Varenicline (Champix in Canada; Chantix in the US) is a non-nicotine oral treatment that, like NRT, has been shown to be effective in helping smokers quit.28
In phase 2 and 3 studies, varenicline typically tripled the abstinence rates compared with placebo.94 Varenicline is an α4β2 nicotinic acetylcholine receptor (nAchR) partial agonist. It was discovered that α4β2-containing nAchRs play a key role in mediating addiction to nicotine. By binding to these receptors, varenicline causes nicotine-like effects, leading to relief of craving, restlessness and other withdrawal symptoms.28 In addition, the effects of inhaled nicotine are blocked because the target receptors are already bound by varenicline, which attenuates the rewarding and satisfying effects of nicotine from smoking.95
Varenicline comes as 0.5 mg and 1mg tablets that can be prescribed as bulk tablets or as a user friendly format consisting of a 4 week “Starter Pack” and two 4 week “Continuation Packs” (total 165 tablets).
There are 3 quit methods:
- In the “fixed quit” method, the patient sets a quit date and starts varenicline 1-2 weeks before the date (quit date is day 8 or 16 of varenicline).
- Using the “flexible quit” approach, the patient chooses to quit anywhere between day 8 and 35 of varenicline (during weeks 2 to 5 of therapy).
- The final method is the “gradual quit” approach where the patient aims to be quit by the end of the 12 weeks of treatment, gradually reducing the number of cigarettes smoked per day until quit at week 12. The patient then continues for a further 12 weeks of varenicline twice daily (0.5 or 1 mg dose).
There are 2 dosing options:
- Dosing Option # 1: The patient starts with 0.5 mg tablets once daily for days 1-3 then twice daily for days 4-7. On day 8, the dose increases to 1 mg twice daily for the remainder of the 11 weeks. This option is easier for patient to use the 1 Starter Pack followed by 2 Continuation Packs.
- Dosing Option #2 is recommended for patients who have quit prior to day 8 or are experiencing side effects at the lower dose. After day 7, the patient remains on the 0.5mg dose twice daily. This is easier using the bulk 0.5 mg tablets but if the patient has purchased the Starter/Continuation pack format, although the tablets are not scored, they can be easily split with a tablet splitter.
The patient can continue for the 12-week course or patients who have successfully quit may choose to remain on varenicline for 24 weeks. A 2010 publication by Knight et al. showed a greater 1 year abstinence rate with successfully quit patients who take a further 12 weeks of therapy (27.7%) versus 12 weeks of therapy (22.9%).
There is currently no data for efficacy of a further 12 weeks of treatment in patients who have not successfully quit after 12 weeks of varenicline therapy.
The efficacy of varenicline was demonstrated in five double-blind, placebo-controlled clinical trials (n= 4190). In four 12-week trials, varenicline demonstrated superior efficacy to placebo, as measured by the 4-week continuous quit rate. In these trials, patients were not allowed to use NRT during the drug treatment phase.28
The Evaluating Adverse Events in a Global Smoking Cessation Study (EAGLES) compared the safety and efficacy of varenicline, bupropion, NRT patch and placebo in over 8,000 patients with and without pre-existing psychiatric disorders from 2011-2015 involving 43 centers and 16 countries. In the EAGLES study, varenicline showed superior efficacy to bupropion, nicotine patch and placebo at the end of treatment (9-12 weeks) (varenicline 33.5%, NRT 23.4%, bupropion 22.6%, placebo 12.5%) and follow-up (9-24 weeks) (varenicline 21.8% bupropion 16.2% NRT 15.7%, placebo 9.4%). This was the largest clinical trial of smoking cessation agents compared head-to-head and was a post marketing double blinded, randomized, triple-dummy, placebo-controlled and active-controlled trial.
The use of varenicline in combination with NRT patches shows some differing results. A 2014 study by Koegelenberg et al., the authors concluded that the combination of varenicline and a nicotine patch was more efficacious than varenicline alone in smoking cessation.96 However another 2014 study by Ram et al., involving smokers of >20 cigarettes/day, did not show higher rates of abstinence in varenicline versus varenicline and NRT patch combination at 12 and 24 weeks. In contrast, this same study did show a significantly higher abstinence at 12 and 24 weeks in varenicline and NRT patch in those who smoked >29 cigarettes/day versus varenicline alone.
In 2015, Cheng et al. published a systematic review and meta-analysis on 3 randomized, controlled studies involving 904 patients. Their results showed that both the early and late outcomes were in favour of combination varenicline and NRT patch versus varenicline alone especially if pre-cessation NRT patch is used. Adverse events were similar in both groups except for an increase in skin reactions in the combination group.
Given that varenicline and NRT work on the same receptor, it is unclear how the increased benefit is derived. It is possible that there is not a complete saturation of the nicotinic receptor subtype with varenicline.97
Prescribing considerations – Adverse events/Warnings
In clinical trials with varenicline, the most frequent adverse events were nausea (30%), insomnia (18%), headache (15%) and abnormal dreams (13%). Discontinuation rates due to adverse events in Phase II and III trials were similar to placebo (12 vs. 10%).28
In February 2017, following previous actions from Europe and the FDA, Health Canada removed the Black Box warning of severe neuropsychiatric side effects (depression, mood, agitation, hostility, and suicide related events). This was in light of the results of the EAGLES study. In patients without pre-existing psychiatric illness, varenicline was not found to have an increased incidence of neuropsychiatric side effects compared to placebo (varenicline 1.3%, 2.2% bupropion, 2.5% nicotine patch and 2.4% placebo). In patients with pre-existing psychiatric disorders, there were more reported adverse psychiatric events in each group than in the non pre-existing psychiatric group. However, the neuropsychiatric events reported in the varenicline treated group were no different than placebo (varenicline 6.5%, 6.7% bupropion, 5.2% in nicotine patch and 4.9% in placebo). The labelling for varenicline still lists serious adverse events/warnings such as mood changes, psychosis, hallucinations, paranoia, delusions, homicidal ideation and aggression.
When prescribing patients varenicline, frequent follow-up is recommended when the patient first starts the varenicline, each time the dosage is increased, and then frequently until the patient quits with continued follow-up until the end of the 12 (or 24) week course of therapy.
Bupropion is a non-nicotine oral treatment for smoking cessation originally developed as an antidepressant. Its precise mechanism of action is unknown; however, it is a weak inhibitor of dopamine and noradrenaline uptake and has also been shown to antagonize nAchR function.98 Bupropion can be used alone or in conjunction with NRT. Prior to prescribing bupropion it is recommended that consideration be given to using NRT alone.99
In a double-blind clinical trial, bupropion (50 and 300 mg/day) was shown to be significantly more effective than placebo, as measured by the 4-week abstinence rate. In addition, bupropion (7 weeks at 300 mg/day) was more effective than placebo in helping patients maintain continuous abstinence through 6 months of the study.99
Prescribing considerations – Warnings
There have been clinical trial and post-marketing reports with SSRIs and newer anti-depressants, including bupropion, of severe agitation-type events (e.g., hostility, aggression) coupled with self-harm or harm to others. Rigorous clinical monitoring for suicidal ideation and other behavioural changes is recommended.99
Bupropion should not be prescribed over 300 mg/day due to the risk of seizures.99 The most common adverse events were dry mouth (11%) and insomnia (31%).