FDA Issues Update on QT Prolongation Risk With Ondansetron

Roxanne Nelson

Disclosures

June 29, 2012

June 29, 2012 — A single 32-mg intravenous dose of ondansetron (Zofran, GlaxoSmithKline [ondansetron hydrochloride], and generics) may affect QT interval prolongation, the US Food and Drug Administration (FDA) announced today. This, in turn, can predispose patients to develop an abnormal and potentially fatal heart arrhythmia known as torsades de pointes.

In an FDA Drug Safety Communication posted today, the agency says the use of a single 32-mg intravenous dose of ondansetron should be avoided. New information from a recently completed clinical study suggests that QT prolongation occurs in a dose-dependent manner, and specifically at a single intravenous dose of 32 mg.

Ondansetron is a 5-HT3 receptor antagonist and has been approved to prevent the nausea and vomiting associated with initial and repeat courses of emetogenic cancer chemotherapy, as well as postoperative nausea and/or vomiting. Changes in electrocardiogram have been observed in patients receiving this agent, including QT interval prolongation. Torsades de pointes has also been reported in some patients receiving ondansetron.

In September 2011, the FDA notified healthcare professionals and patients of an ongoing safety review and labeling changes for ondansetron, and noted that drug labels were being revised to include a warning to avoid use in patients with congenital long QT syndrome because of the heightened risk for torsades de pointes. At that time, the FDA required drug manufacturer GlaxoSmithKline to conduct a thorough study to determine the degree to which ondansetron might cause QT interval prolongation.

The FDA's preliminary review of the data indicates that QT prolongation occurs in a dose-dependent manner and at the highest tested single intravenous dose of 32 mg. The maximum mean difference in QTcF from placebo after baseline correction was 20 milliseconds. At the lower single intravenous dose of 8 mg, the maximum mean difference in QTcF from placebo after baseline correction was 6 milliseconds.

Individuals who may be at a higher risk for QT prolongation with ondansetron include those with congenital long QT syndrome, congestive heart failure, or bradyarrhythmias, or patients taking concomitant medications that prolong the QT interval. Electrolyte abnormalities including hypokalemia or hypomagnesemia should be corrected before receiving this agent.

GlaxoSmithKline has announced that the 32-mg single intravenous dose will be removed from the drug label. The updated label will state that ondansetron can continue to be used in both adult and pediatric patients with chemotherapy-induced nausea and vomiting at the lower intravenous dose recommended on the label: a dose of 0.15 mg/kg administered every 4 hours for 3 doses, with no single intravenous dose exceeding 16 mg because of the risk for QT prolongation. The manufacturer will also include information from the new clinical study in the updated drug label.

The FDA says that the agency will evaluate the final study results when the information becomes available and will work with the manufacturer to explore an alternative single-dose regimen that is both safe and effective.

The agency also emphasizes that this new information on QT prolongation does not change any of the recommended oral dosing regimens for ondansetron, including the single oral dose of 24 mg for chemotherapy-induced nausea and vomiting. The announcement also does not apply to the recommended lower intravenous dose to prevent postoperative nausea and vomiting.

As part of the ongoing safety review of ondansetron, the FDA continues to assess data about the risk for QT prolongation and will update the public when more information becomes available.

More information about today's announcement is available on the FDA's Web site.

To report adverse events related to ondansetron, contact MedWatch, the FDA's safety information and adverse event reporting program, by telephone at 1-800-FDA-1088; by fax at 1-800-FDA-0178; online at https://www.accessdata.fda.gov/scripts/medwatch/medwatch-online.htm; or with postage-paid FDA form 3500, available at http://www.fda.gov/MedWatch/getforms.htm; or by mail to MedWatch, 5600 Fishers Lane, Rockville, Maryland 20852-9787.

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