- Varenicline is a nicotinic receptor partial agonist drug for smoking cessation.
- It can more than double the chances of long-term quitting.
- In a network meta-analysis it was found to be more effective than bupropion, more effective than NRT monotherapy and similar in effect to combination NRT.
- Smokers using varenicline should be advised to report unusual mood changes, depression, behaviour disturbance and suicidal thoughts and if these occur to stop using the medicine.
- The target quit day is in the second week of treatment. Patients who are not ready to quit at that time should continue to use varenicline for several more weeks as the rate of successful cessation rises during the standard 12-week treatment period.
- Longer term use (a second 12-week course) reduces relapse for up to one year in people who have successfully quit at the end of week 12.
Varenicline was developed specifically for smoking cessation. It acts at the nicotinic acetylcholine (ACh) receptor in the reward centre in the brain. Varenicline binds with high affinity at the α4β2 nicotinic ACh receptor, where it acts as a partial agonist to alleviate symptoms of craving and withdrawal. At the same time, if a cigarette is smoked, the drug prevents inhaled nicotine from activating the α4β2 receptor sufficiently to cause the pleasure and reward response. This mechanism may explain why quitting can occur later in a course of treatment with varenicline.
Varenicline at standard dose can increase the chances of successful long-term smoking cessation between two- and three-fold compared with pharmacologically unassisted quit attempts.96,100 A Cochrane meta-analysis of 14 trials of varenicline found it more than doubled sustained abstinence rates at 6 months’ follow-up (risk ratio [RR] 2.27, 95% confidence interval [CI] 2.20 to 2.55).96 In two randomised, double blind clinical trials with identical study designs, varenicline was compared to both bupropion and to placebo.119,120 All three groups received brief behavioural counselling. When the results of these studies were combined in a meta-analysis, the abstinence rate for varenicline was significantly better at 1 year than bupropion (odds ratio [OR] 1.58; 95% CI: 1.22–2.05), and placebo (OR 2.96; 95% CI: 2.12–4.12, p≤0.0001).100
A Cochrane meta-analysis found that varenicline monotherapy is more effective than NRT monotherapy but of similar efficacy to combination NRT (patch and oral form).121
Prolonged use of varenicline has also been shown to reduce relapse. In subjects who stopped smoking at the end of 12 weeks of treatment, an additional 12 weeks of treatment was more beneficial than placebo in maintaining abstinence to the end of treatment and to 1 year from the start of treatment. However, the difference in continuous abstinence for weeks 13–52 between intervention and control groups was modest.122 The benefit appears to be maintained only for the period of use of varenicline. There is limited evidence on the use of varenicline in combination with other therapies. A study examining varenicline plus nicotine patch found a benefit at 26 weeks, but not at 52 weeks.123
There is increasing evidence of the efficacy of varenicline in special populations. Psychiatric comorbidity is common in smokers and varenicline has been found to be safe and effective in smokers with stable current depression or a past history of the same. The odds ratio for abstinence from weeks 9–52 was 2.36 (1.4–3.98) versus placebo.124 There is also evidence that varenicline is safe and effective to assist cessation in people with schizophrenia.125,126
After initial marketing, there were concerns about a possible association between varenicline and mood changes, depression, behaviour disturbance and suicidal ideation. However, subsequent meta-analyses of randomised controlled trials (Tonstad 2010; Gibbons 2013) and observational studies (Thomas 2015; Gibbons 2013; Meyer 2013) did not support a causal link.
The EAGLES trial (Anthenelli 2016) has given further reassurance. This large randomised controlled trial of 8,144 smokers in 16 countries was requested by and designed in conjunction with the US Food and Drug Administration and the European Medicines Agency. Participants were randomised to receive ether varenicline, bupropion, nicotine patch or placebo. Half of the participants in each group had a history of current or past mental illness. The study did not find a significant increase in the rates of moderate-to-severe neuropsychiatric adverse events in those taking varenicline compared to those using placebo, bupropion or nicotine patch, in smokers with or without mental illness. As expected, those with mental illness in all treatment groups had higher rates of neuropsychiatric adverse events than those without mental illness.
Patients quitting smoking with any method are at some risk of increased psychological stress, especially those with a history of mental illness. Clinicians should monitor all patients for these changes, whether taking varenicline or not, and advise prompt reporting of adverse events. The risk does not appear to be greater for those taking varenicline.’
- Tonstad S, Davies S, Flammer M, Russ C, Hughes J. Psychiatric adverse events in randomized, double-blind, placebo-controlled clinical trials of varenicline: a pooled analysis. Drug Saf 2010;33(4):289-301.
- Gibbons RD, Brown CH, Hur K, Davis J, Mann JJ. Suicidal thoughts and behaviour with antidepressant treatment: reanalysis of the randomized placebo-controlled studies of fluoxetine and venlafaxine. Arch Gen Psychiatry 2012;69(6):580-7.
- Thomas KH, Martin RM, Knipe DW, Higgins JP, Gunnell D. Risk of neuropsychiatric adverse events associated with varenicline: systematic review and meta-analysis. BMJ 2015;350:h1109.
- Meyer TE, Taylor LG, Xie S, Graham DJ, Mosholder AD, Williams JR, Money D, Ouellet-Hellstrom RP, Coster TS. Neuropsychiatric events in varenicline and nicotine replacement patch users in the Military Health System. Addition 2013;108(1):203-10.
- Anthenelli RM, Benowitz NL, West R, St Aubin L, McRae T, Lawrence D, Ascher J, Russ C, Krishen A,Evins AE. Neuropsychiatric safety and efficacy of varenicline, bupropion, and nicotine patch in smokers with and without psychiatric disorders (EAGLES): a double-blind, randomised, placebo-controlled clinical trial. www.thelancet.com 2016 http://dx.doi.org/10.1016/S0140-6736(16)30272-0
Nausea is the most common adverse effect of varenicline and was reported in studies of almost 30% of smokers, although less than 3% discontinued treatment due to nausea. Abnormal dreams were also more common in the varenicline group (13.1%) than either the bupropion (5.9%) or placebo groups (3.5%). No clinically meaningful drug interactions have been identified.
Varenicline is excreted almost entirely by the kidneys. For people with creatinine clearance <30 mL/min, the recommended daily dosage is 1 mg/day
(0.5 mg/day for 3 days then increasing to 1 mg/day). Avoid varenicline in end-stage renal failure in favour of other approaches to smoking cessation. Dose adjustment is not routinely required in elderly people or in people with hepatic impairment.131
Availability of varenicline on the PBS
Varenicline is available in Australia on the PBS as short-term adjunctive therapy for nicotine dependence. It can be prescribed for up to 24 weeks of continuous therapy for smoking cessation for smokers who are enrolled in a support and counselling program and who are abstinent at 12 weeks. Making use of the Closing the Gap PBS co-payment can further reduce the cost for Aboriginal and Torres Strait Islander people.
The first script is a starter pack lasting 4 weeks (including dose titration), followed by a maintenance batch for 8 weeks of treatment. There needs to be at least a 6-month gap between commencing varenicline and a subsequent course of bupropion, and vice versa.
A third authority prescription is required for a final 12 weeks of treatment, for those who respond to the first 12 weeks (Table 6). The medicine can be taken whole with water and food to help reduce nausea.
Table 6. Varenicline dosing guidelines
A course of varenicline requires two or three authority prescriptions.
- An initial 4 weeks of treatment (including dose titration)
Smokers should start varenicline and then set a quit date 1–2 weeks after starting, but a later quit date is sometimes appropriate. The exact date can be determined on the basis of perceived effects of the drug. The recommended dose of varenicline is 1 mg twice per day following a 1-week titration as follows:
Days 1–3 0.5 mg once per day
Days 4–7 0.5 mg twice per day
Day 8 on 1 mg twice per day until the end of the 4-week course
- A further 8 weeks of treatment: continue with 1 mg twice per day until the end of the standard treatment week course
- To reduce a replapse, a further 12 weeks of treatment for those who successfully quit at 12 weeks: continue with 1 mg twice per day until the end of the 12-week course
Health professionals should check for updated PBS listings at www.pbs.gov.au
Varenicline is an efficacious smoking cessation treatment. Level I
Varenicline should be recommended to smokers who have been assessed as clinically suitable for this medication and should be provided in combination with counselling. Strength A
- Cahill K, Stead LF, Lancaster T. Nicotine receptor partial agonists for smoking cessation. Cochrane Database Syst Rev. 2012 Apr 18;4:CD006103.
- Aubin H-J, Bobak A, Britton JR, et al. Varenicline versus transdermal nicotine patch for smoking cessation results from a randomised open-label trial. Thorax 2008;63:717–24.
- Wu P, Wilson K, Dimoulas P, Mills EJ. Effectiveness of smoking cessation therapies: a systematic review and meta-analysis. BMC Public Health 2006;6:300.
- Gonzales D, Rennard SI, Nides M, et al. Varenicline, an alpha4beta2 nicotinic acetylcholine receptor partial agonist, vs sustained-release bupropion and placebo for smoking cessation: a randomized controlled trial. J Am Med Assoc 2006;296:47–55.
- Jorenby DE, Hays JT, Rigotti NA, et al. Efficacy of varenicline, an alpha4beta2 nicotinic acetylcholine receptor partial agonist, vs placebo or sustained-release bupropion for smoking cessation. J Am Med Assoc 2006;296:56–63.
- Cahill K, Stevens S, Perera R, Lancaster T. Pharmacological interventions for smoking cessation: an overview and network meta-analysis. Cochrane Database Syst Rev. 2013 May 31;5:CD009329.
- Tonstad S, Tønnesen P, Hajek P, et al. Effect of maintenance therapy with varenicline on smoking cessation: a randomized controlled trial. J Am Med Assoc 2006;296:64–71.
- Ebbert JO, Hatsukami DK, Croghan IT, Schroeder DR, Allen SS, Hays JT, Hurt RD. Combination varenicline and bupropion SR for tobacco-dependence treatment in cigarette smokers: a randomized trial. JAMA 2014 8;311(2):155-63.
- Anthenelli RM, Morris C, Ramey TS, Dubrava SJ, Tsilkos K, Russ C, Yunis C. Effects of varenicline on smoking cessation in adults with stably treated current or past major depression: a randomized trial. Ann Intern Med 2013 159(6):390−400.
- Williams JM, Anthenelli RM, Morris CD, Treadow J, Thompson JR, Yunis C, George TP. A randomized, double-blind, placebo-controlled study evaluating the safety and efficacy of varenicline for smoking cessation in patients with schizophrenia or schizoaffective disorder. J Clin Psychiatry 2012;73(5):654−60.
- Pachas GN, Cather C, Pratt SA, et al. Varenicline for smoking cessation in schizophrenia: safety and effectiveness in a 12-week, open-label trial. J Dual Diagn 2012;8(2):117−125.
- Moore TJ, Furberg CD, Glenmullen J, Maltsberger JT, Singh S. Suicidal behavior and depression in smoking cessation treatments. PLoS ONE 2011;6(11): e27016.
- Gibbons RD, Mann JJ. Varenicline, smoking cessation, and neuropsychiatric adverse events. Am J Psychiatry. 2013 Dec 1;170(12):1460-7.
- Singh S, Loke YK, Spangler JG, Furberg CD. Risk of serious adverse cardiovascular events associated with varenicline: a systematic review and meta-analysis. CMAJ 2011 Jul 4. DOI:10.1503/cmaj.110218.
- Prochaska JJ, Hilton JF. Risk of cardiovascular serious adverse events associated with varenicline use for tobacco cessation: systematic review and meta-analysis. BMJ 2012;344:e2856.
- Pfizer Australia Pty Ltd. Champix product information, 29 July 2009.