Varenicline

Varenicline
Names
Trade namesChampix, Chantix, others
IUPAC name
  • 7,8,9,10-Tetrahydro-6,10-methano-6H-pyrazino[2,3-h] [3]benzazepine
Clinical data
WHO AWaReUnlinkedWikibase error: ⧼unlinkedwikibase-error-statements-entity-not-set⧽
Pregnancy
category
  • AU: B3
  • US: C (Risk not ruled out)
    Routes of
    use    		By mouth
    External links
    AHFS/Drugs.comMonograph
    MedlinePlusa606024
    Legal
    License data
    Legal status
    Pharmacokinetics
    Protein binding<20%
    MetabolismLimited (<10%)
    Elimination half-life24 hours
    ExcretionKidney (81–92%)
    Chemical and physical data
    FormulaC13H13N3
    Molar mass211.267 g·mol−1
    3D model (JSmol)
    SMILES
    • n1c2cc3c(cc2ncc1)[C@@H]4CNC[C@H]3C4
    InChI
    • InChI=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+ checkY
    • Key:JQSHBVHOMNKWFT-DTORHVGOSA-N checkY

    Varenicline, sold under the trade name Champix among others, is a medication used help people stop smoking.[1] It is the recommended initial treatment together with behavioral support.[2][3] It helps one of every 11 people who smoke, stop for at least six months.[4] Varenicline is taken by mouth.[1]

    Common side effects include unusual dreams, nausea, and constipation.[1] Serious side effects may include depression, anxiety, seeing or hearing things that others do not, allergic reactions, thoughts of suicide, and seizures.[1] There is no clear harm from use in human pregnancy but such use has not been well studied and there may be harm in pregnancy in other animals.[5] It works by binding to a type of nicotinic acetylcholine receptors in the brain, decreasing the ability of nicotine to attach, and thus reducing the desire to smoke.[1]

    Varenicline was approved for medical use in the United States and Europe in 2006.[1][6] It is on the World Health Organization's List of Essential Medicines.[7] As of 2020 it costs about 440 USD in the United States for the first month (7.60 USD per tablet).[8][9] In the United Kingdom this amount is about 55 pounds.[3] It may become avaliable as a generic medication in the US in 2020.[8]

    Medical uses

    Varenicline is used to help people stop smoking tobacco. While effective less than 20% of people treated with varenicline remain abstinent from smoking at one year.[10] It is more effective than bupropion (odds ratio 1.40) and nicotine replacement therapies (NRT) (odds ratio 1.56).[11][2]

    A 2013 Cochrane review 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. Varenicline was more efficacious than bupropion or NRT and as effective as combination NRT for tobacco smoking cessation.[12][13]

    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.[14]

    While it may be used in people with mental health problems, this group should be monitored closely.[3] It is recommended that people reduce the amount of alcohol they drink when on varenicline.[15]

    Dosage

    The dose in adult is typically 0.5 mg once a day for the first three days, than 0.5 mg twice a day for the next four days, followed by 1 mg twice a day for a total of 12 weeks.[1] An additional 12 weeks may be used if treatment has been successful.[1]

    Side effects

    Mild nausea is the most common side effect and is seen in approximately 30% of people though this rarely (<3%) results in stopping the medication.[13] 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. 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.[16][17] 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%).[18]

    Mental health

    In 2007, the US FDA had 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. In 2009, the US FDA required varenicline to carry a boxed warning that the drug should be stopped if any of these symptoms are experienced.[19]

    A 2014 review did not find evidence of an increased suicide risk.[20] Other analyses have reached the same conclusion and found no increased risk of neuropsychiatric side effects with varenicline.[12][13] 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.[21]

    In 2016 the FDA removed the black box warning.[22] People are still advised to stop the medication if they "notice any side effects on mood, behavior, or thinking."[22][23][24]

    Heart 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."[25]

    A prior 2011 review had found increased risk of cardiovascular events compared with placebo.[26] Expert commentary in the same journal raised doubts about the methodology of the review,[27][28] concerns which were echoed by the European Medicines Agency and subsequent reviews.[29][30] 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 reviews have found no increase in overall or serious adverse cardiovascular events (including for individuals at risk of developing cardiovascular disease) associated with varenicline use.[30][31][32][33]

    Pregnancy

    Varenicline has not been tested in pregnant women and therefore is not recommended in this group.[34] 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.[35] An alternate drug is preferred for smoking cessation during breastfeeding due to lack of information and based on the animal studies on nicotine.[36]

    Mechanism of action

    Varenicline is a nicotinic agonist and has a high-affinity partial agonist for the α4β2 nicotinic acetylcholine receptor subtype (nACh) that leads to the release of dopamine in the nucleus accumbens when activated, and therefore, has the capacity to reduce the feelings of craving and withdrawal caused by smoking cessation.[37] 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.

    Varenicline displays full agonism on α7 nicotinic acetylcholine receptors and is a partial agonist on the α4β2, α3β4, and α6β2 subtypes.[38][39][40] 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.[13]

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

    History

    Use of Cytisus plant as a smoking substitute during World War II[42] led to use as a cessation aid in eastern Europe and extraction of cytisine.[43] Cytisine analogs led to varenicline at Pfizer.[44][45][46]

    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.[47] The agency's approval of the drug came on May 11, 2006.[14] 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.[6]

    Society and culture

    Cost

    As of 2020 it costs about 440 USD in the United States for the first month (7.60 USD per tablet).[8][9] In the United Kingdom this amount is about 55 pounds.[3]

    • Varenicline costs (US)
      Varenicline costs (US)
    • Varenicline prescriptions (US)
      Varenicline prescriptions (US)

    References

    1. 1 2 3 4 5 6 7 8 "Varenicline tartrate Monograph for Professionals". Drugs.com. Archived from the original on 12 August 2020. Retrieved 19 August 2020.
    2. 1 2 Leone, Frank T.; Zhang, Yuqing; Evers-Casey, Sarah; Evins, A. Eden; Eakin, Michelle N.; Fathi, Joelle; Fennig, Kathleen; Folan, Patricia; Galiatsatos, Panagis; Gogineni, Hyma; Kantrow, Stephen; Kathuria, Hasmeena; Lamphere, Thomas; Neptune, Enid; Pacheco, Manuel C.; Pakhale, Smita; Prezant, David; Sachs, David P. L.; Toll, Benjamin; Upson, Dona; Xiao, Dan; Cruz-Lopes, Luciane; Fulone, Izabela; Murray, Rachael L.; O’Brien, Kelly K.; Pavalagantharajah, Sureka; Ross, Stephanie; Zhang, Yuan; Zhu, Meng; Farber, Harold J. (15 July 2020). "Initiating Pharmacologic Treatment in Tobacco-Dependent Adults. An Official American Thoracic Society Clinical Practice Guideline". American Journal of Respiratory and Critical Care Medicine. 202 (2): e5–e31. doi:10.1164/rccm.202005-1982ST.
    3. 1 2 3 4 BNF 79 : March 2020. London: Royal Pharmaceutical Society. 2020. p. 515. ISBN 9780857113658.
    4. ↑ Crawford, P; Cieslak, D (September 2017). "Varenicline for Smoking Cessation". American Family Physician. 96 (5): Online. PMID 28925657. Archived from the original on 2019-05-26. Retrieved 2019-05-26.
    5. ↑ "Varenicline Use During Pregnancy". Drugs.com. Archived from the original on 27 January 2021. Retrieved 19 August 2020.
    6. 1 2 European Medicines Agency (2011-01-28). "EPAR summary for the public. Champix varenicline". London. Archived from the original on 2011-07-20. Retrieved 2011-02-14.
    7. ↑ World Health Organization (2021). World Health Organization model list of essential medicines: 22nd list (2021). Geneva: World Health Organization. hdl:10665/345533. WHO/MHP/HPS/EML/2021.02.
    8. 1 2 3 "Varenicline Prices, Coupons & Savings Tips". GoodRx. Retrieved 19 August 2020.
    9. 1 2 "NADAC as of 2020-08-19 | Data.Medicaid.gov". Centers for Medicare and Medicaid Services. Retrieved 19 August 2020.{{cite web}}: CS1 maint: url-status (link)
    10. ↑ Rosen LJ, Galili T, Kott J, Goodman M, Freedman LS (May 2018). "Diminishing benefit of smoking cessation medications during the first year: a meta-analysis of randomized controlled trials". Addiction. 113 (5): 805–816. doi:10.1111/add.14134. PMC 5947828. PMID 29377409.
    11. ↑ Mills EJ, Wu P, Spurden D, Ebbert JO, Wilson K (September 2009). "Efficacy of pharmacotherapies for short-term smoking abstinance: a systematic review and meta-analysis". Harm Reduction Journal. 6: 25. doi:10.1186/1477-7517-6-25. PMC 2760513. PMID 19761618.
    12. 1 2 Cahill K, Stevens S, Perera R, Lancaster T (May 2013). "Pharmacological interventions for smoking cessation: an overview and network meta-analysis". The Cochrane Database of Systematic Reviews (Systematic Review & Meta-Analysis). 5 (5): CD009329. doi:10.1002/14651858.CD009329.pub2. PMID 23728690.
    13. 1 2 3 4 Elrashidi MY, Ebbert JO (June 2014). "Emerging drugs for the treatment of tobacco dependence: 2014 update". Expert Opinion on Emerging Drugs (Review). 19 (2): 243–60. doi:10.1517/14728214.2014.899580. PMID 24654737.
    14. 1 2 U.S. Food and Drug Administration.FDA Approves Novel Medication for Smoking Cessation Archived 2017-01-18 at the Wayback Machine. Press release, 11 May 2006.
    15. ↑ Research, Center for Drug Evaluation and (18 June 2019). "Drug Safety and Availability - FDA Drug Safety Communication: FDA updates label for stop smoking drug Chantix (varenicline) to include potential alcohol interaction, rare risk of seizures, and studies of side effects on mood, behavior, or thinking". www.fda.gov. Archived from the original on 24 November 2017. Retrieved 20 November 2017.
    16. ↑ Leung LK, Patafio FM, Rosser WW (September 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.
    17. ↑ American Cancer Society. "Cancer Drug Guide: Varenicline". Archived from the original on 2008-06-30. Retrieved 2008-01-19.
    18. ↑ "DailyMed - CHANTIX- varenicline tartrate". nih.gov. Archived from the original on 2014-04-22. Retrieved 2014-04-21.
    19. ↑ FDA. "Public Health Advisory: FDA Requires New Boxed Warnings for the Smoking Cessation Drugs Chantix and Zyban". Archived from the original on 2010-10-19. Retrieved 2009-07-01.
    20. ↑ Hughes JR (January 2016). "Varenicline as a Cause of Suicidal Outcomes". Nicotine & Tobacco Research. 18 (1): 2–9. doi:10.1093/ntr/ntu275. PMID 25572451.
    21. ↑ Kotz D, Viechtbauer W, Simpson C, van Schayck OC, West R, Sheikh A (October 2015). "Cardiovascular and neuropsychiatric risks of varenicline: a retrospective cohort study". The Lancet. Respiratory Medicine (retrospective cohort). 3 (10): 761–8. doi:10.1016/S2213-2600(15)00320-3. PMC 4593936. PMID 26355008.
    22. 1 2 Commissioner, Office of the. "Safety Alerts for Human Medical Products - Chantix (varenicline) and Zyban (bupropion): Drug Safety Communication - Mental Health Side Effects Revised". www.fda.gov. Archived from the original on 20 December 2016. Retrieved 20 December 2016.
    23. ↑ Palmer G, Massey V (May 1969). "Electron paramagnetic resonance and circular dichroism studies on milk xanthine oxidase". The Journal of Biological Chemistry. 244 (10): 2614–20. doi:10.1186/1753-6561-9-S1-A31. PMC 4306032.
    24. ↑ Yeung E, Bachi B, Long B, Lee J, Chao Y (2015). "Varenicline and Depression: a Literature Review" (PDF). World Journal of Medical Education and Research. 9 (1): 24–29. Archived (PDF) from the original on 2017-04-15. Retrieved 2017-04-14.
    25. ↑ "FDA Drug Safety Communication: Chantix (varenicline) may increase the risk of certain cardiovascular adverse events in patients with cardiovascular disease". 2011-06-16. Archived from the original on 2019-04-24. Retrieved 2019-12-16.
    26. ↑ Singh S, Loke YK, Spangler JG, Furberg CD (September 2011). "Risk of serious adverse cardiovascular events associated with varenicline: a systematic review and meta-analysis". CMAJ. 183 (12): 1359–66. doi:10.1503/cmaj.110218. PMC 3168618. PMID 21727225.
    27. ↑ Takagi H, Umemoto T (September 2011). "Varenicline: quantifying the risk". CMAJ. 183 (12): 1404, author reply 1405, 1407. doi:10.1503/cmaj.111-2063. PMC 3168634. PMID 21896705.
    28. ↑ Samuels L (September 2011). "Varenicline: cardiovascular safety". CMAJ. 183 (12): 1407–8, author reply 1408. doi:10.1503/cmaj.111-2073. PMC 3168639. PMID 21896709.
    29. ↑ "European Medicine Agency confirms positive benefit-risk balance for Champix". 2011-07-21. Archived from the original on 2018-02-21. Retrieved 2021-11-10.
    30. 1 2 Prochaska JJ, Hilton JF (May 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 3344735. PMID 22563098.
    31. ↑ 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. PMC 4258065. PMID 24323793.
    32. ↑ 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.
    33. ↑ 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.
    34. ↑ Claire, Ravinder; Chamberlain, Catherine; Davey, Mary-Ann; Cooper, Sue E.; Berlin, Ivan; Leonardi-Bee, Jo; Coleman, Tim (4 March 2020). "Pharmacological interventions for promoting smoking cessation during pregnancy". The Cochrane Database of Systematic Reviews. 3: CD010078. doi:10.1002/14651858.CD010078.pub3. ISSN 1469-493X. PMC 7059898. PMID 32129504.
    35. ↑ 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 3352787. PMID 22586193.
    36. ↑ "LactMed". nih.gov. Archived from the original on 2019-04-11. Retrieved 2014-04-21.
    37. ↑ Tashkin DP (August 2015). "Smoking Cessation in Chronic Obstructive Pulmonary Disease". Seminars in Respiratory and Critical Care Medicine. 36 (4): 491–507. doi:10.1055/s-0035-1555610. PMID 26238637.
    38. ↑ Mihalak KB, Carroll FI, Luetje CW (September 2006). "Varenicline is a partial agonist at alpha4beta2 and a full agonist at alpha7 neuronal nicotinic receptors". Molecular Pharmacology. 70 (3): 801–5. doi:10.1124/mol.106.025130. PMID 16766716.
    39. ↑ Mineur YS, Picciotto MR (December 2010). "Nicotine receptors and depression: revisiting and revising the cholinergic hypothesis". Trends in Pharmacological Sciences. 31 (12): 580–6. doi:10.1016/j.tips.2010.09.004. PMC 2991594. PMID 20965579.
    40. ↑ Bordia T, Hrachova M, Chin M, McIntosh JM, Quik M (August 2012). "Varenicline is a potent partial agonist at α6β2* nicotinic acetylcholine receptors in rat and monkey striatum". The Journal of Pharmacology and Experimental Therapeutics. 342 (2): 327–34. doi:10.1124/jpet.112.194852. PMC 3400806. PMID 22550286.
    41. ↑ Obach RS, Reed-Hagen AE, Krueger SS, Obach BJ, O'Connell TN, Zandi KS, Miller S, Coe JW (January 2006). "Metabolism and disposition of varenicline, a selective alpha4beta2 acetylcholine receptor partial agonist, in vivo and in vitro". Drug Metabolism and Disposition. 34 (1): 121–30. doi:10.1124/dmd.105.006767. PMID 16221753.
    42. ↑ Seeger R (January 1992). "[Cytisine as an aid for smoking cessation]". Medizinische Monatsschrift Fur Pharmazeuten. 15 (1): 20–1. PMID 1542278.
    43. ↑ Prochaska JJ, Das S, Benowitz NL (August 2013). "Cytisine, the world's oldest smoking cessation aid". BMJ. 347: f5198. doi:10.1136/bmj.f5198. PMID 23974638.
    44. ↑ 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 (May 2005). "Varenicline: an alpha4beta2 nicotinic receptor partial agonist for smoking cessation". Journal of Medicinal Chemistry. 48 (10): 3474–7. doi:10.1021/jm050069n. PMID 15887955.
    45. ↑ Schwartz JL (1979). "Review and evaluation of methods of smoking cessation, 1969-77. Summary of a monograph". Public Health Reports. 94 (6): 558–63. PMC 1431736. PMID 515342.
    46. ↑ Etter JF (2006). "Cytisine for smoking cessation: a literature review and a meta-analysis". Archives of Internal Medicine. 166 (15): 1553–9. doi:10.1001/archinte.166.15.1553. PMID 16908787.
    47. ↑ Kuehn BM (February 2006). "FDA speeds smoking cessation drug review". JAMA. 295 (6): 614. doi:10.1001/jama.295.6.614. PMID 16467225.
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