Drugs

, Volume 69, Issue 10, pp 1319–1338

Varenicline

A Novel Pharmacotherapy for Smoking Cessation
Review Article

Abstract

Varenicline is an orally administered small molecule with partial agonist activity at the α4β2 nicotinic acetylcholine receptor. Varenicline was approved by both the US FDA and the European Medicines Agency of the EU in 2006 as an aid to smoking cessation. Subsequently, varenicline has been approved in over 80 other countries.

Varenicline is almost entirely absorbed following oral administration, and absorption is unaffected by food, smoking or the time of day. Varenicline undergoes only minimal metabolism and approximately 90% of the drug is excreted in the urine unchanged. Varenicline has a mean elimination half-life after repeated administration of approximately 24 hours in smokers. The area under the plasma concentration-time curve is increased in patients with moderate or severe renal failure. No clinically relevant varenicline-drug interactions have been identified.

In two identical, randomized, double-blind, phase III clinical trials in healthy, motivated-to-quit, mainly Caucasian smokers aged 18–75 years in the US, 12 weeks of treatment with varenicline 1 mg twice daily was associated with significantly higher abstinence rates over weeks 9–12 than sustained-release bupropion 150 mg twice daily or placebo. In a separate phase III trial, an additional 12 weeks of treatment in smokers achieving abstinence in the first 12 weeks was associated with greater abstinence through to week 52 than placebo treatment. Varenicline treatment was also associated with significantly higher rates of abstinence than placebo treatment in randomized, double-blind, clinical trials in smokers in China, Japan, Korea, Singapore, Taiwan and Thailand. In a randomized, open-label, multi-national, phase III trial, varenicline treatment was associated with a significantly higher rate of abstinence than transdermal nicotine-replacement therapy. In these trials, varenicline treatment was associated with lower urge to smoke and satisfaction from smoking in relapsers than placebo or active comparators.

In the two US phase III trials, 12 weeks of treatment with varenicline 1 mg twice daily had an acceptable safety and tolerability profile. Nausea and abnormal dreams were the most common adverse events that occurred in more varenicline than placebo recipients. The incidence and prevalence of nausea were greatest in weeks 1 and 2 of treatment, and declined thereafter. The prevalence of early adverse effects can be reduced by individual dose titration. Adverse events associated with varenicline therapy have been reported in post-marketing surveillance, including neuropsychiatric events such as depressed mood, agitation, changes in behaviour, suicidal ideation and suicide. Currently, it is unclear whether the association of varenicline therapy with these adverse events is causal, coincidental or related to smoking cessation.

Given the greater efficacy of varenicline compared with other pharmacotherapies, and the high risk of morbidity and mortality associated with continued smoking, varenicline is a valuable pharmacological aid to smoking cessation.

Supplementary material

40265_2012_69101319_MOESM1_ESM.pdf (144 kb)
Supplementary material, approximately 148 KB.

References

  1. 1.
    Mathers CD, Loncar D. Projections of global mortality and burden of disease from 2002 to 2030. PLoS Med 2006 Nov; 3(11): e442PubMedCrossRefGoogle Scholar
  2. 2.
    Doll R, Peto R, Boreham J, et al. Mortality in relation to smoking: 50 years’ observations on male British doctors. BMJ 2004 Jun 26; 328(7455): 1519PubMedCrossRefGoogle Scholar
  3. 3.
    Shearer J, Shanahan M. Cost effectiveness analysis of smoking cessation interventions. Aust N Z J Public Health 2006 Oct; 30(5): 428–34PubMedCrossRefGoogle Scholar
  4. 4.
    Warner KE. Cost effectiveness of smoking-cessation therapies: interpretation of the evidence and implications for coverage. Pharmacoeconomics 1997 Jun; 11(6): 538–49PubMedCrossRefGoogle Scholar
  5. 5.
    Hughes JR, Stead LF, Lancaster T. Antidepressants for smoking cessation. Cochrane Database Syst Rev 2007 Jan 24; (1): CD000031Google Scholar
  6. 6.
    Stead L, Perera R, Bullen C, et al. Nicotine replacement therapy for smoking cessation. Cochrane Database Syst Rev 2008 Jan 23; (1): CD000146Google Scholar
  7. 7.
    Cahill K, Stead LF, Lancaster T. Nicotine receptor partial agonists for smoking cessation. Cochrane Database Syst Rev 2007 Jan 24; (1): CD006103Google Scholar
  8. 8.
    US Department of Health and Human Services. The health consequences of smoking: nicotine addiction: a report of the Surgeon General. Rockville (MD): US Department of Health and Human Services, 1988Google Scholar
  9. 9.
    Jarvis MJ. Why people smoke. BMJ 2004 Jan 31; 328(7434): 277–9PubMedCrossRefGoogle Scholar
  10. 10.
    Di Chiara G. Role of dopamine in the behavioural actions of nicotine related to addiction. Eur J Pharmacol 2000 Mar 30; 393(1–3): 295–314PubMedCrossRefGoogle Scholar
  11. 11.
    Maskos U, Molles BE, Pons S, et al. Nicotine reinforcement and cognition restored by targeted expression of nicotinic receptors. Nature 2005 Jul 7; 436(7047): 103–7PubMedCrossRefGoogle Scholar
  12. 12.
    Tapper AR, McKinney SL, Nashmi R, et al. Nicotine activation of α4* receptors: sufficient for reward, tolerance, and sensitization. Science 2004 Nov 5; 306(5698): 1029–32PubMedCrossRefGoogle Scholar
  13. 13.
    Picciotto MR, Zoli M, Rimondini R, et al. Acetylcholine receptors containing the β2 subunit are involved in the reinforcing properties of nicotine. Nature 1998 Jan 8; 391(6663): 173–7PubMedCrossRefGoogle Scholar
  14. 14.
    Whiting PJ, Lindstrom JM. Characterization of bovine and human neuronal nicotinic acetylcholine receptors using monoclonal antibodies. J Neurosci 1988 Sep; 8(9): 3395–404PubMedGoogle Scholar
  15. 15.
    Corringer PJ, Le Novère N, Changeux JP. Nicotinic receptors at the amino acid level. Annu Rev Pharmacol Toxicol 2000; 40: 431–58PubMedCrossRefGoogle Scholar
  16. 16.
    Coe JW, Brooks PR, Vetelino MG, et al. Varenicline: an α4β2 nicotinic receptor partial agonist for smoking cessation. J Med Chem 2005 May 19; 48(10): 3474–7PubMedCrossRefGoogle Scholar
  17. 17.
    Tutka P, Zatonski W. Cytisine for the treatment of nicotine addiction: from a molecule to therapeutic efficacy. Pharmacol Rep 2006 Nov–Dec; 58(6): 777–98PubMedGoogle Scholar
  18. 18.
    Etter JF. Cytisine for smoking cessation: a literature review and a meta-analysis. Arch Intern Med 2006 Aug 14–28; 166(15): 1553–9PubMedCrossRefGoogle Scholar
  19. 19.
    Pfizer Inc. Chantix (varenicline tartrate) US prescribing information [online]. Available from URL: http://www.chantix.com/content/Prescribing_Information.jsp [Accessed 2008 Nov 4]
  20. 20.
    Rollema H, Chambers LK, Coe JW, et al. Pharmacological profile of the α4β2 nicotinic acetylcholine receptor partial agonist varenicline, an effective smoking cessation aid. Neuropharmacology 2007 Mar; 52(3): 985–94PubMedCrossRefGoogle Scholar
  21. 21.
    Mihalak KB, Carroll FI, Luetje CW. Varenicline is a partial agonist at α4β2 and a full agonist at a7 neuronal nicotinic receptors. Mol Pharmacol 2006 Sep; 70(3): 801–5PubMedCrossRefGoogle Scholar
  22. 22.
    Obach RS, Reed-Hagen AE, Krueger SS, et al. Metabolism and disposition of varenicline, a selective α4β2 acetylcholine receptor partial agonist, in vivo and in vitro. Drug Metab Dispos 2006 Jan; 34(1): 121–30PubMedCrossRefGoogle Scholar
  23. 23.
    Faessel HM, Gibbs MA, Clark DJ, et al. Multiple-dose pharmacokinetics of the selective nicotinic receptor partial agonist, varenicline, in healthy smokers. J Clin Pharmacol 2006 Dec; 46(12): 1439–48PubMedCrossRefGoogle Scholar
  24. 24.
    Burstein AH, Fullerton T, Clark DJ, et al. Pharmacokinetics, safety, and tolerability after single and multiple oral doses of varenicline in elderly smokers. J Clin Pharmacol 2006 Nov; 46(11): 1234–40PubMedCrossRefGoogle Scholar
  25. 25.
    Xiao Y, Lv Y, Zhang X, et al. The pharmacokinetic and tolerability profile of varenicline in healthy Chinese volunteers. Int J Clin Pharmacol 2009 Apr; 47(4): 246–54Google Scholar
  26. 26.
    Pfizer Inc. Chantix (varenicline tartrate) European prescribing information [online]. Available from URL: http://www.emea.europa.eu/humandocs/PDFs/EPAR/champix/H-699-PI-en.pdf [Accessed 2008 Nov 4]
  27. 27.
    Faessel HM, Smith BJ, Gibbs MA, et al. Single-dose pharmacokinetics of varenicline, a selective nicotinic receptor partial agonist, in healthy smokers and nonsmokers. J Clin Pharmacol 2006 Sep; 46(9): 991–8PubMedCrossRefGoogle Scholar
  28. 28.
    Feng B, Obach RS, Burstein AH, et al. Effect of human renal cationic transporter inhibition on the pharmacokinetics of varenicline, a new therapy for smoking cessation: an in vitro-in vivo study. Clin Pharmacol Ther 2008 Apr; 83(4): 567–76PubMedCrossRefGoogle Scholar
  29. 29.
    Burstein AH, Clark DJ, O’Gorman M, et al. Lack of pharmacokinetic and pharmacodynamic interactions between a smoking cessation therapy, varenicline, and warfarin: an in vivo and in vitro study. J Clin Pharmacol 2007 Nov; 47(11): 1421–9PubMedCrossRefGoogle Scholar
  30. 30.
    Faessel HM, Burstein AH, Troutman MD, et al. Lack of a pharmacokinetic interaction between a new smoking cessation therapy, varenicline, and digoxin in adult smokers. Eur J Clin Pharmacol 2008 Nov; 64(11): 1101–9PubMedCrossRefGoogle Scholar
  31. 31.
    Hughes JR, Benowitz N, Hatsukami D, et al. Clarification of SRNT workgroup guidelines for measures in clinical trials of smoking cessation therapies. Nicotine Tob Res 2004 Oct; 6(5): 863–4PubMedCrossRefGoogle Scholar
  32. 32.
    Nides M, Oncken C, Gonzales D, et al. Smoking cessation with varenicline, a selective α4β2 nicotinic receptor partial agonist: results from a 7-week, randomized, placebo- and bupropion-controlled trial with 1-year follow-up. Arch Intern Med 2006 Aug 14–28; 166(15): 1561–8PubMedCrossRefGoogle Scholar
  33. 33.
    Oncken C, Gonzales D, Nides M, et al. Efficacy and safety of the novel selective nicotinic acetylcholine receptor partial agonist, varenicline, for smoking cessation. Arch Intern Med 2006 Aug 14–28; 166(15): 1571–7PubMedCrossRefGoogle Scholar
  34. 34.
    Niaura R, Hays JT, Jorenby DE, et al. The efficacy and safety of varenicline for smoking cessation using a flexible dosing strategy in adult smokers: a randomized controlled trial. Curr Med Res Opin 2008 Jul; 24(7): 1931–41PubMedCrossRefGoogle Scholar
  35. 35.
    Nakamura M, Oshima A, Fujimoto Y, et al. Efficacy and tolerability of varenicline, an α4β2 nicotinic acetylcholine receptor partial agonist, in a 12-week, randomized, placebo-controlled, dose-response study with 40-week follow-up for smoking cessation in Japanese smokers. Clin Ther 2007 Jun; 29(6): 1040–56PubMedCrossRefGoogle Scholar
  36. 36.
    Gonzales D, Rennard SI, Nides M, et al. Varenicline, an α4β2 nicotinic acetylcholine receptor partial agonist, vs sustained-release bupropion and placebo for smoking cessation: a randomized controlled trial. JAMA 2006 Jul 5; 296(1): 47–55PubMedCrossRefGoogle Scholar
  37. 37.
    Jorenby DE, Hays JT, Rigotti NA, et al. Efficacy of varenicline, an α4β2 nicotinic acetylcholine receptor partial agonist, vs placebo or sustained-release bupropion for smoking cessation: a randomized controlled trial. JAMA 2006 Jul 5; 296(1): 56–63PubMedCrossRefGoogle Scholar
  38. 38.
    Tonstad S, Tønnesen P, Hajek P, et al. Effect of maintenance therapy with varenicline on smoking cessation: a randomized controlled trial. JAMA 2006 Jul 5; 296(1): 64–71PubMedCrossRefGoogle Scholar
  39. 39.
    Aubin HJ, Bobak A, Britton JR, et al. Varenicline versus transdermal nicotine patch for smoking cessation: results from a randomised open-label trial. Thorax 2008 Aug; 63(8): 717–24PubMedCrossRefGoogle Scholar
  40. 40.
    Tsai ST, Cho HJ, Cheng HS, et al. A randomized, placebo-controlled trial of varenicline, a selective α4β2 nicotinic acetylcholine receptor partial agonist, as a new therapy for smoking cessation in Asian smokers. Clin Ther 2007 Jun; 29(6): 1027–39PubMedCrossRefGoogle Scholar
  41. 41.
    Wang C, Xiao D, Chan KP, et al. Varenicline for smoking cessation: a placebo-controlled, randomized study. Respirology 2009 Apr; 14(3): 384–92PubMedCrossRefGoogle Scholar
  42. 42.
    Fiore MC. US Public Health Service clinical practice guideline: treating tobacco use and dependence. Respir Care 2000 Oct; 45(10): 1200–62PubMedGoogle Scholar
  43. 43.
    Nides M, Glover ED, Reus VI, et al. Varenicline versus bupropion SR or placebo for smoking cessation: a pooled analysis. Am J Health Behav 2008 Nov–Dec; 32(6): 664–75PubMedCrossRefGoogle Scholar
  44. 44.
    Hughes JR, Hatsukami D. Signs and symptoms of tobacco withdrawal. Arch Gen Psychiatry 1986 Mar; 43(3): 289–94PubMedCrossRefGoogle Scholar
  45. 45.
    Cox LS, Tiffany ST, Christen AG. Evaluation of the brief questionnaire of smoking urges (QSU-brief) in laboratory and clinical settings. Nicotine Tob Res 2001 Feb; 3(1): 7–16PubMedCrossRefGoogle Scholar
  46. 46.
    Cappelleri JC, Bushmakin AG, Baker CL, et al. Confirmatory factor analyses and reliability of the modified cigarette evaluation questionnaire. Addict Behav 2007 May; 32(5): 912–23PubMedCrossRefGoogle Scholar
  47. 47.
    West R, Baker CL, Cappelleri JC, et al. Effect of varenicline and bupropion SR on craving, nicotine withdrawal symptoms, and rewarding effects of smoking during a quit attempt. Psychopharmacology (Berl) 2008 Apr; 197(3): 371–7CrossRefGoogle Scholar
  48. 48.
    Patterson F, Jepson C, Strasser AA, et al. Varenicline improves mood and cognition during smoking abstinence. Biol Psychiatry 2009, Jan; 65(2): 144–9PubMedCrossRefGoogle Scholar
  49. 49.
    Williams KE, Reeves KR, Billing Jr CB, et al. A double-blind study evaluating the long-term safety of varenicline for smoking cessation. Curr Med Res Opin 2007 Apr; 23(4): 793–801PubMedCrossRefGoogle Scholar
  50. 50.
    Parsons AC, Shraim M, Inglis J, et al. Interventions for preventing weight gain after smoking cessation. Cochrane Database Syst Rev (Online) 2009; (1): CD006219Google Scholar
  51. 51.
    US Food and Drug Administration. Information for healthcare professionals: Varenicline (marketed as Chantix) [online]. Available from URL: http://www.fda.gov/cder/drug/InfoSheets/HCP/vareniclineHCP.htm [Accessed 2008 Nov 4]
  52. 52.
    Cahill K, Stead L, Lancaster T. A preliminary benefit-risk assessment of varenicline in smoking cessation. Drug Saf 2009; 32(2): 119–35PubMedCrossRefGoogle Scholar
  53. 53.
    Pfizer Inc. Medication guide Chantix® (varenicline) tablets [online]. Available from URL: http://www.pfizer.com/files/products/ppi_chantix.pdf [Accessed 2009 Mar 26]
  54. 54.
    Tonstad S, Davies S, Flammer M, et al. Incidence of depression in randomized, double-blind, placebo-controlled varenicline clinical trials [abstract]. 10th Annual Conference of SRNT Europe; 2008 Sep 23–26; Rome. Available from URL: http://www.srnt.org/meeting/europdf/AbstractBookSRNTEurope2008.pdf [Accessed 2009 May 28]
  55. 55.
    Russ C, Davies S, Flammer M, et al. Incidence of psychiatric adverse events other than depression in randomized, double-blind, placebo-controlled varenicline clinical trials. 10th Annual Conference of SRNT Europe; 2008 Sep 23–26; Rome. Available from URL: http://www.srnt.org/meeting/europdf/AbstractBookSRNTEurope2008.pdf [Accessed 2009 May 28]
  56. 56.
    Stapleton JA, Watson L, Spirling LI, et al. Varenicline in the routine treatment of tobacco dependence: a pre-post comparison with nicotine replacement therapy and an evaluation in those with mental illness. Addiction 2008 Jan; 103(1): 146–54PubMedCrossRefGoogle Scholar
  57. 57.
    McClure JB, Swan GE, Jack L, et al. Mood, side-effects and smoking outcomes among persons with and without probable lifetime depression taking varenicline. J Gen Intern Med 2009 May; 24(5): 563–9PubMedCrossRefGoogle Scholar
  58. 58.
    Evins AE, Goff DC. Varenicline treatment for smokers with schizophrenia: a case series [letter]. J Clin Psychiatry 2008 Jun; 69(6): 1016PubMedCrossRefGoogle Scholar
  59. 59.
    McColl SL, Burstein AH, Reeves KR, et al. Human abuse liability of the smoking cessation drug varenicline in smokers and nonsmokers. Clin Pharmacol Ther 2008 Apr; 83(4): 607–14PubMedCrossRefGoogle Scholar
  60. 60.
    Freedman R. Exacerbation of schizophrenia by varenicline [letter]. Am J Psychiatry 2007 Aug; 164(8): 1269PubMedCrossRefGoogle Scholar
  61. 61.
    Kohen I, Kremen N. Varenicline-induced manic episode in a patient with bipolar disorder. Am J Psychiatry 2007 Aug; 164(8): 1269–70PubMedCrossRefGoogle Scholar
  62. 62.
    Popkin MK. Exacerbation of recurrent depression as a result of treatment with varenicline [letter]. Am J Psychiatry 2008 Jun; 165(6): 774PubMedCrossRefGoogle Scholar
  63. 63.
    Pirmoradi P, Roshan S, Nadeem SS. Neuropsychiatric disturbance after initiation of varenicline in a patient with a history of alcohol abuse and major depression. Am J Health Syst Pharm 2008 Sep 1; 65(17): 1624–6PubMedCrossRefGoogle Scholar
  64. 64.
    Pumariega AJ, Nelson R, Rotenberg L. Varenicline-induced mixed mood and psychotic episode in a patient with a past history of depression. CNS Spectr 2008 Jun; 13(6): 511–4PubMedGoogle Scholar
  65. 65.
    Moore TJ, Cohen MR, Furberg CD. Strong safety signal seen for new varenicline risks [online]. Available from URL: http://www.ismp.org/docs/vareniclineStudy.asp [Accessed 2008 Nov 4]
  66. 66.
    Hauben M, Wilson G, Reich L. A preliminary quantitative analysis of the spontaneous reporting of selected adverse events with chantix in the US FDA adverse event reporting system data base [abstract]. 10th Annual Conference of SRNT Europe; 2008 Sep 23–26; Rome. Available from URL: http://www.srnt.org/meeting/europdf/AbstractBookSRNTEurope2008.pdf [Accessed 2009 May 28]
  67. 67.
    American Psychiatric Association. Diagnostic and statistical manual of mental disorders. 4th ed. Washington, DC: American Psychiatric Association, 1995Google Scholar

Copyright information

© Adis Data Information BV 2009

Authors and Affiliations

  • Carlos Jiménez-Ruiz
    • 1
  • Ivan Berlin
    • 2
  • Thomas Hering
    • 3
  1. 1.Smokers ClinicCommunity of MadridMadridSpain
  2. 2.Department of PharmacologyHôpital Pitié-Salpêtrière-Faculté de Médicine, Université P.&M. Curie-INSERM U894ParisFrance
  3. 3.German Association of PulmonologistsBerlinGermany

Personalised recommendations