Chantix and Zyban to Receive Boxed Warnings for Serious Neuropsychiatric Symptoms

Neil Osterweil

July 01, 2009

July 1, 2009 — The smoking-cessation drugs varenicline (Chantix, Pfizer) and bupropion (Zyban, GlaxoSmithKline) must carry a boxed warning in their labeling that use of the drugs has been associated with serious mental health events, the US Food and Drug Administration (FDA) announced today.

The drugs' makers must also develop patient medication guides highlighting the risk for serious neuropsychiatric symptoms in patients who use the products. Reported symptoms include changes in behavior, hostility, agitation, depressed mood, suicidality, and attempted suicide.

Similar warnings will be required for bupropion marketed as the antidepressant Wellbutrin and for generic versions of bupropion. They already have black box warnings for suicidal behavior in treating psychiatric disorders.

If patients report experiencing agitation, depressed mood, changes in behavior that are not typical of nicotine withdrawal, or if they experience suicidal thoughts or behavior, the FDA recommends that clinicians advise patients to stop taking varenicline or bupropion immediately.

The warnings are based on reviews of postmarketing adverse event reports for the drugs. Since its approval in 2006, varenicline has been associated with 98 completed suicides and 188 attempts. Bupropion, approved for smoking cessation in 1997, has been associated with 14 completed suicides and 17 attempts during its marketing history.

The reports include observations of a temporal link between use of the drugs and either suicidal events or the occurrence of suicidal ideation and suicidal behavior in patients who had no history of psychiatric illness, Curtis Rosebraugh, MD, director of the FDA’s Office of Drug Evaluation II, said during a media briefing.

The symptoms have occurred in patients both with and without a history of psychiatric symptoms, tend to occur shortly after the patient starts on the medication, and usually end when the medication is stopped, "although we do have some reports of people that continue to have symptoms after the medication is stopped, and in a few cases experiencing problems after the medication is stopped, " Dr. Rosebraugh said.

People who continue to experience psychiatric symptoms after discontinuing one of the drugs should continued to be monitored until the symptoms stop, he added.

He emphasized that the numbers come from crude reporting only and have not been verified.

"The reports themselves are convincing enough to be convincing. We don't have rates on these things — they're just more than you'd expect," commented Robert J. Temple, MD, director of the FDA's Office of Drug Evaluation I.

Some of the symptoms reported could be caused by nicotine withdrawal, Dr. Temple acknowledged, but he added that "if some of this is nicotine withdrawal, it really doesn't matter. What this tells you is, in someone who is on these drugs trying to quit smoking, you need to watch them for these events."

Although both drugs are associated with serious adverse events, they have been shown to be effective at helping patients quit smoking, and the FDA is not advising against their use for that purpose, nor is their use contraindicated in any specific patient population, said Dr. Rosebraugh.

"I think it's important to note that varenicline and Zyban are effective smoking-cessation aids. The possible risk of serious adverse events while using these drugs should always be weighed against the significant health benefits of quitting smoking," he said.

The FDA is requiring Pfizer and GlaxoSmithKline to conduct a clinical trial to determine the incidence of neuropsychiatric symptoms in people who are trying to quit smoking, including smokers with and without a history of mental health disorders.

More information is available on the FDA's MedWatch Web site.

Any adverse events associated with varenicline or bupropion should be communicated to the FDA's MedWatch reporting program by telephone at 1-800-FDA-1088, by fax at 1-800-FDA-0178, online at, or by mail to 5600 Fishers Lane, Rockville, Maryland 20852-9787.


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