Review of: Anthenelli RM et al, Lancet 2016;387(10037):2507–2520

Varenicline (Chantix) and bupropion (Zyban and others) are effective treatments for tobacco use disorder, but their use (and sales) took a big hit in 2009 when the FDA slapped both with black box warnings linking them to psychiatric complications, including suicidal ideation. Although these concerns did not appear in clinical trials, the FDA responded primarily to numerous post-marketing case reports. Clinicians began to steer clear of these agents, especially after a cottage industry cropped up suing for psychiatric damages purportedly caused by them. To allow removal of the warning, the FDA required the manufacturers of Chantix and Zyban (Pfizer and GlaxoSmithKline, respectively) to perform a sufficiently large randomized trial that adequately assessed these safety issues. The result is the massive and complicated Pfizer- and GSK-sponsored “EAGLES” trial—a somewhat tortured acronym of “Evaluating Adverse Events in a Global Smoking Cessation Study.”

This randomized, double-blind clinical trial recruited 8144 smokers ages 18–75 from 140 centers in 16 countries. Subjects were split into 2 cohorts, one with and the other without psychiatric disorders. Each cohort was then divided into 4 treatment groups in a 1:1:1:1 ratio: varenicline (target dose 1 mg BID), bupropion SR (150 mg BID), transdermal nicotine patch (21 mg/day with taper), or placebo. The treatment phase lasted 12 weeks, followed by a 12-week non-treatment follow-up phase. Subjects were assessed for both tobacco abstinence and for 16 categories of neuropsychiatric symptoms. The main goal was to determine whether the treatments differed in terms of serious psychiatric side effects.

Not surprisingly, there were more reported neuropsychiatric adverse events in the psychiatric cohort (5.8%) than in the non-psychiatric cohort (2.1%). However, the overall incidence of these events was the same in each of the 4 treatment groups. In fact, anxiety and depression symptoms improved about equivalently in all groups. The most common adverse events by treatment group were nausea (varenicline 25%), insomnia (bupropion 12%), abnormal dreams (nicotine patch 12%), and headache (placebo 10%). Rates of suicidal ideation and behavior overall were quite low, but in the psychiatric cohort they were non-significantly higher in the placebo and varenicline groups. The lone completed suicide was in the non-psychiatric placebo group.

All 3 of the active treatments were more effective for tobacco abstinence than placebo, but varenicline was superior to both bupropion and nicotine patch.

CATR’s Take
The EAGLES study has been criticized for its use of an unvalidated scale for adverse events. Further, the FDA raised concerns over inconsistencies in EAGLES’ data collection, but ultimately found that, even when unreliable data were excluded, the results seemed consistent with the study’s conclusions. As a result, the FDA removed the black box warning for varenicline, and it modified the warning for Zyban by removing language about serious psychiatric effects in patients quitting smoking.

These agents, particularly varenicline, can help patients stop smoking, and serious psychiatric adverse effects seem relatively rare. So, we can all breathe somewhat easier in prescribing varenicline and bupropion for smoking cessation. But as with all psychotropic agents, it would be prudent to employ reasonable screening, discussion of risks, and monitoring measures with these agents, particularly in patients who have preexisting psychiatric symptoms.