Varenicline
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Varenicline
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| Systematic (IUPAC) name | |
| 7,8,9,10-tetrahydro-6,10-methano- 6H-pyrazino(2,3-h)(3)benzazepine |
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| Identifiers | |
| CAS number | 375815-87-5 |
| ATC code | N07 |
| PubChem | |
| Chemical data | |
| Formula | C13H13N3 |
| Mol. mass | 211.267 g/mol |
| SMILES | & |
| Pharmacokinetic data | |
| Bioavailability | ? |
| Protein binding | <20% |
| Metabolism | Limited (<10%) |
| Half life | 24 hours |
| Excretion | Renal (81–92%) |
| Therapeutic considerations | |
| Licence data |
, |
| Pregnancy cat. |
C(US) |
| Legal status |
℞ Prescription only |
| Routes | Oral |
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 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 in stopping smoking.
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[edit] 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]
The FDA has approved its use for twelve weeks. If smoking cessation has been achieved it may be continued for another twelve weeks.[2]
Varenicline has not been tested in children, 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.
[edit] 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.[3]
[edit] Pharmacokinetics
Most of the active compound is excreted renally (92-93%). A small proportion is glucuronidated, oxidated, N-formylated or conjugated to a hexose.[4] The elimination half-life is about 24 hours.
[edit] Side Effects
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.[5]
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. FDA is aware of the highly-publicized case of Carter Albrecht who was shot to death by his neighbour after, in the apparent state of delirium, hitting his girlfriend and trying to force the entry in the neighbor's house.[6] Although in this case the delirium appeared to be caused by taking varenicline with a high dose of alcohol, FDA asked Pfizer for additional cases that might be similar. The FDA also recommended that health care professionals and patients watch for behavioral and mood changes.[7]
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.[8]
On Sunday, May 25, 2008, The LA 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.[9]
[edit] History
Varenicline was discovered at Pfizer through the research aimed at modifying the structure of cytisine,[10] a European smoking cessation aid and also a partial α4β2-nicotinic antagonist.[11][12]
Varenicline received a "priority review" by the U.S. Food and Drug Administration 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.[13] The agency's approval of the drug came on May 11, 2006.[2]. 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.
[edit] Footnotes
- ^ 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:. PMID 16820547.
- ^ a b U.S. Food and Drug Administration. FDA Approves Novel Medication for Smoking Cessation. Press release, 11 May 2006.
- ^ 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:. PMID 16766716.
- ^ 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.
- ^ American Cancer Society. Cancer Drug Guide: Varenicline. Retrieved on 2008-01-19.
- ^ ABC News: Did Quit-Smoking Pill Lead to Man's Death?. Retrieved on 2007-12-15.
- ^ Early Communication About an Ongoing Safety Review: Varenicline (marketed as Chantix). United States Food and Drug Administration (November 20 2007). Retrieved on 2007-11-21.
- ^ Saul, Stephanie. "F.A.A. Bans Antismoking Drug, Citing Side Effects", New York Times, 2008-05-22. Retrieved on 2008-05-22.
- ^ Alonso-Zaldivar, Ricardo. "Drug taken to stop smoking is linked to traffic mishaps", Los Angeles Times, 2008-05-25. Retrieved on 2008-05-25.
- ^ 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:. PMID 15887955.
- ^ 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. Full text at PMC: 1431736
- ^ Etter JF (2006). "Cytisine for smoking cessation: a literature review and a meta-analysis". Arch. Intern. Med. 166 (15): 1553–9. doi:. PMID 16908787.
- ^ Kuehn BM (2006). "FDA speeds smoking cessation drug review". JAMA 295 (6): 614. doi:. PMID 16467225.
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