Timothy O'Shea, MS, PharmD
Timothy O'Shea, MS, PharmD, is a Clinical Pharmacist working at a regional health insurance plan on the east coast. Additionally he works per diem at a nationwide retail pharmacy chain. He graduated from MCPHS University - Boston in 2015 and subsequently completed a PGY-1 Managed Care Pharmacy Residency. He completed his M.S. in Health Services Administration, with a focus on Health Economics and Outcomes, in 2018. His professional interests include pharmacy legislation and managed care pharmacy. He can be followed on Twitter at @toshea125.
This warning was required due to a significant number of reports submitted to the FDA’s Adverse Event Reporting System (AERS) regarding adverse psychiatric effects with varenicline. This was further seen in a 2011 study published in PLOS One that examined 12 years of case reports submitted to the FDA’s AERS database.
Of the 3249 reported cases of suicidal or self-injurious behavior or depression among smokers attempting to quit, 2925 (90%) were attributed to varenicline. This risk was disproportionally high compared with both nicotine replacement products (OR=8.4; 95% CI: 6.8-10.4) and bupropion (OR=2.9; 95% CI: 2.5-3.4).
Although the mechanism for varenicline-induced psychiatric effects is not fully understood, it has been theorized that its effects on modulating dopamine release, the mechanism through which the drug aids in smoking cessation, may alter mood. Another possible mechanism may be through its action as a partial nicotinic agonist, since nicotine receptors could influence impulsivity and aggression.
However, recent evidence has not found any increased risk of psychiatric or behavioral symptoms with varenicline.
An 2013 article published in British Medical Journal detailed the largest study assessing the risk between varenicline use and psychiatric outcomes. The authors examined a cohort of 119,546 smokers, among whom 81,545 used nicotine replacement products, 6741 received bupropion, and 31,260 took varenicline.
In the study, Cox regression analyses showed no evidence that patients prescribed varenicline had higher risks of fatal or non-fatal self harm (HR=0.88, 95% CI: 0.52-1.49) or treated depression (HR=0.75, 95% CI: 0.65 to 0.87) compared with those prescribed nicotine replacement therapy.
Five other studies, consisting of thousands of smokers, also found no statistically increased risk of depression-like symptoms associated with varenicline therapy. Additionally, 2 meta-analyses of clinical trial data, conducted by Pfizer, showed no increased risk with varenicline.
In October 2014, the FDA held a meeting to review the risk of psychiatric and behavioral side effects with varenicline after Pfizer applied to have the black box warning removed.
Despite the information presented, the FDA advisory committee voted overwhelmingly that varenicline should continue to carry a boxed warning about the risk of neuropsychiatric events, stating that the clinical evidence presented contained major limitations.
Of the 18 voting members, 11 indicated that the warning should be retained pending the outcome of a phase 4 clinical trial, which is currently underway to further define the risk. Six said the language should be modified and strengthened, and only 1 panelist voted to remove the warning.
Much more recently, the FDA updated the Warnings and Precautions section of Chantix's label to include information on several studies showing no increased risk of neuropsychiatric side effects with the drug.
So, what does this mean for health care professionals? Although the majority of the evidence does not support an increased risk of psychiatric side effects with varenicline therapy, there have still been more case reports involving varenicline than any other FDA-approved smoking cessation therapy.
Therefore, until further information is published, varenicline should be used cautiously in patients with a psychiatric history or high predisposition to psychiatric events. If no other FDA-approved smoking cessation therapies can be used in these patients, then they should undergo extra monitoring and follow-up to assess for changes in behavior or mood.
- FDA: Boxed Warning on Serious Mental Health Events to be Required for Chantix and Zyban. Food and Drug Administration. 1 July 2009. Web. 07 Mar. 2015.
- Gever, J. "FDA Panel: Chantix Boxed Warning Should Stay." Medpage Today. 10 Oct. 2014. Web. 07 Mar. 2015.
- Joint Meeting of the Psychopharmacologic Drugs Advisory Committee and Drug Safety and Risk Management Advisory Committee: Chantix and Serious Neuropsychiatric Adverse Events. Food and Drug Administration. 16 October 2014. Web. 07 Mar. 2015.
- Moore T, Furberg C, Glenmullen J, et al. Suicidal behavior and depression in smoking cessation treatments. PLoS One. 2011;6(11):e27016.
- Thomas K, Martin R, Davies N, et al. Smoking cessation treatment and risk of depression, suicide, and self harm in the Clinical Practice Research Datalink: prospective cohort study. BMJ. 2013; 347:f5704.