Although the FDA announced it is conducting a safety review of the antinausea drug Zofran (ondansetron, ondansetron hydrochloride and their generics) because of its potential to increase the risk for cardiac arrhythmias, some experts say the drug is still useful in many patients, provided it is appropriately monitored.

Zofran, used to prevent nausea and vomiting caused by surgery, cancer chemotherapy and radiation therapy, is a serotonin type 3-receptor (5-HT₃) antagonist. The FDA previously noted cardiovascular safety concerns indicating Zofran could prolong the QT interval of the electrocardiogram, which can lead to the potentially fatal heart rhythm known as torsades de pointes.

In September, the agency announced it had reviewed all available information and added a new warning that Zofran should not be used in patients with congenital long QT syndrome because these patients are at particular risk for developing torsades de pointes. (Previous versions of the labels for ondansetron included a warning about QT interval prolongation.) The FDA also added recommendations for electrocardiogram monitoring in patients with electrolyte abnormalities, congestive heart failure and brady-arrhythmias, or in patients taking other medications that can lead to QT prolongation.

Furthermore, the FDA is requiring drug manufacturer GlaxoSmithKline to conduct a study to determine the extent to which Zofran may cause QT interval prolongation.

The FDA action is a deja vu moment for the anesthesia community, coming a decade after the agency in 2001 pushed for a black-box warning on another anti-emetic, droperidol. Many anesthesiologists felt then that the label change, which effectively removed droperidol from the armamentarium of drugs for postoperative nausea and vomiting, was an over-reaction.

How Much Concern Warranted?

Despite all the concern, some clinicians said there’s no reason to be nervous, in part because the relationship between 5-HT₃ antagonists and QT prolongation has been well known for years.

Last December, the FDA issued a warning about the use of the injection form of Anzemet (dolasetron mesylate) in pediatric and adult cancer patients with underlying heart conditions or heart rate abnormalities. The previous October, the agency changed the label for Kytril (granisetron hydrochloride) to state that the drug should be used with caution in patients with pre-existing arrhythmias or cardiac conduction disorders.

The anesthesiology literature also has documented QT prolongation as a potential side effect of onsansetron therapy. In fact, two studies published in the journal Anesthesiology helped prompt the FDA review of Zoftran. The first study, by Charbit et al at Beaujon University Hospital in Paris, showed that onsansetron and droperidol increased the QT interval by 17 to 20 milliseconds in patients with postoperative nausea and vomiting (2008;109:206-212). The second study, also by Charbit et al, showed that the drug combination increased QT prolongation in healthy volunteers by an average of 28 milliseconds (2005;102:1094-1100).

“As anesthesiologists we see QTc prolongations in the range of 20 to 30 milliseconds with virtually every anesthetic we provide,” said Christian C. Apfel, MD, PhD, associate professor of anesthesia, epidemiology and biostatistics at the University of California, San Francisco, an an expert in postoperative nausea and vomiting. “And since anesthesia-related complications in otherwise healthy individuals are exceptionally rare—on the order of 1 in every 300,000 cases—it is hard for us to imagine that the use of ondansetron or droperidol, both which have a much smaller effect on the QTc interval, as Dr. [Paul] White et al. have demonstrated for droperidol in a well-designed randomized controlled trial, can lead to any meaningful cardiac outcomes.”

However, Dr. Apfel added, the challenge for clinicians is that even young and healthy-looking individuals may have mutations on the HERG receptor, a potassium receptor in the cardiac rhythmogenic circuitry, and thus be at considerably higher risk for severe arrhythmias or cardiac arrest than the average population.

“This may be the tip of the iceberg we are seeing and why alternatives like palonosetron [Aloxi, Eisai], which does not possess the class-specific QTc prolongation effect, may be safer,” he said. “And this might be even more relevant for chemotherapy where higher doses are used.”

The fact that multiple 5-HT₃ agents have been implicated has caused some experts, like Dr. Apfel, who has consulted for Eisai, to suggest QT prolongation is a class effect; others still claim it is agent-specific. (Earlier this year, a medical officer at the FDA chimed in by stating in a clinical review that QT prolongation and other electrocardiographic changes are indeed “class effects” of 5-HT₃ antagonists.)

James Kalus, PharmD, senior manager for patient care services in the Department of Pharmacy Services at Henry Ford Hospital in Detroit, said he and others continue to use Zofran, although they monitor for heart arrhythmias in specific patient populations, such as those with low potassium and magnesium or those who take other medications that cause QT prolongation.

Many antiemetics have similar risks, Dr. Kalus said, and some of the newer ones could be considerably more expensive. “At this point, I don’t have a sense of the magnitude of the QT interval increase,” he noted. “An increase of 30 is worrisome; an increase of 60 is bad; but for a 10-millisecond increase, it may not be a big deal.

“Should [the FDA warning] be taken seriously? Yes, but I don’t think we should throw [ondansetron] away since we don’t know the magnitude of the problem. About 20% of drugs we use regularly have similar risks.”

Strength of Data Questioned

Cynthia Sanoski, PharmD, chair of the Department of Pharmacy Practice at the Jefferson School of Pharmacy at Thomas Jefferson University, in Philadelphia, said the data on QT prolongation from Zofran “is not the strongest evidence in the world. But if you use it in the wrong type of patient—someone with heart issues or on other drugs causing QT prolongation—it could result in a life-threatening emergency.” Physicians had been “giving out Zofran like water,” she added, but the FDA warning gives a reason to pause and take steps like checking patients’ magnesium and potassium levels before administering the medicine.

Ali McBride, PharmD, clinical pharmacy specialist at Barnes-Jewish Hospital in St. Louis, said clinicians may be liable if they don’t take steps to monitor patients on 5-HT₃ drugs for QT prolongation. “The problem is that nobody has determined, with any degree of scientific rationale, just how much monitoring is required; how often it should be performed; and by whom,” he said. “I can tell you that there is a lot of concern and confusion on this issue among hematology/oncology pharmacists, and I’m not sure we know where to turn for answers.”

Dr. McBride also echoed Dr. Kalus’ point that there could be considerable financial fallout if clinicians switch from ondansetron to a branded drug such as Aloxi that reportedly does not cause heart-rhythm abnormalities. Such a switch “could be a pharmacy budget buster, especially on the inpatient side,” he said.

Could the switching strategy ultimately be a cost saver, by reducing Zofran-induced rehospitalizations and lawsuits? “That argument could be made,” Dr. Mc Bride said. “But there is still a large ‘silo’ mentality in health systems. Those drug budgets are often viewed in a vacuum. If there is a big uptick in drug spending, eyebrows will definitely be raised, and not everyone will have the patience to wait for downstream savings to accrue.”

Risk Not Limited 5-HT₃ Drugs

Other types of drugs also can cause QT prolongation, Dr. Sanoski said, including Celexa (citalopram hydrobromide). In August, the FDA announced that Celexas no longer should be given at daily doses of more than 40 mg because of the side effect. But with antidepressants, she pointed out, there are so many options that a different drug can easily be selected. With nausea and vomiting, in contrast, “there are not a lot of great alternatives to the 5-HT3 receptor antagonists such as Zofran. In most cases you are probably still going give the drug and document accordingly. I don’t see this as being any different from other drugs in this class of medications that have gotten the same warnings with regard to QT prolongation.”