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Varenicline
Systematic (IUPAC) name
7,8,9,10-tetrahydro- 6,10-methano- 6H-pyrazino (2,3-h)(3) benzazepine
Identifiers
CAS number 249296-44-4 375815-87-5
ATC code N07BA03
PubChem 170361
ChemSpider 4470510
Chemical data
Formula C 13H13N3  
Mol. mass 211.267 g/mol
SMILES eMolecules & PubChem
Pharmacokinetic data
Bioavailability  ?
Protein binding <20%
Metabolism Limited (<10%)
Half life 24 hours
Excretion Renal (81–92%)
Therapeutic considerations
Licence data

EU EMEA:linkUS FDA:link

Pregnancy cat. C(US)
Legal status Prescription only
Routes Oral
 Yes check.svgY(what is this?)  (verify)

Varenicline (trade name Chantix in the USA and Champix in 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. In this respect, it is similar to cytisine and different from the nicotinic antagonist, bupropion, and nicotine replacement therapies (NRTs) like nicotine patches (commonly, "the patch") and nicotine gum. As a partial agonist, it both reduces cravings for and decreases the pleasurable effects of cigarettes and other tobacco products, and through these mechanisms it can assist some patients to quit smoking.

Contents

Indications

Varenicline is indicated for (suggested for use in) smoking cessation. It is an alternative to NRTs and agonist medication and has demonstrated greater efficacy than them in comparable studies.[1] after one year, the rate of continuous abstinence was 10% for placebo, 15% for bupropion, and 23% for varenicline.[2]

The U.S. Food and Drug Administration (FDA) has approved its use for twelve weeks. If smoking cessation has been achieved it may be continued for another twelve weeks.[3]

Varenicline has not been tested in those under 18 years old, or pregnant women, and therefore is not recommended for use by these groups. Women currently breastfeeding should also avoid this product, since varenicline may pass into the breast milk, leading to unknown effects on the child.

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.[4]

Acting as an agonist varenicline binds to, and partially stimulates, the receptor without creating a full nicotine effect on the release of dopamine. Varenicline also competitively binds to α4β2 receptors blocking the ability of nicotine to stimulate the central nervous mesolimbic dopamine system.

Pharmacokinetics

Most of the active compound is excreted renally (92–93%). A small proportion is glucuronidated, oxidated, N-formylated or conjugated to a hexose.[5] The elimination half-life is about 24 hours.

Side effects

Common

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.[6]

Depression and suicide

In November 2007, the FDA announced it had received post-marketing reports that patients using Chantix for smoking cessation had experienced several serious symptoms, 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.[7] In May 2008, Pfizer updated the safety information associated with Chantix, noting that "some patients have reported changes in behavior, agitation, depressed mood, suicidal thoughts or actions." [8]

The Institute for Safe Medication Practices (ISMP) conducted an analysis of post-marketing adverse effects reports received by the FDA. According to this analysis, in the fourth quarter of 2007 varenicline accounted for more reports of serious side effects than any other drug. Suicidal acts and ideation, psychosis, and hostility or aggression, including homicidal ideation, were the most prominent psychiatric side effects. Multiple reports suggested that varenicline may be related to the loss of glycemic control and new onset of diabetes, heart rhythm disturbances, skin reactions, vision disturbances, seizures, abnormal muscle spasms and other movement disorders. ISMP noted that the reports do not establish causality and only identify potential causes, and concluded that further research and a priority review of the data by the FDA is necessary.[9]

A study conducted by Group Health Center for Health Studies, SRI International, and Free & Clear, Inc., published in the Journal of General Internal Medicine on February 24, 2009, concluded that people with a history of depression are not qualitatively more susceptible to the reported psychiatric side effects of varenicline than people with no history of depression. [10]

On June 4, 2009, the FDA announced it was evaluating varenicline for additional potential side effects, including angioedema, serious skin reactions, visual impairment, and accidental injury. [11] On July 1, 2009, the Food and Drug Administration required varenicline and Zyban (bupropion) to carry a black box warning, the agency's strongest safety warning, due to side effects including depression, suicidal thoughts, and suicidal actions. [12]

A cohort study published in November 2009 analyzed medical records of 80,660 persons attempting to quit smoking (10,973 of which were using Varenicline) and found no evidence of an increased risk of depression, self-harm and suicidality, although a small increase could not be ruled out on statistical grounds.[13]

History

Varenicline was discovered at Pfizer through the research aimed at modifying the structure of cytisine.[14][15][16]

Varenicline received a "priority review" by the 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.[17] The agency's approval of the drug came on May 11, 2006.[3] Beginning August 1, 2006, varenicline has been available for sale in the United States, and on September 29, 2006, it was approved for sale in the European Union.

Controversy

  • On September 3, 2007, musician Carter Albrecht was shot and killed by his girlfriend's neighbor. Albrecht's girlfriend and others close to him have publicly claimed that Chantix contributed to the erratic behavior which led to his death. [18]
  • On Thursday, May 22, 2008, The New York Times reported that the U.S. Federal Aviation Administration (F.A.A.) had announced the day before a ban on the use of Chantix (varenicline tartrate) for both pilots and air traffic controllers, due to concerns with possible adverse neuropsychiatric effects which could be detrimental to public safety.[19]
  • On Sunday, May 25, 2008, The Los Angeles Times reported that over 2 dozen traffic accidents had been linked to Chantix and reported to the FDA. Warnings had previously been issued by Pfizer regarding the risks of Chantix while driving. However, these warnings have largely been ignored by doctors and patients.[20]
  • On October 23, 2008, the Institute for Safe Medication Practices issued an analysis of prescription drug-related injuries reported to the FDA during the first quarter of 2008. According to the report, varenicline had more reported incidents than any other drug, with 1001 new cases of adverse effects and 50 more deaths reported. (Heparin, the drug with the second highest number of injury reports, had 779 new cases, most of which were connected to a contaminant inadvertently introduced into the drug in early 2008). In comparison, the ISMP reported that in the first quarter of 2008 there were 17 serious injury reports for nicotine-replacement products, and 44 reports for bupropion (sold as Zyban as a smoking cessation medication). Varenicline did not rank in the ten drugs with the most related deaths, but did rank first in reports of suicide or self-injury, with 228 reports citing these effects. The ISMP noted that the high number of varenicline-related injury reports may be related to the publicity surrounding the medication's potential side effects. [22]
  • On January 15, 2009, the Institute for Safe Medication Practices issued its analysis of prescription drug-related injuries reported to the FDA during the second quarter of 2008. During this period there were 910 newly-reported cases of serious injury attributed to Varenicline, including 38 deaths. In addition to the above-reported psychiatric effects, the report noted increasing evidence linking Varenicline to "potentially life-threatening allergic reactions." According to the report, Varenicline had the second-highest number of new injury reports during this quarter. By comparison, Digoxin had the highest number, with 1882 injury reports and 650 associated deaths, the majority of which were linked to a manufacturing quality control problem and subsequent recall of the Digitek brand of Digoxin. [23]
  • On February 4, 2009, Health Canada announced that it had received more than 800 complaints from Canadian users, many of them reporting mood swings, depression or suicidal thoughts.[24]

See also

  • Drug Discovery and Development: Nicotinic Acetylcholine Receptor Agonists

References

  1. ^ Jorenby D E, Hays J T, Rigotti N A, Azoulay S, Watsky E J, Williams K E, Billing C B, Gong J, Reeves K R (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.  
  2. ^ Jorenby D E, Hays J T, Rigotti N A, Azoulay S, Watsky E J, Williams K E, Billing C B, Gong J, Reeves K R (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.  
  3. ^ a b U.S. Food and Drug Administration. FDA Approves Novel Medication for Smoking Cessation. Press release, 11 May 2006.
  4. ^ 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): 801–5. doi:10.1124/mol.106.025130. PMID 16766716.  
  5. ^ Obach RS, Reed-Hagen AE, Krueger SS, Obach BJ, O'Connell TN, Zandi KS, Miller S, Coe JW. Metabolism and disposition of varenicline, a selective alpha4beta2 acetylcholine receptor partial agonist, in vivo and in vitro. Drug Metab Dispos 2006;34:121-30. PMID 16221753.
  6. ^ American Cancer Society. "Cancer Drug Guide: Varenicline". http://www.cancer.org/docroot/CDG/content/CDG_Varenicline.asp. Retrieved 2008-01-19.  
  7. ^ "Early Communication About an Ongoing Safety Review: Varenicline (marketed as Chantix)". United States Food and Drug Administration. November 20 2007. http://www.fda.gov/cder/drug/early_comm/varenicline.htm. Retrieved 2007-11-21.  
  8. ^ "Important Information about Chantix". http://www.chantix.com/content/important_info_about_chantix.jsp. Retrieved 2008-05.  
  9. ^ Institute for Safe Medication Practices. "Strong Safety Signal Seen for New Varenicline Risks". http://www.ismp.org/quarterwatch/chantixReport.asp.  
  10. ^ McClure JB, Swan GE, Jack L, et al. (May 2009). "Mood, side-effects and smoking outcomes among persons with and without probable lifetime depression taking varenicline". J Gen Intern Med 24 (5): 563–9. doi:10.1007/s11606-009-0926-8. PMID 19238488. PMC 2669860. http://www.springerlink.com/content/77207452k3822r3v/fulltext.html.  
  11. ^ FDA. "Potential Signals of Serious Risks/New Safety Information Identified from the Adverse Event Reporting System (AERS) between October – December 2008". http://www.springerlink.com/content/77207452k3822r3v/. Retrieved 2009-03-02.  
  12. ^ Aiden Standard. "FDA requires Chantix, Zyban to have warning". http://www.aikenstandard.com/Nation/f0340-BC-US-FDA-ChantixWarnin-3rdLd-Writethru-07-01-0564. Retrieved 2009-07-01.  
  13. ^ Gunnell D, Irvine D, Wise L, Davies C, Martin RM (2009). "Varenicline and suicidal behaviour: a cohort study based on data from the General Practice Research Database". BMJ 339: b3805. doi:10.1136/bmj.b3805. PMID 19797344. PMC 2755726. http://www.bmj.com/cgi/content/full/339/oct01_1/b3805.  
  14. ^ Coe JW, Brooks PR, Vetelino MG, et al. (2005). "Varenicline: an alpha4beta2 nicotinic receptor partial agonist for smoking cessation". J. Med. Chem. 48 (10): 3474–7. doi:10.1021/jm050069n. PMID 15887955.  
  15. ^ Schwartz JL (1979). "Review and evaluation of methods of smoking cessation, 1969–77. Summary of a monograph". Public Health Rep 94 (6): 558–63. PMID 515342.  
  16. ^ Etter JF (2006). "Cytisine for smoking cessation: a literature review and a meta-analysis". Arch. Intern. Med. 166 (15): 1553–9. doi:10.1001/archinte.166.15.1553. PMID 16908787. http://archinte.ama-assn.org/cgi/content/full/166/15/1553.  
  17. ^ Kuehn BM (2006). "FDA speeds smoking cessation drug review". JAMA 295 (6): 614. doi:10.1001/jama.295.6.614. PMID 16467225.  
  18. ^ "Did Quit-Smoking Pill Lead to Man's Death?". abcnews.com. 2007-09-19. http://www.abcnews.go.com/GMA/OnCall/story?id=3623085&page=1. Retrieved 2007-10-25.  
  19. ^ Saul, Stephanie (2008-05-22). "F.A.A. Bans Antismoking Drug, Citing Side Effects". New York Times. http://www.nytimes.com/2008/05/22/business/22drug.html. Retrieved 2008-05-22.  
  20. ^ Alonso-Zaldivar, Ricardo (2008-05-25). "Drug taken to stop smoking is linked to traffic mishaps". Los Angeles Times. http://www.latimes.com/news/nationworld/nation/la-na-smokedrug25-2008may25,0,6554950.story. Retrieved 2008-05-25.  
  21. ^ Hudson, Audrey (2008-06-17). "VA Testing Drugs on War Veterans". The Washington Times: p. A1.  
  22. ^ Institute for Safe Medication Practices. "Quarter Watch: 2008 Quarter 1". http://www.ismp.org/QuarterWatch/2008Q1.pdf. Retrieved 2008-10-23.  
  23. ^ Institute for Safe Medication Practices. "Quarter Watch: 2008 Quarter 2". http://www.ismp.org/quarterwatch/200901.pdf. Retrieved 2009-01-15.  
  24. ^ "Over 800 complaints on quit-smoking aid reported to Health Canada". CBC. February 4, 22009. http://www.cbc.ca/health/story/2009/02/04/champix.html. Retrieved 2009-02-09.  

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