Varenicline is a partial agonist of the nicotinic acetylcholine receptor and is used to help in smoking cessation. Varenicline has been associated with a low rate of serum enzyme elevations during therapy and, since approval and its widescale use, with rare instances of clinically apparent mild liver injury.


Varenicline (var en' i kleen) is a partial agonist of the α4 β2 nicotinic acetylcholine receptor and appears to act by blocking the binding of nicotine to this receptor while providing partial agonist effect thus relieving nicotine craving. Use of varenicline in a program to stop smoking has been shown to increase the rate of smoking cessation and to decrease relapse. Varenicline was approved for use in the United States in 2006 and is widely used in smoking cessation programs. Varenicline is available in tablets of 0.5 and 1 mg under the brand name Chantix. The usually recommended regimen is to start with 0.5 mg once daily and increase to a maintenance dose of 1 mg twice daily, continuing therapy for at least 12 weeks after smoking cessation. Common side effects include nausea, vivid dreams, insomnia, anxiety, depression, dizziness, drowsiness, headache, dry mouth, and change in appetite, some of the symptoms being those of nicotine withdrawal. Varenicline has been reported to cause hypersensitivity reactions including Stevens Johnson syndrome.


Varenicline has not been associated with rates of serum enzyme elevations during therapy greater than occurs with placebo therapy, but information on these abnormalities is limited and occasional instances of asymptomatic ALT elevations leading to drug discontinuation have been reported. In prelicensure pivotal registration trials in several thousand patients, varenicline was not associated with cases of jaundice or hepatitis. Since licensure, rare case reports of serum enzyme elevations without jaundice arising within 4 weeks of starting varenicline have been published, but largely in patients with other causes of liver injury (alcoholic liver disease, hepatitis C). The injury was self-limited in course and not associated with immunoallergic or autoimmune features. In Iceland, a single case of varenicline hepatotoxicity has been reported (Case 1), there having been an estimated 20,000 persons treated with the drug in the country since its introduction.

Likelihood score: C (probable rare cause of clinically apparent liver injury).

Mechanism of Injury

The mechanism by which varenicline might cause liver injury is not known. Varenicline undergoes minimal hepatic metabolism and is excreted largely unchanged in the urine.

Outcome and Management

The rare reports of hepatotoxicity attributed to varenicline therapy have been mild and self-limiting. Varenicline has not been linked to cases of acute liver failure, chronic hepatitis or vanishing bile duct syndrome.

Agents in clinical use to aid in smoking cessation and to treat nicotine withdrawal symptoms include bupropion, nicotine, and varenicline.

Drug Class: Substance Abuse Treatment Agents


Case 1. Mild acute hepatitis arising 3 weeks after starting varenicline.(1)

A 50 year old woman developed nausea and fatigue 3 weeks after starting varenicline for smoking cessation. She stopped the medication promptly but during the next week developed itching, dark urine, and jaundice. She had no history of liver disease, alcohol abuse, risk factors for viral hepatitis or drug allergies. Her other medical conditions included hypertension and cerebral aneurysm for which she was taking atenolol, amlodipine and a thiazide diuretic. On examination, she was jaundiced but had no signs of chronic liver disease. Blood tests showed a total serum bilirubin of 5.6 mg/dL, ALT 466 U/L, AST 207 U/L, alkaline phosphatase 249 U/L and GGT 976 U/L. There was no fever, rash or peripheral eosinophilia. Tests for hepatitis A, B, C, E and Epstein Barr virus and cytomegalovirus were negative as well serum autoantibodies. An abdominal CT scan showed no liver or biliary abnormalities. She was not admitted to the hospital, did not undergo liver biopsy and received no specific therapy. Her routine medications were continued. Over the next few weeks she improved (Table) and liver tests were normal or near normal when she was seen 6 weeks after onset.

Key Points

Laboratory Values


The patient developed a mild, self-limited acute hepatitis 3 weeks after starting varenicline. Other diagnoses were carefully ruled out. Very few cases of varenicline hepatotoxicity have been described, and most were not completely convincing because of the presence of other liver diseases. This case with a latency of 3 weeks and a self-limited mild course of a mixed hepatitis is reasonably convincing. Varenicline has little hepatic metabolism and it is given in low doses (2 mg daily), and thus does not have features usually associated with hepatotoxicity.



Varenicline – Chantix®


Substance Abuse Treatment Agents


Product labeling at DailyMed, National Library of Medicine, NIH



Mogensen H, Björnsson ES. Varenicline-induced acute liver injury with jaundice. Hepatology. 2015;61:2110–1. [PubMed: 25820383]


References updated: 22 July 2020

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    (Among 1959 Australian adults admitted with smoking related illnesses to 3 hospitals between 2008 and 2011 who were treated with counseling with or without varenicline, smoking cessation was more frequent with varenicline which was well tolerated, common adverse events being nausea [16% vs 1.5%], abnormal dreams [6% vs 1%], headache [6% vs 1.5%], insomnia [5% vs 2%] and dizziness [2% vs 0.5%]; no mention of ALT elevations or hepatotoxicity).