ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
1.
CHAMPIX 0.5 mg film-coated tablets
2.
Each film-coated tablet contains 0.5 mg of varenicline (as tartrate).
Excipient(s)
:
For a full list of excipients, see section 6.1.
3.
Film-coated tablet
0.5 mg film-coated tablets: White, capsular-shaped, biconvex tablets debossed with “
Pfizer
” on one
side and “CHX 0.5” on the other side.
4.
CHAMPIX is indicated for smoking cessation in adults.
Posology
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.
CHAMPIX is for oral use. 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 who cannot tolerate adverse effects of CHAMPIX may have the dose lowered temporarily or
permanently to 0.5 mg twice daily.
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 (see section 5.1).
No data are available on the efficacy of an additional 12 weeks course of treatment for patients who
do not succeed in stopping smoking during initial therapy or who relapse after treatment.
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).
2
Special populations
Patients with renal insufficiency
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 events 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).
Patients with hepatic impairment
No dosage adjustment is necessary for patients with hepatic impairment (see section 5.2).
Dosing in elderly patients
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.
Paediatric population
The safety and efficacy of CHAMPIX in children or adolescents below 18 years have not yet been
established. Currently available data are described in section 5.2 but no recommendation on a
posology can be made.
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
Hypersensitivity to the active substance or to any of the excipients.
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. Not all patients had stopped smoking at the
time of onset of symptoms and not all patients had known pre-existing psychiatric illness. Clinicians
should be aware of the possible emergence of significant depressive symptomatology in patients
undergoing a smoking cessation attempt, and should advise patients accordingly. Champix should be
discontinued immediately if agitation, depressed mood or changes in behaviour or thinking that are of
concern for the doctor, the patient, family or caregivers are observed, or if the patient develops
suicidal ideation or suicidal behaviour. In many post-marketing cases, resolution of symptoms after
3
discontinuation of varenicline was reported although in some cases the symptoms persisted; therefore,
ongoing follow up should be provided until symptoms resolve.
Depressed mood, rarely including suicidal ideation and suicide attempt, may be a symptom of nicotine
withdrawal. In addition, smoking cessation, with or without pharmacotherapy, has been associated
with exacerbation of underlying psychiatric illness (e.g. depression).
History of psychiatric illness
The safety and efficacy of Champix in patients with serious psychiatric illness such as schizophrenia,
bipolar disorder and major depressive disorder has not been established. Care should be taken with
patients with a history of psychiatric illness and patients should be advised accordingly.
Epilepsy
There is no clinical experience with CHAMPIX in patients with epilepsy.
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.
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.
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
4
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 is limited clinical data on any potential interaction between alcohol and varenicline.
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.
Pregnanc
y
There are no adequate data from the use of CHAMPIX in pregnant women. Studies in animals have
shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown. CHAMPIX
should not be used during pregnancy.
Breastfeeding
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).
CHAMPIX may have minor or moderate influence on the ability to drive and use machines.
CHAMPIX may cause dizziness and somnolence 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.
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
5
of the CHAMPIX studies to distinguish between adverse events associated with study drug treatment
or those possibly associated with nicotine withdrawal.
Clinical trials included approximately 4,000 patients treated with CHAMPIX for up to 1 year (average
exposure 84 days). In general, when adverse reactions occurred, onset was in the first week of
therapy; severity was generally mild to moderate and there were no differences by age, race or gender
with regard to the incidence of adverse reactions.
In patients treated with the recommended dose of 1mg BID 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.
The treatment discontinuation rate due to adverse events was 11.4% for varenicline compared with
9.7% for placebo. In this group, the discontinuation rates for the most common adverse events 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).
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)). Reported postmarketing adverse events are
also included for which frequency is not known. Within each frequency grouping, undesirable effects
are presented in order of decreasing seriousness.
System Organ
Class
Adverse Drug Reactions
Infections and infestations
Uncommon Bronchitis, nasopharyngitis, sinusitis, fungal infection, viral infection,.
Metabolism and nutrition disorders
Common Increased appetite
Uncommon Anorexia, decreased appetite, polydipsia
Psychiatric disorders
Very common Abnormal dreams, insomnia
Uncommon Panic reaction, bradyphrenia, thinking abnormal, mood swings
Not Known* Suicidal ideation, depression, psychosis, hallucinations, anxiety,
aggressive and irrational behaviour
Nervous system disorders
Very common
Headache
Uncommon
Tremor, coordination abnormal, dysarthria, hypertonia, restlessness,
dysphoria, hypoaesthesia, hypogeusia, lethargy, libido increased, libido
decreased
Cardiac disorders
Uncommon
Atrial fibrillation, palpitations
Not Known*
Myocardial infarction
Eye disorders
Uncommon Scotoma, scleral discolouration, eye pain, mydriasis, photophobia,
myopia, lacrimation increased
Ear and labyrinth disorders
Uncommon Tinnitus
Respiratory, thoracic and mediastinal disorders
Uncommon Dyspnoea, cough, hoarseness, pharyngolaryngeal pain, throat irritation,
respiratory tract congestion, sinus congestion, post nasal drip,
rhinorrhoea, snoring
Gastrointestinal disorders
6
Common
Somnolence, dizziness, dysgeusia
System Organ
Class
Adverse Drug Reactions
Very common Nausea
Common Vomiting, constipation, diarrhoea, abdominal distension, stomach
discomfort, dyspepsia, flatulence, dry mouth
Uncommon Haematemesis, haematochezia, gastritis, gastrooesophageal reflux
disease, abdominal pain, change of bowel habit, abnormal faeces,
eructation, aphthous stomatitis, gingival pain, tongue coated
Skin and subcutaneous tissue disorders
Uncommon Rash generalised, erythema, pruritus, acne, hyperhidrosis, night sweats
Not Known* Severe cutaneous reactions, including Stevens Johnson Syndrome and
Erythema Multiforme, angiodema
Musculoskeletal and connective tissue disorders
Uncommon Joint stiffness, muscle spasms, chest wall pain, costochondritis
Renal and urinary disorders
Uncommon Glycosuria, nocturia, polyuria
Reproductive system and breast disorders
Uncommon Menorrhagia, vaginal discharge, sexual dysfunction
General disorders and administration site conditions
Common
Fatigue
Uncommon
Chest discomfort, chest pain, pyrexia, feeling cold, asthenia, circadian
rhythm sleep disorder, malaise, cyst
Investigations
Uncommon Blood pressure increased, electrocardiogram ST segment depression,
electrocardiogram T wave amplitude decreased, heart rate increased,
liver function test abnormal, platelet count decreased, weight increased,
semen abnormal, C-reactive protein increased, blood calcium decreased
* Reported postmarketing adverse events are also included for which frequency is not known
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.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Active substances 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,
t
he 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
7
nicotinic receptors (α3β4 Ki=84 nM, α7 Ki= 620 nM, α1βγδ Ki= 3,400 nM), or to non-nicotinic
receptors and transporters (Ki > 1
μ
M, 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
The efficacy of CHAMPIX in smoking cessation was demonstrated in 3 clinical trials involving
chronic cigarette smokers (≥ 10 cigarettes per day). 2619 patients received CHAMPIX 1mg 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 randomized 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 randomized to
8
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. The odds of maintaining abstinence
at week 24, following an additional 12 weeks of treatment with CHAMPIX, were 2.47 times those for
placebo (p<0.0001). Superiority to placebo for CA was maintained through week 52 (Odds
Ratio=1.35, p=0.0126).
The key results are summarised in the following table:
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)
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.
Subjects with Cardiovascular Disease
The efficacy and safety of varenicline has been evaluated in cardiovascular compromised smokers.
Efficacy and safety was similar to that observed in studies with non-cardiovascular compromised
smokers. 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). There was a low incidence of
cardiovascular events in both the varenicline and placebo treatment groups.
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%
9
Placebo, (n = 251)
8.8%
5.6%
Odds ratio
(CHAMPIX vs Placebo)
8.40
p<0.0001
4.04
p<0.0001
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).
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
medications, as demonstrated in specific pharmacokinetic studies and in population pharmacokinetic
analyses.
Patients with 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 Insufficiency:
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).
10
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:
Adolescents:
When 22 adolescents aged 12 to 17 years (inclusive) received a single 0.5 mg and 1 mg
dose of varenicline the pharmacokinetics of varenicline was approximately dose proportional between
the 0.5 mg and 1 mg doses. Systemic exposure, as assessed by AUC (0-inf), and renal clearance of
varenicline were comparable to adults. An increase of 30% in C
max
and a shorter elimination half-life
(10.9 hr) were observed in adolescents compared with adults (see section 4.2).
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.
6.1 List of excipients
Core Tablet
Cellulose, Microcrystalline
Calcium Hydrogen Phosphate Anhydrous
Croscarmellose Sodium
Silica, Colloidal Anhydrous
Magnesium Stearate
Film Coating
Hypromellose
Titanium Dioxide (E171)
Macrogols
Triacetin
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
2 years
6.4 Special precautions for storage
This medicinal product does not require any special storage conditions
11
6.5 Nature and contents of container
Treatment initiation packs
Aclar / PVC / blisters with aluminium foil backing containing one 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.
Aclar / PVC / blisters with aluminium foil backing containing one 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.
Aclar / 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 a second clear blister of 28 x 1 mg film-coated tablets in secondary
heat sealed card packaging.
Maintenance packs
Aclar / PVC blisters with aluminium foil backing in a pack containing 28 x 0.5 mg film-coated tablets
in secondary heat sealed card packaging.
Aclar / 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) blue white tablet container 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 and other handling
No special requirements.
7.
Pfizer Limited
Ramsgate Road
Sandwich
Kent
CT13 9NJ
UK
8.
EU/1/06/360/003
EU/1/06/360/008
EU/1/06/360/012
EU/1/06/360/006
EU/1/06/360/007
EU/1/06/360/001
9.
26 September 2006
12
13
1.
CHAMPIX 1 mg film-coated tablets
2.
Each film-coated tablet contains 1 mg of varenicline (as tartrate).
Excipient(s)
:
For a full list of excipients, see section 6.1.
3.
Film-coated tablet
1 mg film-coated tablets: Light blue, capsular-shaped, biconvex tablets debossed with “
Pfizer
” on one
side and “CHX 1.0” on the other side.
4.
CHAMPIX is indicated for smoking cessation in adults.
Posology
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.
CHAMPIX is for oral use. 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 who cannot tolerate adverse effects of CHAMPIX may have the dose lowered temporarily or
permanently to 0.5 mg twice daily.
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 (see section 5.1).
No data are available on the efficacy of an additional 12 weeks course of treatment for patients who
do not succeed in stopping smoking during initial therapy or who relapse after treatment.
14
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).
Special populations
Patients with renal insufficiency
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 events 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).
Patients with hepatic impairment
No dosage adjustment is necessary for patients with hepatic impairment (see section 5.2).
Dosing in elderly patients
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.
Paediatric population
The safety and efficacy of CHAMPIX in children or adolescents below 18 years have not yet been
established. Currently available data are described in section 5.2 but no recommendation on a
posology can be made
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
Hypersensitivity to the active substance or to any of the excipients.
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. Not all patients had stopped smoking at the
time of onset of symptoms and not all patients had known pre-existing psychiatric illness. Clinicians
should be aware of the possible emergence of significant depressive symptomatology in patients
undergoing a smoking cessation attempt, and should advise patients accordingly. Champix should be
15
discontinued immediately if agitation, depressed mood or changes in behaviour or thinking that are of
concern for the doctor, the patient, family or caregivers are observed, or if the patient develops
suicidal ideation or suicidal behaviour. In many post-marketing cases, resolution of symptoms after
discontinuation of varenicline was reported, although in some cases the symptoms persisted;
therefore, ongoing follow up should be provided until symptoms resolve.
Depressed mood, rarely including suicidal ideation and suicide attempt, may be a symptom of nicotine
withdrawal. In addition, smoking cessation, with or without pharmacotherapy, has been associated
with the exacerbation of underlying psychiatric illness (e.g. depression).
History of psychiatric illness
The safety and efficacy of Champix in patients with serious psychiatric illness such as schizophrenia,
bipolar disorder and major depressive disorder has not been established. Care should be taken with
patients with a history of psychiatric illness and patients should be advised accordingly.
Epilepsy
There is no clinical experience with CHAMPIX in patients with epilepsy.
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.
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.
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.
16
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 is limited clinical data on any potential interaction between alcohol and varenicline.
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.
Pregnancy
There are no adequate data from the use of CHAMPIX in pregnant women. Studies in animals have
shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown. CHAMPIX
should not be used during pregnancy.
Breastfeeding
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).
CHAMPIX may have minor or moderate influence on the ability to drive and use machines.
CHAMPIX may cause dizziness and somnolence 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.
17
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 events associated with study drug treatment
or those possibly associated with nicotine withdrawal.
Clinical trials included approximately 4,000 patients treated with CHAMPIX for up to 1 year (average
exposure 84 days). In general, when adverse reactions occurred, onset was in the first week of
therapy; severity was generally mild to moderate and there were no differences by age, race or gender
with regard to the incidence of adverse reactions.
In patients treated with the recommended dose of 1mg BID 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.
The treatment discontinuation rate due to adverse events was 11.4% for varenicline compared with
9.7% for placebo. In this group, the discontinuation rates for the most common adverse events 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).
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)). Reported postmarketing adverse events are
also included for which frequency is not known .Within each frequency grouping, undesirable effects
are presented in order of decreasing seriousness.
System Organ
Class
Adverse Drug Reactions
Infections and infestations
Uncommon Bronchitis, nasopharyngitis, sinusitis, fungal infection, viral infection,.
Metabolism and nutrition disorders
Common Increased appetite
Uncommon Anorexia, decreased appetite, polydipsia
Psychiatric disorders
Very common Abnormal dreams, insomnia
Uncommon Panic reaction, bradyphrenia, thinking abnormal, mood swings
Not Known* Suicidal ideation, depression, psychosis, hallucinations, anxiety,
aggressive and irrational behaviour
Nervous system disorders
Very common
Headache
Common
Somnolence, dizziness, dysgeusia
Uncommon
Tremor, coordination abnormal, dysarthria, hypertonia, restlessness,
dysphoria, hypoaesthesia, hypogeusia, lethargy, libido increased, libido
decreased
Cardiac disorders
Uncommon
Atrial fibrillation, palpitations
Not Known*
Myocardial Infarction
Eye disorders
Uncommon Scotoma, scleral discolouration, eye pain, mydriasis, photophobia,
myopia, lacrimation increased
Ear and labyrinth disorders
Uncommon
Tinnitus
18
System Organ
Class
Adverse Drug Reactions
Respiratory, thoracic and mediastinal disorders
Uncommon Dyspnoea, cough, hoarseness, pharyngolaryngeal pain, throat irritation,
respiratory tract congestion, sinus congestion, post nasal drip,
rhinorrhoea, snoring
Gastrointestinal disorders
Very common Nausea
Common Vomiting, constipation, diarrhoea, abdominal distension, stomach
discomfort, dyspepsia, flatulence, dry mouth
Uncommon Haematemesis, haematochezia, gastritis, gastrooesophageal reflux
disease, abdominal pain, change of bowel habit, abnormal faeces,
eructation, aphthous stomatitis, gingival pain, tongue coated
Skin and subcutaneous tissue disorders
Uncommon Rash generalised, erythema, pruritus, acne, hyperhidrosis, night sweats
Not Known* Severe cutaneous reactions, including Stevens Johnson Syndrome and
Erythema Multiforme, angiodema,
Musculoskeletal and connective tissue disorders
Uncommon Joint stiffness, muscle spasms, chest wall pain, costochondritis
Renal and urinary disorders
Uncommon Glycosuria, nocturia, polyuria
Reproductive system and breast disorders
Uncommon Menorrhagia, vaginal discharge, sexual dysfunction
General disorders and administration site conditions
Common
Fatigue
Uncommon
Chest discomfort, chest pain, pyrexia, feeling cold, asthenia, circadian
rhythm sleep disorder, malaise, cyst
Investigations
Uncommon Blood pressure increased, electrocardiogram ST segment depression,
electrocardiogram T wave amplitude decreased, heart rate increased,
liver function test abnormal, platelet count decreased, weight increased,
semen abnormal, C-reactive protein increased, blood calcium decreased
* Reported postmarketing adverse events are also included for which frequency is not known
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.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Active substances 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.
19
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,
t
he 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 > 1
μ
M, 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
The efficacy of CHAMPIX in smoking cessation was demonstrated in 3 clinical trials involving
chronic cigarette smokers (≥ 10 cigarettes per day). 2619 patients received CHAMPIX 1mg 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 randomized 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
20
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 randomized 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. The odds of maintaining abstinence
at week 24, following an additional 12 weeks of treatment with CHAMPIX, were 2.47 times those for
placebo (p<0.0001). Superiority to placebo for CA was maintained through week 52 (Odds
Ratio=1.35, p=0.0126).
The key results are summarised in the following table:
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)
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.
Subjects with Cardiovascular Disease
The efficacy and safety of varenicline has been evaluated in cardiovascular compromised smokers.
Efficacy and safety was similar to that observed in studies with non-cardiovascular compromised
smokers. 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). There was a low incidence of
cardiovascular events in both the varenicline and placebo treatment groups.
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.
21
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
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).
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
medications, as demonstrated in specific pharmacokinetic studies and in population pharmacokinetic
analyses.
Patients with 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 Insufficiency:
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
22
> 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:
Adolescents:
When 22 adolescents aged 12 to 17 years (inclusive) received a single 0.5 mg and 1 mg
dose of varenicline the pharmacokinetics of varenicline was approximately dose proportional between
the 0.5 mg and 1 mg doses. Systemic exposure, as assessed by AUC (0-inf), and renal clearance of
varenicline were comparable to adults. An increase of 30% in C
max
and a shorter elimination half-life
(10.9 hr) were observed in adolescents compared with adults (see section 4.2).
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.
6.1 List of excipients
Core Tablet
Cellulose, Microcrystalline
Calcium Hydrogen Phosphate Anhydrous
Croscarmellose Sodium
Silica, Colloidal Anhydrous
Magnesium Stearate
Film Coating
Hypromellose
Titanium Dioxide (E171)
Macrogols
Indigo Carmine Aluminium Lake E132
Triacetin
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
2 years
23
6.4 Special precautions for storage
This medicinal product does not require any special storage conditions
6.5 Nature and contents of container
Treatment initiation packs
Aclar / PVC / blisters with aluminium foil backing containing one 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.
Aclar / PVC / blisters with aluminium foil backing containing one 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.
Aclar / 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 a second clear blister of 28 x 1 mg film-coated tablets in secondary
heat sealed card packaging.
Maintenance packs
Aclar / PVC blisters with aluminium foil backing in a pack containing 28 x 1 mg film-coated tablets
in secondary heat sealed card packaging.
Aclar / PVC blisters with aluminium foil backing in a pack containing 56 x 1 mg film-coated tablets
in secondary heat sealed card packaging.
Aclar / PVC / blisters with aluminium foil backing in a pack containing 28 x 1 mg film-coated tablets
in a carton.
Aclar / PVC / blisters with aluminium foil backing in a pack containing 56 x 1 mg film-coated tablets
in a carton.
Aclar / PVC / blisters with aluminium foil backing in a pack containing 112 x 1 mg film-coated
tablets in a carton.
Aclar / PVC / blisters with aluminium foil backing in a pack containing 140 x 1 mg film-coated
tablets in a carton.
High-density polyethylene (HDPE) blue white tablet container 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 and other handling
No special requirements.
7.
Pfizer Limited
Ramsgate Road
Sandwich
Kent
CT13 9NJ
UK
24
8.
EU/1/06/360/003
EU/1/06/360/008
EU/1/06/360/012
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/1/06/360/002
9.
25
ANNEX II
A.
MANUFACTURING AUTHORISATION HOLDER(S)
RESPONSIBLE FOR BATCH RELEASE
B.
CONDITIONS OF THE MARKETING AUTHORISATION
26
A. MANUFACTURING AUTHORISATION HOLDER RESPONSIBLE FOR BATCH
RELEASE
Name and address of the manufacturer(s) responsible for batch release
Pfizer Manufacturing Deutschland GmbH
Heinrich-Mack-Strasse 35
D-89257 Illertissen
Germany
B. CONDITIONS OF THE MARKETING AUTHORISATION
•
Medicinal product subject to medical prescription.
•
CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND
EFFECTIVE USE OF THE MEDICINAL PRODUCT
Not applicable.
•
OTHER CONDITIONS
Pharmacovigilance system
The MAH must ensure that the system of pharmacovigilance, presented in Module 1.8.1. of the
Marketing Authorisation, is in place and functioning before and whilst the product is on the market.
Risk Management Plan
The MAH commits to performing the studies and additional pharmacovigilance activities detailed in
the Pharmacovigilance Plan, as agreed in version 4.0 of the Risk Management Plan (RMP) presented
in Module 1.8.2. of the Marketing Authorisation and any subsequent updates of the RMP agreed by
the CHMP.
As per the CHMP Guideline on Risk Management Systems for medicinal products for human use, any
updated RMP should be submitted at the same time as the following Periodic Safety Update Report
(PSUR).
In addition, an updated RMP should be submitted
•
When new information is received that may impact on the current Safety Specification,
Pharmacovigilance Plan or risk minimisation activities
•
Within 60 days of an important (pharmacovigilance or risk minimisation) milestone being
reached
•
At the request of the EMEA
27
ANNEX III
LABELLING AND PACKAGE LEAFLET
28
A. LABELLING
29
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.
CHAMPIX 0.5 mg and 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.
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.
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
Do not use if box has been opened
KEEP THE PACKAGE INTACT
8.
EXPIRY DATE
EXP: MM/YYYY
9.
SPECIAL STORAGE CONDITIONS
30
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Pfizer Limited
Sandwich
Kent
CT13 9NJ
United Kingdom
EU/1/06/360/003
13. BATCH NUMBER
Lot:
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
START AT DAY 1
The day I stop smoking should be between day 8 and day 14.
The day I stop smoking will be ______________.
Week 1
Week 2
Numbers 1 to 14
sun as symbol
moon as symbol
16. INFORMATION IN BRAILLE
CHAMPIX
0.5 mg
1 mg
31
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS
Blister Pack of 11 x 0.5 mg varenicline film-coated tablets, Heat Sealed Card
1.
CHAMPIX 0.5 mg
Varenicline
2.
Pfizer Ltd (as MA Holder Logo)
3.
EXPIRY DATE
EXP: MM/YYYY
4.
BATCH NUMBER
Lot:
5.
OTHER
32
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS
Blister Pack of 14 x 1 mg varenicline film-coated tablets, Heat Sealed Card
1.
CHAMPIX 1 mg
Varenicline
2.
Pfizer Ltd (as MA Holder Logo)
3.
EXPIRY DATE
EXP: MM/YYYY
4.
BATCH NUMBER
Lot:
5.
OTHER
33
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 x 1 mg varenicline film-coated tablets – inner and outer labelling
1.
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.
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.
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
Do not use if box has been opened
KEEP THE PACKAGE INTACT
8.
EXPIRY DATE
EXP: MM/YYYY
34
9.
SPECIAL STORAGE CONDITIONS
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Pfizer Limited
Sandwich
Kent
CT13 9NJ
United Kingdom
EU/1/06/360/012
13. BATCH NUMBER
Lot:
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
START AT DAY 1
The day I stop smoking should be between day 8 and day 14.
The day I stop smoking will be ______________.
Week 1
Week 2
Week 3
Week 4
Numbers 1 to 28
sun as symbol
moon as symbol
16. INFORMATION IN BRAILLE
CHAMPIX
0.5 mg
1 mg
35
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.
CHAMPIX 0.5 mg
CHAMPIX 1 mg
Varenicline
2.
Pfizer Ltd (as MA Holder Logo)
3.
EXPIRY DATE
EXP: MM/YYYY
4.
BATCH NUMBER
Lot:
5.
OTHER
36
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS
Blister Pack of 28 x 1 mg varenicline film-coated tablets, Heat Sealed Card
1.
CHAMPIX 1 mg
Varenicline
2.
Pfizer Ltd (as MA Holder Logo)
3.
EXPIRY DATE
EXP: MM/YYYY
4.
BATCH NUMBER
Lot:
5.
OTHER
37
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
Maintenance pack
Heat sealed card pack containing either 2 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.
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.
28 film-coated tablets
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 REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
Do not use if box has been opened
KEEP THE PACKAGE INTACT
8.
EXPIRY DATE
EXP: MM/YYYY
38
9.
SPECIAL STORAGE CONDITIONS
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Pfizer Limited
Sandwich
Kent
CT13 9NJ
United Kingdom
EU/1/06/360/004
EU/1/06/360/005
13. BATCH NUMBER
Lot:
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
numbers 1 to 14
numbers 1 to 28
sun as symbol
moon as symbol
16. INFORMATION IN BRAILLE
CHAMPIX 1 mg
39
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.
CHAMPIX 1 mg
Varenicline
2.
Pfizer Ltd (as MA Holder Logo)
3.
EXPIRY DATE
EXP: MM/YYYY
4.
BATCH NUMBER
Lot:
5.
OTHER
40
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
Maintenance pack
Heat sealed card pack containing either 2 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.
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.
28 film-coated tablets
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 REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
Do not use if box has been opened
KEEP THE PACKAGE INTACT
8.
EXPIRY DATE
EXP: MM/YYYY
41
9.
SPECIAL STORAGE CONDITIONS
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Pfizer Limited
Sandwich
Kent
CT13 9NJ
United Kingdom
EU/1/06/360/006
EU/1/06/360/007
13. BATCH NUMBER
Lot:
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
numbers 1 to 14
numbers 1 to 28
sun as symbol
moon as symbol
16. INFORMATION IN BRAILLE
CHAMPIX 0.5 mg
42
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.
CHAMPIX 0.5 mg
Varenicline
2.
Pfizer Ltd (as MA Holder Logo)
3.
EXPIRY DATE
EXP: MM/YYYY
4.
BATCH NUMBER
Lot:
5.
OTHER
43
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.
CHAMPIX 0.5 mg and 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.
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.
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
Do not use if box has been opened
8.
EXPIRY DATE
EXP: MM/YYYY
9.
SPECIAL STORAGE CONDITIONS
44
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Pfizer Limited
Sandwich
Kent
CT13 9NJ
United Kingdom
EU/1/06/360/008
13. BATCH NUMBER
Lot
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
CHAMPIX
0.5 mg
1 mg
45
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS
Blister Pack of 11 x 0.5 mg varenicline film-coated tablets
1.
CHAMPIX 0.5 mg
Varenicline
2.
Pfizer Ltd (as MA Holder Logo)
3.
EXPIRY DATE
EXP: MM/YYYY
4.
BATCH NUMBER
Lot:
5.
OTHER
sun as symbol
moon as symbol
46
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS
Blister Pack of 14 x 1 mg varenicline film-coated tablets
1.
CHAMPIX 1 mg
Varenicline
2.
Pfizer Ltd (as MA Holder Logo)
3.
EXPIRY DATE
EXP: MM/YYYY
4.
BATCH NUMBER
Lot:
5.
OTHER
sun as symbol
moon as symbol
47
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.
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.
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.
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
Do not use if box has been opened
8.
EXPIRY DATE
EXP: MM/YYYY
48
9.
SPECIAL STORAGE CONDITIONS
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Pfizer Limited
Sandwich
Kent
CT13 9NJ
United Kingdom
EU/1/06/360/009
EU/1/06/360/010
EU/1/06/360/011
EU/1/06/360/013
13. BATCH NUMBER
Lot:
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
CHAMPIX 1 mg
49
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS
Blister Pack of 14 x 1 mg varenicline film-coated tablets
1.
CHAMPIX 1 mg
Varenicline
2.
Pfizer Ltd (as MA Holder Logo)
3.
EXPIRY DATE
EXP: MM/YYYY
4.
BATCH NUMBER
Lot:
5.
OTHER
sun as symbol
moon as symbol
50
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
High-density polyethylene (HDPE) bottle packaging for 56 x 1 mg varenicline film-coated tablets
1.
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.
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 REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
Do not use if box has been opened
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
51
Pfizer Limited
Sandwich
Kent
CT13 9NJ
United Kingdom
EU/1/06/360/002
13. BATCH NUMBER
Lot:
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
CHAMPIX 1 mg
52
PARTICULARS TO APPEAR ON THE THE IMMEDIATE PACKAGING
High-density polyethylene (HDPE) bottle label for 56 x 1 mg varenicline film-coated tablets
1.
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.
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 REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
Do not use if box has been opened
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
53
Pfizer Limited
Sandwich
Kent
CT13 9NJ
United Kingdom
EU/1/06/360/002
13. BATCH NUMBER
Lot:
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
54
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
High-density polyethylene (HDPE) bottle packaging for 56 x 0.5 mg varenicline film-coated tablets
1.
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.
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 REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
Do not use if box has been opened
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
55
Pfizer Limited
Sandwich
Kent
CT13 9NJ
United Kingdom
EU/1/06/360/001
13. BATCH NUMBER
Lot:
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
CHAMPIX 0.5 mg
56
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.
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.
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 REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
Do not use if box has been opened
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
57
Pfizer Limited
Sandwich
Kent
CT13 9NJ
United Kingdom
EU/1/06/360/001
13. BATCH NUMBER
Lot:
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
58
B. PACKAGE LEAFLET
59
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.
-
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. Do not pass it on to others. It may harm them, even
if their symptoms are the same as yours.
-
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet,
please tell your doctor or pharmacist.
In this leaflet
:
1. What CHAMPIX is and what it is used for
2. Before you take CHAMPIX
3. How to take CHAMPIX
4. Possible side effects
5.
How to store CHAMPIX
6.
Further information
1.
WHAT CHAMPIX IS AND WHAT IT IS USED FOR
CHAMPIX is a a non-nicotine medicine which is used to help you stop smoking.
CHAMPIX can help to relieve the craving and withdrawal symptoms associated with stopping
smoking.
Although you are not recommended to smoke after your quit date, CHAMPIX can also reduce the
enjoyment of cigarettes if you do smoke when on treatment. (The quit date is the day in the second
week of treatment when you will stop smoking, see Section 3.)
2.
BEFORE YOU TAKE CHAMPIX
Do not take CHAMPIX
-
If you are allergic (hypersensitive) to varenicline tartrate or any of the other ingredients of
CHAMPIX
Take special care with 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, your family or doctor or if you develop suicidal
thoughts or behaviours you should stop your treatment and contact your doctor immediately.
Taking other medicines
Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines,
including medicines obtained without a prescription.
60
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 drugs work. Therefore, in some cases an adjustment of the dose
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.
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 illness. If you have a history of psychiatric illness you
should discuss this with your doctor or pharmacist.
Depressed mood may appear during smoking cessation with or without treatment. Depression, rarely
including suicidal thoughts and suicide attempt, has been reported in patients undergoing a smoking
cessation attempt. These feelings have also been reported while attempting to quit smoking with
CHAMPIX. If these symptoms persist when you stop taking CHAMPIX, your doctor should continue
to monitor you closely until you are feeling better.
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.
Effect of CHAMPIX on other drugs
CHAMPIX is not expected to affect the way other drugs work.
Effect of other drugs on CHAMPIX
Due to the way in which varenicline tartrate is removed from the body, it is not expected that other
drugs will affect the way in which CHAMPIX works.
Use of CHAMPIX with other therapies for smoking cessation
The safety and benefits of taking CHAMPIX in combination with other medicines for stopping
smoking have not been studied. CHAMPIX in combination with other smoking cessation therapies is
therefore not recommended.
CHAMPIX is not recommended for use in children or adolescents below 18 years.
Taking CHAMPIX with food and drink
CHAMPIX can be taken with or without food.
Pregnancy
You should not take CHAMPIX while you are pregnant.
Talk to your doctor if you are intending to become pregnant. If you want to start treatment with
CHAMPIX, your treatment should be timed so that you have completed the course before becoming
pregnant.
Breast-feeding
Although it was not studied, CHAMPIX may pass into breast milk. You should ask your doctor or
pharmacist for advice before taking CHAMPIX.
61
Driving and using machines
CHAMPIX may produce dizziness and sleepiness. You should not drive, operate complex machinery
or engage in any other potentially hazardous activities until you know whether this medication affects
your ability to perform these activities.
3.
HOW TO TAKE CHAMPIX
You are more likely to stop smoking if you are motivated to stop. Your doctor and pharmacist can
provide advice, support and sources of further information to help ensure your attempt to stop
smoking is successful.
Always take CHAMPIX exactly as your doctor has told you. You should check with your doctor or
pharmacist if you are not sure.
Before starting your course of CHAMPIX you should 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 tablets should be swallowed whole with water.
The usual dose for adults which you should follow from Day 1 is described in the following table:
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.
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.
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.
In smoking cessation therapy, risk of returning to smoking may be elevated in the period immediately
following the end of treatment. Your doctor may decide to gradually lower your dose of CHAMPIX at
the end of treatment.
If you have problems with your kidneys, you should speak to your doctor before taking CHAMPIX.
You may need a lower dose.
62
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 almost time for 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.
If you have any further questions on the use of this product, ask your doctor or pharmacist.
4.
POSSIBLE SIDE EFFECTS
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.
Like all medicines, CHAMPIX can cause side effects, although not everybody gets them.
If you are taking CHAMPIX and develop agitation, depressed mood, changes in behaviour or suicidal
thoughts you should stop your treatment and contact your doctor immediately.
-
Very common side effects which may affect more than 1 person in 10 are listed below:
o
Headache, difficulty sleeping, abnormal dreams
o
Nausea
-
Common side effects which may affect more than 1 person in 100 are listed below:
o
Increased appetite, changes in the way things taste, dry mouth
o
Sleepiness, tiredness, dizziness
o
Vomiting, constipation, diarrhoea, feeling bloated, stomach discomfort, indigestion,
flatulence
-
Uncommon side effects which may affect more than 1 person in 1, 000 are listed below:
o
Chest infection, discomfort or pain, inflammation of the sinuses,
o
Fever, feeling cold, feeling weak or unwell, viral infection, shortness of breath, cough,
hoarseness, throat pain and irritation, congested sinuses, runny nose, snoring
o
Loss of appetite, feeling thirsty, increased weight
o
Feeling of panic, difficulty thinking, mood swings
o
Tremor, difficulty with coordination, difficulty with speech, less sensitive to touch,
increased muscle tension, restlessness,
o
Heart rhythm disturbances, increased blood pressure, increased heart rate
63
o
Disturbed vision, eyeball discolouration, eye pain, dilated pupils, shortsightedness,
sensitivity to light, watery eyes
o
Ringing in the ears
o
Blood in vomit, irritated stomach and heartburn, abdominal pain, abnormal stools, red
blood in stools, belching, mouth ulcers, pain in the gums, coated tongue
o
Skin rash, cyst, fungal infection, reddening of the skin, itching, acne, increased sweating
o
Chest wall and rib pain, stiff joints, muscle spasms
o
Glucose in urine, increased urine volume and frequency
o
Increased menstrual flow, vaginal discharge, changes in sex drive or ability
-
There have been post-marketing reports of heart attack, hallucinations, changes in thinking or
behaviour (such as aggression and irrational behaviour), depression, and suicidal thoughts in
people attempting to quit smoking with CHAMPIX. There have also been reports of serious
allergic reactions including angioedema (swelling of the face, mouth, or throat) and 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). You should stop taking
CHAMPIX and contact your doctor immediately if you develop swelling of the face, mouth or
throat, or if your skin starts to peel or blister.
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please
tell your doctor or pharmacist.
5.
HOW TO STORE CHAMPIX
Keep out of the reach and sight of children.
Do not use CHAMPIX after the expiry date which is stated on the card packaging or carton. The
expiry date refers to the last day of that month.
This medicine does not require any special storage conditions.
Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to
dispose of medicines no longer required. These measures will help to protect the environment.
6.
FURTHER INFORMATION
What CHAMPIX contains
-
The active substance is 0.5 mg varenicline and 1 mg varenicline respectively
-
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)
Macrogols
Triacetin
64
Tablet film coating - CHAMPIX 1 mg film-coated tablets
Hypromellose
Titanium dioxide (E171)
Macrogols
Indigo Carmine Aluminium Lake (E132)
Triacetin
What CHAMPIX 0.5 mg and 1 mg film-coated tablets look 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:
Not all pack sizes may be marketed.
-
A 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.
-
A 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 x CHAMPIX 1 mg film-coated tablets in
card packaging.
-
A follow-on (maintenance) pack containing 2 clear blisters of 14 x CHAMPIX 1 mg film-
coated tablets in card packaging.
-
A follow-on (maintenance) pack containing 2 clear blisters of 28 x CHAMPIX 1 mg film-
coated tablets in card packaging.
-
A follow-on (maintenance) pack containing 2 clear blisters of 14 x CHAMPIX 0.5 mg film-
coated tablets in card packaging.
-
A follow-on (maintenance) pack containing 2 clear blisters of 28 x CHAMPIX 0.5 mg film-
coated tablets in card packaging.
-
A 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.
-
A follow-on (maintenance) pack containing 2 clear blisters of 14 x CHAMPIX 1 mg film-
coated tablets in a carton.
-
A follow-on (maintenance) pack containing 4 clear blisters of 14 x CHAMPIX 1 mg film-
coated tablets in a carton.
-
A follow-on (maintenance) pack containing 8 clear blisters of 14 x CHAMPIX 1 mg film-
coated tablets in a carton.
-
A follow-on (maintenance) pack containing 10 clear blisters of 14 x CHAMPIX 1 mg film-
coated tablets in a carton.
-
A sealed blue white HDPE bottle pack, with a child resistant screw cap, in a carton, containing
56 x CHAMPIX 1 mg film-coated tablets.
-
A sealed blue white HDPE bottle pack, with a child resistant screw cap, in a carton, containing
56 x CHAMPIX 0.5 mg film-coated tablets.
Marketing Authorisation Holder
Pfizer Limited
Sandwich
Kent
CT13 9NJ
United Kingdom
65
Manufacturer
Pfizer Manufacturing Deutschland GmbH
Heinrich-Mack-Str. 35
D-89257 Illertissen
Germany
For any information about this medicinal product, 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
Luxembourg/Luxemburg
Pfizer S.A.
Tél/Tel: + 32 (0)2 554 62 11
България
Пфайзер Люксембург САРЛ,
Клон България
Тел.: +359 2 970 4333
Magyarország
Pfizer Kft.
Tel.: +36 1 488 37 00
Česká republika
Pfizer s.r.o.
Tel: + 420 283 004 111
Malta
V.J. Salomone Pharma Ltd.
Tel : +356 21220174
Danmark
Pfizer ApS
Tlf: + 45 44 20 11 00
Nederland
Pfizer bv
Tel: +31 (0)10 406 43 01
Deutschland
Pfizer Pharma GmbH
Tel: +49 (0)30 550055-51000
Norge
Pfizer AS
Tlf: +47 67 52 61 00
Eesti
Pfizer Luxembourg SARL Eesti filiaal
Tel: + 372 6 405 328
Österreich
Pfizer Corporation Austria Ges.m.b.H.
Tel.: +43 (0)1 521 15-0
Ελλάδα
Pfizer Hellas A.E.
Τηλ: + 30 210 6785 800
Polska
Pfizer Polska Sp. z o.o.
Tel.: + 48 22 335 61 00
España
Pfizer S.A.
Tel: + 34 91 490 99 00
Portugal
Laboratórios Pfizer, Lda.
Tel: + 351 214 235 500
France
Pfizer
Tél: + 33 (0)1 58 07 34 40
România
Pfizer România S.R.L.
Tel: +40 (0)21 207 28 00
66
Ireland
Pfizer Healthcare Ireland
Slovenija
Pfizer Luxembourg SARL, Pfizer, podružnica za
svetovanje s področja farmacevtske dejavnosti,
Ljubljana
Tel: + 386 (0) 1 52 11 400
Tel: 1800 633 363 (toll free)
+44 (0) 1304 616161
Ísland
Icepharma hf.
Simi: +354 540 8000
Slovenská republika
Pfizer Luxembourg SARL, organizačná zložka
Tel: +421-2-3355 5500
Italia
Pfizer Italia S.r.l.
Tel: + 39 06 33 18 21
Suomi/Finland
Pfizer Oy
Puh/Tel: + 358 (0)9 43 00 40
Κύπρος
GEO. PAVLIDES & ARAOUZOS LTD
Τηλ: + 35 722 818 087
Sverige
Pfizer 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
Lietuva
Pfizer Luxembourg SARL filialas Lietuvoje
Tel. +3705 2514000
This leaflet was last approved in.
Detailed information on this medicine is available on the European Medicines Agency web site:
http://www.ema.europa.eu/
67
Source: European Medicines Agency
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