PART I: HEALTH PROFESSIONAL INFORMATION 3

SUMMARY PRODUCT INFORMATION 3 INDICATIONS AND CLINICAL USE 3 CONTRAINDICATIONS 3 WARNINGS AND PRECAUTIONS 4 ADVERSE REACTIONS 8 DRUG INTERACTIONS 13 DOSAGE AND ADMINISTRATION 16 OVERDOSAGE 18 ACTION AND CLINICAL PHARMACOLOGY 18 STORAGE AND STABILITY 21 DOSAGE FORMS, COMPOSITION AND PACKAGING 21

PART II: SCIENTIFIC INFORMATION 22

PHARMACEUTICAL INFORMATION 22 CLINICAL TRIALS 23 DETAILED PHARMACOLOGY 28 TOXICOLOGY 29 REFERENCES 32

PART III: CONSUMER INFORMATION. 35

CHAMPIX *

(varenicline tartrate tablets)

PART I: HEALTH PROFESSIONAL INFORMATION SUMMARY PRODUCT INFORMATION

CONTRAINDICATIONS

Patients who are hypersensitive to varenicline or to any ingredient in the formulation or component of the container.

WARNINGS AND PRECAUTIONS

General

Neuropsychiatric symptoms: ADVERSE REACTIONS, Post-Marketing Experience

(see also

).

There have been rare post-marketing reports of serious neuropsychiatric symptoms with CHAMPIX, including depressed mood, agitation, hostility, changes in behaviour, suicidal ideation and suicide, as well as worsening of pre-existing psychiatric illness (previously diagnosed or not). There are a number of confounding factors which may have contributed, including effects of nicotine withdrawal due to partial or complete smoking discontinuation; concomitant, or history of psychiatric conditions; and the concomitant use of other CNS drugs and/or alcohol. However, there are cases for which these confounding factors did not appear to be present, including cases where symptoms occurred within the first week of initiating CHAMPIX, and prior to initiating smoking cessation. There have been other cases where symptoms developed following cessation of CHAMPIX therapy. It is not known whether these events are occurring at a rate and severity which is different from the background rate for smoking cessation in the general population, or in the psychiatric population (treated or untreated), or different from the rates for other drugs in the class of smoking cessation. Patients with serious psychiatric illness such as schizophrenia, bipolar disorder, and major depressive disorder were excluded from the pre-marketing studies of CHAMPIX and the safety and efficacy of CHAMPIX in such patients has not been studied (see also Special Populations, Use of CHAMPIX in Patients with Concomitant Conditions).

Recommendations regarding Neuropsychiatric Symptoms:

All patients attempting to quit smoking with CHAMPIX, their families and caregivers should be alerted about the need to monitor for these symptoms. Patients should be instructed to stop taking CHAMPIX and contact their healthcare provider immediately if they have or if their families or caregivers observe depressed mood, agitation, hostility or changes in behavior, that are not typical for the patient, or if the patient has suicidal ideation or suicidal behavior.

Patients with concomitant psychiatric conditions, even if well controlled, or with a history of psychiatric symptoms, should be diligently monitored.

Concomitant Illness: Special Populations, Patients with Concomitant Conditions

The full consequences of using this product in patients with concomitant illness have not been established, and caution should be exercised (see

).

Nicotine replacement therapy (NRT): The concomitant use of NRT with CHAMPIX (varenicline tartrate) may result in an increase in adverse reactions. In a clinical drug interaction study (N=24), the incidences of nausea, headache, vomiting, dizziness, dyspepsia and fatigue were greater for the combination of NRT and varenicline than for NRT alone (see DRUG INTERACTIONS). The safety and efficacy of the combination treatment with CHAMPIX and NRT have not been studied. Due to the proposed mechanism of action of varenicline, it is not anticipated that co-administration with NRT would confer additional benefit compared with CHAMPIX alone.

Effect of smoking-cessation:

Physiological changes resulting from smoking-cessation, with or without treatment with CHAMPIX, may alter the pharmacokinetics or pharmacodynamics of some drugs for which dosage adjustment may be necessary (examples include theophylline, warfarin and insulin). As smoking induces cytochrome P450 (CYP) isoenzyme 1A2, smoking- cessation may result in an increase of plasma levels of CYP1A2 substrates.

Nausea:

Nausea was the most common adverse event associated with CHAMPIX treatment. Nausea was generally described as mild or moderate and often transient; however, for some subjects, it was persistent over several months. The incidence of nausea was dose-dependent. Initial dose-titration was beneficial in reducing the occurrence of nausea. Nausea was reported by approximately 30% of patients treated with CHAMPIX 1.0 mg BID after an initial week of dose titration. In patients taking CHAMPIX 0.5 mg BID, the incidence of nausea was 16% following initial titration. Approximately 3% of subjects treated with CHAMPIX 1.0 mg BID in studies involving 12 weeks of treatment discontinued treatment prematurely because of nausea. For patients with intolerable nausea, dose reduction should be considered.

Carcinogenesis and Mutagenesis

Carcinogenesis

: Lifetime carcinogenicity studies were performed in CD-1 mice and Sprague Dawley rats. There was no evidence of a carcinogenic effect in mice administered varenicline by oral gavage for 2 years at doses up to 20 mg/kg/day (47 times the maximum recommended human daily exposure based on the area under the curve (AUC). Rats were administered varenicline (1, 5, and 15 mg/kg/day) by oral gavage for 2 years. In male rats (n=65 per sex per dose group), incidences of hibernoma (tumor of the brown fat) was increased at the mid dose (1 tumor, 5 mg/kg/day, 23 times the maximum recommended human daily exposure based on AUC) and at the maximum dose (2 tumors, 15 mg/kg/day, 67 times the maximum recommended human daily exposure based on AUC). The clinical relevance of this finding to humans has not been established. There was no evidence of carcinogenicity in female rats.

Mutagenesis: Varenicline was not genotoxic, with or without metabolic activation, in the following assays: Ames bacterial mutation assay; mammalian CHO/HGPRT assay; and tests for cytogenetic aberrations in vivo in rat bone marrow and in vitro in human lymphocytes.

Dependence/Tolerance

Animal Studies

The subjective nicotine-like effects of varenicline were investigated in drug discrimination studies. At 1.0 mg/kg, there was complete substitution of varenicline for nicotine in a paradigm of nicotine-associated lever pressing for food reward. In an efficacy model, varenicline pretreatment dose-dependently reduced nicotine self administration under a fixed-ratio schedule. Under a progressive ratio schedule rats worked harder for nicotine than for varenicline.

Human Studies

The rewarding potential of varenicline (1 mg and 3 mg doses) was compared with that of amphetamines in subjects experienced with psychomotor stimulants. The pattern for both smokers and non-smokers was consistent with a profile of a drug that, while having some pharmacological activity, did not produce amphetamine-like subjective effects.

Driving/Operating Machinery

CHAMPIX may cause dizziness and somnolence and therefore patients should be advised to avoid driving a car or operating hazardous machinery until they are reasonably certain that CHAMPIX does not affect them adversely.

Sexual Function / Reproduction

Impairment of Fertility:

There was no evidence of impairment of fertility in either male or female Sprague-Dawley rats administered varenicline succinate up to 15 mg/kg/day (67 and 36 times, respectively, the maximum recommended human daily exposure based on AUC at 1.0 mg BID). However, a decrease in fertility was noted in the offspring of pregnant rats who were administered varenicline succinate at an oral dose of 15 mg/kg/day (36 times the maximum recommended human daily exposure based on AUC at 1.0 mg BID). This decrease in fertility in the offspring of treated female rats was not evident at an oral dose of 3 mg/kg/day (9 times the maximum recommended human daily exposure based on AUC at 1.0 mg BID).

Special Populations

Use of CHAMPIX in Patients with Concomitant Conditions:

Psychiatric Patients

The use of CHAMPIX has not been studied in psychiatric patients. Smoking-cessation with or without pharmacotherapy, has been associated with the exacerbation of underlying psychiatric illness; the impact on this population of a smoking-cessation product with nicotinic partial agonist properties is unknown. Care should be taken with patients with a history of psychiatric illness and patients should be advised accordingly.

Patients with Epilepsy

The use of CHAMPIX has not been studied in patients with epilepsy.

Patients with Irritable Bowel or Other Gastrointestinal (GI) Problems

The use of CHAMPIX has not been studied in patients with irritable bowel syndrome or other GI problems.

Patients Exposed to Chemotherapy

The use of CHAMPIX has not been studied in patients exposed to emetogenic chemotherapy.

Pregnant Women

There are no adequate data from the use of CHAMPIX in pregnant women. Studies in animals have shown reproductive toxicity (see TOXICOLOGY). The potential risk for humans is unknown. CHAMPIX should not be used during pregnancy.

Nonteratogenic effects

Varenicline succinate has been shown to have an adverse effect on the fetus in animal reproduction studies. Administration of varenicline succinate to pregnant rabbits resulted in reduced fetal weights at an oral dose of 30 mg/kg/day (50 times the human AUC at 1.0 mg BID); this reduction was not evident following treatment with 10 mg/kg/day (23 times the maximum recommended daily human exposure based on AUC). In addition, in the offspring of pregnant rats treated with varenicline succinate there were decreases in fertility and increases in auditory startle response at an oral dose of 15 mg/kg/day (36 times the maximum recommended human daily exposure based on AUC at 1.0 mg BID).

Nursing Women

Animal studies have shown that varenicline can be transferred to nursing pups. It is not known whether varenicline is excreted in human milk. Because many drugs are excreted in human milk and because the potential for adverse reactions in nursing infants from CHAMPIX is unknown, a decision should be made whether to discontinue nursing or to discontinue the drug.

Pediatrics (<18 years of age)

Safety and efficacy of CHAMPIX in pediatric patients have not been established; therefore, CHAMPIX is not recommended for use in patients under 18 years of age.

Geriatrics (>65 years of age)

A combined single and multiple-dose pharmacokinetic study demonstrated that the pharmacokinetics of 1.0 mg varenicline given once daily (QD) or BID to 16 healthy elderly male and female smokers (aged 65-75 years) 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 older individuals cannot be ruled out. Varenicline is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. 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 DOSAGE AND ADMINISTRATION, Special Populations: Geriatrics).

Renal Impairment

A multiple dose pharmacokinetic study was conducted in patients with normal renal function, with mild, moderate, or severe renal impairment (estimated creatinine clearance: >80 mL/min, >50 and <= 80 mL/min, >=30 and <=50 mL/min, and <30 mL/min, respectively) or end-stage renal disease (ESRD). Varenicline pharmacokinetics was unchanged in subjects with mild renal impairment. Relative to subjects with normal renal function, varenicline exposure increased 1.5- fold in patients with moderate renal impairment and 2.1-fold in patients with severe renal impairment. In subjects with ESRD, varenicline was efficiently removed by hemodialysis. The recommended dose of CHAMPIX is reduced in patients with severe renal impairment. CHAMPIX is not recommended in patients with ESRD. (See ACTION AND CLINICAL PHARMACOLOGY, Special Populations and Conditions: Renal Impairment, and DOSAGE AND ADMINISTRATION, Special Populations: Patients with Impaired Renal Function).

DRUG INTERACTIONS

Overview

Based on varenicline pharmacokinetic characteristics, and clinical experience to date, it appears unlikely that CHAMPIX would produce or be subject to clinically meaningful drug interactions. Drug interaction studies were performed with varenicline and: cimetidine, metformin, digoxin, warfarin, transdermal nicotine and bupropion. No clinically meaningful pharmacokinetic drug interactions have been identified, other than potential for interaction with cimetidine in patients with severe renal impairment (see Cimetidine, below).

Drugs cleared by, or which affect, cytochrome P450 enzymes

In vitro

studies demonstrated that varenicline does not inhibit cytochrome P450 enzymes (IC50

>6400 ng/mL). The P450 enzymes tested for inhibition were: 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, and 3A4/5. Also, in human hepatocytes in vitro, varenicline did not induce the activity of cytochrome P450 enzymes 1A2 and 3A4. Therefore, varenicline is unlikely to alter the pharmacokinetics of compounds that are primarily metabolised by cytochrome P450 enzymes. Furthermore, since metabolism of varenicline represents less than 10% of its clearance, drugs known to affect the cytochrome P450 system are unlikely to alter the pharmacokinetics of CHAMPIX (see ACTION AND CLINICAL PHARMACOLOGY: Pharmacokinetics) and therefore a dose adjustment of CHAMPIX should not be required for these types of drugs.

Drugs cleared by, or which affect, renal secretion

In vitro

studies demonstrated that varenicline does not inhibit human renal transport proteins at therapeutic concentrations. Therefore, drugs that are cleared by renal secretion (eg, metformin - see below) are unlikely to be affected by varenicline.

In vitro studies demonstrated the active renal secretion of varenicline is mediated by the human organic cation transporter, hOCT2. In patients with normal renal function coadministration with inhibitors of hOCT2 does not require a dose adjustment of CHAMPIX as the increase in systemic exposure to CHAMPIX is not expected to be clinically meaningful except in cases of severe renal impairment, (see Cimetidine, and Other Inhibitors of hOCT2 below).

Drug-Drug Interactions

Drug-drug interaction studies were limited to approximately two week studies in healthy young adult volunteers who smoked.

Single dosing for one of the two drugs:

Cimetidine: Co-administration of varenicline (2 mg single dose) with an hOCT2 inhibitor, cimetidine (300 mg four times daily (QID) at steady-state) to 12 smokers increased the systemic exposure of varenicline by 29% (90% CI: 21.5%, 36.9%) due to a reduction in varenicline renal clearance. No dosage adjustment is recommended based on concomitant cimetidine administration in subjects with normal renal function or in patients with mild to moderate renal impairment. In patients with severe renal impairment, the concomitant use of cimetidine and varenicline should be avoided. (See DOSAGE AND ADMINISTRATION, Recommended Dose and Dosage Adjustment: Special Populations, Patients with Impaired Renal Function). Other inhibitors of hOCT2: Other inhibitors of hOCT2 have not been directly studied. Cimetidine causes greater in vivo drug interactions with renally cleared compounds than other inhibitors of hOCT2. Consequently, co-administration of other inhibitors of hOCT2 with varenicline would not require dosage adjustment in patients with normal renal function or moderate renal impairment. In patients with severe renal impairment, the concomitant use of varenicline and other inhibitors of hOCT2, such as trimethoprim, ranitidine or levofloxacin should be avoided. (See DOSAGE AND ADMINISTRATION, Recommended Dose and Dosage Adjustment: Special Populations, Patients with Impaired Renal Function).

Co-administration with Other Drugs Eliminated via hOCT2:

Based on the lack of interaction between varenicline and metformin, interactions between varenicline and other cationic drugs eliminated via hOCT2 are unlikely.

Warfarin: Varenicline (1 mg BID steady-state) did not alter the pharmacokinetics of a single 25 mg dose of (R, S)-warfarin in 24 smokers. Prothrombin time (INR) was not affected by CHAMPIX. Smoking-cessation itself may result in changes to warfarin pharmacokinetics (see WARNINGS AND PRECAUTIONS, General).

Multiple dosing for both drugs:

Metformin:

When co-administered to 30 smokers, varenicline (1 mg BID) did not alter the steady-state pharmacokinetics of metformin (500 mg BID), which is a substrate of hOCT2. Metformin had no effect on varenicline steady-state pharmacokinetics.

Digoxin:

Varenicline (1 mg BID) did not alter the steady-state pharmacokinetics of digoxin administered as a 0.25 mg daily dose in 18 smokers. Steady-state pharmacokinetics of varenicline remained unchanged by digoxin co-administration.

Use with other therapies for smoking-cessation: Safety and efficacy of varenicline in combination with other smoking-cessation therapies, such as bupropion or nicotine replacement therapy, have not been studied.

Bupropion:

Varenicline (1 mg BID) did not alter the steady-state pharmacokinetics of bupropion (150 mg BID) in 46 smokers. Steady-state pharmacokinetics of varenicline remained unchanged by bupropion co-administration.

Nicotine replacement therapy (NRT):

When varenicline (1 mg BID) and NRT (transdermal, 21 mg/day) were co-administered to 24 smokers for 12 days, there was a statistically significant decrease in average systolic blood pressure (mean 2.6 mmHg) measured on the final day of the study. In this study, the incidence of nausea, headache, vomiting, dizziness, dyspepsia and

fatigue were greater for the combination of varenicline and NRT than for NRT alone. Due to the partial agonist nicotinic activity of varenicline, it is not anticipated that co-administration with NRT would confer additional benefits compared with CHAMPIX alone, and may result in increased side effects (see WARNINGS AND PRECAUTIONS, General).

Drug-Food Interactions

Oral bioavailability of CHAMPIX is unaffected by food.

Drug-Herb Interactions

CHAMPIX has no known drug-herb interactions.

Drug-Laboratory Interactions

CHAMPIX has no known drug-laboratory test interactions.

DOSAGE AND ADMINISTRATION

Dosing Considerations

Smoking-cessation therapies are more likely to succeed for patients who are motivated to stop smoking and who are provided additional counselling and /or support services. Physicians should review the patient's overall smoking-cessation plan that includes treatment with CHAMPIX. There is little clinical experience with doses above the maximum recommended dose of 1 mg BID. The response rates observed for 1.0 mg BID and 0.5 mg BID were 23% and 19% respectively (see CLINCAL TRIAL)

Patients with Impaired Renal Function

For patients with severe renal impairment, daily dosage should be adjusted accordingly (see Recommended Dose and Dosage Adjustment: Special Populations, Patients with Impaired Renal Function, below)

Recommended Dose and Dosage Adjustment

Adults

To optimize opportunity for the success of the therapy, patients should be titrated up to the maximum recommended dose of 1 mg twice daily, using the following 1-week titration schedule: Days 1 - 3: 0.5 mg once daily Days 4 - 7: 0.5 mg twice daily Days 8 - End of treatment: 1.0 mg twice daily Patients who cannot tolerate adverse effects of CHAMPIX may have the dose lowered temporarily or permanently. The patient should set a date to stop smoking. CHAMPIX dosing should start 1-2 weeks before this date. Patients should be treated with CHAMPIX for 12 weeks. For patients who have successfully stopped smoking at the end of 12 weeks, an additional course of 12 weeks treatment with CHAMPIX may be considered. No data are available on the efficacy of an additional 12 week course of treatment for patients who do not succeed in stopping smoking or who relapse after treatment. Dose tapering may be considered. Regardless of whether the treatment course is 12 or 24 weeks, risk of smoking-cessation relapse is elevated in the period immediately following the end of drug treatment (see CLINICAL TRIALS). In addition, dose tapering may help minimize discontinuation symptoms (eg, increase in irritability, urge to smoke, depression, and/or insomnia), observed in up to 3% of patients at the end of treatment.

Special Populations

Patients with Impaired Renal Function:

No dosage adjustment is necessary for patients with mild (estimated creatinine clearance >50 mL/min and < 80 mL/min) to moderate (estimated creatinine clearance >=30 mL/min and

<

50 mL/min) renal impairment. For patients who experience intolerable adverse events, dosing may be reduced.

For patients with severe renal impairment, the recommended dose of CHAMPIX is 0.5 mg twice daily. Dosing should begin at 0.5 mg once daily for the first 3 days then increased to 0.5 mg twice daily. Based on insufficient clinical experience with CHAMPIX in patients with end-stage renal disease, treatment is not recommended in this patient population (see also WARNINGS AND PRECAUTIONS, Special Populations: Renal Impairment).

Patients with Hepatic Impairment:

No dosage adjustment is necessary for patients with hepatic impairment. Psychiatric Patients, Patients with Epilepsy, Patients undergoing Chemotherapy, Patients with GI disturbances such as irritable bowel, and in general, patients with heart disease or COPD: The use of CHAMPIX has not been studied in these patient populations (see WARNINGS AND PRECAUTIONS, Special Populations).

Dosing in Elderly Patients:

No dosage adjustment is necessary for elderly patients with normal renal function. However, varenicline is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. 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 WARNINGS AND PRECAUTIONS, Special Populations: Geriatrics).

Use in Children:

Safety and effectiveness of CHAMPIX in pediatric patients have not been established; therefore, CHAMPIX is not recommended for use in patients under 18 years of age.

Administration

CHAMPIX is given orally with or without food (see ACTION AND CLINICAL PHARMACOLOGY).

OVERDOSAGE

Symptoms

Consistent with its pharmacological profile, CHAMPIX resulted in increased incidences of nausea and vomiting when given at doses greater than the recommended dose of 1 mg BID.

Treatment

Varenicline has been shown to be dialyzed in patients with end-stage renal disease (see ACTION AND CLINICAL PHARMACOLOGY, Special Populations and Conditions: Renal Insufficiency), however, there is no experience with dialysis following overdose.

ACTION AND CLINICAL PHARMACOLOGY

Mechanism of Action

The efficacy of CHAMPIX in smoking-cessation is believed to be a result of varenicline's partial agonist activity at the a4b2 nicotinic acetylcholine receptor (ie agonist activity to a lesser degree than nicotine), while simultaneously preventing nicotine binding (ie antagonist activity).

In vitro

, varenicline binds with higher affinity to the a4b2 receptor subtype than to other common nicotinic receptors (>500-fold a3b4; >3,500-fold a7; >20,000-fold a1bgd), or to non- nicotinic receptors and transporters (> 2,000-fold).

Electrophysiology studies in vitro and neurochemical studies in vivo have shown that varenicline acts as a partial agonist at a4b2 nicotinic acetylcholine receptors. In the absence of nicotine, varenicline's agonist activity is at a significantly lower level than nicotine, but sufficient to activate the central nervous mesolimbic dopamine system, believed to be the neuronal mechanism underlying reinforcement and reward experienced upon smoking. In the presence of nicotine, which competes for the same human a4b2 nicotinic acetylcholine receptor (nAChR) binding site, varenicline prevented nicotine from activating the a4b2 receptor, since it has higher affinity for this site and this prevented full stimulation of the central nervous mesolimbic dopamine system. Varenicline is also a partial agonist at a3b4 receptors, but a full agonist at a7 receptors and a full agonist at 5-HT3 receptors. Varenicline has moderate affinity for the 5-HT3 serotonergic receptor (Ki=350 nM), at which it acts as a weak, full agonist (EC50=0.96 mM). Varenicline-induced nausea shortly after dosing, when gastrointestinal levels are predicted to be temporarily high, may be due to activation of this peripheral receptor, in addition to a possible role for peripheral a3b4 and/or central a4b2 nAChRs.

Pharmacokinetics

Table 2. Summary of Mean with Standard Deviation Varenicline Pharmacokinetic Parameters in Adult Male and Female Smokers

aDerived from three multiple-dose studies (N=103); +N=64; ++N=46 bTmax presented as median [range]

c

Apparent clearance and central volume of distribution estimated from a population PK analysis conducted on pooled data from 1878 subjects (49.2% females); presented as typical value (interindividual coefficient of variation)

Absorption:

Maximum plasma concentrations of varenicline occur typically within 3-4 hours after oral administration. Following administration of multiple oral doses of varenicline to healthy volunteers, steady-state conditions were reached within 4 days. Varenicline exhibits linear kinetics when given as single (0.1 to 3 mg) or repeated (1 to 3 mg/day) doses.

In a mass balance study, absorption of varenicline is virtually complete after oral administration and systemic availability is high. Oral bioavailability of varenicline is unaffected by food or time-of-day dosing. Distribution: Plasma protein binding of varenicline is low (<20%) and independent of both age and renal function.

Metabolism:

Varenicline tartrate undergoes minimal metabolism, with approximately 92% of recovered drug-related entity in urine being unchanged varenicline. Metabolite profiles (for circulation and urine) were similar for smokers and non-smokers, and are from the following minor routes of metabolism: N-carbomyl glucuronidation, N-formylation and conjugation with a hexose sugar.

Elimination:

The elimination half-life of varenicline tartrate is approximately 24 hours. Renal elimination of varenicline is the major elimination route, primarily through glomerular filtration along with active tubular secretion via the organic cationic transporter, OCT2.

Special Populations and Conditions

There were no clinically meaningful differences seen in varenicline tartrate pharmacokinetics due to being elderly, race, gender, smoking status, or use of concomitant medications, as demonstrated in specific pharmacokinetic studies and in population pharmacokinetic analyses.

Pediatrics:

When 22 adolescent smokers aged 12 to 17 years (inclusive) received a single

0.5 mg and 1.0 mg dose of varenicline the pharmacokinetics of varenicline was approximately dose proportional between the 0.5 mg and 1 mg doses. Systemic exposure, as assessed by AUC0-[? ], and renal clearance of varenicline tartrate were comparable to those of an adult population. An increase of 30% in Cmax and a shorter elimination half-life (10.9 hr) were observed in adolescents compared with adults. Because the safety and effectiveness of varenicline in pediatric patients have not been established, varenicline is not recommended for use in patients under 18 years of age.

Geriatrics:

A combined single and multiple-dose pharmacokinetic study demonstrated that the pharmacokinetics of 1 mg varenicline given once or twice daily to 16 healthy elderly male and female smokers (aged 65-75 years) for 7 consecutive days was similar to that of younger subjects.

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 DOSAGE AND ADMINISTRATION, Special Populations: Geriatrics).

Hepatic Insufficiency: DOSAGE AND ADMINISTRATION

Due to the absence of significant hepatic metabolism, varenicline tartrate pharmacokinetics should be unaffected in patients with hepatic insufficiency, except in the case that there is accompanying renal compromise (see

). The potential for clinically meaningful drug interactions between varenicline and metabolic inhibitors/inducers is low.

Renal Impairment:

Varenicline tartrate pharmacokinetics were studied in subjects with normal, mild, moderate, severe renal impairment and end-stage renal disease (n=6 per arm), following

0.5 mg once daily administration for 12 days. Varenicline pharmacokinetics were essentially unchanged in subjects with mild renal impairment (estimated creatinine clearance >50 mL/min and <=80 mL/min). In patients with moderate renal impairment (estimated creatinine clearance >=30 mL/min and

<=

50 mL/min), varenicline exposure [AUCt] increased 1.5-fold compared with subjects with normal renal function (estimated creatinine clearance >80 mL/min).

In subjects with severe renal impairment (estimated creatinine clearance <30 mL/min), varenicline exposure [AUCt] was increased 2.1-fold. In subjects with end-stage renal disease (ESRD), undergoing a three hour session of hemodialysis for three days a week, varenicline exposure [AUCt] was increased 2.7-fold; varenicline was efficiently removed by hemodialysis (see DOSAGE AND ADMINISTRATION, Recommended Dose and Dosage Adjustment: Special Populations, Patients with Impaired Renal Function).

STORAGE AND STABILITY

Store at room temperature (15-30oC).

DOSAGE FORMS, COMPOSITION AND PACKAGING

CHAMPIX is supplied for oral administration in two strengths: 0.5 mg: capsular biconvex, white to off-white, film-coated tablet debossed with "Pfizer" on one side and "CHX 0.5" on the other side. Each tablet contains 0.5 mg of varenicline (as tartrate). Supplied in high-density polyethylene (HDPE) bottles of 56 tablets and in blister strips of 11 tablets. 1.0 mg: capsular biconvex, light blue film-coated tablet debossed with "Pfizer" on one side and "CHX 1.0" on the other side. Each tablet contains 1.0 mg of varenicline (as tartrate). Supplied in high-density polyethylene (HDPE) bottles of 56 tablets and in blister strips of 14 tablets. Initial dosing pack: Includes 0.5 mg tablets in blister strips of 11 tablets and 1.0 mg tablets in blister strips of 14 tablets. Nonmedicinal ingredients are microcrystalline cellulose, anhydrous dibasic calcium phosphate, croscarmellose sodium, colloidal silicon dioxide and magnesium stearate. The film-coating contains hypromellose, titanium dioxide, polyethylene glycol and triacetin. The 1.0 mg tablet also contains FD&C Blue #2/Indigo Carmine Aluminum Lake as a colouring agent.

PART II: SCIENTIFIC INFORMATION

PHARMACEUTICAL INFORMATION

Drug Substance

Proper name : Varenicline tartrate Chemical name: 7,8,9,10-tetrahydro-6,10-methano-6H-pyrazino[2,3-h][3]benzazepine, (2R,3R)-2,3-dihydroxybutanedioate (1:1) Molecular formula: C13H13N3 * C4H6O6 Molecular weight: 361.35 Daltons Structural formula:

OH

R

R COO H N

OH

N N

Physicochemical properties: Varenicline tartrate powder is a white to off-white to slightly yellow solid which is highly soluble in water.

CLINICAL TRIALS

The efficacy of CHAMPIX (varenicline tartrate) in smoking-cessation was demonstrated in five double-blind, placebo-controlled clinical trials in which a total of 4190 chronic cigarette smokers (>=10 cigarettes per day) received varenicline. Patients set a date to stop smoking (target quit date, or TQD) of 1 week after treatment initiation. For four of the studies, the primary outcome was based on 12 weeks of drug treatment, with a subsequent 40 weeks of double-blind assessment, post drug-treatment. Of these four, two included a bupropion SR arm. The fifth study assessed the effect of 12 weeks of double-blind treatment on maintenance of abstinence achieved during a prior 12 weeks of open-label varenicline.

The four smoking cessation studies with 12 weeks treatment:

Primary Objective:

A comparison of varenicline to placebo, and additionally in each of the two studies with a bupropion SR arm comparison of varenicline (1 mg BID) to buproprion SR.

Primary endpoint:

Abstinence Responder rate was defined as % of patients for whom 4-week continuous abstinence from Week 9 through Week 12 (4 Week-Continuous Quit Rate, or 4W- CQR) was recorded. Abstinence from smoking was determined on a weekly basis, by patient self-report and measurement of expired carbon monoxide levels (CO). Abstinence was defined as self-report of not even a puff of a cigarette, and by having CO measurements of <=10 ppm. Intent-to-treat population was used, and patients who discontinued drug treatment early were eligible as responders, provided they chose to remain in the study.

Key secondary endpoint:

Continuous Abstinence Rate (CAR) was defined as the proportion of all patients who reported that they did not smoke (not even a puff of a cigarette) from Week 9 through to Week 52 (ie, including the 40-week non-drug treatment period), and had an exhaled CO measurement of <=10 ppm.

Study 1; 12-week randomized dose comparison: This study compared CHAMPIX 0.5 mg BID (n=253) and 1.0 mg BID (n=253) with placebo (n=121). Each treatment arm had two different regimens - with or without a week of dose titration - in order to explore the effect on tolerability. The titrated and non-titrated groups were pooled for efficacy analysis.

Study 2; 12-week flexible dose study: This study (n=312) examined the effect of patient-directed dosing strategy of CHAMPIX or placebo. After an initial one week titration to a dose 0.5 mg BID, patients could adjust their dosage as often as they wished between 0.5 mg QD to 1.0 mg BID. Sixty-nine percent (69%) of patients titrated to the maximum allowable dose at any time during the study. For 44% of patients, the modal dose selected was 1.0 mg BID; for 52% of the study patients, the modal dose selected was 1.0 mg/day or less.

Study 3 and Study 4; Identical 12-week studies with active comparator arm: Two identical double-blinded clinical trials prospectively compared the efficacy of CHAMPIX (1.0 mg BID) to placebo, and to sustained release bupropion (150 mg BID) in the absence of NRT in smoking-cessation. Patients received treatment for 12 weeks and then were followed for a total study duration of 52 weeks. The CHAMPIX dosage of 1.0 mg BID was achieved using a titration of 0.5 mg once daily for the initial 3 days followed by 0.5 mg BID for the next 4 days. The bupropion dosage of 150 mg BID was achieved using a 3-day titration of 150 mg once daily.

Study Results

Primary Endpoint

In all four studies, the primary endpoint for CHAMPIX (ie, 4W-CQR from Week 9 to Week 12) demonstrated statistical superiority to placebo and in the subset of the two identical studies, statistical superiority to bupropion SR was also demonstrated with CHAMPIX 1.0 mg BID dose. No patients were allowed to use NRT during the drug treatment phase, and those who did were considered treatment failures. The 4W-CQR (weeks 9-12) for all four studies are shown in Table 3.

Table 3. Continuous Quit Rate, Week 9 through 12 across different studies

Study 1 45% * n=253

51% *

n=253

12%

n=121

Study 2 40% *

12% n=155

Study 3 44% *#

30%+a n=329

17% n=344

Study 4 44% *#

30%+a n=340

18% n=340

P<0.0001 CHAMPIX vs placebo

+

P<0.001 Bupropion SR vs placebo

# P<0.0001 CHAMPIX 1.0 mg BID vs Bupropion SR

a

Statistical comparison of bupropion SR vs placebo was not protocol-specified.

Figure 1. Continuous Quit Rate, Week 9 through 12 across different studies

CQR 9-12

60%

50%

40%

30%

20%

10%

0%

CHAMPIX

CHAMPIX Placebo CHAMPIX

Placebo CHAMPIX Bupropion

Placebo CHAMPIX Bupropion

Placebo

0.5 mg BID

1.0 mg BID

SR 150 mg

BID

1.0 mg BID

SR 150 mg BID

STUDY 1 STUDY 2 STUDY 3 STUDY 4

Secondary Endpoints:

In all four studies, a key secondary endpoint for CHAMPIX (ie, CAR Week 9 through 52) demonstrated statistical superiority to placebo. The CAR Weeks 9 through 52 for all four studies are shown in Table 4.

Table 4. Continuous Abstinence Rate, Week 9 through 52 across different studies

Study 1 19% * n=253

22.9% *

n=253

4.1%

n=121

y 2

22.3% *

7.7% n=155

y 3

22.1% *

16.4%+ a

n=329

8.4% n=344

Study 4 23% *

15% a

n=340

10.3% n=340

P<0.0001 CHAMPIX vs placebo

+

P<0.001 Bupropion SR vs placebo

a

Statistical comparison of bupropion SR vs placebo was not protocol-specified.

Figure 2. Continuous Abstinence Rate, Week 9 through 52 across different studies

CA 9-52

35%

30%

25%

20%

15%

10%

5%

%CHAMPIX

0.5 mg BID

CHAMPIX

1.0 mg BID

Placebo CHAMPIX Flexible

Placebo CHAMPIX

1.0 mg BID

Bupropion SR

150 mg BID

Placebo CHAMPIX

1.0 mg BID

Bupropion SR

150 mg BID

Placebo

STUDY 1 STUDY 2 STUDY 3 STUDY 4

Urge to Smoke and Withdrawal Symptoms

Based on the responses to the Brief Questionnaire of Smoking Urges and the Minnesota Nicotine Withdrawal Scale, as measured in the 12-week treatment period, craving and urge to smoke were significantly reduced in patients randomized to CHAMPIX compared to those randomized to placebo, as were negative affect withdrawal symptoms (depressed mood; irritability, frustration, or anger; anxiety; difficulty concentrating).

Maintenance of Abstinence Study

The fifth study assessed the benefit of an additional 12 weeks of CHAMPIX therapy on the maintenance of abstinence. Patients received open-label CHAMPIX 1.0 mg BID for 12 weeks. Patients who were abstinent for 7 continuous days at Week 12 were then randomized to double- blind treatment with either CHAMPIX (1.0 mg BID, n=602) or placebo (n=604) for an additional 12 weeks, and then followed for a total study duration of 52 weeks. The primary study endpoint was the CO-confirmed CAR (defined as above) from Week 13 through Week 24 in the double-blind treatment phase. A key secondary endpoint was the CAR for Week 13 through Week 52. Superiority to placebo was shown for both the primary and secondary endpoints (see Table 5). The CAR from Week 13 through Week 24 was higher for patients continuing treatment with CHAMPIX (70.6%) than for patients switching to placebo (49.8%). Superiority to placebo was also maintained during the 28-week post-treatment follow-up (CHAMPIX 44.0% versus placebo 37.1% at Week 52). This study showed the benefit of an additional 12 weeks of treatment with CHAMPIX 1.0 mg BID for the maintenance of smoking-cessation, compared to placebo. A statistically significant difference was maintained at Week 52, the final week of the study.

Table 5. Maintenance Study Results

CHAMPIX N=602

Placebo N=604 (%)

CAR wk 13-24 70.6 * 49.8

CAR wk 13-52 44.0 * * 37.1

P<0.0001 CHAMPIX vs placebo

* * P<0.01 CHAMPIX vs placebo

(CAR) continuous abstinence rate

Figure 3. Continuous Abstinence Rate from Week 13 through Week 52 Maintenance Study

Varenicline Placebo

Responders (%)

Phase

Nontreatment Follow-up

12 16 20 24 28 32 36 40 44 48 52

Study Week

Note: Subjects at Week 12 were those who were abstinent during the last week of open- label varenicline treatment and were randomized and received treatment in the double- blind phase.

DETAILED PHARMACOLOGY

Preclinical Pharmacology

In vitro and in vivo experiments demonstrate that varenicline performs as expected for a partial agonist of the a4 b2 nicotinic receptor subtype. For example, dopamine turnover and microdialysis results in rats demonstrate that varenicline has a reduced ability to activate the mesolimbic dopamine system relative to nicotine, and in fact varenicline can attenuate the activating effects of nicotine on this system. While varenicline does substitute for nicotine in a discrimination paradigm, varenicline was shown to be less reinforcing than nicotine in rats trained to self-administer nicotine, and pretreatment with varenicline significantly decreased nicotine self-administration. Finally, in a withdrawal study in rats and a study assessing withdrawal in monkeys there were no observed behaviours or responses consistent with withdrawal effects.

In vivo and in vitro data demonstrate that varenicline is well absorbed after oral administration. Protein binding of varenicline is low and similar across species. It readily distributes throughout the body with increased but reversible association with melanin-containing tissues. Varenicline was shown to not interact with major human drug metabolizing CYPs. A substantial portion (75% - 93% of dose) of varenicline was excreted as unchanged drug in all species examined, with most drug-related material excreted in urine. Metabolites were minor and those observed in human circulation and excreta were also observed in one or more animal species. In vitro data suggest that renal excretion of varenicline occurs by both passive filtration and an active transport process (likely via renal transporter OCT2).

TOXICOLOGY

The toxicology program was conducted to characterize the toxicity and dose response in the appropriate nonclinical species of the rat and monkey. No evidence of any unique toxicity or adverse pharmacological effects of varenicline in the expected range of human plasma exposure was observed in animals.

Acute and Repeated-Dose Toxicity

The toxicology program was conducted to characterize the toxicity and dose response in the appropriate nonclinical species of the rat and monkey. Effects were seen primarily in the gastrointestinal tract and the central nervous system (CNS) ie, tremors and convulsions at exposure multiples greater than those observed in humans. These changes were reversible.

Acute Toxicity

Acute oral studies in rat (30, 100, 200, and 300 mg/kg) and monkey (3 mg/kg) and intravenous (IV) studies in monkeys (0.08-0.3 mg/kg) were conducted. In the single-dose study in rats, the findings were in the gastrointestinal system (decreased body weight and loose stool) and CNS (tremors and convulsions). The onset of the CNS clinical signs was rapid and occurred immediately to 2.5 hours post-dosing. All findings were reversed by the end of the 14-day observation period. There was one death in rats dosed at 300 mg/kg PO, a dose associated with exposure approximately 300-fold above expected human exposure. The single-dose no observed adverse effect level (NOAEL) in monkeys was 0.2 mg/kg (0.1 mg/kg BID) corresponding to an exposure of approximately 1.2-fold above expected human exposure. In a single-dose oral study in monkeys at 3 mg/kg, the findings were also in the gastrointestinal system (emesis) and CNS (tremors). In addition electrocardiogram changes (decreased HR and QT interval and increased PRQ and P wave) were observed. Clinical signs (emesis and tremors) occurred at similar exposures after both oral gavage and IV dosing, both associated with exposure approximately 2- to 4-fold above expected human exposure. All of the findings occurred within ~1-4 hours post-dosing and were not present the next day.

Repeated-Dose Toxicity

Table 6. Repeat-Dose Gavage Pivotal Studies in Rats and Monkeys

Rats:

The no-observed adverse effect level (NOAEL) in rats was 10 mg/kg/day in the 3- and 6-month studies, which corresponds to Cmax and AUC values that are 68 and 50 times those at the maximum recommended human dose (MRHD), respectively. The NOAELs in both studies were based on decreases in body weight and food consumption, which were attributed to decreases in gastric motility. In the 6-week and 3-month rat studies at 30 mg/kg/day (associated with exposures of approximately 75- to 140-fold above expected human exposure) the findings were in the gastrointestinal tract; decreases in body weight, food consumption, and intestinal dilatation, which were consistent with decreases in gastric motility. At >=10 mg/kg/day (associated with exposures of approximately 40- to 65-fold above expected human exposure), there were slight increases in alkaline phosphatase (ALP), alanine transaminase (ALT), and/or total bilirubin. In addition, hepatocellular single-cell necrosis was observed in a 10 day study, at 100 mg/kg/day. At >=30 mg/kg/day, there were slight increases in hematocrit and hemoglobin. Similar changes were seen in mice and other rat studies, but not monkeys. The changes may be secondary to stress of decreased food consumption and dehydration. In the 6-month rat study, findings were also in the gastrointestinal tract (decreases in body weight and food consumption). In this study, there were no biologically meaningful hepatic changes as compared to the marginal hepatic findings observed in the shorter-term studies.

Monkeys:

The NOAEL in cynomolgus monkeys was 0.2 mg/kg/day (0.1 mg/kg BID) in the first 9-month study. There were also no findings in the second 9-month study at this dose, which was the low dose. The next dose up (0.4 mg/kg/day) showed sporadic emesis and loose stools. The Cmax and AUC at 0.2 mg/kg/day in monkeys was approximately 3-fold the human exposure at MRHD. There were no findings in the 6-week, 3-month, or the first 9-month study, at doses up to 0.2 mg/kg/day. In the second 9-month monkey study, the main finding at 0.4 mg/kg/day (0.2 mg/kg BID) was sporadic emesis. One female monkey was found dead at this dose of megacolon, secondary to colonic torsion and ischemic necrosis. Megacolon is an uncommon spontaneous finding in monkeys. This finding was likely secondary to the gastrointestinal dysfunction (loose stools) that was evident prior to and during treatment, although drug treatment can not be excluded. Colonic torsion was not observed in other monkeys with equivalent or higher doses. At 1.2 mg/kg/day (0.6 mg/kg BID) - approximately 10- to 12-fold above expected human exposure - all animals were euthanized or removed from study after 3-8 weeks of treatment due to body weight loss (>15% in 10 of 12 monkeys) associated with emesis and decreased food consumption. Decreases in core body temperature of 1-2 degrees Celcius were observed (and had also been seen in an earlier monkey study at 0.6 mg/kg/day, and were also seen in mice; body temperature perturbation is a well-known effect of nicotine). There were no treatment-related microscopic findings in any of the animals. Dosing was discontinued and the surviving animals at 1.2 mg/kg/day (0.6 mg/kg BID) were monitored for ~1 month. The clinical signs ceased and body weight returned to pretreatment levels within a month.

REFERENCES

Acri JB, Grunberg NE, Morse DE. Effects of nicotine on the acoustic startle reflex amplitude in rats. Psychopharmacology (Berl). 1991; 104(2):244-8. Al-Hachim GM, Mahmoud FA. Prenatal nicotine and CNS development. Epilepsia. 1985 Nov- Dec; 26(6):661-5. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Washington, DC: American Psychiatric Association; 1994. Baldi A, Santini M, Mellone P, Esposito V, Groeger AM, Caputi M, et al. Mediastinal hibernoma: a case report. J Clin Pathol. 2004 Sep; 57(9):993-4. Burstein AH, Fullerton T, Clark DJ, Faessel HM. Pharmacokinetics, safety, and tolerability after single and multiple oral doses of varenicline in elderly smokers. J Clin Pharmacol. 2006 Nov; 46(11):1234-40. Cappelleri JC, Bushmakin AG, Baker CL, Merikle E, Olufade AO, Gilbert DG. Revealing the multidimensional framework of the Minnesota nicotine withdrawal scale. Curr Med Res Opin. 2005 May; 21(5):749-60. Coe JW, Brooks PR, Vetelino MG, Wirtz MC, Arnold EP, Huang J, et al. Varenicline: an alpha4beta2 nicotinic receptor partial agonist for smoking-cessation. J Med Chem. 2005 May 19; 48(10):3474-7. Faessel HM, Smith BJ, Gibbs MA, Gobey JS, Clark DJ, Burstein AH. Single-dose pharmacokinetics of varenicline, a selective nicotinic receptor partial agonist, in healthy smokers and nonsmokers. J Clin Pharmacol. 2006 Sep; 46(9):991-8. Faessel HM, Gibbs MA, Clark DJ, Rohrbacher K, Stolar M, Burstein AH. Multiple-dose pharmacokinetics of the selective nicotinic receptor partial agonist, varenicline, in healthy smokers. J Clin Pharmacol. 2006 Dec; 46(12):1439-48. Gonzales D, Rennard SI, Nides M, Oncken C, Azoulay S, Billing CB, Watsky EJ, Gong J, Williams KE, Reeves KR. Varenicline, an alpha4beta2 nicotinic acetylcholine receptor partial agonist, vs sustained-release bupropion and placebo for smoking-cessation: a randomized controlled trial. JAMA. 2006 Jul 5; 296(1):47-55. Hughes JR, Keely JP, Niaura RS, Ossip-Klein DJ, Richmond RL, Swan GE. Measures of abstinence in clinical trials: issues and recommendations. Nicotine Tob Res. 2003 Feb; 5(1):13-

1. Erratum in: Nicotine Tob Res. 2003 Aug; 5(4):603.

Jorenby DE, Hays JT, Rigotti NA, Azoulay S, Watsky EJ, Williams KE, Billing CB, Gong J, Reeves KR. Efficacy of varenicline, an alpha4beta2 nicotinic acetylcholine receptor partial agonist, vs placebo or sustained-release bupropion for smoking-cessation: a randomized controlled trial. JAMA. 2006 Jul 5; 296(1):56-63. Erratum in: JAMA. 2006 Sep 20; 296(11):1355. Lean ME, James WP, Jennings G, Trayhurn P. Brown adipose tissue uncoupling protein content in human infants, children and adults. Clin Sci (Lond). 1986 Sep; 71(3):291-7. Maskos U, Molles BE, Pons S, Besson M, Guiard BP, Guilloux JP, et al. Nicotine reinforcement and cognition restored by targeted expression of nicotinic receptors. Nature. 2005 Jul 7; 436(7047):103-7. Nides M, Oncken C, Gonzales D, Rennard S, Watsky EJ, Anziano R, Reeves KR. Smoking- cessation with varenicline, a selective alpha4beta2 nicotinic receptor partial agonist: results from a 7-week, randomized, placebo- and bupropion-controlled trial with 1-year follow-up. Arch Intern Med. 2006 Aug 14-28; 166(15):1561-8. Obach RS, Reed-Hagen AE, Krueger SS, Obach BJ, O'Connell TN, Zandi KS, et al. Metabolism and disposition of varenicline, a selective alpha4beta2 acetylcholine receptor partial agonist, in vivo and in vitro. Drug Metab Dispos. 2006 Jan; 34(1):121-30. Oncken C, Gonzales D, Nides M, Rennard S, Watsky E, Billing CB, Anziano R, Reeves K. Efficacy and safety of the novel selective nicotinic acetylcholine receptor partial agonist, varenicline, for smoking-cessation. Arch Intern Med. 2006 Aug 14-28; 166(15):1571-7. Rollema H, Chambers LK, Coe JW, Glowa J, Hurst RS, Lebel LA, et al. Pharmacological profile of the alpha(4)beta(2) nicotinic acetylcholine receptor partial agonist varenicline, an effective smoking-cessation aid. Neuropharmacology. 2006 Dec 6; [Epub ahead of print http://dx.doi.org/10.1016/j.neuropharm.2006.10.016] Sell H, Deshaies Y, Richard D. The brown adipocyte: update on its metabolic role. Int J Biochem Cell Biol. 2004 Nov; 36(11):2098-104. SRNT Subcommittee on Biochemical Verification. Biochemical verification of tobacco use and cessation. Nicotine Tob Res. 2002 May; 4(2):149-59. Tapper AR, McKinney SL, Nashmi R, Schwarz J, Deshpande P, Labarca C, et al. Nicotine activation of alpha4 receptors: sufficient for reward, tolerance, and sensitization. Science. 2004 Nov 5; 306(5698):1029-32. Tonstad S, Tonnesen P, Hajek P, Williams KE, Billing CB, Reeves KR; Varenicline Phase 3 Study Group. Effect of maintenance therapy with varenicline on smoking-cessation: a randomized controlled trial. JAMA. 2006 Jul 5; 296(1):64-71. Ward MM, Swan GE, Jack LM. Self-reported abstinence effects in the first month after smoking-cessation. Addict Behav. 2001 May-Jun; 26(3):311-27. West R, Hajek P, Stead L, Stapleton J. Outcome criteria in smoking-cessation trials: proposal for a common standard. Addiction. 2005 Mar; 100(3):299-303.

PART III: CONSUMER INFORMATION

PrCHAMPIX(r)

(varenicline tartrate tablets)

Read this information each time you refill your prescription in case new information has been added.

This leaflet is part III of a three-part "Product Monograph" published when CHAMPIX was approved for sale in Canada and is designed specifically for Consumers. This leaflet is a summary and will not tell you everything about CHAMPIX. Contact your doctor or pharmacist if you have any questions about the drug.

ABOUT THIS MEDICATION

What the medication is used for:

CHAMPIX is a prescription medicine which is used to help motivated adults stop smoking.

What it does:

CHAMPIX can help to relieve the craving and withdrawal symptoms associated with stopping smoking.

CHAMPIX does not contain nicotine, but it has been shown to affect the nicotine receptor that is thought to be most related to smoking addiction. CHAMPIX can affect this receptor in two opposite ways: it acts like a weaker version of nicotine, and also blocks nicotine from getting to the receptor because it binds more tightly. Although it is thought that this may be, in part, how CHAMPIX works, it is not known exactly how the drug works in people.

To increase the chances of success, CHAMPIX should be used in combination with supportive counselling as recommended by your doctor or pharmacist.

When it should not be used:

Do not take CHAMPIX

• If you are allergic (hypersensitive) to varenicline tartrate

or any of the other ingredients of CHAMPIX. (see list below).

If you are using nicotine replacement therapy, such as patches, gum or inhaler. The combination of CHAMPIX

and nicotine replacement therapy is not expected to

improve your chances of quitting, and may result in more side effects than with CHAMPIX alone.

What the medicinal ingredient is:

Varenicline tartrate

What the important nonmedicinal ingredients are:

The non-medicinal ingredients are microcrystalline cellulose,

anhydrous dibasic calcium phosphate, croscarmellose sodium, colloidal silicon dioxide and magnesium stearate. The film- coating contains hypromellose, titanium dioxide, polyethylene glycol and triacetin. The 1 mg tablet also contains FD&C Blue

#2/Indigo Carmine Aluminum Lake as a colouring agent.

What dosage forms it comes in:

CHAMPIX is available as film-coated tablets. The 0.5 mg tablets are white and the 1 mg tablets are light blue.

WARNINGS AND PRECAUTIONS

BEFORE you use CHAMPIX talk to your doctor or pharmacist if:

• You have experienced depression or other mental health

problems. CHAMPIX has not been studied in people with mental health problems, and therefore your doctor will be monitoring you closely for new or worsened emotional or behavioral problems while on CHAMPIX.

You are taking or have recently taken any other medicines, including medicines obtained without a prescription.

You have any problems with your kidneys, as you may need a lower dose of CHAMPIX.

The effects of changes in your body resulting from stopping smoking, with or without treatment with CHAMPIX, may alter the way other drugs work. Tell your doctor if you take:

• Insulin

• Asthma medicines (theophylline)

• Blood thinner (warfarin)

as an adjustment of the dose of these medicines may be necessary

once you are smoke-free.

New or Worsened Emotional or Behavioral Problems

Quitting smoking can be associated with changes in mood and behaviour, with or without taking medication to help quit. A small

number of patients taking CHAMPIX may experience unusual feelings of agitation, depressed mood, hostility changes in

behavior or have impulsive or disturbing thoughts such as thoughts of self-harm or harm to others. Stop taking CHAMPIX

and tell your doctor right away if you experience these symptoms

in a way that is not typical for you, or if you have thoughts of self-harm or harm to others. In a few cases, these symptoms have occurred after stopping CHAMPIX (see SIDE EFFECTS AND WHAT TO DO ABOUT THEM).

Pregnancy

Talk to your doctor if you are pregnant or planning to become pregnant.

You should not take CHAMPIX while you are pregnant. It is unknown if CHAMPIX will harm your unborn baby.

It is best to stop smoking before you get pregnant.

Breastfeeding

You should ask your doctor or pharmacist for advice before

taking any medication, including CHAMPIX, if you are breastfeeding, as the medecine may pass into breast milk.

CHAMPIX is not recommended for use in children under 18 years of age.

Driving and using machines

Do not engage in potentially hazardous tasks, such as driving a car or operating dangerous machines, until you are sure that this

medication does not affect your mental alertness or physical coordination.

INTERACTIONS WITH THIS MEDICATION

Use of CHAMPIX with other therapies for smoking-cessation

: The safety and benefits of taking CHAMPIX in combination with other medicines for stopping smoking have not been studied. Taking CHAMPIX in combination with other smoking-cessation therapies (eg., nicotine replacement therapy) is therefore not recommended. Using CHAMPIX in combination with nicotine replacement therapies (eg., patch. gum or inhaler) is not likely to increase your chances of quitting smoking, and it may result in more side effects than with CHAMPIX alone.

The maximum dose that could be prescribed to you is 2 mg/day. If you are experiencing problematic side effects, talk with your

doctor who may reduce your dose temporarily or permanently. You should take CHAMPIX for 12 weeks.

If you have stopped smoking after 12 weeks of treatment, your doctor may recommend additional weeks of CHAMPIX treatment.

CHAMPIX may be taken with or without food.

REMEMBER:

This medication has been prescribed specifically for you. Do not give it to anyone else.

Can I smoke while taking CHAMPIX?

PROPER USE OF THIS MEDICATION

You are more likely to stop smoking if you are motivated to stop. Your doctor and pharmacist can provide advice, support and sources of further information to help ensure your attempt to stop smoking is successful.

Always take CHAMPIX exactly as your doctor has told you. You should check with your doctor or pharmacist if you are not sure.

Before starting your course of CHAMPIX you should decide on a date in the second week of treatment (between Day 8 and Day 14) when you will stop smoking. This lets CHAMPIX build up in your body. You can keep smoking during this time. You should write your quit date on the CHAMPIX pack as a reminder. If you slip after that target date, keep trying. Some people need a few weeks for CHAMPIX to work best.

Usual dose:

The usual dose for adults which you should follow from Day 1 is described in the following table:

You can keep smoking prior to your quitting date. However, before starting your course of CHAMPIX you should decide on a date in the second week of treatment (between Day 8 and Day 14) when you will stop smoking.

Continuing to smoke after your quit date will reduce your chance of breaking your smoking addiction.

Overdose:

If you accidentally take more CHAMPIX than your doctor

prescribed, you must seek medical advice or go to the nearest hospital emergency department immediately. Take your medication with you.

Missed Dose:

Do not take a double dose to make up for a forgotten tablet. It is important that you take CHAMPIX regularly at the same time

each day. If you forget to take a dose, take it as soon as you

remember, as long as it is within a few hours of the missed dose. If it is longer than that since the missed dose, or if you do not remember whether you took a dose or not, then skip that dose, and wait to take the next dose at the correct time.

If you have any further questions on the use of this product, ask your doctor or pharmacist.

SIDE EFFECTS AND WHAT TO DO ABOUT THEM

Whether you are taking medication to stop smoking or not the following are symptoms you may feel: depressed, short-tempered, frustrated or angry, nervous, impatient; have difficulty concentrating. Your appetite may increase, and you may gain some weight.

Like all medicines, CHAMPIX can cause side effects, although not everybody gets them.

The common side effects are mostly mild to moderate and these usually occur in the first weeks of treatment.

The most common side effects include:

• Nausea

• Vomiting

• Trouble sleeping

• Headache

• Abnormal dreams (vivid, unusual, or increased dreaming;

rarely may include nightmares)

Constipation

Gas

Tell your doctor immediately if you experience unusual feelings of agitation depressed mood, hostility, changes in behavior or suicidal thoughts. Stop taking CHAMPIX if you experience these symptoms in a way that is not typical for you, or if you have thoughts of self-harm or harm to others. These symptoms have been reported in patients trying to stop smoking with or without CHAMPIX. It is not known if these symptoms are related to CHAMPIX (see WARNINGS AND PRECAUTIONS).

This is not a complete list of side effects. For any unexpected effects while taking CHAMPIX, contact your doctor or pharmacist.

HOW TO STORE IT

Store CHAMPIX at room temperature (15degC - 30degC). Keep out of the reach of children.

REPORTING SUSPECTED SIDE EFFECTS

To monitor drug safety, Health Canada through the Canada Vigilance Program collects information on

serious and unexpected side effects of drugs. If you suspect you have had a serious or unexpected reaction to this drug you may notify Canada Vigilance:

By toll-free telephone: 866-234-2345 By toll-free fax: 866-678-6789

Online: www.healthcanada.gc.ca/medeffect By email: CanadaVigilance @hc-sc.gc.ca

By regular mail:

Canada Vigilance National Office Marketed Health Products Safety and Effectiveness Information Bureau Marketed Health Products Directorate Health Products and Food Branch Health Canada

Tunney's Pasture, AL 0701C Ottawa ON K1A 0K9

NOTE:

Should you require information related to the management of the side effect, please contact your health care provider before notifying Canada Vigilance. The Canada Vigilance Program does not provide medical advice.

MORE INFORMATION

This document plus the full product monograph, prepared for health professionals can be found at:

http://www.Pfizer.ca

or by contacting the sponsor, Pfizer Canada Inc., at: 1-800-463-6001

This leaflet was prepared by Pfizer Canada Inc.

17,300 TransCanada Highway, Kirkland, Quebec H9J 2M5 Last revised: May 15, 2007