FDA Drug Safety Update

Implications for Pediatric Health Care Providers

Marcia L. Buck, Pharm.D., FCCP, FPPAG


Pediatr Pharm. 2012;18(10) 

In This Article

Risk for Drug-induced QTc Prolongation

Two commonly used drugs, ondansetron and clarithromycin, have received additional safety labeling in response to new information on their potential to produce prolongation of the corrected QT interval (QTc) on electro-cardiogram (ECG) and place patients at risk for the development of torsades de pointes. While the prescribing information for both of these drugs already included this adverse effect, this new information has prompted a strengthening of the warning.

On June 29, 2012, the FDA issued a drug safety communication to inform prescribers of the results of a recently completed study from GlaxoSmithKline suggesting that one of the current ondansetron dosing options for prevention of chemotherapy-induced nausea and vomiting, a single 32 mg IV dose, was associated with an unacceptable prolongation of the QTc.[12] The study, requested by the FDA to assess the drug's potential to cause arrhythmias, demonstrated a dose-dependent prolongation of the QTc. A single IV dose of 32 mg, the highest dose studied, produced a maximum mean difference in QTc from baseline of 20 msec. In comparison, an 8 mg IV dose produced only a 6 msec difference. As a result of these findings, the manufacturer has voluntarily removed this dose from the product's prescribing information. The recommended IV dosing for adults and children remains 0.15 mg/kg given every 4 hours for three doses, with a single IV dose maximum of 16 mg. Oral dosing recommendations were not altered.

Although ondansetron produced no significant effect on the QTc interval in two pediatric clinical studies,[13,14] there have been cases of ventricular tachycardia resulting from ondansetron use in children with underlying congenital QTc prolongation. In 2010, McKechnie and Froese described a previously healthy 11-year-old girl who developed polymorphic ventricular tachycardia within minutes of receiving ondansetron 0.1 mg/kg and dimenhydrinate 0.4 mg/kg IV for prevention of post-operative nausea and vomiting.[15] An ECG revealed a significantly prolonged QTc of 590 msec that decreased to 490 msec by the following day, but did not normalize after the drugs had been eliminated. The patient was subsequently diagnosed with congenital QT prolongation.

Clarithromycin received new labeling in July 2012 to strengthen the warning regarding QTc prolongation, making the use of this drug in patients with a known history of QTc prolongation or ventricular arrhythmias a contraindication.[16] This follows the announcement of a similar change to the prescribing information for azithromycin earlier this year.[17]

QTc prolongation resulting from clarithromycin use has been reported in children as well as adults. In 2006, Germanakis and colleagues studied the effect of clarithromycin on the QTc interval in 28 children being treated for respiratory tract infections.[18] The QTc was measured prior to starting clarithromycin and again 24 hours after the initiation of therapy. There was a statistically significant increase of 22 msec in the mean QTc after treatment (95% CI 14-30 msec, p < 0.001), but the results were not felt to be clinically significant overall. However, there were seven cases of clinically significant prolongation of the QTc (> 440 msec) identified.