View source for Varenicline

{{Short description|Nicotinic receptor agonist}}
{{Infobox drug
| Verifiedfields = changed
| Watchedfields = changed
| verifiedrevid = 470629155
| drug_name =
| INN =
| type = <!-- empty -->
| image = Varenicline.svg
| width = 190
| alt =
| image2 = Varenicline ball-and-stick model.png
| width2 =
| alt2 =
| caption =

<!-- Clinical data -->
| pronounce =
| tradename = Champix, Chantix, Tyrvaya, others
| Drugs.com = {{drugs.com|monograph|varenicline}}
| MedlinePlus = a606024
| licence_EU = yes
| DailyMedID = Varenicline
| pregnancy_AU = B3
| pregnancy_AU_comment =
| pregnancy_category=
| routes_of_administration = [[Oral administration|By mouth]], [[Nasal administration|Nasal spray]]
| class =
| ATC_prefix = N07
| ATC_suffix = BA03
| ATC_supplemental = <!-- scheduled to be S01XA28 in 2023 -->

<!-- Legal status -->
| legal_AU = S4
| legal_AU_comment = <ref>{{cite web | title=Champix Product Information | website=Therapeutic Goods Administration (TGA) | date=26 September 2021 | url=https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2010-PI-06102-3 | access-date=26 September 2021}}</ref><ref>{{cite web | title=Champix varenicline (as tartrate) 0.5 mg and 1.0 mg tablet blister pack | website=Therapeutic Goods Administration (TGA) | url=https://tga-search.clients.funnelback.com/s/search.html?collection=tga-artg&profile=record&meta_i=124940 | access-date=26 September 2021}}</ref>
| legal_BR = <!-- OTC, A1, A2, A3, B1, B2, C1, C2, C3, C4, C5, D1, D2, E, F -->
| legal_BR_comment =
| legal_CA = Rx-only
| legal_CA_comment =
| legal_DE = <!-- Anlage I, II, III or Unscheduled -->
| legal_DE_comment =
| legal_NZ = <!-- Class A, B, C -->
| legal_NZ_comment =
| legal_UK = POM
| legal_UK_comment = <ref name="Champix SmPC">{{cite web | title=Champix 0.5 mg film-coated tablets - Summary of Product Characteristics (SmPC) | website=(emc) | url=https://www.medicines.org.uk/emc/product/266/smpc | access-date=26 September 2021}}</ref>
| legal_US = Rx-only
| legal_US_comment = <ref name="Chantix FDA label" /><ref name="Tyrvaya FDA label">{{cite web | title=Tyrvaya- varenicline spray | website=DailyMed | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=014c93dc-5737-479c-a9f0-aaadac1ac298 | access-date=22 October 2021}}</ref>
| legal_EU = Rx-only
| legal_EU_comment = <ref name="Champix EPAR" />
| legal_UN = <!-- N I, II, III, IV / P I, II, III, IV -->
| legal_UN_comment =
| legal_status = <!-- For countries not listed above -->

<!-- Pharmacokinetic data -->
| bioavailability =
| protein_bound = <20%
| metabolism = Limited (<10%)
| metabolites =
| onset =
| elimination_half-life = 24 hours
| duration_of_action =
| excretion = [[Kidney]] (81–92%)

<!-- Identifiers -->
| CAS_number_Ref = {{cascite|correct|??}}
| CAS_number = 249296-44-4
| CAS_supplemental = 375815-87-5
| PubChem = 5310966
| IUPHAR_ligand = 5459
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
| DrugBank = DB01273
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID = 4470510
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = W6HS99O8ZO
| KEGG_Ref = {{keggcite|changed|kegg}}
| KEGG = D08669
| ChEBI_Ref = {{ebicite|changed|EBI}}
| ChEBI = 84500
| ChEMBL_Ref = {{ebicite|correct|EBI}}
| ChEMBL = 1076903
| NIAID_ChemDB =
| PDB_ligand =
| synonyms = OC-01

<!-- Chemical and physical data -->
| IUPAC_name = 7,8,9,10-Tetrahydro-6,10-methano-6''H''-pyrazino[2,3-h] [3]benzazepine
| C=13 | H=13 | N=3
| SMILES = n1c2cc3c(cc2ncc1)[C@@H]4CNC[C@H]3C4
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| StdInChI = 1S/C13H13N3/c1-2-16-13-5-11-9-3-8(6-14-7-9)10(11)4-12(13)15-1/h1-2,4-5,8-9,14H,3,6-7H2/t8-,9+
| StdInChI_comment =
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
| StdInChIKey = JQSHBVHOMNKWFT-DTORHVGOSA-N
| density =
| density_notes =
| melting_point =
| melting_high =
| melting_notes =
| boiling_point =
| boiling_notes =
| solubility =
| sol_units =
| specific_rotation =
}}

'''Varenicline''' (trade name '''Chantix''' and '''Champix''') is a [[medication]] used for [[smoking cessation]].<ref name="Chantix FDA label" /><ref name="Champix EPAR" /> Varenicline is also used for the treatment of [[dry eye disease]].<ref name="Tyrvaya FDA label" /><ref>{{cite press release | title=Oyster Point Pharma Announces FDA Approval of Tyrvaya (varenicline solution) Nasal Spray for the Treatment of the Signs and Symptoms of Dry Eye Disease | publisher=Oyster Point Pharma | via=PR Newswire | date=18 October 2021 | url=https://www.prnewswire.com/news-releases/oyster-point-pharma-announces-fda-approval-of-tyrvaya-varenicline-solution-nasal-spray-for-the-treatment-of-the-signs-and-symptoms-of-dry-eye-disease-301402070.html | access-date=22 October 2021}}</ref>

The most common side-effects include nausea (feeling sick), insomnia (difficulty sleeping), abnormal dreams, headache and nasopharyngitis (inflammation of the nose and throat).<ref name="Champix EPAR" />

It is a high-affinity [[partial agonist]] for the α4β2 [[nicotinic acetylcholine receptor]] subtype (nACh) that leads to the release of the [[neurotransmitter]] [[dopamine]] in the [[nucleus accumbens]] reward center of the brain when activated, and therefore, has the capacity to reduce the feelings of craving and withdrawal caused by smoking cessation.<ref>{{cite journal | vauthors = Tashkin DP | title = Smoking Cessation in Chronic Obstructive Pulmonary Disease | journal = Seminars in Respiratory and Critical Care Medicine | volume = 36 | issue = 4 | pages = 491–507 | date = August 2015 | pmid = 26238637 | doi = 10.1055/s-0035-1555610 }}</ref> In this respect it is similar to [[cytisine]] and different from the [[nicotinic antagonist]] [[bupropion]] and [[nicotine replacement therapy|nicotine replacement therapies]] (NRTs) like [[nicotine patch]]es and [[nicotine gum]]. It is estimated that varenicline [[Number needed to treat|successfully helps one of every eleven people]] who smoke remain abstinent from tobacco at six months.<ref name="CrawfordNNT">{{cite journal |last1=Crawford |first1=P |last2=Cieslak |first2=D |title=Varenicline for Smoking Cessation |journal=American Family Physician |date=September 2017 |volume=96 |issue=5 |pages=Online |pmid=28925657 |url=https://www.aafp.org/afp/2017/0901/od1.html}}</ref>

It is on the [[WHO Model List of Essential Medicines|World Health Organization's List of Essential Medicines]].<ref name="WHO21st">{{cite book | vauthors = ((World Health Organization)) | title = World Health Organization model list of essential medicines: 21st list 2019 | year = 2019 | hdl = 10665/325771 | author-link = World Health Organization | publisher = World Health Organization | location = Geneva | id = WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO | hdl-access=free }}</ref><ref name="WHO22nd">{{cite book | vauthors = ((World Health Organization)) | title = World Health Organization model list of essential medicines: 22nd list (2021) | year = 2021 | hdl = 10665/345533 | author-link = World Health Organization | publisher = World Health Organization | location = Geneva | id = WHO/MHP/HPS/EML/2021.02 | hdl-access=free }}</ref> It is available as a generic medication.<ref>{{cite web | title=Varenicline: FDA-Approved Drugs | website=U.S. Food and Drug Administration (FDA) | url=https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=201785 | access-date=24 September 2021}}</ref> In 2020, it was the 275th most commonly prescribed medication in the United States, with more than 1{{nbsp}}million prescriptions.<ref>{{cite web | title = The Top 300 of 2020 | url = https://clincalc.com/DrugStats/Top300Drugs.aspx | website = ClinCalc | access-date = 7 October 2022}}</ref><ref>{{cite web | title = Varenicline - Drug Usage Statistics | website = ClinCalc | url = https://clincalc.com/DrugStats/Drugs/Varenicline | access-date = 7 October 2022}}</ref>

==Medical uses==
Varenicline is used to help people stop smoking tobacco ([[smoking cessation]]). A meta-analysis found that less than 20% of people treated with varenicline remain abstinent from smoking at one year.<ref>{{cite journal |vauthors=Rosen LJ, Galili T, Kott J, Goodman M, Freedman LS |title=Diminishing benefit of smoking cessation medications during the first year: a meta-analysis of randomized controlled trials |journal=Addiction |volume=113 |issue=5 |pages=805–816 |date=May 2018 |pmid=29377409 |pmc=5947828 |doi=10.1111/add.14134 }}</ref> In a 2009 [[meta-analysis]] varenicline was found to be more effective than [[bupropion]] ([[odds ratio]] 1.40) and [[nicotine replacement therapy|nicotine replacement therapies]] (NRT) (odds ratio 1.56).<ref name="Mills2009">{{cite journal | vauthors = Mills EJ, Wu P, Spurden D, Ebbert JO, Wilson K | title = Efficacy of pharmacotherapies for short-term smoking abstinance: a systematic review and meta-analysis | journal = Harm Reduction Journal | volume = 6 | pages = 25 | date = September 2009 | pmid = 19761618 | pmc = 2760513 | doi = 10.1186/1477-7517-6-25 }}</ref>

A 2013 Cochrane overview and network meta-analysis concluded that varenicline is the most effective medication for tobacco cessation and that smokers were nearly three times more likely to quit tobacco use while on varenicline than with placebo treatment. Varenicline was more efficacious than bupropion or NRT and as effective as combination NRT for tobacco smoking cessation.<ref name="Cochrane2013">{{cite journal | vauthors = Cahill K, Stevens S, Perera R, Lancaster T | title = Pharmacological interventions for smoking cessation: an overview and network meta-analysis | journal = The Cochrane Database of Systematic Reviews | volume = 5 | issue = 5 | pages = CD009329 | date = May 2013 | pmid = 23728690 | doi = 10.1002/14651858.CD009329.pub2 | type = Systematic Review & Meta-Analysis | pmc = 8406789 }}</ref><ref name=Elrashidi2014/>

Varenicline has not been tested in those under 18 years old or pregnant women and therefore is not recommended for use by these groups.<ref>{{Cite journal|last1=Claire|first1=Ravinder|last2=Chamberlain|first2=Catherine|last3=Davey|first3=Mary-Ann|last4=Cooper|first4=Sue E.|last5=Berlin|first5=Ivan|last6=Leonardi-Bee|first6=Jo|last7=Coleman|first7=Tim|date=4 March 2020|title=Pharmacological interventions for promoting smoking cessation during pregnancy|journal=The Cochrane Database of Systematic Reviews|volume=2020|issue=3|pages=CD010078|doi=10.1002/14651858.CD010078.pub3|issn=1469-493X|pmc=7059898|pmid=32129504}}</ref> Varenicline is considered a [[Pregnancy category|class C]] pregnancy drug, as animal studies have shown no increased risk of congenital anomalies; however, no data from human studies is available.<ref>{{cite journal | vauthors = Cressman AM, Pupco A, Kim E, Koren G, Bozzo P | title = Smoking cessation therapy during pregnancy | journal = Canadian Family Physician | volume = 58 | issue = 5 | pages = 525–7 | date = May 2012 | pmid = 22586193 | pmc = 3352787 }}</ref> An observational study is currently being conducted assessing for malformations related to varenicline exposure, but has no results yet.<ref>{{ClinicalTrialsGov|NCT01290445|Varenicline Pregnancy Cohort Study}}</ref> An alternate drug is preferred for smoking cessation during breastfeeding due to lack of information and based on the animal studies on nicotine.<ref>{{cite web|url=http://toxnet.nlm.nih.gov/cgi-bin/sis/htmlgen?LACT|title=LactMed|work=nih.gov}}</ref>

==Side effects==
Mild [[nausea]] is the most common side effect and is seen in approximately 30% of people taking varenicline though this rarely (<3%) results in discontinuation of the medication.<ref name=Elrashidi2014/> Other less common side effects include [[headache]], [[insomnia|difficulty sleeping]], and vivid dreams. Rare side effects reported by people taking varenicline compared to placebo include [[dysgeusia|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 of 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.<ref>{{cite journal | vauthors = Leung LK, Patafio FM, Rosser WW | title = Gastrointestinal adverse effects of varenicline at maintenance dose: a meta-analysis | journal = BMC Clinical Pharmacology | volume = 11 | issue = 1 | pages = 15 | date = September 2011 | pmid = 21955317 | pmc = 3192741 | doi = 10.1186/1472-6904-11-15 }}</ref><ref>{{cite web |url=http://www.cancer.org/docroot/CDG/content/CDG_Varenicline.asp |author=American Cancer Society |title=Cancer Drug Guide: Varenicline |access-date=2008-01-19 |archive-date=2008-06-30 |archive-url=https://web.archive.org/web/20080630100804/http://www.cancer.org/docroot/CDG/content/CDG_Varenicline.asp |url-status=dead }}</ref> 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%).<ref name="Chantix FDA label">{{cite web | title=Chantix- varenicline tartrate tablet, film coated Chantix- varenicline tartrate kit | website=DailyMed | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=f0ff4f27-5185-4881-a749-c6b7a0ca5696 | access-date=26 September 2021}}</ref>

===Depression and suicide===
In 2007, the US FDA had announced it had received post-marketing reports of [[suicidal ideation|thoughts of suicide]] and occasional [[Suicide#Suicidal gestures and attempts|suicidal behavior]], erratic behavior, and drowsiness among people using varenicline for smoking cessation. In 2009, the US FDA required varenicline to carry a [[black box warning|boxed warning]] that the drug should be stopped if any of these symptoms are experienced.<ref name="aikenstandard">{{cite web|url=https://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/DrugSafetyInformationforHeathcareProfessionals/PublicHealthAdvisories/ucm169988.htm|author=FDA|title=Public Health Advisory: FDA Requires New Boxed Warnings for the Smoking Cessation Drugs Chantix and Zyban|website=[[Food and Drug Administration]]|access-date=2009-07-01}}</ref>

A 2014 [[systematic review]] did not find evidence of an increased [[suicide]] risk.<ref>{{cite journal | vauthors = Hughes JR | title = Varenicline as a Cause of Suicidal Outcomes | journal = Nicotine & Tobacco Research | volume = 18 | issue = 1 | pages = 2–9 | date = January 2016 | pmid = 25572451 | doi = 10.1093/ntr/ntu275 | doi-access = free }}</ref> Other analyses have reached the same conclusion and found no increased risk of neuropsychiatric side effects with varenicline.<ref name="Cochrane2013"/><ref name=Elrashidi2014/> 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.<ref name="Kotz2015">{{cite journal | vauthors = Kotz D, Viechtbauer W, Simpson C, van Schayck OC, West R, Sheikh A | title = Cardiovascular and neuropsychiatric risks of varenicline: a retrospective cohort study | journal = The Lancet. Respiratory Medicine | volume = 3 | issue = 10 | pages = 761–8 | date = October 2015 | pmid = 26355008 | pmc = 4593936 | doi = 10.1016/S2213-2600(15)00320-3 | type = retrospective cohort }}</ref>

In 2016 the FDA removed the black box warning.<ref name="Com2016">{{cite web |last1=Food and Drug Administration |date=16 December 2016 |title=Safety Alerts for Human Medical Products - Chantix (varenicline) and Zyban (bupropion): Drug Safety Communication - Mental Health Side Effects Revised |url=https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-fda-revises-description-mental-health-side-effects-stop-smoking |url-status=live |archive-url=https://web.archive.org/web/20220127170039/https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-fda-revises-description-mental-health-side-effects-stop-smoking |archive-date=27 January 2022 |access-date=10 March 2022 |website=www.fda.gov |language=en}}</ref> People are still advised to stop the medication if they "notice any side effects on mood, behavior, or thinking."<ref name=Com2016/><ref>{{cite journal | vauthors = Palmer G, Massey V | title = Electron paramagnetic resonance and circular dichroism studies on milk xanthine oxidase | journal = The Journal of Biological Chemistry | volume = 244 | issue = 10 | pages = 2614–20 | date = May 1969 | pmc = 4306032 | doi = 10.1186/1753-6561-9-S1-A31 | pmid = 4306032 }}</ref><ref>{{Cite journal | vauthors = Yeung E, Bachi B, Long B, Lee J, Chao Y | date = 2015 | title = Varenicline and Depression: a Literature Review | url = http://wjmer.co.uk/library/downloads/pdf/vol_9_1.pdf | journal = World Journal of Medical Education and Research |volume=9 | issue = 1 |pages=24–29}}</ref>

===Cardiovascular disease===
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."<ref name="FDA.org">{{cite news | title =FDA Drug Safety Communication: Chantix (varenicline) may increase the risk of certain cardiovascular adverse events in patients with cardiovascular disease| date =2011-06-16| url =https://www.fda.gov/Drugs/DrugSafety/ucm259161.htm}}</ref>

A prior 2011 review had found increased risk of cardiovascular events compared with placebo.<ref>{{cite journal | vauthors = Singh S, Loke YK, Spangler JG, Furberg CD | title = Risk of serious adverse cardiovascular events associated with varenicline: a systematic review and meta-analysis | journal = CMAJ | volume = 183 | issue = 12 | pages = 1359–66 | date = September 2011 | pmid = 21727225 | pmc = 3168618 | doi = 10.1503/cmaj.110218 }}</ref> Expert commentary in the same journal raised doubts about the methodology of the review,<ref>{{cite journal | vauthors = Takagi H, Umemoto T | title = Varenicline: quantifying the risk | journal = CMAJ | volume = 183 | issue = 12 | pages = 1404; author reply 1405, 1407 | date = September 2011 | pmid = 21896705 | pmc = 3168634 | doi = 10.1503/cmaj.111-2063 }}</ref><ref>{{cite journal | vauthors = Samuels L | title = Varenicline: cardiovascular safety | journal = CMAJ | volume = 183 | issue = 12 | pages = 1407–8; author reply 1408 | date = September 2011 | pmid = 21896709 | pmc = 3168639 | doi = 10.1503/cmaj.111-2073 }}</ref> concerns which were echoed by the [[European Medicines Agency]] and subsequent reviews.<ref name="EMA.europa.eu">{{cite news| title =European Medicine Agency confirms positive benefit-risk balance for Champix| date =2011-07-21| url =http://www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/news/2011/07/news_detail_001314.jsp&mid=WC0b01ac058004d5c1&murl=menus/news_and_events/news_and_events.jsp&jsenabled=true| access-date =2021-11-10| archive-date =2018-02-21| archive-url =https://web.archive.org/web/20180221222441/http://www.ema.europa.eu/ema/index.jsp?curl=pages%2Fnews_and_events%2Fnews%2F2011%2F07%2Fnews_detail_001314.jsp&mid=WC0b01ac058004d5c1&murl=menus%2Fnews_and_events%2Fnews_and_events.jsp&jsenabled=true| url-status =dead}}</ref><ref name="Prochaska2012"/> 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 systematic reviews and meta-analyses have found no increase in overall or serious adverse cardiovascular events (including for individuals at risk of developing cardiovascular disease) associated with varenicline use.<ref name="Prochaska2012">{{cite journal | vauthors = Prochaska JJ, Hilton JF | title = Risk of cardiovascular serious adverse events associated with varenicline use for tobacco cessation: systematic review and meta-analysis | journal = BMJ | volume = 344 | pages = e2856 | date = May 2012 | pmid = 22563098 | pmc = 3344735 | doi = 10.1136/bmj.e2856 | type = Systematic Review & Meta-Analysis }}</ref><ref name="Mills2014">{{cite journal | vauthors = Mills EJ, Thorlund K, Eapen S, Wu P, Prochaska JJ | title = Cardiovascular events associated with smoking cessation pharmacotherapies: a network meta-analysis | journal = Circulation | volume = 129 | issue = 1 | pages = 28–41 | date = January 2014 | pmid = 24323793 | pmc = 4258065 | doi = 10.1161/CIRCULATIONAHA.113.003961 | type = Network Meta-Analysis }}</ref><ref name="Pipe2014">{{cite journal | vauthors = Pipe AL | title = Network meta-analysis demonstrates the safety of pharmacotherapy for smoking cessation in cardiovascular patients | journal = Evidence-Based Medicine | volume = 19 | issue = 5 | pages = 193 | date = October 2014 | pmid = 24917603 | doi = 10.1136/eb-2014-110030 | s2cid = 40856313 | type = Review & Commentary }}</ref><ref name="Rowland2014">{{cite journal | vauthors = Rowland K | title = ACP Journal Club. Review: Nicotine replacement therapy increases CVD events; bupropion and varenicline do not | journal = Annals of Internal Medicine | volume = 160 | issue = 8 | pages = JC2 | date = April 2014 | pmid = 24733219 | doi = 10.7326/0003-4819-160-8-201404150-02002 | s2cid = 37165486 | type = Review & Commentary }}</ref>

==Mechanism of action==
Varenicline displays full [[agonist|agonism]] on [[Α7 nicotinic acetylcholine receptor|α<sub>7</sub>]] [[Alpha-7 nicotinic receptor| ]] [[nicotinic acetylcholine receptor]]s and is a [[partial agonist]] on the [[Α4β2 nicotinic|α<sub>4</sub>β<sub>2</sub>]], [[Α3β4-nAChR|α<sub>3</sub>β<sub>4</sub>]], and [[α6β2|α<sub>6</sub>β<sub>2</sub>]] subtypes.<ref name="pmid16766716">{{cite journal | vauthors = Mihalak KB, Carroll FI, Luetje CW | title = Varenicline is a partial agonist at alpha4beta2 and a full agonist at alpha7 neuronal nicotinic receptors | journal = Molecular Pharmacology | volume = 70 | issue = 3 | pages = 801–5 | date = September 2006 | pmid = 16766716 | doi = 10.1124/mol.106.025130 | s2cid = 14562170 }}</ref><ref name="pmid20965579">{{cite journal | vauthors = Mineur YS, Picciotto MR | title = Nicotine receptors and depression: revisiting and revising the cholinergic hypothesis | journal = Trends in Pharmacological Sciences | volume = 31 | issue = 12 | pages = 580–6 | date = December 2010 | pmid = 20965579 | pmc = 2991594 | doi = 10.1016/j.tips.2010.09.004 }}</ref><ref>{{cite journal | vauthors = Bordia T, Hrachova M, Chin M, McIntosh JM, Quik M | title = Varenicline is a potent partial agonist at α6β2* nicotinic acetylcholine receptors in rat and monkey striatum | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 342 | issue = 2 | pages = 327–34 | date = August 2012 | pmid = 22550286 | pmc = 3400806 | doi = 10.1124/jpet.112.194852 }}</ref> In addition, it is a weak agonist on the [[α3β2|α<sub>3</sub>β<sub>2</sub>]] containing receptors.

Varenicline's partial agonism on the α<sub>4</sub>β<sub>2</sub> receptors rather than nicotine's full agonism produces less effect of [[dopamine]] release than nicotine's. This α<sub>4</sub>β<sub>2</sub> 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.<ref name=Elrashidi2014>{{cite journal | vauthors = Elrashidi MY, Ebbert JO | title = Emerging drugs for the treatment of tobacco dependence: 2014 update | journal = Expert Opinion on Emerging Drugs | volume = 19 | issue = 2 | pages = 243–60 | date = June 2014 | pmid = 24654737 | doi = 10.1517/14728214.2014.899580 | s2cid = 207484687 | type = Review }}</ref>

==Pharmacokinetics==
Most of the active compound is excreted by the [[kidney]]s (92–93%). A small proportion is [[glucuronidation|glucuronidated]], oxidised, ''N''-formylated or conjugated to a [[hexose]].<ref>{{cite journal | vauthors = Obach RS, Reed-Hagen AE, Krueger SS, Obach BJ, O'Connell TN, Zandi KS, Miller S, Coe JW | title = Metabolism and disposition of varenicline, a selective alpha4beta2 acetylcholine receptor partial agonist, in vivo and in vitro | journal = Drug Metabolism and Disposition | volume = 34 | issue = 1 | pages = 121–30 | date = January 2006 | pmid = 16221753 | doi = 10.1124/dmd.105.006767 | s2cid = 18746784 }}</ref> The elimination half-life is about 24 hours.

==History==
Use of ''[[Cytisus]]'' plants as a smoking substitutes during [[World War II]]<ref>{{cite journal | vauthors = Seeger R | title = [Cytisine as an aid for smoking cessation] | journal = Medizinische Monatsschrift für Pharmazeuten | volume = 15 | issue = 1 | pages = 20–1 | date = January 1992 | pmid = 1542278 }}</ref> led to use as a cessation aid in eastern Europe and extraction of cytisine.<ref>{{cite journal | vauthors = Prochaska JJ, Das S, Benowitz NL | title = Cytisine, the world's oldest smoking cessation aid | journal = BMJ | volume = 347 | pages = f5198 | date = August 2013 | pmid = 23974638 | doi = 10.1136/bmj.f5198 | s2cid = 31845933 | url = https://escholarship.org/uc/item/8qq3r737 }}</ref>  [[Cytisine]] [[Structural analog|analogs]] led to varenicline at [[Pfizer]].<ref>{{cite journal | vauthors = Coe JW, Brooks PR, Vetelino MG, Wirtz MC, Arnold EP, Huang J, Sands SB, Davis TI, Lebel LA, Fox CB, Shrikhande A, Heym JH, Schaeffer E, Rollema H, Lu Y, Mansbach RS, Chambers LK, Rovetti CC, Schulz DW, Tingley FD, O'Neill BT | title = Varenicline: an alpha4beta2 nicotinic receptor partial agonist for smoking cessation | journal = Journal of Medicinal Chemistry | volume = 48 | issue = 10 | pages = 3474–7 | date = May 2005 | pmid = 15887955 | doi = 10.1021/jm050069n }}</ref><ref name="pmid515342">{{cite journal | vauthors = Schwartz JL | title = Review and evaluation of methods of smoking cessation, 1969-77. Summary of a monograph | journal = Public Health Reports | volume = 94 | issue = 6 | pages = 558–63 | year = 1979 | pmid = 515342 | pmc = 1431736 }}</ref><ref name="pmid16908787">{{cite journal | vauthors = Etter JF | title = Cytisine for smoking cessation: a literature review and a meta-analysis | journal = Archives of Internal Medicine | volume = 166 | issue = 15 | pages = 1553–9 | year = 2006 | pmid = 16908787 | doi = 10.1001/archinte.166.15.1553 | doi-access = free }}</ref>

Varenicline received a "priority review" by the US FDA in February 2006, shortening the usual ten-month review period to six months because of its demonstrated effectiveness in [[clinical trial]]s and perceived lack of safety issues.<ref name="pmid16467225">{{cite journal | vauthors = Kuehn BM | title = FDA speeds smoking cessation drug review | journal = JAMA | volume = 295 | issue = 6 | pages = 614 | date = February 2006 | pmid = 16467225 | doi = 10.1001/jama.295.6.614 }}</ref> The agency's approval of the drug came on May 11, 2006.<ref name=FDA2006>{{cite press release | title=FDA Approves Novel Medication for Smoking Cessation | website=U.S. Food and Drug Administration (FDA) | date=11 May 2006 | url=https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/2006/ucm108651.htm | archive-url=https://web.archive.org/web/20090710031708/https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/2006/ucm108651.htm | archive-date=10 July 2009 | url-status=dead | access-date=26 September 2021}}</ref><ref>{{cite web | title=Drug Approval Package: Chantix (Varenicline) NDA #021928 | website=U.S. Food and Drug Administration (FDA) | date=16 June 2006  | url=https://www.accessdata.fda.gov/drugsatfda_docs/nda/2006/021928_s000_ChantixTOC.cfm | access-date=26 September 2021}}</ref> On September 29, 2006, it was approved for sale in the [[European Union]].<ref name="Champix EPAR">{{cite web | title=Champix EPAR | website=[[European Medicines Agency]] (EMA) | url=https://www.ema.europa.eu/en/medicines/human/EPAR/champix | access-date=26 September 2021}} Text was copied from this source which is © European Medicines Agency. Reproduction is authorized provided the source is acknowledged.</ref>

On September 16, 2021, Pfizer announced a recall of "all lots of its anti-smoking treatment, Chantix [Varenicline], due to high levels of cancer-causing agents called [[nitrosamine]]s in the pills".<ref>{{Cite news|url=https://www.reuters.com/business/healthcare-pharmaceuticals/pfizer-recalls-all-lots-anti-smoking-drug-over-carcinogen-presence-2021-09-16/|title=Pfizer recalls all lots of anti-smoking drug over carcinogen presence|newspaper=Reuters|date=16 September 2021}}</ref> This followed a July 2, 2021 announcement by the FDA that it was "alerting patients and health care professionals to Pfizer's voluntary recall of nine lots of the smoking cessation drug" and further recalls by Pfizer on July 19 and Aug. 8.<ref>{{cite web | title=FDA Updates and Press Announcements on Nitrosamine in in Varenicline | website=U.S. Food and Drug Administration | date=17 September 2021 | url=https://www.fda.gov/drugs/drug-safety-and-availability/fda-updates-and-press-announcements-nitrosamine-varenicline-chantix | access-date=26 September 2021}}</ref> On June 24, Pfizer had paused distribution of Chantix worldwide;<ref>{{Cite web|url=https://khn.org/morning-breakout/carcinogen-contamination-halts-sales-of-smoking-cessation-drug/|title=Carcinogen Contamination Halts Sales of Smoking-Cessation Drug|date=25 June 2021}}</ref> "[t]he distribution halt [wa]s out of an abundance of caution, pending further testing, the company said in an email.<ref>{{Cite news|url=https://www.bloomberg.com/news/articles/2021-06-24/pfizer-pauses-chantix-distribution-after-finding-carcinogen|title = Pfizer Pauses Chantix Distribution After Finding Carcinogen|newspaper = Bloomberg.com|date = 24 June 2021}}</ref> According to the Pfizer Inc. 2020 Form 10-K Annual Report, high-revenue products by the company include[d] Chantix/Champix (varenicline) to treat nicotine addiction, [which] had $919 million in 2020 revenues.<ref>[https://s21.q4cdn.com/317678438/files/doc_financials/2020/ar/PFE-2020-Form-10K-FINAL.pdfPfizer] {{dead link|date=January 2022}}</ref>

In October 2021, US FDA approved [[Oyster Point Pharma]] to market Tyrvaya as a new route of varenicline administration through nasal spray for the treatment of dry eye disease.<ref>{{cite news |last1=Harrison |first1=Laird |title=FDA Approves First Nasal Spray for Dry Eye |url=https://www.webmd.com/eye-health/news/20211027/nasal-spray-for-dry-eye |access-date=27 April 2022 |work=WenMD Health News |date=27 October 2021}}</ref>

== References ==
{{reflist}}

== External links ==
* {{cite web | url = https://druginfo.nlm.nih.gov/drugportal/name/varenicline | publisher = U.S. National Library of Medicine | work = Drug Information Portal | title = Varenicline }}
* {{ClinicalTrialsGov|NCT03636061|Clinical Trial to Evaluate the Efficacy of OC-01 Nasal Spray on Signs and Symptoms of Dry Eye Disease (The ONSET-1 Study)}}
* {{ClinicalTrialsGov|NCT04036292|Evaluating the Efficacy and Safety of OC-01 (Varenicline) Nasal Spray on Dry Eye Disease}}

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{{Antiaddictives}}
{{Nicotinic acetylcholine receptor modulators}}
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[[Category:Quinoxalines]]
[[Category:Smoking cessation]]
[[Category:World Health Organization essential medicines]]