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|Mol. mass||211.267 g/mol|
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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 nicotine addiction. Varenicline is a nicotinic receptor partial agonist—it stimulates nicotine receptors more weakly than nicotine itself does. 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.
Varenicline is indicated for smoking cessation. 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. 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).
A Cochrane systematic review concluded that varenicline improved the likelihood of successfully quitting smoking by two- to three-fold relative to pharmacologically unassisted attempts. Varenicline was more efficacious than bupropion in this regard but not statistically superior to NRT.
The 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.
Varenicline has not been tested in those under 18 years old or pregnant women and therefore is not recommended for use by these groups. 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 observational study is currently being conducted assessing for malformations related to varenicline exposure, but has no results yet. An alternate drug is preferred for smoking cessation during breastfeeding due to lack of information and based on the animal studies on nicotine.
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 five subjects taking varenicline at maintenance doses (1 mg 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. Incidence of nausea is dose-dependent: incidence of nausea was higher in patients taking 1 mg twice a day (30%) versus placebo (10%) as compared to patients taking 0.5 mg twice a day (16%) versus placebo (11%).
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 side-effects, 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. 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."
As of July 1, 2009, the US Food and Drug Administration requires 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.
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."
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. Expert commentary in the same issue of CMAJ raised doubts about the methodology of the review, concerns which were echoed by the European Medicines Agency. 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, a meta analysis published in BMJ in 2012 included all double-blind RCTs of varenicline vs. placebo (including 8 trials with no events among 1596 participants), focused on events occurring during drug exposure or within 30 days after discontinuation, and analyzed findings using 4 summary estimates. The BMJ meta-analysis found no significant increase in cardiovascular serious adverse events associated with varenicline use for any of the measures, and found negligible variation in the evidence over 22 independent trials with 9,232 subjects.
BMJ published an article later that year that reported on a national cohort study in Denmark with 35,852 smokers using either bupropion or varenicline. This study found no significant differences in the rates of cardiovascular events by drug.
Despite the discussion in academic circles, to date, no direct experimental evidence suggests varenicline's action at the α3β4 and/or α7 nAChRs results in cardiovascular effects.
Mechanism of action
Varenicline displays full agonism on α7/5-HT3 nicotinic acetylcholine receptors. And it is a partial agonist on the α4β2, α3β4, and α6β2 subtypes. In addition, it's a weak agonist on the α3β2 containing receptors.
Varenicline's partial agonism on the α3β4 receptors rather than nicotine's full agonism produces less effect of dopamine release than nicotine's. This α3β4 competitive binding, reduces the ability of nicotine to bind and stimulate the mesolimbic dopamine system -similar in method to the action of buprenorphine in the treatment of opioid addiction.
Use of Cytisus plant as a smoking substitute during World War 2 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 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. The agency's approval of the drug came on May 11, 2006. 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.
- Jorenby DE, Hays JT, Rigotti NA, Azoulay S, Watsky EJ, Williams KE, Billing CB, Gong J, Reeves KR (2006). "Efficacy of varenicline, an alpha4beta2 nicotinic acetylcholine receptor partial agonist, vs placebo or sustained-release bupropion for smoking cessation: a randomized controlled trial". JAMA 296 (1): 56–63. doi:10.1001/jama.296.1.56. PMID 16820547.
- Mills EJ, Wu P, Spurden D, Ebbert JO, Wilson K (2009). "Efficacy of pharmacotherapies for short-term smoking abstinance: a systematic review and meta-analysis". Harm Reduct J 6: 25. doi:10.1186/1477-7517-6-25. PMC 2760513. PMID 19761618.
- Cahill K, Stead LF, Lancaster T (2012). Cahill, Kate, ed. "Nicotine receptor partial agonists for smoking cessation". Cochrane Database Syst Rev 4: CD006103. doi:10.1002/14651858.CD006103.pub6. PMID 22513936.
- U.S. Food and Drug Administration.FDA Approves Novel Medication for Smoking Cessation. Press release, 11 May 2006.
- Cressman, AM; Pupco, A; Kim, E; Koren, G; Bozzo, P (May 2012). "Smoking cessation therapy during pregnancy.". Canadian family physician Medecin de famille canadien 58 (5): 525–7. PMC 3352787. PMID 22586193.
- Leung, LK; Patafio, FM, Rosser, WW (September 28, 2011). "Gastrointestinal adverse effects of varenicline at maintenance dose: a meta-analysis". BMC clinical pharmacology 11 (1): 15. doi:10.1186/1472-6904-11-15. PMC 3192741. PMID 21955317.
- American Cancer Society. "Cancer Drug Guide: Varenicline". Retrieved 2008-01-19.
- "Early Communication About an Ongoing Safety Review: Varenicline (marketed as Chantix)". United States Food and Drug Administration. November 20, 2007. Archived from the original on 2007-12-05. Retrieved 2007-11-21.
- "Important Information about Chantix". Retrieved May 2008.
- FDA. "Public Health Advisory: FDA Requires New Boxed Warnings for the Smoking Cessation Drugs Chantix and Zyban". Retrieved 2009-07-01.
- "FDA Drug Safety Communication: Chantix (varenicline) may increase the risk of certain cardiovascular adverse events in patients with cardiovascular disease". 2011-06-16.
- Singh, S; Loke, YK, Spangler, JG, Furberg, CD (Sep 6, 2011). "Risk of serious adverse cardiovascular events associated with varenicline: a systematic review and meta-analysis" (PDF). CMAJ : Canadian Medical Association 183 (12): 1359–66. doi:10.1503/cmaj.110218. PMC 3168618. PMID 21727225.
- Takagi, H; Umemoto, T (Sep 6, 2011). "Varenicline: quantifying the risk". CMAJ : Canadian Medical Association 183 (12): 1404. doi:10.1503/cmaj.111-2063. PMC 3168634. PMID 21896705.
- Samuels, L (Sep 6, 2011). "Varenicline: cardiovascular safety". CMAJ : Canadian Medical Association 183 (12): 1407–08. doi:10.1503/cmaj.111-2073. PMC 3168639. PMID 21896709.
- "European Medicine Agency confirms positive benefit-risk balance for Champix.". 2011-07-21.
- Prochaska JJ, Hilton JF; Hilton (2012). "Risk of cardiovascular serious adverse events associated with varenicline use for tobacco cessation: systematic review and meta-analysis". BMJ 344: e2856. doi:10.1136/bmj.e2856. PMC 3344735. PMID 22563098.
- Svanström, H; Pasternak B; Hviid A. (November 2012). "Use of varenicline for smoking cessation and risk of serious cardiovascular events: nationwide cohort study". BMJ 345 (345): e7176. doi:10.1136/bmj.e7176. PMC 3493624. PMID 23138033. Retrieved 3 March 2013.
- Benowitz, Neal. "Basic and Clinical Pharmacology of Varenicline". CA Tobacco-Related Disease Research Program. Retrieved 3 March 2013.
- Mihalak KB, Carroll FI, Luetje CW; Carroll; Luetje (2006). "Varenicline is a partial agonist at alpha4beta2 and a full agonist at alpha7 neuronal nicotinic receptors". Mol. Pharmacol. 70 (3): 801–805. doi:10.1124/mol.106.025130. PMID 16766716.
- Mineur YS, Picciotto MR; Picciotto (December 2010). "Nicotine receptors and depression: revisiting and revising the cholinergic hypothesis". Trends Pharmacol. Sci. 31 (12): 580–6. doi:10.1016/j.tips.2010.09.004. PMC 2991594. PMID 20965579.
- Rollema H, Chambers LK, Coe JW et al. (March 2007). "Pharmacological profile of the alpha4beta2 nicotinic acetylcholine receptor partial agonist varenicline, an effective smoking cessation aid". Neuropharmacology 52 (3): 985–994. doi:10.1016/j.neuropharm.2006.10.016. PMID 17157884.
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- Obach, RS; Reed-Hagen, AE; Krueger, SS; Obach, BJ; O'Connell, TN; Zandi, KS; Miller, S; Coe, JW (2006). "Metabolism and disposition of varenicline, a selective alpha4beta2 acetylcholine receptor partial agonist, in vivo and in vitro". Drug metabolism and disposition: the biological fate of chemicals 34 (1): 121–130. doi:10.1124/dmd.105.006767. PMID 16221753.
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- Prochaska, BMJ 347:f5198 2013 http://www.bmj.com/content/347/bmj.f5198
- Coe JW, Brooks PR, Vetelino MG et al. (2005). "Varenicline: an alpha4beta2 nicotinic receptor partial agonist for smoking cessation". J. Med. Chem. 48 (10): 3474–3477. doi:10.1021/jm050069n. PMID 15887955.
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