HIGHLIGHTS OF PRESCRIBING INFORMATION
`These highlights do not include all the information needed to use
`
`
`CHANTIX safely and effectively. See full prescribing information for
`
`
`CHANTIX.
`
`
`CHANTIX® (varenicline) Tablets
`Initial U.S. Approval: 2006
`
`
`WARNING: SERIOUS NEUROPSYCHIATRIC EVENTS
`
`See full prescribing information for complete boxed warning.
`
`
`
`
`
`• Serious neuropsychiatric events have been reported in patients taking
`
`
`CHANTIX. (5.1 and 6.2)
`
`
`• Advise patients and caregivers that the patient should stop taking
`
`CHANTIX and contact a healthcare provider immediately if agitation,
`hostility, depressed mood, or changes in behavior or thinking that are
`not typical for the patient are observed, or if the patient develops
`suicidal ideation or suicidal behavior while taking CHANTIX or
`shortly after discontinuing CHANTIX. (5.1 and 6.2)
`
`
`• Weigh the risks of CHANTIX against benefits of its use. CHANTIX
`
`
`has been demonstrated to increase the likelihood of abstinence from
`
`smoking for as long as one year compared to treatment with placebo.
`
`
`The health benefits of quitting smoking are immediate and
`substantial. (5.1 and 6.2)
`
`
`• Provide patients with appropriate educational materials and counseling to
`
`
`support the quit attempt. (2.1)
`
`
`---------------------DOSAGE FORMS AND STRENGTHS----------------------
`
`Tablets: 0.5 mg and 1 mg (3)
`
`-------------------------------CONTRAINDICATIONS------------------------------
`History of serious hypersensitivity or skin reactions to CHANTIX (4)
`
`-----------------------WARNINGS AND PRECAUTIONS-----------------------­
`
`
`• Angioedema and hypersensitivity reactions: Such reactions, including
`angioedema, infrequently life threatening, have been reported. Instruct
`patients to discontinue CHANTIX and immediately seek medical care if
`
`symptoms occur. (5.2 and 6.2)
`
`
`
`• Serious skin reactions: Rare, potentially life-threatening skin reactions
`
`have been reported. Instruct patients to discontinue CHANTIX and contact
`a healthcare provider immediately at first appearance of skin rash with
`mucosal lesions. (5.3 and 6.2)
`
`
`• Accidental injury: Accidental injuries (e.g., traffic accidents) have been
`
`
`reported. Instruct patients to use caution driving or operating machinery
`until they know how CHANTIX may affect them. (5.4)
`
`• Nausea: Nausea is the most common adverse reaction (up to 30%
`incidence rate). Dose reduction may be helpful. (5.5)
`
`
`
`
`
`------------------------------ADVERSE REACTIONS-------------------------------
`Most common adverse reactions (>5% and twice the rate seen in placebo-
`treated patients) were nausea, abnormal (e.g., vivid, unusual, or strange)
`
`
`dreams, constipation, flatulence, and vomiting. (6.1)
`
`
`To report SUSPECTED ADVERSE REACTIONS, contact Pfizer Inc at
`1-800-438-1985 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
`
`------------------------------DRUG INTERACTIONS-------------------------------
`
`• Other smoking cessation therapies: Safety and efficacy in combination
`with other smoking cessation therapies has not been established.
`Coadministration of varenicline and transdermal nicotine resulted in a high
`rate of discontinuation due to adverse events. (7.1)
`
`
`• Effect of smoking cessation: Pharmacokinetics or pharmacodynamics of
`certain drugs may be altered due to smoking cessation with CHANTIX,
`
`necessitating dose adjustment. (7.2)
`
`
`
`
`
`
`
`
`
`----------------------------RECENT MAJOR CHANGES--------------------------
`Boxed Warning
`7/2009
`
`
`
`
`Contraindications
`3/2010
`
`
`Known Hypersensitivity (4)
` 7/2009
`Warnings and Precautions
`
`
`
`
`Neuropsychiatric Symptoms and Suicidality (5.1), Angioedema and
`
`Hypersensitivity Reactions (5.2), Serious Skin Reactions (5.3),
`Accidental Injury (5.4)
`
`----------------------------INDICATIONS AND USAGE---------------------------
`CHANTIX is a nicotinic receptor partial agonist indicated for use as an aid to
`
`smoking cessation treatment. (1 and 2.1)
`
`
`
`----------------------DOSAGE AND ADMINISTRATION-----------------------
`
`
`• Begin CHANTIX dosing one week before the date set by the patient to
`stop smoking. (2.1)
`
`
`• Starting week: 0.5 mg once daily on days 1-3 and 0.5 mg twice daily on
`
`
`days 4-7. (2.1)
`
`
`• Continuing weeks: 1 mg twice daily for a total of 12 weeks. (2.1)
`
`• An additional 12 weeks of treatment is recommended for successful
`
`quitters to increase likelihood of long-term abstinence. (2.1)
`
`
`• Renal impairment: Reduce the dose in patients with severe renal
`impairment (estimated creatinine clearance <30 mL/min). (2.2)
`
`
`• Consider dose reduction for patients who cannot tolerate adverse effects.
`
`(2.1)
`
`• Another attempt at treatment is recommended for those who fail to stop
`
`smoking or relapse when factors contributing to the failed attempt have
`been addressed. (2.1)
`
`_______________________________________________________________________________________________________________________________________
`
`
`
`-----------------------USE IN SPECIFIC POPULATIONS------------------------
`
`• Pregnancy: CHANTIX should be used during pregnancy only if the
`potential benefit justifies the potential risk to the fetus (8.1)
`
`• Nursing Mothers: Discontinue drug or nursing taking into consideration
`importance of drug to mother (8.3)
`
`
`
`• Pediatric Use: Safety and effectiveness not established (8.4)
`
`• Renal Impairment: Dosage adjustment is required for severe renal
`impairment (2.2, 8.6)
`
`
`
`See 17 for PATIENT COUNSELING INFORMATION and Medication
`Guide
`
`
`
`
`
`
`
`
`
`
`Revised: 04/2010
`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`WARNING: SERIOUS NEUROPSYCHIATRIC EVENTS
`
`INDICATIONS AND USAGE
`1
`
`2 DOSAGE AND ADMINISTRATION
`
`2.1 Usual Dosage for Adults
`2.2 Dosage in Special Populations
`
`3 DOSAGE FORMS AND STRENGTHS
`
`4 CONTRAINDICATIONS
`
`5 WARNINGS AND PRECAUTIONS
`5.1 Neuropsychiatric Symptoms and Suicidality
`5.2 Angioedema and Hypersensitivity Reactions
`5.3 Serious Skin Reactions
`5.4 Accidental Injury
`
`5.5 Nausea
`
`
`6 ADVERSE REACTIONS
`6.1 Clinical Trials Experience
`6.2 Postmarketing Experience
`
`7 DRUG INTERACTIONS
`7.1 Use With Other Drugs for Smoking Cessation
`7.2 Effect of Smoking Cessation on Other Drugs
`
`8 USE IN SPECIFIC POPULATIONS
`8.1 Pregnancy
`
`8.3 Nursing Mothers
`8.4 Pediatric Use
`8.5 Geriatric Use
`
`8.6 Renal Impairment
`
`9 DRUG ABUSE AND DEPENDENCE
`9.1 Controlled Substance
`9.3 Dependence
`10 OVERDOSAGE
`
`11 DESCRIPTION
`12 CLINICAL PHARMACOLOGY
`
`12.1 Mechanism of Action
`12.3 Pharmacokinetics
`
`
`13 NONCLINICAL TOXICOLOGY
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`
`
`14 CLINICAL STUDIES
`14.1 Initiation of Abstinence
`14.2 Urge to Smoke
`14.3 Long-Term Abstinence
`
`16 HOW SUPPLIED/STORAGE AND HANDLING
`
`17 PATIENT COUNSELING INFORMATION
`Medication Guide
`
`17.1 Set Quit Date and Continue to Attempt to Quit if Lapse
`
`17.2 How To Take
`17.3 Starting Week Dosage
`17.4 Continuing Weeks Dosage
`17.5 Dosage Adjustment for CHANTIX or Other Drugs
`17.6 Counseling and Support
`17.7 Neuropsychiatric Symptoms
`
`17.8 History of Psychiatric Illness
`
`Pfizer Ex. 2001, p. 1
`
`

`

`17.9 Nicotine Withdrawal
`
` 17.10 Angioedema
`17.11 Serious Skin Reactions
`
`17.12 Driving or Operating Machinery
`17.13 Vivid, Unusual, or Strange Dreams
`_______________________________________________________________________________________________________________________________________
`
`
`17.14 Pregnancy and Lactation
`
`*Sections or subsections omitted from the full prescribing information are not
`listed.
`
`
`FULL PRESCRIBING INFORMATION
`
`
`Consider a temporary or permanent dose reduction in patients who cannot
`
`tolerate the adverse effects of CHANTIX.
`
`
`2.2 Dosage in Special Populations
`
`Patients with Impaired Renal Function: No dosage adjustment is
`
`necessary for patients with mild to moderate renal impairment. For patients
`with severe renal impairment (estimated creatinine clearance <30 mL/min), the
`
`recommended starting dose of CHANTIX is 0.5 mg once daily. The dose may
`then be titrated as needed to a maximum dose of 0.5 mg twice a day. For
`patients with end-stage renal disease undergoing hemodialysis, a maximum
`
`dose of 0.5 mg once daily may be administered if tolerated [see Use in Specific
`
`
`Populations (8.6) and Clinical Pharmacology (12.3)].
`Elderly and Patients with Impaired Hepatic Function: No dosage
`
`adjustment is necessary for patients with hepatic impairment. Because elderly
`patients are more likely to have decreased renal function, care should be taken
`
`in dose selection, and it may be useful to monitor renal function [see Use in
`
`Specific Populations (8.5)].
`
`DOSAGE FORMS AND STRENGTHS
`Capsular, biconvex tablets: 0.5 mg (white to off-white, debossed with
`
`
`
`"Pfizer" on one side and "CHX 0.5" on the other side) and 1 mg (light blue,
`debossed with "Pfizer" on one side and "CHX 1.0" on the other side)
`
`
`CONTRAINDICATIONS
`CHANTIX is contraindicated in patients with a known history of serious
`hypersensitivity reactions or skin reactions to CHANTIX
`
`
`
`5 WARNINGS AND PRECAUTIONS
`
`5.1 Neuropsychiatric Symptoms and Suicidality
`Serious neuropsychiatric symptoms have been reported in patients being
`treated with CHANTIX [see Boxed Warning and Adverse Reactions (6.2)].
`These postmarketing reports have included changes in mood (including
`
`depression and mania), psychosis, hallucinations, paranoia, delusions, homicidal
`ideation, hostility, agitation, anxiety, and panic, as well as suicidal ideation,
`suicide attempt, and completed suicide. Some reported cases may have been
`complicated by the symptoms of nicotine withdrawal in patients who stopped
`
`smoking. Depressed mood may be a symptom of nicotine withdrawal.
`
`
`Depression, rarely including suicidal ideation, has been reported in smokers
`
`undergoing a smoking cessation attempt without medication. However, some of
`these symptoms have occurred in patients taking CHANTIX who continued to
`
`smoke. When symptoms were reported, most were during CHANTIX
`
`treatment, but some were following discontinuation of CHANTIX therapy.
`
`These events have occurred in patients with and without pre-existing
`
`psychiatric disease; some patients have experienced worsening of their
`
`psychiatric illnesses. All patients being treated with CHANTIX should be
`
`observed for neuropsychiatric symptoms or worsening of pre-existing
`
`illness such as
`psychiatric
`illness.
`Patients with serious psychiatric
`
`
`schizophrenia, bipolar disorder, and major depressive disorder did not
`
`participate in the premarketing studies of CHANTIX, and the safety and
`
`efficacy of CHANTIX in such patients has not been established.
`Advise patients and caregivers that the patient should stop taking
`
`CHANTIX and contact a healthcare provider immediately if agitation,
`
`depressed mood, changes in behavior or thinking that are not typical for the
`patient are observed, or if the patient develops suicidal ideation or suicidal
`behavior. In many postmarketing cases, resolution of symptoms after
`discontinuation of CHANTIX was reported, although in some cases the
`
`symptoms persisted, therefore, ongoing monitoring and supportive care should
`be provided until symptoms resolve.
`
`The risks of CHANTIX should be weighed against the benefits of its use.
`
`CHANTIX has been demonstrated to increase the likelihood of abstinence from
`
`smoking for as long as one year compared to treatment with placebo. The
`health benefits of quitting smoking are immediate and substantial.
`
`
`
`3
`
`
`4
`
`
`
`
`5.2 Angioedema and Hypersensitivity Reactions
`There have been postmarketing reports of hypersensitivity reactions
`
`
`including angioedema in patients treated with CHANTIX [see Adverse
`
`Reactions (6.2), and Patient Counseling Information (17.10)]. Clinical signs
`
`
`included swelling of the face, mouth (tongue, lips, and gums), extremities, and
`neck (throat and larynx). There were infrequent reports of life-threatening
`
`requiring emergent medical attention due
`angioedema
`to
`respiratory
`
`WARNING: SERIOUS NEUROPSYCHIATRIC EVENTS
`
`
`Serious neuropsychiatric events including, but not limited to,
`
`depression, suicidal ideation, suicide attempt and completed suicide have
`been reported in patients taking CHANTIX. Some reported cases may have
`
`been complicated by the symptoms of nicotine withdrawal in patients who
`
`stopped smoking. Depressed mood may be a symptom of nicotine
`
`withdrawal. Depression, rarely including suicidal ideation, has been
`
`reported in smokers undergoing a smoking cessation attempt without
`
`medication. However, some of these symptoms have occurred in patients
`taking CHANTIX who continued to smoke.
`
`All patients being treated with CHANTIX should be observed
`for neuropsychiatric symptoms including changes in behavior, hostility,
`agitation, depressed mood, and suicide-related events, including ideation,
`behavior, and attempted suicide. These symptoms, as well as worsening of
`
`pre-existing psychiatric illness and completed suicide, have been reported
`in some patients attempting to quit smoking while taking CHANTIX in the
`
`
`postmarketing experience. When symptoms were reported, most were
`during CHANTIX treatment, but some were following discontinuation of
`CHANTIX therapy.
`These events have occurred in patients with and without pre­
`existing psychiatric disease. Patients with serious psychiatric illness such as
`schizophrenia, bipolar disorder, and major depressive disorder did not
`participate in the premarketing studies of CHANTIX, and the safety and
`
`efficacy of CHANTIX in such patients has not been established.
`
`Advise patients and caregivers that the patient should stop
`
`
`taking CHANTIX and contact a healthcare provider immediately if
`
`agitation, hostility, depressed mood, or changes in behavior or thinking
`
`that are not typical for the patient are observed, or if the patient develops
`suicidal ideation or suicidal behavior. In many postmarketing cases,
`resolution of symptoms after discontinuation of CHANTIX was reported,
`
`although in some cases the symptoms persisted; therefore, ongoing
`
`monitoring and supportive care should be provided until symptoms
`
`
`resolve.
`
`The risks of CHANTIX should be weighed against the benefits of
`
`
`its use. CHANTIX has been demonstrated to increase the likelihood of
`
`abstinence from smoking for as long as one year compared to treatment
`
`with placebo. The health benefits of quitting smoking are immediate and
`substantial. [see Warnings and Precautions (5.1) and Adverse Reactions
`6.2)]
`
`
`
`INDICATIONS AND USAGE
`1
`CHANTIX is indicated for use as an aid to smoking cessation treatment.
`
`
`2
`
`DOSAGE AND ADMINISTRATION
`
`
`2.1 Usual Dosage for Adults
`Smoking cessation therapies are more likely to succeed for patients who
`
`are motivated to stop smoking and who are provided additional advice and
`support. Provide patients with appropriate educational materials and counseling
`
`to support the quit attempt.
`
`The patient should set a date to stop smoking. Begin CHANTIX dosing
`
`one week before this date.
`
`CHANTIX should be taken after eating and with a full glass of water.
`The recommended dose of CHANTIX is 1 mg twice daily following a 1­
`week titration as follows:
`
`
`Days 1 – 3:
`Days 4 – 7:
`Day 8 – end of treatment:
`
`0.5 mg once daily
`
`0.5 mg twice daily
`1 mg twice daily
`
`
`
`Patients should be treated with CHANTIX for 12 weeks. For patients who
`have successfully stopped smoking at the end of 12 weeks, an additional course
`of 12 weeks’ treatment with CHANTIX is recommended to further increase the
`
`likelihood of long-term abstinence.
`
`
`Patients who do not succeed in stopping smoking during 12 weeks of
`initial therapy, or who relapse after treatment, should be encouraged to make
`
`
`another attempt once factors contributing to the failed attempt have been
`identified and addressed.
`
`
`Pfizer Ex. 2001, p. 2
`
`

`

` compromise. Instruct patients to discontinue CHANTIX and immediately seek
`
`medical care if they experience these symptoms.
`
`
`
`
`
`
`
`5.3 Serious Skin Reactions
` There have been postmarketing reports of rare but serious skin reactions,
`
`
` including Stevens-Johnson Syndrome and erythema multiforme, in patients
` using CHANTIX [see Adverse Reactions (6.2)]. As these skin reactions can be
`
`
` life-threatening, instruct patients to stop taking CHANTIX and contact a
`healthcare provider immediately at the first appearance of a skin rash with
`mucosal lesions or any other signs of hypersensitivity.
`
`
`
` 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 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.
`
`ADVERSE REACTIONS
`The following serious adverse reactions were reported in postmarketing
`experience and are discussed in greater detail in other sections of the labeling:
`
`
`•
`
`
`6
`
`Neuropsychiatric symptoms and suicidality [see Boxed Warning and
`Warnings and Precautions (5.1)
`
`Angioedema and hypersensitivity reactions [see Warnings and
`
`Precautions (5.2)]
`Serious skin reactions [see Warnings and Precautions (5.3)]
`
`
`Accidental injury [see Warnings and Precautions (5.4)]
`
`
`•
`
`
`•
`
`•
`
`
`
`
`In the placebo-controlled studies, the most common adverse events
`
`associated with CHANTIX (>5% and twice the rate seen in placebo-treated
`patients) were nausea, abnormal (vivid, unusual, or strange) dreams,
`
`constipation, flatulence, and vomiting.
`The treatment discontinuation rate due to adverse events in patients dosed
`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 (5.5)].
`
`Table 1 shows the adverse events for CHANTIX and placebo in the 12­
`week fixed dose studies with titration in the first week [Studies 2 (titrated arm
`
`
`only), 4, and 5]. Adverse events were categorized using the Medical Dictionary
`for Regulatory Activities (MedDRA, Version 7.1).
`
`
`MedDRA High Level Group Terms (HLGT) reported in ≥ 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 (≥ 1% in the 1 mg BID CHANTIX Group, and
`
`
`1 mg BID CHANTIX at least 0.5% more than Placebo)
`
`
`CHANTIX
`
`0.5 mg BID
`
`N=129
`
`
`16
`5
`9
`5
`
`1
`
`
`SYSTEM ORGAN CLASS
`
`
`
`High Level Group Term
`
`
` Preferred Term
`GASTROINTESTINAL (GI)
` GI Signs and Symptoms
`
` Nausea
`
` Abdominal Pain *
`
`Flatulence
`
` Dyspepsia
`
` 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/MEDI
`AST
` Respiratory Disorders NEC
`
` Rhinorrhea
`
` Dyspnea
`
` Upper Respiratory Tract
`
` Disorder
`
`SKIN/SUBCUTANEOUS
`
`TISSUE
` Epidermal and Dermal
`
` Conditions
`Rash
`
`
`Pruritis
`
`METABOLISM &
`NUTRITION
` Appetite/General Nutrit.
` Disorders
` Increased appetite
`
` Decreased appetite/
`
` Anorexia
`
`
`* Includes PTs Abdominal (pain, pain upper, pain lower, discomfort,
`
`tenderness, distension) and Stomach discomfort
`
`** Includes PTs Insomnia/Initial insomnia/Middle insomnia/Early morning
`awakening
`
`
`Placebo
`
`
`N=805
`
`
`10
`5
`3
`3
`
`2
`
`
`3
`0
`
`
`4
`
`
`
`
`13
`5
`3
`0
`
`
`13
`
`
`4
`
`2
`0
`
`
`6
`
`
`
`0
`1
`4
`
`
`
`
`
`21
`
`
`
`
`
`
`
`2
`1
`
`
`CHANTIX
`
`1 mg BID
`
`N=821
`
`
`30
`7
`6
`5
`
`5
`
`
`8
`1
`
`
`6
`
`
`
`
`18
`13
`5
`1
`
`
`15
`
`
`5
`
`3
`1
`
`
`7
`
`
`
`1
`1
`5
`
`
`
`
`
`3
`
`1
`
`
`
`
`3
`2
`
`5
`1
`
`
`4
`
`
`
`
`19
`9
`2
`2
`
`
`19
`
`
`8
`
`3
`2
`
`
`4
`
`
`
`0
`2
`7
`
`
`
`
`
`1
`
`0
`
`
`
`
`4
`1
`
`
`
`
`
`The overall pattern and frequency of adverse events during the longer-
`term 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
`
`
`Pfizer Ex. 2001, p. 3
`
`

`

`
`
` use (e.g., nausea was reported in 40% of patients treated with CHANTIX 1 mg
`twice daily in a one-year study, compared to 8% of placebo-treated patients).
`
`Following is a list of treatment-emergent adverse events reported by
`
`patients treated with CHANTIX during all clinical trials. The listing does not
`include those events already listed in the previous tables or elsewhere in
`labeling, those events for which a drug cause was remote, those events which
`were so general as to be uninformative, and those events reported only once
`which did not have a substantial probability of being acutely life-threatening.
`
`Infrequent:
`and Lymphatic System Disorders.
`Blood
`anemia,
`lymphadenopathy. Rare: leukocytosis, splenomegaly, thrombocytopenia.
`
`
`
`Cardiac Disorders. Infrequent: angina pectoris, arrhythmia, bradycardia,
`myocardial infarction, palpitations, tachycardia, ventricular extrasystoles. Rare:
`
`acute coronary syndrome, atrial fibrillation, cardiac flutter, cor pulmonale,
`coronary artery disease.
`
`Ear and Labyrinth Disorders. Infrequent: tinnitus, vertigo. Rare: deafness,
`
`
`Meniere’s disease.
`
`Endocrine Disorders. Infrequent: thyroid gland disorders.
`
`
`Eye Disorders. Infrequent: conjunctivitis, dry eye, eye irritation, eye pain,
`vision blurred, visual disturbance. Rare: acquired night blindness, blindness
`
`
`transient, cataract subcapsular, ocular vascular disorder, photophobia, vitreous
`
`floaters
`
`
`Gastrointestinal Disorders. Frequent: diarrhea. Infrequent: dysphagia,
`
`enterocolitis, eructation, esophagitis, gastritis, gastrointestinal hemorrhage,
`mouth ulceration. Rare: gastric ulcer, intestinal obstruction, pancreatitis acute.
`
`
`General Disorders and Administration Site Conditions. Frequent: chest
`
`pain, edema, influenza-like illness. Infrequent: chest discomfort, chills, pyrexia.
`
`Hepatobiliary Disorders. Infrequent: gall bladder disorder
`
`Investigations. Frequent: liver function test abnormal, weight increased.
`Infrequent: electrocardiogram abnormal, muscle enzyme increased, urine
`
`analysis abnormal.
`
`Metabolism and Nutrition Disorders. Infrequent: diabetes mellitus,
`hyperlipidemia, hypokalemia. Rare: hypoglycemia.
`
`
`Musculoskeletal and Connective Tissue Disorders. Frequent: arthralgia,
`
`back pain, muscle cramp, musculoskeletal pain, myalgia. Infrequent: arthritis,
`
`
`
`
`osteoporosis. Rare: myositis.
`
`Nervous System Disorders. Frequent: disturbance in attention, dizziness,
`
`
`
`sensory disturbance. Infrequent: amnesia, migraine, parosmia, psychomotor
`
`
`
`hyperactivity, restless legs syndrome, syncope, tremor. Rare: balance disorder,
`cerebrovascular accident, convulsion, dysarthria,
`facial palsy, mental
`
`impairment, multiple sclerosis, nystagmus, psychomotor skills impaired,
`
`transient ischemic attack, visual field defect.
`Psychiatric Disorders. Infrequent: disorientation, dissociation, libido
`
`decreased, mood swings, thinking abnormal. Rare: bradyphrenia, euphoric
`
`
`
`mood.
`
`
`Infrequent:
`and Urinary Disorders. Frequent: polyuria.
`Renal
`nephrolithiasis, nocturia, urethral syndrome, urine abnormality. Rare: renal
`failure acute, urinary retention.
`Reproductive System and Breast Disorders. Rare: sexual dysfunction.
`
`
`
`Frequent: menstrual disorder. Infrequent: erectile dysfunction.
`
`
`Respiratory, Thoracic and Mediastinal Disorders. Frequent: epistaxis,
`
`
`respiratory disorders. Infrequent: asthma. Rare: pleurisy, pulmonary embolism.
`
`
`Skin and Subcutaneous Tissue Disorders. Frequent: hyperhidrosis.
`
`Infrequent: acne, dry skin, eczema, erythema, psoriasis, urticaria. Rare:
`
`photosensitivity reaction.
`
`Vascular Disorders. Frequent: hot flush. Infrequent: thrombosis.
`
`
`
`6.2 Postmarketing Experience
`The following adverse events have been reported during post-approval use
`of CHANTIX. Because these events are reported voluntarily from a population
`of uncertain size, it is not possible to reliably estimate their frequency or
`
`establish a causal relationship to drug exposure.
`
`
`There have been reports of depression, mania, psychosis, hallucinations,
`paranoia, delusions, homicidal ideation, aggression, hostility, anxiety, and
`panic, as well as suicidal ideation, suicide attempt, and completed suicide in
`patients attempting to quit smoking while taking CHANTIX [see Boxed
`Warning, Warnings and Precautions (5.1)]. Smoking cessation with or without
`treatment is associated with nicotine withdrawal symptoms and the exacerbation
`
`of underlying psychiatric illness. Not all patients had known pre-existing
`psychiatric illness and not all had discontinued smoking.
`There have been reports of hypersensitivity reactions, including
`angioedema [see Warnings and Precautions (5.2)].
`
`
`There have also been reports of serious skin reactions, including Stevens-
`Johnson Syndrome and erythema multiforme, in patients taking CHANTIX [see
`
`
`
`Warnings and Precautions (5.3)].
`
`
`
`7
`
`DRUG INTERACTIONS
`
`Based on varenicline characteristics and clinical experience to date,
`
`CHANTIX has no clinically meaningful pharmacokinetic drug interactions [see
`Clinical Pharmacology (12.3)].
`
`
`
`7.1 Use With Other Drugs for Smoking Cessation
`Safety and efficacy of CHANTIX in combination with other smoking
`
`cessation therapies have not been studied.
`
`Bupropion: Varenicline (1 mg twice daily) did not alter the steady-state
`
`
`
`pharmacokinetics of bupropion (150 mg twice daily) in 46 smokers. The safety
`
`of the combination of bupropion and varenicline has not been established.
`
`Nicotine replacement therapy (NRT): Although co-administration of
`
`
`varenicline (1 mg twice daily) and transdermal nicotine (21 mg/day) for up to
`12 days did not affect nicotine pharmacokinetics, the incidence of nausea,
`headache, vomiting, dizziness, dyspepsia, and fatigue was greater for the
`combination than for NRT alone. In this study, eight of twenty-two (36%)
`patients treated with the combination of varenicline and NRT prematurely
`discontinued treatment due to adverse events, compared to 1 of 17 (6%) of
`patients treated with NRT and placebo.
`
`
`7.2 Effect of Smoking Cessation on Other Drugs
`
`
`Physiological changes resulting from smoking cessation, with or without
`
`or
`treatment with CHANTIX, may
`alter
`the
`pharmacokinetics
`pharmacodynamics of certain drugs (e.g., theophylline, warfarin, insulin) for
`
`which dosage adjustment may be necessary.
`
`
`8 USE IN SPECIFIC POPULATIONS
`
`8.1 Pregnancy
`
`Pregnancy Category C.
`
`
`There are no adequate and well-controlled studies of CHANTIX use in
`pregnant women. In animal studies, CHANTIX caused decreased fetal weights,
`increased auditory startle response, and decreased fertility in offspring.
`
`CHANTIX should be used during pregnancy only if the potential benefit
`
`justifies the potential risk to the fetus.
`In reproductive and developmental toxicity studies, pregnant rats and
`rabbits received varenicline succinate during organogenesis at oral doses up to
`
`
`
`15 and 30 mg/kg/day, respectively. These exposures were 36 (rats) and 50
`
`
`(rabbits) times the human exposure (based on AUC) at the maximum
`
`recommended human dose (MRHD) of 1 mg BID. While no fetal structural
`abnormalities occurred in either species, reduced fetal weights occurred in
`rabbits at the highest dose (exposures 50 times the human exposure at the
`MRHD based on AUC).
` Fetal weight reduction did not occur at animal
`
`exposures 23 times the human exposure at the MRHD based on AUC.
`
`In a pre- and postnatal development study, pregnant rats received up to 15
`
`mg/kg/day of oral varenicline succinate from organogenesis through lactation.
`
`These resulted in exposures up to 36 times the human exposure (based on AUC)
`
`at the MRHD of 1 mg BID. Decreased fertility and increased auditory startle
`
`response occurred in offspring.
`
`
`
`8.3 Nursing Mothers
`
`It is not known whether CHANTIX is excreted in human milk. In animal
`studies varenicline was excreted in milk of lactating animals. Because many
`
`drugs are excreted in human milk and because of the potential for serious
`
`adverse reactions in nursing infants from CHANTIX, a decision should be made
`
`
`whether to discontinue nursing or to discontinue the drug, taking into account
`
`the importance of the drug to the mother.
`
`
`8.4 Pediatric Use
`Safety and effectiveness of CHANTIX in pediatric patients have not been
`established.
`
`
`8.5 Geriatric Use
`
`A
`combined
`single-
`and multiple-dose pharmacokinetic
`study
`
`demonstrated that the pharmacokinetics of 1 mg varenicline given once daily or
`
`twice daily to 16 healthy elderly male and female smokers (aged 65-75 yrs) for
`7 consecutive days was similar to that of younger subjects. No overall
`
`differences in safety or effectiveness were observed between these subjects and
`younger subjects, and other reported clinical experience has not identified
`
`differences in responses between the elderly and younger patients, but greater
`sensitivity of some old