What is varenicline (Chantix)?

Varenicline Tartrate (Chantix)

Varenicline tartrate is a nonnicotinic partial agonist of the alpha4beta2 subtype of the nicotinic acetylcholine receptor that partially mimics the effects of nicotine in the brain's reward center while competitively inhibiting the binding of nicotine from cigarettes, making it the most effective single pharmacotherapy option for smoking cessation. 1

Mechanism of Action

• Varenicline binds with high affinity and selectivity to α4β2 neuronal nicotinic acetylcholine receptors, stimulating receptor-mediated activity at a significantly lower level than nicotine while simultaneously blocking nicotine's ability to activate these receptors 2
• This dual mechanism helps reduce cravings and withdrawal symptoms while diminishing the rewarding effects of smoking 3
• Varenicline is highly selective for α4β2 receptors compared to other nicotinic receptors (>500-fold α3β4, >3,500-fold α7, >20,000-fold α1βγδ) 2

Chemical Properties

• Varenicline is administered as the tartrate salt, which is a white to off-white to slightly yellow powder 2
• Chemical name: 7,8,9,10-tetrahydro-6,10-methano-6H-pyrazino[2,3-h]3benzazepine, (2R,3R)-2,3-dihydroxybutanedioate (1:1) 2
• Molecular weight: 361.35 Daltons with molecular formula C13H13N3∙C4H6O6 2
• Highly soluble in water 2

Efficacy

• Varenicline increases the odds of smoking cessation by almost 3-fold compared with placebo (OR, 2.88; 95% CI, 2.40–3.47) 1
• More efficacious than bupropion (OR, 1.59; 95% CI, 1.29–1.96) and single forms of nicotine replacement therapy (OR, 1.57; 95% CI, 1.29–1.91) 1
• The EAGLES randomized clinical trial (n=8,144) showed varenicline-treated patients achieved higher abstinence rates than patients receiving placebo (OR, 3.61), nicotine patch (OR, 1.68), and bupropion (OR, 1.75) 1
• Effective for patients with cancer, showing 40% abstinence at 12 weeks with 84% retention 1
• Also effective for smoking reduction in patients unwilling to quit abruptly but willing to gradually reduce cigarette consumption 1

Dosing and Administration

• Standard treatment regimen begins 1-2 weeks prior to quit date 4
• Dosing schedule: 0.5 mg once daily for days 1-3,0.5 mg twice daily for days 4-7, and 1 mg twice daily for weeks 2-12 4
• Standard treatment duration is 12 weeks, with an option for an additional 12 weeks for those who successfully quit to increase long-term abstinence 4
• No dosage adjustment needed for elderly patients or those with mild to moderate renal impairment 2
• For severe renal impairment (creatinine clearance <30 mL/min), dosage adjustment is required 2

Safety Profile

• Generally well-tolerated with common side effects including nausea (28-29%), insomnia (14%), and abnormal dreams (10-13%) 1
• Nausea is typically mild to moderate and diminishes over time 4
• Extensive studies have examined neuropsychiatric and cardiovascular safety 1
• The EAGLES trial (n=8,144) found no significant increase in neuropsychiatric events for varenicline relative to nicotine patch or placebo 1
• Systematic reviews and meta-analyses have not identified a significant link between varenicline and increased risk of serious cardiovascular adverse events 1
• A 2015 retrospective review of 164,766 individuals found neither varenicline nor bupropion posed an elevated risk of cardiovascular or neuropsychiatric events compared with nicotine replacement therapy 1

Clinical Considerations

• Varenicline is not a controlled substance and shows no evidence of dose-escalation to maintain therapeutic effects 2
• Abrupt discontinuation may be associated with irritability and sleep disturbances in up to 3% of patients, suggesting mild physical dependence not associated with addiction 2
• Oral bioavailability is unaffected by food or time-of-day dosing 2
• Maximum plasma concentrations typically occur within 3-4 hours after oral administration 2, 5
• Steady-state conditions are reached within 4 days of repeated dosing 2
• Varenicline is substantially eliminated by renal glomerular filtration along with active tubular secretion 2

Comparative Effectiveness

• Varenicline appears equally effective as combined treatment with more than one form of nicotine replacement therapy 1
• In long-term follow-up, varenicline shows significantly higher continuous abstinence rates at 52 weeks compared to placebo and bupropion 6, 3
• A relapse-prevention study showed significantly improved continuous abstinence rates at 24 weeks with varenicline relative to placebo (70.5% vs 49.6%) 3