FDA Safety Changes: Update on QT Prolongation Risk With Ondansetron
Autor: Marcio Augusto Lacerda | Publicado: 2012-08-14T17:07:00-03:00





Roxanne Nelson



http://www.medscape.org/viewarticle/767798?src=cmemp












CLINICAL CONTEXT

Ondansetron is a 5-HT3 receptor antagonist indicated for prevention of nausea and/or vomiting occurring postoperatively or in association with emetogenic cancer chemotherapy. Electrocardiographic changes reported with ondansetron have included QT interval prolongation and, more rarely, torsades de pointes.

The US Food and Drug Administration (FDA) began an ongoing safety review and labeling changes for ondansetron in September 2011 and also required the manufacturer to conduct a thorough study to examine QT interval prolongation associated with ondansetron.

STUDY SYNOPSIS AND PERSPECTIVE

A single 32-mg intravenous dose of ondansetron (Zofran) may affect QT interval prolongation, the US Food and Drug Administration (FDA) announced. 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, 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 repeated 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 the drug manufacturer 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 maximal mean difference in QTcF from placebo after baseline correction was 20 milliseconds. At the lower single intravenous dose of 8 mg, the maximal 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.

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. Information will also be included 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 the announcement is available on the FDA's&nbsp;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 athttps://www.accessdata.fda.gov/scripts/medwatch/medwatch-online.htm; or with postage-paid FDA form 3500, available at&nbsp;http://www.fda.gov/MedWatch/getforms.htm; or by mail to MedWatch, 5600 Fishers Lane, Rockville, Maryland 20852-9787.

CLINICAL IMPLICATIONS

A new FDA Drug Safety Communication regarding use of ondansetron states that a single 32-mg intravenous dose of ondansetron may cause QT interval prolongation and should be avoided. QT interval prolongation may, in turn, lead to torsades de pointes, an abnormal and potentially fatal heart arrhythmia. No single intravenous dose should exceed 16 mg.
Data reviewed by the FDA regarding QT prolongation associated with use of ondansetron show dose-dependent QT prolongation, as well as at the highest tested single intravenous dose of 32 mg. After baseline correction, the maximal mean difference in QTcF from placebo was 20 milliseconds for the 32-mg single intravenous dose and 6 milliseconds for the 8-mg single intravenous dose.
Risk factors for QT prolongation associated with use of ondansetron include congenital long QT syndrome, congestive heart failure, bradyarrhythmias, or concomitant use of medications that prolong the QT interval. Before ondansetron is administered, electrolyte abnormalities including hypokalemia or hypomagnesemia should be corrected.