Varenicline

Varenicline is a prescription aid to stopping smoking. It is more effective than a single nicotine replacement product and than bupropion, and it can be combined with counselling. It eases withdrawal and craving and reduces the reward of smoking if the patient lapses. A quit date is set 1 to 2 weeks after starting, and treatment lasts 12 weeks, with a second 12-week course for patients who have stopped smoking.

Classification. Smoking cessation aid, nicotinic receptor partial agonist.

Mechanism. Partial agonist at alpha-4 beta-2 nicotinic acetylcholine receptors, which gives enough dopamine release to reduce craving and withdrawal while blocking nicotine from cigarettes.

Pharmacokinetics. Almost fully absorbed orally, peak in 3 to 4 hours, with or without food. Little metabolism (under 10%); excreted unchanged in urine by filtration and active secretion. Half-life about 24 hours. Steady state in about 4 days.

All regimens are oral with no loading dose.

Smoking cessation, adults (fixed quit date schedule).

• Days 1 to 3: 0.5 mg once daily.
• Days 4 to 7: 0.5 mg twice daily.
• From day 8: 1 mg twice daily.
• Set the quit date for day 8 to 14 (or after 1 week of treatment).
• Duration: 12 weeks. If the patient has stopped smoking, a further 12 weeks may be given.

Smoking cessation, flexible schedule (patients not ready to quit). Start 0.5 mg once daily for 3 days, then 0.5 mg twice daily for 4 days, then 1 mg twice daily; reduce smoking by 50% within 4 weeks, by 75% within 8 weeks, and stop by 12 weeks; continue for a further 12 weeks.

Patients who cannot tolerate nausea. Take 0.5 mg twice daily (a lower maintenance dose).

Dose limits. Severe kidney impairment (creatinine clearance under 30 mL/min): start 0.5 mg once daily, increase to a maximum of 0.5 mg twice daily. End-stage kidney disease on haemodialysis: maximum 0.5 mg once daily. Moderate kidney impairment and liver impairment: no adjustment. Older adults: no adjustment.

Contraindications. Hypersensitivity. Use with caution in epilepsy, psychiatric illness and cardiovascular disease, and avoid in pregnancy and breastfeeding.

Serious adverse effects. Neuropsychiatric events (mood change, agitation, aggression, suicidal thoughts), seizures, hypersensitivity reactions including angioedema, severe skin reactions (Stevens-Johnson syndrome, erythema multiforme), cardiovascular events in people with existing disease (small increase), reduced alcohol tolerance and unusual behaviour, drowsiness that impairs driving.

Common adverse effects. Nausea (about 30%), insomnia, abnormal dreams, headache, constipation, flatulence, vomiting, dry mouth, taste change.

Interactions. No important enzyme interactions. Nicotine replacement given with varenicline increases nausea, headache and dizziness. Alcohol tolerance may fall. Cimetidine and other drugs secreted by the kidney tubule may raise levels slightly. Smoking cessation itself can change levels of clozapine, olanzapine, theophylline and warfarin, so monitor those.

Common prescribing errors. Starting without a quit date; not reducing the dose in severe kidney impairment; not warning about nausea and not advising to take it with food; stopping at the first adverse effect; assuming it is unsafe in psychiatric disease without review; not adjusting clozapine or theophylline after stopping smoking.

Special groups.

• Pregnancy: avoid; use behavioural support and nicotine replacement under review.
• Breastfeeding: avoid.
• Children: not licensed for children and adolescents under 18 years in many regions.
• Older adults: no adjustment.
• Kidney impairment: reduce the dose in severe impairment.
• Liver impairment: no adjustment.

Formulations. Tablets 0.5 mg and 1 mg. Take after eating, with a full glass of water, at about the same times each day; evening dosing should not be too late if it disturbs sleep.

Baseline. Smoking history and dependence (time to first cigarette, cigarettes smoked daily), readiness to quit, psychiatric history, seizure history, cardiovascular disease, kidney function, pregnancy status, medicines list for clozapine, olanzapine, theophylline and warfarin.

Monitoring. Review at 1 to 2 weeks, 4 weeks and at the end of treatment. Ask about mood, behaviour and suicidal thoughts at each visit. Check blood pressure in cardiovascular disease. Recheck levels or doses of clozapine, theophylline and warfarin after smoking stops.

Stopping. A taper is not needed; some clinicians reduce to 0.5 mg twice daily for a week to ease any irritability.

Referral and escalation. Refer to a smoking cessation service for counselling. Stop the drug and seek urgent review for suicidal thoughts, agitation, aggression, seizures, angioedema or a severe skin reaction.