Varenicline

• varenicline is the first in a new class of drugs which are selective partial nicotinic receptor agonists. It is licensed for smoking cessation in adults and via its mode of action reduces the severity of the quitter's craving and withdrawal symptoms
  • the alpha4beta2 subtype of nAChR play a central role in the pathophysiology of nicotine dependence. This receptor subtype predominates among all other nicotinic receptor subtypes in the brain, and it has a high affinity for nicotine
  • alpha4beta 2 partial agonists - these compounds have appeal over full agonists because they have the potential to mitigate both the positive and negative reinforcement associated with tobacco smoking
    • blocking nicotine-induced reward by having antagonistic blocking effects at alpha4beta2 receptors; whereas in the absence of nicotine, these compounds' agonistic effects should, theoretically, ameliorate nicotine withdrawal
  • NICE have stated that (1):
    • varenicline is recommended within its licensed indications as an option for smokers who have expressed a desire to quit smoking
    • varenicline should normally be prescribed only as part of a programme of behavioural support
• dosing
  • 1mg twice daily following a 1-week titration period as follows:
    • Days 1-3: 0.5mg once daily
    • Days 4-7: 0.5mg twice daily
    • Days 8 onwards: 1mg twice a day
  • the patient should be set a date to stop smoking. Varenicline should be started 1-2 weeks before this date
  • patients who cannot tolerate adverse effects of varenicline may have the dose lowered temporarily or permanently to 0.5mg bd
  • varenicline should be used for 12 weeks in total but if successful a further 12 weeks may be considered (2)
• efficacy:
  • use of varenicline in smoking cessation
    • phase 3 studies with over 2,000 smokers compared varenicline with bupropion and placebo. In one study the quit rate after 12 weeks was 44% v 30% (bupropion) v 18% (placebo) (3)
      • long term abstinence rates, i.e. 12-52 weeks, were approximately 23% v 16% v 9%
      • during this trial participants were given one-to-one counselling at weekly clinic visits throughout the 12 week period
      • note that following 12-week treatment with varenicline, weight gain was an average of 2.29kg - this compared with 1.52kg in the placebo group and 1.32 kg in the bupropion group
  • use of varenicline to maintain abstinence from smoking (3)
    • smokers who achieved abstinence for at least 7 days at the end of 12 weeks of open-label varenicline treatment and were randomized to receive an additional 12 weeks of varenicline treatment showed significantly greater continuous abstinence in weeks 13 to 24 compared with placebo. This advantage was maintained through the nontreatment follow-up to week 52
    • carbon monoxide-confirmed continuous abstinence rate was significantly higher for the varenicline group than for the placebo group for weeks 13 to 24 (70.5% vs 49.6%; odds ratio [OR], 2.48; 95% confidence interval [CI], 1.95-3.16; P<.001) as well as for weeks 13 to 52 (43.6% vs 36.9%; OR, 1.34; 95% CI, 1.06-1.69; P = .02)
    • adverse events reported in the open-label period were mostly mild; no difference in adverse events between varenicline and placebo was observed during the double-blind period
    • the study authors concluded that varenicline may be an efficacious, safe, and well-tolerated agent for maintaining abstinence from smoking
• adverse effects
  • nausea is common and dose titration may help overcome this. Other common side effects are abnormal dreams, headache and insomnia

Notes:

• the European Medicines Agency (EMEA) issued a statement noting that there have been reports of 'suicidal ideation' (thinking about committing suicide) and suicide attempts in people taking Champix (5). This has led to suggested amendments to the SPC concerning varenicline: 'Depressed mood may be a symptom of nicotine withdrawal. Depression, including suicidal ideation and suicide attempt, has been reported in patients undergoing a smoking cessation attempt. These symptoms have also been reported while attempting to quit smoking with Champix. Clinicians should be aware of the possible emergence of significant depressive symptomatology in patients undergoing a smoking cessation attempt, and should advise patients accordingly.'

The summary of product characteristics must be consulted before prescribing this drug.

Reference:

• (1) NICE (July 2007).Varenicline for smoking cessation
• (2) Coventry PCT (January 2007). New Drug Alert : varenicline (Chapmix).
• (3) Jorenby DE et al. Efficacy of varenicline, an alpha4beta2 nicotinic acetylcholine receptor partial agonist, vs placebo or sustained-release bupropion for smoking cessation: a randomized controlled trial. JAMA. 2006 Jul 5;296(1):56-63.
• (4) Tonstad S et al. Effect of maintenance therapy with varenicline on smoking cessation: a randomized controlled trial.1: JAMA. 2006 Jul 5;296(1):64-71
• (5) EMEA (14/12/07).Questions and answers on the EMEA's action regarding the safety of Champix.