Mental Health Side Effects Label Warning Removed for Anti-Smoking Drugs

On December 16, 2016, the FDA removed from the Chantix (varenicline) drug label and the Zyban (bupropion) drug label the Boxed Warning, the FDA’s most prominent warning, for serious mental health side effects. The existing warning section on both labels that described the side effects on mood, behavior, or thinking, was also updated to include the results from the clinical trial. Chantix and Zyban are prescription medicines that are FDA-approved to help adults quit smoking.


The FDA received and assessed case reports of serious changes in mood and behavior in patients taking Chantix and Zyban. This led the agency to require that a Boxed Warning be added to the labels in 2009 and to require Pfizer Inc., the manufacturer of Chantix, and GlaxoSmithKline, the manufacturer of Zyban, to conduct a large clinical trial. Based on an FDA review of that trial’s results, the FDA determined the risk of serious side effects on mood, behavior, or thinking with Chantix and Zyban was lower than previously suspected.


The clinical trial evaluated the neuropsychiatric safety of Chantix and Zyban for smoking cessation in patients with and without a history of psychiatric disorders. The trial enrolled 8,144 patients at 140 centers in 16 countries, including the U.S., of which 8,058 patients were randomized to Chantix (n=2,016), Zyban (n=2,006), nicotine replacement therapy (NRT) (n=2,022), and placebo (n=2,014). Among the 4,074 patients in the psychiatric history cohort, approximately 70 percent had affective disorders, 19 percent had anxiety disorders, 9 percent had psychotic disorders, and less than 1 percent had borderline personality disorder.


Clinically significant neuropsychiatric adverse effects occurred at a similar frequency of about 3 percent across treatment groups in patients without psychiatric diagnoses. In the cohort of patients with psychiatric diagnoses, there was a higher incidence across groups, and a numerically increased risk associated with Chantix and Zyban (approximately 12 percent), compared to placebo (approximately 10 percent). There was no meaningful difference in risk between Chantix and Zyban.


Although there is still a risk of neuropsychiatric adverse events with Chantix and Zyban, especially in those currently being treated for mental illnesses such as depression, anxiety disorders, or schizophrenia, or who have been treated for mental illnesses in the past, most people who had changes in mood, behavior, or thinking did not have serious consequences such as hospitalization. Therefore, the FDA concluded the results of the trial confirmed that the benefits of taking these drugs for smoking cessation outweighed the risk of neuropsychiatric adverse events.


In addition to Zyban, there are other bupropion products that are approved for psychiatric disorders, including major depressive disorder. The language concerning serious side effects on mood, behavior, or thinking in people taking bupropion for smoking cessation will be removed from the Boxed Warning of those products’ labels as well.


The active ingredient in Zyban is in the antidepressant class; therefore the label carries the class Boxed Warning for suicidality and antidepressant drugs. This language will remain in a Boxed Warning in the labels for Zyban and other bupropion products.


This decision was consistent with the recommendations of external experts at a September 2016 FDA Advisory Committee meeting. The patient Medication Guide that explains the risks associated with the use of the medicines will continue to be provided with every patient prescription; however, the risk evaluation and mitigation strategy (REMS) that formally required the Medication Guide will be removed.


The clinical trial results also confirmed that Chantix, Zyban, and nicotine replacement patches were all more effective for helping people quit smoking than was an inactive treatment called a placebo. These medicines were found to better help people quit smoking regardless of whether or not they had a history of mental illness.


Millions of Americans have serious health problems caused by smoking that can be reduced by quitting. Smoking has been found to harm many organs in the body and diminishes a person’s overall health. The health benefits of quitting smoking are substantial, including decreasing the chances of developing lung disease, heart disease, and some cancers. There are also benefits that are nearly immediate or occur after a short time as a nonsmoker such as improvements in circulation, breathing, and the senses of taste and smell.


See the FDA Drug Safety Communication


See also Medical Law Perspectives, May 2013 Report: Drugs, Dosage, and Damage: Physician Liability for Prescribing or Administering Medication