|Systematic (IUPAC) name|
|7,8,9,10-tetrahydro- 6,10-methano- 6H-pyrazino [2,3-h] benzazepine|
|Licence data||EMA:Link, US FDA:link|
|Pregnancy cat.|| ? (US)|
|Legal status||℞ Prescription only|
|CAS number||249296-44-4 375815-87-5|
|Mol. mass||211.267 g/mol|
| (what is this?) (verify)|
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 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. It is more effective than NRTs and nicotine agonists. 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 nicotine replacement therapy. 
The FDA has approved its use for 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.
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.
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 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.
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. A meta analysis published in the British Medical Journal a year later reached the opposite conclusion, and attributed the results of the Canadian Medical Journal studies to a failure to adjust for differing lengths of follow-up in the treated and control groups..
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.
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.
Varenicline also acts as an agonist at 5-HT3 receptors, which may contribute to mood altering effects of varenicline.
Most of the active compound is excreted renally (92–93%). A small proportion is glucuronidated, oxidated, N-formylated or conjugated to a hexose. The elimination half-life is about 24 hours.
Varenicline was discovered at Pfizer through the research aimed at modifying the structure of cytisine.
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.
- ^ a b 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. http://jama.ama-assn.org/content/296/1/56.full.
- ^ a b 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. http://www.biomedcentral.com/content/pdf/1477-7517-6-25.pdf.
- ^ Cahill K, Stead LF, Lancaster T (2012). "Nicotine receptor partial agonists for smoking cessation". Cochrane Database Syst Rev 4: CD006103. doi:10.1002/14651858.CD006103.pub6. PMID 22513936.
- ^ a b U.S. Food and Drug Administration.FDA Approves Novel Medication for Smoking Cessation. Press release, 11 May 2006.
- ^ Leung, LK; Patafio, FM, Rosser, WW (2011 Sep 28). "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. http://www.biomedcentral.com/1472-6904/11/15.
- ^ American Cancer Society. "Cancer Drug Guide: Varenicline". http://www.cancer.org/docroot/CDG/content/CDG_Varenicline.asp. 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. http://web.archive.org/web/20071205222932/http://www.fda.gov/cder/drug/early_comm/varenicline.htm. Retrieved 2007-11-21.
- ^ "Important Information about Chantix". http://www.chantix.com/content/important_info_about_chantix.jsp. Retrieved 2008-05.
- ^ FDA. "Public Health Advisory: FDA Requires New Boxed Warnings for the Smoking Cessation Drugs Chantix and Zyban". http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/DrugSafetyInformationforHeathcareProfessionals/PublicHealthAdvisories/ucm169988.htm. 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. http://www.fda.gov/Drugs/DrugSafety/ucm259161.htm.
- ^ Singh, S; Loke, YK, Spangler, JG, Furberg, CD (2011 Sep 6). "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. http://www.cmaj.ca/content/early/2011/07/04/cmaj.110218.full.pdf+html.
- ^ Prochaska JJ, Hilton JF (2012). "Risk of cardiovascular serious adverse events associated with varenicline use for tobacco cessation: systematic review and meta-analysis". BMJ 344: e2856. PMC 3344735. PMID 22563098. //www.ncbi.nlm.nih.gov/pmc/articles/PMC3344735/.
- ^ Mihalak KB, Carroll FI, Luetje CW (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.
- ^ 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.
- ^ Mineur YS, Picciotto MR (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. //www.ncbi.nlm.nih.gov/pmc/articles/PMC2991594/.
- ^ 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.
- ^ 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.
- ^ Schwartz JL (1979). "Review and evaluation of methods of smoking cessation, 1969–77. Summary of a monograph". Public Health Rep 94 (6): 558–63. PMC 1431736. PMID 515342. //www.ncbi.nlm.nih.gov/pmc/articles/PMC1431736/.
- ^ Etter JF (2006). "Cytisine for smoking cessation: a literature review and a meta-analysis". Arch. Intern. Med. 166 (15): 1553–1559. doi:10.1001/archinte.166.15.1553. PMID 16908787. http://archinte.ama-assn.org/cgi/content/full/166/15/1553.
- ^ Kuehn BM (2006). "FDA speeds smoking cessation drug review". JAMA 295 (6): 614–614. doi:10.1001/jama.295.6.614. PMID 16467225.
- ^ European Medicines Agency (2011-01-28). "EPAR summary for the public. Champix varenicline". London. http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/000699/human_med_000696.jsp. Retrieved 2011-02-14.
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