General Information

Chantix (varenicline) is a partial nicotinic acetylcholine receptor agonist, designed to partially activate this system while displacing nicotine at its sites of action in the brain.

Chantix is specifically indicated for use as an aid in smoking cessation.

Chantix is supplied as a capsule for oral administration. The recommended initial regimen utilizes a 1-week dosing titration: 0.5 mg once daily on days 1-3, and 0.5 mg twice daily on days 4-7, followed by 1 mg twice daily for 12 weeks, with responders receiving an additional 12-week treatment course to promote long-term abstinence.

Mechanism of Action

Chantix is an alpha-4 beta-2 neuronal nicotinic acetylcholine receptor agonist. The drug shows high selectiviyty for this receptor subclass, relative to other nicotinic receptors (>500-fold alpha-3 beta-4, >3500-fold alpha-7, >20,000-fold alpha-1 beta gamma delta) or non-nicotinic receptors and transporters (>2000-fold). The drug competitively inhibits the ability of nicotine to bind to and activate the alpha-4 beta-2 receptor. The drug exerts mild agonistic activity at this site, though at a level much lower than nicotine; it is presumed that this activation eases withdrawal symptoms.

Clinical Trial Results

Approval of Chantix was based on six clinical trials, which enrolled a combined 3659 chronic smokers (at least 10 cigarettes per day).

Study 1
This dose-ranging placebo-controlled phase II study was designed to investigate the optimum treatment regimen for the drug. Data from the study indicated that total doses of 1 mg or 2 mg daily both promoted successful smoking cessation.

Study 2
This placebo controlled study enrolled 627 patients, who received 0.5 mg or 1 mg Chantix or placebo twice daily for 12 weeks (both with and without initial 1-week dose titration), with subsequent 40 week observational follow-up. Trial data indicated that 45% of subjects in the low-dose group and 51% in the high dose group had CO-confirmed continuous abstinence from weeks 9 to 12, vs. 12% for placebo. Further, 31% of subjects in each group achieved continuous abstinence from 1 week after the initiation of dosing through the end of treatment, vs. 8% for placebo.

Study 3
This placebo-controlled flexible dosing study enrolled 312 subjects, to investigate the effects of a patient-directed dosing strategy. Subjects received an initial regimen of 0.5 mg twice daily, followed by a patient-adjusted schedule of 0.5 mg once or twice daily (freely adjusted). 69% of subjects titrated to the higher dose at some point during the study; the higher dose was modal for 44% of subjects. 40% of subjects had CO-confirmed continuous abstinence for weeks 9-12, vs. 15% for placebo, and 29% maintained continuous abstinence from the 2 weeks after treatment initiation through the end of treatment, vs. 9% for placebo.

Studies 4 & 5
These identical, active- and placebo-controlled studies enrolled 1022 (Study 4) and 1023 (Study 5) subjects, who received 1 mg Chantix twice daily, 150 mg of the approved smoking cessation aid bupropion sustained-release twice daily, or placebo, for 12 weeks, with subsequent 40 week observational follow-up. In Study 4, subjects receiving Chantix achieved superior CO-confirmed smoking abstinence for weeks 9 through 12 (44%), vs. either bupropion (30%) or placebo (17%). Smoking-abstinence rate for bupropion was superior to placebo. 29% of subjects receiving Chantix were continuously smoking-abstinent from week 2 through the end of treatment, vs. 23% for bupropion and 12% for placebo. In Study 5, superior abstinence for weeks 9-12 was achieved with Chantix (44%), vs. 30% for bupropion and 18% for placebo (bupropion was again superior to placebo). 29% of Chantix subjects maintained abstinence for week 2 through the end of treatment, vs. 21% for bupropion and 11% for placebo.

Long-Term Follow-up
Studies 1-5 all included 40 week follow-up periods, which investigated long-term abstinence rates following a course of treatment. For all studies, subjects receiving Chantix were more likely to maintain abstinence than subjects receiving placebo (Study 2: 19% low dose, 23% high dose, vs. 4% placebo; Study 3: 22% flex. dose, vs. 8% placebo; Study 4: 21% high dose, 16% bupropion, vs. 8% placebo; Study 5: 22% high dose, 14% bupropion, vs. 10% placebo). Abstinence rates were not significantly different for Chantix and bupropion.

Study 6
This open label study enrolled 1927 chronic smokers, and was designed to investigate the efficacy of the drug on promoting long-term smoking abstinence. Subjects received 1 mg Chantix twice daily for 12 weeks in a run-in period; subjects achiving abstinence at the end of this regimen were randomized to a double-blind regimens of either continued Chantix therapy (1 mg twice daily) or placebo for an additional 12 weeks, with subsequent 28 week follow-up. Trial data indicated that continuous abstinence for weeks 13 through 24 was higher for subjects receiving continued Chantix therapy (70%) than for placebo (50%); this superiority was maintained through 28 weeks post treatment (54% vs. 39%).