Varenicline is a nicotinic acetylcholine–receptor partial agonist. In the absence of nicotine it has agonist activity (activates nicotinic acetylcholine receptors), whereas in the presence of nicotine it has antagonist activity (blocks nicotine's ability to bind with these receptors). It is thought to work by reducing craving and withdrawal symptoms. As is the case with bupropion, the trial evidence for the effectiveness of varenicline included significant smoking cessation counselling and follow-up support, and exclusion criteria for the trials included broad medical and psychiatric criteria. A comprehensive support and counselling program for smoking cessation should be undertaken on commencement of varenicline. A quit date should be set, and varenicline started one to two weeks before the quit date. The dose should be titrated slowly as follows:

Patients should be followed up 2 to 3 weeks after the original prescription, to monitor progress and provide additional smoking cessation support.

For people with a creatinine clearance of less than 30 mL/min, start with 0.5 mg daily for 3 days, and then increase to 1 mg daily. Avoid using varenicline in patients with end-stage renal disease.

Adverse effects and precautions: A number of adverse effects of varenicline have been reported and, as it is a new drug class, there remains some uncertainty about its safety profile. Nausea was common in clinical trials, with 30% of smokers experiencing nausea. It can also cause drowsiness and dizziness, which may affect a person's ability to drive or operate machinery, so people should be cautious until they know how varenicline affects them. There have been reports of exacerbations of underlying psychiatric illness (eg schizophrenia, bipolar disorder), and careful monitoring is required. It is important to monitor for changes in mood or behaviour following the commencement of varenicline in all patients during the 2 to 3 week follow-up visit, and after treatment is completed. Bupropion and varenicline should not be used in combination, as there are no safety and efficacy data. Combination with nicotine replacement therapy is also not recommended, because of an increased risk of nausea, headache, dyspepsia, fatigue and dizziness.