Varenicline

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.

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.

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.

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. Varenicline should be used cautiously in patients with a history of seizures or other conditions that potentially lower the seizure threshold.

A moderate amount of data on pregnant women indicated no malformative or foetal/neonatal toxicity of varenicline.

Animal studies have shown reproductive toxicity. As a precautionary measure, it is preferable to avoid the use of varenicline during pregnancy.

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.

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.

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.

Summary of adverse reactions

In the list 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.

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, upper- airway cough syndrome, rhinorrhoea

Rare: Laryngeal pain, snoring

Gastrointestinal disorders

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

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.