Drug Interactions between dolasetron and PC-CAP

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 (Fridericia-corrected QT interval) 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. 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 more likely with some drugs or drug combinations, dosage(s), and/or in the presence of underlying risk factors such as congenital long QT syndrome, cardiac disease, and electrolyte disturbances (e.g., hypokalemia, hypomagnesemia).

MANAGEMENT: Caution is recommended if dolasetron is used in combination with cumulative high-dose anthracycline therapy or other drugs that can prolong the QT interval. Hypokalemia and hypomagnesemia must be corrected prior to dolasetron administration and should be monitored as clinically indicated. ECG monitoring is recommended, particularly in certain high risk patient groups such as those with congestive heart failure, bradycardia, renal impairment, and the elderly. Patients should be advised to seek prompt medical attention if they experience symptoms that could indicate the occurrence of torsade de pointes such as dizziness, lightheadedness, palpitation, change in heart rate, shortness of breath, or syncope.

One study has reported that coadministration of caffeine and aspirin lead to a 25% increase in the rate of appearance and 17% increase in maximum concentration of salicylate in the plasma. A significantly higher area under the plasma concentration time curve of salicylate was also reported when both drugs were administered together. The exact mechanism of this interaction has not been specified. Physicians and patients should be aware that coadministration of aspirin and caffeine may lead to higher salicylate levels faster.