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. Mechanism of action Varenicline displays full agonism on α7 nicotinic acetylcholine receptors and is a partial agonist on the α4β2, α3β4, and α6β2 subtypes. 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. 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. The elimination half-life is about 24 hours. History Use of Cytisus plants as a smoking substitutes during World War II led to use as a cessation aid in eastern Europe and extraction of cytisine. Cytisine analogs led to varenicline at Pfizer. 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. The agency's approval of the drug came on May 11, 2006. On September 29, 2006, it was approved for sale in the European Union. On September 16, 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". This followed a July 2, 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 July 19 and Aug. 8. On June 24, Pfizer had paused distribution of Chantix worldwide; "[t]he distribution halt [wa]s out of an abundance of caution, pending further testing, the company said in an email. 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 U.S.