Chemistry:Varenicline

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Short description: Nicotinic receptor agonist
Varenicline
Varenicline.svg
Varenicline ball-and-stick model.png
Clinical data
Pronunciation/vəˈrɛnɪkliːn/ və-REN-i-kleen
Trade namesChampix, Chantix, Tyrvaya, others
Other namesOC-01
AHFS/Drugs.comMonograph
MedlinePlusa606024
License data
Pregnancy
category
  • AU: B3
Routes of
administration		By mouth, nasal spray
Drug classNicotinic agonist
ATC code
Legal status
Legal status
Pharmacokinetic data
Protein binding<20%
MetabolismLimited (<10%)
Elimination half-life24 hours
ExcretionKidney (81–92%)
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
Chemical and physical data
FormulaC13H13N3
Molar mass211.268 g·mol−1
3D model (JSmol)
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Varenicline, sold under the brand names Chantix and Champix among others, is a medication used for smoking cessation[5][7] and for the treatment of dry eye disease.[6][8] It is a nicotinic receptor partial agonist[5] and a cholinergic agonist.[6] When activated, this receptor releases dopamine in the nucleus accumbens, the brain's reward center, thereby reducing cravings and withdrawal symptoms associated with smoking cessation.[9]

Common side effects of varenicline include nausea, insomnia, abnormal dreams, headache, and nasopharyngitis (inflammation of the nose and throat).[7] Despite these potential adverse effects, varenicline has proven efficacy in helping individuals quit smoking. It is estimated that approximately one in eleven smokers who use varenicline successfully remain abstinent from tobacco at six months.[10]

It is on the World Health Organization's List of Essential Medicines.[11] The medication is available as a generic medication.[12] In the United States, varenicline was prescribed over 1 million times in 2020, ranking as the 275th most commonly prescribed medication.[13][14]

Medical uses

Varenicline is indicated for use as an aid to smoking cessation treatment[5] and for the treatment of the signs and symptoms of dry eye disease.[6]

Varenicline is used to help people stop smoking tobacco (smoking cessation). A meta-analysis found that 20% of people treated with varenicline remain abstinent from smoking at one year.[15] In a 2009 meta-analysis, varenicline was found to be more effective than bupropion (odds ratio 1.40) and nicotine replacement therapies (NRT) (odds ratio 1.56).[16]

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 cessation of tobacco smoking.[17][18]

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.[18] Other less common side effects include headache, difficulty sleeping, and vivid dreams. 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 one event of nausea; and for every 24 of 35 treated subjects, there will be an event of constipation or flatulence. Gastrointestinal side-effects lead to discontinuation of the drug in 2% to 8% of people using varenicline.[19][20] 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%).[5]

Depression and suicide

In 2007, the US Food and Drug Administration (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. In 2009, the FDA required varenicline to carry a boxed warning that the medication should be stopped if any of these symptoms are experienced.[21]

A 2014 systematic review (literature research) did not find evidence of an increased suicide risk.[22] Other analyses have reached the same conclusion and found no increased risk of neuropsychiatric side effects with varenicline.[17][18] 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.[23]

In 2016, the FDA removed the black box warning.[24] People are still advised to stop the medication if they "notice any side effects on mood, behavior, or thinking."[24][25][26]

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."[27]

A prior 2011 review had found increased risk of cardiovascular events compared with placebo.[28] Expert commentary in the same journal raised doubts about the methodology of the review,[29][30] concerns which were echoed by the European Medicines Agency and subsequent reviews.[31][32] 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.[32][33][34][35]

Mechanism of action

Varenicline displays full agonism on α7 [[Biology:Alpha-7 nicotinic receptor|]] nicotinic acetylcholine receptors and is a partial agonist on the α4β2, α3β4, and α6β2 subtypes.[36][37][38]

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.[18]

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.[39]

History

Use of Cytisus plants as a smoking substitutes during World War II[40] led to use as a cessation aid in eastern Europe and extraction of cytisine.[41] Cytisine analogs led to varenicline at Pfizer.[42][43][44]

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 trials and perceived lack of safety issues.[45] The agency's approval of the drug came in May 2006.[46][47] In September 2006, it was approved for sale in the European Union.[7]

In September 2021, Pfizer announced a recall of "all lots of its anti-smoking treatment, Chantix [Varenicline], due to high levels of cancer-causing agents called nitrosamines in the pills".[48] This followed a July 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 19 July and 8 August.[49] In June 2021, Pfizer paused distribution of Chantix worldwide;[50] "the distribution halt was out of an abundance of caution, pending further testing", the company said in an email.[51] 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 recorded direct product revenues of more than $1 billion in 2019, $919 million in 2020, and $398 million in 2021 (the lower 2021 revenue was due, in part, to the basic product patent expiration for Chantix in the US in November 2020 and in Europe in September 2021, and the aforementioned Pfizer voluntary recall across multiple markets and a global pause in shipments of Chantix).[52][53]

In October 2021, the 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.[54]

References

  1. ↑ "Champix Product Information". 26 September 2021. https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2010-PI-06102-3. 
  2. ↑ "Champix varenicline (as tartrate) 0.5 mg and 1.0 mg tablet blister pack". https://tga-search.clients.funnelback.com/s/search.html?collection=tga-artg&profile=record&meta_i=124940. 
  3. ↑ "Product information". 22 October 2009. https://health-products.canada.ca/dpd-bdpp/info?lang=eng&code=77655. 
  4. ↑ "Champix 0.5 mg film-coated tablets - Summary of Product Characteristics (SmPC)". https://www.medicines.org.uk/emc/product/266/smpc. 
  5. ↑ 5.0 5.1 5.2 5.3 5.4 "Chantix- varenicline tartrate tablet, film coated Chantix- varenicline tartrate kit". https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=f0ff4f27-5185-4881-a749-c6b7a0ca5696. 
  6. ↑ 6.0 6.1 6.2 6.3 "Tyrvaya- varenicline spray". https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=014c93dc-5737-479c-a9f0-aaadac1ac298. 
  7. ↑ 7.0 7.1 7.2 7.3 "Champix EPAR". 17 September 2018. https://www.ema.europa.eu/en/medicines/human/EPAR/champix.  Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  8. ↑ "Oyster Point Pharma Announces FDA Approval of Tyrvaya (varenicline solution) Nasal Spray for the Treatment of the Signs and Symptoms of Dry Eye Disease" (Press release). Oyster Point Pharma. 18 October 2021. Retrieved 22 October 2021 – via PR Newswire.
  9. ↑ "Smoking Cessation in Chronic Obstructive Pulmonary Disease". Seminars in Respiratory and Critical Care Medicine 36 (4): 491–507. August 2015. doi:10.1055/s-0035-1555610. PMID 26238637. 
  10. ↑ "Varenicline for Smoking Cessation". American Family Physician 96 (5): Online. September 2017. PMID 28925657. https://www.aafp.org/afp/2017/0901/od1.html. Retrieved 26 May 2019. 
  11. ↑ World Health Organization model list of essential medicines: 22nd list (2021). Geneva: World Health Organization. 2021. WHO/MHP/HPS/EML/2021.02. 
  12. ↑ "Varenicline tablet, film coated". 27 January 2023. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=78d1857f-8708-5410-792f-4a3e5e7971a5. 
  13. ↑ "The Top 300 of 2020". https://clincalc.com/DrugStats/Top300Drugs.aspx. 
  14. ↑ "Varenicline - Drug Usage Statistics". https://clincalc.com/DrugStats/Drugs/Varenicline. 
  15. ↑ "Diminishing benefit of smoking cessation medications during the first year: a meta-analysis of randomized controlled trials". Addiction 113 (5): 805–816. May 2018. doi:10.1111/add.14134. PMID 29377409. 
  16. ↑ "Efficacy of pharmacotherapies for short-term smoking abstinance: a systematic review and meta-analysis". Harm Reduction Journal 6: 25. September 2009. doi:10.1186/1477-7517-6-25. PMID 19761618. 
  17. ↑ 17.0 17.1 "Pharmacological interventions for smoking cessation: an overview and network meta-analysis". The Cochrane Database of Systematic Reviews 5 (5): CD009329. May 2013. doi:10.1002/14651858.CD009329.pub2. PMID 23728690. 
  18. ↑ 18.0 18.1 18.2 18.3 "Emerging drugs for the treatment of tobacco dependence: 2014 update". Expert Opinion on Emerging Drugs 19 (2): 243–60. June 2014. doi:10.1517/14728214.2014.899580. PMID 24654737. 
  19. ↑ "Gastrointestinal adverse effects of varenicline at maintenance dose: a meta-analysis". BMC Clinical Pharmacology 11 (1): 15. September 2011. doi:10.1186/1472-6904-11-15. PMID 21955317. 
  20. ↑ American Cancer Society. "Cancer Drug Guide: Varenicline". http://www.cancer.org/docroot/CDG/content/CDG_Varenicline.asp. 
  21. ↑ "Public Health Advisory: FDA Requires New Boxed Warnings for the Smoking Cessation Drugs Chantix and Zyban". https://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/DrugSafetyInformationforHeathcareProfessionals/PublicHealthAdvisories/ucm169988.htm. 
  22. ↑ "Varenicline as a Cause of Suicidal Outcomes". Nicotine & Tobacco Research 18 (1): 2–9. January 2016. doi:10.1093/ntr/ntu275. PMID 25572451. 
  23. ↑ "Cardiovascular and neuropsychiatric risks of varenicline: a retrospective cohort study". The Lancet. Respiratory Medicine 3 (10): 761–8. October 2015. doi:10.1016/S2213-2600(15)00320-3. PMID 26355008. 
  24. ↑ 24.0 24.1 "Safety Alerts for Human Medical Products - Chantix (varenicline) and Zyban (bupropion): Drug Safety Communication - Mental Health Side Effects Revised". 16 December 2016. https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-fda-revises-description-mental-health-side-effects-stop-smoking. 
  25. ↑ "Electron paramagnetic resonance and circular dichroism studies on milk xanthine oxidase". The Journal of Biological Chemistry 244 (10): 2614–20. May 1969. doi:10.1186/1753-6561-9-S1-A31. PMID 4306032. 
  26. ↑ "Varenicline and Depression: a Literature Review". World Journal of Medical Education and Research 9 (1): 24–29. 2015. http://wjmer.co.uk/library/downloads/pdf/vol_9_1.pdf. Retrieved 14 April 2017. 
  27. ↑ "FDA Drug Safety Communication: Chantix (varenicline) may increase the risk of certain cardiovascular adverse events in patients with cardiovascular disease". U.S. Food and Drug Administration (FDA). 16 June 2011. https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-chantix-varenicline-may-increase-risk-certain-cardiovascular-adverse. 
  28. ↑ "Risk of serious adverse cardiovascular events associated with varenicline: a systematic review and meta-analysis". CMAJ 183 (12): 1359–66. September 2011. doi:10.1503/cmaj.110218. PMID 21727225. 
  29. ↑ "Varenicline: quantifying the risk". CMAJ 183 (12): 1404; author reply 1405, 1407. September 2011. doi:10.1503/cmaj.111-2063. PMID 21896705. 
  30. ↑ "Varenicline: cardiovascular safety". CMAJ 183 (12): 1407–8; author reply 1408. September 2011. doi:10.1503/cmaj.111-2073. PMID 21896709. 
  31. ↑ "European Medicine Agency confirms positive benefit-risk balance for Champix". 21 July 2011. 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. 
  32. ↑ 32.0 32.1 "Risk of cardiovascular serious adverse events associated with varenicline use for tobacco cessation: systematic review and meta-analysis". BMJ 344: e2856. May 2012. doi:10.1136/bmj.e2856. PMID 22563098. 
  33. ↑ "Cardiovascular events associated with smoking cessation pharmacotherapies: a network meta-analysis". Circulation 129 (1): 28–41. January 2014. doi:10.1161/CIRCULATIONAHA.113.003961. PMID 24323793. 
  34. ↑ "Network meta-analysis demonstrates the safety of pharmacotherapy for smoking cessation in cardiovascular patients". Evidence-Based Medicine 19 (5): 193. October 2014. doi:10.1136/eb-2014-110030. PMID 24917603. 
  35. ↑ "ACP Journal Club. Review: Nicotine replacement therapy increases CVD events; bupropion and varenicline do not". Annals of Internal Medicine 160 (8): JC2. April 2014. doi:10.7326/0003-4819-160-8-201404150-02002. PMID 24733219. 
  36. ↑ "Varenicline is a partial agonist at alpha4beta2 and a full agonist at alpha7 neuronal nicotinic receptors". Molecular Pharmacology 70 (3): 801–5. September 2006. doi:10.1124/mol.106.025130. PMID 16766716. 
  37. ↑ "Nicotine receptors and depression: revisiting and revising the cholinergic hypothesis". Trends in Pharmacological Sciences 31 (12): 580–6. December 2010. doi:10.1016/j.tips.2010.09.004. PMID 20965579. 
  38. ↑ "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. August 2012. doi:10.1124/jpet.112.194852. PMID 22550286. 
  39. ↑ "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. January 2006. doi:10.1124/dmd.105.006767. PMID 16221753. 
  40. ↑ "[Cytisine as an aid for smoking cessation]". Medizinische Monatsschrift für Pharmazeuten 15 (1): 20–1. January 1992. PMID 1542278. 
  41. ↑ "Cytisine, the world's oldest smoking cessation aid". BMJ 347: f5198. August 2013. doi:10.1136/bmj.f5198. PMID 23974638. https://escholarship.org/uc/item/8qq3r737. Retrieved 13 September 2020. 
  42. ↑ "Varenicline: an alpha4beta2 nicotinic receptor partial agonist for smoking cessation". Journal of Medicinal Chemistry 48 (10): 3474–7. May 2005. doi:10.1021/jm050069n. PMID 15887955. 
  43. ↑ "Review and evaluation of methods of smoking cessation, 1969-77. Summary of a monograph". Public Health Reports 94 (6): 558–63. 1979. PMID 515342. 
  44. ↑ "Cytisine for smoking cessation: a literature review and a meta-analysis". Archives of Internal Medicine 166 (15): 1553–9. 2006. doi:10.1001/archinte.166.15.1553. PMID 16908787. 
  45. ↑ "FDA speeds smoking cessation drug review". JAMA 295 (6): 614. February 2006. doi:10.1001/jama.295.6.614. PMID 16467225. 
  46. ↑ "FDA Approves Novel Medication for Smoking Cessation". U.S. Food and Drug Administration (FDA) (Press release). 11 May 2006. Archived from the original on 10 July 2009. Retrieved 26 September 2021.
  47. ↑ "Drug Approval Package: Chantix (Varenicline) NDA #021928". 16 June 2006. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2006/021928_s000_ChantixTOC.cfm. 
  48. ↑ "Pfizer recalls all lots of anti-smoking drug over carcinogen presence". Reuters. 16 September 2021. https://www.reuters.com/business/healthcare-pharmaceuticals/pfizer-recalls-all-lots-anti-smoking-drug-over-carcinogen-presence-2021-09-16/. 
  49. ↑ "FDA Updates and Press Announcements on Nitrosamine in in Varenicline". 17 September 2021. https://www.fda.gov/drugs/drug-safety-and-availability/fda-updates-and-press-announcements-nitrosamine-varenicline-chantix. 
  50. ↑ "Carcinogen Contamination Halts Sales of Smoking-Cessation Drug". 25 June 2021. https://khn.org/morning-breakout/carcinogen-contamination-halts-sales-of-smoking-cessation-drug/. 
  51. ↑ "Pfizer Pauses Chantix Distribution After Finding Carcinogen". Bloomberg.com. 24 June 2021. https://www.bloomberg.com/news/articles/2021-06-24/pfizer-pauses-chantix-distribution-after-finding-carcinogen. 
  52. ↑ "Pfizer Inc. 2020 Form 10-K Annual Report, 25 February 2021 |access-date=30 December 2022". https://s28.q4cdn.com/781576035/files/doc_financials/2020/AR/PFE-2020-Form-10K-FINAL.pdf. 
  53. ↑ "Pfizer Inc. 2021 Form 10-K Annual Report, 24 Feb 2022 |access-date=30 December 2022". https://s28.q4cdn.com/781576035/files/doc_financials/2021/ar/PFE-2021-Form-10K-FINAL.pdf. 
  54. ↑ "FDA Approves First Nasal Spray for Dry Eye". WebMD. 27 October 2021. https://www.webmd.com/eye-health/news/20211027/nasal-spray-for-dry-eye. 

External links

  • Clinical trial number NCT03636061 for "Clinical Trial to Evaluate the Efficacy of OC-01 Nasal Spray on Signs and Symptoms of Dry Eye Disease (The ONSET-1 Study)" at ClinicalTrials.gov
  • Clinical trial number NCT04036292 for "Evaluating the Efficacy and Safety of OC-01 (Varenicline) Nasal Spray on Dry Eye Disease" at ClinicalTrials.gov



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