Varenicline

Varenicline
Clinical data
Trade names Chantix
AHFS/Drugs.com Monograph
MedlinePlus a606024
License data
Pregnancy
category
  • AU: B3
  • US: C (Risk not ruled out)
Routes of
administration		 Oral
ATC code N07BA03 (WHO)
Legal status
Legal status
Pharmacokinetic data
Protein binding <20%
Metabolism Limited (<10%)
Biological half-life 24 hours
Excretion Renal (81–92%)
Identifiers
CAS Number 249296-44-4 YesY 375815-87-5
PubChem (CID) 5310966
IUPHAR/BPS 5459
DrugBank DB01273 YesY
ChemSpider 4470510 YesY
UNII W6HS99O8ZO YesY
KEGG D08669 N
ChEBI CHEBI:84500 N
ChEMBL CHEMBL1076903 YesY
Chemical and physical data
Formula C13H13N3
Molar mass 211.267 g/mol
3D model (Jmol) Interactive image
 NYesY (what is this?)  (verify)

Varenicline (trade name Chantix and Champix 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.

Medical uses

Varenicline is used for smoking cessation. In a 2009 meta-analysis varenicline was found to be more effective than bupropion (odds ratio 1.40) and NRTs (odds ratio 1.56).[1]

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 on varenicline than with placebo treatment. Varenicline was more efficacious than bupropion or NRT and as effective as combination NRT for tobacco smoking cessation.[2][3]

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.[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.[5] 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.[6] An observational study is currently being conducted assessing for malformations related to varenicline exposure, but has no results yet.[7] An alternate drug is preferred for smoking cessation during breastfeeding due to lack of information and based on the animal studies on nicotine.[8]

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.[3] 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. In a recent meta-analysis paper by Leung et al., 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.[9][10] 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%).[11]

Depression and suicide

In November 2007, the US FDA 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. Since July 1, 2009, the US FDA has required varenicline to carry a boxed warning that the drug should be stopped if any of these symptoms are experienced.[12] The label notes, however, that a pooled analysis of 18 randomized clinical trials including 8,521 people found similar rates of psychiatric events in the treatment and placebo arms, and that similar results have been obtained in four observational studies including 10,000 to 30,000 varenicline users.[13] People are advised to weigh the risks of using varenicline against the benefits of its use, noting that varenicline "has been demonstrated to increase the likelihood of abstinence from smoking for as long as one year compared to treatment with placebo." and that "the health benefits of quitting smoking are immediate and substantial."[13]

A 2014 systematic review did not find evidence of an increased suicide risk.[14] Other analyses have reached the same conclusion and found no increased risk of neuropsychiatric side effects with varenicline.[2][3]

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."[15]

A prior 2011 review had found increased risk of cardiovascular events compared with placebo.[16] Expert commentary in the same journal raised doubts about the methodology of the review,[17][18] concerns which were echoed by the European Medicines Agency and subsequent reviews.[19][20] 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.[20][21][22][23]

Post-marketing surveillance

No evidence for increased risks of cardiovascular events, depression, or self-harm with varenicline versus nicotine replacement therapy has been found in one post-marketing surveillance study.[24]

Mechanism of action

Varenicline displays full agonism on α7 nicotinic acetylcholine receptors and is a partial agonist on the α4β2, α3β4, and α6β2 subtypes.[25][26][27] 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.[3]

Pharmacokinetics

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.[28] The elimination half-life is about 24 hours.

History

Use of Cytisus plant as a smoking substitute during World War II[29] led to use as a cessation aid in eastern Europe and extraction of cytisine.[30] Cytisine analogs led to varenicline at Pfizer.[31][32][33]

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.[34] The agency's approval of the drug came on May 11, 2006.[4] 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.[35]

See also

References

  1. ↑ 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" (PDF). Harm Reduct J. 6: 25. doi:10.1186/1477-7517-6-25. PMC 2760513Freely accessible. PMID 19761618.
  2. 1 2 Cahill K, Stevens S, Perera R, Lancaster T (May 2013). "Pharmacological interventions for smoking cessation: an overview and network meta-analysis". Cochrane Database Syst Rev (Systematic Review & Meta-Analysis). 5: CD009329. doi:10.1002/14651858.CD009329.pub2. PMID 23728690.
  3. 1 2 3 4 Elrashidi MY, Ebbert JO (June 2014). "Emerging drugs for the treatment of tobacco dependence: 2014 update". Expert Opin Emerg Drug (Review). 19 (2): 243–60. doi:10.1517/14728214.2014.899580. PMID 24654737.
  4. 1 2 U.S. Food and Drug Administration.FDA Approves Novel Medication for Smoking Cessation. Press release, 11 May 2006.
  5. ↑ Coleman, Tim; Chamberlain, Catherine; Davey, Mary-Ann; Cooper, Sue E; Leonardi-Bee, Jo; Coleman, Tim (2015). "Pharmacological interventions for promoting smoking cessation during pregnancy". doi:10.1002/14651858.CD010078.pub2.
  6. ↑ Cressman, AM; Pupco, A; Kim, E; Koren, G; Bozzo, P (May 2012). "Smoking cessation therapy during pregnancy.". Canadian Family Physician. 58 (5): 525–7. PMC 3352787Freely accessible. PMID 22586193.
  7. ↑ "Varenicline Pregnancy Cohort Study". clinicaltrials.gov.
  8. ↑ "LactMed". nih.gov.
  9. ↑ 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 3192741Freely accessible. PMID 21955317.
  10. ↑ American Cancer Society. "Cancer Drug Guide: Varenicline". Retrieved 2008-01-19.
  11. ↑ "DailyMed - CHANTIX- varenicline tartrate". nih.gov.
  12. ↑ FDA. "Public Health Advisory: FDA Requires New Boxed Warnings for the Smoking Cessation Drugs Chantix and Zyban". Retrieved 2009-07-01.
  13. 1 2 "www.accessdata.fda.gov" (PDF).
  14. ↑ Hughes, JR (8 January 2015). "Varenicline as a Cause of Suicidal Outcomes.". Nicotine & tobacco research : official journal of the Society for Research on Nicotine and Tobacco. doi:10.1093/ntr/ntu275. PMID 25572451.
  15. ↑ "FDA Drug Safety Communication: Chantix (varenicline) may increase the risk of certain cardiovascular adverse events in patients with cardiovascular disease". 2011-06-16.
  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 3168618Freely accessible. PMID 21727225.
  17. ↑ 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 3168634Freely accessible. PMID 21896705.
  18. ↑ Samuels, L (Sep 6, 2011). "Varenicline: cardiovascular safety". CMAJ : Canadian Medical Association. 183 (12): 1407–08. doi:10.1503/cmaj.111-2073. PMC 3168639Freely accessible. PMID 21896709.
  19. ↑ "European Medicine Agency confirms positive benefit-risk balance for Champix.". 2011-07-21.
  20. 1 2 Prochaska JJ, Hilton JF (2012). "Risk of cardiovascular serious adverse events associated with varenicline use for tobacco cessation: systematic review and meta-analysis". BMJ (Systematic Review & Meta-Analysis). 344: e2856. doi:10.1136/bmj.e2856. PMC 3344735Freely accessible. PMID 22563098.
  21. ↑ Mills EJ, Thorlund K, Eapen S, Wu P, Prochaska JJ (January 2014). "Cardiovascular events associated with smoking cessation pharmacotherapies: a network meta-analysis". Circulation (Network Meta-Analysis). 129 (1): 28–41. doi:10.1161/CIRCULATIONAHA.113.003961. PMID 24323793.
  22. ↑ Pipe AL (October 2014). "Network meta-analysis demonstrates the safety of pharmacotherapy for smoking cessation in cardiovascular patients". Evidence-Based Medicine (Review & Commentary). 19 (5): 193. doi:10.1136/eb-2014-110030. PMID 24917603.
  23. ↑ Rowland K (April 2014). "ACP Journal Club. Review: Nicotine replacement therapy increases CVD events; bupropion and varenicline do not". Annals of Internal Medicine (Review & Commentary). 160 (8): JC2. doi:10.7326/0003-4819-160-8-201404150-02002. PMID 24733219.
  24. ↑ Kotz D, Viechtbauer W, Simpson C, van Schayck OC, West R, Sheikh A (2015). "Cardiovascular and neuropsychiatric risks of varenicline: a retrospective cohort study". Lancet Respir Med (retrospective cohort). 3: 761–768. doi:10.1016/S2213-2600(15)00320-3. PMC 4593936Freely accessible. PMID 26355008.
  25. ↑ 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.
  26. ↑ 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 2991594Freely accessible. PMID 20965579.
  27. ↑ Tanuja Bordia. "Varenicline Is a Potent Partial Agonist at α6β2* Nicotinic Acetylcholine Receptors in Rat and Monkey Striatum". aspetjournals.org.
  28. ↑ 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.
  29. ↑ "[Cytisine as an aid for smoking cessation].". Med Monatsschr Pharm. 15 (1): 20–1. Jan 1992. PMID 1542278.
  30. ↑ Prochaska, BMJ 347:f5198 2013 http://www.bmj.com/content/347/bmj.f5198
  31. ↑ 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 3rd, O'Neill BT (2005). "Varenicline: an alpha4beta2 nicotinic receptor partial agonist for smoking cessation". J. Med. Chem. 48 (10): 3474–3477. doi:10.1021/jm050069n. PMID 15887955.
  32. ↑ 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 1431736Freely accessible. PMID 515342.
  33. ↑ 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.
  34. ↑ Kuehn BM (2006). "FDA speeds smoking cessation drug review". JAMA. 295 (6): 614–614. doi:10.1001/jama.295.6.614. PMID 16467225.
  35. ↑ European Medicines Agency (2011-01-28). "EPAR summary for the public. Champix varenicline". London. Retrieved 2011-02-14.
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