varenicline: prescribing information – dosing, contraindications, interactions, side effects

CHAMPIX is indicated for smoking cessation in adults.

Posology

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

Days 1 – 3:
0.5 mg once daily
Days 4 – 7:
0.5 mg twice daily
Day 8 – End of treatment:
1 mg twice daily

The patient should set a date to stop smoking. CHAMPIX dosing should usually start at 1-2 weeks before this date (see section 5.1). Patients should be treated with CHAMPIX for 12 weeks.

For patients who have successfully stopped smoking at the end of 12 weeks, an additional course of 12 weeks treatment with CHAMPIX at 1 mg twice daily may be considered for the maintenance of abstinence (see section 5.1).

A gradual approach to quitting smoking with CHAMPIX should be considered for patients who are not able or willing to quit abruptly. Patients should reduce smoking during the first 12 weeks of treatment and quit by the end of that treatment period. Patients should then continue taking CHAMPIX for an additional 12 weeks for a total of 24 weeks of treatment (see section 5.1).

Patients who are motivated to quit and who did not succeed in stopping smoking during prior CHAMPIX therapy, or who relapsed after treatment, may benefit from another quit attempt with CHAMPIX (see section 5.1).

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

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

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

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

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

For patients with severe renal impairment (estimated creatinine clearance < 30 ml/min), the recommended dose of CHAMPIX is 1 mg once daily. Dosing should begin at 0.5 mg once daily for the first 3 days then increased to 1 mg once daily. Based on insufficient clinical experience with CHAMPIX in patients with end stage renal disease, treatment is not recommended in this patient population (see section 5.2).

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

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

Method of administration

CHAMPIX is for oral use and the tablets should be swallowed whole with water.
CHAMPIX can be taken with or without food

Posology

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

Days 1 – 3:
0.5 mg once daily
Days 4 – 7:
0.5 mg twice daily
Day 8 – End of treatment:
1 mg twice daily

The patient should set a date to stop smoking. CHAMPIX dosing should usually start 1-2 weeks before this date (see section 5.1). Patients should be treated with CHAMPIX for 12 weeks.

For patients who have successfully stopped smoking at the end of 12 weeks, an additional course of 12 weeks treatment with CHAMPIX at 1 mg twice daily may be considered for the maintenance of abstinence (see section 5.1).

A gradual approach to quitting smoking with CHAMPIX should be considered for patients who are not able or willing to quit abruptly. Patients should reduce smoking during the first 12 weeks of treatment and quit by the end of that treatment period. Patients should then continue taking CHAMPIX for an additional 12 weeks for a total of 24 weeks of treatment (see section 5.1).

Patients who are motivated to quit and who did not succeed in stopping smoking during prior CHAMPIX therapy, or who relapsed after treatment, may benefit from another quit attempt with CHAMPIX (see section 5.1).

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

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

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

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

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

For patients with severe renal impairment (estimated creatinine clearance < 30 ml/min), the recommended dose of CHAMPIX is 1 mg once daily. Dosing should begin at 0.5 mg once daily for the first 3 days then increased to 1 mg once daily. Based on insufficient clinical experience with CHAMPIX in patients with end stage renal disease, treatment is not recommended in this patient population (see section 5.2).

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

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

Method of administration

CHAMPIX is for oral use and the tablets should be swallowed whole with water.
CHAMPIX can be taken with or without food

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

Summary of the safety profile

Smoking cessation with or without treatment is associated with various symptoms. For example, dysphoric or depressed mood; insomnia, irritability, frustration or anger; anxiety; difficulty concentrating; restlessness; decreased heart rate; increased appetite or weight gain have been reported in patients attempting to stop smoking. No attempt has been made in either the design or the analysis of the CHAMPIX studies to distinguish between adverse reactions associated with study drug treatment or those possibly associated with nicotine withdrawal. Adverse drug reactions are based on evaluation of data from pre-marketing phase 2-3 studies and updated based on pooled data from 18 placebo-controlled pre- and post-marketing studies, including approximately 5,000 patients treated with varenicline.

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

Tabulated summary of adverse reactions

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

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

Rare
Suicidal ideation, aggression, panic reaction, thinking abnormal, restlessness, mood swings, depression*, anxiety*, hallucinations*, libido increased, libido decreased Psychosis, somnambulism, abnormal behaviour, dysphoria, bradyphrenia Nervous system disorders Very common Headache Common Somnolence, dizziness, dysgeusia Uncommon Seizure, tremor, lethargy, hypoaesthesia Rare

Not known
Cerebrovascular accident, hypertonia, dysarthria, coordination abnormal, hypogeusia, circadian rhythm sleep disorder Transient loss of consciousness

System Organ
Class
Adverse Drug Reactions
Eye disorders
Uncommon
Rare
Conjunctivitis, eye pain
Scotoma, scleral discolouration, mydriasis, photophobia, myopia, lacrimation increased Ear and labyrinth disorders Uncommon Tinnitus Cardiac disorders Uncommon Myocardial infarction, angina pectoris, tachycardia, palpitations, heart rate increased Rare

Atrial fibrillation, electrocardiogram ST segment depression, electrocardiogram T wave amplitude decreased Vascular disorders Uncommon Blood pressure increased, hot flush Respiratory, thoracic and mediastinal disorders Common Uncommon

Rare
Dyspnoea, cough
Upper respiratory tract inflammation, respiratory tract congestion, dysphonia, rhinitis allergic, throat irritation, sinus congestion, upper- airway cough syndrome, rhinorrhoea Laryngeal pain, snoring Gastrointestinal disorders Very common Nausea Common Gastrooesophageal reflux disease, vomiting, constipation, diarrhoea, abdominal distension, abdominal pain, toothache, dyspepsia, flatulence, dry mouth Uncommon

Rare
Haematochezia, gastritis, change of bowel habit, eructation, aphthous stomatitis, gingival pain Haematemesis, abnormal faeces, tongue coated Skin and subcutaneous tissue disorders Common Uncommon Rash, pruritus Erythema, acne, hyperhidrosis, night sweats Rare Severe cutaneous reactions, including Stevens Johnson Syndrome and Erythema Multiforme, angioedema Musculoskeletal and connective tissue disorders Common Uncommon Rare Arthralgia, myalgia, back pain Muscle spasms, musculoskeletal chest pain Joint stiffness, costochondritis Renal and urinary disorders Uncommon Rare Pollakiuria, nocturia Glycosuria, polyuria Reproductive system and breast disorders Uncommon Rare Menorrhagia Vaginal discharge, sexual dysfunction General disorders and administration site conditions Common Chest pain, fatigue Uncommon Rare Chest discomfort, influenza like illness, pyrexia, asthenia, malaise Feeling cold, cyst Investigations Common Liver function test abnormal Rare Semen analysis abnormal, C-reactive protein increased, blood calcium decreased * Frequencies are estimated from a post-marketing, observational cohort study

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

Summary of the safety profile

Smoking cessation with or without treatment is associated with various symptoms. For example, dysphoric or depressed mood; insomnia, irritability, frustration or anger; anxiety; difficulty concentrating; restlessness; decreased heart rate; increased appetite or weight gain have been reported in patients attempting to stop smoking. No attempt has been made in either the design or the analysis of the CHAMPIX studies to distinguish between adverse reactions associated with study drug treatment or those possibly associated with nicotine withdrawal. Adverse drug reactions are based on evaluation of data from pre-marketing phase 2-3 studies and updated based on pooled data from 18 placebo-controlled pre- and post-marketing studies, including approximately 5,000 patients treated with varenicline.

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

Tabulated summary of adverse reactions

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

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

Rare
Suicidal ideation, aggression, panic reaction, thinking abnormal, restlessness, mood swings, depression*, anxiety*, hallucinations*, libido increased, libido decreased Psychosis, somnambulism, abnormal behaviour, dysphoria, bradyphrenia Nervous system disorders Very common Headache Common Somnolence, dizziness, dysgeusia Uncommon Seizure, tremor, lethargy, hypoaesthesia Rare

Not known
Cerebrovascular accident, hypertonia, dysarthria, coordination abnormal, hypogeusia, circadian rhythm sleep disorder Transient loss of consciousness Eye disorders Uncommon Rare Conjunctivitis, eye pain Scotoma, scleral discolouration, mydriasis, photophobia, myopia, lacrimation increased

System Organ
Class
Adverse Drug Reactions
Ear and labyrinth disorders
Uncommon
Tinnitus
Cardiac disorders
Uncommon
Myocardial infarction, angina pectoris, tachycardia, palpitations, heart rate increased Rare Atrial fibrillation, electrocardiogram ST segment depression, electrocardiogram T wave amplitude decreased Vascular disorders Uncommon Blood pressure increased, hot flush Respiratory, thoracic and mediastinal disorders Common Uncommon Rare Dyspnoea, cough Upper respiratory tract inflammation, respiratory tract congestion, dysphonia, rhinitis allergic, throat irritation, sinus congestion, upper- airway cough syndrome, rhinorrhoea Laryngeal pain, snoring Gastrointestinal disorders Very common Nausea Common Gastrooesophageal reflux disease, vomiting, constipation, diarrhoea, abdominal distension, abdominal pain, toothache, dyspepsia, flatulence, dry mouth Uncommon Rare Haematochezia, gastritis, change of bowel habit, eructation, aphthous stomatitis, gingival pain Haematemesis, abnormal faeces, tongue coated Skin and subcutaneous tissue disorders Common Uncommon Rash, pruritus Erythema, acne, hyperhidrosis, night sweats Rare Severe cutaneous reactions, including Stevens Johnson Syndrome and Erythema Multiforme, angioedema Musculoskeletal and connective tissue disorders Common Uncommon Rare Arthralgia, myalgia, back pain Muscle spasms, musculoskeletal chest pain Joint stiffness, costochondritis Renal and urinary disorders Uncommon Rare Pollakiuria, nocturia Glycosuria, polyuria Reproductive system and breast disorders Uncommon Rare Menorrhagia Vaginal discharge, sexual dysfunction General disorders and administration site conditions Common Chest pain, fatigue Uncommon Rare Chest discomfort, influenza like illness, pyrexia, asthenia, malaise Feeling cold, cyst Investigations Common Liver function test abnormal Rare Semen analysis abnormal, C-reactive protein increased, blood calcium decreased * Frequencies are estimated from a post-marketing, observational cohort study Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare

professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

Summary of the safety profile
Smoking cessation with or without treatment is associated with various symptoms. For example, dysphoric or depressed mood; insomnia, irritability, frustration or anger; anxiety; difficulty concentrating; restlessness; decreased heart rate; increased appetite or weight gain have been reported in patients attempting to stop smoking. No attempt has been made in either the design or the analysis of the CHAMPIX studies to distinguish between adverse reactions associated with study drug treatment or those possibly associated with nicotine withdrawal. Adverse drug reactions are based on evaluation of data from pre-marketing phase 2-3 studies and updated based on pooled data from 18 placebo-controlled pre- and post-marketing studies, including approximately 5,000 patients treated with varenicline.
In patients treated with the recommended dose of 1 mg twice daily following an initial titration period the adverse event most commonly reported was nausea (28.6%). In the majority of cases nausea occurred early in the treatment period, was mild to moderate in severity and seldom resulted in discontinuation.
Tabulated summary of adverse reactions
In the table below all adverse reactions, which occurred at an incidence greater than placebo are listed by system organ class and frequency (very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100) and rare (≥ 1/10,000 to < 1/1,000)). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
System Organ
Class
Adverse Drug Reactions
Infections and infestations
Very common
Nasopharyngitis
Common
Bronchitis, sinusitis
Uncommon
Fungal infection, viral infection
Blood and lymphatic system disorders
Rare
Platelet count decreased
Metabolism and nutrition disorders
Common
Weight increased, decreased appetite, increased appetite
Uncommon
Hyperglycaemia
Rare
Diabetes mellitus, polydipsia
Psychiatric disorders
Very common
Abnormal dreams, insomnia
Uncommon
Rare
Suicidal ideation, aggression, panic reaction, thinking abnormal, restlessness, mood swings, depression*, anxiety*, hallucinations*, libido increased, libido decreased Psychosis, somnambulism, abnormal behaviour, dysphoria, bradyphrenia Nervous system disorders Very common Headache Common Somnolence, dizziness, dysgeusia

System Organ
Class
Adverse Drug Reactions
Uncommon
Seizure, tremor, lethargy, hypoaesthesia
Rare
Not known
Cerebrovascular accident, hypertonia, dysarthria, coordination abnormal, hypogeusia, circadian rhythm sleep disorder Transient loss of consciousness Eye disorders Uncommon Rare Conjunctivitis, eye pain Scotoma, scleral discolouration, mydriasis, photophobia, myopia, lacrimation increased Ear and labyrinth disorders Uncommon Tinnitus Cardiac disorders Uncommon Myocardial infarction, angina pectoris, tachycardia, palpitations, heart rate increased Rare Atrial fibrillation, electrocardiogram ST segment depression, electrocardiogram T wave amplitude decreased Vascular disorders Uncommon Blood pressure increased, hot flush Respiratory, thoracic and mediastinal disorders Common Uncommon Rare Dyspnoea, cough Upper respiratory tract inflammation, respiratory tract congestion, dysphonia, rhinitis allergic, throat irritation, sinus congestion, upper- airway cough syndrome, rhinorrhoea Laryngeal pain, snoring Gastrointestinal disorders Very common Nausea Common Gastrooesophageal reflux disease, vomiting, constipation, diarrhoea, abdominal distension, abdominal pain, toothache, dyspepsia, flatulence, dry mouth Uncommon Rare Haematochezia, gastritis, change of bowel habit, eructation, aphthous stomatitis, gingival pain Haematemesis, abnormal faeces, tongue coated Skin and subcutaneous tissue disorders Common Uncommon Rash, pruritus Erythema, acne, hyperhidrosis, night sweats Rare Severe cutaneous reactions, including Stevens Johnson Syndrome and Erythema Multiforme, angioedema Musculoskeletal and connective tissue disorders Common Uncommon Rare Arthralgia, myalgia, back pain Muscle spasms, musculoskeletal chest pain Joint stiffness, costochondritis Renal and urinary disorders Uncommon Rare Pollakiuria, nocturia Glycosuria, polyuria Reproductive system and breast disorders Uncommon Rare Menorrhagia Vaginal discharge, sexual dysfunction General disorders and administration site conditions Common Chest pain, fatigue Uncommon Rare Chest discomfort, influenza like illness, pyrexia, asthenia, malaise Feeling cold, cyst Investigations Common Liver function test abnormal

System Organ
Class
Adverse Drug Reactions
Rare
Semen analysis abnormal, C-reactive protein increased, blood calcium decreased
* Frequencies are estimated from a post-marketing, observational cohort study
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.
.

Effect of smoking cessation

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

Neuropsychiatric symptoms

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

A large randomised, double-blind, active and placebo-controlled study was conducted to compare the risk of serious neuropsychiatric events in patients with and without a history of psychiatric

disorder treated for smoking cessation with varenicline, bupropion, nicotine replacement therapy patch (NRT) or placebo. The primary safety endpoint was a composite of neuropsychiatric adverse events that have been reported in post-marketing experience.

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

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

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

History of psychiatric disorders

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

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

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

Care should be taken with patients with a history of psychiatric illness and patients should be advised accordingly.
Seizures

In clinical trials and post-marketing experience there have been reports of seizures in patients with or without a history of seizures, treated with CHAMPIX. CHAMPIX should be used cautiously in patients with a history of seizures or other conditions that potentially lower the seizure threshold.

Treatment discontinuation

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

Cardiovascular events

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

Hypersensitivity reactions

There have been post-marketing reports of hypersensitivity reactions including angioedema in patients treated with varenicline. Clinical signs included swelling of the face, mouth (tongue, lips, and gums), neck (throat and larynx) and extremities. There were rare reports of life-threatening angioedema requiring urgent medical attention due to respiratory compromise. Patients experiencing these

symptoms should discontinue treatment with varenicline and contact a health care provider immediately.

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.

Excipient information

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

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

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

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

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

Metformin

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

Cimetidine

Co-administration of cimetidine, with varenicline increased the systemic exposure of varenicline by 29% due to a reduction in varenicline renal clearance. No dosage adjustment is recommended based on concomitant cimetidine administration in subjects with normal renal function or in patients with mild to moderate renal impairment. In patients with severe renal impairment, the concomitant use of cimetidine and varenicline should be avoided.

Digoxin

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

Warfarin

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

Alcohol

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

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

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

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

Breast-feeding

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

Fertility

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

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

CHAMPIX may have minor or moderate influence on the ability to drive and use machines.
CHAMPIX may cause dizziness, somnolence and transient loss of consciousness, and therefore may influence the ability to drive and use machines. Patients are advised not to drive, operate complex machinery or engage in other potentially hazardous activities until it is known whether this medicinal product affects their ability to perform these activities.

No cases of overdose were reported in pre-marketing clinical trials.
In case of overdose, standard supportive measures should be instituted as required.
Varenicline has been shown to be dialyzed in patients with end stage renal disease (see section 5.2), however, there is no experience in dialysis following overdose.
5.
PHARMACOLOGICAL PROPERTIES

Pharmacotherapeutic group: Other nervous system drugs; Drugs used in addictive disorders; Drugs used in nicotine dependence, ATC code: N07BA03 Mechanism of action Varenicline binds with high affinity and selectivity at the α4β2 neuronal nicotinic acetylcholine receptors, where it acts as a partial agonist - a compound that has both agonist activity, with lower intrinsic efficacy than nicotine, and antagonist activities in the presence of nicotine.
Electrophysiology studies in vitro and neurochemical studies in vivo have shown that varenicline binds to the α4β2 neuronal nicotinic acetylcholine receptors and stimulates receptor-mediated activity, but at a significantly lower level than nicotine. Nicotine competes for the same human α4β2 nAChR binding site for which varenicline has higher affinity. Therefore, varenicline can effectively block nicotine's ability to fully activate α4β2 receptors and the mesolimbic dopamine system, the neuronal mechanism underlying reinforcement and reward experienced upon smoking. Varenicline is highly selective and binds more potently to the α4β2 receptor subtype (Ki=0.15 nM) than to other common nicotinic receptors (α3β4 Ki=84 nM, α7 Ki= 620 nM, α1βγδ Ki= 3,400 nM), or to non-nicotinic receptors and transporters (Ki > 1µM, except to 5-HT3 receptors: Ki=350 nM).
Pharmacodynamic effects
The efficacy of CHAMPIX in smoking cessation is a result of varenicline's partial agonist activity at the α4β2 nicotinic receptor where its binding produces an effect sufficient to alleviate symptoms of craving and withdrawal (agonist activity), while simultaneously resulting in a reduction of the rewarding and reinforcing effects of smoking by preventing nicotine binding to α4β2 receptors (antagonist activity).
Clinical efficacy and safety
Smoking cessation therapies are more likely to succeed for patients who are motivated to stop smoking and who are provided with additional advice and support.
The efficacy of CHAMPIX in smoking cessation was demonstrated in 3 clinical trials involving chronic cigarette smokers (≥ 10 cigarettes per day). Two thousand six hundred nineteen

(2619) patients received CHAMPIX 1 mg BID (titrated during the first week), 669 patients received bupropion 150 mg BID (also titrated) and 684 patients received placebo.

Comparative clinical studies
Two identical double-blind clinical trials prospectively compared the efficacy of CHAMPIX (1 mg twice daily), sustained release bupropion (150 mg twice daily) and placebo in smoking cessation. In these 52 week duration studies, patients received treatment for 12 weeks, followed by a 40 week non-treatment phase.

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

Pharmacotherapeutic group: Other nervous system drugs; Drugs used in addictive disorders, Drugs used in nicotine dependence, ATC code: N07BA03 Mechanism of action Varenicline binds with high affinity and selectivity at the α4β2 neuronal nicotinic acetylcholine receptors, where it acts as a partial agonist - a compound that has both agonist activity, with lower intrinsic efficacy than nicotine, and antagonist activities in the presence of nicotine.
Electrophysiology studies in vitro and neurochemical studies in vivo have shown that varenicline binds to the α4β2 neuronal nicotinic acetylcholine receptors and stimulates receptor-mediated activity, but at a significantly lower level than nicotine. Nicotine competes for the same human α4β2 nAChR binding site for which varenicline has higher affinity. Therefore, varenicline can effectively block nicotine's ability to fully activate α4β2 receptors and the mesolimbic dopamine system, the neuronal mechanism underlying reinforcement and reward experienced upon smoking. Varenicline is highly selective and binds more potently to the α4β2 receptor subtype (Ki=0.15 nM) than to other common nicotinic receptors (α3β4 Ki=84 nM, α7 Ki= 620 nM, α1βγδ Ki= 3,400 nM), or to non-nicotinic receptors and transporters (Ki > 1µM, except to 5-HT3 receptors: Ki=350 nM).
Pharmacodynamic effects
The efficacy of CHAMPIX in smoking cessation is a result of varenicline's partial agonist activity at the α4β2 nicotinic receptor where its binding produces an effect sufficient to alleviate symptoms of craving and withdrawal (agonist activity), while simultaneously resulting in a reduction of the rewarding and reinforcing effects of smoking by preventing nicotine binding to α4β2 receptors (antagonist activity).
Clinical efficacy and safety
Smoking cessation therapies are more likely to succeed for patients who are motivated to stop smoking and who are provided with additional advice and support.
The efficacy of CHAMPIX in smoking cessation was demonstrated in 3 clinical trials involving chronic cigarette smokers (≥ 10 cigarettes per day). Two thousand six hundred nineteen (2619) patients received CHAMPIX 1 mg BID (titrated during the first week), 669 patients received bupropion 150 mg BID (also titrated) and 684 patients received placebo.
Comparative clinical studies
Two identical double-blind clinical trials prospectively compared the efficacy of CHAMPIX

(1 mg twice daily), sustained release bupropion (150 mg twice daily) and placebo in smoking cessation. In these 52-week duration studies, patients received treatment for 12 weeks, followed by a 40-week non-treatment phase.

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

Pharmacotherapeutic group: Other nervous system drugs; Drugs used in addictive disorders; Drugs used in nicotine dependence, ATC code: N07BA03 Mechanism of action Varenicline binds with high affinity and selectivity at the α4β2 neuronal nicotinic acetylcholine receptors, where it acts as a partial agonist - a compound that has both agonist activity, with lower intrinsic efficacy than nicotine, and antagonist activities in the presence of nicotine.
Electrophysiology studies in vitro and neurochemical studies in vivo have shown that varenicline binds to the α4β2 neuronal nicotinic acetylcholine receptors and stimulates receptor-mediated activity, but at a significantly lower level than nicotine. Nicotine competes for the same human α4β2 nAChR binding site for which varenicline has higher affinity. Therefore, varenicline can effectively block nicotine's ability to fully activate α4β2 receptors and the mesolimbic dopamine system, the neuronal mechanism underlying reinforcement and reward experienced upon smoking. Varenicline is highly selective and binds more potently to the α4β2 receptor subtype (Ki=0.15 nM) than to other common nicotinic receptors (α3β4 Ki=84 nM, α7 Ki= 620 nM, α1βγδ Ki= 3,400 nM), or to non-nicotinic receptors and transporters (Ki > 1µM, except to 5-HT3 receptors: Ki=350 nM).
Pharmacodynamic effects
The efficacy of CHAMPIX in smoking cessation is a result of varenicline's partial agonist activity at the α4β2 nicotinic receptor where its binding produces an effect sufficient to alleviate symptoms of craving and withdrawal (agonist activity), while simultaneously resulting in a reduction of the rewarding and reinforcing effects of smoking by preventing nicotine binding to α4β2 receptors (antagonist activity).

Clinical efficacy and safety

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

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

Comparative clinical studies
Two identical double-blind clinical trials prospectively compared the efficacy of CHAMPIX (1 mg twice daily), sustained release bupropion (150 mg twice daily) and placebo in smoking cessation. In these 52-week duration studies, patients received treatment for 12 weeks, followed by a 40-week non-treatment phase.

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

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