4.1. Therapeutic indications

Varenicline is indicated for smoking cessation in adults.

4.2. Posology and method of administration

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. Varenicline dosing should usually start at 1-2 weeks before this date (see section 5.1). Patients should be treated with Varenicline for 12 weeks.

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

A gradual approach to quitting smoking with Varenicline 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 Varenicline 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 Varenicline therapy, or who relapsed after treatment, may benefit from another quit attempt with Varenicline (see section 5.1).

Patients who cannot tolerate adverse reactions of Varenicline 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 dose 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 dose 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 Varenicline 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 Varenicline in patients with end stage renal disease, treatment is not recommended in this patient population (see section 5.2).

Hepatic impairment

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

Paediatric population

Varenicline 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

Varenicline Umedica is for oral use and the tablets should be swallowed whole with water.

Varenicline Umedica can be taken with or without food.

4.3. Contraindications

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

4.4. Special warnings and precautions for use

Effect of smoking cessation

Physiological changes resulting from smoking cessation, with or without treatment with Varenicline Umedica, 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 Varenicline 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 Pharmacodynamics 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).

Varenicline 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 Varenicline Umedica. Varenicline 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 Varenicline 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 Varenicline 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.

Maintenance pack, bottle packs:

The bottle contains a desiccant canister. The desiccant should not be swallowed.

4.5. Interaction with other medicinal products and other forms of interaction

Based on varenicline characteristics and clinical experience to date, Varenicline has no clinically meaningful drug interactions. No dose adjustment of Varenicline 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 Varenicline 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 Varenicline in combination with other smoking cessation therapies have not been studied.

4.6. Fertility, pregnancy and lactation

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 Varenicline should be made taking into account the benefit of breast-feeding to the child and the benefit of Varenicline 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).

4.7. Effects on ability to drive and use machines

Varenicline may have minor or moderate influence on the ability to drive and use machines.

Varenicline 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.

4.8. Undesirable effects

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 Varenicline 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

Suicidal ideation, aggression, panic reaction, thinking abnormal, restlessness, mood swings, depression*, anxiety*, hallucinations*, libido increased, libido decreased

Rare

Psychosis, somnambulism, abnormal behaviour, dysphoria, bradyphrenia

Nervous system disorders

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

Eye disorders

Uncommon

Conjunctivitis, eye pain

Rare

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

Dyspnoea, cough

Uncommon

Upper respiratory tract inflammation, respiratory tract congestion, dysphonia, rhinitis allergic, throat irritation, sinus congestion, upperairway cough syndrome, rhinorrhoea

Rare

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

Haematochezia, gastritis, change of bowel habit, eructation, aphthous stomatitis, gingival pain

Rare

Haematemesis, abnormal faeces, tongue coated

Skin and subcutaneous tissue disorders

Common

Rash, pruritus

Uncommon

Erythema, acne, hyperhidrosis, night sweats

Rare

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

Uncommon

Pollakiuria, nocturia

Rare

Glycosuria, polyuria

Reproductive system and breast disorders

Uncommon

Menorrhagia

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

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 Yellow Card Scheme at: http://www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

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.