Varenicline

Varenicline (trade name Chantix in the USA and Champix in Canada, Europe and other countries, marketed by Pfizer, usually in the form of varenicline tartrate), is a prescription medication used to treat smoking addiction. Varenicline stimulates nicotine receptors more weakly than nicotine does, that is, it is a nicotinic receptor partial agonist. 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. As a partial agonist it both reduces cravings for and decreases the pleasurable effects of cigarettes and other tobacco products. Through these mechanisms it can assist some patients to quit smoking.

Medical uses

Varenicline is indicated for smoking cessation. It is more effective than NRTs and nicotine agonists.^[1][2] In a 2006 randomized controlled trial sponsored by Pfizer, after one year the rate of continuous abstinence was 10% for placebo, 15% for bupropion and 23% for varenicline.^[1] In a 2009 meta-analysis of 101 studies funded by Pfizer, varenicline was found to be more effective than bupropion (odds ratio 1.40) and NRTs (odds ratio 1.56).^[2]

A Cochrane systematic review concluded that both varenicline and bupropion improved smoking cessation. More people quit with varenicline than with bupropion, but the difference was not statistically significant.^[3]

The FDA has approved its use for twelve weeks. If smoking cessation has been achieved it may be continued for another twelve weeks.^[4]

Varenicline has not been tested in those under 18 years old or pregnant women and therefore is not recommended for use by these groups.

Adverse effects

Nausea occurs commonly in people taking varenicline. Other less common side effects include headache, difficulty sleeping, and abnormal dreams. Rare side effects reported by people taking varenicline compared to placebo include change in taste, vomiting, abdominal pain, flatulence, and constipation. In a recent meta-analysis paper by Leung et al, it has been estimated that for every 5 subjects taking varenicline at maintenance doses (1mg twice daily), 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 are important factors compromising the compliance of varenicline.^[5][6]

Depression and suicide

In November 2007, the FDA announced it had received post-marketing reports that patients using varenicline for smoking cessation had experienced several serious symptoms, including suicidal ideation and occasional suicidal behavior, erratic behavior, and drowsiness. On February 1, 2008 the FDA issued an alert to further clarify its findings, noting that "it appears increasingly likely that there is an association between Chantix and serious neuropsychiatric symptoms." It is unknown whether the psychiatric symptoms are related to the drug or to nicotine withdrawal symptoms, although not all patients had stopped smoking. The FDA also recommended that health care professionals and patients watch for behavioral and mood changes.^[7] In May 2008, Pfizer updated the safety information associated with varenicline, noting that "some patients have reported changes in behavior, agitation, depressed mood, suicidal thoughts or actions." ^[8] A review of over 80,000 patients in the United Kingdom who had used varenicline showed no increased risk of depression or suicidal thoughts.^[9]

As of July 1, 2009, the US Food and Drug Administration requires Chantix (varenicline) to carry a black box warning, the agency's strongest safety warning, due to public reports of side effects including depression, suicidal thoughts, and suicidal actions.^[10]

Cardiovascular disease

On June 16, 2011, the FDA issued a safety announcement that Chantix may be associated with "a small, increased risk of certain cardiovascular adverse events in patients who have cardiovascular disease."^[11]

On July 4, 2011, four scientists published a review of double-blind studies in the Canadian Medical Association Journal. They found that varenicline has increased risk of serious adverse cardiovascular events compared with placebo.^[12]

Mechanism of action

Varenicline is a partial agonist of the α₄β₂ subtype of the nicotinic acetylcholine receptor. In addition it acts on α₃β₄ and weakly on α₃β₂ and α₆-containing receptors. A full agonism was displayed on α₇-receptors.^[13]

Acting as a partial agonist varenicline binds to, and partially stimulates, the α₄β₂ receptor without producing a full effect like nicotine. Thus varenicline does not greatly increase the downstream release of dopamine. Due to its competitive binding on these receptors, varenicline blocks the ability of nicotine to bind and stimulate the mesolimbic dopamine system, akin to the action of buprenorphine in the treatment of opioid addiction.^[14]

Pharmacokinetics

Most of the active compound is excreted renally (92–93%). A small proportion is glucuronidated, oxidated, N-formylated or conjugated to a hexose.^[15] The elimination half-life is about 24 hours.

History

Varenicline was discovered at Pfizer through the research aimed at modifying the structure of cytisine.^[16][17][18]

Varenicline received a "priority review" by the U.S. Food and Drug Administration (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.^[19] The agency's approval of the drug came on May 11, 2006.^[4] 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.^[20]

See also

• Drug Discovery and Development: Nicotinic Acetylcholine Receptor Agonists

References

External links

• Official website
• FDA Alert