Varenicline

Nicotinic receptor agonist

Common side effects of varenicline include nausea, insomnia, abnormal dreams, headache, and nasopharyngitis (inflammation of the nose and throat). It is on the World Health Organization's List of Essential Medicines. The medication is available as a generic medication. In the United States, varenicline was prescribed over 1million times in 2020, ranking as the 275th most commonly prescribed medication.

Varenicline is indicated for use as an aid to smoking cessation treatment 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). 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. 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%).

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. A 2014 systematic review (literature research) did not find evidence of an increased suicide risk. Other analyses have reached the same conclusion and found no increased risk of neuropsychiatric side effects with varenicline. In 2016, the FDA removed the black box warning. People are still advised to stop the medication if they "notice any side effects on mood, behavior, or thinking."

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." A prior 2011 review had found increased risk of cardiovascular events compared with placebo. Expert commentary in the same journal raised doubts about the methodology of the review, concerns which were echoed by the European Medicines Agency and subsequent reviews.

Varenicline displays full agonism on α7 nicotinic acetylcholine receptors and is a partial agonist on the α4β2, α3β4, and α6β2 subtypes. 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.

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.

Use of Cytisus plants as a smoking substitute 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 in May 2006. In September 2006, it was approved for sale in the European Union. 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". 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. In June 2021, Pfizer paused distribution of Chantix worldwide; "the distribution halt was 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 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). 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.