Physicians' Academy for Cardiovascular Education

No extra neuropsychiatric adverse events with smoking cessation medication

News - Apr. 25, 2016

Results from the largest clinical trial of approved smoking cessation medicines, called EAGLES (Evaluating Adverse Events in a Global Smoking Cessation Study) have been published in The Lancet. This smoking cessation trial included 8,144 adult smokers. In collaboration with the European Medicines’ Agency (EMA) and the US Food and Drug Administrations (FDA), it was designed to compare the neuropsychiatric safety of varenicline and bupropion with placebo and nicotine patch in adult smokers with and without a history of psychiatric disorders. The authors concluded that the trial did not show a significant increase in the incidence of the composite primary safety endpoint of serious neuropsychiatric adverse events with varenicline or bupropion compared to placebo and nicotine patch. Differences between incidence rates were considered significant if their associated 95% confidence intervals (CIs) were entirely above or below zero. Approximately half of the trial participants had a history of psychiatric disorders, either past and in remission or present and clinically stable. The psychiatric diagnoses included primarily depressive, bipolar, anxiety and psychotic disorders.

The EAGLES trial also included an efficacy objective to determine smoking abstinence rates in patients treated with varenicline or bupropion, relative to placebo, during the last four weeks of the 12-week treatment period. Continuous abstinence was also evaluated relative to the nicotine patch. In addition, longer-term abstinence through a 12-week non-treatment follow-up period (weeks 9-24) was evaluated for all treatments. The results showed that patients with and without a history of psychiatric disorders taking varenicline had significantly higher continuous abstinence rates than patients treated with bupropion or nicotine patch during both time periods. Patients treated with each of the medications had higher abstinence rates than those treated with placebo. This is the first placebo-controlled trial of this size to directly compare the efficacy of varenicline, bupropion and nicotine patch to help people quit smoking.

“Clinical practice guidelines recommend that the most effective way for smokers to quit is by combining a smoking cessation medication with counselling. However, smoking cessation support is often underutilized, due in part to misperceptions about the effectiveness and safety of smoking cessation medicines,” said lead study investigator Robert M. Anthenelli, M.D., Professor of Psychiatry, University of California, San Diego, California. “This study offers important new information to prescribers and smokers to help them make an informed decision about smoking cessation treatment options.”

The primary safety endpoint of the EAGLES trial was defined as the occurrence of at least one treatment-emergent severe adverse event of anxiety, depression, feeling abnormal, or hostility and/or the occurrence of at least one treatment-emergent moderate or severe adverse event of agitation, aggression, delusions, hallucinations, homicidal ideation, mania, panic, paranoia, psychosis, suicidal ideation, suicidal behaviour or completed suicide.

The incidence of the primary safety endpoint in patients without a history of psychiatric disorders was 1.3% (varenicline), 2.2% (bupropion), 2.5% (nicotine patch) and 2.4% (placebo). The incidence rates in patients with a history of psychiatric disorders were 6.5% (varenicline), 6.7% (bupropion), 5.2% (nicotine patch) and 4.9% (placebo). In patients without a history of psychiatric disorders, the varenicline–placebo and bupropion–placebo risk differences (RDs) for the primary safety endpoint were −1.28 (95% CI −2.40 to −0.15) and −0.08 (−1.37 to 1.21), respectively. The RDs for varenicline-nicotine patch and bupropion-nicotine patch comparisons were −1.07 (−2.21 to 0.08) and 0.13 (−1.19 to 1.45), respectively. In patients with a history of psychiatric disorders, the varenicline–placebo and bupropion–placebo RDs were 1.59 (−0.42 to 3.59) and 1.78 (−0.24 to 3.81), respectively; the RDs for varenicline-nicotine patch and bupropion-nicotine patch comparisons were 1.22 (−0.81 to 3.25) and 1.42 (−0.63 to 3.46), respectively. Across both patient cohorts, 95% CIs associated with these RDs were lower than or included zero. There were more neuropsychiatric adverse events in the psychiatric cohort than the non-psychiatric cohort across all treatment arms including placebo.
Across the trial population, the most frequent adverse event by treatment group was nausea (25%, varenicline), insomnia (12%, bupropion), abnormal dreams (12%, nicotine patch) and headache (10%, placebo).

The varenicline labeling includes a warning/boxed warning regarding serious neuropsychiatric adverse events that have been reported in some patients attempting to quit smoking while taking varenicline in the post-marketing experience. Some people have had changes in behaviour, hostility, agitation, depressed mood, and suicidal thoughts or actions while using varenicline to help them quit smoking. If the varenicline patient, their family or caregiver notices any of these symptoms or behaviors, they should stop taking varenicline and call their doctor right away. They should tell their doctor about any history of depression or other mental health problems, which could get worse while taking varenicline.


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; published online April 22

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