|Trade names||Champix, Chantix, others|
|Elimination half-life||24 hours|
|Chemical and physical data|
|Molar mass||211.267 g·mol−1|
|3D model (JSmol)|
|(what is this?)|
Varenicline, sold under the trade name Champix among others, is a medication used help people stop smoking. It is the recommended initial treatment together with behavioral support. It helps one of every 11 people who smoke, stop for at least six months. Varenicline is taken by mouth.
Common side effects include unusual dreams, nausea, and constipation. Serious side effects may include depression, anxiety, seeing or hearing things that others do not, allergic reactions, thoughts of suicide, and seizures. There is no clear harm from use in human pregnancy but such use has not been well studied and there may be harm in pregnancy in other animals. It works by binding to a type of nicotinic acetylcholine receptors in the brain, decreasing the ability of nicotine to attach, and thus reducing the desire to smoke.
Varenicline was approved for medical use in the United States and Europe in 2006. As of 2020 it costs about 440 USD in the United States for the first month (7.60 USD per tablet). In the United Kingdom this amount is about 55 pounds. It may become avaliable as a generic medication in the US in 2020.
Varenicline is used to help people stop smoking tobacco. While effective less than 20% of people treated with varenicline remain abstinent from smoking at one year. It is more effective than bupropion (odds ratio 1.40) and nicotine replacement therapies (NRT) (odds ratio 1.56).
A 2013 Cochrane review concluded that varenicline is the most effective medication for tobacco cessation and that smokers were nearly three times more likely to quit on varenicline than with placebo. Varenicline was more efficacious than bupropion or NRT and as effective as combination NRT for tobacco smoking cessation.
The United States' Food and Drug Administration (US FDA) has approved the use of varenicline for up to twelve weeks. If smoking cessation has been achieved it may be continued for another twelve weeks.
The dose in adult is typically 0.5 mg once a day for the first three days, than 0.5 mg twice a day for the next four days, followed by 1 mg twice a day for a total of 12 weeks. An additional 12 weeks may be used if treatment has been successful.
Mild nausea is the most common side effect and is seen in approximately 30% of people though this rarely (<3%) results in stopping the medication. Other less common side effects include headache, difficulty sleeping, and nightmares. Rare side effects reported by people taking varenicline compared to placebo include change in taste, vomiting, abdominal pain, flatulence, and constipation. It has been estimated that for every five subjects taking varenicline at maintenance doses, there will be an event of nausea, and for every 24 and 35 treated subjects, there will be an event of constipation and flatulence, respectively. Gastrointestinal side-effects lead to discontinuation of the drug in 2% to 8% of people using varenicline. Incidence of nausea is dose-dependent: incidence of nausea was higher in people taking a larger dose (30%) versus placebo (10%) as compared to people taking a smaller dose (16%) versus placebo (11%).
In 2007, the US FDA had announced it had received post-marketing reports of thoughts of suicide and occasional suicidal behavior, erratic behavior, and drowsiness among people using varenicline for smoking cessation. In 2009, the US FDA required varenicline to carry a boxed warning that the drug should be stopped if any of these symptoms are experienced.
A 2014 review did not find evidence of an increased suicide risk. Other analyses have reached the same conclusion and found no increased risk of neuropsychiatric side effects with varenicline. No evidence for increased risks of cardiovascular events, depression, or self-harm with varenicline versus nicotine replacement therapy was found in one post-marketing surveillance study.
In June 2011, the US FDA issued a safety announcement that varenicline may be associated with "a small, increased risk of certain cardiovascular adverse events in people who have cardiovascular disease."
A prior 2011 review had found increased risk of cardiovascular events compared with placebo. Expert commentary in the same journal raised doubts about the methodology of the review, concerns which were echoed by the European Medicines Agency and subsequent reviews. Of specific concern were "the low number of events seen, the types of events counted, the higher drop-out rate in people receiving placebo, the lack of information on the timing of events, and the exclusion of studies in which no-one had an event."
In contrast, multiple recent reviews have found no increase in overall or serious adverse cardiovascular events (including for individuals at risk of developing cardiovascular disease) associated with varenicline use.
Varenicline has not been tested in pregnant women and therefore is not recommended in this group. Varenicline is considered a class C pregnancy drug, as animal studies have shown no increased risk of congenital anomalies; however, no data from human studies is available. An alternate drug is preferred for smoking cessation during breastfeeding due to lack of information and based on the animal studies on nicotine.
Mechanism of action
Varenicline is a nicotinic agonist and has a high-affinity partial agonist for the α4β2 nicotinic acetylcholine receptor subtype (nACh) that leads to the release of dopamine in the nucleus accumbens when activated, and therefore, has the capacity to reduce the feelings of craving and withdrawal caused by smoking cessation. In this respect it is similar to cytisine and different from the nicotinic antagonist bupropion and nicotine replacement therapies (NRTs) like nicotine patches and nicotine gum.
Varenicline displays full agonism on α7 nicotinic acetylcholine receptors and is a partial agonist on the α4β2, α3β4, and α6β2 subtypes. In addition, it is a weak agonist on the α3β2 containing receptors.
Varenicline's partial agonism on the α4β2 receptors rather than nicotine's full agonism produces less effect of dopamine release than nicotine's. This α4β2 competitive binding reduces the ability of nicotine to bind and stimulate the mesolimbic dopamine system - similar to the method of action of buprenorphine in the treatment of opioid addiction.
Most of the active compound is excreted by the kidneys (92–93%). A small proportion is glucuronidated, oxidised, N-formylated or conjugated to a hexose. The elimination half-life is about 24 hours.
Use of Cytisus plant as a smoking substitute during World War II led to use as a cessation aid in eastern Europe and extraction of cytisine. Cytisine analogs led to varenicline at Pfizer.
Varenicline received a "priority review" by the US FDA in February 2006, shortening the usual 10-month review period to 6 months because of its demonstrated effectiveness in clinical trials and perceived lack of safety issues. The agency's approval of the drug came on May 11, 2006. On August 1, 2006, varenicline was made available for sale in the United States and on September 29, 2006, was approved for sale in the European Union.
Society and culture
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