Neuropsychiatric Warning in Varenicline and Bupropion Removed

New Year is a time for resolution – specifically many smokers may ponder the idea of quitting. Bravo if you are one of them! After all, smoking cessation products are always in high demand every January.  I came across the press release from Pfizer just before Christmas that the Black Box Warning related to the neuropsychiatric safety in Varenicline as well as Bupropion has been removed.

I thought, how timely and strategic of such a release! It was the perfect time to spread the message, just in time for New Year’s Resolution. I wonder how much effort did Pfizer and GlaxoSmithKline put in to ensure FDA removed the safety warning just before Christmas.   That was my skeptical voice that was talking in my head.

The Black Box Warning was originally put in place due to case reports and post-marketing pharmacovigilance data from around the world revealing possible association between the use of varenicline and buproprion and neuropsychiatric adverse events such as depression, agitation, aggression, hostility and suicidal thoughts and behaviour. As such, FDA  has issued a post-marketing requirement to Pfizer and GlaxoSmithKline to conduct a randomized controlled trial to assess the risk of serious neuropsychiatric adverse events with varenicline and buproprion.

The trial that is responsible for lifting the Black Box Warning is EAGLES, published in the Lancet earlier in 2016.  It was a randomized, double-blind, tripled dummy, placebo-controlled and active-controlled trial evaluating the safety of varenicline, bupropion, nicotine patch and placebo. It also piggy-packed the efficacy trial to evaluate the efficacy of varenicline  in comparison with bupropion, nicotine patch and placebo as well as the efficacy of bupropion and nicotine patch in comparison with placebo.  Below are the key details of the EAGLE trial:



Here are the key results from the trial:

  • The study results were analyzed in two separate cohorts: psychiatric cohort or non-psychiatric cohort.
  • The primary end point was the incidence of a composite measure of moderate and severe neuropsychiatric adverse events.
  • In the non-psychiatric cohort, the primary end point results are noted here for the four treatment arms:
    • Varenicline: 13 of 990 (1.3%)
    • Bupropion: 22 of 989 (2.2%)
    • Nicotine Patch: 25 of 1006 (2.5%)
    • Placebo: 24 of 999 (2.4%)
  • In the psychiatric cohort, the primary end point results are as follow:
    • Varenicline: 67 of 1026 (6.5%)
    • Bupropion: 68 of 1017 (6.7%)
    • Nicotine Patch: 53 of 1016 (5.2%)
    • Placebo: 50 of 1015 (4.9%)
  • While there were more reports of neuropsychiatric adverse events in the psychiatric cohort, there was no difference in the incidence among the four treatment groups within the same cohort.  This is important to note as it suggests the neuropsychiatric adverse events are not associated with the medications used.
  • The most frequent adverse events reported were nausea, insomnia, abnormal dreams and headache.
  • Varenicline has also demonstrated to be more effective than bupropion, nicotine patch and  placebo by having the highest abstinence rates; bupropion and nicotine patch were more effective than placebo.


The main limitation of this trial was its exclusion of participants with substance use disorders within the previous 12 months.  In reality, many smokers may indeed have other substance use disorders such as alcohol or drugs; substance use disorders are also common among the psychiatric population.  This exclusion criterion has limited its application to a large population of smokers.

What now?

While the Black Box Warning is removed in the States, there is still a warning within the product monograph to advise clinicians  to monitor for any unusual psychiatric symptoms for patients on varenicline or bupropion therapies.

Health Canada has not made any changes in the current product monographs of Varenicline and Bupropion yet.

In Ontario, it is within the expanded scope of pharmacists to prescribe varenicline or bupropion as a smoking cessation aid.  However, I wonder how many pharmacists are currently exercising this expanded scope?

Given the incidence of neuropsychiatric  adverse events is higher among individuals with psychiatric diagnoses, should pharmacists be given access to this information from physicians for an accurate assessment? Or should individuals be interested in taking these products be referred to physicians?

The results of EAGLE have certainly opened up some questions for pharmacists to examine before they decide to prescribe varenicline or bupropion as a smoking cessation aid.

If you are interested to quit smoking, here’s a link to some helpful resources.



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My name is Cynthia Leung and I am a practicing pharmacist in Kingston Ontario, Canada. This blog is for me to share my ideas, opinions and perspectives on how medications are used in our health care system. Note that these posts are my own opinions and do not represent the opinions of my current or former employers and / or organizations that I may belong to. Any possible case scenarios described in my posts would be modified to maintain patient confidentiality. This blog is not a platform for professional advise for patients or health care providers and the content is not meant to support any clinical decisions or replace professional opinions. Also the images are either taken or created by the author, or adapted with permissions. I hope you will enjoy reading my posts!

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