CHAMPIX

SUMMARY PRODUCT INFORMATION

Adults
CHAMPIX (varenicline tartrate) is indicated for smoking-cessation treatment in adults, in conjunction with smoking-cessation counselling.

Geriatrics (>65 years of age): No dosage adjustment is necessary for healthy elderly patients. 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).

Pediatrics (<18 years of age): Based on the data submitted and reviewed by Health Canada, the safety and efficacy of CHAMPIX in pediatric patients has not been established; therefore, Health Canada has not authorized an indication for pediatric use (see WARNINGS AND PRECAUTIONS, Special Populations: Pediatrics).

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

Psychiatric Symptoms (in Patients with and without Pre-existing Psychiatric Disorder or Symptoms) (see also ADVERSE REACTIONS, Post-Marketing Experience).

There have been post-marketing reports of serious neuropsychiatric symptoms in patients being treated with CHAMPIX, including anxiety, psychosis, mood swings, depressed mood, agitation, aggression, hostility, changes in behavior or thinking, suicidal ideation, suicidal behavior and suicide, as well as worsening of pre-existing psychiatric disorder (previously diagnosed or not). Not all patients had stopped smoking at the time of onset of symptoms, and not all patients had known pre-existing psychiatric illness, or were using concomitant CNS drugs.

Randomized Study Data: A large randomized, double-blind, active and placebo-controlled study (“EAGLES” study) was conducted to compare the risk of serious neuropsychiatric events in patients with and without a history of psychiatric disorder treated for smoking cessation with varenicline, bupropion, nicotine replacement therapy patch (NRT) or placebo. The primary safety endpoint was a composite of neuropsychiatric adverse events that have been reported in post-marketing experience. The findings were that the use of CHAMPIX, in patients with or without a history of psychiatric disorder, was not associated with an increased risk of serious neuropsychiatric adverse events in the composite primary endpoint compared with placebo (See ACTION AND CLINICAL PHARMACOLOGY, Special Populations and Conditions, Neuropsychiatric Safety Study in Subjects with and without a History of Psychiatric Disorder).

Recommendations: Clinicians should be aware of the possible emergence of serious neuropsychiatric symptoms in patients attempting to quit smoking, with or without treatment.

Alcohol intake: There have been post-marketing reports of patients experiencing increased intoxicating effects of alcohol while taking CHAMPIX. Some cases described unusual and sometimes aggressive behaviour, and were often accompanied by amnesia for the events.

Pre-existing Psychiatric Disorder or Symptoms: Smoking cessation, with or without pharmacotherapy, has been associated with exacerbation of underlying psychiatric illness (e.g. depression, anxiety). Patients with a history of psychiatric symptoms should be monitored for worsening or new symptoms when attempting to quit smoking, regardless of how well controlled symptoms may be when starting smoking cessation treatment. Patients should be instructed to report strongly atypical and concerning symptoms to their healthcare provider, so that dose adjustments of psychiatric medications or CHAMPIX may be considered.

General: Patients should be informed that if they experience thoughts, moods or behaviours that are strongly atypical and concerning while on smoking-cessation medication, including CHAMPIX, the medication should be discontinued immediately, with urgent medical help sought as needed, and the symptoms reported to their healthcare provider.

Angioedema and Hypersensitivity reactions

There have been post-marketing reports of hypersensitivity reactions, including angioedema, in patients treated with CHAMPIX (see ADVERSE REACTIONS, Post-Marketing Experience). Clinical signs included swelling of the face, mouth (tongue, lips and gums), neck (pharynx and larynx) and extremities. There were rare reports of life-threatening angioedema requiring urgent medical attention due to respiratory compromise. Patients experiencing these symptoms should be instructed to discontinue treatment with CHAMPIX and contact a healthcare provider immediately.

Serious Skin Reactions

There have also been post-marketing reports of rare but severe cutaneous reactions, including Stevens-Johnson syndrome and erythema multiforme, in patients using CHAMPIX (see ADVERSE REACTIONS, Post-Marketing Experience). As these skin reactions can be life-threatening, patients should be instructed to discontinue treatment at the first sign of rash or skin reaction and contact a healthcare provider immediately.

Seizures

In clinical trials and post-marketing experience there have been reports of seizures in patients treated with CHAMPIX. Some patients had no history of seizures, whereas others had a history of seizure disorder that was remote or well-controlled. CHAMPIX should be used cautiously in patients with a history of seizures or other conditions that potentially lower the seizure threshold. Advise patients to discontinue CHAMPIX and immediately contact a healthcare provider if they experience a seizure while on treatment (see Special Populations, Use of CHAMPIX in Patients with Concomitant Conditions).

Somnambulism

Cases of somnambulism have been reported post-marketing in patients taking CHAMPIX. Some cases described harmful behavior to self, others, or property. Instruct patients to discontinue CHAMPIX and notify their healthcare provider if they experience somnambulism.

Cardiovascular Events

In a placebo-controlled smoking cessation clinical trial in patients with stable cardiovascular disease (CVD), patients were treated with CHAMPIX 1 mg BID or placebo for 12 weeks, and then followed for another 40 weeks. There were approximately 350 patients per arm.

Serious cardiovascular (CV) events that were reported more frequently in CHAMPIX compared to placebo (difference > 2 subjects) were: non-fatal myocardial infarctions (4 vs. 1, on-treatment phase) and need for coronary revascularization (7 vs. 2, post-treatment phase). The total number of patients that experienced serious CV events in CHAMPIX compared to placebo was: 10 vs. 9 on treatment phase, 16 vs. 11 post-treatment phase, for a total of 25 vs. 20 over the 52 week duration. The serious CV events occurring during the treatment and post-treatment phases were adjudicated by an independent blinded committee.

The study was powered for assessing efficacy (ie quit rates) but not for assessing differences in the occurrence of serious CV events between CHAMPIX and placebo. Therefore, the study was not large enough to allow conclusions regarding the difference in the incidence of CV events reported in the two arms (See also ADVERSE EVENTS, Clinical Trial in Special Populations; and ACTION AND CLINICAL PHARMACOLOGY, Special Population). Physicians are to inform patients of the symptoms of a heart attack and stroke, and instruct them to get emergency medical help right away if they experience any of these symptoms (see also Patient Counselling Information).

The CV safety of CHAMPIX was also evaluated in the Cardiovascular Safety Assessment Study in subjects with and without a history of psychiatric disorder that randomized subjects 1:1:1:1 to CHAMPIX 1 mg BID, bupropion SR 150 mg BID, nicotine replacement therapy patch (NRT) 21 mg/day with taper or placebo for a treatment period of 12 weeks.  Subjects were then followed post-treatment through a period of up to a total of 52 weeks (See ACTION AND CLINICAL PHARMACOLOGY, Special Populations and Conditions, Cardiovascular Safety Assessment Study in Subjects with and without a History of Psychiatric Disease).  Major CV events (CV death, non-fatal MI, non-fatal stroke) were infrequent overall (1/2016 and 4/2014, for patients treated with CHAMPIX and placebo, respectively) during the treatment period. However, because of the relatively low number of events overall and the lack of power for assessing differences between CHAMPIX and placebo, an association between the use of CHAMPIX and an increased risk of CV adverse events cannot be entirely ruled out.

CHAMPIX has not been studied in patients with unstable cardiovascular disease or those with cardiovascular events occurring within two months before study screening. Patients should be advised to notify a health care provider of new or worsening symptoms of cardiovascular disease. The risks of CHAMPIX should be weighed against the benefits of its use in smokers with cardiovascular disease. Smoking is an independent and major risk factor for cardiovascular disease. CHAMPIX has been demonstrated to increase the likelihood of abstinence from smoking for as long as one year compared to treatment with placebo

Accidental Injury, including while Driving, Operating Machinery

There have been post-marketing reports of traffic accidents, near-miss incidents in traffic, and other accidental injuries in patients taking CHAMPIX. In some cases, the patients reported somnolence, dizziness, loss of consciousness (blackouts), seizures or difficulty concentrating.

Therefore, patients should be advised not to engage in potentially hazardous activities, such as driving a car or operating dangerous machines, until they know how CHAMPIX may affect them.

Concomitant Illness The full consequences of using this product in patients with concomitant illness have not been studied, and caution should be exercised (see Special Populations, Use of CHAMPIX in Patients with Concomitant Conditions).

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 (see DOSAGE AND ADMINISTRATION, Recommended Dose and Dosage Adjustment).

Carcinogenesis and Mutagenesis

For animal data, see Part II: TOXICOLOGY section.

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.

Patient Counselling Information

Consumer Information is included in the package of CHAMPIX dispensed to the patient.

Prior to prescribing CHAMPIX, physicians should:

• Discuss with the patient the expected benefits and risks of CHAMPIX, as well as those of all smoking-cessation options.
• Inform the patients that quitting smoking, with or without treatment, may be associated with nicotine withdrawal symptoms (including depression, irritation or agitation) or exacerbation of pre-existing psychiatric disorder.
• Encourage the patient to reveal any history of psychiatric disorder prior to initiating treatment. Patients with such history who are trying to stop smoking should be monitored by their physician for new or worsened psychiatric events.
• Advise patients:
  - not to engage in potentially hazardous tasks, such as driving a car or operating dangerous machines, until they know how CHAMPIX may affect them. In some cases, patients have reported somnolence, dizziness, loss of consciousness, seizures or difficulty concentrating while driving.
  - that some people have reported seizures while taking CHAMPIX and encourage them to report any history of seizures or other factors that can lower seizure threshold. Instruct patients to discontinue CHAMPIX and immediately contact a healthcare provider if they experience a seizure while on treatment.
  - that there have been post-marketing reports of serious neuropsychiatric symptoms in patients being treated with CHAMPIX, including anxiety, psychosis, mood swings, aggression, depressed mood, agitation, hallucinations, hostility, changes in behavior or thinking, suicidal ideation, suicidal behavior and suicide, as well as worsening of pre-existing psychiatric disorder. 
  - that i) new or worse cardiovascular events (heart and stroke) have been reported, primarily in those who already have cardiovascular problems and ii) based on available data, it is not possible to determine whether CHAMPIX increases the risk of cardiovascular events.

For those patients receiving CHAMPIX:

• Patients should be instructed to read the patient information leaflet supplied with every CHAMPIX prescription before starting their CHAMPIX pills. This leaflet is approved by Health Canada and is Part III of the CHAMPIX Product Monograph.
• Patients should also be provided with educational materials and necessary counselling to support an attempt at quitting smoking, including a review of the overall smoking cessation plan with the physician.
• Patients should call 1-800-CHAMPIX for a list of provincial Smoking Cessation resources (toll-free quit line) which can be used to support a quit attempt.
• Patients should be informed that there are three choices in setting a quit date when using CHAMPIX, and discuss with their physician which one is best for them.
• Patients should be instructed on how to titrate CHAMPIX:
  - Beginning at a dose of 0.5 mg per day. Prescribers should explain that one 0.5 mg tablet should be taken daily for the first three days, and then for the next four days, two 0.5 mg tablets should be taken daily: one in the morning and one in the evening.
  - Following this one week of titration, there are two dosing options:
  the dose can remain at 0.5 mg twice daily or can go up to 1.0 mg twice daily, depending on the physician judgment and patient preference. Based on the limited data available, the two-doses do not appear different in terms of either quit rates, or rates of serious psychiatric side effects (see DOSAGE AND ADMINISTRATION, Dosing Considerations).
  -If needed, the dose can be changed depending on how well the patient tolerates CHAMPIX and how effective the doctor and patient consider it is in helping the patient quit smoking.
  - Patients should be informed that the maximum dose of CHAMPIX is 1.0 mg twice a day.
• Patients should be encouraged to continue in their quit attempt if they have early lapses after their quit date.
• Patients should be encouraged to inform friends and family members of their quit attempt which includes treatment with CHAMPIX and ask for their support and help in monitoring for any changes in behavior or thinking that are not typical for the patient.
• Patients should be advised that drinking alcohol may increase the risk of experiencing psychiatric adverse events during treatment with CHAMPIX.
• Patients with pre-existing psychiatric disorder should be instructed that if they develop worsened or new symptoms, to report these to their healthcare provider; dose adjustments of psychiatric medications or CHAMPIX may be considered.
• Patients should be informed that if they experience thoughts, moods or behaviours that are strongly atypical and concerning while on smoking-cessation medication, including CHAMPIX, the medication should be discontinued immediately, urgent medical help sought as needed, and the symptoms reported to their healthcare provider.
• Patients should be informed that:
  - they may experience vivid, unusual or strange dreams during treatment with CHAMPIX.
  - nausea is the most common adverse event associated with CHAMPIX and is usually transient. CHAMPIX should be taken after eating and with a full glass of water. Patients should be advised that if they are persistently troubled by this symptom, a dose reduction may be considered.
  - if they experience sleepwalking, they should discontinue CHAMPIX and notify their healthcare provider.
  - there have been reports of angioedema, with swelling of the face, mouth (tongue, lips and gums) and neck (pharynx and larynx) that can lead to life-threatening respiratory compromise. Patients should be instructed to discontinue CHAMPIX and seek immediate emergency medical attention if they experience these symptoms.
  - serious skin reactions, such as Stevens-Johnson syndrome and erythema multiforme, were reported by some patients taking CHAMPIX. Patients should be advised to stop taking CHAMPIX at the first sign of rash with mucosal lesions or skin reaction and seek immediate emergency medical attention.
• Patients should be instructed to notify their healthcare providers of symptoms of new or worsening cardiovascular events and to seek immediate medical attention if they experience signs and symptoms of myocardial infarction or stroke.

Special Populations

Use of CHAMPIX in Patients with Concomitant Conditions:

Psychiatric Patients

Smoking-cessation with or without pharmacotherapy, has been associated with the exacerbation of underlying psychiatric illness.  Patients with a history of psychiatric symptoms who are attempting to quit smoking should be monitored by a healthcare professional for new or worsened psychiatric events (see DOSAGE AND ADMINISTRATION, Special Populations, Psychiatric Patients; as well as WARNINGS AND PRECAUTIONS, Psychiatric Symptoms in Patients with and without Pre-existing Psychiatric Disorder or Symptoms).

In a large randomized, double-blind, active and placebo-controlled smoking cessation study, use of CHAMPIX was not associated with an increased risk of serious neuropsychiatric adverse events in the composite endpoint compared with placebo, in patients with or without a history of psychiatric disorder (See ACTION AND CLINICAL PHARMACOLOGY, Special Populations and Conditions, Neuropsychiatric Safety Study in Subjects with and without a History of Psychiatric Disorder). Major depressive disorder, bipolar disorder I and II, anxiety, and schizophrenia were the primary baseline psychiatric conditions reported in the study; only patients judged to be clinically stable were included. Current substance abuse was among the conditions that were excluded.

Patients with Epilepsy
The use of CHAMPIX has not been studied in patients with epilepsy. There have been post-marketing reports of seizures in patients using varenicline. It is not known for how many of these there is a prior history or risk of a seizure disorder (see WARNINGS AND PRECAUTIONS, Seizures).

Patients with Diabetes
Smoking cessation, with or without treatment, may be associated with altered glycemic control. There have been post-marketing reports of diabetic patients experiencing loss of glycemic control while taking CHAMPIX. Therefore, increased glycemic monitoring is recommended in diabetic patients, with resultant adjustment of diabetic medications as necessary.

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. Post marketing reports of irritable bowel syndrome, abdominal pain, faecal incontinence and other GI issues have been reported in patients taking CHAMPIX.

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

Pregnant Women

Studies in animals have shown reproductive toxicity (see TOXICOLOGY). The potential risk for humans is not fully known (See ACTION AND CLINICAL PHARMACOLOGY, Special Populations: Pregnant Women). 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)
Based on the data submitted and reviewed by Health Canada, the safety and efficacy of CHAMPIX in pediatric patients has not been established; therefore, Health Canada has not authorized an indication for pediatric use (see WARNINGS AND PRECAUTIONS, Special Populations:Pediatrics).

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).

Adverse Drug Reaction Overview

Clinical Trial Adverse Drug Reactions

Smoking-cessation with or without treatment is associated with various symptoms. For example, dysphoric or depressed mood, insomnia, irritability, frustration or anger, anxiety, difficulty concentrating, restlessness, decreased heart rate, increased appetite or weight gain have been reported in patients attempting to stop smoking.

Overview

Pre-marketing clinical trials included approximately 2300 patients treated for at least 12 weeks, approximately 700 for 6 months, and approximately 100 for one year. In general, onset of adverse events was in the first few weeks of therapy and severity was generally mild to moderate. No differences were observed by age, race or gender with regard to the incidence of adverse reactions, although patient numbers in elderly, and in non-caucasian races were too limited to allow conclusions.

Commonly Observed Adverse Events

The most commonly observed adverse events associated with CHAMPIX (>5% and twice the rate seen in placebo-treated patients) were nausea, abnormal dreams, constipation, flatulence, and vomiting.

For patients exposed to the maximum recommended dose of 1.0 mg BID following initial dosage titration, the incidence of nausea was 30%, compared with 16% in 0.5 mg BID and approximately 10% in placebo-treated patients. Nausea was generally described as mild to moderate and often transient; however, for some subjects, it was persistent throughout the treatment period.

Adverse Events Leading to Discontinuation

In Phase 2 and 3 placebo-controlled studies, the treatment discontinuation rate due to adverse events in patients randomized to 12 weeks treatment with the recommended maximum dose of 1.0 mg BID was 12% for CHAMPIX compared to 10% for placebo. In this group, the adverse events most frequently resulting in treatment discontinuation in CHAMPIX treated patients were as follows: nausea (2.7% vs 0.6% for placebo), insomnia (1.3% vs 1.2% for placebo), fatigue/malaise/asthenia (1.0% vs 0.5% for placebo), and dizziness (0.7% vs 0.4% for placebo).

Table 1 shows the adverse events for CHAMPIX and placebo in the 12-week fixed dose studies with titration in the first week (Studies 1 (titrated arm only), 3, and 4). MedDRA High Level Group Terms (HLGT) reported in ≥5% of patients in the CHAMPIX 1.0 mg BID dose group, and more commonly than in the placebo group, are listed, along with subordinate Preferred Terms (PT) reported in ≥1% of CHAMPIX patients (and at least 0.5% more frequently 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 were only counted once.

* Includes PTs Abdominal (pain, pain upper, pain lower, discomfort, tenderness, distension) and Stomach discomfort
** Includes PTs Insomnia/Initial insomnia/Middle insomnia/Early morning awakening
NEC: Not Elsewhere Classified

Initial dose titration was beneficial in reducing the occurrence of nausea.

An additional 12 weeks of CHAMPIX 1.0 mg BID was well-tolerated in patients who had completed 12 weeks of treatment and had stopped smoking. Adverse events resulted in treatment discontinuation in 1.7% of patients who received CHAMPIX compared with 1.3% of placebo patients.

Safety Study: One-Year, Double-Blind Drug-Treatment
The overall pattern and the frequency of adverse events during a 52-week trial with CHAMPIX 1.0 mg BID (n=251 subjects randomized to CHAMPIX arm, and n=126 to placebo arm) were similar to those described in Table 1, except for the following events which were seen to be increased relative to placebo, as compared to the profile for 12 week drug exposure: nausea (40% vs 8% placebo); and the pooled terms of: abdominal pain (17% vs 3% placebo), and increased blood pressure (11% vs 6% placebo). Few of these events were recorded as severe.

Neuropsychiatric Adverse Events in Randomized, Double-Blind, Placebo-Controlled Clinical Studies of Varenicline

Meta-Analysis of Columbia-Suicide Severity Rating Scale (C-SSRS)

A meta-analysis of 5 randomized, double blind, placebo controlled trials, including 1907 patients (1130 CHAMPIX, 777 placebo), was conducted to assess suicidal ideation and behavior as reported on the C-SSRS. This meta-analysis included one trial (N=127) in patients with a history of schizophrenia or schizoaffective disorder and another trial (N=525) in patients with a history of depression. The results showed no increase in the incidence of suicidal ideation and/or behavior in patients treated with CHAMPIX compared to patients treated with placebo, with a Risk Ratio (RR) of 0.79 (95% Confidence Interval [CI]: 0.46, 1.36), as shown in Table 2. Forty-eight (48) of the 55 patients who reported suicidal ideation or behavior (24 CHAMPIX, 24 placebo) were from the two trials that enrolled patients with a history of schizophrenia, schizoaffective disorder, or depression (see ACTION AND CLINICAL PHARMACOLOGY, Special Populations and Conditions). Few patients reported these events in the other three trials (4 CHAMPIX, 3 placebo).

* Of these, one patient in each treatment arm reported suicidal behavior
** Patients with events up to 30 days after treatment; % are not weighted by study
# RR of incidence rates per 100 patient years

Pooled Data including Ten Smoking Cessation Trials

Table 3 below provides the incidence of all causality, treatment-emergent neuropsychiatric adverse events with varenicline as compared to placebo (≥ 0.2% more than placebo) in adult smokers, adverse event summarized from all randomized, placebo-controlled, double-blind varenicline studies (10 studies) completed by 31 December 2008, regardless of Study Dose or Duration. Four of these are described in the CLINICAL TRIALS section. There were no suicidal and self-injurious behaviors reported (suicide ideation and suicide attempt) in the varenicline group versus 2 events (0.1%) in the placebo group.

MedDRA version 11; included data up to 30 days after last dose of drug
NEC: Not Elsewhere Classified
Number (%) of Subjects with Adverse Events by:
* Psychiatric Disorders System Organ Class: All High Level Group Terms (HLGT)
and Preferred Terms (PTs) reported in each HLGT that are ≥ 0.2 % greater than placebo.
** Nervous System Disorder System Organ Class Selected HLGTs and PTs reported in each HLGT that are ≥ 0.2 % greater than placebo.

Data from One Phase 2 Trial with Two Varenicline Doses

Data are shown from the Phase 2 trial (12 weeks duration) that included both efficacious doses, 0.5 mg BID and 1.0 mg BID (see CLINICAL TRIALS, Study 1).

MedDRA version 11; included data up to 30 days after last dose of drug
NEC: Not Elsewhere Classified
Number (%) of Subjects with Adverse Events by:
* Psychiatric Disorder System Organ Class: High Level Group Terms (HLGT) and Preferred Terms (PT) reported in each HLGT ≥ 1% greater than placebo.
** Nervous System Disorders System Organ Class: Selected HLGTs and PTs reported in each HLGT ≥ 1% greater than placebo.

Additional Clinical Trial Adverse Drug Reactions

The adverse drug reactions listed below are based on evaluation of data from pre-marketing phase 2-3 studies and updated based on a pooled database of a total of 18 placebo-controlled, pre- and post-marketing smoking cessation studies, with approximately 5,000 patients treated with CHAMPIX. All reported events are included except those already listed in Table 1, those too general to be informative, and those not reasonably possibly associated with the use of the drug. In some cases, separate event terms have been consolidated to facilitate meaningful presentation. It is important to emphasize that although the events reported occurred during treatment with CHAMPIX, they were not necessarily caused by it.

The ADRs listed below are presented by the Medical Dictionary for Regulatory Activities (MedDRA, Version 16) System Organ Class (SOC). The variability associated with adverse event reporting and the terminology used to describe adverse events limit the value of the quantitative frequency estimates provided. Events are further classified within system organ class categories and enumerated in order of decreasing frequency using the following definitions: very frequent (occurring in at least 1/10 patients), frequent (occurring in at least 1/100 patients), infrequent (occurring in <1/100 to 1/1000 patients) and rare (occurring in fewer than 1/1000 patients).

Blood and Lymphatic System Disorders: Infrequent: Anemia, Lymphadenopathy. Rare: Leukocytosis, Platelet count decreased, Thrombocytopenia, Splenomegaly.

Cardiac Disorders: Infrequent: Angina pectoris, Electrocardiogram abnormal, Heart rate increased, Myocardial infarction, Palpitations, Tachycardia. Rare: Arrhythmia, Atrial fibrillation, Bradycardia, Cardiac flutter, Coronary artery disease, Cor pulmonale, Acute coronary syndrome, Electrocardiogram ST segment depression, Electrocardiogram T wave amplitude decreased, Ventricular extrasystoles.

Ear and Labyrinth Disorders: Infrequent: Tinnitus, Vertigo. Rare: Deafness, Meniere’s disease.

Endocrine Disorders: Infrequent: Thyroid gland disorders.

Eye Disorders: Infrequent: Conjunctivitis, Eye irritation, Vision blurred, Visual impairment, Eye pain. Rare: Acquired night blindness, Blindness transient, Cataract subcapsular, Dry eye, Mydriasis, Myopia, Lacrimation increased, Ocular vascular disorder, Photophobia, Scleral discolouration, Scotoma, Vitreous floaters.

Gastrointestinal Disorders: Frequent: Diarrhea, Toothache. Infrequent: Change of bowel habit, Aphthous stomatitis, Gingival pain, Dysphagia, Eructation, Gastritis, Gastrointestinal hemorrhage, Hematochezia, Mouth ulceration. Rare: Abnormal feces, Enterocolitis, Esophagitis, Gastric ulcer, Hematemesis, Intestinal obstruction, Pancreatitis acute, Tongue coated.

General Disorders and Administration Site Conditions: Frequent: Chest pain, Irritability. Infrequent: Chest discomfort, Chills, Edema, Influenza like illness, Pyrexia, Thirst. Rare: Cyst, Feeling cold.

Hepatobiliary Disorders: Rare: Gall bladder disorder, Worsening of existing autoimmune hepatitis.

Immune System Disorders: Infrequent: Hypersensitivity. Rare: Drug hypersensitivity.

Infections and Infestations: Very frequent: Nasopharyngitis. Frequent: Bronchitis, Sinusitis. Infrequent: Fungal infection, Gingivitis, Viral infection, Tooth abscess, Urinary Tract Infection.

Investigations: Frequent: Liver function test abnormal, alanine aminotransferase increased, Rare: Muscle enzyme increased, Semen abnormal, C-reactive protein increased, Blood calcium decreased, Urine analysis abnormal.

Metabolism and Nutrition Disorders: Frequent: Weight increased. Infrequent: Diabetes mellitus, Hypoglycemia. Rare: Hyperkalemia, Hyperlipidemia, Hypokalemia, Polydipsia.

Musculoskeletal and Connective Tissue Disorders: Frequent: Arthralgia, Back pain, Myalgia. Infrequent: Arthritis, Musculoskeletal chest pain, Muscle cramp, Musculoskeletal pain, Muscle spasms. Rare: Costochondritis, Joint stiffness, Myositis, Osteoporosis.

Nervous System Disorders: Frequent: Disturbance in attention, Dizziness, Somnolence. Infrequent: Amnesia, Convulsion, Hypoesthesia, Migraine, Parosmia, Syncope, Tremor. Rare: Balance disorder, Cerebrovascular accident, Circadian rhythm sleep disorder, Coordination abnormal, Dysarthria, Hypertonia, Hypogeusia, Mental impairment, Multiple sclerosis, VII^th nerve paralysis, Nystagmus, Psychomotor hyperactivity, Psychomotor skills impaired, Restless legs syndrome, Sensory disturbance, Transient ischemic attack, Visual field defect.

Psychiatric Disorders: Frequent: Agitation, Anxiety, Depression. Infrequent: Aggression, Dissociation, Libido decreased, Libido increased, Mood swings, Panic reaction, Restlessness, Suicidal ideation, Thinking abnormal. Rare: Bradyphrenia, Disorientation, Dysphoria, Emotional disorder, Euphoric mood, Hallucination, Psychotic disorder, Suicide attempt.

Renal and Urinary Disorders: Infrequent: Nocturia, Pollakiuria, Urine abnormality. Rare: Glycosuria, Nephrolithiasis, Polyuria, Renal failure acute, Urethral syndrome, Urinary retention.

Reproductive System and Breast Disorders: Frequent: Menstrual disorder. Infrequent: Erectile dysfunction, Menorrhagia. Rare: Sexual dysfunction, Vaginal discharge.

Respiratory, Thoracic and Mediastinal Disorders: Frequent:Cough, Respiratory disorders. Infrequent: Asthma, Dysphonia, Epistaxis, Rhinitis allergic, Throat irritation, Respiratory tract congestion, Sinus congestion, Rhinorrhea, Upper-airway cough syndrome, Upper respiratory tract inflammation. Rare: Laryngeal pain, Pleurisy, Pulmonary embolism, Snoring.

Skin and Subcutaneous Tissue Disorders: Frequent: Rash. Infrequent: Acne, Dry skin, Eczema, Erythema, Hyperhidrosis, Night sweats, Urticaria. Rare: Dermatitis, Photosensitivity reaction, Psoriasis.

Vascular Disorders: Frequent: Hypertension. Infrequent: Blood pressure increased, Hot flush, Hypotension. Rare: Peripheral ischemia, Thrombosis.
Clinical Trials in Special Populations

Adverse Events in Adolescents: (see ACTION AND CLINICAL PHARMACOLOGY, Special Populations and Conditions, Pediatrics).

Cardiovascular Adverse Events in Pooled Clinical Studies of Varenicline

In pooled data of 14 completed randomized double-blind placebo controlled smoking cessation trials (not including the study in patients with stable cardiovascular disease), the rate of reported treatment-emergent myocardial infarction (MI) or cerebrovascular accident (CVA) related adverse events was: 8 of 3317 (0.24%) patients on CHAMPIX (>1 mg), compared to 4 of 2542 (0.16%) patients on placebo.

Study in patients with Cardiovascular Disease

CHAMPIX was evaluated in a randomized, double-blind, placebo-controlled study of 703 subjects aged 35 to 75 years with stable, documented cardiovascular disease (other than or in addition to hypertension) that had been diagnosed for more than 2 months. Patients were treated with CHAMPIX 1 mg BID or placebo for 12 weeks, and then followed for another 40 weeks post-treatment (See WARNINGS AND PRECAUTIONS, Cardiovascular Events).

There are two partially overlapping data sets of cardiovascular events from the study:

1. Treatment-emergent CV AEs captured via standard clinical trial AE reporting, while on drug treatment, (including, 30 days post-dose); and
2. Pre-specified serious CV events that were adjudicated by an independent blinded committee captured throughout the 52 week duration (ie both “on-treatment” [including 30 days post-dose], and “post-treatment”).

The study was powered for assessing efficacy (ie quit rates) but not for assessing differences in the occurrence of serious CV events between CHAMPIX and placebo.

More cardiovascular events were reported in both arms compared to other studies, as expected due to underlying conditions.

Treatment-emergent cardiovascular events which occurred within 30 days after the last dose, and in at least 3 subjects in either arm, are shown in Table 5.

The adjudicated serious cardiovascular events are shown below in Table 6.

Patients are counted only once within each row per study phase.

As shown in Table 6, the individual serious cardiovascular (CV) events that were reported more frequently in CHAMPIX compared to placebo (difference > 2 subjects) were: non-fatal myocardial infarctions (4 vs. 1, on-treatment phase) and need for coronary revascularization (7 vs. 2, post-treatment phase). Some of the patients requiring coronary revascularization underwent the procedure as part of management of nonfatal MI and hospitalization for angina.

^a one of the events occurred while the subject was taking during the post treatment phase "off-protocol" CHAMPIX or ^b CHAMPIX and other smoking cessation medication.

CHAMPIX was not studied in patients with unstable cardiovascular disease or those with cardiovascular events occurring within two months before screening. (See also: WARNINGS AND PRECAUTIONS, Cardiovascular Events, and ACTION AND CLINICAL PHARMACOLOGY, Special Populations and Conditions)

Cardiovascular Safety Assessment Study in Patients with and without a History of Psychiatric Disorder

The cardiovascular (CV) safety of CHAMPIX was evaluated in the Cardiovascular Safety Assessment Study in subjects with and without a history of psychiatric disorder. Subjects aged 18-75 years, smoking 10 or more cigarettes per day (N=8058) were randomized 1:1:1:1 to CHAMPIX 1 mg BID, bupropion SR 150 mg BID, nicotine replacement therapy patch (NRT) 21 mg/day with taper or placebo for a treatment period of 12 weeks; they were then followed another 12 weeks post-treatment through a period of up to a total of 52 weeks. Of all treated subjects, 1749 (21.7%) had a medium CV risk and 644 (8.0%) had a high CV risk, as defined by Framingham score.

Major adverse cardiovascular event (MACE), were defined as cardiovascular death, non-fatal myocardial infarction or non-fatal stroke during treatment.

Deaths and cardiovascular events were adjudicated by a blinded, independent committee. The study was not powered for assessing differences between CHAMPIX and placebo in the time to MACE

The following table shows the incidence of MACE for all treatment groups during treatment, and cumulative for treatment plus 30 days and through end of study.

Because of the relatively low number of events overall and the lack of power for assessing differences between CHAMPIX and placebo, an association between the use of CHAMPIX and an increased risk of CV adverse events cannot be entirely ruled out.

Post-Marketing Experience

The following adverse events have been reported during post-approval use of CHAMPIX. Because these events are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Psychiatric Symptoms
There have been reports of depressed mood, agitation, aggression, hostility, anxiety, changes in behavior or thinking, mania, psychosis, hallucinations, paranoia, delusions, homicidal ideation, mood swings, suicidal ideation and completed suicide in patients attempting to quit smoking while taking CHAMPIX (see WARNINGS AND PRECAUTIONS, Psychiatric Symptoms in Patients with and without Pre-existing Psychiatric Disorder or Symptoms). Of the cases with information provided, the majority reported possible contributing factors, including primarily prior psychiatric history and/or concurrent psychiatric medications. Smoking status at the time of event onset was not reported in most cases. Patients should be advised that alcohol intake may increase the risk of experiencing psychiatric adverse events. Smoking cessation with or without treatment is associated with nicotine withdrawal symptoms and the exacerbation of underlying psychiatric illness. The role of CHAMPIX in these reports is not known (see also WARNINGS AND PRECAUTIONS, Psychiatric Symptoms in Patients with and without Pre-existing Psychiatric Disorder or Symptoms).

Hypersensitivity and Serious Skin Reactions
There have also been reports of hypersensitivity reactions, including angioedema and of rare but severe cutaneous reactions including Stevens-Johnson syndrome and erythema multiforme in patients taking CHAMPIX (see WARNINGS AND PRECAUTIONS, Angioedema and Hypersensitivity Reactions and Serious Skin Reactions).

Myocardial Infarction and Cerebrovascular Accident
There have been reports of myocardial infarction (MI) and cerebrovascular accident (CVA) including ischemic and hemorrhagic events in patients taking Champix. In the majority of the reported cases, patients had preexisting cardiovascular disease and/or other risk factors. Although smoking is a risk factor for MI and CVA, a contributory role of varenicline cannot be ruled out, based on temporal relationship between medication use and events.

Hyperglycemia and Diabetes Mellitus
Smoking cessation, with or without treatment, may be associated with altered glycemic control. There have been reports of hyperglycemia in patients taking CHAMPIX. While the majority of these cases involved diabetic patients experiencing loss of glycemic control (see Special Populations, Patients with Diabetes), there have also been reports of new onset diabetes in patients with no pre-existing diabetes or pre-diabetes.

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 metabolized 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

Alcohol

Patients should be advised that alcohol intake may increase the risk of experiencing psychiatric adverse events during treatment with CHAMPIX (See WARNINGS and PRECAUTIONS, Psychiatric Symptoms in Patients with and without Pre-existing Psychiatric Disorder or Symptoms ; see also Patient Counselling Information).

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).

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).

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.

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. In the clinical trials on which approval was based, CHAMPIX was used with supportive counselling. Physicians should review the patient’s overall smoking-cessation plan that includes treatment with CHAMPIX.

The majority of clinical evidence in efficacy and safety was based on a 1.0 mg BID dose (see CLINICAL TRIALS). There is little clinical experience with doses above the maximum recommended dose of 1 mg BID.

There is limited data available for dose comparison. In the one randomized clinical trial that included both 1.0 mg BID and 0.5 mg BID arms and that was designed to compare each of the two doses to placebo, and not to each other, the quit rates for 1.0 mg BID (n=253), 0.5 mg BID (n=253) and placebo (n=121) were:

• for Weeks 9 to 12: 51%, 45%, and 12% respectively, and
• for Weeks 9 to 52: 23%, 19% and 4% respectively.

For further information on this study, see CLINICAL TRIAL, study 1.

Based on the limited data available, it cannot be concluded that there is a difference between the two doses in the rate of serious neuropsychiatric events (see ADVERSE REACTIONS, Neuropsychiatric Adverse Events in Randomized Double Blind, Placebo Controlled Clinical Studies of Varenicline).

CHAMPIX should be taken after eating and with a full glass of water.

Patients with Severe Renal Impairment

The maximum recommended dose for this population is 0.5 mg twice daily (see below : Special Populations, Patients with Impaired Renal Function).

Recommended Dose and Dosage Adjustment

Adults

Setting a Quit Date

There are three ways to set a quit date with CHAMPIX:

• Fixed quit approach: The patient sets a date to stop smoking. CHAMPIX dosing should start 1-2 Weeks before this date (see CLINICAL TRIALS).
  or
• Flexible quit approach: The patient begins CHAMPIX and then quits smoking between days 8 and 35 of treatment (ie between Weeks 2 and 5) (see ACTION AND CLINICAL PHARMACOLOGY, Special Populations, Flexibility in Setting a Quit Date).
  or
• Gradual quit approach: The patient starts taking CHAMPIX with a goal to quit smoking by end of 12 weeks of treatment. The patient should gradually reduce smoking during the first 12 weeks of treatment such as 50% reduction or more by 4 weeks of treatment, 75% or more by 8 weeks to reach 100% by 12 weeks (see ACTION AND CLINICAL PHARMACOLOGY, Special Populations).

Dosing Options

Following one week of titration, there is a choice of two doses for CHAMPIX: 0.5 mg BID or 1.0 mg BID.

As shown in the table below, the two titration schedules are identical from Day 1 to Day 7, separating at Day 8 when the patient either remains on 0.5 mg BID or moves up to 1.0 mg BID.

The choice of dosing regimen should be based on physician judgment and patient preference, following discussion with the patient (see also Dosing Considerations).

Once CHAMPIX treatment is initiated, the dose may be changed, temporarily or permanently, according to patient and physician judgments on tolerability and efficacy.

Patients who follow one of the first 2 approaches to setting a quit date (1-2 weeks after starting the treatment or between days 8 and 35 of treatment) 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 with CHAMPIX for patients who have not successfully stopped smoking at the end of 12 weeks.

Patients who follow the third approach to setting a quit date (Week 12) should be treated with CHAMPIX for 24 weeks.

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

Psychiatric Patients
Patients with a history of psychiatric symptoms who are attempting to quit smoking should be monitored by their healthcare professional for new or worsened psychiatric events. Those with a current condition should be clinically stable. Patients should be instructed that if they develop worsened or new symptoms, to report these to their healthcare provider, so that dose adjustments of psychiatric medications and/or CHAMPIX may be considered (see also WARNINGS AND PRECAUTIONS, Special Populations, Psychiatric Patients).

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.

Patients with Epilepsy, Patients undergoing Chemotherapy, and Patients with GI disturbances such as irritable bowel: 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).

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.

Mechanism of Action

The efficacy of CHAMPIX in smoking-cessation is believed to be a result of varenicline's partial agonist activity at the α4β2 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 α4β2 receptor subtype than to other common nicotinic receptors (>500-fold α3β4; >3,500-fold α7; >20,000-fold α1βγδ), 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 α4β2 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 α4β2 nicotinic acetylcholine receptor (nAChR) binding site, varenicline prevented nicotine from activating the α4β2 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 α3β4 receptors, but a full agonist at α7 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 μM). 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 α3β4 and/or central α4β2 nAChRs.

Pharmacokinetics

^aDerived from three multiple-dose studies (N=103); ^†N=64; ^‡N=46

^bTmax presented as median [range]

^cApparent 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:
Based on the data submitted and reviewed by Health Canada, the safety and efficacy of CHAMPIX in pediatric patients has not been established; therefore, Health Canada has not authorized an indication for pediatric use.

Two pharmacokinetic studies have been conducted in adolescent smokers, aged 12-17 inclusive: a single dose study (n= 27), and a multiple dose study (n= 72). Pharmacokinetics were approximately dose-proportional over the 0.5 mg to 2 mg daily dose range studied.(see INDICATIONS AND CLINICAL USE, Special population: Pediatrics).

Steady-state systemic exposure: In the multiple-dose study, patients were stratified by bodyweight (> 55 kg; ≤ 55 kg), and within each bodyweight group, were randomized into three treatment arms (low dose of varenicline, high dose of varenicline and placebo) using a 2:2:1 randomization scheme. Dosing was as follows:

• >55 kg: 0.5 mg BID (n = 14), 1.0 mg BID (n = 14) and placebo (n = 7);
• ≤ 55 kg 0.5 mg QD (n = 15), 0.5 mg BID (n = 14) and placebo (n= 8).

The dosing period was 14 days, with all arms at target dose by Day 8. Patients were allowed to continue smoking at will throughout the study.

In adolescent patients of bodyweight >55 kg, steady-state systemic exposures, as assessed by AUC (0-24), were consistent with those previously observed in the adult population. In adolescent patients of ≤ 55 kg, steady-state systemic exposure for the 0.5 mg BID was on average approximately 40% higher compared to that previously observed in the adult population.

Individual adverse event terms (MedDRA-coded preferred terms) that were reported in more than one patient taking CHAMPIX and more frequently than for placebo were: nausea (most frequent), headache, vomiting, dizziness, pharyngolaryngeal pain, abdominal pain upper, anorexia, flatulence, abnormal dreams, arthralgia, fatigue, and somnolence. Patients ≤55 kg reported more adverse events than patients > 55 kg.

Mood-related events were reported for three patients of 57 in the CHAMPIX arms (anger, mood swings, irritability; none severe), compared with 0 reports in 15 patients in the placebo arms.

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: Dosing in Elderly Patients).

Hepatic Insufficiency: 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 DOSAGE AND ADMINISTRATION). 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 [AUCτ] 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 [AUCτ] 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 [AUCτ] 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).

Patients with Cardiovascular Disease

CHAMPIX was evaluated in a randomized, double-blind, placebo-controlled smoking cessation study of subjects aged 35 to 75 years with stable, documented cardiovascular disease (other than or in addition to hypertension) that had been diagnosed for >2 months. Subjects were randomized to CHAMPIX 1 mg BID (n=353) or placebo (n=350) for 12 weeks of treatment and then were followed for 40 weeks post-treatment. Quit rates were in the range of those from studies in the general population of smokers. Adverse events in this study were quantitatively and qualitatively similar to those observed in studies in the general population of smokers, other than cardiovascular-related events (see also WARNINGS AND PRECAUTIONS, Cardiovascular Events).

Patients with Chronic Obstructive Pulmonary Disease

CHAMPIX was evaluated in a randomized, double-blind, placebo-controlled smoking cessation study of 499 subjects with mild-to-moderate COPD with post-bronchodilator FEV₁/FVC<70% and FEV1 ≥50% of predicted normal value, aged > 35 years. Subjects were randomized and treated with CHAMPIX 1 mg BID (n=248) or placebo (n=251) for 12 weeks and then followed for 40 weeks post-treatment. Quit rates were in the range of those from studies in the general population of smokers. Adverse events in this one-year study were quantitatively and qualitatively similar to those observed in studies in the general population of smokers.

Patients with Stable Schizophrenia or Schizoaffective Disorder (See also below: Neuropsychiatric Safety Study in Subjects with and without a History of Psychiatric Disorder)

CHAMPIX safety and tolerability was assessed in a double-blind study of 128 smokers with stable schizophrenia or schizoaffective disorder, on antipsychotic medication, randomized 2:1 to varenicline (1 mg twice daily) or placebo for 12 weeks with 12-week non-drug follow-up.

Assessments including the Positive and Negative Symptom Scale (PANSS), standard questioning regarding adverse events, and the Columbia Suicide Severity Rating Scale (C-SSRS) occurred weekly through week 13 and at weeks 16, 20 and 24.

Based on adverse event rates, including neuropsychiatric, there were no new safety concerns compared to studies in the general population of smokers. The study discontinuation rate due to neuropsychiatric adverse events in the CHAMPIX arm was 4% (3 /84), compared to 0 (0 /43) in the placebo group.

In this study, there was no overall worsening of schizophrenia in either treatment group as measured by PANSS scores nor worsening of extra-pyramidal signs.

Evaluation of suicidal ideation and behavior (including C-SSRS): Reported lifetime history of suicidality was higher in the patients randomized to the CHAMPIX arm compared to placebo [62% (52 /84) and 51% (22/43) respectively]. During the active treatment period, the rate of C-SSRS endorsement was 11% (9/82) in the CHAMPIX arm and 9% (4/43) in the placebo arm. There were two suicide-related actions by two patients treated with CHAMPIX (attempt through overdose, and preparatory act of collecting pills); both patients had a lifetime history of similar behaviours.

During the 12 week post-treatment phase, the rate of C-SSRS endorsement decreased in the placebo arm to 5% (2/39), while the rate in the CHAMPIX arm remained at 11% (8 / 70). For six of the cases, all in the CHAMPIX arm, the C-SSRS endorsements were the first in the study for those individuals and occurred more than 30 days after last treatment dose.

All incidences of suicidal ideation or behavior during the study, except for one patient treated with CHAMPIX, occurred in patients with a prior history of suicidality.

Patients with Major Depressive Disorder (See also below: Neuropsychiatric Safety Study in Subjects with and without a History of Psychiatric Disorder)

CHAMPIX was evaluated in a randomized, double-blind, placebo-controlled study of 525 subjects with major depressive disorder without psychotic features (DSM-IV TR), on stable antidepressant treatment and/or who experienced a major depressive episode (which was successfully treated) in the past 2 years. Subjects aged 18 to 75 years were randomized to CHAMPIX 1 mg BID (n=256) or placebo (n=269) for a treatment of 12 weeks and then followed for 40 weeks post-treatment. Quit rates in this study were in the range of those from studies in the general population of smokers.

In general, the adverse events in this one-year study were quantitatively and qualitatively similar to those observed in studies in the general population of smokers.

The following psychiatric AEs were more frequent in the CHAMPIX group vs placebo: agitation (6.6% vs. 4.1%), depression (6.6% vs. 4.8%), tension (3.5% vs. 3.0%), hostility (2.0% vs. 0.4%) and restlessness (2.0% vs. 1.9%). No overall worsening of depression was observed during the study in neither CHAMPIX or placebo treatment groups.

The percentage of subjects with suicidal ideation and/or behavior during treatment were 6.0% and 7.5% respectively for the CHAMPIX and placebo groups and 6.2% vs 5.8% for the non-treatment follow-up period. There was one event of intentional self-injury/possible suicide attempt during treatment (Day 73) in a subject with history of alcohol abuse in the placebo group. A possible suicide could not be ruled out in one subject who died by an overdose of illicit drugs 76 days after last dose of study drug in the CHAMPIX group.

Neuropsychiatric Safety Study in Subjects with and without a History of Psychiatric Disorder (see also WARNING AND PRECAUTIONS, Psychiatric Symptoms in Patients with and without Pre-existing Psychiatric Disorder or Symptoms)

CHAMPIX was evaluated in a randomized, double-blind, active and placebo-controlled study that included subjects with a history of psychiatric disorder (psychiatric cohort, N=4074) and subjects without a history of psychiatric disorder (non-psychiatric cohort, N=3984). Excluded psychiatric disorders included current substance abuse, dementias, impulse control and dissociative disorders. Subjects aged 18-75 years, smoking 10 or more cigarettes per day were randomized 1:1:1:1 to varenicline 1 mg BID, bupropion SR 150 mg BID, nicotine replacement therapy patch (NRT) 21 mg/day with taper or placebo for a treatment period of 12 weeks; they were then followed for another 12 weeks post-treatment.

The prospective primary safety endpoint was a composite of the following neuropsychiatric (NPS) adverse events (which mapped from 261 MedDRA preferred terms): severe events of anxiety, depression, feeling abnormal, or hostility; and moderate or severe events of agitation, aggression, delusions, hallucinations, homicidal ideation, mania, panic, paranoia, psychosis, suicidal ideation, suicidal behavior or completed suicide.

The primary diagnoses in the psychiatric cohort of the study were: Affective Disorders ~70%; Anxiety Disorders ~19%; Psychotic Disorders ~ 10%, and Borderline Personality Disorders ~ 1% with all patients judged to be clinically stable.

Table 8 shows the rates of the composite NPS adverse event primary end point by treatment group and the risk differences (RDs) (95% CI) vs placebo in each of the non-psychiatric and psychiatric cohort.

In the psychiatric cohort, there were more events reported in patients in each treatment group compared with the non-psychiatric cohort, and the incidence of events in the composite endpoint was higher for each of the active treatments compared to placebo.

However, in neither cohort (psychiatric or non-psychiatric) was the use of varenicline or bupropion associated with a significantly increased risk, compared with placebo, of NPS primary endpoint AEs (95% CIs were lower than or included zero).

Various sensitivity analyses were performed, including different expansions of the selected AE definitions. The sensitivity analyses did not reveal significantly increased rates of psychiatric adverse events for CHAMPIX compared to placebo, nor compared to the two other treatments (bupropion, NRT).

The totality of psychiatric adverse events in the study is shown below (Table 9) for reference.

Suicidality

The percentage of subjects with suicidal ideation and/or behavior based on the Columbia-Suicide Severity Rating Scale (C-SSRS) was similar between the varenicline and placebo groups for both the non-psychiatric and psychiatric cohort, both during treatment and in the non-treatment follow-up, as shown in Table 10.

There was one completed suicide, which occurred during treatment in a subject treated with placebo, in the non-psychiatric cohort.

For both the psychiatric and non-psychiatric cohorts, the quit rates for all three treatments (varenicline, bupropion, and NRT patches) were significantly greater than those for placebo. The relative efficacy between treatment arms was evaluated. Quit rates for the non-psychiatric cohort were in the range of those from studies in the general population, as were relative rates between treatments for both cohorts (see CLINICAL TRIALS). Comparing the two cohorts, quit rates for the psychiatric cohort were diminished compared to non-psychiatric cohort for all treatment arms, including placebo. These data are limited to 6 months from the start of treatment.

Flexibility in Setting a Quit Date

CHAMPIX was evaluated in a double-blind, placebo-controlled study where patients were instructed to select a quit date between the start of Week 2 of treatment (Day 8) and the end of Week 5 (Day 35) of treatment. It was not required that the quit date be selected prior to starting treatment. Subjects were randomized 3:1 and treated for 12 weeks with CHAMPIX 1 mg BID (n=486) or placebo (n=165) and followed for another 12 weeks post-treatment. Quit rates were in the range of those from studies with a fixed target quit date.

Setting a Quit Date at 12 Weeks of Treatment with a Gradual Reduction in Smoking

CHAMPIX was evaluated in a 52-week double-blind, placebo-controlled trial of subjects who were willing to gradually reduce their smoking over a 12-week period before quitting. Subjects were randomized to either CHAMPIX 1 mg twice daily (n=760) or placebo (n=750) for 24 weeks and followed up post-treatment through week 52. Subjects were instructed to reduce the number of cigarettes smoked by at least 50 percent by the end of the first four weeks of treatment, followed by a further 50 percent reduction from week four to week eight of treatment, with the goal of reaching complete abstinence by 12 weeks. After the initial 12-week reduction phase, subjects continued treatment for another 12 weeks. Quit rates were in the range of those from studies with a target quit date either at 1 week of treatment or between days 8 and 35 of treatment.

The CHAMPIX safety profile in this study was consistent with premarketing studies.

Patients Re-treated with CHAMPIX

CHAMPIX was evaluated in a double-blind, placebo-controlled trial of 494 patients who had made a previous attempt to quit smoking with CHAMPIX, and either did not succeed in quitting or relapsed after treatment. Subjects were randomized 1:1 to CHAMPIX 1 mg BID (n=249) or placebo (n=245) for 12 weeks of treatment and followed for up to 40 weeks post-treatment. Patients included in this study had taken CHAMPIX for a smoking-cessation attempt in the past (for a total treatment duration of a minimum of two weeks), at least three months prior to study entry, and had been smoking for at least four weeks. Quit rates in this study were in the range of those from studies in subjects at their first attempt to quit smoking with CHAMPIX.

Adverse events in this one-year study were quantitatively and qualitatively similar to those from studies in subjects at their first attempt to quit with CHAMPIX.

Pregnant Women

A population-based cohort study compared infants exposed to CHAMPIX in utero (N=335) with infants born to mothers who smoked during pregnancy (N=78,412) and infants born to non-smoking mothers (N=806,438). In this study, infants exposed to CHAMPIX in utero were no more likely to have major congenital malformations (3.6%) than infants born to mothers who smoked during pregnancy (4.3%) or to non-smoking mothers (4.2%). Similarly, infants exposed to CHAMPIX in utero, as compared to infants of smoking and non-smoking mothers, were not at increased risk of stillbirth, (0.3%, 0.5%, 0.3%, respectively), small for gestational age (12.5%, 17.1%, 9.1%), preterm birth (7.5%, 7.9%, 5.8%), or premature rupture of membrane (3.6%, 5.4%, 3.8%).

Store at room temperature (15–30ºC).

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 packs containing 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 packs containing blister strips of 14 or 28 tablets.

Initial dosing pack: Includes one blister containing both 11 x 0.5 mg and 14 x 1.0 mg tablets and a second blister of 28 x 1.0 mg 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.

Control #: 221214
January 22, 2019