Drug Interactions between amoxicillin / clarithromycin / omeprazole and dolasetron

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.

Although some in vitro data indicate synergism between macrolide antibiotics and penicillins, other in vitro data indicate antagonism. When these drugs are given together, neither has predictable therapeutic efficacy. Data are available for erythromycin, although theoretically this interaction could occur with any macrolide. Except for monitoring of the effectiveness of antibiotic therapy, no special precautions appear to be necessary.

Clarithromycin may increase and prolong the omeprazole plasma concentration. The mechanism may be related to clarithromycin inhibition of hepatic cytochrome P450 enzymes responsible for omeprazole metabolism. Coadministration of omeprazole may result in an increase in clarithromycin and 14-(R)-hydroxyclarithromycin plasma concentrations. These increases may be due to the effect of omeprazole on gastric pH.