Champix 0.5 mg or 1 mg FC tablets

CHAMPIX is indicated as an aid to smoking cessation in patients committed to stop smoking, in addition to a behaviour modification programme, for 12 weeks.

All smoking cessation therapies are more likely to succeed in patients who are motivated to stop smoking and who are provided with additional advice and continuous support. Patients should be treated with CHAMPIX for 12 weeks.

Posology

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

• Days 1 u2013 3: 0,5 mg once daily in the evening
• Days 4 u2013 7: 0,5 mg twice daily
• Day 8 u2013 End of treatment: 1 mg twice daily

The patient should set the date to stop smoking. CHAMPIX dosing should start 1 u2013 2 weeks before this date. Patients who do not succeed in stopping smoking during 12 weeks of initial therapy, or who relapse after treatment, should be encouraged to make another attempt once factors contributing to the failed attempt have been identified and addressed.

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. 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. Patients who cannot tolerate adverse reactions of CHAMPIX may have the dose lowered temporarily or permanently. Dose tapering of CHAMPIX is not required at the end of treatment.

Special populations

Patients with renal insufficiency

No dosage adjustment is necessary for patients with mild (estimated creatinine clearance > 50 mL/min and u2264 80 mL/min) to moderate (estimated creatinine clearance u2265 30 mL/min and u2264 50 mL/min) renal impairment. For patients with severe renal impairment, 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. There is insufficient clinical experience with CHAMPIX in patients with end stage renal disease (see section 5.2).

Patients with hepatic impairment

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

Use 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, medical practitioners should consider the renal status of an elderly patient.

Paediatric population

Safety and effectiveness of CHAMPIX in paediatric patients have not been established; therefore, CHAMPIX is not recommended for use in patients under 18 years of age (see section 5.2).

Method of administration

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

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

Effect of smoking cessation

Physiological changes resulting from smoking cessation, with or without treatment with CHAMPIX, may alter the pharmacokinetics or pharmacodynamics of some medicines, for which dosage adjustment may be necessary (examples include theophylline, warfarin and insulin). However, in post-marketing data there were cases of increased international normalised ratio (INR). INR should be monitored more frequently, and the warfarin dose adjusted while using CHAMPIX, and after discontinuation of CHAMPIX (see section 4.5).

Neuropsychiatric symptoms and suicidality

Serious neuropsychiatric symptoms have been reported in patients being treated with CHAMPIX. These post-marketing reports have included changes in behaviour or thinking, changes in mood (including depression and mania), aggressive behaviour, psychosis, hallucinations, paranoia, delusions, homicidal ideation, hostility, agitation, anxiety, and panic, as well as suicidal ideation, suicide attempt, and completed suicide (see section 4.8 u2013 Post-marketing experience). Some reported cases may have been complicated by the symptoms of nicotine withdrawal in patients who stopped smoking. Depressed mood may be a symptom of nicotine withdrawal. Depression, including suicidal ideation, has been reported in smokers undergoing a smoking cessation attempt without medication. However, some of these symptoms have occurred in patients taking CHAMPIX who continued to smoke. When symptoms were reported, most were during CHAMPIX treatment, but some were following discontinuation of CHAMPIX therapy. These events have occurred in patients with and without pre-existing psychiatric disease; some patients have experienced worsening of their psychiatric illnesses. All patients being treated with CHAMPIX should be observed for neuropsychiatric symptoms or worsening of pre-existing psychiatric illness.

Advise patients and caregivers that the patient should stop taking CHAMPIX and contact a medical practitioner immediately if agitation, depressed mood, changes in behaviour or thinking that are not typical for the patient are observed, or if the patient develops suicidal ideation or suicidal behaviour. In many post-marketing cases, resolution of symptoms after discontinuation of CHAMPIX was reported, although in some cases the symptoms persisted, therefore, ongoing monitoring and supportive care should be provided until symptoms resolve.

Medical practitioners 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 CHAMPIX, patients should discontinue CHAMPIX immediately and contact a medical practitioner for re-evaluation of treatment.

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.

Angioedema and hypersensitivity reactions

There have been post-marketing reports of hypersensitivity reactions including angioedema in patients treated with CHAMPIX (see section 4.8 u2013 Post-marketing experience). Clinical signs included swelling of the face, mouth (tongue, lips, and gums), extremities, and neck (throat and larynx). There were reports of life-threatening angioedema requiring urgent medical attention due to respiratory compromise. Patients should be instructed to discontinue CHAMPIX and immediately seek medical care if they experience these symptoms.

Serious skin reactions

There have been post-marketing reports of serious skin reactions, including Stevens-Johnson Syndrome and Erythema Multiforme in patients using CHAMPIX (see section 4.8 u2013 Post-marketing experience). As these skin reactions can be life-threatening, patients should be instructed to stop taking CHAMPIX and contact their medical practitioner immediately at the first appearance of a skin rash with mucosal lesions or any other signs of hypersensitivity.

Cardiovascular effects

In a smoking cessation trial of patients with stable cardiovascular disease, cardiovascular events were reported more frequently in patients treated with CHAMPIX. A meta-analysis of 15 clinical trials, which included the smoking cessation trial of patients with stable cardiovascular disease, had similar results. Cardiovascular events occurred primarily in patients with known cardiovascular disease. Patients should be instructed to notify their medical practitioners of new or worsening cardiovascular symptoms and to seek immediate medical attention if they experience signs and symptoms of myocardial infarction or stroke.

Based on varenicline characteristics and clinical experience to date, CHAMPIX has no clinically meaningful medicine interactions. No dosage adjustment of CHAMPIX or co-administered medicine listed below is recommended. In vitro studies demonstrate that CHAMPIX 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, CHAMPIX was shown to not induce the activity of cytochrome P450 enzymes 1A2 and 3A4. Therefore, CHAMPIX is unlikely to alter the pharmacokinetics of compounds that are primarily metabolised by cytochrome P450 enzymes.

Furthermore, since metabolism of CHAMPIX represents less than 10 % of its clearance, active substances known to affect the cytochrome P450 system are unlikely to alter the pharmacokinetics of CHAMPIX and therefore a dose adjustment of CHAMPIX would not be required. In vitro studies demonstrate that CHAMPIX does not inhibit human renal transport proteins at therapeutic concentrations. Therefore, medicines that are cleared by renal secretion (e.g. metformin u2013 see below) are unlikely to be affected by CHAMPIX.

In vitro studies demonstrate that active renal secretion of CHAMPIX is mediated by the human organic cation transporter, OCT2. Co-administration with inhibitors of OCT2 does not require a dose adjustment of CHAMPIX as the increase in systemic exposure to varenicline is not expected to be clinically meaningful (see cimetidine interaction below). Furthermore since metabolism of CHAMPIX represents less than 10 % of its clearance, medicines known to affect the cytochrome P450 system are unlikely to alter the pharmacokinetics of CHAMPIX (see section 5.2) and therefore a dose adjustment of CHAMPIX would not be required.

Metformin

CHAMPIX (1 mg twice daily) did not affect the pharmacokinetics of metformin (500 mg twice daily), which is a substrate of the organic cation transporter, OCT2. Metformin had no effect on CHAMPIX pharmacokinetics.

Cimetidine

Co-administration of an OCT2 inhibitor, cimetidine (300 mg four times daily), with CHAMPIX (2 mg single dose) increased the systemic exposure of CHAMPIX by 29 % due to a reduction in CHAMPIX renal clearance. No dosage adjustment is recommended based on concomitant cimetidine administration.

Digoxin

CHAMPIX (1 mg twice daily) did not alter the steady-state pharmacokinetics of digoxin administered as a 0,25 mg daily dose.

Warfarin

CHAMPIX (1 mg twice daily) did not alter the pharmacokinetics of a single 25 mg dose of (R, S)-warfarin. Prothrombin time (INR) was not affected by CHAMPIX. Smoking cessation itself may result in changes to warfarin pharmacokinetics. However, in post-marketing data there were cases of increased INR. INR should be monitored more frequently, and the warfarin dose adjusted while using CHAMPIX, and after discontinuation of CHAMPIX (see section 4.4).

Alcohol

There are limited clinical data on any potential interaction between alcohol and CHAMPIX. There have been post marketing reports of increased intoxicating effects of alcohol in patients treated with CHAMPIX. A causal relationship between these events and CHAMPIX use has not been established. Some cases described unusual and sometimes aggressive behaviour and were often accompanied by amnesia for the events. Advise patients to reduce the amount of alcohol they consume while taking CHAMPIX until they know whether CHAMPIX affects their tolerance for alcohol.

Use with other therapies for smoking cessation

Bupropion

CHAMPIX (1 mg twice daily) did not alter the steady-state pharmacokinetics of bupropion (150 mg twice daily). However, the incidence of nausea was doubled with co-administration.

Nicotine replacement therapy (NRT)

When CHAMPIX (1 mg twice daily) and NRT (transdermal 21 mg/day) were co-administered to smokers (N=24) 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.

Women of childbearing potential

Where therapy is initiated, treatment should be timed such that the course is completed before conception occurs.

Pregnancy

The safety of CHAMPIX in human pregnancy has not been established. The use of CHAMPIX in pregnant women is not recommended.

CHAMPIX was not teratogenic in rats and rabbits at oral doses up to 15 and 30 mg/kg/day, respectively (36 and 50-times the maximum recommended human daily exposure based on AUC at 1 mg BD, respectively).

Breastfeeding

The safety of CHAMPIX during lactation has not been established. Mothers on CHAMPIX should therefore not breastfeed their infants.

Patients should be advised to use caution driving or operating machinery until they know how quitting smoking and/or CHAMPIX may affect them.

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.

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.

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 ( u2265 1/10); common ( u2265 1/100 to < 1/10); uncommon ( u2265 1/1 000 to < 1/100); rare ( u2265 1/10 000 to < 1/1 000); very rare (< 1/10 000). The adverse reactions may also be associated with the underlying disease and/or concomitant medications.

System organ class Frequency Adverse drug reactions

Infections and infestations Very common Nasopharyngitis

Common Bronchitis, sinusitis

Uncommon Fungal infection, viral infection

Blood and lymphatic system disorders Uncommon Decreased platelet count

Metabolism and nutrition disorders Common Increased weight, decreased appetite, increased appetite

Uncommon Anorexia, polydipsia

Psychiatric disorders Very common Abnormal dreams, insomnia

Uncommon Panic reaction, bradyphrenia, abnormal thinking, mood swings, increased libido, decreased libido, dysphoria

Nervous system disorders Very common Headache

Common Somnolence, dizziness, dysgeusia, tremor, lethargy, hypoaesthesia, hypertonia, dysarthria, abnormal coordination

Uncommon Restlessness, hypogeusia, circadian rhythm sleep disorder

Cardiac disorders Uncommon Angina pectoris, tachycardia, palpitations, increased heart rate, atrial fibrillation, electrocardiogram ST segment depression, decreased electrocardiogram T wave amplitude

Vascular disorders Uncommon Increased blood pressure, hot flush

Eye disorders Uncommon Conjunctivitis, eye pain, scotoma, scleral discolouration, mydriasis, photophobia, myopia, increased lacrimation

Ear and labyrinth disorders Uncommon Tinnitus

Respiratory, thoracic and mediastinal disorders Common Dyspnoea, cough

Uncommon Upper respiratory tract inflammation, respiratory tract congestion, dysphonia, allergic rhinitis, throat irritation, sinus congestion, upper airway cough syndrome, hoarseness, rhinorrhoea, pharyngolaryngeal pain, snoring, postnasal drip

Gastrointestinal disorders Very common Nausea

Common Gastroesophageal reflux disease, vomiting, constipation, diarrhoea, abdominal distension, abdominal pain, toothache, dyspepsia, flatulence, dry mouth, stomach discomfort

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

Skin and subcutaneous tissue disorders Common Generalised rash, pruritus

Uncommon Erythema, acne, hyperhidrosis, night sweats

Musculoskeletal and connective tissue disorders Common Arthralgia, myalgia, back pain

Uncommon Muscle spasms, chest wall pain, joint stiffness, costochondritis

Renal and urinary disorders Uncommon Pollakiuria, nocturia, glycosuria, polyuria

Reproductive system and breast disorders Uncommon Menorrhagia, vaginal discharge, sexual dysfunction

General disorders and administration site conditions Common Chest pain, fatigue

Uncommon Chest discomfort, influenza-like illness, pyrexia, asthenia, malaise, feeling cold, cyst

Investigations Common Abnormal liver function test

Uncommon Abnormal semen analysis, increased C-reactive protein, decreased blood calcium

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