CHAMPIX ^® 0.5 mg film-coated tablets

CHAMPIX ^® 1 mg film-coated tablets

Each film-coated tablet contains 0.5 mg of varenicline (as tartrate).

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

For a full list of excipients, see section 6.1.

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.

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.

CHAMPIX is indicated for smoking cessation in adults.

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:

Patients who cannot tolerate adverse effects of CHAMPIX may have the dose lowered temporarily or permanently to 0.5 mg twice daily.

CHAMPIX tablets should be swallowed whole with water. CHAMPIX can be taken with or without food.

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).

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 patients

CHAMPIX is not recommended for use in children or adolescents below 18 years of age due to insufficient data on safety and efficacy (see section 5.2).

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.

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 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).

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.

There is no clinical experience with CHAMPIX in patients with epilepsy.

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.

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.

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 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.

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.

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.

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.

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).

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

Post-marketing cases of depression, , suicidal ideation and changes in behaviour (such as aggression and irrational behaviour) or thinking, anxiety, psychosis, mood swings have been reported in patients taking varenicline (see section 4.4). There have also been reports of myocardial infarction, hallucinations and hypersensitivity reactions, such as angioedema and of rare but severe cutaneous reactions, including Stevens Johnson Syndrome and Erythema Multiforme in patients taking varenicline (see section 4.4).

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

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

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

Pharmacotherapeutic group: Active substances used in nicotine dependence, ATC code: N07BA03

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

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

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

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:.

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 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:

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

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 Wk 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.

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.

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).

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.

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).

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.

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.

Core Tablet

Cellulose, Microcrystalline

Calcium Hydrogen Phosphate Anhydrous

Croscarmellose Sodium

Silica, Colloidal Anhydrous

Magnesium Stearate

Film Coating

Hypromellose

Titanium Dioxide (E171)

Macrogols

Triacetin

Not applicable.

2 years

This medicinal product does not require any special storage conditions

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

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.

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

Aclar / PVC blisters with aluminium foil backing in a pack containing 140 x 1 mg film-coated tablets in secondary heat sealed card packaging.

Not all pack sizes may be marketed.

No special requirements.

Pfizer Limited

Ramsgate Road

Sandwich

Kent

CT13 9NJ

UK

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

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/1/06/360/002

EU/1/06/360/013

26/09/2006

3rd December 2009

POM

CI13_0