional 12 weeks of treatment is recommended for successful
`quitters to increase likelihood of long-term abstinence. (2.1)
` Consider a gradual approach to quitting smoking with CHANTIX for
`patients who are sure that they are not able or willing to quit abruptly.
`Patients should begin CHANTIX dosing and reduce smoking by 50% from
`baseline within the first four weeks, by an additional 50% in the next four
`weeks, and continue reducing with the goal of reaching complete
`abstinence by 12 weeks. Continue treatment for an additional 12 weeks,
`for a total of 24 weeks. (2.1)
` Severe Renal Impairment (estimated creatinine clearance less than
`30 mL/min): Begin with 0.5 mg once daily and titrate to 0.5 mg twice
`daily. For patients with end-stage renal disease undergoing hemodialysis, a
`maximum of 0.5 mg daily may be given if tolerated. (2.2)
` Consider dose reduction for patients who cannot tolerate adverse effects.
`(2.1)
` Another attempt at treatment is recommended for those who fail to stop
`smoking or relapse when factors contributing to the failed attempt have
`been addressed. (2.1)
` Provide patients with appropriate educational materials and counseling to
`support the quit attempt. (2.1)
`
`
`
`Reference ID: 4394346
`
`
`---------------------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------------------------
` Neuropsychiatric Adverse Events: Postmarketing reports of serious or
`clinically significant neuropsychiatric adverse events have included
`changes in mood (including depression and mania), psychosis,
`hallucinations, paranoia, delusions, homicidal ideation, aggression,
`Revised: 02/2019
`hostility, agitation, anxiety, and panic, as well as suicidal ideation, suicide
`
`
`
`
`_______________________________________________________________________________________________________________________________________
`
`
`See 17 for PATIENT COUNSELING INFORMATION and Medication
`Guide
`
`

`

`8.6 Renal Impairment
`9 DRUG ABUSE AND DEPENDENCE
`9.1 Controlled Substance
`9.3 Dependence
`10 OVERDOSAGE
`11 DESCRIPTION
`12 CLINICAL PHARMACOLOGY
`12.1 Mechanism of Action
`12.3 Pharmacokinetics
`13 NONCLINICAL TOXICOLOGY
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`14 CLINICAL STUDIES
`14.1
`Initiation of Abstinence
`14.2 Urge to Smoke
`14.3 Long-Term Abstinence
`14.4 Alternative Instructions for Setting a Quit Date
`14.5 Gradual Approach to Quitting Smoking
`14.6 Re-Treatment Study
`14.7 Subjects with Chronic Obstructive Pulmonary Disease
`14.8 Subjects with Cardiovascular Disease and Other Cardiovascular
`Analyses
`14.9 Subjects with Major Depressive Disorder
`14.10 Postmarketing Neuropsychiatric Safety Outcome Trial
`16 HOW SUPPLIED/STORAGE AND HANDLING
`17 PATIENT COUNSELING INFORMATION
`
`*Sections or subsections omitted from the full prescribing information are not
`listed.
`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
` 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 Adverse Events including Suicidality
`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
`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
`_______________________________________________________________________________________________________________________________________
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 4394346
`
`

`

`
`FULL PRESCRIBING INFORMATION
`
`
`2.1 Usual Dosage for Adults
`
`Smoking cessation therapies are more likely to succeed for patients who are motivated to stop smoking and who are provided additional advice and support. Provide
`patients with appropriate educational materials and counseling to support the quit attempt.
`
`The patient should set a date to stop smoking. Begin CHANTIX dosing one week before this date. Alternatively, the patient can begin CHANTIX dosing and then quit
`smoking between days 8 and 35 of treatment.
`
`CHANTIX should be taken orally after eating and with a full glass of water.
`
`The recommended dose of CHANTIX is 1 mg twice daily following a 1-week titration as follows:
`
`
`Days 1 – 3:
`Days 4 – 7:
`Day 8 – end of treatment:
`
`0.5 mg once daily
`0.5 mg twice daily
`1 mg twice daily
`
`
`Patients should be treated with CHANTIX for 12 weeks. For patients who have successfully stopped smoking at the end of 12 weeks, an additional course of 12 weeks
`treatment with CHANTIX is recommended to further increase the likelihood of long-term abstinence.
`
`For patients who are sure that they are not able or willing to quit abruptly, consider a gradual approach to quitting smoking with CHANTIX. Patients should begin
`CHANTIX dosing and reduce smoking by 50% from baseline within the first four weeks, by an additional 50% in the next four weeks, and continue reducing with the
`goal of reaching complete abstinence by 12 weeks. Continue CHANTIX treatment for an additional 12 weeks, for a total of 24 weeks of treatment. Encourage patients
`to attempt quitting sooner if they feel ready [see Clinical Studies (14.5)].
`
`Patients who are motivated to quit, and who did not succeed in stopping smoking during prior CHANTIX therapy for reasons other than intolerability due to adverse
`events or who relapsed after treatment, should be encouraged to make another attempt with CHANTIX once factors contributing to the failed attempt have been
`identified and addressed.
`
`Consider a temporary or permanent dose reduction in patients who cannot tolerate the adverse effects of CHANTIX.
`
`2.2 Dosage in Special Populations
`
`Patients with Impaired Renal Function
`
`No dosage adjustment is necessary for patients with mild to moderate renal impairment. For patients with severe renal impairment (estimated creatinine clearance less
`than 30 mL per min), the recommended starting dose of CHANTIX is 0.5 mg once daily. The dose may then be titrated as needed to a maximum dose of 0.5 mg twice
`daily. For patients with end-stage renal disease undergoing hemodialysis, a maximum dose of 0.5 mg once daily may be administered if tolerated [see Use in Specific
`Populations (8.6), Clinical Pharmacology (12.3)].
`
`Elderly and Patients with Impaired Hepatic Function
`
`No dosage adjustment is necessary for patients with hepatic impairment. Because elderly patients are more likely to have decreased renal function, care should be taken
`in dose selection, and it may be useful to monitor renal function [see Use in Specific Populations (8.5)].
`
`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 Adverse Events including Suicidality
`
`Serious neuropsychiatric adverse events have been reported in patients being treated with CHANTIX [see Adverse Reactions (6.2)]. These postmarketing reports have
`included changes in mood (including depression and mania), psychosis, hallucinations, paranoia, delusions, homicidal ideation, aggression, hostility, agitation, anxiety,
`and panic, as well as suicidal ideation, suicide attempt, and completed suicide. Some patients who stopped smoking may have been experiencing symptoms of nicotine
`withdrawal, including depressed mood. Depression, rarely including suicidal ideation, has been reported in smokers undergoing a smoking cessation attempt without
`medication. However, some of these adverse events occurred in patients taking CHANTIX who continued to smoke.
`
`Neuropsychiatric adverse events occurred in patients without and with pre-existing psychiatric disease; some patients experienced worsening of their psychiatric
`illnesses. Some neuropsychiatric adverse events, including unusual and sometimes aggressive behavior directed to oneself or others, may have been worsened by
`concomitant use of alcohol [see Warnings and Precautions (5.3), Adverse Reactions (6.2)]. Observe patients for the occurrence of neuropsychiatric adverse events.
`Advise patients and caregivers that the patient should stop taking CHANTIX and contact a healthcare provider immediately if agitation, depressed mood, or changes in
`
`
`Reference ID: 4394346
`
` 1
`
`
`
`INDICATIONS AND USAGE
`
`
`CHANTIX is indicated for use as an aid to smoking cessation treatment.
`
`
`
`DOSAGE AND ADMINISTRATION
`
` 2
`
`

`

`
`behavior or thinking that are not typical for the patient are observed, or if the patient develops suicidal ideation or suicidal behavior. The healthcare provider should
`evaluate the severity of the symptoms and the extent to which the patient is benefiting from treatment, and consider options including dose reduction, continued
`treatment under closer monitoring, or discontinuing treatment. In many postmarketing cases, resolution of symptoms after discontinuation of CHANTIX was reported.
`However, the symptoms persisted in some cases; therefore, ongoing monitoring and supportive care should be provided until symptoms resolve.
`
`The neuropsychiatric safety of CHANTIX was evaluated in a randomized, double-blind, active and placebo-controlled study that included patients without a history of
`psychiatric disorder (non-psychiatric cohort, N=3912) and patients with a history of psychiatric disorder (psychiatric cohort, N=4003). In the non-psychiatric cohort,
`CHANTIX was not associated with an increased incidence of clinically significant neuropsychiatric adverse events in a composite endpoint comprising anxiety,
`depression, feeling abnormal, hostility, agitation, aggression, delusions, hallucinations, homicidal ideation, mania, panic, and irritability. In the psychiatric cohort, there
`were more events reported in each treatment group compared to the non-psychiatric cohort, and the incidence of events in the composite endpoint was higher for each
`of the active treatments compared to placebo: Risk Differences (RDs) (95%CI) vs. placebo were 2.7% (-0.05, 5.4) for CHANTIX, 2.2% (-0.5, 4.9) for bupropion, and
`0.4% (-2.2, 3.0) for transdermal nicotine. In the non-psychiatric cohort, neuropsychiatric adverse events of a serious nature were reported in 0.1% of CHANTIX-treated
`patients and 0.4% of placebo-treated patients. In the psychiatric cohort, neuropsychiatric events of a serious nature were reported in 0.6% of CHANTIX-treated patients,
`with 0.5% involving psychiatric hospitalization. In placebo-treated patients, serious neuropsychiatric events occurred in 0.6%, with 0.2% requiring psychiatric
`hospitalization [see Clinical Studies (14.10)].
`
`5.2 Seizures
`
`During clinical trials and the postmarketing experience, there have been reports of seizures in patients treated with CHANTIX. Some patients had no history of seizures,
`whereas others had a history of seizure disorder that was remote or well-controlled. In most cases, the seizure occurred within the first month of therapy. Weigh this
`potential risk against the potential benefits before prescribing CHANTIX in patients with a history of seizures or other factors that can lower the seizure threshold.
`Advise patients to discontinue CHANTIX and contact a healthcare provider immediately if they experience a seizure while on treatment [see Adverse Reactions (6.2)].
`
`5.3 Interaction with Alcohol
`
`There have been postmarketing reports of patients experiencing increased intoxicating effects of alcohol while taking CHANTIX. Some cases described unusual and
`sometimes aggressive behavior, and were often accompanied by amnesia for the events. Advise patients to reduce the amount of alcohol they consume while taking
`CHANTIX until they know whether CHANTIX affects their tolerance for alcohol [see Adverse Reactions (6.2)].
`
`5.4 Accidental Injury
`
`There have been postmarketing reports of traffic accidents, near-miss incidents in traffic, or other accidental injuries in patients taking CHANTIX. In some cases, the
`patients reported somnolence, dizziness, loss of consciousness or difficulty concentrating that resulted in impairment, or concern about potential impairment, in driving
`or operating machinery. Advise patients to use caution driving or operating machinery or engaging in other potentially hazardous activities until they know how
`CHANTIX may affect them.
`
`5.5 Cardiovascular Events
`
` comprehensive evaluation of cardiovascular (CV) risk with CHANTIX suggests that patients with underlying CV disease may be at increased risk; however, these
`concerns must be balanced with the health benefits of smoking cessation. CV risk has been assessed for CHANTIX in randomized controlled trials (RCT) and
`meta-analyses of RCTs. In a smoking cessation trial in patients with stable CV disease, CV events were infrequent overall; however, nonfatal myocardial infarction
`(MI) and nonfatal stroke occurred more frequently in patients treated with CHANTIX compared to placebo. All-cause and CV mortality was lower in patients treated
`with CHANTIX [see Clinical Studies (14.8)]. This study was included in a meta-analysis of 15 CHANTIX efficacy trials in various clinical populations that showed an
`increased hazard ratio for Major Adverse Cardiovascular Events (MACE) of 1.95; however, the finding was not statistically significant (95% CI: 0.79, 4.82). In the
`large postmarketing neuropsychiatric safety outcome trial, an analysis of adjudicated MACE events was conducted for patients while in the trial and during a 28-week
`non-treatment extension period. Few MACE events occurred during the trial; therefore, the findings did not contribute substantively to the understanding of CV risk
`with CHANTIX. Instruct patients to notify their healthcare providers of new or worsening CV symptoms and to seek immediate medical attention if they experience
`signs and symptoms of MI or stroke [see Clinical Studies (14.10)].
`
`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), extremities, and neck (throat and larynx). There were
`infrequent reports of life-threatening angioedema requiring emergent medical attention due to respiratory compromise. Instruct patients to discontinue CHANTIX and
`immediately seek medical care if they experience these symptoms.
`
`5.8 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 of a skin rash with mucosal lesions or any other signs of hypersensitivity.
`
`5.9 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. The 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
`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
`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.
`
`
` A
`
`Reference ID: 4394346
`
`

`

`
`
`
`ADVERSE REACTIONS
`
`6
`
`The following serious adverse reactions were reported in postmarketing experience and are discussed in greater detail in other sections of the labeling:
`
` 
`
`Neuropsychiatric Adverse Events including Suicidality [see Warnings and Precautions (5.1)]
`Seizures [see Warnings and Precautions (5.2)]
`Interaction with Alcohol [see Warnings and Precautions (5.3)]
`Accidental Injury [see Warnings and Precautions (5.4)]
`Cardiovascular Events [see Warnings and Precautions (5.5)]
`Somnambulism [see Warnings and Precautions (5.6)]
`Angioedema and Hypersensitivity Reactions [see Warnings and Precautions (5.7)]
`Serious Skin Reactions [see Warnings and Precautions (5.8)]
`
`
`
`
`
`
`
`
`
`
`In the placebo-controlled premarketing 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 with 1 mg twice daily was 12% for CHANTIX, compared to 10% for placebo in studies of
`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
`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).
`
`Smoking cessation, with 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.
`
`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)].
`
`Table 1 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
`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 ≥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 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)
`SYSTEM ORGAN CLASS
`CHANTIX
`CHANTIX
`Placebo
`High Level Group Term
`0.5 mg BID
`1 mg BID
`
`Preferred Term
`N=129
`N=821
`N=805
`GASTROINTESTINAL (GI)
`
` GI Signs and Symptoms
`
` Nausea
`10
` Abdominal Pain *
`5
` Flatulence
`3
` Dyspepsia
`3
` Vomiting
`2
` 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
`
`16
`5
`9
`5
`1
`
`
`5
`1
`
`4
`
`
`
`19
`9
`2
`2
`
`19
`
`30
`7
`6
`5
`5
`
`
`8
`1
`
`6
`
`
`
`18
`13
`5
`1
`
`15
`
`3
`0
`
`
`4
`
`
`
`13
`5
`3
`0
`
`
`13
`
`
`
`
`Reference ID: 4394346
`
`

`

` NEC
` Dysgeusia
` Somnolence
` Lethargy
`GENERAL DISORDERS
` General Disorders NEC
` Fatigue/Malaise/Asthenia
`RESPIR/THORACIC/MEDIAST
` Respiratory Disorders NEC
` Rhinorrhea
` Dyspnea
` Upper Respiratory Tract
` Disorder
`SKIN/SUBCUTANEOUS TISSUE
` Epidermal and Dermal
` Conditions
` Rash
` Pruritis
`METABOLISM and NUTRITION
` Appetite/General Nutrition
` Disorders
` Increased appetite
` Decreased appetite/
` Anorexia
`* Includes PTs Abdominal (pain, pain upper, pain lower, discomfort, tenderness, distension) and Stomach discomfort
`** Includes PTs Insomnia/Initial insomnia/Middle insomnia/Early morning awakening
`
`5
`3
`1
`
`7
`
`1
`1
`5
`
`
`
`3
`1
`
`
`
`3
`2
`
`4
`2
`0
`
`
`6
`
`
`0
`1
`4
`
`
`
`
`2
`1
`
`
`
`2
`1
`
`
`
`8
`3
`2
`
`4
`
`0
`2
`7
`
`
`
`1
`0
`
`
`
`4
`1
`
`
`The overall pattern and frequency of adverse events during the longer-term premarketing trials was similar to those described in Table 1, though several of the most
`common events were reported by a greater proportion of patients with long-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 premarketing clinical trials and updated based on pooled
`data from 18 placebo-controlled pre- and postmarketing studies, including approximately 5,000 patients treated with varenicline. Adverse events were categorized using
`MedDRA, Version 16.0. 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.
`
`Blood and Lymphatic System Disorders. Infrequent: anemia, lymphadenopathy. Rare: leukocytosis, splenomegaly, thrombocytopenia.
`Cardiac Disorders. Infrequent: angina pectoris, myocardial infarction, palpitations, tachycardia. Rare: acute coronary syndrome, arrhythmia, atrial fibrillation,
`bradycardia, cardiac flutter, cor pulmonale, coronary artery disease, ventricular extrasystoles.
`Ear and Labyrinth Disorders. Infrequent: tinnitus, vertigo. Rare: deafness, Meniere’s disease.
`Endocrine Disorders. Infrequent: thyroid gland disorders.
`Eye Disorders. Infrequent: conjunctivitis, eye irritation, eye pain, vision blurred, visual impairment. Rare: blindness transient, cataract subcapsular, dry eye, night
`blindness, ocular vascular disorder, photophobia, vitreous floaters.
`Gastrointestinal Disorders. Frequent: diarrhea, toothache. Infrequent: dysphagia, eructation, gastritis, gastrointestinal hemorrhage, mouth ulceration. Rare:
`enterocolitis, esophagitis, gastric ulcer, intestinal obstruction, pancreatitis acute.
`General Disorders and Administration Site Conditions. Frequent: chest pain. Infrequent: chest discomfort, chills, edema, influenza-like illness, pyrexia.
`Hepatobiliary Disorders. Rare: gall bladder disorder.
`Investigations. Frequent: liver function test abnormal, weight increased. Infrequent: electrocardiogram abnormal. Rare: muscle enzyme increased, urine analysis
`abnormal.
`Metabolism and Nutrition Disorders. Infrequent: diabetes mellitus, hypoglycemia. Rare: hyperlipidemia, hypokalemia.
`Musculoskeletal and Connective Tissue Disorders. Frequent: arthralgia, back pain, myalgia. Infrequent: arthritis, muscle cramp, musculoskeletal pain. Rare: myositis,
`osteoporosis.
`Nervous System Disorders. Frequent: disturbance in attention, dizziness. Infrequent: amnesia, convulsion, migraine, parosmia, syncope, tremor. Rare: balance disorder,
`cerebrovascular accident, dysarthria, mental impairment, multiple sclerosis, VIIth nerve paralysis, nystagmus, psychomotor hyperactivity, psychomotor skills impaired,
`restless legs syndrome, sensory disturbance, transient ischemic attack, visual field defect.
`Psychiatric Disorders. Infrequent: dissociation, libido decreased, mood swings, thinking abnormal. Rare: bradyphrenia, disorientation, euphoric mood.
`Renal and Urinary Disorders. Infrequent: nocturia, pollakiuria, urine abnormality. Rare: nephrolithiasis, polyuria, renal failure acute, urethral syndrome, urinary
`retention.
`Reproductive System and Breast Disorders. Frequent: menstrual disorder. Infrequent: erectile dysfunction. Rare: sexual dysfunction.
`Respiratory, Thoracic and Mediastinal Disorders. Frequent: respiratory disorders. Infrequent: asthma, epistaxis, rhinitis allergic, upper respiratory tract inflammation.
`Rare: pleurisy, pulmonary embolism.
`Skin and Subcutaneous Tissue Disorders. Infrequent: acne, dry skin, eczema, erythema, hyperhidrosis, urticaria. Rare: photosensitivity reaction, psoriasis.
`Vascular Disorders. Infrequent: hot flush. Rare: thrombosis.
`
`CHANTIX has also been studied in postmarketing trials including (1) a trial conducted in patients with chronic obstructive pulmonary disease (COPD), (2) a trial
`conducted in generally healthy patients (similar to those in the premarketing studies) in which they were allowed to select a quit date between days 8 and 35 of
`treatment (“alternative quit date instruction trial”), (3) a trial conducted in patients who did not succeed in stopping smoking during prior CHANTIX therapy, or who
`relapsed after treatment (“re-treatment trial”), (4) a trial conducted in patients with stable cardiovascular disease, (5) a trial conducted in patients with stable
`schizophrenia or schizoaffective disorder, (6) a trial conducted in patients with major depressive disorder, (7) a postmarketing neuropsychiatric safety outcome trial in
`patients without or with a history of psychiatric disorder, (8) a non-treatment extension of the postmarketing neuropsychiatric safety outcome trial that assessed CV
`safety, (9) a trial in patients who were not able or willing to quit abruptly and who were instructed to quit gradually (“gradual approach to quitting smoking trial”).
`
`
`
`
`Reference ID: 4394346
`
`

`

`
`Table 2. Cardiovascular Mortality and Nonfatal Cardiovascular Events (%) with a Frequency >1% in Either Treatment Group in the Trial of Patients with
`Stable Cardiovascular Disease
`CHANTIX
`1 mg BID
`N=353
`
`
`
`Adverse Events ≥1% in either treatment group
` Up to 30 days after treatment
`
`Angina pectoris
`
`Chest pain
`
`Peripheral edema
`
`Hypertension
`
`Palpitations
`Adjudicated Cardiovascular Mortality (up to 52 weeks)
`Adjudicated Nonfatal Serious Cardiovascular Events ≥1% in
`either treatment group
` Up to 30 days after treatment
`
`Nonfatal MI
`
`Hospitalization for angina pectoris
` Beyond 30 days after treatment and up to 52 weeks
`
`Need for coronary revascularization*
`
`Hospitalization for angina pectoris
`
`New diagnosis of peripheral vascular disease (PVD)
`or admission for a PVD procedure
`*some procedures were part of management of nonfatal MI and hospitalization for angina
`
`3.7
`2.5
`2.0
`1.4
`0.