Psychiatric, Suicide Risks Lead to Warning on Smoking-Cessation Drugs

After reviewing postmarketing reports, the Food and Drug Administration (FDA) has ordered a boxed warning for two smoking-cessation drugs, varenicline and bupropion, regarding the risks of neuropsychiatric adverse reactions and suicide.

In addition to the boxed warning in the product labels, the drugs' manufacturers are required to develop medication guides to inform patients about these risks. Buproprion already carries another boxed warning about suicidality risk in children, adolescents, and young adults that is standard for all antidepressants.

In the July 1 announcement of the new safety alert, the FDA urged health care professionals to explain the neuropsychiatric risks to patients receiving treatment for smoking cessation. Patients should be told to “stop taking varenicline or bupropion and contact a health care provider immediately if they experience agitation, depressed mood, and any changes in behavior that are not typical of nicotine withdrawal, or if they experience suicidal thoughts or behaviors,” the agency stated.

The FDA analyzed hundreds of postmarketing case reports of neuropsychiatric symptoms and suicidal thoughts or behaviors suspected of being connected to the use of smoking-cessation aids. Between its approval in 2006 and November 2007, varenicline was linked to 116 cases of suicidal ideation and 37 suicidal behaviors, including 19 deaths, according to a review published in FDA Drug Safety Newsletter (volume 2, number 1). For bupropion, 46 cases of suicidal ideation and 29 of suicidal behaviors, including 10 deaths, were associated with the drug since 1997, when it was approved for smoking cessation as Zyban.

In the review, suicidal behaviors referred to reports that included the phrases “completed suicide,” “attempted suicide,”“ intentional self-injury,” “self-injurious behavior,”“ suicidal behavior,” “multiple drug overdose,”“ gun-shot wound,” “intentional misuse,” and“ overdose.”

Half of the patients with varenicline-linked suicidal ideation and behaviors had a known history of psychiatric disorders, a quarter had no psychiatric history, and psychiatric-disorder history was unknown for the rest.

FDA reviewers also considered adverse-event reports associated with nicotine-replacement patches such as Nicoderm, Habitrol, and Prostep, but found no clear link to suicidal ideation or behaviors.

Because the FDA's adverse-event reporting system relies on spontaneous, voluntary reports from health care professionals and the public, the case numbers probably have underestimated the true frequency of suicidal ideation and behaviors. Both drugs have been sold in millions of units since receiving approval, according to the agency.

At a press briefing on July 1, Curtis Rosebraugh, M.D., director of the FDA's Office of Drug Evaluation II, acknowledged that nicotine withdrawal itself can cause psychiatric symptoms similar to those suspected with varenicline and bupropion, and this overlap makes it difficult to analyze the true effects of the drugs. He also emphasized that neither drug has been deemed contraindicated in any patient population and that the risks must be weighed carefully with the health benefits of smoking cessation.

“The question for clinicians to consider is what the relative risks are between drug-related adverse events and the consequences of smoking,” John Newcomer, M.D., told Psychiatric News. Newcomer is the Gregory B. Couch Professor of Psychiatry and a professor of psychology and medicine at Washington University in St. Louis School of Medicine.“ The risk of failing to achieve smoking cessation is clear and large. The FDA warning is nicely phrased to point out the need for careful clinical evaluation of the risks and benefits of these drugs.” He pointed out that smoking cessation has been shown to result in rapid and substantial reduction in the risk of cardiovascular and pulmonary diseases.

Smoking cessation may have particularly high priority in psychiatry because certain psychiatric disorders, such as schizophrenia, are associated with much higher rates of smoking than are found among the general population. Meanwhile, psychiatric patients taking antipsychotic and other medications are already facing elevated risks of metabolic and cardiovascular diseases, with smoking potentially multiplying those risks.

“Psychiatric populations may or may not be more susceptible to the neuropsychiatric effects of the [smoking-cessation] drugs, but we do not have the answer now,” said Newcomer. An ongoing clinical trial of varenicline in patients with schizophrenia may eventually provide data on this question.

Monitoring for psychiatric symptoms emerging while a person is taking smoking-cessation medications is important. “The [drug-related] adverse events are very difficult to disentangle from smoking cessation itself,” said Newcomer. He pointed out that, for the average patient, the side effects of varenicline or bupropion appear to be incremental above the side effects of nicotine withdrawal, which should be monitored regardless of the smoking-cessation method.

For now, clinicians should “sit down with the patient and make careful decisions together,” Newcomer recommended.

The FDA alert is posted at<www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/DrugSafetyInformationforHeathcareProfessionals/ucm169986.htm>. The agency's postmarketing review of suicidal ideation and behaviors is posted at<www.fda.gov/downloads/Drugs/DrugSafety/DrugSafetyNewsletter/UCM107318.pdf>.▪