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Varenicline ball-and-stick model.png
Clinical data
Trade names Champix, Chantix, others
AHFS/ Monograph
MedlinePlus a606024
License data
  • AU: B3
  • US: C (Risk not ruled out)
Routes of
By mouth
ATC code
Legal status
Legal status
Pharmacokinetic data
Protein binding <20%
Metabolism Limited (<10%)
Elimination half-life 24 hours
Excretion Renal (81–92%)
CAS Number
PubChem CID
Chemical and physical data
Formula C13H13N3
Molar mass 211.267 g/mol
3D model (JSmol)
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Varenicline (trade name Chantix and Champix), is a prescription medication used to treat nicotine addiction. It both reduces cravings for and decreases the pleasurable effects of cigarettes and other tobacco products.

It is a high-affinity partial agonist for the α4β2 nicotinic acetylcholine receptor subtype (nACH) that leads to the release of dopamine in the nucleus accumbens when activated, and therefore, has the capacity to reduce the feelings of craving and withdrawal caused by smoking cessation.[1] In this respect it is similar to cytisine and different from the nicotinic antagonist bupropion and nicotine replacement therapies (NRTs) like nicotine patches and nicotine gum.

Medical uses[edit]

Varenicline is used for smoking cessation. In a 2009 meta-analysis varenicline was found to be more effective than bupropion (odds ratio 1.40) and NRTs (odds ratio 1.56).[2]

A 2013 Cochrane overview and network meta-analysis concluded that varenicline is the most effective medication for tobacco cessation and that smokers were nearly three times more likely to quit on varenicline than with placebo treatment. Varenicline was more efficacious than bupropion or NRT and as effective as combination NRT for tobacco smoking cessation.[3][4]

The United States' Food and Drug Administration (US FDA) has approved the use of varenicline for up to twelve weeks. If smoking cessation has been achieved it may be continued for another twelve weeks.[5]

Varenicline has not been tested in those under 18 years old or pregnant women and therefore is not recommended for use by these groups.[6] Varenicline is considered a class C pregnancy drug, as animal studies have shown no increased risk of congenital anomalies, however, no data from human studies is available.[7] An observational study is currently being conducted assessing for malformations related to varenicline exposure, but has no results yet.[8] An alternate drug is preferred for smoking cessation during breastfeeding due to lack of information and based on the animal studies on nicotine.[9]

Side effects[edit]

Mild nausea is the most common side effect and is seen in approximately 30% of people taking varenicline though this rarely (<3%) results in discontinuation of the medication.[4] Other less common side effects include headache, difficulty sleeping, and nightmares. Rare side effects reported by people taking varenicline compared to placebo include change in taste, vomiting, abdominal pain, flatulence, and constipation. It has been estimated that for every five subjects taking varenicline at maintenance doses, there will be an event of nausea, and for every 24 and 35 treated subjects, there will be an event of constipation and flatulence respectively. Gastrointestinal side-effects lead to discontinuation of the drug in 2% to 8% of people using varenicline.[10][11] Incidence of nausea is dose-dependent: incidence of nausea was higher in people taking a larger dose (30%) versus placebo (10%) as compared to people taking a smaller dose (16%) versus placebo (11%).[12]

Depression and suicide[edit]

In 2007, the US FDA had announced it had received post-marketing reports of thoughts of suicide and occasional suicidal behavior, erratic behavior, and drowsiness among people using varenicline for smoking cessation. In 2009, the US FDA required varenicline to carry a boxed warning that the drug should be stopped if any of these symptoms are experienced.[13]

A 2014 systematic review did not find evidence of an increased suicide risk.[14] Other analyses have reached the same conclusion and found no increased risk of neuropsychiatric side effects with varenicline.[3][4] No evidence for increased risks of cardiovascular events, depression, or self-harm with varenicline versus nicotine replacement therapy has been found in one post-marketing surveillance study.[15]

In 2016 the FDA removed the black box warning.[16] People are still advised to stop the medication if they "notice any side effects on mood, behavior, or thinking."[16][17][18]

Cardiovascular disease[edit]

In June 2011, the US FDA issued a safety announcement that varenicline may be associated with "a small, increased risk of certain cardiovascular adverse events in people who have cardiovascular disease."[19]

A prior 2011 review had found increased risk of cardiovascular events compared with placebo.[20] Expert commentary in the same journal raised doubts about the methodology of the review,[21][22] concerns which were echoed by the European Medicines Agency and subsequent reviews.[23][24] Of specific concern were "the low number of events seen, the types of events counted, the higher drop-out rate in people receiving placebo, the lack of information on the timing of events, and the exclusion of studies in which no-one had an event."

In contrast, multiple recent systematic reviews and meta-analyses have found no increase in overall or serious adverse cardiovascular events (including for individuals at risk of developing cardiovascular disease) associated with varenicline use.[24][25][26][27]


It is recommended that people reduce the amount of alcohol they drink.[28]

Mechanism of action[edit]

Varenicline displays full agonism on α7 nicotinic acetylcholine receptors and is a partial agonist on the α4β2, α3β4, and α6β2 subtypes.[29][30][31] In addition, it is a weak agonist on the α3β2 containing receptors.

Varenicline's partial agonism on the α4β2 receptors rather than nicotine's full agonism produces less effect of dopamine release than nicotine's. This α4β2 competitive binding reduces the ability of nicotine to bind and stimulate the mesolimbic dopamine system - similar to the method of action of buprenorphine in the treatment of opioid addiction.[4]


Most of the active compound is excreted by the kidneys (92–93%). A small proportion is glucuronidated, oxidised, N-formylated or conjugated to a hexose.[32] The elimination half-life is about 24 hours.


Use of Cytisus plant as a smoking substitute during World War II[33] led to use as a cessation aid in eastern Europe and extraction of cytisine.[34] Cytisine analogs led to varenicline at Pfizer.[35][36][37]

Varenicline received a "priority review" by the US FDA in February 2006, shortening the usual 10-month review period to 6 months because of its demonstrated effectiveness in clinical trials and perceived lack of safety issues.[38] The agency's approval of the drug came on May 11, 2006.[5] On August 1, 2006, varenicline was made available for sale in the United States and on September 29, 2006, was approved for sale in the European Union.[39]

See also[edit]


  1. ^ Tashkin, Donald P. (2015). "Smoking Cessation in Chronic Obstructive Pulmonary Disease". Seminars In Respiratory & Critical Care Medicine. 36: 491–507. doi:10.1055/s-0035-1555610. 
  2. ^ Mills EJ, Wu P, Spurden D, Ebbert JO, Wilson K (2009). "Efficacy of pharmacotherapies for short-term smoking abstinance: a systematic review and meta-analysis" (PDF). Harm Reduct J. 6: 25. doi:10.1186/1477-7517-6-25. PMC 2760513Freely accessible. PMID 19761618. 
  3. ^ a b Cahill K, Stevens S, Perera R, Lancaster T (May 2013). "Pharmacological interventions for smoking cessation: an overview and network meta-analysis". Cochrane Database Syst Rev (Systematic Review & Meta-Analysis). 5 (5): CD009329. doi:10.1002/14651858.CD009329.pub2. PMID 23728690. 
  4. ^ a b c d Elrashidi MY, Ebbert JO (June 2014). "Emerging drugs for the treatment of tobacco dependence: 2014 update". Expert Opin Emerg Drug (Review). 19 (2): 243–60. doi:10.1517/14728214.2014.899580. PMID 24654737. 
  5. ^ a b U.S. Food and Drug Administration.FDA Approves Novel Medication for Smoking Cessation. Press release, 11 May 2006.
  6. ^ Coleman, Tim; Chamberlain, Catherine; Davey, Mary-Ann; Cooper, Sue E; Leonardi-Bee, Jo; Coleman, Tim (2015). "Pharmacological interventions for promoting smoking cessation during pregnancy". Reviews. doi:10.1002/14651858.CD010078.pub2. 
  7. ^ Cressman, AM; Pupco, A; Kim, E; Koren, G; Bozzo, P (May 2012). "Smoking cessation therapy during pregnancy". Canadian Family Physician. 58 (5): 525–7. PMC 3352787Freely accessible. PMID 22586193. 
  8. ^ "Varenicline Pregnancy Cohort Study". 
  9. ^ "LactMed". 
  10. ^ Leung, LK; Patafio, FM; Rosser, WW (September 28, 2011). "Gastrointestinal adverse effects of varenicline at maintenance dose: a meta-analysis". BMC Clinical Pharmacology. 11 (1): 15. doi:10.1186/1472-6904-11-15. PMC 3192741Freely accessible. PMID 21955317. 
  11. ^ American Cancer Society. "Cancer Drug Guide: Varenicline". Retrieved 2008-01-19. 
  12. ^ "DailyMed - CHANTIX- varenicline tartrate". 
  13. ^ FDA. "Public Health Advisory: FDA Requires New Boxed Warnings for the Smoking Cessation Drugs Chantix and Zyban". Retrieved 2009-07-01. 
  14. ^ Hughes, JR (8 January 2015). "Varenicline as a Cause of Suicidal Outcomes". Nicotine & tobacco research : official journal of the Society for Research on Nicotine and Tobacco. 18 (1): 2–9. doi:10.1093/ntr/ntu275. PMID 25572451. 
  15. ^ Kotz D, Viechtbauer W, Simpson C, van Schayck OC, West R, Sheikh A (2015). "Cardiovascular and neuropsychiatric risks of varenicline: a retrospective cohort study". Lancet Respir Med (retrospective cohort). 3 (10): 761–768. doi:10.1016/S2213-2600(15)00320-3. PMC 4593936Freely accessible. PMID 26355008. 
  16. ^ a b Commissioner, Office of the. "Safety Alerts for Human Medical Products - Chantix (varenicline) and Zyban (bupropion): Drug Safety Communication - Mental Health Side Effects Revised". Retrieved 20 December 2016. 
  17. ^ Yeung, EYH; Long, S; Bachi, BL; Lee, J; Chao, Y (2015-01-14). "The psychiatric effects of varenicline on patients with depression". BMC Proceedings. 9 (Suppl 1): A31. doi:10.1186/1753-6561-9-S1-A31. ISSN 1753-6561. PMC 4306032Freely accessible. 
  18. ^ Yeung, E; Bachi, B; Long, S; Lee, J; Chao, Y (2015). "Varenicline and Depression: a Literature Review" (PDF). World Journal of Medical Education and Research. 9 (1): 24–29. 
  19. ^ "FDA Drug Safety Communication: Chantix (varenicline) may increase the risk of certain cardiovascular adverse events in patients with cardiovascular disease". 2011-06-16. 
  20. ^ Singh, S; Loke, YK, Spangler, JG, Furberg, CD (Sep 6, 2011). "Risk of serious adverse cardiovascular events associated with varenicline: a systematic review and meta-analysis" (PDF). CMAJ : Canadian Medical Association Journal. 183 (12): 1359–66. doi:10.1503/cmaj.110218. PMC 3168618Freely accessible. PMID 21727225. 
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  22. ^ Samuels, L (Sep 6, 2011). "Varenicline: cardiovascular safety". CMAJ : Canadian Medical Association Journal. 183 (12): 1407–08. doi:10.1503/cmaj.111-2073. PMC 3168639Freely accessible. PMID 21896709. 
  23. ^ "European Medicine Agency confirms positive benefit-risk balance for Champix". 2011-07-21. 
  24. ^ a b Prochaska JJ, Hilton JF (2012). "Risk of cardiovascular serious adverse events associated with varenicline use for tobacco cessation: systematic review and meta-analysis". BMJ (Systematic Review & Meta-Analysis). 344: e2856. doi:10.1136/bmj.e2856. PMC 3344735Freely accessible. PMID 22563098. 
  25. ^ Mills EJ, Thorlund K, Eapen S, Wu P, Prochaska JJ (January 2014). "Cardiovascular events associated with smoking cessation pharmacotherapies: a network meta-analysis". Circulation (Network Meta-Analysis). 129 (1): 28–41. doi:10.1161/CIRCULATIONAHA.113.003961. PMC 4258065Freely accessible. PMID 24323793. 
  26. ^ Pipe AL (October 2014). "Network meta-analysis demonstrates the safety of pharmacotherapy for smoking cessation in cardiovascular patients". Evidence-Based Medicine (Review & Commentary). 19 (5): 193. doi:10.1136/eb-2014-110030. PMID 24917603. 
  27. ^ Rowland K (April 2014). "ACP Journal Club. Review: Nicotine replacement therapy increases CVD events; bupropion and varenicline do not". Annals of Internal Medicine (Review & Commentary). 160 (8): JC2. doi:10.7326/0003-4819-160-8-201404150-02002. PMID 24733219. 
  28. ^ Research, Center for Drug Evaluation and. "Drug Safety and Availability - FDA Drug Safety Communication: FDA updates label for stop smoking drug Chantix (varenicline) to include potential alcohol interaction, rare risk of seizures, and studies of side effects on mood, behavior, or thinking". 
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External links[edit]