FDA: Dolasetron mesylate IV no longer indicated for CINV

Key Points

Intravenous (IV) dolasetron mesylate (Anzemet) should no longer be used to prevent nausea and vomiting associated with cancer chemotherapy (CINV) in adult or pediatric patients due to an associated dose-dependant increase in QTc prolongation, according to a recent FDA drug safety communication.

This FDA action is in response to a randomized, placebo- and active- (moxifloxacin 400 mg) controlled crossover study of IV dolasetron mesylate in 80 healthy adults. In this trial, dolasetron mesylate IV was found to increase the QTc interval (corrected for heart rate using Fridericia's formula) on day 4 compared to placebo (after baseline correction) by as much as 14.1 ms (maximum mean change) in patients receiving the FDA-approved 100-mg dose and 36.6 ms in those receiving a supratherapeutic dose of 300 mg IV. Furthermore, the PR and QRS intervals were also prolonged by IV dolasetron mesylate. The maximum mean prolongation in the PR versus placebo was 9.8 and 33.1 ms for 100-mg and 300-mg doses, respectively.

While the affect of dolasetron mesylate IV on QTc interval prolongation has not been directly evaluated in pediatric patients, modeling based upon pharmacokinetic data suggests similar clinically relevant changes in QTc interval (predicted interval increase of 22.5 ms for the recommended 1.8 mg/kg CINV dose).

According to FDA, dolasetron mesylate IV may still be used for the prevention and treatment of PONV because the lower doses appear less likely to affect the QTc, PR, or QRS intervals. However, the CINV indication will be removed from the IV product's label and a stronger warning regarding the drug's affect on the electrical activity of the heart and its propensity to cause abnormal heart rhythms will be added to both the IV and oral formulation prescribing information.

SOURCES

FDA. FDA Drug Safety Communication: Abnormal Heart Rhythms Associated with Use of Anzemet (Dolasetron Mesylate) [Safety Communication]. Available at: http://www.fda.gov/Drugs/DrugSafety/ucm237081.htm. Accessed December 17, 2010.

FDA. Guidance for Industry E14 Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic Potential for Non-Antiarrhythmic Drugs. October 2005. Available at: http://www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM129357.pdf. Accessed December 17, 2010.

Anzemet [package insert]. Bridgewater, NJ: Sanofi-Aventis U.S. LLC; 2009.