Champix

1 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX I 
 

SUMMARY OF PRODUCT CHARACTERISTICS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 



 

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1. NAME OF THE MEDICINAL PRODUCT 
 
CHAMPIX 0.5 mg film-coated tablets 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each film-coated tablet contains 0.5 mg of varenicline (as tartrate). 
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Film-coated tablet of 4 mm x 8 mm 
 
White, capsular-shaped, biconvex tablets debossed with “Pfizer” on one side and “CHX 0.5” on the 
other side. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
CHAMPIX is indicated for smoking cessation in adults. 
 
4.2 Posology and method of administration 
 
Posology 
 
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 at 1-2 weeks 
before 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 
12 weeks treatment with CHAMPIX at 1 mg twice daily may be considered for the maintenance of 
abstinence (see section 5.1).  
 
A gradual approach to quitting smoking with CHAMPIX should be considered for patients who are 
not able or willing to quit abruptly. Patients should reduce smoking during the first 12 weeks of 
treatment and quit by the end of that treatment period. Patients should then continue taking CHAMPIX 
for 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 temporarily 
or permanently to 0.5 mg twice daily. 
 



 

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In smoking cessation therapy, risk for relapse to smoking is elevated in the period immediately 
following the end of treatment. In patients with a high risk of relapse, dose tapering may be considered 
(see section 4.4).  
 
Elderly 
No dosage adjustment is necessary for elderly patients (see section 5.2). Because elderly patients are 
more likely to have decreased renal function, prescribers should consider the renal status of an elderly 
patient. 
 
Renal impairment 
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 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), the 
recommended dose of CHAMPIX is 1 mg once daily. Dosing should begin at 0.5 mg once daily for 
the 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 patient 
population (see section 5.2). 
 
Hepatic impairment 
No dosage adjustment is necessary for patients with hepatic impairment (see section 5.2). 
 
Paediatric population 
CHAMPIX is not recommended for use in paediatric patients because its efficacy in this population 
was not demonstrated (see sections 5.1 and 5.2). 
 
Method of administration 
 
CHAMPIX is for oral use and the tablets should be swallowed whole with water. 
CHAMPIX can be taken with or without food 
 
4.3 Contraindications 
 
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. 
 
4.4 Special warnings and precautions for use 
 
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 dosage 
adjustment may be necessary (examples include theophylline, warfarin and insulin). As smoking 
induces 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 quit 
smoking with CHAMPIX in the post-marketing experience.  
 
A large randomised, double-blind, active and placebo-controlled study was conducted to compare 
the risk of serious neuropsychiatric events in patients with and without a history of psychiatric 



 

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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 use of varenicline 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 section 5.1 Pharmacodynamic properties - Study in Subjects with and 
without a History of Psychiatric Disorder).  
  
Depressed mood, rarely including suicidal ideation and suicide attempt, may be a symptom of nicotine 
withdrawal. 
 
Clinicians should be aware of the possible emergence of serious neuropsychiatric symptoms in 
patients attempting to quit smoking with or without treatment. If serious neuropsychiatric symptoms 
occur whilst on varenicline treatment, patients should discontinue varenicline immediately and 
contact a healthcare professional for re-evaluation of treatment. 
 
History of psychiatric disorders 
 
Smoking cessation, with or without pharmacotherapy, has been associated with exacerbation of 
underlying psychiatric illness (e.g. depression). 
 
CHAMPIX smoking cessation studies have provided data in patients with a history of psychiatric 
disorders (see section 5.1).  
 
In a smoking cessation clinical trial, neuropsychiatric adverse events were reported more frequently in 
patients with a history of psychiatric disorders compared to those without a history of psychiatric 
disorders, regardless of treatment (see section 5.1). 
 
Care should be taken with patients with a history of psychiatric illness and patients should be 
advised accordingly. 

Seizures 
 
In clinical trials and post-marketing experience there have been reports of seizures in patients with or 
without a history of seizures, treated with CHAMPIX. CHAMPIX should be used cautiously in 
patients with a history of seizures or other conditions that potentially lower the seizure threshold.  
 
Treatment discontinuation 
 
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 the 
patient accordingly and discuss or consider the need for dose tapering. 
 
Cardiovascular events 
 
Patients taking CHAMPIX should be instructed to notify their doctor of new or worsening 
cardiovascular symptoms and to seek immediate medical attention if they experience signs and 
symptoms of myocardial infarction or stroke (see section 5.1). 
 
Hypersensitivity reactions 
 
There have been post-marketing reports of hypersensitivity reactions including angioedema in patients 
treated 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 angioedema 
requiring urgent medical attention due to respiratory compromise. Patients experiencing these 



 

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symptoms should discontinue treatment with varenicline and contact a health care provider 
immediately. 
 
Cutaneous reactions 
 
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 can 
be life threatening, patients should discontinue treatment at the first sign of rash or skin reaction and 
contact a healthcare provider immediately. 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
Based on varenicline characteristics and clinical experience to date, CHAMPIX has no clinically 
meaningful drug interactions. No dosage adjustment of CHAMPIX or co-administered medicinal 
products listed below is recommended. 
 
In vitro studies indicate that varenicline is unlikely to alter the pharmacokinetics of compounds that 
are primarily metabolised by cytochrome P450 enzymes. 
 
Furthermore since metabolism of varenicline represents less than 10% of its clearance, active 
substances known to affect the cytochrome P450 system are unlikely to alter the pharmacokinetics of 
varenicline (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 at 
therapeutic concentrations. Therefore, active substances that are cleared by renal secretion (e.g., 
metformin - see below) are unlikely to be affected by varenicline.  
 
Metformin  
 
Varenicline did not affect the pharmacokinetics of metformin. Metformin had no effect on varenicline 
pharmacokinetics. 
 
Cimetidine 
 
Co-administration of cimetidine, with varenicline increased the systemic exposure of varenicline by 
29% 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. 
 
Digoxin  
 
Varenicline did not alter the steady-state pharmacokinetics of digoxin. 
 
Warfarin  
 
Varenicline did not alter the pharmacokinetics of warfarin. Prothrombin time (INR) was not affected 
by varenicline. Smoking cessation itself may result in changes to warfarin pharmacokinetics (see 
section 4.4). 
 
Alcohol  
 
There are limited clinical data on any potential interaction between alcohol and varenicline. There 
have been post marketing reports of increased intoxicating effects of alcohol in patients treated with 
varenicline. A causal relationship between these events and varenicline use has not been established. 
 



 

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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 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 was greater for the combination than for NRT alone. 
 
Safety and efficacy of CHAMPIX in combination with other smoking cessation therapies have not 
been studied.  
 
4.6 Fertility, pregnancy and lactation 
 
Pregnancy 
 
A moderate amount of data on pregnant women indicated no malformative or foetal/neonatal toxicity 
of varenicline (see section 5.1). 
 
Animal studies have shown reproductive toxicity (see section 5.3). As a precautionary measure, it is 
preferable to avoid the use of varenicline during pregnancy (see section 5.1). 
 
Breast-feeding 
 
It is unknown whether varenicline is excreted in human breast milk. Animal studies suggest that 
varenicline is excreted in breast milk. A decision on whether to continue/discontinue breast-feeding or 
to continue/discontinue therapy with CHAMPIX should be made taking into account the benefit of 
breast-feeding to the child and the benefit of CHAMPIX therapy to the woman. 
 
Fertility 
 
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 in 
the rat (see section 5.3). 
 
4.7 Effects on ability to drive and use machines 
 
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 may 
influence the ability to drive and use machines. Patients are advised not to drive, operate complex 
machinery or engage in other potentially hazardous activities until it is known whether this medicinal 
product affects their ability to perform these activities. 
 
4.8 Undesirable effects 
 
Summary of the safety profile 
 
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. No attempt has been made in either the design or the analysis 
of the CHAMPIX studies to distinguish between adverse reactions associated with study drug 
treatment or those possibly associated with nicotine withdrawal. Adverse drug reactions are based on 



 

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evaluation of data from pre-marketing phase 2-3 studies and updated based on pooled data from 
18 placebo-controlled pre- and post-marketing studies, including approximately 5,000 patients treated 
with varenicline. 
 
In patients treated with the recommended dose of 1 mg twice daily following an initial titration period 
the adverse event most commonly reported was nausea (28.6%). In the majority of cases nausea 
occurred early in the treatment period, was mild to moderate in severity and seldom resulted in 
discontinuation. 
 
Tabulated summary of adverse reactions 
 
In the table below all adverse reactions, which occurred at an incidence greater than placebo are listed 
by 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 
Class 

Adverse Drug Reactions 

Infections and infestations 
Very common Nasopharyngitis 
Common Bronchitis, sinusitis 
Uncommon Fungal infection, viral infection 
Blood and lymphatic system disorders 
Rare Platelet count decreased 
Metabolism and nutrition disorders 
Common 
Uncommon 

Weight increased, decreased appetite, increased appetite 
Hyperglycaemia 

Rare Diabetes mellitus, polydipsia 
Psychiatric disorders 
Very common Abnormal dreams, insomnia 
Uncommon 
 
 
Rare 

Suicidal ideation, aggression, panic reaction, thinking abnormal, 
restlessness, mood swings, depression*, anxiety*, hallucinations*, libido 
increased, libido decreased 
Psychosis, somnambulism, abnormal behaviour, dysphoria, bradyphrenia 

Nervous system disorders 
Very common Headache 
Common Somnolence, dizziness, dysgeusia 
Uncommon Seizure, tremor, lethargy, hypoaesthesia 
Rare 
 
Not known 

Cerebrovascular accident, hypertonia, dysarthria, coordination abnormal, 
hypogeusia, circadian rhythm sleep disorder 
Transient loss of consciousness 

Eye disorders 
Uncommon 
Rare 

Conjunctivitis, eye pain  
Scotoma, scleral discolouration, mydriasis, photophobia, myopia, 
lacrimation increased 

Ear and labyrinth disorders 
Uncommon Tinnitus 
Cardiac disorders 
Uncommon Myocardial infarction, angina pectoris, tachycardia, palpitations, heart 

rate increased 
Rare 
 

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

Vascular disorders 
Uncommon Blood pressure increased, hot flush 
Respiratory, thoracic and mediastinal disorders 



 

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System Organ 
Class 

Adverse Drug Reactions 

Common 
Uncommon 
 
 
Rare 

Dyspnoea, cough 
Upper respiratory tract inflammation, respiratory tract congestion, 
dysphonia, rhinitis allergic, throat irritation, sinus congestion, upper- 
airway cough syndrome, rhinorrhoea 
Laryngeal pain, snoring 

Gastrointestinal disorders 
Very common Nausea  
Common Gastrooesophageal reflux disease, vomiting, constipation, diarrhoea, 

abdominal distension, abdominal pain, toothache, dyspepsia, flatulence, 
dry mouth 

Uncommon 
 
Rare 

Haematochezia, gastritis, change of bowel habit, eructation, aphthous 
stomatitis, gingival pain 
Haematemesis, abnormal faeces, tongue coated 

Skin and subcutaneous tissue disorders 
Common 
Uncommon 

Rash, pruritus 
Erythema, acne, hyperhidrosis, night sweats 

Rare Severe cutaneous reactions, including Stevens Johnson Syndrome and 
Erythema Multiforme, angioedema 

Musculoskeletal and connective tissue disorders 
Common 
Uncommon 
Rare 

Arthralgia, myalgia, back pain 
Muscle spasms, musculoskeletal chest pain 
Joint stiffness, costochondritis 

Renal and urinary disorders 
Uncommon 
Rare 

Pollakiuria, nocturia 
Glycosuria, polyuria 

Reproductive system and breast disorders 
Uncommon 
Rare 

Menorrhagia 
Vaginal discharge, sexual dysfunction 

General disorders and administration site conditions 
Common Chest pain, fatigue 
Uncommon 
Rare 

Chest discomfort, influenza like illness, pyrexia, asthenia, malaise 
Feeling cold, cyst 

Investigations 
Common Liver function test abnormal  
Rare Semen analysis abnormal, C-reactive protein increased, blood calcium 

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

 
Reporting of suspected adverse reactions 
 
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It 
allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare 
professionals are asked to report any suspected adverse reactions via the national reporting system 
listed in Appendix V. 
 
4.9 Overdose 
 
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. 
 



 

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5. PHARMACOLOGICAL PROPERTIES 
 
5.1  Pharmacodynamic properties 
 
Pharmacotherapeutic group: Other nervous system drugs; Drugs used in addictive disorders; Drugs 
used in nicotine dependence, ATC code: N07BA03 
 
Mechanism of action 
 
Varenicline binds with high affinity and selectivity at the α4β2 neuronal nicotinic acetylcholine 
receptors, where it acts as a partial agonist - a compound that has both agonist activity, with lower 
intrinsic efficacy than nicotine, and antagonist activities in the presence of nicotine. 
 
Electrophysiology studies in vitro and neurochemical studies in vivo have shown that varenicline 
binds 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 nAChR 
binding site for which varenicline has higher affinity. Therefore, varenicline can effectively block 
nicotine's ability to fully activate α4β2 receptors and the mesolimbic dopamine system, the neuronal 
mechanism underlying reinforcement and reward experienced upon smoking. Varenicline is highly 
selective and binds more potently to the α4β2 receptor subtype (Ki=0.15 nM) than to other common 
nicotinic receptors (α3β4 Ki=84 nM, α7 Ki= 620 nM, α1βγδ Ki= 3,400 nM), or to non-nicotinic 
receptors and transporters (Ki > 1µM, except to 5-HT3 receptors: Ki=350 nM). 
 
Pharmacodynamic effects 
 
The efficacy of CHAMPIX in smoking cessation is a result of varenicline's partial agonist activity at 
the α4β2 nicotinic receptor where its binding produces an effect sufficient to alleviate symptoms of 
craving and withdrawal (agonist activity), while simultaneously resulting in a reduction of the 
rewarding and reinforcing effects of smoking by preventing nicotine binding to α4β2 receptors 
(antagonist activity). 
 
Clinical efficacy and safety 
 
Smoking cessation therapies are more likely to succeed for patients who are motivated to stop 
smoking and who are provided with additional advice and support. 
 
The efficacy of CHAMPIX in smoking cessation was demonstrated in 3 clinical trials involving 
chronic 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 received 
bupropion 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 smoking cessation. In 
these 52 week duration studies, patients received treatment for 12 weeks, followed by a 40 week 
non-treatment phase. 
 
The primary endpoint of the two studies was the carbon monoxide (CO) confirmed, 4 week continuous 
quit rate (4W-CQR) from week 9 through week 12. The primary endpoint for CHAMPIX 
demonstrated 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 did 
not 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. 



 

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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  
CHAMPIX vs. placebo 

3.91 
p < 0.0001 

3.13 
p < 0.0001 

3.85 
p < 0.0001 

2.66 
p < 0.0001 

Odds ratio  
CHAMPIX vs. bupropion 

1.96 
p < 0.0001 

1.45 
p = 0.0640 

1.89 
p < 0.0001 

1.72 
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 significantly 
reduced in patients randomised to CHAMPIX in comparison with placebo. CHAMPIX also 
significantly reduced reinforcing effects of smoking that can perpetuate smoking behaviour in patients 
who smoke during treatment compared with placebo. The effect of varenicline on craving, withdrawal 
and reinforcing effects of smoking were not measured during the non-treatment long-term follow-up 
phase. 
 
Maintenance of abstinence study 
The third study assessed the benefit of an additional 12 weeks of CHAMPIX therapy on the 
maintenance of abstinence. Patients in this study (n=1,927) received open-label CHAMPIX 1 mg 
twice daily for 12 weeks. Patients who stopped smoking by Week 12 were then randomised to receive 
either CHAMPIX (1 mg twice daily) or placebo for an additional 12 weeks for a total study duration 
of 52 weeks. 
 
The primary study endpoint was the CO-confirmed continuous abstinence rate from week 13 through 
week 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 daily 
for the maintenance of smoking cessation compared to placebo; superiority to placebo for CA was 
maintained through week 52. The key results are summarised in the following table: 
 
Continuous Abstinence Rates in Subjects Treated with Champix versus Placebo 
 
 CHAMPIX 

n=602 
Placebo 
n=604 

Difference 
(95% CI) 

Odds ratio 
(95% CI) 

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

2.47 
(1.95, 3.15) 

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

1.35 
(1.07, 1.70) 

*CA: Continuous Abstinence Rate 

 
There is currently limited clinical experience with the use of CHAMPIX among black people to 
determine 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 of 
quitting between weeks 1 and 5 of treatment. In this 24-week study, patients received treatment for 
12 weeks followed by a 12 week non-treatment follow up phase. The 4 week (week 9-12) CQR for 
varenicline and placebo was 53.9% and 19.4%, respectively (difference=34.5%, 95% CI: 



 

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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 quit 
date within 1-2 weeks, could be offered to start treatment and then choose their own quit date within 
5 weeks. 
 
Study in subjects 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 who experienced an adverse event of a concern during previous treatment 
were 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 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.  
 
Patients treated with CHAMPIX had a superior rate of CO-confirmed abstinence during weeks 9 
through 12 and from weeks 9 through 52 compared to subjects treated with placebo. The key results 
are summarised in the following table: 
 
Continuous Abstinence Rates in Subjects Treated with Champix versus Placebo 
 

 CHAMPIX 
n=249 

Placebo 
n=245 

Odds ratio (95% CI), 
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 who 
were not able or willing to quit smoking within four weeks, but were willing to gradually reduce their 
smoking over a 12 week period before quitting. Subjects were randomised 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. Subjects treated with 
CHAMPIX had a significantly higher Continuous Abstinence Rate compared with placebo; the key 
results are summarised in the following table: 
 
Continuous Abstinence Rates in Subjects Treated with Champix versus Placebo 
 
 CHAMPIX 

n=760 
Placebo 
n=750 

Odds ratio (95% CI), 
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 with 
stable, cardiovascular disease (other than, or in addition to, hypertension) that had been diagnosed for 



 

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more 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 for 
varenicline 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 following 
adjudicated events occurred with a frequency ≥ 1% in either treatment group during treatment (or in 
the 30-day period after treatment): nonfatal myocardial infarction (1.1% vs. 0.3% for CHAMPIX and 
placebo, respectively), and hospitalisation for angina pectoris (0.6% vs. 1.1%). During non-treatment 
follow 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 vascular 
disease (PVD) or admission for a PVD procedure (1.4% vs. 0.6%). Some of the patients requiring 
coronary revascularisation underwent the procedure as part of management of nonfatal MI and 
hospitalisation for angina. Cardiovascular death occurred in 0.3% of patients in the CHAMPIX arm 
and 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 in 
the 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, and 
nonfatal stroke. These events included in the endpoint were adjudicated by a blinded, independent 
committee. Overall, a small number of MACE occurred during treatment in the trials included in the 
meta-analysis (CHAMPIX 7 [0.17%]; placebo 2 [0.07%]). Additionally, a small number of MACE 
occurred 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 are equivalent to an estimated increase of 6.5 MACE events and 6.3 MACE events 
per 1,000 patient-years, respectively of exposure. The hazard ratio for MACE was higher in patients 
with cardiovascular risk factors in addition to smoking compared with that in patients without 
cardiovascular 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 without 
a 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 6293 
subjects who completed the parent study (N=8058) and followed them through week 52. Of all 
subjects 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 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 following table shows the incidence of MACE and Hazard Ratios vs placebo for all treatment 
groups during treatment, and cumulative for treatment plus 30 days and through end of study. 
 



 

13 

 CHAMPIX 
N=2016 

Bupropion 
N=2006 

NRT 
N=2022 

Placebo 
N=2014 

During treatment 

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

(95% CI) vs 
placebo 

0.29 (0.05, 1.68) 0.50 (0.10, 2.50) 0.29 (0.05, 1.70)  

During treatment plus 30 days 
MACE, n (%) 1 (0.05) 2 (0.10) 2 (0.10) 4 (0.20) 

Hazard Ratio 
(95% CI) vs 
placebo 

0.29 (0.05, 1.70) 0.51 (0.10, 2.51) 0.50 (0.10, 2.48)  

Through end of study 
MACE, n (%) 3 (0.15) 9 (0.45) 6 (0.30) 8 (0.40) 

Hazard Ratio 
(95% CI) vs 
placebo 

0.39 (0.12, 1.27) 1.09 (0.42, 2.83) 0.75 (0.26, 2.13)  

 
The use of CHAMPIX, bupropion, and NRT was not associated with an increased risk of CV AEs in 
smokers treated for up to 12 weeks and followed for up to 1 year compared to placebo, although 
because 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 with  
mild-moderate COPD was demonstrated in a randomised double-blind placebo-controlled clinical 
trial. In this 52-week duration study, patients received treatment for 12 weeks, followed by a 40-week 
non-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 was 
comparable 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 the 
following table: 
 
 4W CQR CA Wk 9-52 

CHAMPIX, (n = 248)  42.3% 18.5% 

Placebo, (n = 251)  8.8% 5.6% 

Odds ratio  
(CHAMPIX vs. Placebo)  

8.40 
p < 0.0001 

4.04 
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 in 525 subjects 
with a history of major depression in the past two years or under current stable treatment. The 
cessation rates in this population were similar to those reported in the general population. Continuous 
abstinence rate between weeks 9-12 was 35.9% in the varenicline treatment group versus 15.6% in the 
placebo 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 subjects 
taking varenicline were nausea (27.0% vs. 10.4% on placebo), headache (16.8% vs. 11.2%), abnormal 
dreams (11.3% vs. 8.2%), insomnia (10.9% vs. 4.8%) and irritability (10.9% vs. 8.2%). Psychiatric 
scales showed no differences between the varenicline and placebo groups and no overall worsening of 
depression, or other psychiatric symptoms, during the study in either treatment group. 
 



 

14 

Study in subjects with stable schizophrenia or schizoaffective disorder  
Varenicline safety and tolerability was assessed in a double-blind study of 128 smokers with stable 
schizophrenia 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% on 
placebo), headache (10.7% vs. 18.6% on placebo) and vomiting (10.7% vs. 9.3% on placebo). Among 
reported neuropsychiatric adverse events, insomnia was the only event reported in either treatment 
group 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 psychiatric 
scales and there were no overall changes in extra-pyramidal signs. In the varenicline group compared 
to 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 of 
treatment). During the active treatment period, the incidence of suicide-related events was similar 
between the varenicline-treated and the placebo-treated subjects (11 vs. 9.3%, respectively). The 
percentage of subjects with suicide-related events in the active treatment phase compared to 
post-treatment phase was unchanged in the varenicline group; in the placebo group, this percentage 
was lower in the post-treatment phase. Although there were no completed suicides, there was one 
suicidal attempt in a varenicline-treated subject whose lifetime history included several similar 
attempts. The limited data available from this single smoking cessation study are not sufficient to 
allow for definitive conclusions to be drawn about the safety in patients with schizophrenia or 
schizoaffective 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 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). 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 a treatment 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 events 
of 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 by 
treatment group and the risk differences (RDs) (95% CI) vs placebo in the non-psychiatric cohort.  
 



 

15 

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,  
n (%) 

13 (1.3) 
 

22 (2.2) 
 

25 (2.5) 
 

24 (2.4) 
 

RD (95% CI) vs Placebo  -1.28 
(-2.40, -0.15) 

-0.08 
(-1.37, 1.21) 

-0.21           
(-1.54,1.12) 

 

Composite NPS AE 
Endpoint of severe intensity 
n (%) 

1 (0.1) 4 (0.4) 3 (0.3) 5 (0.5) 

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 or 
lower 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 NPS 
adverse events in the composite primary endpoint compared with placebo (95% CIs were lower than 
or 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 during 
treatment and in the non- treatment follow-up, as shown in the following table: 
 

 Non-psychiatric Cohort 
N=3984 

Varenicline 
 

N=990 
n (%) 

Bupropion 
 

N=989 
n (%) 

NRT 
 

N=1006 
n (%) 

Placebo 
 

N=999 
n (%) 

During treatment 
Number assessed 988 983 996 995 
Suicidal 
behaviour and/or 
ideation 

7 (0.7) 4 (0.4) 3 (0.3) 7 (0.7) 

Suicidal 
behaviour 

0 0 1 (0.1) 1 (0.1) 

Suicidal 
ideation 

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

During follow up 
Number assessed 807 816 800 805 
Suicidal 
behaviour and/or 
ideation 

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

Suicidal 
behaviour 

0 1 (0.1) 0 0 

Suicidal 
ideation 

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 in 
the non-psychiatric cohort. 



 

16 

The following table shows the rates of the composite NPS adverse event primary endpoint by 
treatment group and the RDs (95% CI) vs placebo in the psychiatric cohort. The individual 
components 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 
Primary Endpoint, n (%) 

67 (6.5) 
 

68 (6.7) 
 

53 (5.2) 
 

50 (4.9) 
 

RD (95% CI) vs Placebo  1.59                 
(-0.42, 3.59) 

1.78                
 (-0.24, 3.81) 

0.37             
(-1.53, 2.26) 

 

NPS AE Primary 
Endpoint Components n 
(%): 

Anxietya 
Depressiona 
Feeling abnormala 
Hostilitya 
Agitationb 
Aggressionb 
Delusionsb 
Hallucinationsb 
Homicidal ideationb 
Maniab 
Panicb 
Paranoiab 
Psychosisb 
Suicidal behaviourb 
Suicidal ideationb 
Completed suicideb 

 

 
5 (0.5) 
6 (0.6) 

0 
0 

25 (2.4) 
14 (1.4) 
1 (0.1) 
5 (0.5) 

0 
7 (0.7) 
7 (0.7) 
1 (0.1) 
4 (0.4) 
1 (0.1) 
5 (0.5) 

0 

 

 
4 (0.4) 
4 (0.4) 
1 (0.1) 

0 
29 (2.9) 
9 (0.9) 
1 (0.1) 
4 (0.4) 

0 
9 (0.9) 

16 (1.6) 
0 

2 (0.2) 
1 (0.1) 
2 (0.2) 

0 

 
 
 

6 (0.6) 
7 (0.7) 

0 
0 

21 (2.1) 
7 (0.7) 
1 (0.1) 
2 (0.2) 

0 
3 (0.3) 

13 (1.3) 
0 

3 (0.3) 
0 

3 (0.3) 
0 

 
 
 

2 (0.2) 
6 (0.6) 

0 
0 

22 (2.2) 
8 (0.8) 

0 
2 (0.2) 

0 
6 (0.6) 
7 (0.7) 
2 (0.2) 
1 (0.1) 
1 (0.1) 
2 (0.2) 

0 
Composite NPS AE 
Endpoint of severe 
intensity n (%) 

14 (1.4) 14 (1.4) 14 (1.4) 13 (1.3) 

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

therapy patch 

 

There were more events reported in patients in the psychiatric cohort 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, the use of varenicline, 
bupropion and NRT in the psychiatric cohort was not associated with a significantly increased risk 
of NPS adverse events in the composite primary endpoint compared with placebo (95% CIs 
included zero). 
 
In the psychiatric cohort, 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 during treatment and in the non- treatment follow-up, as shown in the following 
table: 
 



 

17 

 Psychiatric Cohort 
N=4074 

Varenicline 
 

N=1026 
n (%) 

Bupropion 
 

N=1017 
n (%) 

NRT 
 

N=1016 
n (%) 

Placebo 
 

N=1015 
n (%) 

During treatment 
Number assessed 1017 1012 1006 1006 
Suicidal 
behaviour and/or 
ideation 

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

Suicidal 
behaviour 

0 1 (0.1) 0 2 (0.2) 

Suicidal 
ideation 

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

During follow up 
Number assessed 833 836 824 791 
Suicidal 
behaviour and/or 
ideation 

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

Suicidal 
behaviour 

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

Suicidal 
ideation 

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 were 
similar to those observed in premarketing studies. 

In both cohorts, subjects treated with varenicline demonstrated statistical superiority of 
CO-confirmed abstinence 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: 

 



 

18 

 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 neuropsychiatric 
events with varenicline compared to placebo. In addition, independent observational studies have not 
supported an increased risk of serious neuropsychiatric events in patients treated with varenicline 
compared to patients prescribed nicotine replacement therapy (NRT) or bupropion.  

Treatment discontinuation  
The treatment discontinuation rate due to adverse reactions was 11.4% for varenicline compared with 
9.7% for placebo. In this group, the discontinuation rates for the most common adverse reactions in 
varenicline 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% for 
placebo). 
 
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 reported 
on 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 of 
suicidal ideation and/or behaviour in patients treated with varenicline compared to patients treated 
with placebo, as shown in the table below. Of the 55 patients who reported suicidal ideation or 
behaviour, 48 (24 varenicline, 24 placebo) were from the two trials that enrolled patients with a history 
of schizophrenia/ schizoaffective disorder, or of depression. Few patients reported these events in the 
other three trials (4 varenicline, 3 placebo). 



 

19 

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

 Varenicline 
(N=1130) 

Placebo 
(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 to 
assess the neuropsychiatric safety of varenicline. These trials included the 5 trials described above that 
used the C-SSRS, and a total of 8521 patients (5072 varenicline, 3449 placebo), some of which had 
psychiatric conditions. The results showed a similar incidence of combined neuropsychiatric adverse 
events, other than sleep disorders, in patients treated with varenicline compared to patients treated with 
placebo, with a risk ratio (RR) of 1.01 (95% CI: 0.89-1.15). Pooled data from these 18 trials showed a 
similar incidence rate of individual categories of psychiatric events in patients treated with varenicline 
compared 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 and 
disturbances. 
 
Psychiatric Adverse Events Occurring in ≥ 1% of Patients from Pooled Data from 18 Clinical 
Trials:  
 

 Varenicline 
(N=5072) 

Placebo 
(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 adjusted 
analyses, compared the risk of serious neuropsychiatric events, including neuropsychiatric 
hospitalizations and fatal and non-fatal self-harm, in patients treated with varenicline versus patients 
prescribed NRT or bupropion. All studies were retrospective cohort studies and included patients with 
and without a psychiatric history. All studies used statistical methods to control for confounding 
factors, including preferential prescribing of varenicline to healthier patients, although there is the 
possibility of residual confounding. 

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



 

20 

occurrence of detected suicide was rare during the three months after patients initiated any drug 
treatment (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) 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 as compared to infants 
born 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%). 
 
Paediatric Population 
 
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 least 
5 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 age 
and 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 dose 
group) or 0.5 mg twice daily (low dose group), while patients with a body weight ≤55 kg received 
0.5 mg twice daily (high dose group) or 0.5 mg once daily (low dose group). Patients received 
treatment for 12 weeks, followed by a non-treatment period of 40 weeks, along with age-appropriate 
counseling throughout the study. 
 
The following table from the above paediatric study shows a comparison of continuous abstinence 
rates (CAR) from weeks 9-12, confirmed by urine cotinine test, for the full analysis set overall study 
population and the 12-17 year old population. 
 
CAR 9-12 (%) Overall 

n/N (%) 
12-to-17-Year Olds 

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, 4.89) [0.0347]* 
* This p value is not considered statistically significant. The prespecified statistical testing procedures stopped testing 

after the high-dose varenicline vs Placebo treatment comparison in the overall study did not achieve statistical 

significance. 

 
CI=confidence interval; N=number of subjects randomised; n=the number of subjects who, at each visit from weeks 9 to 
12 (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. 

 
5.2 Pharmacokinetic properties  
 
Absorption 
 
Maximum plasma concentrations of varenicline occur typically within 3-4 hours after oral 
administration. Following administration of multiple oral doses to healthy volunteers, steady-state 
conditions were reached within 4 days. Absorption is virtually complete after oral administration and 
systemic availability is high. Oral bioavailability of varenicline is unaffected by food or time-of-day 
dosing. 
 



 

21 

Distribution 
 
Varenicline distributes into tissues, including the brain. Apparent volume of distribution averaged 
415 litres (%CV= 50) at steady-state. Plasma protein binding of varenicline is low (< 20%) and 
independent of both age and renal function. In rodents, varenicline is transferred through the placenta 
and excreted in milk.  
 
Biotransformation 
 
Varenicline undergoes minimal metabolism with 92% excreted unchanged in the urine and less than 
10% excreted as metabolites. Minor metabolites in urine include varenicline N-carbamoylglucuronide 
and hydroxyvarenicline. In circulation, varenicline comprises 91% of drug-related material. Minor 
circulating 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 the 
activity of cytochrome P450 enzymes 1A2 and 3A4. Therefore, varenicline is unlikely to alter the 
pharmacokinetics of compounds that are primarily metabolised by cytochrome P450 enzymes. 
 
Elimination 
 
The elimination half-life of varenicline is approximately 24 hours. Renal elimination of varenicline is 
primarily through glomerular filtration along with active tubular secretion via the organic cationic 
transporter, 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/day 
doses. 
 
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 specific 
pharmacokinetic studies and in population pharmacokinetic analyses. 
 
Hepatic impairment 
Due to the absence of significant hepatic metabolism, varenicline pharmacokinetics should be 
unaffected in patients with hepatic impairment (see section 4.2). 
 
Renal impairment  
Varenicline pharmacokinetics were 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 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 was increased 2.1-fold. In subjects with end-stage-renal disease (ESRD), varenicline was 
efficiently removed by haemodialysis (see section 4.2).  
 
Elderly  
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 renal 
function please refer to section 4.2. 
 



 

22 

Paediatric population 
Single and multiple-dose pharmacokinetics of varenicline have been investigated in paediatric patients 
aged 12 to 17 years old (inclusive) and were approximately dose-proportional over the 0.5 mg to 2 mg 
daily 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 the 
adult population. CHAMPIX is not recommended in paediatric patients because its efficacy in this 
population was not demonstrated (see sections 4.2 and 5.1). 
 
5.3 Preclinical safety data  
 
Non-clinical data reveal no special hazard for humans based on conventional studies of safety 
pharmacology, repeated dose toxicity, genotoxicity, fertility and embryo-foetal development. In male 
rats 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 were 
decreases in fertility and increases in the auditory startle response (see section 4.6). These effects were 
observed only at exposures considered sufficiently in excess of the maximum human exposure 
indicating little relevance to clinical use. Nonclinical data indicate varenicline has reinforcing 
properties albeit with lower potency than nicotine. In clinical studies in humans, varenicline showed 
low abuse potential. 
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Tablets’ core 
 
Cellulose, Microcrystalline 
Calcium Hydrogen Phosphate Anhydrous 
Croscarmellose Sodium 
Silica, Colloidal Anhydrous 
Magnesium Stearate 
 
Film coating  
 
Hypromellose 
Titanium Dioxide (E171) 
Macrogol 400 
Triacetin 
 
6.2 Incompatibilities 
 
Not applicable. 
 
6.3 Shelf life 
 
Bottles: 2 years 
Blisters: 3 years 
 
6.4 Special precautions for storage 
 
Blisters: Store below 30°C 
HDPE Bottle: This medicinal product does not require any special storage conditions 
 



 

23 

6.5 Nature and contents of container 
 
Maintenance packs 
 
PCTFE/PVC blisters with aluminium foil backing in a pack containing 28 x 0.5 mg film-coated tablets 
in secondary heat sealed card packaging. 
 
PCTFE/PVC blisters with aluminium foil backing in a pack containing 56 x 0.5 mg film-coated tablets 
in secondary heat sealed card packaging. 
 
PVC blisters with aluminium foil backing in a pack containing 28 x 0.5 mg film-coated tablets in 
secondary heat sealed card packaging. 
 
PVC blisters with aluminium foil backing in a pack containing 56 x 0.5 mg film-coated tablets in 
secondary heat sealed card packaging. 
 
High-density polyethylene (HDPE) bottle with polypropylene child resistant closure and an aluminium 
foil/polyethylene induction seal containing 56 x 0.5 mg film-coated tablets 
 
Not all pack sizes may be marketed. 
 
6.6 Special precautions for disposal  
 
No special requirements. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
Pfizer Europe MA EEIG 
Boulevard de la Plaine 17 
1050 Bruxelles 
Belgium 
 
 
8. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/06/360/001 
EU/1/06/360/006 
EU/1/06/360/007 
EU/1/06/360/017 
EU/1/06/360/018 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 26 September 2006 
Date of latest renewal: 29 June 2016  
 
 
10. DATE OF REVISION OF THE TEXT 
 
Detailed information on this product is available on the website of the European Medicines Agency 
http://www.ema.europa.eu/  
 
 



 

24 

1. NAME OF THE MEDICINAL PRODUCT 
 
CHAMPIX 1 mg film-coated tablets 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each film-coated tablet contains 1 mg of varenicline (as tartrate). 
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
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” on 
the other side. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
CHAMPIX is indicated for smoking cessation in adults. 
 
4.2 Posology and method of administration 
 
Posology 
 
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 weeks 
before 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 12 
weeks treatment with CHAMPIX at 1 mg twice daily may be considered for the maintenance of 
abstinence (see section 5.1). 
  
A gradual approach to quitting smoking with CHAMPIX should be considered for patients who are 
not able or willing to quit abruptly. Patients should reduce smoking during the first 12 weeks of 
treatment and quit by the end of that treatment period. Patients should then continue taking CHAMPIX 
for 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 temporarily 
or permanently to 0.5 mg twice daily. 
 



 

25 

In smoking cessation therapy, risk for relapse to smoking is elevated in the period immediately 
following the end of treatment. In patients with a high risk of relapse, dose tapering may be considered 
(see section 4.4).  
 
Elderly 
No dosage adjustment is necessary for elderly patients (see section 5.2). Because elderly patients are 
more likely to have decreased renal function, prescribers should consider the renal status of an elderly 
patient. 
 
Renal impairment 
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 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), the 
recommended dose of CHAMPIX is 1 mg once daily. Dosing should begin at 0.5 mg once daily for 
the 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 patient 
population (see section 5.2). 
 
Hepatic impairment 
No dosage adjustment is necessary for patients with hepatic impairment (see section 5.2). 
 
Paediatric population 
CHAMPIX is not recommended for use in paediatric patients because its efficacy in this population 
was not demonstrated (see sections 5.1 and 5.2). 
 
Method of administration 
 
CHAMPIX is for oral use and the tablets should be swallowed whole with water. 
CHAMPIX can be taken with or without food 
 
4.3 Contraindications 
 
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. 
 
4.4 Special warnings and precautions for use 
 
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 dosage 
adjustment may be necessary (examples include theophylline, warfarin and insulin). As smoking 
induces 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 quit 
smoking with CHAMPIX in the post-marketing experience.  
 
A large randomised, double-blind, active and placebo-controlled 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 



 

26 

patch (NRT) or placebo. The primary safety endpoint was a composite of neuropsychiatric adverse 
events that have been reported in post-marketing experience.  
 
The use of varenicline 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 section 5.1 Pharmacodynamic properties - Study in Subjects with and 
without a History of Psychiatric Disorder).  
 
Depressed mood, rarely including suicidal ideation and suicide attempt, may be a symptom of 
nicotine withdrawal. 
 
Clinicians should be aware of the possible emergence of serious neuropsychiatric symptoms in 
patients attempting to quit smoking with or without treatment. If serious neuropsychiatric symptoms 
occur whilst on varenicline treatment, patients should discontinue varenicline immediately and 
contact a healthcare professional for re-evaluation of treatment.  
 
History of psychiatric disorders 
 
Smoking cessation, with or without pharmacotherapy, has been associated with exacerbation of 
underlying psychiatric illness (e.g. depression). 
 
CHAMPIX smoking cessation studies have provided data in patients with a history of psychiatric 
disorders (see section 5.1).  
 
In a smoking cessation clinical trial, neuropsychiatric adverse events were reported more frequently in 
patients with a history of psychiatric disorders compared to those without a history of psychiatric 
disorders, regardless of treatment (see section 5.1). 
 
Care should be taken with patients with a history of psychiatric illness and patients should be advised 
accordingly. 
 
Seizures 
 
In clinical trials and post-marketing experience there have been reports of seizures in patients with or 
without a history of seizures, treated with CHAMPIX. CHAMPIX should be used cautiously in 
patients with a history of seizures or other conditions that potentially lower the seizure threshold.  
 
Treatment discontinuation 
 
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 the 
patient accordingly and discuss or consider the need for dose tapering. 
 
Cardiovascular events 
 
Patients taking CHAMPIX should be instructed to notify their doctor of new or worsening 
cardiovascular symptoms and to seek immediate medical attention if they experience signs and 
symptoms of myocardial infarction or stroke (see section 5.1). 
 
Hypersensitivity reactions 
 
There have been post-marketing reports of hypersensitivity reactions including angioedema in patients 
treated 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 angioedema 
requiring urgent medical attention due to respiratory compromise. Patients experiencing these 
symptoms should discontinue treatment with varenicline and contact a health care provider 
immediately.  



 

27 

 
Cutaneous reactions 
 
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 can 
be life threatening, patients should discontinue treatment at the first sign of rash or skin reaction and 
contact a healthcare provider immediately. 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
Based on varenicline characteristics and clinical experience to date, CHAMPIX has no clinically 
meaningful drug interactions. No dosage adjustment of CHAMPIX or co-administered medicinal 
products listed below is recommended. 
 
In vitro studies indicate that varenicline is unlikely to alter the pharmacokinetics of compounds that 
are primarily metabolised by cytochrome P450 enzymes. 
 
Furthermore since metabolism of varenicline represents less than 10% of its clearance, active 
substances known to affect the cytochrome P450 system are unlikely to alter the pharmacokinetics of 
varenicline (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 at 
therapeutic concentrations. Therefore, active substances that are cleared by renal secretion  
(e.g., metformin - see below) are unlikely to be affected by varenicline.  
 
Metformin 
 
Varenicline did not affect the pharmacokinetics of metformin. Metformin had no effect on varenicline 
pharmacokinetics. 
 
Cimetidine 
 
Co-administration of cimetidine, with varenicline increased the systemic exposure of varenicline by 
29% 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. 
 
Digoxin 
 
Varenicline did not alter the steady-state pharmacokinetics of digoxin. 
 
Warfarin 
 
Varenicline did not alter the pharmacokinetics of warfarin. Prothrombin time (INR) was not affected 
by varenicline. Smoking cessation itself may result in changes to warfarin pharmacokinetics (see 
section 4.4). 
 
Alcohol 
 
There are limited clinical data on any potential interaction between alcohol and varenicline. There 
have been post marketing reports of increased intoxicating effects of alcohol in patients treated with 
varenicline. A causal relationship between these events and varenicline use has not been established. 
 



 

28 

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 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 was greater for the combination than for NRT alone. 
 
Safety and efficacy of CHAMPIX in combination with other smoking cessation therapies have not 
been studied.  
 
4.6 Fertility, pregnancy and lactation 
 
Pregnancy 
 
A moderate amount of data on pregnant women indicated no malformative or foetal/neonatal toxicity 
of varenicline (see section 5.1). 
 
Animal studies have shown reproductive toxicity (see section 5.3). As a precautionary measure, it is 
preferable to avoid the use of varenicline during pregnancy (see section 5.1). 
 
Breast-feeding 
 
It is unknown whether varenicline is excreted in human breast milk. Animal studies suggest that 
varenicline is excreted in breast milk. A decision on whether to continue/discontinue breast-feeding or 
to continue/discontinue therapy with CHAMPIX should be made taking into account the benefit of 
breast-feeding to the child and the benefit of CHAMPIX therapy to the woman. 
 
Fertility 
 
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 in 
the rat (see section 5.3). 
 
4.7 Effects on ability to drive and use machines 
 
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 may 
influence the ability to drive and use machines. Patients are advised not to drive, operate complex 
machinery or engage in other potentially hazardous activities until it is known whether this medicinal 
product affects their ability to perform these activities. 
 
4.8 Undesirable effects 
 
Summary of the safety profile 
 
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. No attempt has been made in either the design or the analysis 
of the CHAMPIX studies to distinguish between adverse reactions associated with study drug 
treatment or those possibly associated with nicotine withdrawal. Adverse drug reactions are based on 
evaluation of data from pre-marketing phase 2-3 studies and updated based on pooled data from 



 

29 

18 placebo-controlled pre- and post-marketing studies, including approximately 5,000 patients treated 
with varenicline. 
 
In patients treated with the recommended dose of 1 mg twice daily following an initial titration period 
the adverse event most commonly reported was nausea (28.6%). In the majority of cases nausea 
occurred early in the treatment period, was mild to moderate in severity and seldom resulted in 
discontinuation. 
 
Tabulated summary of adverse reactions 
 
In the table below all adverse reactions, which occurred at an incidence greater than placebo are listed 
by 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 
Class 

Adverse Drug Reactions 

Infections and infestations 
Very common Nasopharyngitis 
Common Bronchitis, sinusitis 
Uncommon Fungal infection, viral infection 
Blood and lymphatic system disorders 
Rare Platelet count decreased 
Metabolism and nutrition disorders 
Common Weight increased, decreased appetite, increased appetite 
Uncommon Hyperglycaemia 
Rare Diabetes mellitus, polydipsia 
Psychiatric disorders 
Very common Abnormal dreams, insomnia 
Uncommon 
 
 
Rare 

Suicidal ideation, aggression, panic reaction, thinking abnormal, 
restlessness, mood swings, depression*, anxiety*, hallucinations*, libido 
increased, libido decreased 
Psychosis, somnambulism, abnormal behaviour, dysphoria, bradyphrenia 

Nervous system disorders 
Very common Headache 
Common Somnolence, dizziness, dysgeusia 
Uncommon Seizure, tremor, lethargy, hypoaesthesia 
Rare 
 
Not known 

Cerebrovascular accident, hypertonia, dysarthria, coordination abnormal, 
hypogeusia, circadian rhythm sleep disorder 
Transient loss of consciousness 

Eye disorders 
Uncommon 
Rare 

Conjunctivitis, eye pain  
Scotoma, scleral discolouration, mydriasis, photophobia, myopia, 
lacrimation increased 

Ear and labyrinth disorders 
Uncommon Tinnitus 
Cardiac disorders 
Uncommon Myocardial infarction, angina pectoris, tachycardia, palpitations, heart 

rate increased 
Rare 
 

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

Vascular disorders 
Uncommon Blood pressure increased, hot flush 
Respiratory, thoracic and mediastinal disorders 
Common 
Uncommon 

Dyspnoea, cough 



 

30 

System Organ 
Class 

Adverse Drug Reactions 

 
 
Rare 

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

Gastrointestinal disorders 
Very common Nausea  
Common Gastrooesophageal reflux disease, vomiting, constipation, diarrhoea, 

abdominal distension, abdominal pain, toothache, dyspepsia, flatulence, 
dry mouth 

Uncommon 
 
Rare 

Haematochezia, gastritis, change of bowel habit, eructation, aphthous 
stomatitis, gingival pain 
Haematemesis, abnormal faeces, tongue coated 

Skin and subcutaneous tissue disorders 
Common 
Uncommon 

Rash, pruritus 
Erythema, acne, hyperhidrosis, night sweats 

Rare Severe cutaneous reactions, including Stevens Johnson Syndrome and 
Erythema Multiforme, angioedema 

Musculoskeletal and connective tissue disorders 
Common 
Uncommon 
Rare 

Arthralgia, myalgia, back pain 
Muscle spasms, musculoskeletal chest pain 
Joint stiffness, costochondritis 

Renal and urinary disorders 
Uncommon 
Rare 

Pollakiuria, nocturia 
Glycosuria, polyuria 

Reproductive system and breast disorders 
Uncommon 
Rare 

Menorrhagia 
Vaginal discharge, sexual dysfunction 

General disorders and administration site conditions 
Common Chest pain, fatigue 
Uncommon 
Rare 

Chest discomfort, influenza like illness, pyrexia, asthenia, malaise 
Feeling cold, cyst 

Investigations 
Common Liver function test abnormal  
Rare Semen analysis abnormal, C-reactive protein increased, blood calcium 

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

 
Reporting of suspected adverse reactions 
 
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It 
allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare 
professionals are asked to report any suspected adverse reactions via the national reporting system 
listed in Appendix V. 
 
4.9 Overdose 
 
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. 
 
 



 

31 

5. PHARMACOLOGICAL PROPERTIES 
 
5.1  Pharmacodynamic properties 
 
Pharmacotherapeutic group: Other nervous system drugs; Drugs used in addictive disorders, Drugs 
used in nicotine dependence, ATC code: N07BA03 
 
Mechanism of action 
 
Varenicline binds with high affinity and selectivity at the α4β2 neuronal nicotinic acetylcholine 
receptors, where it acts as a partial agonist - a compound that has both agonist activity, with lower 
intrinsic efficacy than nicotine, and antagonist activities in the presence of nicotine.  
 
Electrophysiology studies in vitro and neurochemical studies in vivo have shown that varenicline 
binds 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 nAChR 
binding site for which varenicline has higher affinity. Therefore, varenicline can effectively block 
nicotine's ability to fully activate α4β2 receptors and the mesolimbic dopamine system, the neuronal 
mechanism underlying reinforcement and reward experienced upon smoking. Varenicline is highly 
selective and binds more potently to the α4β2 receptor subtype (Ki=0.15 nM) than to other common 
nicotinic receptors (α3β4 Ki=84 nM, α7 Ki= 620 nM, α1βγδ Ki= 3,400 nM), or to non-nicotinic 
receptors and transporters (Ki > 1µM, except to 5-HT3 receptors: Ki=350 nM). 
 
Pharmacodynamic effects 
 
The efficacy of CHAMPIX in smoking cessation is a result of varenicline's partial agonist activity at 
the α4β2 nicotinic receptor where its binding produces an effect sufficient to alleviate symptoms of 
craving and withdrawal (agonist activity), while simultaneously resulting in a reduction of the 
rewarding and reinforcing effects of smoking by preventing nicotine binding to α4β2 receptors 
(antagonist activity). 
 
Clinical efficacy and safety 
 
Smoking cessation therapies are more likely to succeed for patients who are motivated to stop 
smoking and who are provided with additional advice and support. 
 
The efficacy of CHAMPIX in smoking cessation was demonstrated in 3 clinical trials involving 
chronic 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 received 
bupropion 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 smoking 
cessation. In these 52-week duration studies, patients received treatment for 12 weeks, followed by a 
40-week non-treatment phase. 
 
The primary endpoint of the two studies was the carbon monoxide (CO) confirmed, 4-week 
continuous quit rate (4W-CQR) from week 9 through week 12. The primary endpoint for CHAMPIX 
demonstrated 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 did 
not 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: 
 



 

32 

  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  
CHAMPIX vs. placebo 

3.91 
p < 0.0001 

3.13 
p < 0.0001 

3.85 
p < 0.0001 

2.66 
p < 0.0001 

Odds ratio  
CHAMPIX vs. bupropion 

1.96 
p < 0.0001 

1.45 
p = 0.0640 

1.89 
p < 0.0001 

1.72 
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 significantly 
reduced in patients randomised to CHAMPIX in comparison with placebo. CHAMPIX also 
significantly reduced reinforcing effects of smoking that can perpetuate smoking behaviour in patients 
who smoke during treatment compared with placebo. The effect of varenicline on craving, withdrawal 
and reinforcing effects of smoking were not measured during the non-treatment long-term follow-up 
phase. 
 
Maintenance of abstinence study 
The third study assessed the benefit of an additional 12 weeks of CHAMPIX therapy on the 
maintenance of abstinence. Patients in this study (n=1,927) received open-label CHAMPIX 1 mg 
twice daily for 12 weeks. Patients who stopped smoking by Week 12 were then randomised to receive 
either CHAMPIX (1 mg twice daily) or placebo for an additional 12 weeks for a total study duration 
of 52 weeks. 
 
The primary study endpoint was the CO-confirmed continuous abstinence rate from week 13 through 
week 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 daily 
for the maintenance of smoking cessation compared to placebo; superiority to placebo for CA was 
maintained through week 52. The key results are summarised in the following table: 
 
Continuous Abstinence Rates in Subjects Treated with Champix versus Placebo 
 
 CHAMPIX 

n=602 
Placebo 
n=604 

Difference 
(95% CI) 

Odds ratio 
(95% CI) 

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

2.47 
(1.95, 3.15) 

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

1.35 
(1.07, 1.70) 

*CA: Continuous Abstinence Rate 
 
There is currently limited clinical experience with the use of CHAMPIX among black people to 
determine 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 of 
quitting between weeks 1 and 5 of treatment. In this 24-week study, patients received treatment for 
12 weeks followed by a 12 week non-treatment follow up phase. The 4 week (week 9-12) CQR for 
varenicline 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 quit 
date within 1-2 weeks, could be offered to start treatment and then choose their own quit date within 
5 weeks. 
 



 

33 

Study in subjects 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 who experienced an adverse event of a concern during previous treatment 
were 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 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.  
 
Patients treated with CHAMPIX had a superior rate of CO-confirmed abstinence during weeks 
9 through 12 and from weeks 9 through 52 compared to subjects treated with placebo. The key results 
are summarised in the following table: 
 
Continuous Abstinence Rates in Subjects Treated with Champix versus Placebo 
 
 CHAMPIX 

n=249 
Placebo 
n=245 

Odds ratio (95% CI), 
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 who 
were not able or willing to quit smoking within four weeks, but were willing to gradually reduce their 
smoking over a 12 week period before quitting. Subjects were randomised 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. Subjects treated with 
CHAMPIX had a significantly higher Continuous Abstinence Rate compared with placebo; the key 
results are summarised in the following table: 
 
Continuous Abstinence Rates in Subjects Treated with Champix versus Placebo 
 
 CHAMPIX 

n=760 
Placebo 
n=750 

Odds ratio (95% CI), 
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 with 
stable, cardiovascular disease (other than, or in addition to, hypertension) that had been diagnosed for 
more 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 for 



 

34 

varenicline 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 following 
adjudicated events occurred with a frequency ≥ 1% in either treatment group during treatment (or in 
the 30-day period after treatment): nonfatal myocardial infarction (1.1% vs. 0.3% for CHAMPIX and 
placebo, respectively), and hospitalisation for angina pectoris (0.6% vs. 1.1%). During non-treatment 
follow 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 vascular 
disease (PVD) or admission for a PVD procedure (1.4% vs. 0.6%). Some of the patients requiring 
coronary revascularisation underwent the procedure as part of management of nonfatal MI and 
hospitalisation for angina. Cardiovascular death occurred in 0.3% of patients in the CHAMPIX arm 
and 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 in 
the 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, and 
nonfatal stroke. These events included in the endpoint were adjudicated by a blinded, independent 
committee. Overall, a small number of MACE occurred during treatment in the trials included in the 
meta-analysis (CHAMPIX 7 [0.17%]; placebo 2 [0.07%]). Additionally, a small number of MACE 
occurred 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 are 
equivalent to an estimated increase of 6.5 MACE events and 6.3 MACE events per 
1,000 patient-years, respectively of exposure. The hazard ratio for MACE was higher in patients with 
cardiovascular risk factors in addition to smoking compared with that in patients without 
cardiovascular 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 without 
a 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 6293 
subjects who completed the parent study (N=8058) and followed them through week 52. Of all 
subjects 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 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 following table shows the incidence of MACE and Hazard Ratios vs placebo for all treatment 
groups during treatment, and cumulative for treatment plus 30 days and through end of study. 
 



 

35 

 CHAMPIX 
N=2016 

Bupropion 
N=2006 

NRT 
N=2022 

Placebo 
N=2014 

During treatment 

MACE, n (%) 1 (0.05) 2 (0.10) 1 (0.05) 4 (0.20) 
    Hazard Ratio 
(95% CI) vs 
placebo 

0.29 (0.05, 1.68) 0.50 (0.10, 2.50) 0.29 (0.05, 1.70)  

During treatment plus 30 days 
MACE, n (%) 1 (0.05) 2 (0.10) 2 (0.10) 4 (0.20) 
   Hazard Ratio 
(95% CI) vs 
placebo 

0.29 (0.05, 1.70) 0.51 (0.10, 2.51) 0.50 (0.10, 2.48)  

Through end of study 
MACE, n (%) 3 (0.15) 9 (0.45) 6 (0.30) 8 (0.40) 
   Hazard Ratio 
(95% CI) vs 
placebo 

0.39 (0.12, 1.27) 1.09 (0.42, 2.83) 0.75 (0.26, 2.13)  

 
The use of CHAMPIX, bupropion, and NRT was not associated with an increased risk of CV AEs in 
smokers treated for up to 12 weeks and followed for up to 1 year compared to placebo, although 
because 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 with  
mild-moderate COPD was demonstrated in a randomised double-blind placebo-controlled clinical 
trial. In this 52-week duration study, patients received treatment for 12 weeks, followed by a 40-week 
non-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 was 
comparable 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 the 
following table: 
 
 4W CQR CA Wk 9-52 

CHAMPIX, (n = 248)  42.3% 18.5% 

Placebo, (n = 251)  8.8% 5.6% 

Odds ratio  
(CHAMPIX vs. Placebo)  

8.40 
p < 0.0001 

4.04 
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 subjects 
with a history of major depression in the past two years or under current stable treatment. The 
cessation rates in this population were similar to those reported in the general population. Continuous 
abstinence rate between weeks 9-12 was 35.9% in the varenicline treatment group versus 15.6% in the 
placebo 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 subjects 
taking varenicline were nausea (27.0% vs. 10.4% on placebo), headache (16.8% vs. 11.2%), abnormal 
dreams (11.3% vs. 8.2%), insomnia (10.9% vs. 4.8%) and irritability (10.9% vs. 8.2%). Psychiatric 
scales showed no differences between the varenicline and placebo groups and no overall worsening of 
depression, or other psychiatric symptoms, during the study in either treatment group. 
 



 

36 

Study in subjects with stable schizophrenia or schizoaffective disorder  
Varenicline safety and tolerability was assessed in a double-blind study of 128 smokers with stable 
schizophrenia 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% on 
placebo), headache (10.7% vs. 18.6% on placebo) and vomiting (10.7% vs. 9.3% on placebo). Among 
reported neuropsychiatric adverse events, insomnia was the only event reported in either treatment 
group 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 psychiatric 
scales and there were no overall changes in extra-pyramidal signs. In the varenicline group compared 
to 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 of 
treatment). During the active treatment period, the incidence of suicide-related events was similar 
between the varenicline-treated and the placebo-treated subjects (11 vs. 9.3%, respectively). The 
percentage of subjects with suicide-related events in the active treatment phase compared to 
post-treatment phase was unchanged in the varenicline group; in the placebo group, this percentage 
was lower in the post-treatment phase. Although there were no completed suicides, there was one 
suicidal attempt in a varenicline-treated subject whose lifetime history included several similar 
attempts. The limited data available from this single smoking cessation study are not sufficient to 
allow for definitive conclusions to be drawn about the safety in patients with schizophrenia or 
schizoaffective 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 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). 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 a 
treatment 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 events 
of 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 by 
treatment 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,  
n (%) 

13 (1.3) 
 

22 (2.2) 
 

25 (2.5) 
 

24 (2.4) 
 

RD (95% CI) vs Placebo  -1.28 
(-2.40, -0.15) 

-0.08 
(-1.37, 1.21) 

-0.21           
(-1.54,1.12) 

 

Composite NPS AE 
Endpoint of severe intensity 
n (%) 

1 (0.1) 4 (0.4) 3 (0.3) 5 (0.5) 

AE, adverse event; NRT=Nicotine replacement therapy patch 

 



 

37 

The rates of events in the composite endpoint were low across all treatment groups and were similar or 
lower 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 NPS 
adverse events in the composite primary endpoint compared with placebo (95% CIs were lower than 
or 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 during 
treatment and in the non- treatment follow-up, as shown in the following table: 
 

 Non-psychiatric Cohort 
N=3984 

Varenicline 
 

N=990 
n (%) 

Bupropion 
 

N=989 
n (%) 

NRT 
 

N=1006 
n (%) 

Placebo 
 

N=999 
n (%) 

During treatment 
Number assessed 988 983 996 995 
Suicidal 
behaviour and/or 
ideation 

7 (0.7) 4 (0.4) 3 (0.3) 7 (0.7) 

Suicidal 
behaviour 

0 0 1 (0.1) 1 (0.1) 

Suicidal 
ideation 

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

During follow up 
Number assessed 807 816 800 805 
Suicidal 
behaviour and/or 
ideation 

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

Suicidal 
behaviour 

0 1 (0.1) 0 0 

Suicidal 
ideation 

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 in 
the non-psychiatric cohort. 

The following table shows the rates of the composite NPS adverse event primary endpoint by 
treatment group and the RDs (95% CI) vs placebo in the psychiatric cohort. The individual 
components 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 
Primary Endpoint, n (%) 

67 (6.5) 
 

68 (6.7) 
 

53 (5.2) 
 

50 (4.9) 
 

RD (95% CI) vs Placebo  1.59                 
(-0.42, 3.59) 

1.78                
 (-0.24, 3.81) 

0.37             
(-1.53, 2.26) 

 



 

38 

NPS AE Primary 
Endpoint Components n 
(%): 

Anxietya 
Depressiona 
Feeling abnormala 
Hostilitya 
Agitationb 
Aggressionb 
Delusionsb 
Hallucinationsb 
Homicidal ideationb 
Maniab 
Panicb 
Paranoiab 
Psychosisb 
Suicidal behaviourb 
Suicidal ideationb 
Completed suicideb 

 

 

5 (0.5) 
6 (0.6) 

0 
0 

25 (2.4) 
14 (1.4) 
1 (0.1) 
5 (0.5) 

0 
7 (0.7) 
7 (0.7) 
1 (0.1) 
4 (0.4) 
1 (0.1) 
5 (0.5) 

0 

 

 

4 (0.4) 
4 (0.4) 
1 (0.1) 

0 
29 (2.9) 
9 (0.9) 
1 (0.1) 
4 (0.4) 

0 
9 (0.9) 

16 (1.6) 
0 

2 (0.2) 
1 (0.1) 
2 (0.2) 

0 

 

 

6 (0.6) 
7 (0.7) 

0 
0 

21 (2.1) 
7 (0.7) 
1 (0.1) 
2 (0.2) 

0 
3 (0.3) 

13 (1.3) 
0 

3 (0.3) 
0 

3 (0.3) 
0 

 

 

2 (0.2) 
6 (0.6) 

0 
0 

22 (2.2) 
8 (0.8) 

0 
2 (0.2) 

0 
6 (0.6) 
7 (0.7) 
2 (0.2) 
1 (0.1) 
1 (0.1) 
2 (0.2) 

0 
Composite NPS AE 
Endpoint of severe 
intensity n (%) 

14 (1.4) 14 (1.4) 14 (1.4) 13 (1.3) 

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

therapy patch 

 

There were more events reported in patients in the psychiatric cohort 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, the use of varenicline, 
bupropion and NRT in the psychiatric cohort was not associated with a significantly increased risk 
of NPS adverse events in the composite primary endpoint compared with placebo (95% CIs 
included zero). 
 
In the psychiatric cohort, 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 during treatment and in the non- treatment follow-up, as shown in the following 
table: 
 

 Psychiatric Cohort 
N=4074 

Varenicline 
 

N=1026 
n (%) 

Bupropion 
 

N=1017 
n (%) 

NRT 
 

N=1016 
n (%) 

Placebo 
 

N=1015 
n (%) 

During treatment 
Number assessed 1017 1012 1006 1006 
Suicidal 
behaviour and/or 
ideation 

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

Suicidal 
behaviour 

0 1 (0.1) 0 2 (0.2) 

Suicidal 
ideation 

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



 

39 

During follow up 
Number assessed 833 836 824 791 
Suicidal 
behaviour and/or 
ideation 

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

Suicidal 
behaviour 

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

Suicidal 
ideation 

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 were 
similar to those observed in premarketing studies.  

In both cohorts, subjects treated with varenicline demonstrated statistical superiority of CO-confirmed 
abstinence 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 neuropsychiatric 
events with varenicline compared to placebo. In addition, independent observational studies have not 
supported an increased risk of serious neuropsychiatric events in patients treated with varenicline 
compared to patients prescribed nicotine replacement therapy (NRT) or bupropion.  



 

40 

Treatment discontinuation  
The treatment discontinuation rate due to adverse reactions was 11.4% for varenicline compared with 
9.7% for placebo. In this group, the discontinuation rates for the most common adverse reactions in 
varenicline 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% for 
placebo). 
 
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 reported 
on 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 of 
suicidal ideation and/or behaviour in patients treated with varenicline compared to patients treated 
with placebo, as shown in the table below. Of the 55 patients who reported suicidal ideation or 
behaviour, 48 (24 varenicline, 24 placebo) were from the two trials that enrolled patients with a history 
of schizophrenia/ schizoaffective disorder, or of depression. Few patients reported these events in the 
other three trials (4 varenicline, 3 placebo). 
 
Number of Patients and Risk Ratio for Suicidal Ideation and/or Behaviour Reported on C-SSRS 
from a Meta-Analysis of 5 Clinical Trials Comparing Varenicline to Placebo: 
 

 Varenicline 
(N=1130) 

Placebo 
(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 to 
assess the neuropsychiatric safety of varenicline. These trials included the 5 trials described above that 
used the C-SSRS, and a total of 8521 patients (5072 varenicline, 3449 placebo), some of which had 
psychiatric conditions. The results showed a similar incidence of combined neuropsychiatric adverse 
events, other than sleep disorders, in patients treated with varenicline compared to patients treated with 
placebo, with a risk ratio (RR) of 1.01 (95% CI: 0.89-1.15). Pooled data from these 18 trials showed a 
similar incidence rate of individual categories of psychiatric events in patients treated with varenicline 
compared 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 and 
disturbances. 
 



 

41 

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

 Varenicline 
(N=5072) 

Placebo 
(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 adjusted 
analyses, compared the risk of serious neuropsychiatric events, including neuropsychiatric 
hospitalizations and fatal and non-fatal self-harm, in patients treated with varenicline versus patients 
prescribed NRT or bupropion. All studies were retrospective cohort studies and included patients with 
and without a psychiatric history. All studies used statistical methods to control for confounding 
factors, including preferential prescribing of varenicline to healthier patients, although there is the 
possibility of residual confounding. 

Two of the studies found no difference in risk of neuropsychiatric hospitalisations between varenicline 
users and nicotine patch users (Hazard Ratio [HR] 1.14; 95% Confidence Interval [CI]: 0.56–2.34 in 
the first study, and 0.76; 95% CI: 0.40-1.46 in the second study). The power to detect differences in 
these two studies was limited. The third study reported no difference in risk of psychiatric adverse 
events diagnosed during an emergency department visit or inpatient admission between varenicline 
users and bupropion users (HR 0.85; 95% CI: 0.55-1.30). Based on post marketing reports, bupropion 
may 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. The 
occurrence of detected suicide was rare during the three months after patients initiated any drug 
treatment (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) 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 as compared to infants 
born 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%).  
 
Paediatric Population 
 
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 least 
5 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 age 
and 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 dose 
group) or 0.5 mg twice daily (low dose group), while patients with a body weight ≤55 kg received 
0.5 mg twice daily (high dose group) or 0.5 mg once daily (low dose group). Patients received 
treatment for 12 weeks, followed by a non-treatment period of 40 weeks, along with age-appropriate 
counseling throughout the study. 
 



 

42 

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

n/N (%) 
12-to-17-Year Olds 

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, 4.89) [0.0347]* 
* This p value is not considered statistically significant. The prespecified statistical testing procedures stopped testing 

after the high-dose varenicline vs Placebo treatment comparison in the overall study did not achieve statistical 

significance. 

 
CI=confidence interval; N=number of subjects randomised; n=the number of subjects who, at each visit from weeks 9 to 
12 (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. 

 
5.2 Pharmacokinetic properties  
 
Absorption 
 
Maximum plasma concentrations of varenicline occur typically within 3-4 hours after oral 
administration. Following administration of multiple oral doses to healthy volunteers, steady-state 
conditions were reached within 4 days. Absorption 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 
 
Varenicline distributes into tissues, including the brain. Apparent volume of distribution averaged 
415 litres (%CV= 50) at steady-state. Plasma protein binding of varenicline is low (< 20%) and 
independent of both age and renal function. In rodents, varenicline is transferred through the placenta 
and excreted in milk.  
 
Biotransformation 
 
Varenicline undergoes minimal metabolism with 92% excreted unchanged in the urine and less than 
10% excreted as metabolites. Minor metabolites in urine include varenicline N-carbamoylglucuronide 
and hydroxyvarenicline. In circulation, varenicline comprises 91% of drug-related material. Minor 
circulating 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 the 
activity of cytochrome P450 enzymes 1A2 and 3A4. Therefore, varenicline is unlikely to alter the 
pharmacokinetics of compounds that are primarily metabolised by cytochrome P450 enzymes. 
 
Elimination 
 
The elimination half-life of varenicline is approximately 24 hours. Renal elimination of varenicline is 
primarily through glomerular filtration along with active tubular secretion via the organic cationic 
transporter, OCT2 (see section 4.5). 
 



 

43 

Linearity/Non linearity 
 
Varenicline exhibits linear kinetics when given as single (0.1 to 3 mg) or repeated 1 to 3 mg/day 
doses. 
 
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 specific 
pharmacokinetic studies and in population pharmacokinetic analyses. 
 
Hepatic impairment 
Due to the absence of significant hepatic metabolism, varenicline pharmacokinetics should be 
unaffected in patients with hepatic impairment. (see section 4.2). 
 
Renal impairment 
Varenicline pharmacokinetics were 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 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 was increased 2.1-fold. In subjects with end-stage-renal disease (ESRD), varenicline was 
efficiently removed by haemodialysis (see section 4.2).  
 
Elderly 
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 renal 
function please refer to section 4.2. 
 
Paediatric population 
Single and multiple-dose pharmacokinetics of varenicline have been investigated in paediatric patients 
aged 12 to 17 years old (inclusive) and were approximately dose-proportional over the 0.5 mg to 2 mg 
daily 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 the 
adult population. CHAMPIX is not recommended in paediatric patients because its efficacy in this 
population was not demonstrated (see sections 4.2 and 5.1). 
 
5.3 Preclinical safety data  
 
Non-clinical data reveal no special hazard for humans based on conventional studies of safety 
pharmacology, repeated dose toxicity, genotoxicity, fertility and embryo-foetal development. In male 
rats 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 were 
decreases in fertility and increases in the auditory startle response (see section 4.6). These effects were 
observed only at exposures considered sufficiently in excess of the maximum human exposure 
indicating little relevance to clinical use. Nonclinical data indicate varenicline has reinforcing 
properties albeit with lower potency than nicotine. In clinical studies in humans, varenicline showed 
low abuse potential. 
 
 



 

44 

6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Tablets’ core 
 
Cellulose, Microcrystalline 
Calcium Hydrogen Phosphate Anhydrous 
Croscarmellose Sodium 
Silica, Colloidal Anhydrous 
Magnesium Stearate 
 
Film coating 
 
Hypromellose 
Titanium Dioxide (E171) 
Macrogol 400 
Indigo Carmine Aluminium Lake E132 
Triacetin  
 
6.2 Incompatibilities 
 
Not applicable. 
 
6.3 Shelf life 
 
Bottles: 2 years 
Blisters: 3 years 
 
6.4 Special precautions for storage 
 
Blisters: Store below 30°C 
HDPE Bottle: This medicinal product does not require any special storage conditions 
 
6.5 Nature and contents of container 
 
Maintenance packs 
 
PCTFE/PVC blisters with aluminium foil backing in a pack containing 28 x 1 mg film-coated tablets 
in secondary heat sealed card packaging. 
 
PCTFE/PVC blisters with aluminium foil backing in a pack containing 56 x 1 mg film-coated tablets 
in secondary heat sealed card packaging. 
 
PCTFE/PVC blisters with aluminium foil backing in a pack containing 28 x 1 mg film-coated tablets 
in a carton. 
 
PCTFE/PVC blisters with aluminium foil backing in a pack containing 56 x 1 mg film-coated tablets 
in a carton. 
 
PCTFE/PVC blisters with aluminium foil backing in a pack containing 112 x 1 mg film-coated tablets 
in a carton. 
 
PCTFE/PVC blisters with aluminium foil backing in a pack containing 140 x 1 mg film-coated tablets 
in a carton. 
 



 

45 

PVC blisters with aluminium foil backing in a pack containing 28 x 1 mg film-coated tablets in 
secondary heat sealed card packaging. 
 
PVC blisters with aluminium foil backing in a pack containing 56 x 1 mg film-coated tablets in 
secondary heat sealed card packaging. 
 
PVC blisters with aluminium foil backing in a pack containing 28 x 1 mg film-coated tablets in a 
carton. 
 
PVC blisters with aluminium foil backing in a pack containing 56 x 1 mg film-coated tablets in a 
carton. 
 
PVC blisters with aluminium foil backing in a pack containing 112 x 1 mg film-coated tablets in a 
carton. 
 
PVC blisters with aluminium foil backing in a pack containing 140 x 1 mg film-coated tablets in a 
carton. 
 
High-density polyethylene (HDPE) bottle with polypropylene child resistant closure and an aluminium 
foil / polyethylene induction seal containing 56 x 1 mg film-coated tablets 
 
Not all pack sizes may be marketed. 
 
6.6 Special precautions for disposal  
 
No special requirements. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
Pfizer Europe MA EEIG 
Boulevard de la Plaine 17 
1050 Bruxelles 
Belgium 
 
 
8. MARKETING AUTHORISATION NUMBER(S)  
 
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 
EU/1/06/360/015 
EU/1/06/360/016 
EU/1/06/360/020 
EU/1/06/360/021 
EU/1/06/360/022 
EU/1/06/360/024 
 
 



 

46 

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 26 September 2006 
Date of latest renewal: 29 June 2016 
 
 
10. DATE OF REVISION OF THE TEXT 
 
Detailed information on this product is available on the website of the European Medicines Agency 
http://www.ema.europa.eu/  



 

47 

1. NAME OF THE MEDICINAL PRODUCT 
 
CHAMPIX 0.5 mg film-coated tablets 
CHAMPIX 1 mg film-coated tablets 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each 0.5 mg film-coated tablet contains 0.5 mg of varenicline (as tartrate). 
Each 1 mg film-coated tablet contains 1 mg of varenicline (as tartrate). 
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Film-coated tablets 
 
0.5 mg film-coated tablets of 4mm x 8mm: White, capsular-shaped, biconvex tablets debossed with 
“Pfizer” on one side and “CHX 0.5” on the other side. 
 
1 mg film-coated tablets of 5mm x 10mm: Light blue, capsular-shaped, biconvex tablets debossed 
with “Pfizer” on one side and “CHX 1.0” on the other side. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
CHAMPIX is indicated for smoking cessation in adults. 
 
4.2 Posology and method of administration 
 
Posology 
 
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 at 1-2 weeks 
before 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 
12 weeks treatment with CHAMPIX at 1 mg twice daily may be considered for the maintenance of 
abstinence (see section 5.1).  
 
A gradual approach to quitting smoking with CHAMPIX should be considered for patients who are 
not able or willing to quit abruptly. Patients should reduce smoking during the first 12 weeks of 
treatment and quit by the end of that treatment period. Patients should then continue taking CHAMPIX 
for an additional 12 weeks for a total of 24 weeks of treatment (see section 5.1). 
 



 

48 

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 temporarily 
or permanently to 0.5 mg twice daily. 
 
In smoking cessation therapy, risk for relapse to smoking is elevated in the period immediately 
following the end of treatment. In patients with a high risk of relapse, dose tapering may be considered 
(see section 4.4).  
 
Elderly 
No dosage adjustment is necessary for elderly patients (see section 5.2). Because elderly patients are 
more likely to have decreased renal function, prescribers should consider the renal status of an elderly 
patient. 
 
Renal impairment 
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 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), the 
recommended dose of CHAMPIX is 1 mg once daily. Dosing should begin at 0.5 mg once daily for 
the 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 patient 
population (see section 5.2). 
 
Hepatic impairment 
No dosage adjustment is necessary for patients with hepatic impairment (see section 5.2). 
 
Paediatric population 
CHAMPIX is not recommended for use in paediatric patients because its efficacy in this population 
was not demonstrated (see sections 5.1 and 5.2). 
 
Method of administration 
 
CHAMPIX is for oral use and the tablets should be swallowed whole with water. 
CHAMPIX can be taken with or without food 
 
4.3 Contraindications 
 
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. 
 
4.4 Special warnings and precautions for use 
 
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 dosage 
adjustment may be necessary (examples include theophylline, warfarin and insulin). As smoking 
induces CYP1A2, smoking cessation may result in an increase of plasma levels of CYP1A2 substrates. 
 



 

49 

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 quit 
smoking with CHAMPIX in the post-marketing experience.  
 
A large randomised, double-blind, active and placebo-controlled 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 use of varenicline 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 section 5.1 Pharmacodynamic properties - Study in Subjects with and 
without a History of Psychiatric Disorder).  
 
Depressed mood, rarely including suicidal ideation and suicide attempt, may be a symptom of 
nicotine withdrawal. 
 
Clinicians should be aware of the possible emergence of serious neuropsychiatric symptoms in 
patients attempting to quit smoking with or without treatment. If serious neuropsychiatric symptoms 
occur whilst on varenicline treatment, patients should discontinue varenicline immediately and 
contact a healthcare professional for re-evaluation of treatment.  
 
History of psychiatric disorders  
 
Smoking cessation, with or without pharmacotherapy, has been associated with exacerbation of 
underlying psychiatric illness (e.g. depression). 
 
CHAMPIX smoking cessation studies have provided data in patients with a history of psychiatric 
disorders (see section 5.1).  
 
In a smoking cessation clinical trial, neuropsychiatric adverse events were reported more frequently in 
patients with a history of psychiatric disorders compared to those without a history of psychiatric 
disorders, regardless of treatment (see section 5.1). 
 
Care should be taken with patients with a history of psychiatric illness and patients should be advised 
accordingly. 
 
Seizures  
 
In clinical trials and post-marketing experience there have been reports of seizures in patients with or 
without a history of seizures, treated with CHAMPIX. CHAMPIX should be used cautiously in 
patients with a history of seizures or other conditions that potentially lower the seizure threshold. 
 
Treatment discontinuation  
 
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 the 
patient accordingly and discuss or consider the need for dose tapering. 
 



 

50 

Cardiovascular events  
 
Patients taking CHAMPIX should be instructed to notify their doctor of new or worsening 
cardiovascular symptoms and to seek immediate medical attention if they experience signs and 
symptoms of myocardial infarction or stroke (see section 5.1). 
 
Hypersensitivity reactions 
 
There have been post-marketing reports of hypersensitivity reactions including angioedema in patients 
treated 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 angioedema 
requiring urgent medical attention due to respiratory compromise. Patients experiencing these 
symptoms should discontinue treatment with varenicline and contact a health care provider 
immediately. 
 
Cutaneous reactions 
 
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 can 
be life threatening, patients should discontinue treatment at the first sign of rash or skin reaction and 
contact a healthcare provider immediately. 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
Based on varenicline characteristics and clinical experience to date, CHAMPIX has no clinically 
meaningful drug interactions. No dosage adjustment of CHAMPIX or co-administered medicinal 
products listed below is recommended. 
 
In vitro studies indicate that varenicline is unlikely to alter the pharmacokinetics of compounds that 
are primarily metabolised by cytochrome P450 enzymes. 
 
Furthermore since metabolism of varenicline represents less than 10% of its clearance, active 
substances known to affect the cytochrome P450 system are unlikely to alter the pharmacokinetics of 
varenicline (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 at 
therapeutic concentrations. Therefore, active substances that are cleared by renal secretion (e.g., 
metformin - see below) are unlikely to be affected by varenicline.  
 
Metformin 
 
Varenicline did not affect the pharmacokinetics of metformin. Metformin had no effect on varenicline 
pharmacokinetics. 
 
Cimetidine 
 
Co-administration of cimetidine, with varenicline increased the systemic exposure of varenicline by 
29% 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. 
 
Digoxin 
 
Varenicline did not alter the steady-state pharmacokinetics of digoxin. 
 



 

51 

Warfarin 
 
Varenicline did not alter the pharmacokinetics of warfarin. Prothrombin time (INR) was not affected 
by varenicline. Smoking cessation itself may result in changes to warfarin pharmacokinetics (see 
section 4.4). 
 
Alcohol 
 
There are limited clinical data on any potential interaction between alcohol and varenicline. There 
have been post marketing reports of increased intoxicating effects of alcohol in patients treated with 
varenicline. 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 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 was greater for the combination than for NRT alone. 
 
Safety and efficacy of CHAMPIX in combination with other smoking cessation therapies have not 
been studied.  
 
4.6 Fertility, pregnancy and lactation 
 
Pregnancy 
 
A moderate amount of data on pregnant women indicated no malformative or foetal/neonatal toxicity 
of varenicline (see section 5.1). 
 
Animal studies have shown reproductive toxicity (see section 5.3). As a precautionary measure, it is 
preferable to avoid the use of varenicline during pregnancy (see section 5.1). 
 
Breast-feeding 
 
It is unknown whether varenicline is excreted in human breast milk. Animal studies suggest that 
varenicline is excreted in breast milk. A decision on whether to continue/discontinue breast-feeding or 
to continue/discontinue therapy with CHAMPIX should be made taking into account the benefit of 
breast-feeding to the child and the benefit of CHAMPIX therapy to the woman. 
 
Fertility 
 
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 in 
the rat (see section 5.3). 
 
4.7 Effects on ability to drive and use machines 
 
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 may 
influence the ability to drive and use machines. Patients are advised not to drive, operate complex 



 

52 

machinery or engage in other potentially hazardous activities until it is known whether this medicinal 
product affects their ability to perform these activities. 
 
4.8 Undesirable effects 
 
Summary of the safety profile 
 
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. No attempt has been made in either the design or the analysis 
of the CHAMPIX studies to distinguish between adverse reactions associated with study drug 
treatment or those possibly associated with nicotine withdrawal. Adverse drug reactions are based on 
evaluation of data from pre-marketing phase 2-3 studies and updated based on pooled data from 
18 placebo-controlled pre- and post-marketing studies, including approximately 5,000 patients treated 
with varenicline. 
 
In patients treated with the recommended dose of 1 mg twice daily following an initial titration period 
the adverse event most commonly reported was nausea (28.6%). In the majority of cases nausea 
occurred early in the treatment period, was mild to moderate in severity and seldom resulted in 
discontinuation. 
 
Tabulated summary of adverse reactions 
 
In the table below all adverse reactions, which occurred at an incidence greater than placebo are listed 
by 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 
Class 

Adverse Drug Reactions 

Infections and infestations 
Very common Nasopharyngitis 
Common Bronchitis, sinusitis 
Uncommon Fungal infection, viral infection 
Blood and lymphatic system disorders 
Rare Platelet count decreased 
Metabolism and nutrition disorders 
Common Weight increased, decreased appetite, increased appetite 
Uncommon Hyperglycaemia 
Rare Diabetes mellitus, polydipsia 
Psychiatric disorders 
Very common Abnormal dreams, insomnia 
Uncommon 
 
 
Rare 

Suicidal ideation, aggression, panic reaction, thinking abnormal, 
restlessness, mood swings, depression*, anxiety*, hallucinations*, libido 
increased, libido decreased 
Psychosis, somnambulism, abnormal behaviour, dysphoria, bradyphrenia 

Nervous system disorders 
Very common Headache 
Common Somnolence, dizziness, dysgeusia 
Uncommon Seizure, tremor, lethargy, hypoaesthesia 
Rare 
 
Not known 

Cerebrovascular accident, hypertonia, dysarthria, coordination abnormal, 
hypogeusia, circadian rhythm sleep disorder 
Transient loss of consciousness 



 

53 

System Organ 
Class 

Adverse Drug Reactions 

Eye disorders 
Uncommon 
Rare 

Conjunctivitis, eye pain  
Scotoma, scleral discolouration, mydriasis, photophobia, myopia, 
lacrimation increased 

Ear and labyrinth disorders 
Uncommon Tinnitus 
Cardiac disorders 
Uncommon Myocardial infarction, angina pectoris, tachycardia, palpitations, heart 

rate increased 
Rare 
 

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

Vascular disorders 
Uncommon Blood pressure increased, hot flush 
Respiratory, thoracic and mediastinal disorders 
Common 
Uncommon 
 
 
Rare 

Dyspnoea, cough 
Upper respiratory tract inflammation, respiratory tract congestion, 
dysphonia, rhinitis allergic, throat irritation, sinus congestion, upper- 
airway cough syndrome, rhinorrhoea 
Laryngeal pain, snoring 

Gastrointestinal disorders 
Very common Nausea  
Common Gastrooesophageal reflux disease, vomiting, constipation, diarrhoea, 

abdominal distension, abdominal pain, toothache, dyspepsia, flatulence, 
dry mouth 

Uncommon 
 
Rare 

Haematochezia, gastritis, change of bowel habit, eructation, aphthous 
stomatitis, gingival pain 
Haematemesis, abnormal faeces, tongue coated 

Skin and subcutaneous tissue disorders 
Common 
Uncommon 

Rash, pruritus 
Erythema, acne, hyperhidrosis, night sweats 

Rare Severe cutaneous reactions, including Stevens Johnson Syndrome and 
Erythema Multiforme, angioedema 

Musculoskeletal and connective tissue disorders 
Common 
Uncommon 
Rare 

Arthralgia, myalgia, back pain 
Muscle spasms, musculoskeletal chest pain 
Joint stiffness, costochondritis 

Renal and urinary disorders 
Uncommon 
Rare 

Pollakiuria, nocturia 
Glycosuria, polyuria 

Reproductive system and breast disorders 
Uncommon 
Rare 

Menorrhagia 
Vaginal discharge, sexual dysfunction 

General disorders and administration site conditions 
Common Chest pain, fatigue 
Uncommon 
Rare 

Chest discomfort, influenza like illness, pyrexia, asthenia, malaise 
Feeling cold, cyst 

Investigations 
Common Liver function test abnormal  
Rare Semen analysis abnormal, C-reactive protein increased, blood calcium 

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

 



 

54 

Reporting of suspected adverse reactions 
 
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It 
allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare 
professionals are asked to report any suspected adverse reactions via the national reporting system 
listed in Appendix V. 
. 
4.9 Overdose 
 
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. 
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1  Pharmacodynamic properties 
 
Pharmacotherapeutic group: Other nervous system drugs; Drugs used in addictive disorders; Drugs 
used in nicotine dependence, ATC code: N07BA03 
 
Mechanism of action 
 
Varenicline binds with high affinity and selectivity at the α4β2 neuronal nicotinic acetylcholine 
receptors, where it acts as a partial agonist - a compound that has both agonist activity, with lower 
intrinsic efficacy than nicotine, and antagonist activities in the presence of nicotine. 
 
Electrophysiology studies in vitro and neurochemical studies in vivo have shown that varenicline 
binds 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 nAChR 
binding site for which varenicline has higher affinity. Therefore, varenicline can effectively block 
nicotine's ability to fully activate α4β2 receptors and the mesolimbic dopamine system, the neuronal 
mechanism underlying reinforcement and reward experienced upon smoking. Varenicline is highly 
selective and binds more potently to the α4β2 receptor subtype (Ki=0.15 nM) than to other common 
nicotinic receptors (α3β4 Ki=84 nM, α7 Ki= 620 nM, α1βγδ Ki= 3,400 nM), or to non-nicotinic 
receptors and transporters (Ki > 1µM, except to 5-HT3 receptors: Ki=350 nM). 
 
Pharmacodynamic effects 
 
The efficacy of CHAMPIX in smoking cessation is a result of varenicline's partial agonist activity at 
the α4β2 nicotinic receptor where its binding produces an effect sufficient to alleviate symptoms of 
craving and withdrawal (agonist activity), while simultaneously resulting in a reduction of the 
rewarding and reinforcing effects of smoking by preventing nicotine binding to α4β2 receptors 
(antagonist activity). 
 
Clinical efficacy and safety 
 
Smoking cessation therapies are more likely to succeed for patients who are motivated to stop 
smoking and who are provided with additional advice and support. 
 
The efficacy of CHAMPIX in smoking cessation was demonstrated in 3 clinical trials involving 
chronic cigarette smokers ( 10 cigarettes per day). Two thousand six hundred nineteen (2619) 



 

55 

patients received CHAMPIX 1 mg BID (titrated during the first week), 669 patients received 
bupropion 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 smoking cessation. In 
these 52-week duration studies, patients received treatment for 12 weeks, followed by a 40-week  
non-treatment phase. 
 
The primary endpoint of the two studies was the carbon monoxide (CO) confirmed, 4-week 
continuous quit rate (4W-CQR) from week 9 through week 12. The primary endpoint for CHAMPIX 
demonstrated 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 did 
not 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  
CHAMPIX vs. placebo 

3.91 
p < 0.0001 

3.13 
p < 0.0001 

3.85 
p < 0.0001 

2.66 
p < 0.0001 

Odds ratio  
CHAMPIX vs. bupropion 

1.96 
p < 0.0001 

1.45 
p = 0.0640 

1.89 
p < 0.0001 

1.72 
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 significantly 
reduced in patients randomised to CHAMPIX in comparison with placebo. CHAMPIX also 
significantly reduced reinforcing effects of smoking that can perpetuate smoking behaviour in patients 
who smoke during treatment compared with placebo. The effect of varenicline on craving, withdrawal 
and reinforcing effects of smoking were not measured during the non-treatment long-term follow-up 
phase. 
 
Maintenance of abstinence study 
 
The third study assessed the benefit of an additional 12 weeks of CHAMPIX therapy on the 
maintenance of abstinence. Patients in this study (n=1,927) received open-label CHAMPIX 1 mg 
twice daily for 12 weeks. Patients who stopped smoking by Week 12 were then randomised to receive 
either CHAMPIX (1 mg twice daily) or placebo for an additional 12 weeks for a total study duration 
of 52 weeks. 
 
The primary study endpoint was the CO-confirmed continuous abstinence rate from week 13 through 
week 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 daily 
for the maintenance of smoking cessation compared to placebo; superiority to placebo for CA was 
maintained through week 52. The key results are summarised in the following table: 
 



 

56 

Continuous Abstinence Rates in Subjects Treated with Champix versus Placebo 
 
 CHAMPIX 

n=602 
Placebo 
n=604 

Difference 
(95% CI) 

Odds ratio 
(95% CI) 

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

2.47 
(1.95, 3.15) 

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

1.35 
(1.07, 1.70) 

*CA: Continuous Abstinence Rate 

 
There is currently limited clinical experience with the use of CHAMPIX among black people to 
determine 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 of 
quitting between weeks 1 and 5 of treatment. In this 24-week study, patients received treatment for 
12 weeks followed by a 12 week non-treatment follow up phase. The 4 week (week 9-12) CQR for 
varenicline 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 quit date within 1-2 weeks, 
could be offered to start treatment and then choose their own quit date within 5 weeks. 
 
Study in subjects 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 who experienced an adverse event of a concern during previous treatment 
were 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 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.  
 
Patients treated with CHAMPIX had a superior rate of CO-confirmed abstinence during weeks 9 
through 12 and from weeks 9 through 52 compared to subjects treated with placebo. The key results 
are summarised in the following table: 
 
Continuous Abstinence Rates in Subjects Treated with Champix versus Placebo 
 

 CHAMPIX 
n=249 

Placebo 
n=245 

Odds ratio (95% CI), 
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 
 
Gradual approach to quitting smoking 
CHAMPIX was evaluated in a 52-week double-blind placebo-controlled study of 1,510 subjects who 
were not able or willing to quit smoking within four weeks, but were willing to gradually reduce their 
smoking over a 12 week period before quitting. Subjects were randomised 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. Subjects treated with 



 

57 

CHAMPIX had a significantly higher Continuous Abstinence Rate compared with placebo; the key 
results are summarised in the following table: 
 
Continuous Abstinence Rates in Subjects Treated with Champix versus Placebo 
 
 CHAMPIX 

n=760 
Placebo 
n=750 

Odds ratio (95% CI), 
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 with 
stable, cardiovascular disease (other than, or in addition to, hypertension) that had been diagnosed for 
more 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 for 
varenicline 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 following 
adjudicated events occurred with a frequency ≥ 1% in either treatment group during treatment (or in 
the 30-day period after treatment): nonfatal myocardial infarction (1.1% vs. 0.3% for CHAMPIX and 
placebo, respectively), and hospitalisation for angina pectoris (0.6% vs. 1.1%). During non-treatment 
follow 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 vascular 
disease (PVD) or admission for a PVD procedure (1.4% vs. 0.6%). Some of the patients requiring 
coronary revascularisation underwent the procedure as part of management of nonfatal MI and 
hospitalisation for angina. Cardiovascular death occurred in 0.3% of patients in the CHAMPIX arm 
and 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 in 
the 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, and 
nonfatal stroke. These events included in the endpoint were adjudicated by a blinded, independent 
committee. Overall, a small number of MACE occurred during treatment in the trials included in the 
meta-analysis (CHAMPIX 7 [0.17%]; placebo 2 [0.07%]). Additionally, a small number of MACE 
occurred 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 are 
equivalent to an estimated increase of 6.5 MACE events and 6.3 MACE events per 1,000 
patient-years, respectively of exposure. The hazard ratio for MACE was higher in patients with 
cardiovascular risk factors in addition to smoking compared with that in patients without 
cardiovascular 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. 
 



 

58 

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 without 
a 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 6293 
subjects who completed the parent study (N=8058) and followed them through week 52.  Of all 
subjects 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 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 following table shows the incidence of MACE and Hazard Ratios vs placebo for all treatment 
groups during treatment, and cumulative for treatment plus 30 days and through end of study. 
 

 CHAMPIX 
N=2016 

Bupropion 
N=2006 

NRT 
N=2022 

Placebo 
N=2014 

During treatment 

MACE, n (%) 1 (0.05) 2 (0.10) 1 (0.05) 4 (0.20) 
    Hazard Ratio 
(95% CI) vs 
placebo 

0.29 (0.05, 1.68) 0.50 (0.10, 2.50) 0.29 (0.05, 1.70)  

During treatment plus 30 days 
MACE, n (%) 1 (0.05) 2 (0.10) 2 (0.10) 4 (0.20) 
   Hazard Ratio 
(95% CI) vs 
placebo 

0.29 (0.05, 1.70) 0.51 (0.10, 2.51) 0.50 (0.10, 2.48)  

Through end of study 
MACE, n (%) 3 (0.15) 9 (0.45) 6 (0.30) 8 (0.40) 
   Hazard Ratio 
(95% CI) vs 
placebo 

0.39 (0.12, 1.27) 1.09 (0.42, 2.83) 0.75 (0.26, 2.13)  

 
The use of CHAMPIX, bupropion, and NRT was not associated with an increased risk of CV AEs in 
smokers treated for up to 12 weeks and followed for up to 1 year compared to placebo, although 
because 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 with  
mild-moderate COPD was demonstrated in a randomised double-blind placebo-controlled clinical 
trial. In this 52-week duration study, patients received treatment for 12 weeks, followed by a 40-week 
non-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 was 
comparable 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 the 
following table: 
 
 4W CQR CA Wk 9-52 

CHAMPIX, (n = 248)  42.3% 18.5% 

Placebo, (n = 251)  8.8% 5.6% 

Odds ratio  
(CHAMPIX vs. Placebo)  

8.40 
p < 0.0001 

4.04 
p < 0.0001 

 



 

59 

Study in subjects with a history of major depressive disorder 
The efficacy of varenicline was confirmed in a randomised placebo-controlled trial in 525 subjects 
with a history of major depression in the past two years or under current stable treatment. The 
cessation rates in this population were similar to those reported in the general population. Continuous 
abstinence rate between weeks 9-12 was 35.9% in the varenicline treatment group versus 15.6% in the 
placebo 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 subjects 
taking varenicline were nausea (27.0% vs. 10.4% on placebo), headache (16.8% vs. 11.2%), abnormal 
dreams (11.3% vs. 8.2%), insomnia (10.9% vs. 4.8%) and irritability (10.9% vs. 8.2%). Psychiatric 
scales showed no differences between the varenicline and placebo groups and no overall worsening of 
depression, 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 stable 
schizophrenia 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% on 
placebo), headache (10.7% vs. 18.6% on placebo) and vomiting (10.7% vs. 9.3% on placebo). Among 
reported neuropsychiatric adverse events, insomnia was the only event reported in either treatment 
group 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 psychiatric 
scales and there were no overall changes in extra-pyramidal signs. In the varenicline group compared 
to 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 of 
treatment). During the active treatment period, the incidence of suicide-related events was similar 
between the varenicline-treated and the placebo-treated subjects (11 vs. 9.3%, respectively). The 
percentage of subjects with suicide-related events in the active treatment phase compared to 
post-treatment phase was unchanged in the varenicline group; in the placebo group, this percentage 
was lower in the post-treatment phase. Although there were no completed suicides, there was one 
suicidal attempt in a varenicline-treated subject whose lifetime history included several similar 
attempts. The limited data available from this single smoking cessation study are not sufficient to 
allow for definitive conclusions to be drawn about the safety in patients with schizophrenia or 
schizoaffective 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 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). 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 a 
treatment 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 events 
of 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 by 
treatment group and the risk differences (RDs) (95% CI) vs placebo in the non-psychiatric cohort. 
 



 

60 

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,  
n (%) 

13 (1.3) 
 

22 (2.2) 
 

25 (2.5) 
 

24 (2.4) 
 

RD (95% CI) vs Placebo  -1.28 
(-2.40, -0.15) 

-0.08 
(-1.37, 1.21) 

-0.21           
(-1.54,1.12) 

 

Composite NPS AE 
Endpoint of severe intensity 
n (%) 

1 (0.1) 4 (0.4) 3 (0.3) 5 (0.5) 

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 or 
lower 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 NPS 
adverse events in the composite primary endpoint compared with placebo (95% CIs were lower than 
or 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 during 
treatment and in the non- treatment follow-up, as shown in the following table: 
 

 Non-psychiatric Cohort 
N=3984 

Varenicline 
 

N=990 
n (%) 

Bupropion 
 

N=989 
n (%) 

NRT 
 

N=1006 
n (%) 

Placebo 
 

N=999 
n (%) 

During treatment 
Number assessed 988 983 996 995 
Suicidal 
behaviour and/or 
ideation 

7 (0.7) 4 (0.4) 3 (0.3) 7 (0.7) 

Suicidal 
behaviour 

0 0 1 (0.1) 1 (0.1) 

Suicidal 
ideation 

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

During follow up 
Number assessed 807 816 800 805 
Suicidal 
behaviour and/or 
ideation 

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

Suicidal 
behaviour 

0 1 (0.1) 0 0 

Suicidal 
ideation 

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 in 
the non-psychiatric cohort. 



 

61 

The following table shows the rates of the composite NPS adverse event primary endpoint by 
treatment group and the RDs (95% CI) vs placebo in the psychiatric cohort. The individual 
components 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 
Primary Endpoint, n (%) 

67 (6.5) 
 

68 (6.7) 
 

53 (5.2) 
 

50 (4.9) 
 

RD (95% CI) vs Placebo  1.59                 
(-0.42, 3.59) 

1.78                
 (-0.24, 3.81) 

0.37             
(-1.53, 2.26) 

 

NPS AE Primary 
Endpoint Components n 
(%): 

Anxietya 
Depressiona 
Feeling abnormala 
Hostilitya 
Agitationb 
Aggressionb 
Delusionsb 
Hallucinationsb 
Homicidal ideationb 
Maniab 
Panicb 
Paranoiab 
Psychosisb 
Suicidal behaviourb 
Suicidal ideationb 
Completed suicideb 

 

 
5 (0.5) 
6 (0.6) 

0 
0 

25 (2.4) 
14 (1.4) 
1 (0.1) 
5 (0.5) 

0 
7 (0.7) 
7 (0.7) 
1 (0.1) 
4 (0.4) 
1 (0.1) 
5 (0.5) 

0 

 

 
4 (0.4) 
4 (0.4) 
1 (0.1) 

0 
29 (2.9) 
9 (0.9) 
1 (0.1) 
4 (0.4) 

0 
9 (0.9) 

16 (1.6) 
0 

2 (0.2) 
1 (0.1) 
2 (0.2) 

0 

 
 
 

6 (0.6) 
7 (0.7) 

0 
0 

21 (2.1) 
7 (0.7) 
1 (0.1) 
2 (0.2) 

0 
3 (0.3) 

13 (1.3) 
0 

3 (0.3) 
0 

3 (0.3) 
0 

 
 
 

2 (0.2) 
6 (0.6) 

0 
0 

22 (2.2) 
8 (0.8) 

0 
2 (0.2) 

0 
6 (0.6) 
7 (0.7) 
2 (0.2) 
1 (0.1) 
1 (0.1) 
2 (0.2) 

0 
Composite NPS AE 
Endpoint of severe 
intensity n (%) 

14 (1.4) 14 (1.4) 14 (1.4) 13 (1.3) 

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

There were more events reported in patients in the psychiatric cohort 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, the use of varenicline, 
bupropion and NRT in the psychiatric cohort was not associated with a significantly increased risk 
of NPS adverse events in the composite primary endpoint compared with placebo (95% CIs 
included zero). 
 
In the psychiatric cohort, 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 during treatment and in the non- treatment follow-up, as shown in the following 
table: 
 



 

62 

 Psychiatric Cohort 
N=4074 

Varenicline 
 

N=1026 
n (%) 

Bupropion 
 

N=1017 
n (%) 

NRT 
 

N=1016 
n (%) 

Placebo 
 

N=1015 
n (%) 

During treatment 
Number assessed 1017 1012 1006 1006 
Suicidal behaviour 
and/or ideation 

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

Suicidal 
behaviour 

0 1 (0.1) 0 2 (0.2) 

Suicidal ideation 27 (2.7) 15 (1.5) 20 (2.0) 25 (2.5) 
During follow up 
Number assessed 833 836 824 791 
Suicidal behaviour 
and/or ideation 

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

Suicidal 
behaviour 

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

Suicidal ideation 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 were 
similar to those observed in premarketing studies. 

In both cohorts, subjects treated with varenicline demonstrated statistical superiority of CO-confirmed 
abstinence 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%) 



 

63 

 Non-psychiatric Cohort Psychiatric Cohort 
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 neuropsychiatric 
events with varenicline compared to placebo. In addition, independent observational studies have not 
supported an increased risk of serious neuropsychiatric events in patients treated with varenicline 
compared to patients prescribed nicotine replacement therapy (NRT) or bupropion.  

Treatment discontinuation  
The treatment discontinuation rate due to adverse reactions was 11.4% for varenicline compared with 
9.7% for placebo. In this group, the discontinuation rates for the most common adverse reactions in 
varenicline 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% for 
placebo). 
 
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 reported 
on 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 of 
suicidal ideation and/or behaviour in patients treated with varenicline compared to patients treated 
with placebo, as shown in the table below. Of the 55 patients who reported suicidal ideation or 
behaviour, 48 (24 varenicline, 24 placebo) were from the two trials that enrolled patients with a history 
of schizophrenia/ schizoaffective disorder, or of depression. Few patients reported these events in the 
other three trials (4 varenicline, 3 placebo). 
 
Number of Patients and Risk Ratio for Suicidal Ideation and/or Behaviour Reported on C-SSRS 
from a Meta-Analysis of 5 Clinical Trials Comparing Varenicline to Placebo: 
 

 Varenicline 
(N=1130) 

Placebo 
(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 to 
assess the neuropsychiatric safety of varenicline. These trials included the 5 trials described above that 
used the C-SSRS, and a total of 8521 patients (5072 varenicline, 3449 placebo), some of which had 
psychiatric conditions. The results showed a similar incidence of combined neuropsychiatric adverse 
events, other than sleep disorders, in patients treated with varenicline compared to patients treated with 
placebo, with a risk ratio (RR) of 1.01 (95% CI: 0.89-1.15). Pooled data from these 18 trials showed a 
similar incidence rate of individual categories of psychiatric events in patients treated with varenicline 
compared to patients treated with placebo. The table below describes the most frequently (≥ 1%) 



 

64 

reported categories of adverse events related to psychiatric safety other than sleep disorders and 
disturbances. 
 
Psychiatric Adverse Events Occurring in ≥ 1% of Patients from Pooled Data from 18 Clinical 
Trials:  
 

 Varenicline 
(N=5072) 

Placebo 
(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 adjusted 
analyses, compared the risk of serious neuropsychiatric events, including neuropsychiatric 
hospitalizations and fatal and non-fatal self-harm, in patients treated with varenicline versus patients 
prescribed NRT or bupropion. All studies were retrospective cohort studies and included patients with 
and without a psychiatric history. All studies used statistical methods to control for confounding 
factors, including preferential prescribing of varenicline to healthier patients, although there is the 
possibility of residual confounding. 

Two of the studies found no difference in risk of neuropsychiatric hospitalisations between varenicline 
users and nicotine patch users (Hazard Ratio [HR] 1.14; 95% Confidence Interval [CI]: 0.56–2.34 in 
the first study, and 0.76; 95% CI: 0.40-1.46 in the second study). The power to detect differences in 
these two studies was limited. The third study reported no difference in risk of psychiatric adverse 
events diagnosed during an emergency department visit or inpatient admission between varenicline 
users and bupropion users (HR 0.85; 95% CI: 0.55-1.30). Based on post marketing reports, bupropion 
may 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. The 
occurrence of detected suicide was rare during the three months after patients initiated any drug 
treatment (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) 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 as compared to infants 
born 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%).  
 
Paediatric Population 
 
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 least 
5 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 age 
and 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 dose 
group) or 0.5 mg twice daily (low dose group), while patients with a body weight ≤55 kg received 
0.5 mg twice daily (high dose group) or 0.5 mg once daily (low dose group). Patients received 



 

65 

treatment for 12 weeks, followed by a non-treatment period of 40 weeks, along with age-appropriate 
counseling throughout the study. 
 
The following table from the above paediatric study shows a comparison of continuous abstinence 
rates (CAR) from weeks 9-12, confirmed by urine cotinine test, for the full analysis set overall study 
population and the 12-17 year old population. 
 
CAR 9-12 (%) Overall 

n/N (%) 
12-to-17-Year Olds 

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, 4.89) [0.0347]* 
* This p value is not considered statistically significant. The prespecified statistical testing procedures stopped testing 

after the high-dose varenicline vs Placebo treatment comparison in the overall study did not achieve statistical 

significance. 

 
CI=confidence interval; N=number of subjects randomised; n=the number of subjects who, at each visit from weeks 9 to 
12 (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. 

 
5.2 Pharmacokinetic properties  
 
Absorption 
 
Maximum plasma concentrations of varenicline occur typically within 3-4 hours after oral 
administration. Following administration of multiple oral doses to healthy volunteers, steady-state 
conditions were reached within 4 days. Absorption 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 
 
Varenicline distributes into tissues, including the brain. Apparent volume of distribution averaged 
415 litres (%CV= 50) at steady-state. Plasma protein binding of varenicline is low (< 20%) and 
independent of both age and renal function. In rodents, varenicline is transferred through the placenta 
and excreted in milk.  
 
Biotransformation 
 
Varenicline undergoes minimal metabolism with 92% excreted unchanged in the urine and less than 
10% excreted as metabolites. Minor metabolites in urine include varenicline N-carbamoylglucuronide 
and hydroxyvarenicline. In circulation, varenicline comprises 91% of drug-related material. Minor 
circulating 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 the 
activity of cytochrome P450 enzymes 1A2 and 3A4. Therefore, varenicline is unlikely to alter the 
pharmacokinetics of compounds that are primarily metabolised by cytochrome P450 enzymes. 
 



 

66 

Elimination 
 
The elimination half-life of varenicline is approximately 24 hours. Renal elimination of varenicline is 
primarily through glomerular filtration along with active tubular secretion via the organic cationic 
transporter, 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/day 
doses. 
 
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 specific 
pharmacokinetic studies and in population pharmacokinetic analyses. 
 
Hepatic impairment 
Due to the absence of significant hepatic metabolism, varenicline pharmacokinetics should be 
unaffected in patients with hepatic impairment. (see section 4.2). 
 
Renal impairment 
Varenicline pharmacokinetics were 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 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 was increased 2.1-fold. In subjects with end-stage-renal disease (ESRD), varenicline was 
efficiently removed by haemodialysis (see section 4.2).  
 
Elderly  
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 renal 
function please refer to section 4.2. 
 
Paediatric population  
Single and multiple-dose pharmacokinetics of varenicline have been investigated in paediatric patients 
aged 12 to 17 years old (inclusive) and were approximately dose-proportional over the 0.5 mg to 2 mg 
daily 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 the 
adult population. CHAMPIX is not recommended in paediatric patients because its efficacy in this 
population was not demonstrated (see sections 4.2 and 5.1). 
 
5.3 Preclinical safety data  
 
Non-clinical data reveal no special hazard for humans based on conventional studies of safety 
pharmacology, repeated dose toxicity, genotoxicity, fertility and embryo-foetal development. In male 
rats 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 were 
decreases in fertility and increases in the auditory startle response (see section 4.6). These effects were 
observed only at exposures considered sufficiently in excess of the maximum human exposure 
indicating little relevance to clinical use. Nonclinical data indicate varenicline has reinforcing 
properties albeit with lower potency than nicotine. In clinical studies in humans, varenicline showed 
low abuse potential. 



 

67 

 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Tablets’ core 
 
0.5 mg and 1 mg Tablets  
Cellulose, Microcrystalline 
Calcium Hydrogen Phosphate Anhydrous 
Croscarmellose Sodium 
Silica, Colloidal Anhydrous 
Magnesium Stearate 
 
Film coating  
 
0.5 mg Tablet 
Hypromellose 
Titanium Dioxide (E171) 
Macrogol 400 
Triacetin 
 
1 mg Tablet 
 
Hypromellose 
Titanium Dioxide (E171) 
Indigo Carmine Aluminium Lake E132 
Macrogol 400 
Triacetin 
 
6.2 Incompatibilities 
 
Not applicable. 
 
6.3 Shelf life 
 
Blisters: 3 years 
 
6.4 Special precautions for storage 
 
Store below 30°C 
 
6.5 Nature and contents of container 
 
Treatment initiation packs 
 
PCTFE/PVC blisters with aluminium foil backing containing 1 clear blister of 11 x 0.5 mg film-coated 
tablets and a second clear blister of 14 x 1 mg film-coated tablets in secondary heat sealed card 
packaging. 
 
PCTFE/PVC blisters with aluminium foil backing containing 1 clear blister of 11 x 0.5 mg film-coated 
tablets and a second clear blister containing 14 x 1 mg film-coated tablets in a carton. 
 



 

68 

PCTFE/PVC blisters with aluminium foil backing containing 1 clear blister of 11 x 0.5 mg and 14 x 
1 mg film-coated tablets and 1 clear blister of 28 or 2 clear blisters of 14 x 1 mg film-coated tablets in 
secondary heat sealed card packaging. 
 
PVC blisters with aluminium foil backing containing 1 clear blister of 11 x 0.5 mg film-coated tablets 
and a second clear blister of 14 x 1 mg film-coated tablets in secondary heat sealed card packaging. 
 
PVC blisters with aluminium foil backing containing 1 clear blister of 11 x 0.5 mg film-coated tablets 
and a second clear blister containing 14 x 1 mg film-coated tablets in a carton. 
 
PVC blisters with aluminium foil backing containing 1 clear blister of 11 x 0.5 mg and 14 x 1 mg 
film-coated tablets and 1 clear blister of 28 or 2 clear blisters of 14 x 1 mg film-coated tablets in 
secondary heat sealed card packaging. 
 
One outer carton containing: 
 
PCTFE/PVC blisters with aluminium foil backing containing one clear blister of 11 x 0.5 mg and 14 x 
1 mg film-coated tablets and 1 clear blister of 28 or 2 clear blisters of 14 x 1 mg film-coated tablets in 
one secondary heat sealed card pack and PCTFE/PVC blisters with aluminium foil backing in two 
secondary heat sealed card packs each containing 56 x 1 mg film-coated tablets. 
 
One outer carton containing: 
 
PVC blisters with aluminium foil backing containing one clear blister of 11 x 0.5 mg and 14 x 1 mg 
film-coated tablets and 1 clear blister of 28 or 2 clear blisters of 14 x 1 mg film-coated tablets in one 
secondary heat sealed card pack and PVC blisters with aluminium foil backing in two secondary heat 
sealed card packs each containing 56 x 1 mg film-coated tablets. 
 
Not all pack sizes may be marketed. 
 
6.6 Special precautions for disposal  
 
No special requirements. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
Pfizer Europe MA EEIG 
Boulevard de la Plaine 17 
1050 Bruxelles 
Belgium 
 
 
8. MARKETING AUTHORISATION NUMBER(S)  
 
Treatment initiation packs: 
 
EU/1/06/360/003  
EU/1/06/360/008  
EU/1/06/360/012 
EU/1/06/360/014 
EU/1/06/360/019 
EU/1/06/360/023 
EU/1/06/360/025 
EU/1/06/360/026 
 



 

69 

 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 26 September 2006 
Date of latest renewal: 29 June 2016  
 
 
10. DATE OF REVISION OF THE TEXT 
 
Detailed information on this product is available on the website of the European Medicines Agency 
http://www.ema.europa.eu/  
 

  



 

70 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX II 
 

A. MANUFACTURER(S) RESPONSIBLE FOR BATCH 
RELEASE 

 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY 

AND USE 
 

C. OTHER CONDITIONS AND REQUIREMENTS OF THE 
 MARKETING AUTHORISATION 

 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO 

 THE SAFE AND EFFECTIVE USE OF THE MEDICINAL 
 PRODUCT 

 



 

71 

A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE 
 
Name and address of the manufacturer(s) responsible for batch release 
 
R-Pharm Germany GmbH 
Heinrich-Mack-Str. 35, 89257 Illertissen 
Germany 
 
Pfizer Manufacturing Deutschland GmbH 
Betriebsstätte Freiburg 
Mooswaldallee 1 
79090 Freiburg 
Germany 
 
Pfizer Italia S.r.l.  
Località Marino del Tronto, 63100  
Ascoli Piceno (AP)  
Italy 
 
The printed package leaflet of the medicinal product must state the name and address of the 
manufacturer responsible for the release of the concerned batch. 
 
 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 
 
Medicinal product subject to medical prescription. 
 
 
C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 

AUTHORISATION 
 
 Periodic Safety Update Reports 
 
The requirements for submission of periodic safety update reports for this medicinal product are set 
out in the list of Union reference dates (EURD list) provided for under Article 107c(7) of Directive 
2001/83/EC and any subsequent updates published on the European medicines web-portal. 
 
 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 
 EFFECTIVE USE OF THE MEDICINAL PRODUCT 
 
 Risk Management Plan (RMP) 
 
The MAH shall perform the required pharmacovigilance activities and interventions detailed in the 
agreed RMP presented in Module 1.8.2 of the Marketing Authorisation and any agreed subsequent 
updates of the RMP. 
 
An updated RMP should be submitted: 

 At the request of the European Medicines Agency; 
Whenever the risk management system is modified, especially as the result of new information 
being received that may lead to a significant change to the benefit/risk profile or as the result of 
an important (pharmacovigilance or risk minimisation) milestone being reached. 

 
 Obligation to conduct post-authorisation measures 
 
Not Applicable. 



 

72 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX III 
 

LABELLING AND PACKAGE LEAFLET 
  



 

73 

 
 
 
 
 
 

  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

A. LABELLING 
  



 

74 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING  
 
Maintenance pack 
Heat sealed card pack containing either 2 or 4 blister packs of 14 x 0.5 mg varenicline film-coated 
tablets or 2 blister packs of 28 x 0.5 mg varenicline film-coated tablets– inner and outer labelling 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
CHAMPIX 0.5 mg 
Film-coated tablets 
Varenicline  
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each tablet contains 0.5 mg varenicline (as tartrate). 
 
 
3. LIST OF EXCIPIENTS 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Maintenance pack containing 
28 film-coated tablets 
56 film-coated tablets 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Oral use 
Read the package leaflet before use 
numbers 1 to 14 
numbers 1 to 28 
sun as symbol 
moon as symbol 
 
Do not use if box has been opened. 
 
Keep the package intact 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 



 

75 

7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP: MM/YYYY 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
Store below 30°C 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Pfizer Europe MA EEIG 
Boulevard de la Plaine 17 
1050 Bruxelles 
Belgium 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/06/360/006 
EU/1/06/360/007  
EU/1/06/360/017 
EU/1/06/360/018 
 
 
13. BATCH NUMBER 
 
Lot: 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
CHAMPIX 0.5 mg 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE   
 
2D barcode carrying the unique identifier included. 
 



 

76 

 
18. UNIQUE IDENTIFIER – HUMAN READABLE DATA 
 
PC: 
SN: 
NN:  
 
 

  



 

77 

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
Blister pack of 14 x 0.5 mg and 28 x 0.5 mg varenicline film-coated tablets, heat sealed card 

 
 

1. NAME OF THE MEDICINAL PRODUCT 
 
CHAMPIX 0.5 mg 
Varenicline 
 
 

2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
Pfizer Europe MA EEIG (as MA Holder Logo) 
 
 

3. EXPIRY DATE 
 
EXP: MM/YYYY 
 
 

4. BATCH NUMBER 
 
Lot: 
 
 

5. OTHER 
 
 
  



 

78 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
Maintenance pack 
Heat sealed card pack containing either 2 or 4 blister packs of 14 x 1 mg varenicline film-coated 
tablets or 2 blister packs of 28 x 1 mg varenicline film-coated tablets– inner and outer labelling 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
CHAMPIX 1 mg 
Film-coated tablets 
Varenicline  
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each tablet contains 1 mg varenicline (as tartrate). 
 
 
3. LIST OF EXCIPIENTS 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Maintenance pack containing 
28 film-coated tablets 
56 film-coated tablets 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Oral use 
Read the package leaflet before use 
numbers 1 to 14 
numbers 1 to 28 
sun as symbol 
moon as symbol 
 
Do not use if box has been opened. 
 
Keep the package intact 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 



 

79 

7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP: MM/YYYY 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
Store below 30°C 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE  

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Pfizer Europe MA EEIG 
Boulevard de la Plaine 17 
1050 Bruxelles 
Belgium 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/06/360/004 
EU/1/06/360/005 
EU/1/06/360/015 
EU/1/06/360/016 
 
 
13. BATCH NUMBER 
 
Lot: 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
CHAMPIX 1 mg 
 
 



 

80 

17. UNIQUE IDENTIFIER – 2D BARCODE   
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER – HUMAN READABLE DATA 
 
PC: 
SN: 
NN:  
 
 

  



 

81 

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
Blister pack of 14 x 1 mg and 28 x 1 mg varenicline film-coated tablets, heat sealed card 

 
 

1. NAME OF THE MEDICINAL PRODUCT 
 
CHAMPIX 1 mg 
Varenicline 
 
 

2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
Pfizer Europe MA EEIG (as MA Holder Logo) 
 
 

3. EXPIRY DATE 
 
EXP: MM/YYYY 
 
 

4. BATCH NUMBER 
 
Lot: 
 
 

5. OTHER 
 
 
  



 

82 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
Maintenance pack 
Carton pack containing 2 blister packs of 14 x 1 mg varenicline film-coated tablets or 4 blister packs 
of 14 x 1 mg varenicline film-coated tablets or 8 blister packs of 14 x 1 mg varenicline film-coated 
tablets or 10 blister packs of 14 x 1 mg varenicline film-coated tablets 
 
 

1. NAME OF THE MEDICINAL PRODUCT 
 
CHAMPIX 1 mg 
Film-coated tablets 
Varenicline  
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each tablet contains 1 mg varenicline (as tartrate). 
 
 
3. LIST OF EXCIPIENTS 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
28 Film-coated tablets 
56 Film-coated tablets 
112 Film-coated tablets 
140 Film-coated tablets 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Oral use. 
Read the package leaflet before use. 
 
Do not use if box has been opened. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP: MM/YYYY 
 
 



 

83 

9. SPECIAL STORAGE CONDITIONS 
 
Store below 30°C 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Pfizer Europe MA EEIG 
Boulevard de la Plaine 17 
1050 Bruxelles 
Belgium 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/06/360/009 
EU/1/06/360/010 
EU/1/06/360/011 
EU/1/06/360/013 
EU/1/06/360/020 
EU/1/06/360/021 
EU/1/06/360/022 
EU/1/06/360/024 
 
 
13. BATCH NUMBER 
 
Lot: 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
CHAMPIX 1 mg 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE   
 
2D barcode carrying the unique identifier included. 
 
 



 

84 

18. UNIQUE IDENTIFIER – HUMAN READABLE DATA 
 
PC: 
SN: 
NN:  
 
  



 

85 

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
Blister pack of 14 x 1 mg varenicline film-coated tablets 

 
 

1. NAME OF THE MEDICINAL PRODUCT 
 
CHAMPIX 1 mg 
Varenicline  
 
 

2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
Pfizer Europe MA EEIG (as MA Holder Logo) 
 
 

3. EXPIRY DATE 
 
EXP: MM/YYYY 
 
 

4. BATCH NUMBER 
 
Lot: 
 
 

5. OTHER 
 
sun as symbol 
moon as symbol 
 
 
  



 

86 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
2-week treatment initiation pack 
Heat sealed card pack containing 1 blister pack of 11 x 0.5 mg varenicline film-coated tablets and 
1 blister pack of 14 x 1 mg varenicline film-coated tablets – inner and outer labelling 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
CHAMPIX 0.5 mg 
CHAMPIX 1 mg 
Film-coated tablets 
Varenicline 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each tablet contains 0.5 mg or 1 mg varenicline (as tartrate). 
 
 
3. LIST OF EXCIPIENTS 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Initiation pack containing 
Film-coated tablets 
11 x 0.5 mg and 14 x 1 mg  
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Oral use. 
Read the package leaflet before use. 
 
Start at day 1 
The day you stop smoking should usually be between day 8 and day 14. 
To quit gradually, please refer to package leaflet for dosing instructions. 
 
Week 1 
Week 2 
 
Numbers 1 to 14 
sun as symbol 
moon as symbol 
 
Do not use if box has been opened. 
 
Keep the package intact 
Does not contain a tablet 
 
 



 

87 

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 
OF THE SIGHT AND REACH OF CHILDREN 

 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP: MM/YYYY 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
Store below 30°C 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Pfizer Europe MA EEIG 
Boulevard de la Plaine 17 
1050 Bruxelles 
Belgium 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/06/360/003 
EU/1/06/360/014 
 
 
13. BATCH NUMBER 
 
Lot: 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 



 

88 

16. INFORMATION IN BRAILLE 
 
CHAMPIX  
0.5 mg  
1 mg 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE   
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER – HUMAN READABLE DATA 
 
PC: 
SN: 
NN: 
 

 
  



 

89 

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
Blister pack of 11 x 0.5 mg varenicline film-coated tablets, heat sealed card 

 
 

1. NAME OF THE MEDICINAL PRODUCT 
 
CHAMPIX 0.5 mg 
Varenicline 
 
 

2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
Pfizer Europe MA EEIG (as MA Holder Logo) 
 
 

3. EXPIRY DATE 
 
EXP 
 
 

4. BATCH NUMBER 
 
Lot 
 
 

5. OTHER 
 
 

  



 

90 

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
Blister pack of 14 x 1 mg varenicline film-coated tablets, heat sealed card 

 
 

1. NAME OF THE MEDICINAL PRODUCT 
 
CHAMPIX 1 mg 
Varenicline 
 
 

2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
Pfizer Europe MA EEIG (as MA Holder Logo) 
 
 

3. EXPIRY DATE 
 
EXP 
 
 

4. BATCH NUMBER 
 
Lot 
 
 

5. OTHER 
 

 
  



 

91 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
Treatment initiation pack 
Carton pack with 1 blister pack of 11 x 0.5 mg varenicline film-coated tablets and 1 blister pack of 
14 x 1 mg varenicline film-coated tablets 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
CHAMPIX 0.5 mg 
CHAMPIX 1 mg 
Film-coated tablets 
Varenicline  
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each tablet contains 0.5 mg or 1 mg varenicline (as tartrate). 
 
 
3. LIST OF EXCIPIENTS 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Film-coated tablets 
11 x 0.5 mg and 14 x 1 mg  
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Oral use. 
Read the package leaflet before use. 
 
Do not use if box has been opened. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP: MM/YYYY 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
Store below 30°C 
 



 

92 

 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Pfizer Europe MA EEIG 
Boulevard de la Plaine 17 
1050 Bruxelles 
Belgium 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/06/360/008  
EU/1/06/360/019 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
CHAMPIX 
0.5 mg  
1 mg 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE   
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER – HUMAN READABLE DATA 
 
PC: 
SN: 
NN:  
 
  



 

93 

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
Blister pack of 11 x 0.5 mg varenicline film-coated tablets 

 
 

1. NAME OF THE MEDICINAL PRODUCT 
 
CHAMPIX 0.5 mg  
Varenicline  
 
 

2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
Pfizer Europe MA EEIG (as MA Holder Logo) 
 
 

3. EXPIRY DATE 
 
EXP: MM/YYYY 
 
 

4. BATCH NUMBER 
 
Lot: 
 
 

5. OTHER 
 
sun as symbol 
moon as symbol 
 
 

  



 

94 

 
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
Blister pack of 14 x 1 mg varenicline film-coated tablets 

 
 

1. NAME OF THE MEDICINAL PRODUCT 
 
CHAMPIX 1 mg 
Varenicline  
 
 

2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
Pfizer Europe MA EEIG (as MA Holder Logo) 
 
 

3. EXPIRY DATE 
 
EXP: MM/YYYY 
 
 

4. BATCH NUMBER 
 
Lot: 
 
 

5. OTHER 
 
sun as symbol 
moon as symbol 
 
 
  



 

95 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
4-week treatment initiation pack 
Heat sealed card pack containing 1 blister pack of 11 x 0.5 mg and 14 x 1 mg varenicline film-coated 
tablets and 1 blister pack of 28 or 2 blister packs of 14 x 1 mg varenicline film-coated tablets – inner 
and outer labelling 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
CHAMPIX 0.5 mg  
CHAMPIX 1 mg  
Film-coated tablets 
Varenicline 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each tablet contains 0.5 mg or 1 mg varenicline (as tartrate). 
 
 
3. LIST OF EXCIPIENTS 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
4-week treatment initiation pack containing: 
11 x 0.5 mg film-coated tablets 
and  
42 x 1 mg film-coated tablets 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Oral use. 
Read the package leaflet before use. 
 
Start at Day 1 
The day you stop smoking should usually be between day 8 and day 14. 
To quit gradually, please refer to package leaflet for dosing instructions. 
 
Week 1 
Week 2-4 
 
Numbers 1 to 28 
sun as symbol 
moon as symbol 
 
Do not use if box has been opened. 
 
Keep the package intact 
Does not contain any tablets 
 
 



 

96 

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 
OF THE SIGHT AND REACH OF CHILDREN 

 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP: MM/YYYY 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
Store below 30°C 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Pfizer Europe MA EEIG 
Boulevard de la Plaine 17 
1050 Bruxelles 
Belgium 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/06/360/012 
EU/1/06/360/023 
 
 
13. BATCH NUMBER 
 
Lot: 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 



 

97 

16. INFORMATION IN BRAILLE 
 
CHAMPIX  
0.5 mg  
1 mg 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE   
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER – HUMAN READABLE DATA 
 
PC: 
SN: 
NN: 
 
 

  



 

98 

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
Blister pack of 11 x 0.5 mg and 14 x 1 mg varenicline film-coated tablets, heat sealed card 

 
 

1. NAME OF THE MEDICINAL PRODUCT 
 
CHAMPIX 0.5 mg 
CHAMPIX 1 mg 
Varenicline 
 
 

2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
Pfizer Europe MA EEIG (as MA Holder Logo) 
 
 

3. EXPIRY DATE 
 
EXP: MM/YYYY 
 
 

4. BATCH NUMBER 
 
Lot: 
 
 

5. OTHER 
 
 

  



 

99 

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
One blister pack of 28 or 2 blister packs of 14 x 1 mg varenicline film-coated tablets, heat sealed card 

 
 

1. NAME OF THE MEDICINAL PRODUCT 
 
CHAMPIX 1 mg 
Varenicline 
 
 

2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
Pfizer Europe MA EEIG (as MA Holder Logo) 
 
 

3. EXPIRY DATE 
 
EXP: MM/YYYY 
 
 

4. BATCH NUMBER 
 
Lot: 
 
 

5. OTHER 
 
 



 

100 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
12-week Treatment Initiation Pack 
One Outer Carton Pack containing: 
1 x heat sealed card pack containing 11 x 0.5 mg and 14 x 1 mg varenicline film-coated tablets and 
1 blister pack of 28 or 2 blister packs of 14 x 1 mg varenicline film-coated tablets and 2 x heat sealed 
card packs each containing 2 blister packs of 28 or 4 blister packs of 14 x 1 mg varenicline film-coated 
tablets – outer and inner labelling. 
 
Contains Blue Box 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
CHAMPIX 0.5 mg  
CHAMPIX 1 mg  
Film-coated tablets 
Varenicline 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each tablet contains 0.5 mg or 1 mg varenicline (as tartrate). 
 
 
3. LIST OF EXCIPIENTS 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
12-week Treatment Initiation Pack  
containing: 
11 x 0.5 mg film-coated tablets 
and  
154 x 1 mg film-coated tablets 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Oral use. 
Read the package leaflet before use. 
 
Start at Day 1 
The day you stop smoking should usually be between day 8 and day 14. 
To quit gradually, please refer to package leaflet for dosing instructions. 
 
Do not use if box has been opened. 
 
Keep the package intact 
 
 



 

101 

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 
OF THE SIGHT AND REACH OF CHILDREN 

 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP: MM/YYYY 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
Store below 30°C 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Pfizer Europe MA EEIG 
Boulevard de la Plaine 17 
1050 Bruxelles 
Belgium 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/06/360/025 
EU/1/06/360/026 
 
 
13. BATCH NUMBER 
 
Lot: 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 



 

102 

16. INFORMATION IN BRAILLE 
 
CHAMPIX  
0.5 mg  
1 mg 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE   
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER – HUMAN READABLE DATA 
 
PC: 
SN: 
NN: 



 

103 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
INTERMEDIATE CARTON 
4-week treatment initiation pack 
Heat sealed card pack containing 1 blister pack of 11 x 0.5 mg and 14 x 1 mg varenicline film-coated 
tablets and 1 blister pack of 28 or 2 blister packs of 14 x 1 mg varenicline film-coated tablets – inner 
and outer labelling. 
 
Contains No Blue Box 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
CHAMPIX 0.5 mg  
CHAMPIX 1 mg  
Film-coated tablets 
Varenicline 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each tablet contains 0.5 mg or 1 mg varenicline (as tartrate). 
 
 
3. LIST OF EXCIPIENTS 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
4-week treatment initiation pack containing: 
11 x 0.5 mg film-coated tablets 
and  
42 x 1 mg film-coated tablets 
 
Can’t be sold separately. 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Oral use. 
Read the package leaflet before use. 
 
Start at Day 1 
The day you stop smoking should usually be between day 8 and day 14. 
To quit gradually, please refer to package leaflet for dosing instructions. 
 
Week 1 
Week 2-4 
 
Numbers 1 to 28 
sun as symbol 
moon as symbol 
 
Do not use if box has been opened. 
 



 

104 

Keep the package intact 
Does not contain any tablets 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP: MM/YYYY 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
Store below 30°C 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Pfizer Europe MA EEIG 
Boulevard de la Plaine 17 
1050 Bruxelles 
Belgium 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/06/360/025 
EU/1/06/360/026 
 
 

13. BATCH NUMBER 
 
Lot: 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 



 

105 

15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
CHAMPIX  
0.5 mg  
1 mg 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE   
 
Not Applicable 
 
 
18. UNIQUE IDENTIFIER – HUMAN READABLE DATA 
 
Not Applicable 
 
 
  



 

106 

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
Blister pack of 11 x 0.5 mg and 14 x 1 mg varenicline film-coated tablets, heat sealed card 

 
 

1. NAME OF THE MEDICINAL PRODUCT 
 
CHAMPIX 0.5 mg 
CHAMPIX 1 mg 
Varenicline 
 
 

2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
Pfizer Europe MA EEIG (as MA Holder Logo) 
 
 

3. EXPIRY DATE 
 
EXP: MM/YYYY 
 
 

4. BATCH NUMBER 
 
Lot: 
 
 

5. OTHER 
 
 
  



 

107 

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
One blister pack of 28 or 2 blister packs of 14 x 1 mg varenicline film-coated tablets, heat sealed card 

 
 

1. NAME OF THE MEDICINAL PRODUCT 
 
CHAMPIX 1 mg 
Varenicline 
 
 

2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
Pfizer Europe MA EEIG (as MA Holder Logo) 
 
 

3. EXPIRY DATE 
 
EXP: MM/YYYY 
 
 

4. BATCH NUMBER 
 
Lot: 
 
 

5. OTHER 
 
 



 

108 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
INTERMEDIATE CARTON 
Maintenance pack 
Heat sealed card pack containing 2 blister packs of 28 or 4 blister packs of 14 x 1 mg varenicline 
film-coated tablets– inner and outer labelling 
 
Contains No Blue Box 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
CHAMPIX 1 mg 
Film-coated tablets 
Varenicline  
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each tablet contains 1 mg varenicline (as tartrate). 
 
 
3. LIST OF EXCIPIENTS 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Maintenance pack containing 
56 film-coated tablets 
 
Can’t be sold separately. 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Oral use. 
Read the package leaflet before use. 
numbers 1 to 14 
numbers 1 to 28 
sun as symbol 
moon as symbol 
 
Do not use if box has been opened. 
 
Keep the package intact 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 



 

109 

7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP: MM/YYYY 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
Store below 30°C 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE  

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Pfizer Europe MA EEIG 
Boulevard de la Plaine 17 
1050 Bruxelles 
Belgium 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/06/360/025 
EU/1/06/360/026 
 
 
13. BATCH NUMBER 
 
Lot: 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
CHAMPIX 1 mg 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE   
 
Not Applicable 
 
 



 

110 

18. UNIQUE IDENTIFIER – HUMAN READABLE DATA 
 
Not Applicable 
 
 
  



 

111 

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
One blister pack of 28 or 2 blister packs of 14 x 1 mg varenicline film-coated tablets, heat sealed card 

 
 

1. NAME OF THE MEDICINAL PRODUCT 
 
CHAMPIX 1 mg 
Varenicline 
 
 

2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
Pfizer Europe MA EEIG (as MA Holder Logo) 
 
 

3. EXPIRY DATE 
 
EXP: MM/YYYY 
 
 

4. BATCH NUMBER 
 
Lot: 
 
 

5. OTHER 
 
 
  



 

112 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING  
 
High-density polyethylene (HDPE) bottle packaging for 56 x 0.5 mg varenicline film-coated tablets 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
CHAMPIX 0.5 mg 
Film-coated tablets 
Varenicline  
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each tablet contains 0.5 mg varenicline (as tartrate). 
 
 
3. LIST OF EXCIPIENTS 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
56 Film-coated tablets 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Oral use. 
Read the package leaflet before use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP: MM/YYYY 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 



 

113 

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Pfizer Europe MA EEIG 
Boulevard de la Plaine 17 
1050 Bruxelles 
Belgium 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/06/360/001  
 
 
13. BATCH NUMBER 
 
Lot: 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
CHAMPIX 0.5 mg 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE   
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER – HUMAN READABLE DATA 
 
PC: 
SN: 
NN:  
 
 
  



 

114 

PARTICULARS TO APPEAR ON THE THE IMMEDIATE PACKAGING  
 
High-density polyethylene (HDPE) bottle label for 56 x 0.5 mg varenicline film-coated tablets 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
CHAMPIX 0.5 mg 
Film-coated tablets 
Varenicline  
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each tablet contains 0.5 mg varenicline (as tartrate). 
 
 
3. LIST OF EXCIPIENTS 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
56 Film-coated tablets 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Oral use. 
Read the package leaflet before use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP: MM/YYYY 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 



 

115 

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Pfizer Europe MA EEIG (as MA Holder Logo) 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/06/360/001  
 
 
13. BATCH NUMBER 
 
Lot: 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE   
 
Not Applicable 
 
 
18. UNIQUE IDENTIFIER – HUMAN READABLE DATA 
 
Not Applicable 
 
 
  



 

116 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING  
 
High-density polyethylene (HDPE) bottle packaging for 56 x 1 mg varenicline film-coated tablets 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
CHAMPIX 1 mg 
Film-coated tablets 
Varenicline  
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each tablet contains 1 mg varenicline (as tartrate). 
 
 
3. LIST OF EXCIPIENTS 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
56 Film-coated tablets 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Oral use. 
Read the package leaflet before use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP: MM/YYYY 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 



 

117 

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Pfizer Europe MA EEIG 
Boulevard de la Plaine 17 
1050 Bruxelles 
Belgium 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/06/360/002  
 
 
13. BATCH NUMBER 
 
Lot: 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
CHAMPIX 1 mg 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE   
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER – HUMAN READABLE DATA 
 
PC: 
SN: 
NN:  
 
 
  



 

118 

PARTICULARS TO APPEAR ON THE THE IMMEDIATE PACKAGING  
 
High-density polyethylene (HDPE) bottle label for 56 x 1 mg varenicline film-coated tablets 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
CHAMPIX 1 mg 
Film-coated tablets 
Varenicline  
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each tablet contains 1 mg varenicline (as tartrate). 
 
 
3. LIST OF EXCIPIENTS 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
56 Film-coated tablets 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Oral use. 
Read the package leaflet before use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP: MM/YYYY 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 



 

119 

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Pfizer Europe MA EEIG (as MA Holder Logo) 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/06/360/002  
 
 
13. BATCH NUMBER 
 
Lot: 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE   
 
Not Applicable 
 
 
18. UNIQUE IDENTIFIER – HUMAN READABLE DATA 
 
Not Applicable 
 
  



 

120 

 
 
 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B. PACKAGE LEAFLET 
 



 

121 

Package leaflet: Information for the user 
 

CHAMPIX 0.5 mg film-coated tablets 
CHAMPIX 1 mg film-coated tablets 

Varenicline 
 
 

Read all of this leaflet carefully before you start taking this medicine because it contains 
important information for you. 
 
- Keep this leaflet. You may need to read it again. 
- If you have any further questions, ask your doctor or pharmacist. 
- This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, 

even if their signs of illness are the same as yours. 
- If you get any side effects, talk to your doctor or pharmacist. This includes any possible side 

effects not listed in this leaflet. See section 4. 
 
What is in this leaflet 
 
1. What CHAMPIX is and what it is used for 
2. What you need to know before you take CHAMPIX  
3. How to take CHAMPIX  
4. Possible side effects 
5. How to store CHAMPIX  
6. Contents of the pack and other information 
 
 
1. What CHAMPIX is and what it is used for 
 
CHAMPIX contains the active substance varenicline. CHAMPIX is a medicine which is used in adults 
to help them stop smoking. 
 
CHAMPIX can help to relieve the craving and withdrawal symptoms associated with stopping 
smoking.  
 
CHAMPIX can also reduce the enjoyment of cigarettes if you do smoke when on treatment. 
  
 
2. What you need to know before you take CHAMPIX 
 
Do not take CHAMPIX: 
 
- If you are allergic to varenicline or any of the other ingredients of this medicine (listed in 

section 6) 
 
Warnings and precautions 
Talk to your doctor or pharmacist before taking CHAMPIX. 
 
There have been reports of depression, suicidal ideation and behaviour and suicide attempts in patients 
taking CHAMPIX. If you are taking CHAMPIX and develop agitation, depressed mood, changes in 
behaviour that are of concern to you or your family or if you develop suicidal thoughts or behaviours 
you should stop taking CHAMPIX and contact your doctor immediately for treatment assessment. 
 



 

122 

The effects of stopping smoking 
The effects of changes in your body resulting from stopping smoking, with or without treatment with 
CHAMPIX, may alter the way other medicines work. Therefore, in some cases an adjustment of the 
dose may be necessary. See below under ‘Other medicines and CHAMPIX’ for further details. 
 
For some people, stopping smoking with or without treatment has been associated with an increased 
risk of experiencing changes in thinking or behaviour, feelings of depression and anxiety and can be 
associated with a worsening of psychiatric disorder. If you have a history of psychiatric disorder you 
should discuss this with your doctor.  
 
Heart symptoms 
New or worse heart or blood vessel (cardiovascular) problems have been reported primarily in people 
who already have cardiovascular problems. Tell your doctor if you have any changes in symptoms 
during treatment with CHAMPIX. Get emergency medical help right away if you have symptoms of a 
heart attack or stroke.  
 
Seizures 
Tell your doctor if you have experienced seizures or have epilepsy before your start CHAMPIX 
treatment. Some people have reported seizures while taking CHAMPIX.  
 
Hypersensitivity reactions 
Stop taking CHAMPIX and tell your doctor immediately if you experience any of the following signs 
and symptoms that may indicate a serious allergic reaction: swelling of the face, lips, tongue, gums, 
throat or body and/or difficulty breathing, wheezing.  
 
Skin reactions 
Potentially life-threatening skin rashes (Stevens-Johnson syndrome and Erythema Multiforme) have 
been reported with the use of CHAMPIX. If you develop a rash or if your skin starts to peel or blister 
you should stop taking CHAMPIX and seek emergency medical help. 
  
Children and adolescents 
CHAMPIX is not recommended for use in paediatric patients as efficacy was not demonstrated. 
 
Other medicines and CHAMPIX 
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other 
medicines. 
 
In some cases as a result of stopping smoking, with or without CHAMPIX, an adjustment of the dose 
of other medicines may be necessary. Examples include theophylline (a medicine to treat breathing 
problems), warfarin (a medicine to reduce blood clotting), and insulin (a medicine to treat diabetes). If 
in doubt, you should consult your doctor or pharmacist. 
 
If you have severe kidney disease you should avoid taking cimetidine (a medicine used for gastric 
problems) at the same time as CHAMPIX as this may cause increased blood levels of CHAMPIX.  
 
Use of CHAMPIX with other therapies for smoking cessation 
Consult your doctor before using CHAMPIX in combination with other smoking cessation therapies. 
 
CHAMPIX with food and drink 
There have been some reports of increased intoxicating effects of alcohol in patients taking 
CHAMPIX. However, it is not known if CHAMPIX actually increases alcohol intoxication.  
 
Pregnancy and breast-feeding 
If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask 
your doctor or pharmacist for advice before taking this medicine. 
It is preferable to avoid the use of CHAMPIX while you are pregnant. Talk to your doctor if you are 
intending to become pregnant. 



 

123 

 
Although it was not studied, CHAMPIX may pass into breast milk. You should ask your doctor or 
pharmacist for advice before taking CHAMPIX. 
 
Driving and using machines 
CHAMPIX may be linked with dizziness, sleepiness and transient loss of consciousness. You should 
not drive, operate complex machinery or engage in any other potentially hazardous activities until you 
know whether this medicine affects your ability to perform these activities. 
 
 
3. How to take CHAMPIX 
 
Always take this medicine exactly as your doctor has told you. Check with your doctor or pharmacist 
if you are not sure. 
 
You are more likely to stop smoking if you are motivated to stop. Your doctor and pharmacist can 
provide advice, support and sources of further information to help ensure your attempt to stop smoking 
is successful. 
 
Before starting your course of CHAMPIX you should usually decide on a date in the second week of 
treatment (between day 8 and day 14) when you will stop smoking. If you are not willing or able to set 
a target quit date within 2 weeks, you may choose your own target quit date within 5 weeks after 
starting treatment. You should write this date on the pack as a reminder.  
 
CHAMPIX comes as a white tablet (0.5 mg) and a light blue tablet (1 mg). You start with the white 
tablet and then usually go to the light blue tablet. See the chart below for the usual dosing instructions 
which you should follow from Day 1. 
 

Week 1 Dose 
Day 1 - 3 From day 1 to day 3, you should take one white CHAMPIX 0.5 mg film-coated tablet once 

a day. 
 

Day 4 - 7 From day 4 to day 7, you should take one white CHAMPIX 0.5 mg film-coated tablet twice 
daily, once in the morning and once in the evening, at about the same time each day. 

 
Week 2  
Day 8 – 14  From day 8 to day 14, you should take one light blue CHAMPIX 1 mg film-coated tablet 

twice daily, once in the morning and once in the evening, at about the same time each day. 
 

 
Weeks 3 - 12  
Day 15 -  
end of 
treatment 

From day 15 until the end of treatment, you should take one light blue CHAMPIX 1 mg 
film-coated tablet twice daily, once in the morning and once in the evening, at about the 
same time each day. 
 

 
After 12 weeks of treatment, if you have stopped smoking, your doctor may recommend an additional 
12 weeks of treatment with CHAMPIX 1 mg film-coated tablets twice daily to help avoid returning 
back to smoking. 
 
If you are not able or willing to quit smoking straight away, you should reduce smoking during the 
first 12 weeks of treatment and quit by the end of that treatment period. You should then continue to 
take CHAMPIX 1 mg film-coated tablets twice daily for a further 12 weeks resulting in a total of 
24 weeks of treatment. 
 
Should you experience adverse effects that you cannot tolerate your doctor may decide to reduce your 
dose temporarily or permanently to 0.5 mg twice daily.  



 

124 

 
If you have problems with your kidneys, you should speak to your doctor before taking CHAMPIX. 
You may need a lower dose. 
  
Champix is for oral use. 
The tablets should be swallowed whole with water and can be taken with or without food. 
 
If you take more CHAMPIX than you should 
If you accidentally take more CHAMPIX than your doctor prescribed, you must seek medical advice 
or go to the nearest hospital casualty department immediately. Take your box of tablets with you. 
 
If you forget to take CHAMPIX  
Do not take a double dose to make up for a forgotten tablet. It is important that you take CHAMPIX 
regularly at the same time each day. If you forget to take a dose, take it as soon as you remember. If, it 
is within 3-4 hours before your next dose, do not take the tablet that you have missed.  
 
If you stop taking CHAMPIX 
It has been shown in clinical trials that taking all doses of your medicine at the appropriate times and 
for the recommended duration of treatment described above will increase your chances of stopping 
smoking. Therefore, unless your doctor instructs you to stop treatment, it is important to keep taking 
CHAMPIX, according to the instructions described in the table above. 
 
In smoking cessation therapy, risk of returning to smoking may be elevated in the period immediately 
following the end of treatment. You may temporarily experience increased irritability, urge to smoke, 
depression and/or sleep disturbances when you stop taking CHAMPIX. Your doctor may decide to 
gradually lower your dose of CHAMPIX at the end of treatment. 
 
If you have any further questions on the use of this medicine, ask your doctor or pharmacist. 
 
 
4. Possible side effects 
 
Like all medicines, this medicine can cause side effects, although not everybody gets them. 
 
Giving up smoking with or without treatment can cause various symptoms. These could include 
changes of mood (like feeling depressed, irritable, frustrated or anxious), sleeplessness, difficulty 
concentrating, decreased heart rate and increased appetite or weight gain. 
 
You should be aware of the possible emergence of serious neuropsychiatric symptoms, such as 
agitation, depressed mood, or changes in behaviour during a quit attempt with or without CHAMPIX 
and you should contact a doctor or pharmacist if you experience such symptoms. 
 
Serious side effects of either an uncommon or rare frequency have occurred in people attempting to 
quit smoking with CHAMPIX: seizure, stroke, heart attack, suicidal thoughts, loss of contact with 
reality and unable to think or judge clearly (psychosis), changes in thinking or behaviour (such as 
aggression and abnormal behaviour). There have also been reports of severe skin reactions including 
Erythema Multiforme (a type of rash) and Stevens-Johnson Syndrome (a serious illness with blistering 
of the skin, mouth, around the eyes or genitals) and serious allergic reactions including angioedema 
(swelling of the face, mouth, or throat). 
 
- Very common: may affect more than 1 in 10 people  
 

o Inflammation of the nose and throat, abnormal dreams, difficulty sleeping, headache,  
o Nausea  

 



 

125 

- Common: may affect up to 1 in 10 people  
 

o Chest infection, inflammation of the sinuses 
o Increased weight, decreased appetite, increased appetite 
o Sleepiness, dizziness, changes in the way things taste 
o Shortness of breath, cough 
o Heartburn, vomiting, constipation, diarrhoea, feeling bloated, abdominal pain, toothache, 

indigestion, flatulence, dry mouth 
o Skin rash, itching 
o Joint ache, muscle ache, back pain 
o Chest pain, tiredness 

 
- Uncommon: may affect up to 1 in 100 people  
 

o Fungal infection, viral infection 
o Feeling of panic, difficulty thinking, restlessness, mood swings, depression, anxiety, 

hallucinations, changes in sex drive 
o Seizure, tremor, feeling sluggish, less sensitive to touch 
o Conjunctivitis, eye pain 
o Ringing in the ears 
o Angina, rapid heart rate, palpitations, increased heart rate 
o Increased blood pressure, hot flush 
o Inflammation of nose, sinuses and throat, congestion of nose, throat and chest, 

hoarseness, hay fever, throat irritation, congested sinuses, excess mucous from nose 
causing cough, runny nose 

o Red blood in stools, irritated stomach, change of bowel habit, belching, mouth ulcers, 
pain in the gums 

o Reddening of the skin, acne, increased sweating, night sweats 
o Muscle spasms, chest wall pain 
o Abnormally frequent urination, urination at night 
o Increased menstrual flow 
o Chest discomfort, flu like illness, fever, feeling weak or unwell 
o High blood sugar 
o Heart attack 
o Suicidal thoughts 
o Changes in thinking or behaviour (such as aggression) 

 
- Rare: may affect up to 1 in 1,000 people  

 
o Excessive thirst 
o Feeling unwell or unhappy, slow thinking 
o Stroke 
o Increased muscle tension, difficulty with speech, difficulty with coordination, reduced 

sense of taste, altered sleep pattern 
o Disturbed vision, eyeball discolouration, dilated pupils, sensitivity to light, 

shortsightedness, watery eyes 
o Irregular heart beat or heart rhythm disturbances 
o Throat pain, snoring 
o Blood in vomit, abnormal stools, coated tongue 
o Stiff joints, rib pain 
o Glucose in urine, increased urine volume and frequency 
o Vaginal discharge, changes in sexual ability 
o Feeling cold, cyst 
o Diabetes 
o Sleep walking 
o Loss of contact with reality and unable to think or judge clearly (psychosis) 
o Abnormal behaviour 



 

126 

o Severe skin reactions including Erythema Multiforme (a type of rash) and Stevens-
Johnson Syndrome (a serious illness with blistering of the skin, mouth, around the eyes or 
genitals)  

o Serious allergic reactions including angioedema (swelling of the face, mouth, or throat) 
 
- Not known 

 
o Transient loss of consciousness 

 
Reporting of side effects 
If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects 
not listed in this leaflet. You can also report side effects directly via the national reporting system 
listed in Appendix V. By reporting side effects you can help provide more information on the safety of 
this medicine. 
 
 
5. How to store CHAMPIX 
 
Keep this medicine out of the sight and reach of children. 
 
Do not use this medicine after the expiry date which is stated on the card packaging or carton after 
EXP. The expiry date refers to the last day of that month. 
 
Blisters: Store below 30°C 
Bottle: This medicine does not require any special storage conditions. 
 
Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to 
throw away medicines you no longer use. These measures will help protect the environment. 
 
 
6. Contents of the pack and other information 
 
What CHAMPIX contains 
- The active substance is varenicline. 
- Each 0.5 mg film-coated tablet contains 0.5 mg of varenicline (as tartrate). 
- Each 1 mg film-coated tablet contains 1 mg of varenicline (as tartrate). 
- The other ingredients are: 
 

Tablet Core - CHAMPIX 0.5 mg and 1 mg film-coated tablets  
Cellulose, Microcrystalline 
Calcium Hydrogen Phosphate Anhydrous 
Croscarmellose Sodium 
Silica, Colloidal Anhydrous 
Magnesium Stearate 

 
Tablet film coating - CHAMPIX 0.5 mg film-coated tablets  
Hypromellose 
Titanium dioxide (E171) 
Macrogol 400 
Triacetin 

 



 

127 

Tablet film coating - CHAMPIX 1 mg film-coated tablets  
Hypromellose 
Titanium dioxide (E171) 
Macrogol 400 
Indigo Carmine Aluminium Lake (E132) 
Triacetin 

 
What CHAMPIX looks like and contents of the pack 
- CHAMPIX 0.5 mg film-coated tablets are white, film-coated, modified capsular shaped tablets, 

marked “Pfizer” and “CHX 0.5” 
 
- CHAMPIX 1 mg film-coated tablets are light blue film-coated, modified capsular shaped 

tablets, marked “Pfizer” and “CHX 1.0” 
 
CHAMPIX is available in the following pack presentations: 
 
- Treatment initiation pack containing 2 blisters; 1 clear blister of 11 x CHAMPIX 0.5 mg 

film-coated tablets and 1 clear blister of 14 x CHAMPIX 1 mg film-coated tablets in card 
packaging. 

- Treatment initiation pack containing 2 blisters; 1 clear blister of 11 x CHAMPIX 0.5 mg and 
14 x 1 mg film-coated tablets and 1 clear blister of 28 or 2 clear blisters of 14 x CHAMPIX 
1 mg film-coated tablets in card packaging. 

- Treatment initiation pack in an outer carton containing 1 pack with 1 clear blister of 
11 x CHAMPIX 0.5 mg and 14 x 1 mg film-coated tablets and 1 clear blister of 28 or 2 clear 
blisters of 14 x CHAMPIX 1 mg film-coated tablets in card packaging and 2 packs each 
containing 2 clear blisters of 28 or 4 clear blisters of 14 x CHAMPIX 1 mg film-coated tablets in 
card packaging. 

- Follow-on (maintenance) packs containing 2 or 4 clear blisters of 14 or 2 clear blisters of 
28 x CHAMPIX 1 mg film-coated tablets in card packaging. 

- Follow-on (maintenance) packs containing 2 or 4 clear blisters of 14 or 2 clear blisters of 
28 x CHAMPIX 0.5 mg film-coated tablets in card packaging. 

- Treatment initiation pack containing 2 blisters; 1 clear blister of 11 x CHAMPIX 0.5 mg 
film-coated tablets and 1 clear blister of 14 x CHAMPIX 1 mg film-coated tablets in a carton. 

- Follow-on (maintenance) packs containing 2, 4, 8, or 10 clear blisters of 14 x CHAMPIX 1 mg 
film-coated tablets in a carton. 

- Sealed white HDPE bottle pack, with a child resistant screw cap, in a carton, containing 
56 x CHAMPIX 1 mg film-coated tablets. 

- Sealed white HDPE bottle pack, with a child resistant screw cap, in a carton, containing 
56 x CHAMPIX 0.5 mg film-coated tablets. 

 
Not all pack sizes may be marketed. 
 
Marketing Authorisation Holder 
Pfizer Europe MA EEIG 
Boulevard de la Plaine 17 
1050 Bruxelles 
Belgium 
 
Manufacturer 
R-Pharm Germany GmbH 
Heinrich-Mack-Str. 35, 89257 Illertissen 
Germany 
 
or 
 



 

128 

Pfizer Manufacturing Deutschland GmbH 
Betriebsstätte Freiburg 
Mooswaldallee 1 
79090 Freiburg 
Germany 
 
or 
 
Pfizer Italia S.r.l.  
Località Marino del Tronto, 63100  
Ascoli Piceno (AP)  
Italy 
 
For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder: 
 
België/Belgique/Belgien 
Pfizer S.A./N.V. 
Tél/Tel: + 32 (0)2 554 62 11 
 

Lietuva 
Pfizer Luxembourg SARL filialas Lietuvoje 
Tel. +3705 2514000 
 

България  
Пфайзер Люксембург САРЛ,  
Клон България  
Тел.: +359 2 970 4333 
 

Luxembourg/Luxemburg 
Pfizer S.A. 
Tél/Tel: + 32 (0)2 554 62 11 
 

Česká republika 
Pfizer PFE, spol. s r.o. 
Tel: + 420 283 004 111 
 

Magyarország 
Pfizer Kft. 
Tel.: +36 1 488 37 00 
 

Danmark 
Pfizer ApS 
Tlf: + 45 44 20 11 00 
 

Malta 
Vivian Corporation Ltd. 
Tel: +356 21344610 
 

Deutschland 
Pfizer Pharma GmbH 
Tel: +49 (0)30 550055-51000 
 

Nederland 
Pfizer bv 
Tel: +31 (0)10 406 43 01 
 

Eesti 
Pfizer Luxembourg SARL Eesti filiaal 
Tel: +372 666 7500 
 

Norge 
Pfizer Norge AS 
Tlf: +47 67 52 61 00 
 

Ελλάδα 
PFIZER ΕΛΛΑΣ Α.Ε.,  
Τηλ.: +30 210 67 85 800 
 

Österreich 
Pfizer Corporation Austria Ges.m.b.H. 
Tel.: +43 (0)1 521 15-0 
 

España 
Pfizer, S.L. 
Tel: + 34 91 490 99 00 
 

Polska 
Pfizer Polska Sp. z o.o. 
Tel.: + 48 22 335 61 00 
 

France 
Pfizer 
Tél: + 33 (0)1 58 07 34 40 
 

Portugal 
Pfizer Biofarmacêutica, Sociedade Unipessoal Lda 
Tel: +351 21 423 5500 
 



 

129 

Hrvatska 
Pfizer Croatia d.o.o. 
Tel: + 385 1 3908 777 
 

România 
Pfizer România S.R.L. 
Tel: +40 (0)21 207 28 00 
 

Ireland 
Pfizer Healthcare Ireland 
 
Tel: 1800 633 363 (toll free) 
+44 (0) 1304 616161 
 

Slovenija 
Pfizer Luxembourg SARL, Pfizer, podružnica za 
svetovanje s področja farmacevtske dejavnosti, 
Ljubljana 
Tel: + 386 (0) 1 52 11 400 
 

Ísland 
Icepharma hf. 
Simi: +354 540 8000  
 

Slovenská republika 
Pfizer Luxembourg SARL, organizačná zložka  
Tel: +421-2-3355 5500 
 

Italia 
Pfizer S.r.l. 
Tel: +39 06 33 18 21 
 

Suomi/Finland 
Pfizer Oy 
Puh/Tel: + 358 (0)9 43 00 40 
 

Κύπρος 
PFIZER ΕΛΛΑΣ Α.Ε. (CYPRUS BRANCH), 
Τηλ: +357 22 817690 
 

Sverige 
Pfizer Innovations AB 
Tel: + 46 (0)8 550 520 00 
 

Latvija 
Pfizer Luxembourg SARL filiāle Latvijā 
Tel: + 371 670 35 775 
 

United Kingdom 
Pfizer Limited 
Tel: + 44 (0) 1304 616161 
 

 
This leaflet was last revised in  
 
Other sources of information 
 
Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu/ 
 
 


	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE
	B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
	C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETINGAUTHORISATION
	D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE ANDEFFECTIVE USE OF THE MEDICINAL PRODUCT
	A. LABELLING
	B. PACKAGE LEAFLET