- 1. Name of the medicinal product
- 2. Qualitative and quantitative composition
- 3. Pharmaceutical form
- 4. Clinical particulars
- 4.1 Therapeutic indications
- 4.2 Posology and method of administration
- 4.3 Contraindications
- 4.4 Special warnings and precautions for use
- 4.5 Interaction with other medicinal products and other forms of interaction
- 4.6 Fertility, pregnancy and lactation
- 4.7 Effects on ability to drive and use machines
- 4.8 Undesirable effects
- 4.9 Overdose
- 5. Pharmacological properties
- 5.1 Pharmacodynamic properties
- 5.2 Pharmacokinetic properties
- 5.3 Preclinical safety data
- 6. Pharmaceutical particulars
- 6.1 List of excipients
- 6.2 Incompatibilities
- 6.3 Shelf life
- 6.4 Special precautions for storage
- 6.5 Nature and contents of container
- 6.6 Special precautions for disposal and other handling
- 7. Marketing authorisation holder
- 8. Marketing authorisation number(s)
- 9. Date of first authorisation/renewal of the authorisation
- 10. Date of revision of the text
- Legal category
PosologyThe 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|
Patients with renal impairmentNo 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).
Patients with hepatic impairmentNo dosage adjustment is necessary for patients with hepatic impairment (see section 5.2).
Dosing in elderly patientsNo 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 populationThe 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 administrationCHAMPIX is for oral use and the tablets should be swallowed whole with water.CHAMPIX can be taken with or without food
Effect of smoking cessationPhysiological 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 symptomsChanges 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 disordersSmoking 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.
SeizuresIn 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 discontinuationAt 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 eventsIn a trial of patients with stable cardiovascular disease (CVD) certain cardiovascular events were reported more frequently in patients treated with CHAMPIX (see section 5.1). A meta-analysis of 15 clinical trials, which included the smoking cessation trial of patients with stable CVD, had similar results (see section 5.1). 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.
Hypersensitivity reactionsThere 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 reactionsThere 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.
Breast-feedingIt 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.
FertilityThere 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).
Summary of the safety profileSmoking 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.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 1 mg 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 reactions was 11.4% for varenicline compared with 9.7% for placebo. In this group, the discontinuation rates for the most common adverse reactions in varenicline treated patients were as follows: nausea (2.7% vs. 0.6% for placebo), headache (0.6% vs. 1.0% for placebo), insomnia (1.3% vs. 1.2% for placebo), and abnormal dreams (0.2% vs. 0.2% for placebo).
Tabulated summary of adverse reactionsIn 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)). Adverse drug reactions listed in the table below 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. Reported postmarketing adverse reactions are also included for which frequency is not known (cannot be estimated from the available data). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
|System Organ Class||Adverse Drug Reactions|
|Infections and infestations|
|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|
|Not Known||Diabetes mellitus, hyperglycaemia|
|Very common||Abnormal dreams, insomnia|
|Uncommon||Panic reaction, thinking abnormal, restlessness, mood swings, depression*, anxiety*, hallucinations*, libido increased, libido decreased|
|Not Known||Suicidal ideation, psychosis, aggression, abnormal behaviour, somnambulism|
|Nervous system disorders|
|Common||Somnolence, dizziness, dysgeusia|
|Uncommon||Seizure, tremor, lethargy, hypoaesthesia|
|Rare||Cerebrovascular accident, hypertonia, dysarthria, coordination abnormal, hypogeusia, circadian rhythm sleep disorder|
|Uncommon||Conjunctivitis, eye pain|
|Rare||Scotoma, scleral discolouration, mydriasis, photophobia, myopia, lacrimation increased|
|Ear and labyrinth disorders|
|Uncommon||Angina pectoris, tachycardia, palpitations, heart rate increased|
|Rare||Atrial fibrillation, electrocardiogram ST segment depression, electrocardiogram T wave amplitude decreased|
|Not Known||Myocardial infarction|
|Uncommon||Blood pressure increased, hot flush|
|Respiratory, thoracic and mediastinal disorders|
|Uncommon||Upper respiratory tract inflammation, respiratory tract congestion, dysphonia, rhinitis allergic, throat irritation, sinus congestion, upper- airway cough syndrome, rhinorrhoea|
|Rare||Laryngeal pain, snoring|
|Common||Gastrooesophageal reflux disease, vomiting, constipation, diarrhoea, abdominal distension, abdominal pain, toothache, dyspepsia, flatulence, dry mouth|
|Uncommon||Haematochezia, gastritis, change of bowel habit, eructation, aphthous stomatitis, gingival pain|
|Rare||Haematemesis, abnormal faeces, tongue coated|
|Skin and subcutaneous tissue disorders|
|Uncommon||Erythema, acne, hyperhidrosis, night sweats|
|Not Known||Severe cutaneous reactions, including Stevens Johnson Syndrome and Erythema Multiforme, angioedema|
|Musculoskeletal and connective tissue disorders|
|Common||Arthralgia, myalgia, back pain|
|Uncommon||Muscle spasms, musculoskeletal chest pain|
|Rare||Joint stiffness, costochondritis|
|Renal and urinary disorders|
|Reproductive system and breast disorders|
|Rare||Vaginal discharge, sexual dysfunction|
|General disorders and administration site conditions|
|Common||Chest pain, fatigue|
|Uncommon||Chest discomfort, influenza like illness, pyrexia, asthenia, malaise|
|Rare||Feeling cold, cyst|
|Common||Liver function test abnormal|
|Rare||Semen analysis abnormal, C-reactive protein increased, blood calcium decreased|
|* Frequencies are estimated from a post-marketing, observational cohort study|
Reporting of suspected adverse reactionsReporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product.
United KingdomHealthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at www.mhra.gov.uk/yellowcard.
IrelandHealthcare professionals are asked to report any suspected adverse reactions via HPRA Pharmacovigilance, Earlsfort Terrace, IRL - Dublin 2; Tel: +353 1 6764971; Fax: +353 1 6762517. Website: www.hpra.ie; E-mail: email@example.com.
Mechanism of actionVarenicline 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 effectsThe 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 safetyThe 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 studiesTwo 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|
|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 smokingAcross both Studies 1 and 2 during active treatment, craving and withdrawal were significantly reduced in patients randomised to CHAMPIX in comparison with placebo. CHAMPIX also significantly reduced reinforcing effects of smoking that can perpetuate smoking behaviour in patients who smoke during treatment compared with placebo. The effect of varenicline on craving, withdrawal and reinforcing effects of smoking were not measured during the non-treatment long-term follow-up phase.
Maintenance of abstinence studyThe third study assessed the benefit of an additional 12 weeks of CHAMPIX therapy on the maintenance of abstinence. Patients in this study (n=1,927) received open-label CHAMPIX 1 mg twice daily for 12 weeks. Patients who stopped smoking by Week 12 were then randomised to receive either CHAMPIX (1 mg twice daily) or placebo for an additional 12 weeks for a total study duration of 52 weeks.The primary study endpoint was the CO-confirmed continuous abstinence rate from week 13 through week 24 in the double-blind treatment phase. A key secondary endpoint was the continuous abstinence (CA) rate for week 13 through week 52. This study showed the benefit of an additional 12-week treatment with CHAMPIX 1 mg twice daily for the maintenance of smoking cessation compared to placebo; superiority to placebo for CA was maintained through week 52. The key results are summarised in the following table:
Continuous Abstinence Rates in Subjects Treated with Champix versus Placebo
|CHAMPIX n=602||Placebo n=604||Difference (95% CI)||Odds ratio (95% CI)|
|CA* wk 13-24||70.6%||49.8%||20.8% (15.4%, 26.2%)||2.47 (1.95, 3.15)|
|CA* wk 13-52||44.0%||37.1%||6.9% (1.4%,12.5%)||1.35 (1.07, 1.70)|
Flexible quit date between weeks 1 and 5The efficacy and safety of varenicline has been evaluated in smokers who had the flexibility of quitting between weeks 1 and 5 of treatment. In this 24-week study, patients received treatment for 12 weeks followed by a 12 week non-treatment follow up phase. The 4 week (week 9-12) CQR for varenicline and placebo was 53.9% and 19.4%, respectively (difference=34.5%, 95% CI: 27.0% - 42.0%) and the CA week 9-24 was 35.2% (varenicline) vs. 12.7% (placebo) (difference=22.5%, 95% CI: 15.8% - 29.1%). Patients who are not willing or able to set the target quit date within 1-2 weeks, could be offered to start treatment and then choose their own quit date within 5 weeks.
Study in subjects re-treated with CHAMPIX:CHAMPIX was evaluated in a double-blind, placebo-controlled trial of 494 patients who had made a previous attempt to quit smoking with CHAMPIX, and either did not succeed in quitting or relapsed after treatment. Subjects who experienced an adverse event of a concern during previous treatment were excluded. Subjects were randomised 1:1 to CHAMPIX 1 mg twice daily (N=249) or placebo (N=245) for 12 weeks of treatment and followed for up to 40 weeks post-treatment. Patients included in this study had taken CHAMPIX for a smoking-cessation attempt in the past (for a total treatment duration of a minimum of two weeks), at least three months prior to study entry, and had been smoking for at least four weeks. Patients treated with CHAMPIX had a superior rate of CO-confirmed abstinence during weeks 9 through 12 and from weeks 9 through 52 compared to subjects treated with placebo. The key results are summarised in the following table:
Continuous Abstinence Rates in Subjects Treated with Champix versus Placebo
|CHAMPIX n=249||Placebo n=245||Odds ratio (95% CI), p value|
|CA* wk 9-12||45.0%||11.8%||7.08 (4.34, 11.55) p<0.0001|
|CA* wk 9-52||20.1%||3.3%||9.00 (3.97, 20.41) p<0.0001|
Gradual approach to quitting smokingCHAMPIX was evaluated in a 52-week double-blind placebo-controlled study of 1,510 subjects who were not able or willing to quit smoking within four weeks, but were willing to gradually reduce their smoking over a 12 week period before quitting. Subjects were randomised to either CHAMPIX 1 mg twice daily (n=760) or placebo (n=750) for 24 weeks and followed up post-treatment through week 52. Subjects were instructed to reduce the number of cigarettes smoked by at least 50 percent by the end of the first four weeks of treatment, followed by a further 50 percent reduction from week four to week eight of treatment, with the goal of reaching complete abstinence by 12 weeks. After the initial 12-week reduction phase, subjects continued treatment for another 12 weeks. Subjects treated with CHAMPIX had a significantly higher Continuous Abstinence Rate compared with placebo; the key results are summarised in the following table:
Continuous Abstinence Rates in Subjects Treated with Champix versus Placebo
|CHAMPIX n=760||Placebo n=750||Odds ratio (95% CI), p value|
|CA* wk 15-24||32.1%||6.9%||8.74 (6.09, 12.53) p<0.0001|
|CA* wk 21-52||27.0%||9.9%||4.02 (2.94, 5.50) p<0.0001|
|*CA: Continuous Abstinence Rate|
Subjects with cardiovascular diseaseCHAMPIX was evaluated in a randomised, double-blind, placebo-controlled study of subjects with stable, cardiovascular disease (other than, or in addition to, hypertension) that had been diagnosed for more than 2 months. Subjects were randomised to CHAMPIX 1 mg twice daily (n=353) or placebo (n=350) for 12 weeks and then were followed for 40 weeks post-treatment. The 4 week CQR for varenicline and placebo was 47.3% and 14.3%, respectively and the CA week 9-52 was 19.8% (varenicline) vs. 7.4% (placebo). Deaths and serious cardiovascular events were adjudicated by a blinded, committee. The following adjudicated events occurred with a frequency ≥ 1% in either treatment group during treatment (or in the 30-day period after treatment): nonfatal myocardial infarction (1.1% vs. 0.3% for CHAMPIX and placebo, respectively), and hospitalisation for angina pectoris (0.6% vs. 1.1%). During non-treatment follow up to 52 weeks, the adjudicated events included need for coronary revascularisation (2.0% vs. 0.6%), hospitalisation for angina pectoris (1.7% vs. 1.1%), and new diagnosis of peripheral vascular disease (PVD) or admission for a PVD procedure (1.4% vs. 0.6%). Some of the patients requiring coronary revascularisation underwent the procedure as part of management of nonfatal MI and hospitalisation for angina. Cardiovascular death occurred in 0.3% of patients in the CHAMPIX arm and 0.6% of patients in the placebo arm over the course of the 52-week study.A meta-analysis of 15 clinical trials of ≥ 12 weeks treatment duration, including 7002 patients (4190 CHAMPIX, 2812 placebo), was conducted to systematically assess the cardiovascular safety of CHAMPIX. The study in patients with stable cardiovascular disease described above was included in the meta-analysis. The key cardiovascular safety analysis included occurrence and timing of a composite endpoint of Major Adverse Cardiovascular Events (MACE), defined as cardiovascular death, nonfatal MI, and nonfatal stroke. These events included in the endpoint were adjudicated by a blinded, independent committee. Overall, a small number of MACE occurred during treatment in the trials included in the meta-analysis (CHAMPIX 7 [0.17%]; placebo 2 [0.07%]). Additionally, a small number of MACE occurred up to 30 days after treatment (CHAMPIX 13 [0.31%]; placebo 6 [0.21%]). The meta-analysis showed that exposure to CHAMPIX resulted in a hazard ratio for MACE of 2.83 (95% confidence interval from 0.76 to 10.55, p=0.12) for patients during treatment and 1.95 (95% confidence interval from 0.79 to 4.82, p=0.15) for patients up to 30 days after treatment. These are equivalent to an estimated increase of 6.5 MACE events and 6.3 MACE events per 1,000 patient-years, respectively of exposure. The hazard ratio for MACE was higher in patients with cardiovascular risk factors in addition to smoking compared with that in patients without cardiovascular risk factors other than smoking. There were similar rates of all-cause mortality (CHAMPIX 6 [0.14%]; placebo 7 [0.25%]) and cardiovascular mortality (CHAMPIX 2 [0.05%]; placebo 2 [0.07%]) in the CHAMPIX arms compared with the placebo arms in the meta-analysis.
Subjects with mild-moderate chronic obstructive pulmonary disease (COPD)The efficacy and safety of CHAMPIX (1 mg twice daily) for smoking cessation in subjects with mild-moderate COPD was demonstrated in a randomised double-blind placebo-controlled clinical trial. In this 52-week duration study, patients received treatment for 12 weeks, followed by a 40-week non-treatment follow-up phase. The primary endpoint of the study was the CO-confirmed, 4-week Continuous Quit Rate (4W CQR) from week 9 through week 12 and a key secondary endpoint was the Continuous Abstinence (CA) from Week 9 through Week 52. The safety profile of varenicline was comparable to what was reported in other trials in the general population, including pulmonary safety. The results for the 4W CQR (weeks 9 through 12) and CA rate (weeks 9 through 52) are shown in the following table:
|4W CQR||CA Wk 9-52|
|CHAMPIX, (n = 248)||42.3%||18.5%|
|Placebo, (n = 251)||8.8%||5.6%|
|Odds ratio (CHAMPIX vs. Placebo)||8.40 p < 0.0001||4.04 p < 0.0001|
Study in subjects with a history of major depressive disorder:The efficacy of varenicline was confirmed in a randomised placebo-controlled trial in 525 subjects with a history of major depression in the past two years or under current stable treatment. The cessation rates in this population were similar to those reported in the general population. Continuous abstinence rate between weeks 9-12 was 35.9% in the varenicline treatment group versus 15.6% in the placebo group (OR 3.35 (95% CI 2.16-5.21)) and between weeks 9-52 was 20.3% versus 10.4% respectively (OR 2.36 (95% CI 1.40-3.98)). The most common adverse events (≥ 10%) in subjects taking varenicline were nausea (27.0% vs. 10.4% on placebo), headache (16.8% vs. 11.2%), abnormal dreams (11.3% vs. 8.2%), insomnia (10.9% vs. 4.8%) and irritability (10.9% vs. 8.2%). Psychiatric scales showed no differences between the varenicline and placebo groups and no overall worsening of depression, or other psychiatric symptoms, during the study in either treatment group.
Study in subjects with stable schizophrenia or schizoaffective disorder:Varenicline safety and tolerability was assessed in a double-blind study of 128 smokers with stable schizophrenia or schizoaffective disorder, on antipsychotic medication, randomised 2:1 to varenicline (1 mg twice daily) or placebo for 12 weeks with 12-week non-drug follow-up. The most common adverse events in subjects taking varenicline were nausea (23.8% vs. 14.0% on placebo), headache (10.7% vs. 18.6% on placebo) and vomiting (10.7% vs. 9.3% on placebo). Among reported neuropsychiatric adverse events, insomnia was the only event reported in either treatment group in ≥ 5% of subjects at a rate higher in the varenicline group than in placebo (9.5% vs. 4.7%). Overall, there was no worsening of schizophrenia in either treatment group as measured by psychiatric scales and there were no overall changes in extra-pyramidal signs. In the varenicline group compared to placebo, a higher proportion of subjects reported suicidal ideation or behaviour prior to enrolment (lifetime history) and after the end of active treatment period (on Days 33 to 85 after the last dose of drugs). During the active treatment period, the incidence of suicide-related events was similar between the varenicline-treated and the placebo-treated subjects (11 vs. 9.3%, respectively). The percentage of subjects with suicide-related events in the active treatment phase compared to post-treatment phase was unchanged in the varenicline group; in the placebo group, this percentage was lower in the post-treatment phase. Although there were no completed suicides, there was one suicidal attempt in a varenicline-treated subject whose lifetime history included several similar attempts. The limited data available from this single smoking cessation study are not sufficient to allow for definitive conclusions to be drawn about the safety in patients with schizophrenia or schizoaffective disorder.Neuropsychiatric Safety Study in Subjects with and without a History of Psychiatric Disorder: Varenicline was evaluated in a randomised, double-blind, active and placebo-controlled study that included subjects with a history of psychiatric disorder (psychiatric cohort, N=4074) and subjects without a history of psychiatric disorder (non-psychiatric cohort, N=3984). Subjects aged 18-75 years, smoking 10 or more cigarettes per day were randomised 1:1:1:1 to varenicline 1 mg BID, bupropion SR 150 mg BID, nicotine replacement therapy patch (NRT) 21 mg/day with taper or placebo for a treatment period of 12 weeks; they were then followed for another 12 weeks post-treatment. The primary safety endpoint was a composite of the following neuropsychiatric (NPS) adverse events: severe events of anxiety, depression, feeling abnormal, or hostility, and/or moderate or severe events of agitation, aggression, delusions, hallucinations, homicidal ideation, mania, panic, paranoia, psychosis, suicidal ideation, suicidal behaviour or completed suicide.The following table shows the rates of the composite NPS adverse event primary endpoint by treatment group and the risk differences (RDs) (95% CI) vs placebo in the non-psychiatric cohort. In addition, the table shows the subset of the composite NPS AE endpoint of severe intensity:
|Number of Patients Treated||990||989||1006||999|
|Composite NPS AE Primary Endpoint, n (%)||13 (1.3)||22 (2.2)||25 (2.5)||24 (2.4)|
|RD (95% CI) vs Placebo||-1.28 (-2.40, -0.15)||-0.08 (-1.37, 1.21)||-0.21 (-1.54,1.12)|
|Composite NPS AE Endpoint of severe intensity n (%)||1 (0.1)||4 (0.4)||3 (0.3)||5 (0.5)|
|Non-psychiatric Cohort N=3984|
|Varenicline N=990n (%)||Bupropion N=989n (%)||NRTN=1006n (%)||Placebo N=999n (%)|
|Suicidal behaviour and/or ideation||7 (0.7)||4 (0.4)||3 (0.3)||7 (0.7)|
|Suicidal behaviour||0||0||1 (0.1)||1 (0.1)|
|Suicidal ideation||7 (0.7)||4 (0.4)||3 (0.3)||6 (0.6)|
|During follow up|
|Suicidal behaviour and/or ideation||3 (0.4)||2 (0.2)||3 (0.4)||4 (0.5)|
|Suicidal behaviour||0||1 (0.1)||0||0|
|Suicidal ideation||3 (0.4)||2 (0.2)||3 (0.4)||4 (0.5)|
|Number of Patients Treated||1026||1017||1016||1015|
|Composite NPS AE Primary Endpoint, n (%)||67 (6.5)||68 (6.7)||53 (5.2)||50 (4.9)|
|RD (95% CI) vs Placebo||1.59 (-0.42, 3.59)||1.78 (-0.24, 3.81)||0.37 (-1.53, 2.26)|
|NPS AE Primary Endpoint Components n (%):AnxietyaDepressionaFeeling abnormalaHostilityaAgitationbAggressionbDelusionsbHallucinationsbHomicidal ideationbManiabPanicbParanoiabPsychosisbSuicidal behaviourbSuicidal ideationbCompleted suicideb|
5 (0.5) 6 (0.6) 0 0 25 (2.4) 14 (1.4) 1 (0.1) 5 (0.5) 0 7 (0.7) 7 (0.7) 1 (0.1) 4 (0.4) 1 (0.1) 5 (0.5) 0
4 (0.4) 4 (0.4) 1 (0.1) 0 29 (2.9) 9 (0.9) 1 (0.1) 4 (0.4) 0 9 (0.9) 16 (1.6) 0 2 (0.2) 1 (0.1) 2 (0.2) 0
6 (0.6) 7 (0.7) 0 0 21 (2.1) 7 (0.7) 1 (0.1) 2 (0.2) 0 3 (0.3) 13 (1.3) 0 3 (0.3) 0 3 (0.3) 0
2 (0.2) 6 (0.6) 0 0 22 (2.2) 8 (0.9) 0 2 (0.2) 0 6 (0.6) 7 (0.7) 2 (0.2) 1 (0.1) 1 (0.1) 2 (0.2) 0
|Composite NPS AE Endpoint of severe intensity n (%)||14 (1.4)||14 (1.4)||14 (1.4)||13 (1.3)|
|Varenicline N=1026n (%)||Bupropion N=1017n (%)||NRTN=1016n (%)||Placebo N=1015n (%)|
|Suicidal behaviour and/or ideation||27 ( 2.7)||15 ( 1.5)||20 (2.0)||25 ( 2.5)|
|Suicidal behaviour||0||1 (0.1)||0||2 (0.2)|
|Suicidal ideation||27 ( 2.7)||15 ( 1.5)||20 (2.0)||25 ( 2.5)|
|During follow up|
|Suicidal behaviour and/or ideation||14 (1.7)||4 (0.5)||9 (1.1)||11 (1.4)|
|Suicidal behaviour||1 (0.1)||0||1 (0.1)||1 (0.1)|
|Suicidal ideation||14 (1.7)||4 (0.5)||9 (1.1)||11 (1.4)|
|Non-psychiatric Cohort||Psychiatric Cohort|
|CA 9-12 n/N (%)|
|Varenicline||382/1005 (38.0%)||301/1032 (29.2%)|
|Bupropion||261/1001 (26.1%)||199/1033 (19.3%)|
|NRT||267/1013 (26.4%)||209/1025 (20.4%)|
|Placebo||138/1009 (13.7%)||117/1026 (11.4%)|
|Treatment Comparisons: Odds ratio (95% CI), p value|
|Varenicline vs Placebo||4.00 (3.20, 5.00), P<0.0001||3.24 (2.56, 4.11) , P<0.0001|
|Bupropion vs Placebo||2.26 (1.80, 2.85) , P<0.0001||1.87 (1.46, 2.39) , P<0.0001|
|NRT vs Placebo||2.30 (1.83, 2.90) , P<0.0001||2.00 (1.56, 2.55) , P<0.0001|
|Varenicline vs Bupropion||1.77 (1.46, 2.14) , P<0.0001||1.74 (1.41, 2.14) , P<0.0001|
|Varenicline vs NRT||1.74 (1.43, 2.10) , P<0.0001||1.62 (1.32, 1.99) , P<0.0001|
|CA 9-24 n/N (%)|
|Varenicline||256/1005 (25.5%)||189/1032 (18.3%)|
|Bupropion||188/1001 (18.8%)||142/1033 (13.7%)|
|NRT||187/1013 (18.5%)||133/1025 (13.0%)|
|Placebo||106/1009 (10.5%)||85/1026 (8.3%)|
|Treatment Comparisons: Odds ratio (95% CI), p value|
|Varenicline vs Placebo||2.99 (2.33, 3.83), P<0.0001||2.50 (1.90, 3.29) , P<0.0001|
|Bupropion vs Placebo||2.00 (1.54, 2.59), P<0.0001||1.77 (1.33, 2.36) , P<0.0001|
|NRT vs Placebo||1.96 (1.51, 2.54), P<0.0001||1.65 (1.24, 2.20), P=0.0007|
|Varenicline vs Bupropion||1.49 (1.20, 1.85) P=0.0003||1.41 (1.11, 1.79), P=0.0047|
|Varenicline vs NRT||1.52 (1.23, 1.89), P=0.0001||1.51 (1.19, 1.93), P=0.0008|
Neuropsychiatric Safety Meta-analyses and Observational Studies:Analyses of clinical trial data did not show evidence of an increased risk of serious neuropsychiatric events with varenicline compared to placebo. In addition, independent observational studies have not supported an increased risk of serious neuropsychiatric events in patients treated with varenicline compared to patients prescribed nicotine replacement therapy (NRT) or bupropion. Analyses of Clinical Trials: A meta-analysis of 5 randomised, double blind, placebo controlled trials, including 1907 patients (1130 varenicline, 777 placebo), was conducted to assess suicidal ideation and behaviour as reported on the Columbia-Suicide Severity Rating Scale (C-SSRS). This meta-analysis included one trial (N=127) in patients with a history of schizophrenia or schizoaffective disorder and another trial (N=525) in patients with a history of depression. The results showed no increase in the incidence of suicidal ideation and/or behaviour in patients treated with varenicline compared to patients treated with placebo, as shown in the table below. Of the 55 patients who reported suicidal ideation or behaviour, 48 (24 varenicline, 24 placebo) were from the two trials that enrolled patients with a history of schizophrenia/ schizoaffective disorder, or of depression. Few patients reported these events in the other three trials (4 varenicline, 3 placebo).Number of Patients and Risk Ratio for Suicidal Ideation and/or Behaviour Reported on C-SSRS from a Meta-Analysis of 5 Clinical Trials Comparing Varenicline to Placebo:
|Patients with suicidal ideation and/or behaviour* [n (%)]**||28 (2.5)||27 (3.5)|
|Patient-years of exposure||325||217|
|Risk Ratio # (RR; 95% CI)||0.79 (0.46, 1.36)|
|* Of these, one patient in each treatment arm reported suicidal behaviour ** Patients with events up to 30 days after treatment; % are not weighted by study # RR of incidence rates per 100 patient years|
Psychiatric Adverse Events Occurring in ≥ 1% of Patients from Pooled Data from 18 Clinical Trials:
|Anxiety disorders and symptoms||253 (5.0)||206 (6.0)|
|Depressed mood disorders and disturbances||179 (3.5)||108 (3.1)|
|Mood disorders and disturbances NEC*||116 (2.3)||53 (1.5)|
|* NEC = Not Elsewhere Classified Counts (percentages) corresponds to the number of patients reporting the event|
AbsorptionMaximum 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.
DistributionVarenicline 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.
BiotransformationVarenicline 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.
EliminationThe 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 linearityVarenicline exhibits linear kinetics when given as single (0.1 to 3 mg) or repeated 1 to 3 mg/day doses.
Pharmacokinetics in special patient populationsThere are no clinically meaningful differences in varenicline pharmacokinetics due to age, race, gender, smoking status, or use of concomitant medicinal products, as demonstrated in specific pharmacokinetic studies and in population pharmacokinetic analyses.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).Patients with renal impairment: Varenicline pharmacokinetics were unchanged in subjects with mild renal impairment (estimated creatinine clearance > 50 ml/min and ≤ 80 ml/min). In patients with moderate renal impairment (estimated creatinine clearance ≥ 30 ml/min and ≤ 50 ml/min), varenicline exposure increased 1.5-fold compared with subjects with normal renal function (estimated creatinine clearance > 80 ml/min). In subjects with severe renal impairment (estimated creatinine clearance < 30 ml/min), varenicline exposure was increased 2.1-fold. In subjects with end-stage-renal disease (ESRD), varenicline was efficiently removed by haemodialysis (see section 4.2). Elderly: The pharmacokinetics of varenicline in elderly patients with normal renal function (aged 65-75 years) is similar to that of younger adult subjects (see section 4.2). For elderly patients with reduced renal function please refer to section 4.2.Paediatric population: Single and multiple-dose pharmacokinetics of varenicline have been investigated in pediatric patients aged 12 to 17 years old (inclusive) and were approximately dose-proportional over the 0.5 mg to 2 mg daily dose range studied. Steady-state systemic exposure in adolescent patients of bodyweight > 55 kg, as assessed by AUC (0-24), was comparable to that noted for the same doses in the adult population. When 0.5 mg BID was given, steady-state daily exposure of varenicline was, on average, higher (by approximately 40%) in adolescent patients with bodyweight ≤ 55 kg compared to that noted in the adult population. Efficacy and safety has not been demonstrated in the paediatric population below 18 years of age and no recommendation on a posology can be made (see section 4.2).
Maintenance packsPCTFE / PVC blisters with aluminium foil backing in a pack containing 28 x 0.5 mg film-coated tablets in secondary heat sealed card packaging.PCTFE / PVC blisters with aluminium foil backing in a pack containing 56 x 0.5 mg film-coated tablets in secondary heat sealed card packaging.PVC blisters with aluminium foil backing in a pack containing 28 x 0.5 mg film-coated tablets in secondary heat sealed card packaging.PVC blisters with aluminium foil backing in a pack containing 56 x 0.5 mg film-coated tablets in secondary heat sealed card packaging.High-density polyethylene (HDPE) blue white tablet container with polypropylene child resistant closure and an aluminium foil / polyethylene induction seal containing 56 x 0.5 mg film-coated tabletsPCTFE / PVC blisters with aluminium foil backing in a pack containing 28 x 1 mg film-coated tablets in secondary heat sealed card packaging.PCTFE / PVC blisters with aluminium foil backing in a pack containing 56 x 1 mg film-coated tablets in secondary heat sealed card packaging.PCTFE / PVC blisters with aluminium foil backing in a pack containing 28 x 1 mg film-coated tablets in a carton.PCTFE / PVC blisters with aluminium foil backing in a pack containing 56 x 1 mg film-coated tablets in a carton.PCTFE / PVC blisters with aluminium foil backing in a pack containing 112 x 1 mg film-coated tablets in a carton.PCTFE / PVC blisters with aluminium foil backing in a pack containing 140 x 1 mg film-coated tablets in a carton.PVC blisters with aluminium foil backing in a pack containing 28 x 1 mg film-coated tablets in secondary heat sealed card packaging.PVC blisters with aluminium foil backing in a pack containing 56 x 1 mg film-coated tablets in secondary heat sealed card packaging.PVC blisters with aluminium foil backing in a pack containing 28 x 1 mg film-coated tablets in a carton.PVC blisters with aluminium foil backing in a pack containing 56 x 1 mg film-coated tablets in a carton.PVC blisters with aluminium foil backing in a pack containing 112 x 1 mg film-coated tablets in a carton.PVC blisters with aluminium foil backing in a pack containing 140 x 1 mg film-coated tablets in a carton.High-density polyethylene (HDPE) blue white tablet container with polypropylene child resistant closure and an aluminium foil / polyethylene induction seal containing 56 x 1 mg film-coated tabletsNot all pack sizes may be marketed.
Ref: CI 32_0
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