Eli Lilly and Co. announced September 29 that it was complying with a
request from the U.S. Food and Drug Administration (FDA) to add a"
black-box" warning to the product labeling for atomoxetine
The added language will focus on "uncommon reports of suicidal
thoughts among children and adolescents" taking the drug. In conjunction
with the action, the FDA issued a Public Health Advisory and updated its
online "Healthcare Professional Information Sheet" for the
Atomoxetine, a selective norepinephrine reuptake inhibitor (SNRI), is
approved in the United States for treatment of attention-deficit/hyperactivity
disorder (ADHD) in adults and children aged 6 and older.
In separate statements, both Lilly and the FDA said that the action was
taken as a result of the company's submission of an "analysis of
adverse-event data from its Strattera clinical-trials database that identified
a small but statistically significant increased risk of suicidal thoughts
among Strattera-treated children and adolescents" compared with patients
in those trials taking placebo.
The FDA also requested that Lilly develop a medication guide for patients
The FDA has no statutory authority to require specific labeling or
medication guides. Rather, it is limited to requesting action from a drug
manufacturer and normally must negotiate final labeling language with the
company. If a drug maker does not agree with the agency's request, the FDA has
the option to declare the product under discussion "misbranded"
and begin legal proceedings that could result in the product's removal from
the market. That process is cumbersome, however, and has rarely been used.
The director of the FDA Center for Drug Evaluation and Research, Steven
Galson, M.D., characterized the action as "another example of the agency
acting swiftly to alert the public to significant drug safety information
needed to use a drug in a safe manner." Yet, in this instance, the
option of adding a black-box warning to the atomoxetine label was suggested by
Lilly itself when it submitted data from 12 clinical trials involving
approximately 2,200 children and adolescents.
The data were requested by the FDA (and other regulators around the globe)
as part of an ongoing review of safety data relating to psychiatric
medications. Specifically, the agency asked Lilly for data on "possibly
suicide-related" adverse events occurring in any of the
placebo-controlled trials of atomoxetine. Suicide-related adverse events
include both suicidal thoughts and behaviors.
Lilly submitted the dataset to the FDA and other regulators on September
15. The company also submitted two analyses of the adverse-event data. Data
from 12 pediatric trials were submitted (eight involving patients who had only
ADHD, the others involving patients with ADHD and comorbidities such as major
depression or anxiety). Nine trials of the drug in adults were submitted,
three concerning ADHD and six involving major depression.
Of the 2,200 children and adolescents studied, 1,357 received the drug, and
851 received placebo. Five "possibly suicide-related" cases were
identified in patients taking atomoxetine (0.37 percent), and no cases
appeared in those taking placebo. A sixth case was identified and classified
as a suicide attempt in a patient taking the drug. All of the cases represent
spontaneously reported adverse events. None of the clinical trials' protocols
appear to have used standardized measurements of suicidal thinking or
According to the Centers for Disease Control and Prevention, 17 percent of
adolescents think about suicide a year. Among high school students, 12 percent
of girls and 5 percent of boys attempt suicide a year. Ultimately, 2 per
100,000 girls and 12 per 100,000 boys die as a result of such attempts. In the
United States, this translates into approximately 2,000 young people who die
as a result of suicide.
Overall, pediatric patients taking atomoxetine were deemed to be about 2.5
times more likely to have a "possibly suicide-related" event than
those who took placebo. A Lilly meta-analysis of suicide-related behaviors in
the placebo-controlled atomoxetine studies showed that of six events, five
involved suicidal ideation, while only one involved actual suicidal behavior.
Of these events, all occurred in males under age 12. There were no completed
The Lilly analysis further noted that the "number needed to
harm" for suicidal ideation was 271 for all pediatric patients in the
clinical trials. That is, 271 patients would have to be given atomoxetine
before one patient would experience a "possibly suicide-related"
event. In contrast, only four patients would need to receive medication to
have one pediatric patient experience a remission (defined as greater than or
equal to a 40 percent reduction in the ADHD Rating Scale total score).
Analysis of the nine adult trials showed no increased risk of"
possibly suicide-related" events.
Other regulatory agencies announced similar updates to approved product
labeling in their jurisdictions, including Canada, the European Union, and
Australia. In Canada, the warning will appear similar to that in the United
States, as a boxed, bolded warning in the product labeling. In most countries
of the European Union, the information will appear under the "Special
Warnings" section of the label. However, the United Kingdom's Medicines
and Healthcare Products Regulatory Agency said it is "looking into the
health risks and benefits of [atomoxetine]," and new labeling may be
announced soon. In Australia, the new warning will appear as a"
The FDA's MedWatch notification on Strattera is posted at<www.gda.gov/medwatch/safety/2005/safety05.htm>.
Links to the agency's Public Health Advisory and Healthcare Professional
Information Sheet are posted there as well. ▪