Smoking cessation drugs get boxed warning.(NEWS)

Accumulating reports of serious neuropsychiatric symptoms associated with the smoking cessation medications varenicline and bupropion have prompted the Food and Drug Administration to require new boxed warnings for the drugs.

The warnings, which went into effect July 1, highlight symptoms that include changes in behavior, hostility, agitation, depressed mood, suicidal thoughts and behavior, and suicide.

The manufacturers also are required to revise the plain-language medication guides that come with the drugs.

The requirements will affect the drugs that are specifically indicated for smoking cessation--Chantix (varenicline), manufactured by Pfizer Inc., and Zyban (bupropion), manufactured by Glaxo smithKline--as well as the generic and branded formulations of bupropion (Wellbutrin, Aplenzin) that already carry a boxed warning about the risk of suicidal thinking and behavior in the treatment of psychiatric disorders.

The FDA previously informed the public about the possibility of serious neuropsychiatric symptoms with varenicline in November 2007, and later issued a public health advisory in February 2008.

However, the new cases involving Zyban took the agency by "surprise," Dr. Curtis Rosebraugh, director of the Office of Drug Evaluation II at the FDA's Center for Drug Evaluation and Research, said in a press telebriefing.

Dr. Rosebraugh said that symptoms "have occurred in patients with and without a history of psychiatric illness. They tend to occur shortly after starting the medication and usually end when the medication is stopped, although we do have some reports of people who continue to have symptoms after stopping the medication and, in a few cases, [patients began] experiencing problems after the medication was stopped. Therefore, people who discontinue treatment because of these events should be monitored until their symptoms fully resolve."

Through adverse event spontaneous reporting systems, the agency has received reports of completed suicides in 98 cases involving varenicline and 14 cases involving bupropion, as well as reports of suicide attempts in 188 cases with varenicline and 17 cases with bupropion, according to Dr. Rosebraugh.

However, he cautioned that some of the cases may be duplicates because the FDA has not "been through every one of the individual reports to see if there are repeat reports."

Dr. Rosebraugh noted that it has been difficult to evaluate the cases "because people who stop smoking without using medications can have similar symptoms due to nicotine withdrawal, such as depression, annxiety, irritability, restlessness, and sleep disturbances." Yet some of the cases of adverse events have occurred while people continued smoking on the medications.

The difference in the number of reported cases of suicide and suicide attempts with Chantix in comparison to Zyban probably reflects the greater market penetration of Chantix and previous media reports of changes in behavior with it, Dr. Rosebraugh said, nothing that it would be premature to compare each drug's potential risk for triggering neuropsychiatric symptoms.

The FDA also is requiring the manufacturers to conduct a clinical trial to determine the incidence of these symptoms in smokers with and without a history of mental health disorders who are trying to quit smoking.

Despite the warnings, Dr. Rosebraugh said "varenicline and Zyban are effective smoking cessation aids. The possible risk of serious adverse events occurring should always be weighed against the significant health benefits of quitting smoking."

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