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Results of Largest Pharmacotherapy Smoking Cessation Trial Prompts Debate over Varenicline’s Black Box Warning

By: Nicollette Pacheco, PharmD Candidate c/o 2017

It is an easy decision to include a black box warning on a drug label in response to clinically significant drug safety information. The decision to remove such a warning, on the other hand, has recently proven to be a more difficult decision.

Varenicline (Chantix®) was approved in 2006 for use as an aid to smoking cessation treatment. Mechanistically, the drug competitively binds to nicotinic acetylcholine receptors with a higher affinity and selectivity than nicotine, stimulating receptor-mediated activity at a lower level than nicotine itself.1 Because of its significant potential benefit to public health as a smoking cessation agent, the FDA placed a priority on its review for approval in order to expedite the drug approval process. After its approval, Pfizer began reporting neuropsychiatric events such as suicidality and behavior/mood changes in patients using varenicline. In response to these reports, the Food and Drug Administration required the manufacturers of both varenicline and bupropion (Zyban®), another smoking cessation agent, to include a black box warning that highlights the risk of serious mental health events while taking these drugs.2

In addition to the boxed warning, the FDA also required the development of a sufficiently large randomized controlled trial to collect data on smoking cessation treatments and their correlation to neuropsychiatric events. While this large study was underway in 2011, several smaller retrospective observational studies were published that suggested no significant association between varenicline use and neuropsychiatric events. The Psychopharmacology Drugs and Risk Management Advisory Committee of the FDA met in review of this retrospective data and its impact on the label in 2014 and ruled to keep the boxed warning in the label. While the smaller trials were sufficiently impactful to raise questions about the validity of the boxed warning, they were ultimately not reliable enough to determine causality and remove the warning altogether.3

The neuropsychiatric safety and efficacy of varenicline, bupropion, and nicotine patch in smokers with and without psychiatric disorders (EAGLES) trial was completed in 2016 and was the first trial to provide definitive evidence on the relative safety and effectiveness of smoking cessation treatments in smokers with psychiatric disorders compared to those without psychiatric disorders. The study did not show a significant increase in the rates of moderate-to-severe neuropsychiatric events with either varenicline or bupropion relative to nicotine patches or placebo in those with or without psychiatric disorders. The Psychopharmacology Drugs and Risk Management Advisory Committee met once more in September 2016 to discuss varenicline’s boxed warning, this time with results from the largest trial of smoking cessation pharmacotherapy to date.4 Of the 19 panel members, 10 voted to remove the boxed warning completely, 4 voted to rephrase it, and 5 voted to keep the warning as is. As an ongoing process, the FDA will make its official decision based on the results of this vote and the opinions of the panel.5 Since there is considerable indecision among the committee members, the FDA is likely to carefully weigh each option.

The FDA’s intrinsic role as a public health agency often means that their requirements err on the side of caution; at times, boxed warnings can be issued expeditiously before all the data is collected. While this conservative stance effectively mitigates potential patient harm, it may also create a false warning that can only be disproven by subsequent data.3This boxed warning is a major consideration when prescribers compare the risks of smoking cessation medications with the benefits of smoking cessation itself. The EAGLES study provides new data that will help prescribers weigh the risks of smoking-related illness and death with the risks of smoking cessation medication.

Patients with psychiatric disorders smoke at a rate two- to three-times higher than the general population and are more prone to smoking-related illness. The presence of a boxed warning regarding neuropsychiatric events has drastically affected the use of efficacious smoking cessation medications in these patients and may have prevented their access to beneficial treatment.4 Data from the EAGLES trial depicts the risk of neuropsychiatric events more reliably than the data that initially prompted the inclusion of the boxed warning and should therefore be included in the product’s label. The majority of the committee felt that the data from the EAGLES trial was sufficient to promote safe use of these medications in patients with and without psychiatric disorders in practice.6 Revisions to the varenicline label to accurately reflect the risk of developing suicidal ideations and mood changes will allow both prescribers and patients to make well-informed decisions about smoking cessation.

Although the slight majority of 10 panel members voted to remove the boxed warning completely, 9 members still voted to keep the warning or to make revisions to the warning.5 Upon completion of the EAGLES trial, the FDA conducted its own sensitivity analysis with the study’s results to determine the validity of the trial. The main area of criticism of the trial stems from adverse event severity coding, which was found to be inconsistent among investigators involved in the study. The FDA determined that this variability may have lowered the number of primary outcome events in the studies, creating a bias towards its null finding. Committee members that ruled to keep the boxed warning felt that removing the warning would send the wrong message, while leaving it in the label would certainly not cause any harm.7

When post-marketing reports of a drug show adverse events that were previously unknown, the FDA utilizes several tools to minimize patient harm. Recommending additional safety trials, REMS programs, label amendments, and marketing authorization restrictions all serve to mitigate patient harm. The FDA must also act when the validity of these tools is called into question in response to emerging data.3

UPDATE: The FDA has reached a verdict on varenicline labeling since the time that this article was written in October 2016. Upon review of the EAGLES trial, the FDA ruled that the risk of serious side effects on mood, behavior, or thinking with varenicline and bupropion is lower than previously suspected, and removed this Boxed Warning from both drugs’ labels. The Warnings and Precautions section of the labels will also be updated to include the results reported from this clinical trial. This decision was reached on December 16, 2016.8



  1. Chantix® (Varenicline) [package insert]. New York, NY; Pfizer Inc; Revised 08/01/2016.
  2. Riley K. FDA: boxed warning on serious mental health events to be required for Chantix and Zyban. U.S. Food and Drug Administration. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm170100.htm. Published 07/01/2009. Last Updated 04/17/2013.
  3. Yeh JS, Sarpatwari A, Kesselheim AS. Ethical and practical considerations in removing black box warnings from drug labels. Drug Saf. 2016;39(8):709-14. doi: 10.1007/s40264-016-0419-8.
  4. Anthenelli RM, Benowitz NL, West R, et al. Neuropsychiatric safety and efficacy of varenicline, bupropion, and nicotine patch in smokers with and without psychiatric disorders (EAGLES): a double-blind, randomised, placebo-controlled clinical trial. Lancet. 2016; 387:2507-20.
  5. Staton T. UPDATED: No more black box for Pfizer’s Chantix? After split panel backing, it’s up to the FDA. FiercePharma. http://www.fiercepharma.com/pharma/no-more-black-box-for-pfizer-s-chantix-after-split-backing-from-experts-it-s-up-to-fda. Published 09/15/2016.
  6. Basen R. FDA panel splits on softening Chantix warning. MedPage Today. http://www.medpagetoday.com/Pulmonology/Smoking/60236. Published 09/14/2016. Last Updated 09/15/2016.
  7. Serious neuropsychiatric adverse events with drugs for smoking cessation. U.S. Food and Drug Administration. http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/PsychopharmacologicDrugsAdvisoryCommittee/UCM520103.pdf. Published 09/14/2016.
  8. FDA Drug Safety Communication: FDA revises description of mental health side effects of the stop-smoking medicines Chantix (varenicline) and Zyban (bupropion) to reflect clinical trial findings. U.S. Food and Drug Administration. https://www.fda.gov/Drugs/DrugSafety/ucm532221.htm. Published 1/5/2017.
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