Drug Interactions between dolasetron and flecainide

MONITOR CLOSELY: Dolasetron can cause dose-related prolongation of the QT interval via its pharmacologically active metabolite, hydrodolasetron. Theoretically, coadministration with other agents that can prolong the QT interval may result in additive effects and increased risk of ventricular arrhythmias including torsade de pointes and sudden death. In a study of 80 healthy adult subjects, maximum mean difference in QTcF from placebo after baseline-correction was 14.1 ms for the 100 mg dose and 36.6 ms for the supratherapeutic 300 mg dose of dolasetron administered intravenously. Dolasetron 300 mg once daily produced mean peak plasma concentration (Cmax) values of dolasetron mesylate and hydrodolasetron on day 4 that were approximately 3-fold higher than those observed with the therapeutic 100 mg dose. Based on exposure-response analysis in healthy volunteers, QTc interval prolongations appear to be associated with concentrations of hydrodolasetron. Using the established exposure-response relationship, the mean predicted increase in QTcF interval was 16.0 ms for renally impaired subjects and 17.9 ms for elderly subjects following an oral dose of 100 mg. In clinical trials, ECG interval prolongations usually returned to baseline within 6 to 8 hours after administration, but lasted more than 24 hours in some patients. In general, the risk of an individual agent or a combination of agents causing ventricular arrhythmia in association with QT prolongation is largely unpredictable but may be increased by certain underlying risk factors such as congenital long QT syndrome, cardiac disease, and electrolyte disturbances (e.g., hypokalemia, hypomagnesemia). In addition, the extent of drug-induced QT prolongation is dependent on the particular drug(s) involved and dosage(s) of the drug(s).

MONITOR CLOSELY: Dolasetron has been shown to cause dose-dependent prolongation of the PR and QRS intervals. There have been reports of second- and third-degree atrioventricular block, cardiac arrest, and serious ventricular arrhythmias including fatalities in both adult and pediatric patients. Theoretically, coadministration with other agents that prolong the PR interval (e.g., beta blockers; calcium channel blockers; some protease inhibitors such as atazanavir, lopinavir and saquinavir; digitalis; lacosamide; mefloquine; moricizine) or QRS interval (e.g., flecainide; moricizine; quinidine) may result in additive effects and increased risk of bradycardia and heart block. Other risk factors include underlying structural heart disease, preexisting conduction abnormalities, advanced age, sick sinus syndrome, atrial fibrillation with slow ventricular response, and myocardial ischemia. In a study of 80 healthy adult subjects, maximum mean difference in PR interval from placebo after baseline-correction was 9.8 ms and 33.1 ms for the 100 mg and supratherapeutic 300 mg dose of dolasetron, respectively. The maximum mean difference in QRS interval from placebo after baseline-correction was 3.5 ms for the 100 mg dose and 13 ms for the supratherapeutic 300 mg dose of dolasetron. Over 25% of the subjects treated with the 300 mg dose had an absolute PR over 200 ms and absolute QRS over 110 ms after treatment. A change from baseline of 25% or greater was noted in several of these subjects.

MANAGEMENT: Caution is advised if dolasetron is used concomitantly with other agents that prolong the QT, PR and/or QRS interval, especially in the elderly and patients with known risk factors. An ECG should be obtained in these patients before initiating dolasetron and periodically during treatment. Patients should be advised to seek medical attention if they experience dizziness, lightheadedness, fainting, palpitations, irregular heartbeat, shortness of breath, or syncope. Dolasetron should be avoided in patients with complete heart block or at risk for complete heart block, unless they have an implanted pacemaker.