Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2019 Publisher: Pfizer Europe MA EEIG, Boulevard de la Plaine 17, 1050, Bruxelles, Belgium
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
Physiological changes resulting from smoking cessation, with or without treatment with CHAMPIX, may alter the pharmacokinetics or pharmacodynamics of some medicinal products, for which dosage adjustment may be necessary (examples include theophylline, warfarin and insulin). As smoking induces CYP1A2, smoking cessation may result in an increase of plasma levels of CYP1A2 substrates.
Changes in behaviour or thinking, anxiety, psychosis, mood swings, aggressive behaviour, depression, suicidal ideation and behaviour and suicide attempts have been reported in patients attempting to quit smoking with CHAMPIX in the post-marketing experience.
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.
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.
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.
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.
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).
There have been post-marketing reports of hypersensitivity reactions including angioedema in patients treated with varenicline. Clinical signs included swelling of the face, mouth (tongue, lips, and gums), neck (throat and larynx) and extremities. There were rare reports of life-threatening angioedema requiring urgent medical attention due to respiratory compromise. Patients experiencing these symptoms should discontinue treatment with varenicline and contact a health care provider immediately.
There have also been post-marketing reports of rare but severe cutaneous reactions, including Stevens-Johnson Syndrome and Erythema Multiforme in patients using varenicline. As these skin reactions can be life threatening, patients should discontinue treatment at the first sign of rash or skin reaction and contact a healthcare provider immediately.
Based on varenicline characteristics and clinical experience to date, CHAMPIX has no clinically meaningful drug interactions. No dosage adjustment of CHAMPIX or co-administered medicinal products listed below is recommended.
In vitro studies indicate that varenicline is unlikely to alter the pharmacokinetics of compounds that are primarily metabolised by cytochrome P450 enzymes.
Furthermore, since metabolism of varenicline represents less than 10% of its clearance, active substances known to affect the cytochrome P450 system are unlikely to alter the pharmacokinetics of varenicline (see section 5.2) and therefore a dose adjustment of CHAMPIX would not be required.
In vitro studies demonstrate that varenicline does not inhibit human renal transport proteins at therapeutic concentrations. Therefore, active substances that are cleared by renal secretion (e.g. metformin – see below) are unlikely to be affected by varenicline.
Varenicline did not affect the pharmacokinetics of metformin. Metformin had no effect on varenicline pharmacokinetics.
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.
Varenicline did not alter the steady-state pharmacokinetics of digoxin.
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).
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.
Varenicline did not alter the steady-state pharmacokinetics of bupropion.
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.
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).
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.
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.
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.
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.
Very common: Nasopharyngitis
Common: Bronchitis, sinusitis
Uncommon: Fungal infection, viral infection
Rare: Platelet count decreased
Common: Weight increased, decreased appetite, increased appetite
Uncommon: Hyperglycaemia
Rare: Diabetes mellitus, polydipsia
Very common: Abnormal dreams, insomnia
Uncommon: Suicidal ideation, aggression, panic reaction, thinking abnormal, restlessness, mood swings, depression*, anxiety*, hallucinations*, libido increased, libido decreased
Rare: Psychosis, somnambulism, abnormal behaviour, dysphoria, bradyphrenia
Very common: Headache
Common: Somnolence, dizziness, dysgeusia
Uncommon: Seizure, tremor, lethargy, hypoaesthesia
Rare: Cerebrovascular accident, hypertonia, dysarthria, coordination abnormal, hypogeusia, circadian rhythm sleep disorder
Not known: Transient loss of consciousness
Uncommon: Conjunctivitis, eye pain
Rare: Scotoma, scleral discolouration, mydriasis, photophobia, myopia, lacrimation increased
Uncommon: Tinnitus
Uncommon: Myocardial infarction, angina pectoris, tachycardia, palpitations, heart rate increased
Rare: Atrial fibrillation, electrocardiogram ST segment depression, electrocardiogram T wave amplitude decreased
Uncommon: Blood pressure increased, hot flush
Common: Dyspnoea, cough
Uncommon: Upper respiratory tract inflammation, respiratory tract congestion, dysphonia, rhinitis allergic, throat irritation, sinus congestion, upper- airway cough syndrome, rhinorrhoea
Rare: Laryngeal pain, snoring
Very common: Nausea
Common: Gastroesophageal 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
Common: Rash, pruritus
Uncommon: Erythema, acne, hyperhidrosis, night sweats
Rare: Severe cutaneous reactions, including Stevens Johnson Syndrome and Erythema Multiforme, angioedema
Common: Arthralgia, myalgia, back pain
Uncommon: Muscle spasms, musculoskeletal chest pain
Rare: Joint stiffness, costochondritis
Uncommon: Pollakiuria, nocturia
Rare: Glycosuria, polyuria
Uncommon: Menorrhagia
Rare: Vaginal discharge, sexual dysfunction
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 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 Kingdom: Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.
Ireland: Healthcare 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: medsafety@hpra.ie.
Not applicable.
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