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Varenicline

A Review of its Use as an Aid to Smoking Cessation Therapy

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Summary

Abstract

Varenicline is an orally administered α4β2 nicotinic acetylcholine (ACh) receptor partial agonist. It has been approved by the US FDA (Chantix™) and the European Commission (Champix®) for use as an aid to smoking cessation therapy.

Varenicline is an effective and generally well tolerated treatment for use in smokers who want to quit. In two well designed, phase III trials, 12 weeks’ treatment with varenicline was associated with significantly higher continuous abstinence rates at weeks 9–12 than placebo or bupropion sustained-release (SR). In the longer term, continuous abstinence rates for weeks 9 through 52 demonstrated that the odds of remaining abstinent were 2.7 to 3.1 times higher with 12 weeks of varenicline treatment than with placebo; the significant difference between varenicline and bupropion SR was also maintained in the longer term in one trial. Moreover, varenicline appeared to attenuate the urge to smoke, negative affect withdrawal symptoms and the reinforcing effects of smoking. Among those achieving abstinence, an additional 12 weeks of varenicline therapy helped increase the likelihood of long-term abstinence. Thus, varenicline is a valuable new agent for use as an aid to smoking cessation treatment.

Pharmacological Properties

Varenicline has high affinity for α4β2 nicotinic ACh receptors. It demonstrated partial agonist activity, while also antagonising the nicotine response, in both in vitro and in vivo studies.

Varenicline is almost completely absorbed following oral administration, with high systemic availability. Steady state was reached within 4 days following repeat administration of the drug. Varenicline undergoes minimal metabolism and is primarily excreted renally as unchanged drug, with an elimination half-life of approximately 24 hours. The area under the plasma concentration-time curve for varenicline is increased in patients with moderate or severe renal impairment or end-stage renal disease.

Therapeutic Efficacy

The efficacy of 12 weeks’ therapy with oral varenicline 1mg twice daily as an aid to smoking cessation was compared with that of bupropion SR 150mg twice daily and placebo in two randomised, double-blind, multicentre, phase III trials. The carbon monoxide (CO)-confirmed continuous abstinence rates during weeks 9–12 (primary endpoint) and weeks 9–24 were significantly higher in varenicline recipients than in bupropion SR or placebo recipients in both trials. In the longer-term, CO-confirmed continuous abstinence rates for weeks 9 through 52 demonstrated that the odds of remaining abstinent were 2.7 to 3.1 times higher with 12 weeks of varenicline treatment than with placebo. A significant difference favouring varenicline over bupropion SR was seen at this timepoint in one trial, but not in the other trial.

Varenicline ameliorated the urge to smoke and the reinforcing effects of smoking to a significantly greater extent than placebo, although its effect on withdrawal symptoms was less consistent. However, in both trials, varenicline reduced negative affect withdrawal symptoms to a significantly greater extent than placebo.

In a phase III maintenance of abstinence trial, smokers received open-label varenicline 1mg twice daily for 12 weeks; abstinent participants were then randomised in a double-blind fashion to receive varenicline 1mg twice daily or placebo for an additional 12 weeks. An additional 12 weeks of varenicline was significantly more effective than placebo in maintaining abstinence. The CO-confirmed continuous abstinence rate was significantly higher in varenicline than in placebo recipients for weeks 13–24 (primary endpoint) and weeks 13–52.

Tolerability

Twelve weeks’ therapy with varenicline 1mg twice daily was generally well tolerated in the two phase III trials comparing varenicline with bupropion SR and placebo. The most commonly reported adverse events (occurring in more varenicline than placebo recipients) included nausea and abnormal dreams. Among participants who achieved abstinence, mean bodyweight gain between baseline and week 12 (across studies) was 2.37–2.89kg in varenicline recipients, 1.88–2.12kg in bupropion SR recipients and 2.92–3.15kg in placebo recipients. Discontinuation of treatment because of adverse events occurred in 8.6–10.5%, 12.6–15.2% and 7.3–9.0% of participants in the corresponding treatment groups.

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Notes

  1. 1 The use of trade names is for product identification purposes only and does not imply endorsement.

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Authors and Affiliations

  1. Wolters Kluwer Health Adis, 41 Centorian Drive, Private Bag 65901, Mairangi Bay, Auckland, 1311, New Zealand

    Gillian M. Keating & M. Asif A. Siddiqui

  2. Wolters Kluwer Health, Conshohocken, Pennsylvania, USA

    Gillian M. Keating & M. Asif A. Siddiqui

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  1. Gillian M. Keating
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  2. M. Asif A. Siddiqui
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Corresponding author

Correspondence to Gillian M. Keating.

Additional information

Various sections of the manuscript reviewed by: W.C. Bailey, University of Alabama at Birmingham Lung Health Center, Birmingham, Alabama, USA; J. Foulds, Tobacco Dependence Program, School of Public Health, University of Medicine and Dentistry of New Jersey, New Brunswick, New Jersey, USA; P. Hajek, Barts and The London, Queen Mary’s School of Medicine and Dentistry, London, England; D.E. Jorenby, Center for Tobacco Research and Intervention, University of Wisconsin Medical School, Madison, Wisconsin, USA; A. McEwen, Cancer Research UK Health Behaviour Unit, Department of Epidemiology and Public Health, University College London, London, England; M.L. Muramoto, University of Arizona College of Medicine, Program for Nicotine and Tobacco Research, Tucson, Arizona, USA; M.B. Steinberg, Tobacco Dependence Program, School of Public Health, University of Medicine and Dentistry of New Jersey, New Brunswick, New Jersey, USA; S. Tonstad, Department of Preventive Cardiology, Ullevåal University Hospital and University of Oslo, Oslo, Norway.

Data Selection

Sources: Medical literature published in any language since 1980 on ‘varenicline’, identified using MEDLINE and EMBASE, supplemented by AdisBase (a proprietary database of Adis). Additional references were identified from the reference lists of published articles. Bibliographical information, including contributory unpublished data, was also requested from the company developing the drug.

Search strategy: MEDLINE and AdisBase search term was ‘varenicline’. EMBASE search terms were ‘varenicline’ or ‘CP-526555’. Searches were last updated 2 Oct 2006.

Selection: Studies of varenicline in smoking cessation. Inclusion of studies was based mainly on the methods section of the trials. When available, large, well controlled trials with appropriate statistical methodology were preferred. Relevant pharmacodynamic and pharmacokinetic data are also included.

Index terms: Varenicline, smoking cessation, pharmacodynamics, pharmacokinetics, therapeutic use, tolerability.

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Keating, G.M., Siddiqui, M.A.A. Varenicline. CNS Drugs 20, 945–960 (2006). https://doi.org/10.2165/00023210-200620110-00007

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