CHAMPIX 1mg tablets medication leaflet

CHAMPIX 1 mg film-coated tablets

Each film-coated tablet contains 1 mg of varenicline (as tartrate).

For the full list of excipients, see section 6.1.

Film-coated tablet of 5 mm x 10 mm

Light blue, capsular-shaped, biconvex tablets debossed with “Pfizer” on one side and “CHX 1.0” onthe other side.

CHAMPIX is indicated for smoking cessation in adults.

The recommended dose is 1 mg varenicline twice daily following a 1-week titration as follows:

Days 1 - 3: 0.5 mg once daily

Days 4 - 7: 0.5 mg twice daily

Day 8 - End of treatment: 1 mg twice daily

The patient should set a date to stop smoking. CHAMPIX dosing should usually start 1-2 weeksbefore this date (see section 5.1). 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 12weeks treatment with CHAMPIX at 1 mg twice daily may be considered for the maintenance ofabstinence (see section 5.1).

A gradual approach to quitting smoking with CHAMPIX should be considered for patients who arenot able or willing to quit abruptly. Patients should reduce smoking during the first 12 weeks oftreatment and quit by the end of that treatment period. Patients should then continue taking CHAMPIXfor an additional 12 weeks for a total of 24 weeks of treatment (see section 5.1).

Patients who are motivated to quit and who did not succeed in stopping smoking during prior

CHAMPIX therapy, or who relapsed after treatment, may benefit from another quit attempt with

CHAMPIX (see section 5.1).

Patients who cannot tolerate adverse reactions of CHAMPIX may have the dose lowered temporarilyor permanently to 0.5 mg twice daily.

In smoking cessation therapy, risk for relapse to smoking is elevated in the period immediatelyfollowing the end of treatment. In patients with a high risk of relapse, dose tapering may be considered(see section 4.4).

No dosage adjustment is necessary for elderly patients (see section 5.2). Because elderly patients aremore likely to have decreased renal function, prescribers should consider the renal status of an elderlypatient.

No dosage adjustment is necessary for patients with mild (estimated creatinine clearance > 50 ml/minand ≤ 80 ml/min) to moderate (estimated creatinine clearance ≥ 30 ml/min and ≤ 50 ml/min) renalimpairment.

For patients with moderate renal impairment who experience adverse reactions that are not tolerable,dosing may be reduced to 1 mg once daily.

For patients with severe renal impairment (estimated creatinine clearance < 30 ml/min), therecommended dose of CHAMPIX is 1 mg once daily. Dosing should begin at 0.5 mg once daily forthe first 3 days then increased to 1 mg once daily. Based on insufficient clinical experience with

CHAMPIX in patients with end stage renal disease, treatment is not recommended in this patientpopulation (see section 5.2).

No dosage adjustment is necessary for patients with hepatic impairment (see section 5.2).

CHAMPIX is not recommended for use in paediatric patients because its efficacy in this populationwas not demonstrated (see sections 5.1 and 5.2).

CHAMPIX is for oral use and the tablets should be swallowed whole with water.

CHAMPIX can be taken with or without food

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Effect of smoking cessation

Physiological changes resulting from smoking cessation, with or without treatment with CHAMPIX,may alter the pharmacokinetics or pharmacodynamics of some medicinal products, for which dosageadjustment may be necessary (examples include theophylline, warfarin and insulin). As smokinginduces CYP1A2, smoking cessation may result in an increase of plasma levels of CYP1A2 substrates.

Neuropsychiatric symptoms

Changes in behaviour or thinking, anxiety, psychosis, mood swings, aggressive behaviour, depression,suicidal ideation and behaviour and suicide attempts have been reported in patients attempting to quitsmoking with CHAMPIX in the post-marketing experience.

A large randomised, double-blind, active and placebo-controlled study was conducted to comparethe risk of serious neuropsychiatric events in patients with and without a history of psychiatricdisorder treated for smoking cessation with varenicline, bupropion, nicotine replacement therapypatch (NRT) or placebo. The primary safety endpoint was a composite of neuropsychiatric adverseevents that have been reported in post-marketing experience.

The use of varenicline in patients with or without a history of psychiatric disorder was not associatedwith an increased risk of serious neuropsychiatric adverse events in the composite primary endpointcompared with placebo (see section 5.1 Pharmacodynamic properties - Study in Subjects with andwithout a History of Psychiatric Disorder).

Depressed mood, rarely including suicidal ideation and suicide attempt, may be a symptom ofnicotine withdrawal.

Clinicians should be aware of the possible emergence of serious neuropsychiatric symptoms inpatients attempting to quit smoking with or without treatment. If serious neuropsychiatric symptomsoccur whilst on varenicline treatment, patients should discontinue varenicline immediately andcontact a healthcare professional for re-evaluation of treatment.

History of psychiatric disorders

Smoking cessation, with or without pharmacotherapy, has been associated with exacerbation ofunderlying psychiatric illness (e.g. depression).

CHAMPIX smoking cessation studies have provided data in patients with a history of psychiatricdisorders (see section 5.1).

In a smoking cessation clinical trial, neuropsychiatric adverse events were reported more frequently inpatients with a history of psychiatric disorders compared to those without a history of psychiatricdisorders, regardless of treatment (see section 5.1).

Care should be taken with patients with a history of psychiatric illness and patients should be advisedaccordingly.

In clinical trials and post-marketing experience there have been reports of seizures in patients with orwithout a history of seizures, treated with CHAMPIX. CHAMPIX should be used cautiously inpatients with a history of seizures or other conditions that potentially lower the seizure threshold.

At the end of treatment, discontinuation of CHAMPIX was associated with an increase in irritability,urge to smoke, depression, and/or insomnia in up to 3% of patients. The prescriber should inform thepatient accordingly and discuss or consider the need for dose tapering.

Patients taking CHAMPIX should be instructed to notify their doctor of new or worseningcardiovascular symptoms and to seek immediate medical attention if they experience signs andsymptoms of myocardial infarction or stroke (see section 5.1).

There have been post-marketing reports of hypersensitivity reactions including angioedema in patientstreated with varenicline. Clinical signs included swelling of the face, mouth (tongue, lips, and gums),neck (throat and larynx) and extremities. There were rare reports of life-threatening angioedemarequiring urgent medical attention due to respiratory compromise. Patients experiencing thesesymptoms should discontinue treatment with varenicline and contact a health care providerimmediately.

There have also been post-marketing reports of rare but severe cutaneous reactions, including Stevens-

Johnson Syndrome and Erythema Multiforme in patients using varenicline. As these skin reactions canbe life threatening, patients should discontinue treatment at the first sign of rash or skin reaction andcontact a healthcare provider immediately.

This medicinal product contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially‘sodium-free’.

Based on varenicline characteristics and clinical experience to date, CHAMPIX has no clinicallymeaningful drug interactions. No dosage adjustment of CHAMPIX or co-administered medicinalproducts listed below is recommended.

In vitro studies indicate that varenicline is unlikely to alter the pharmacokinetics of compounds thatare primarily metabolised by cytochrome P450 enzymes.

Furthermore since metabolism of varenicline represents less than 10% of its clearance, activesubstances known to affect the cytochrome P450 system are unlikely to alter the pharmacokinetics ofvarenicline (see section 5.2) and therefore a dose adjustment of CHAMPIX would not be required.

In vitro studies demonstrate that varenicline does not inhibit human renal transport proteins attherapeutic concentrations. Therefore, active substances that are cleared by renal secretion(e.g., metformin - see below) are unlikely to be affected by varenicline.

Varenicline did not affect the pharmacokinetics of metformin. Metformin had no effect on vareniclinepharmacokinetics.

Cimetidine

Co-administration of cimetidine, with varenicline increased the systemic exposure of varenicline by29% due to a reduction in varenicline renal clearance. No dosage adjustment is recommended basedon concomitant cimetidine administration in subjects with normal renal function or in patients withmild to moderate renal impairment. In patients with severe renal impairment, the concomitant use ofcimetidine and varenicline should be avoided.

Varenicline did not alter the steady-state pharmacokinetics of digoxin.

Varenicline did not alter the pharmacokinetics of warfarin. Prothrombin time (INR) was not affectedby varenicline. Smoking cessation itself may result in changes to warfarin pharmacokinetics (seesection 4.4).

Alcohol

There are limited clinical data on any potential interaction between alcohol and varenicline. Therehave been post marketing reports of increased intoxicating effects of alcohol in patients treated withvarenicline. A causal relationship between these events and varenicline use has not been established.

Use with other therapies for smoking cessation

Bupropion

Varenicline did not alter the steady-state pharmacokinetics of bupropion.

Nicotine replacement therapy (NRT)

When varenicline and transdermal NRT were co-administered to smokers for 12 days, there was astatistically significant decrease in average systolic blood pressure (mean 2.6 mmHg) measured on thefinal day of the study. In this study, the incidence of nausea, headache, vomiting, dizziness, dyspepsia,and fatigue was greater for the combination than for NRT alone.

Safety and efficacy of CHAMPIX in combination with other smoking cessation therapies have notbeen studied.

A moderate amount of data on pregnant women indicated no malformative or foetal/neonatal toxicityof varenicline (see section 5.1).

Animal studies have shown reproductive toxicity (see section 5.3). As a precautionary measure, it ispreferable to avoid the use of varenicline during pregnancy (see section 5.1).

It is unknown whether varenicline is excreted in human breast milk. Animal studies suggest thatvarenicline is excreted in breast milk. A decision on whether to continue/discontinue breast-feeding orto continue/discontinue therapy with CHAMPIX should be made taking into account the benefit ofbreast-feeding to the child and the benefit of CHAMPIX therapy to the woman.

There are no clinical data on the effects of varenicline on fertility.

Non-clinical data revealed no hazard for humans based on standard male and female fertility studies inthe rat (see section 5.3).

CHAMPIX may have minor or moderate influence on the ability to drive and use machines.

CHAMPIX may cause dizziness, somnolence and transient loss of consciousness, and therefore mayinfluence the ability to drive and use machines. Patients are advised not to drive, operate complexmachinery or engage in other potentially hazardous activities until it is known whether this medicinalproduct affects their ability to perform these activities.

Smoking cessation with or without treatment is associated with various symptoms. For example,dysphoric or depressed mood; insomnia, irritability, frustration or anger; anxiety; difficultyconcentrating; restlessness; decreased heart rate; increased appetite or weight gain have been reportedin patients attempting to stop smoking. No attempt has been made in either the design or the analysisof the CHAMPIX studies to distinguish between adverse reactions associated with study drugtreatment or those possibly associated with nicotine withdrawal. Adverse drug reactions are based onevaluation of data from pre-marketing phase 2-3 studies and updated based on pooled data from18 placebo-controlled pre- and post-marketing studies, including approximately 5,000 patients treatedwith varenicline.

In patients treated with the recommended dose of 1 mg twice daily following an initial titration periodthe adverse event most commonly reported was nausea (28.6%). In the majority of cases nauseaoccurred early in the treatment period, was mild to moderate in severity and seldom resulted indiscontinuation.

In the table below all adverse reactions, which occurred at an incidence greater than placebo are listedby system organ class and frequency (very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon(≥ 1/1,000 to < 1/100) and rare (≥ 1/10,000 to < 1/1,000)). Within each frequency grouping,undesirable effects are presented in order of decreasing seriousness.

System Organ Adverse Drug Reactions

Class

Very common Nasopharyngitis

Common Bronchitis, sinusitis

Uncommon Fungal infection, viral infection

Rare Platelet count decreased

Common Weight increased, decreased appetite, increased appetite

Uncommon Hyperglycaemia

Rare Diabetes mellitus, polydipsia

Very common Abnormal dreams, insomnia

Uncommon Suicidal ideation, aggression, panic reaction, thinking abnormal,restlessness, mood swings, depression*, anxiety*, hallucinations*, libidoincreased, libido decreased

Rare Psychosis, somnambulism, abnormal behaviour, dysphoria, bradyphrenia

Very common Headache

Common Somnolence, dizziness, dysgeusia

Uncommon Seizure, tremor, lethargy, hypoaesthesia

Rare Cerebrovascular accident, hypertonia, dysarthria, coordination abnormal,hypogeusia, circadian rhythm sleep disorder

Not known Transient loss of consciousness

Uncommon Conjunctivitis, eye pain

Rare Scotoma, scleral discolouration, mydriasis, photophobia, myopia,lacrimation increased

System Organ Adverse Drug Reactions

Class

Ear and labyrinth disorders

Uncommon Tinnitus

Uncommon Myocardial infarction, angina pectoris, tachycardia, palpitations, heartrate increased

Rare Atrial fibrillation, electrocardiogram ST segment depression,electrocardiogram T wave amplitude decreased

Uncommon Blood pressure increased, hot flush

Common Dyspnoea, cough

Uncommon Upper respiratory tract inflammation, respiratory tract congestion,dysphonia, rhinitis allergic, throat irritation, sinus congestion, upper-airway cough syndrome, rhinorrhoea

Rare Laryngeal pain, snoring

Very common Nausea

Common Gastrooesophageal reflux disease, vomiting, constipation, diarrhoea,abdominal distension, abdominal pain, toothache, dyspepsia, flatulence,dry mouth

Uncommon Haematochezia, gastritis, change of bowel habit, eructation, aphthousstomatitis, gingival pain

Rare Haematemesis, abnormal faeces, tongue coated

Common Rash, pruritus

Uncommon Erythema, acne, hyperhidrosis, night sweats

Rare Severe cutaneous reactions, including Stevens Johnson Syndrome and

Erythema Multiforme, angioedema

Common Arthralgia, myalgia, back pain

Uncommon Muscle spasms, musculoskeletal chest pain

Rare Joint stiffness, costochondritis

Uncommon Pollakiuria, nocturia

Rare Glycosuria, polyuria

Uncommon Menorrhagia

Rare Vaginal discharge, sexual dysfunction

Common Chest pain, fatigue

Uncommon Chest discomfort, influenza like illness, pyrexia, asthenia, malaise

Rare Feeling cold, cyst

Common Liver function test abnormal

Rare Semen analysis abnormal, C-reactive protein increased, blood calciumdecreased

* Frequencies are estimated from a post-marketing, observational cohort study

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

No cases of overdose were reported in pre-marketing clinical trials.

In case of overdose, standard supportive measures should be instituted as required.

Varenicline has been shown to be dialyzed in patients with end stage renal disease (see section 5.2),however, there is no experience in dialysis following overdose.

Pharmacotherapeutic group: Other nervous system drugs; Drugs used in addictive disorders, Drugsused in nicotine dependence, ATC code: N07BA03

Varenicline binds with high affinity and selectivity at the α4β2 neuronal nicotinic acetylcholinereceptors, where it acts as a partial agonist - a compound that has both agonist activity, with lowerintrinsic efficacy than nicotine, and antagonist activities in the presence of nicotine.

Electrophysiology studies in vitro and neurochemical studies in vivo have shown that vareniclinebinds to the α4β2 neuronal nicotinic acetylcholine receptors and stimulates receptor-mediated activity,but at a significantly lower level than nicotine. Nicotine competes for the same human α4β2 nAChRbinding site for which varenicline has higher affinity. Therefore, varenicline can effectively blocknicotine's ability to fully activate α4β2 receptors and the mesolimbic dopamine system, the neuronalmechanism underlying reinforcement and reward experienced upon smoking. Varenicline is highlyselective and binds more potently to the α4β2 receptor subtype (Ki=0.15 nM) than to other commonnicotinic receptors (α3β4 Ki=84 nM, α7 Ki= 620 nM, α1βγδ Ki= 3,400 nM), or to non-nicotinicreceptors and transporters (Ki > 1µM, except to 5-HT3 receptors: Ki=350 nM).

The efficacy of CHAMPIX in smoking cessation is a result of varenicline's partial agonist activity atthe α4β2 nicotinic receptor where its binding produces an effect sufficient to alleviate symptoms ofcraving and withdrawal (agonist activity), while simultaneously resulting in a reduction of therewarding and reinforcing effects of smoking by preventing nicotine binding to α4β2 receptors(antagonist activity).

Smoking cessation therapies are more likely to succeed for patients who are motivated to stopsmoking and who are provided with additional advice and support.

The efficacy of CHAMPIX in smoking cessation was demonstrated in 3 clinical trials involvingchronic cigarette smokers (≥ 10 cigarettes per day). Two thousand six hundred nineteen (2619)patients received CHAMPIX 1 mg BID (titrated during the first week), 669 patients receivedbupropion 150 mg BID (also titrated) and 684 patients received placebo.

Comparative clinical studies

Two identical double-blind clinical trials prospectively compared the efficacy of CHAMPIX(1 mg twice daily), sustained release bupropion (150 mg twice daily) and placebo in smokingcessation. In these 52-week duration studies, patients received treatment for 12 weeks, followed by a40-week non-treatment phase.

The primary endpoint of the two studies was the carbon monoxide (CO) confirmed, 4-weekcontinuous quit rate (4W-CQR) from week 9 through week 12. The primary endpoint for CHAMPIXdemonstrated statistical superiority to bupropion and placebo.

After the 40 week non-treatment phase, a key secondary endpoint for both studies was the Continuous

Abstinence Rate (CA) at week 52. CA was defined as the proportion of all subjects treated who didnot smoke (not even a puff of a cigarette) from Week 9 through Week 52 and did not have an exhaled

CO measurement of > 10 ppm. The 4W-CQR (weeks 9 through 12) and CA rate (weeks 9 through 52)from studies 1 and 2 are included in the following table:

Study 1 (n=1022) Study 2 (n=1023)4W CQR CA Wk 9-52 4W CQR CA Wk 9-52

CHAMPIX 44.4% 22.1% 44.0% 23.0%

Bupropion 29.5% 16.4% 30.0% 15.0%

Placebo 17.7% 8.4% 17.7% 10.3%

Odds ratio 3.91 3.13 3.85 2.66

CHAMPIX vs. placebo p < 0.0001 p < 0.0001 p < 0.0001 p < 0.0001

Odds ratio 1.96 1.45 1.89 1.72

CHAMPIX vs. bupropion p < 0.0001 p = 0.0640 p < 0.0001 p = 0.0062

Patient reported craving, withdrawal and reinforcing effects of smoking

Across both Studies 1 and 2 during active treatment, craving and withdrawal were significantlyreduced in patients randomised to CHAMPIX in comparison with placebo. CHAMPIX alsosignificantly reduced reinforcing effects of smoking that can perpetuate smoking behaviour in patientswho smoke during treatment compared with placebo. The effect of varenicline on craving, withdrawaland reinforcing effects of smoking were not measured during the non-treatment long-term follow-upphase.

Maintenance of abstinence study

The third study assessed the benefit of an additional 12 weeks of CHAMPIX therapy on themaintenance of abstinence. Patients in this study (n=1,927) received open-label CHAMPIX 1 mgtwice daily for 12 weeks. Patients who stopped smoking by Week 12 were then randomised to receiveeither CHAMPIX (1 mg twice daily) or placebo for an additional 12 weeks for a total study durationof 52 weeks.

The primary study endpoint was the CO-confirmed continuous abstinence rate from week 13 throughweek 24 in the double-blind treatment phase. A key secondary endpoint was the continuous abstinence(CA) rate for week 13 through week 52.

This study showed the benefit of an additional 12-week treatment with CHAMPIX 1 mg twice dailyfor the maintenance of smoking cessation compared to placebo; superiority to placebo for CA wasmaintained through week 52. The key results are summarised in the following table:

Continuous Abstinence Rates in Subjects Treated with Champix versus Placebo

CHAMPIX Placebo Difference Odds ration=602 n=604 (95% CI) (95% CI)

CA* wk 13-24 70.6% 49.8% 20.8% 2.47(15.4%, 26.2%) (1.95, 3.15)

CA* wk 13-52 44.0% 37.1% 6.9% 1.35(1.4%, 12.5%) (1.07, 1.70)

*CA: Continuous Abstinence Rate

There is currently limited clinical experience with the use of CHAMPIX among black people todetermine clinical efficacy.

Flexible quit date between weeks 1 and 5

The efficacy and safety of varenicline has been evaluated in smokers who had the flexibility ofquitting between weeks 1 and 5 of treatment. In this 24-week study, patients received treatment for12 weeks followed by a 12 week non-treatment follow up phase. The 4 week (week 9-12) CQR forvarenicline and placebo was 53.9% and 19.4%, respectively (difference=34.5, 95% CI:27.0% - 42.0%) and the CA week 9-24 was 35.2% (varenicline) vs. 12.7% (placebo)(difference=22.5%, 95% CI: 15.8% - 29.1%). Patients who are not willing or able to set the target quitdate within 1-2 weeks, could be offered to start treatment and then choose their own quit date within5 weeks.

Study in subjects re-treated with CHAMPIX

CHAMPIX was evaluated in a double-blind, placebo-controlled trial of 494 patients who had made aprevious attempt to quit smoking with CHAMPIX, and either did not succeed in quitting or relapsedafter treatment. Subjects who experienced an adverse event of a concern during previous treatmentwere excluded. Subjects were randomised 1:1 to CHAMPIX 1 mg twice daily (N=249) or placebo(N=245) for 12 weeks of treatment and followed for up to 40 weeks post-treatment. Patients includedin this study had taken CHAMPIX for a smoking-cessation attempt in the past (for a total treatmentduration of a minimum of two weeks), at least three months prior to study entry, and had beensmoking for at least four weeks.

Patients treated with CHAMPIX had a superior rate of CO-confirmed abstinence during weeks9 through 12 and from weeks 9 through 52 compared to subjects treated with placebo. The key resultsare summarised in the following table:

Continuous Abstinence Rates in Subjects Treated with Champix versus Placebo

CHAMPIX Placebo Odds ratio (95% CI),n=249 n=245 p value

CA* wk 9-12 45.0% 11.8% 7.08 (4.34, 11.55),p<0.0001

CA* wk 9-52 20.1% 3.3% 9.00 (3.97, 20.41),p<0.0001

*CA: Continuous Abstinence Rate

Gradual approach to quitting smoking

CHAMPIX was evaluated in a 52-week double-blind placebo-controlled study of 1,510 subjects whowere not able or willing to quit smoking within four weeks, but were willing to gradually reduce theirsmoking over a 12 week period before quitting. Subjects were randomised to either CHAMPIX 1 mgtwice 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 endof the first four weeks of treatment, followed by a further 50 percent reduction from week four toweek eight of treatment, with the goal of reaching complete abstinence by 12 weeks. After the initial12-week reduction phase, subjects continued treatment for another 12 weeks. Subjects treated with

CHAMPIX had a significantly higher Continuous Abstinence Rate compared with placebo; the keyresults are summarised in the following table:

Continuous Abstinence Rates in Subjects Treated with Champix versus Placebo

CHAMPIX Placebo Odds ratio (95% CI),n=760 n=750 p value

CA* wk 15-24 32.1% 6.9% 8.74 (6.09, 12.53)p<0.0001

CA* wk 21-52 27.0% 9.9% 4.02 (2.94, 5.50)p<0.0001

*CA: Continuous Abstinence Rate

The CHAMPIX safety profile in this study was consistent with that of pre-marketing studies.

Subjects with cardiovascular disease

CHAMPIX was evaluated in a randomised, double-blind, placebo-controlled study of subjects withstable, cardiovascular disease (other than, or in addition to, hypertension) that had been diagnosed formore than 2 months. Subjects were randomised to CHAMPIX 1 mg twice daily (n=353) or placebo(n=350) for 12 weeks and then were followed for 40 weeks post-treatment. The 4 week CQR forvarenicline and placebo was 47.3% and 14.3%, respectively and the CA week 9-52 was 19.8%(varenicline) vs. 7.4% (placebo).

Deaths and serious cardiovascular events were adjudicated by a blinded, committee. The followingadjudicated events occurred with a frequency ≥ 1% in either treatment group during treatment (or inthe 30-day period after treatment): nonfatal myocardial infarction (1.1% vs. 0.3% for CHAMPIX andplacebo, respectively), and hospitalisation for angina pectoris (0.6% vs. 1.1%). During non-treatmentfollow up to 52 weeks, the adjudicated events included need for coronary revascularisation (2.0% vs.0.6%), hospitalisation for angina pectoris (1.7% vs. 1.1%), and new diagnosis of peripheral vasculardisease (PVD) or admission for a PVD procedure (1.4% vs. 0.6%). Some of the patients requiringcoronary revascularisation underwent the procedure as part of management of nonfatal MI andhospitalisation for angina. Cardiovascular death occurred in 0.3% of patients in the CHAMPIX armand 0.6% of patients in the placebo arm over the course of the 52-week study.

A meta-analysis of 15 clinical trials of ≥ 12 weeks treatment duration, including 7002 patients(4190 CHAMPIX, 2812 placebo), was conducted to systematically assess the cardiovascular safety of

CHAMPIX. The study in patients with stable cardiovascular disease described above was included inthe meta-analysis.

The key cardiovascular safety analysis included occurrence and timing of a composite endpoint of

Major Adverse Cardiovascular Events (MACE), defined as cardiovascular death, nonfatal MI, andnonfatal stroke. These events included in the endpoint were adjudicated by a blinded, independentcommittee. Overall, a small number of MACE occurred during treatment in the trials included in themeta-analysis (CHAMPIX 7 [0.17%]; placebo 2 [0.07%]). Additionally, a small number of MACEoccurred up to 30 days after treatment (CHAMPIX 13 [0.31%]; placebo 6 [0.21%]).

The meta-analysis showed that exposure to CHAMPIX resulted in a hazard ratio for MACE of 2.83(95% confidence interval from 0.76 to 10.55, p=0.12) for patients during treatment and 1.95 (95%confidence interval from 0.79 to 4.82, p=0.15) for patients up to 30 days after treatment. These areequivalent to an estimated increase of 6.5 MACE events and 6.3 MACE events per1,000 patient-years, respectively of exposure. The hazard ratio for MACE was higher in patients withcardiovascular risk factors in addition to smoking compared with that in patients withoutcardiovascular risk factors other than smoking. There were similar rates of all-cause mortality(CHAMPIX 6 [0.14%]; placebo 7 [0.25%]) and cardiovascular mortality (CHAMPIX 2 [0.05%];placebo 2 [0.07%]) in the CHAMPIX arms compared with the placebo arms in the meta-analysis.

Cardiovascular safety assessment study in subjects with and without a history of psychiatric disorder

The cardiovascular (CV) safety of CHAMPIX was evaluated in the Study in Subjects with and withouta History of Psychiatric Disorder (parent study; see section 5.1 - Neuropsychiatric safety) and its non-treatment extension, the Cardiovascular Safety Assessment Study, which enrolled 4595 of the 6293subjects who completed the parent study (N=8058) and followed them through week 52. Of allsubjects treated in the parent study, 1749 (21.7%) had a medium CV risk and 644 (8.0%) had a high

CV risk, as defined by Framingham score.

The primary CV endpoint was the time to major adverse cardiovascular events (MACE), defined ascardiovascular death, non-fatal myocardial infarction or non-fatal stroke during treatment. Deaths andcardiovascular events were adjudicated by a blinded, independent committee.

The following table shows the incidence of MACE and Hazard Ratios vs placebo for all treatmentgroups during treatment, and cumulative for treatment plus 30 days and through end of study.

CHAMPIX Bupropion NRT Placebo

N=2016 N=2006 N=2022 N=2014

MACE, n (%) 1 (0.05) 2 (0.10) 1 (0.05) 4 (0.20)

Hazard Ratio 0.29 (0.05, 1.68) 0.50 (0.10, 2.50) 0.29 (0.05, 1.70)(95% CI) vsplacebo

During treatment plus 30 days

MACE, n (%) 1 (0.05) 2 (0.10) 2 (0.10) 4 (0.20)

Hazard Ratio 0.29 (0.05, 1.70) 0.51 (0.10, 2.51) 0.50 (0.10, 2.48)(95% CI) vsplacebo

Through end of study

MACE, n (%) 3 (0.15) 9 (0.45) 6 (0.30) 8 (0.40)

Hazard Ratio 0.39 (0.12, 1.27) 1.09 (0.42, 2.83) 0.75 (0.26, 2.13)(95% CI) vsplacebo

The use of CHAMPIX, bupropion, and NRT was not associated with an increased risk of CV AEs insmokers treated for up to 12 weeks and followed for up to 1 year compared to placebo, althoughbecause of the relatively low number of events overall, an association cannot be entirely ruled out.

Subjects with mild-moderate chronic obstructive pulmonary disease (COPD)

The efficacy and safety of CHAMPIX (1 mg twice daily) for smoking cessation in subjects withmild-moderate COPD was demonstrated in a randomised double-blind placebo-controlled clinicaltrial. In this 52-week duration study, patients received treatment for 12 weeks, followed by a 40-weeknon-treatment follow-up phase. The primary endpoint of the study was the CO-confirmed, 4-week

Continuous Quit Rate (4W CQR) from week 9 through week 12 and a key secondary endpoint was the

Continuous Abstinence (CA) from Week 9 through Week 52. The safety profile of varenicline wascomparable to what was reported in other trials in the general population, including pulmonary safety.

The results for the 4W CQR (weeks 9 through 12) and CA rate (weeks 9 through 52) are shown in thefollowing table:

4W CQR CA Wk 9-52

CHAMPIX, (n = 248) 42.3% 18.5%

Placebo, (n = 251) 8.8% 5.6%

Odds ratio 8.40 4.04(CHAMPIX vs. Placebo) p < 0.0001 p < 0.0001

Study in subjects with a history of major depressive disorder

The efficacy of varenicline was confirmed in a randomised placebo-controlled trial of 525 subjectswith a history of major depression in the past two years or under current stable treatment. Thecessation rates in this population were similar to those reported in the general population. Continuousabstinence rate between weeks 9-12 was 35.9% in the varenicline treatment group versus 15.6% in theplacebo group (OR 3.35 (95% CI 2.16-5.21)) and between weeks 9-52 was 20.3% versus 10.4%respectively (OR 2.36 (95% CI 1.40-3.98)). The most common adverse events (≥ 10%) in subjectstaking varenicline were nausea (27.0% vs. 10.4% on placebo), headache (16.8% vs. 11.2%), abnormaldreams (11.3% vs. 8.2%), insomnia (10.9% vs. 4.8%) and irritability (10.9% vs. 8.2%). Psychiatricscales showed no differences between the varenicline and placebo groups and no overall worsening ofdepression, or other psychiatric symptoms, during the study in either treatment group.

Study in subjects with stable schizophrenia or schizoaffective disorder

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

The most common adverse events in subjects taking varenicline were nausea (23.8% vs. 14.0% onplacebo), headache (10.7% vs. 18.6% on placebo) and vomiting (10.7% vs. 9.3% on placebo). Amongreported neuropsychiatric adverse events, insomnia was the only event reported in either treatmentgroup in ≥ 5% of subjects at a rate higher in the varenicline group than in placebo (9.5% vs. 4.7%).

Overall, there was no worsening of schizophrenia in either treatment group as measured by psychiatricscales and there were no overall changes in extra-pyramidal signs. In the varenicline group comparedto placebo, a higher proportion of subjects reported suicidal ideation or behaviour prior to enrolment(lifetime history) and after the end of active treatment period (on Days 33 to 85 after the last dose oftreatment). During the active treatment period, the incidence of suicide-related events was similarbetween the varenicline-treated and the placebo-treated subjects (11 vs. 9.3%, respectively). Thepercentage of subjects with suicide-related events in the active treatment phase compared topost-treatment phase was unchanged in the varenicline group; in the placebo group, this percentagewas lower in the post-treatment phase. Although there were no completed suicides, there was onesuicidal attempt in a varenicline-treated subject whose lifetime history included several similarattempts. The limited data available from this single smoking cessation study are not sufficient toallow for definitive conclusions to be drawn about the safety in patients with schizophrenia orschizoaffective disorder.

Neuropsychiatric Safety Study in Subjects with and without a History of Psychiatric Disorder:

Varenicline was evaluated in a randomised, double-blind, active and placebo-controlled study thatincluded subjects with a history of psychiatric disorder (psychiatric cohort, N=4074) and subjectswithout a history of psychiatric disorder (non-psychiatric cohort, N=3984). Subjects aged 18-75 years,smoking 10 or more cigarettes per day were randomised 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 atreatment period of 12 weeks; they were then followed for another 12 weeks post-treatment.

The primary safety endpoint was a composite of the following neuropsychiatric (NPS) adverse events:severe events of anxiety, depression, feeling abnormal, or hostility, and/or moderate or severe eventsof agitation, aggression, delusions, hallucinations, homicidal ideation, mania, panic, paranoia,psychosis, suicidal ideation, suicidal behaviour or completed suicide.

The following table shows the rates of the composite NPS adverse event primary endpoint bytreatment group and the risk differences (RDs) (95% CI) vs placebo in the non-psychiatric cohort.

In addition, the table shows the subset of the composite NPS AE endpoint of severe intensity:

Non-psychiatric Cohort

N=3984

Varenicline Bupropion NRT Placebo

Number of Patients Treated 990 989 1006 999

Composite NPS AE Primary

Endpoint, 13 (1.3) 22 (2.2) 25 (2.5) 24 (2.4)n (%)

RD (95% CI) vs Placebo -1.28 -0.08 -0.21(-2.40, -0.15) (-1.37, 1.21) (-1.54,1.12)

Composite NPS AE

Endpoint of severe intensity 1 (0.1) 4 (0.4) 3 (0.3) 5 (0.5)n (%)

AE, adverse event; NRT=Nicotine replacement therapy patch

The rates of events in the composite endpoint were low across all treatment groups and were similar orlower for each of the active treatments compared to placebo. The use of varenicline, bupropion and

NRT in the non-psychiatric cohort was not associated with a significantly increased risk of NPSadverse events in the composite primary endpoint compared with placebo (95% CIs were lower thanor included zero).

The percentage of subjects with suicidal ideation and/or behaviour based on the Columbia-Suicide

Severity Rating Scale (C-SSRS) was similar between the varenicline and placebo groups duringtreatment and in the non- treatment follow-up, as shown in the following table:

Non-psychiatric Cohort

N=3984

Varenicline Bupropion NRT Placebo

N=990 N=989 N=1006 N=999n (%) n (%) n (%) n (%)

Number assessed 988 983 996 995

Suicidalbehaviour and/or 7 (0.7) 4 (0.4) 3 (0.3) 7 (0.7)ideation

Suicidalbehaviour 0 0 1 (0.1) 1 (0.1)

Suicidalideation 7 (0.7) 4 (0.4) 3 (0.3) 6 (0.6)

During follow up

Number assessed 807 816 800 805

Suicidalbehaviour and/or 3 (0.4) 2 (0.2) 3 (0.4) 4 (0.5)ideation

Suicidalbehaviour 0 1 (0.1) 0 0

Suicidalideation 3 (0.4) 2 (0.2) 3 (0.4) 4 (0.5)

NRT=Nicotine replacement therapy patch

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

The following table shows the rates of the composite NPS adverse event primary endpoint bytreatment group and the RDs (95% CI) vs placebo in the psychiatric cohort. The individualcomponents of the endpoint are also shown.

In addition, the table shows the subset of the composite NPS AE endpoint of severe intensity:

Psychiatric Cohort

N=4074

Varenicline Bupropion NRT Placebo

Number of Patients

Treated 1026 1017 1016 1015

Composite NPS AE 67 (6.5) 68 (6.7) 53 (5.2) 50 (4.9)

Primary Endpoint, n (%)

RD (95% CI) vs Placebo 1.59 1.78 0.37(-0.42, 3.59) (-0.24, 3.81) (-1.53, 2.26)

NPS AE Primary

Endpoint Components n(%):

Anxietya 5 (0.5) 4 (0.4) 6 (0.6) 2 (0.2)

Depressiona 6 (0.6) 4 (0.4) 7 (0.7) 6 (0.6)

Feeling abnormala 0 1 (0.1) 0 0

Hostilitya 0 0 0 0

Agitationb 25 (2.4) 29 (2.9) 21 (2.1) 22 (2.2)

Aggressionb 14 (1.4) 9 (0.9) 7 (0.7) 8 (0.8)

Delusionsb 1 (0.1) 1 (0.1) 1 (0.1) 0

Hallucinationsb 5 (0.5) 4 (0.4) 2 (0.2) 2 (0.2)

Homicidal ideationb 0 0 0 0

Maniab 7 (0.7) 9 (0.9) 3 (0.3) 6 (0.6)

Panicb 7 (0.7) 16 (1.6) 13 (1.3) 7 (0.7)

Paranoiab 1 (0.1) 0 0 2 (0.2)

Psychosisb 4 (0.4) 2 (0.2) 3 (0.3) 1 (0.1)

Suicidal behaviourb 1 (0.1) 1 (0.1) 0 1 (0.1)

Suicidal ideationb 5 (0.5) 2 (0.2) 3 (0.3) 2 (0.2)

Completed suicideb 0 0 0 0

Composite NPS AE

Endpoint of severe 14 (1.4) 14 (1.4) 14 (1.4) 13 (1.3)intensity n (%)

AE, adverse event; aGrade = severe intensity AE; bGrade = moderate and severe intensity AE; NRT=Nicotine replacementtherapy patch

There were more events reported in patients in the psychiatric cohort in each treatment groupcompared with the non-psychiatric cohort, and the incidence of events in the composite endpointwas higher for each of the active treatments compared to placebo. However, the use of varenicline,bupropion and NRT in the psychiatric cohort was not associated with a significantly increased riskof NPS adverse events in the composite primary endpoint compared with placebo (95% CIsincluded zero).

In the psychiatric cohort, the percentage of subjects with suicidal ideation and/or behaviour basedon the Columbia-Suicide Severity Rating Scale (C-SSRS) was similar between the varenicline andplacebo groups during treatment and in the non- treatment follow-up, as shown in the followingtable:

Psychiatric Cohort

N=4074

Varenicline Bupropion NRT Placebo

N=1026 N=1017 N=1016 N=1015n (%) n (%) n (%) n (%)

Number assessed 1017 1012 1006 1006

Suicidalbehaviour and/or 27 (2.7) 15 (1.5) 20 (2.0) 25 (2.5)ideation

Suicidalbehaviour 0 1 (0.1) 0 2 (0.2)

Suicidalideation 27 (2.7) 15 (1.5) 20 (2.0) 25 (2.5)

During follow up

Number assessed 833 836 824 791

Suicidalbehaviour and/or 14 (1.7) 4 (0.5) 9 (1.1) 11 (1.4)ideation

Suicidalbehaviour 1 (0.1) 0 1 (0.1) 1 (0.1)

Suicidalideation 14 (1.7) 4 (0.5) 9 (1.1) 11 (1.4)

NRT=Nicotine replacement therapy patch

There were no completed suicides reported in the psychiatric cohort.

The most commonly reported adverse events in subjects treated with varenicline in this study weresimilar to those observed in premarketing studies.

In both cohorts, subjects treated with varenicline demonstrated statistical superiority of CO-confirmedabstinence during weeks 9 through 12 and 9 through 24 compared to subjects treated with bupropion,nicotine patch and placebo (please see table below).

The key efficacy results are summarised in the following table:

Non-psychiatric Cohort Psychiatric Cohort

CA 9-12 n/N (%)

Varenicline 382/1005 (38.0%) 301/1032 (29.2%)

Bupropion 261/1001 (26.1%) 199/1033 (19.3%)

NRT 267/1013 (26.4%) 209/1025 (20.4%)

Placebo 138/1009 (13.7%) 117/1026 (11.4%)

Treatment Comparisons: Odds ratio (95% CI), p value

Varenicline vs Placebo 4.00 (3.20, 5.00), P<0.0001 3.24 (2.56, 4.11), P<0.0001

Bupropion vs Placebo 2.26 (1.80, 2.85), P<0.0001 1.87 (1.46, 2.39), P<0.0001

NRT vs Placebo 2.30 (1.83, 2.90), P<0.0001 2.00 (1.56, 2.55), P<0.0001

Varenicline vs Bupropion 1.77 (1.46, 2.14), P<0.0001 1.74 (1.41, 2.14), P<0.0001

Varenicline vs NRT 1.74 (1.43, 2.10), P<0.0001 1.62 (1.32, 1.99), P<0.0001

CA 9-24 n/N (%)

Varenicline 256/1005 (25.5%) 189/1032 (18.3%)

Bupropion 188/1001 (18.8%) 142/1033 (13.7%)

NRT 187/1013 (18.5%) 133/1025 (13.0%)

Placebo 106/1009 (10.5%) 85/1026 (8.3%)

Treatment Comparisons: Odds ratio (95% CI), p value

Varenicline vs Placebo 2.99 (2.33, 3.83), P<0.0001 2.50 (1.90, 3.29), P<0.0001

Bupropion vs Placebo 2.00 (1.54, 2.59), P<0.0001 1.77 (1.33, 2.36), P<0.0001

NRT vs Placebo 1.96 (1.51, 2.54), P<0.0001 1.65 (1.24, 2.20), P=0.0007

Varenicline vs Bupropion 1.49 (1.20, 1.85), P=0.0003 1.41 (1.11, 1.79), P=0.0047

Varenicline vs NRT 1.52 (1.23, 1.89), P=0.0001 1.51 (1.19, 1.93), P=0.0008

CA = continuous abstinence rate; CI = confidence interval; NRT=Nicotine replacement therapy patch

Neuropsychiatric Safety Meta-analyses and Observational Studies:

Analyses of clinical trial data did not show evidence of an increased risk of serious neuropsychiatricevents with varenicline compared to placebo. In addition, independent observational studies have notsupported an increased risk of serious neuropsychiatric events in patients treated with vareniclinecompared to patients prescribed nicotine replacement therapy (NRT) or bupropion.

The treatment discontinuation rate due to adverse reactions was 11.4% for varenicline compared with9.7% for placebo. In this group, the discontinuation rates for the most common adverse reactions invarenicline treated patients were as follows: nausea (2.7% vs. 0.6% for placebo), headache (0.6% vs.1.0% for placebo), insomnia (1.3% vs. 1.2% for placebo), and abnormal dreams (0.2% vs. 0.2% forplacebo).

Analyses of Clinical Trials:

A meta-analysis of 5 randomised, double-blind, placebo controlled trials, including 1907 patients(1130 varenicline, 777 placebo), was conducted to assess suicidal ideation and behaviour as reportedon the Columbia-Suicide Severity Rating Scale (C-SSRS). This meta-analysis included one trial(N=127) in patients with a history of schizophrenia or schizoaffective disorder and another trial(N=525) in patients with a history of depression. The results showed no increase in the incidence ofsuicidal ideation and/or behaviour in patients treated with varenicline compared to patients treatedwith placebo, as shown in the table below. Of the 55 patients who reported suicidal ideation orbehaviour, 48 (24 varenicline, 24 placebo) were from the two trials that enrolled patients with a historyof schizophrenia/ schizoaffective disorder, or of depression. Few patients reported these events in theother three trials (4 varenicline, 3 placebo).

Number of Patients and Risk Ratio for Suicidal Ideation and/or Behaviour Reported on C-SSRSfrom a Meta-Analysis of 5 Clinical Trials Comparing Varenicline to Placebo:

Varenicline Placebo(N=1130) (N=777)

Patients with suicidal ideation and/or behaviour* [n (%)]** 28 (2.5) 27 (3.5)

Patient-years of exposure 325 217

Risk Ratio # (RR; 95% CI) 0.79 (0.46, 1.36)

* Of these, one patient in each treatment arm reported suicidal behaviour

** Patients with events up to 30 days after treatment; % are not weighted by study# RR of incidence rates per 100 patient years

A meta-analysis of 18 double-blind, randomised, placebo-controlled clinical trials was conducted toassess the neuropsychiatric safety of varenicline. These trials included the 5 trials described above thatused the C-SSRS, and a total of 8521 patients (5072 varenicline, 3449 placebo), some of which hadpsychiatric conditions. The results showed a similar incidence of combined neuropsychiatric adverseevents, other than sleep disorders, in patients treated with varenicline compared to patients treated withplacebo, with a risk ratio (RR) of 1.01 (95% CI: 0.89-1.15). Pooled data from these 18 trials showed asimilar incidence rate of individual categories of psychiatric events in patients treated with vareniclinecompared to patients treated with placebo. The table below describes the most frequently (≥ 1%)reported categories of adverse events related to psychiatric safety other than sleep disorders anddisturbances.

Psychiatric Adverse Events Occurring in ≥ 1% of Patients from Pooled Data from 18 Clinical

Trials:

Varenicline Placebo(N=5072) (N=3449)

Anxiety disorders and symptoms 253 (5.0) 206 (6.0)

Depressed mood disorders and disturbances 179 (3.5) 108 (3.1)

Mood disorders and disturbances NEC* 116 (2.3) 53 (1.5)

* NEC = Not Elsewhere Classified

Counts (percentages) corresponds to the number of patients reporting the event

Observational Studies

Four observational studies, each including 10,000 to 30,000 users of varenicline in the adjustedanalyses, compared the risk of serious neuropsychiatric events, including neuropsychiatrichospitalizations and fatal and non-fatal self-harm, in patients treated with varenicline versus patientsprescribed NRT or bupropion. All studies were retrospective cohort studies and included patients withand without a psychiatric history. All studies used statistical methods to control for confoundingfactors, including preferential prescribing of varenicline to healthier patients, although there is thepossibility of residual confounding.

Two of the studies found no difference in risk of neuropsychiatric hospitalisations between vareniclineusers and nicotine patch users (Hazard Ratio [HR] 1.14; 95% Confidence Interval [CI]: 0.56-2.34 inthe first study, and 0.76; 95% CI: 0.40-1.46 in the second study). The power to detect differences inthese two studies was limited. The third study reported no difference in risk of psychiatric adverseevents diagnosed during an emergency department visit or inpatient admission between vareniclineusers and bupropion users (HR 0.85; 95% CI: 0.55-1.30). Based on post marketing reports, bupropionmay be associated with neuropsychiatric adverse events.

The fourth study showed no evidence of a higher risk of fatal and non-fatal self- harm (HR of 0.88;95% CI: 0.52-1.49) in patients prescribed varenicline compared to patients prescribed NRT. Theoccurrence of detected suicide was rare during the three months after patients initiated any drugtreatment (two cases in 31,260 varenicline users and six cases in 81,545 NRT users).

Pregnancy Cohort Study

A population-based cohort study compared infants exposed to CHAMPIX in utero (N=335) withinfants born to mothers who smoked during pregnancy (N=78,412) and infants born to non-smokingmothers (N=806,438). In this study, infants exposed to CHAMPIX in utero as compared to infantsborn to mothers who smoked during pregnancy had lower rates of congenital malformations(3.6% vs 4.3%), stillbirth (0.3% vs 0.5%), preterm birth (7.5% vs 7.9%), small for gestational age(12.5% vs 17.1%), and premature rupture of membrane (3.6% vs 5.4%).

The efficacy and safety of varenicline was evaluated in a randomised, double-blind,placebo-controlled study of 312 patients aged 12 to 19 years, who smoked an average of at least5 cigarettes per day during the 30 days prior to recruitment, and had a score of at least 4 on the

Fagerstrom Test for Nicotine Dependence scale. Patients were stratified by age (12-16 years of ageand 17-19 years of age) and by body weight (≤55 kg and >55 kg). Following two-week titration,patients randomised to varenicline with a body weight >55 kg received 1 mg twice daily (high dosegroup) or 0.5 mg twice daily (low dose group), while patients with a body weight ≤55 kg received0.5 mg twice daily (high dose group) or 0.5 mg once daily (low dose group). Patients receivedtreatment for 12 weeks, followed by a non-treatment period of 40 weeks, along with age-appropriatecounseling throughout the study.

The following table from the above paediatric study shows a comparison of continuous abstinencerates (CAR) from weeks 9-12, confirmed by urine cotinine test, for the full analysis set overall studypopulation and the 12-17 year old population.

CAR 9-12 (%) Overall 12-to-17-Year Oldsn/N (%) n/N (%)

High-Dose Varenicline 22/109 (20.2%) 15/80 (18.8%)

Low-Dose Varenicline 28/103 (27.2%) 25/78 (32.1%)

Placebo 18/100 (18.0%) 13/76 (17.1%)

Treatment Comparisons Odds ratio in CAR 9-12 (95% CI) [p-value]

High-Dose Varenicline vs Placebo 1.18 (0.59, 2.37) [0.6337] 1.13 (0.50, 2.56) [0.7753]

Low-Dose Varenicline vs Placebo 1.73 (0.88, 3.39) [0.1114] 2.28 (1.06, pct. 4.89) [0.0347]*

* This p value is not considered statistically significant. The prespecified statistical testing procedures stopped testingafter the high-dose varenicline vs Placebo treatment comparison in the overall study did not achieve statisticalsignificance.

CI=confidence interval; N=number of subjects randomised; n=the number of subjects who, at each visit from weeks 9 to12 (inclusive), reported no smoking and no use of other nicotine-containing products since the last study visit/last contact(on the Nicotine Use Inventory) and at any of these visits were confirmed to have quit based on urine cotinine test.

Maximum plasma concentrations of varenicline occur typically within 3-4 hours after oraladministration. Following administration of multiple oral doses to healthy volunteers, steady-stateconditions were reached within 4 days. Absorption is virtually complete after oral administration andsystemic availability is high. Oral bioavailability of varenicline is unaffected by food or time-of-daydosing.

Varenicline distributes into tissues, including the brain. Apparent volume of distribution averaged415 litres (%CV= 50) at steady-state. Plasma protein binding of varenicline is low (< 20%) andindependent of both age and renal function. In rodents, varenicline is transferred through the placentaand excreted in milk.

Varenicline undergoes minimal metabolism with 92% excreted unchanged in the urine and less than10% excreted as metabolites. Minor metabolites in urine include varenicline N-carbamoylglucuronideand hydroxyvarenicline. In circulation, varenicline comprises 91% of drug-related material. Minorcirculating metabolites include varenicline N-carbamoylglucuronide and N-glucosylvarenicline.

In vitro studies demonstrate that varenicline does not inhibit cytochrome P450 enzymes(IC50 > 6,400 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 was shown to not induce theactivity of cytochrome P450 enzymes 1A2 and 3A4. Therefore, varenicline is unlikely to alter thepharmacokinetics of compounds that are primarily metabolised by cytochrome P450 enzymes.

The elimination half-life of varenicline is approximately 24 hours. Renal elimination of varenicline isprimarily through glomerular filtration along with active tubular secretion via the organic cationictransporter, OCT2 (see section 4.5).

Linearity/Non linearity

Varenicline exhibits linear kinetics when given as single (0.1 to 3 mg) or repeated 1 to 3 mg/daydoses.

Pharmacokinetics in special patient populations

There are no clinically meaningful differences in varenicline pharmacokinetics due to age, race,gender, smoking status, or use of concomitant medicinal products, as demonstrated in specificpharmacokinetic studies and in population pharmacokinetic analyses.

Due to the absence of significant hepatic metabolism, varenicline pharmacokinetics should beunaffected in patients with hepatic impairment. (see section 4.2).

Varenicline pharmacokinetics were unchanged in subjects with mild renal impairment (estimatedcreatinine 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 increased 1.5-foldcompared with subjects with normal renal function (estimated creatinine clearance > 80 ml/min). Insubjects with severe renal impairment (estimated creatinine clearance < 30 ml/min), vareniclineexposure was increased 2.1-fold. In subjects with end-stage-renal disease (ESRD), varenicline wasefficiently removed by haemodialysis (see section 4.2).

The pharmacokinetics of varenicline in elderly patients with normal renal function (aged 65-75 years)is similar to that of younger adult subjects (see section 4.2). For elderly patients with reduced renalfunction please refer to section 4.2.

Single and multiple-dose pharmacokinetics of varenicline have been investigated in paediatric patientsaged 12 to 17 years old (inclusive) and were approximately dose-proportional over the 0.5 mg to 2 mgdaily dose range studied. Steady-state systemic exposure in adolescent patients of bodyweight > 55 kg,as assessed by AUC (0-24), was comparable to that noted for the same doses in the adult population.

When 0.5 mg twice daily was given, steady-state daily exposure of varenicline was, on average, higher(by approximately 40%) in adolescent patients with bodyweight ≤ 55 kg compared to that noted in theadult population. CHAMPIX is not recommended in paediatric patients because its efficacy in thispopulation was not demonstrated (see sections 4.2 and 5.1).

Non-clinical data reveal no special hazard for humans based on conventional studies of safetypharmacology, repeated dose toxicity, genotoxicity, fertility and embryo-foetal development. In malerats dosed for 2 years with varenicline, there was a dose-related increase in the incidence of hibernoma(tumour of the brown fat). In the offspring of pregnant rats treated with varenicline there weredecreases in fertility and increases in the auditory startle response (see section 4.6). These effects wereobserved only at exposures considered sufficiently in excess of the maximum human exposureindicating little relevance to clinical use. Nonclinical data indicate varenicline has reinforcingproperties albeit with lower potency than nicotine. In clinical studies in humans, varenicline showedlow abuse potential.

Tablets’ core

Cellulose, Microcrystalline

Calcium Hydrogen Phosphate Anhydrous

Croscarmellose Sodium

Silica, Colloidal Anhydrous

Magnesium Stearate

Hypromellose

Titanium Dioxide (E171)

Macrogol 400

Indigo Carmine Aluminium Lake E132

Triacetin

Not applicable.

Bottles: 2 years

Blisters: 3 years

Blisters: Store below 30°C

HDPE Bottle: This medicinal product does not require any special storage conditions

PCTFE/PVC blisters with aluminium foil backing in a pack containing 28 x 1 mg film-coated tabletsin secondary heat sealed card packaging.

PCTFE/PVC blisters with aluminium foil backing in a pack containing 56 x 1 mg film-coated tabletsin secondary heat sealed card packaging.

PCTFE/PVC blisters with aluminium foil backing in a pack containing 28 x 1 mg film-coated tabletsin a carton.

PCTFE/PVC blisters with aluminium foil backing in a pack containing 56 x 1 mg film-coated tabletsin a carton.

PCTFE/PVC blisters with aluminium foil backing in a pack containing 112 x 1 mg film-coated tabletsin a carton.

PCTFE/PVC blisters with aluminium foil backing in a pack containing 140 x 1 mg film-coated tabletsin a carton.

High-density polyethylene (HDPE) bottle with polypropylene child resistant closure and an aluminiumfoil/polyethylene induction seal containing 56 x 1 mg film-coated tablets

Not all pack sizes may be marketed.

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Pfizer Europe MA EEIG

Boulevard de la Plaine 171050 Bruxelles

Belgium

EU/1/06/360/002

EU/1/06/360/004

EU/1/06/360/005

EU/1/06/360/009

EU/1/06/360/010

EU/1/06/360/011

EU/1/06/360/013

Date of first authorisation: 26 September 2006

Date of latest renewal: 29 June 2016

Detailed information on this product is available on the website of the European Medicines Agencyhttp://www.ema.europa.eu/