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
Credit: iStockphoto ©Lukasz Witczak
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"
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
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
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
For now, clinicians should "sit down with the patient and make
careful decisions together," Newcomer recommended.