May 15, 2013
New Study Raises Questions About FDA Warning
Ann Arbor, MI—In 2011, the FDA issued a safety communication saying that the antidepressant citalopram hydrobromide, marketed as Celexa as well as generic formulations, should no longer be used at doses greater than 40 mg per day because it can cause abnormal changes in the electrical activity of the heart.
In March of this year, the agency took the issue a step further, saying that citalopram use at any dose is discouraged in patients with certain conditions because of the risk of QT prolongation. The revised drug label was changed to include cautions when the drug must be used and to describe the necessity of lower doses in patients older than 60 years.
A new study out of the University of Michigan and the Ann Arbor Veterans Affairs health system, however, takes issue with the FDA’s warnings. In the report published by the American Journal of Psychiatry, researchers say they found no increased risk for abnormal heart rhythms or death in patients who took daily doses of more than 40 mg before or after the warning took effect.
“Our findings raise questions about the continued legitimacy of the FDA warning and provide support for the question of whether the warning will do more harm than good,” says lead author Kara Zivin, PhD, assistant professor of psychiatry at Michigan and research investigator at the VA Center for Clinical Management Research.
For the study, researchers analyzed data from more than 600,000 Veterans Health Administration patients who received citalopram prescriptions between 2004 and 2009. Also examined were patient outcomes for more than 300,000 patients who were prescribed a similar antidepressant, sertraline, which does not have an FDA warning.
No elevated risks of ventricular arrhythmia or death related to higher dosages of citalopram were uncovered. In fact, the authors point out, higher dosages were associated with fewer adverse outcomes than lower dosages, which were similar to the comparison drug, sertraline.
According to study results, citalopram daily doses greater than 40 mg were associated with lower risks of ventricular arrhythmia (adjusted hazard ratio = 0.68, 95% CI = 0.61–0.76), all-cause mortality (adjusted hazard ratio = 0.94, 95% CI = 0.90–0.99), and noncardiac mortality (adjusted hazard ratio = 0.90, 95% CI = 0.86–0.96) compared with daily doses of 1 to 20 mg. Overall, no increased risks of cardiac mortality were found, according to the researchers.
Citalopram daily doses of 21 to 40 mg, meanwhile, were associated with lower risks of ventricular arrhythmia (adjusted hazard ratio = 0.80, 95% CI = 0.74–0.86) compared with dosages of 1 to 20 mg/day, but did not have significantly different risks of any cause of mortality.
“These results raise questions regarding the continued merit of the FDA warning,” the authors write.
“For some patients, a dosage higher than 40 milligrams per day can be very beneficial,” according to senior author Helen Kales, MD, associate professor of psychiatry and VA researcher. “Unfortunately the FDA's warning may have made attaining such a prescription more difficult.”
The authors call for further studies on the possible link between citalopram and cardiac risks, while admitting that their results might create a quandary for health care providers.
Zivin asks, “Should dosages be modified for those with risk factors for cardiac complications? Should health care providers alter how they prescribe this drug to new patients, or order ECGs for patients at risk before writing a new prescription? Or should patients be switched to other antidepressants with similar profiles, but no warning? These are all things clinicians need to consider.”
She adds, “Currently, clinicians whose patients benefit from high dosages of citalopram must choose between following the FDA’s warning or risking worsening depression if patients receive too low a dosage.”
|U.S. Pharmacist Social Connect