Drug Interaction Report

GENERALLY AVOID: Arsenic trioxide can cause QT interval prolongation and complete atrioventricular block. 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. During clinical studies involving 40 patients receiving arsenic trioxide for acute promyelocytic leukemia, 16 of them (40%) had at least one ECG tracing with a QTc interval greater than 500 msec. Prolongation of QTc was observed between 1 and 5 weeks after arsenic trioxide infusion and returned towards baseline by the end of 8 weeks. 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).

MANAGEMENT: If possible, medications that are known to prolong the QT interval should be discontinued prior to initiating therapy with arsenic trioxide and withheld for at least several weeks after completion of therapy. Caution is advised if concomitant use cannot be avoided. Patients should have frequent ECGs and be monitored for arrhythmias when QT interval is prolonged. An absolute QT interval exceeding 500 msec will require immediate action to correct concomitant risk factors, if any, as well as a thorough assessment of the need for continued therapy. Patients who develop syncope or arrhythmia should be hospitalized for clinical and laboratory monitoring. Arsenic trioxide should be temporarily discontinued until symptoms resolve, the QTc interval regresses to below 460 msec, and electrolyte abnormalities are corrected.

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.

Grapefruit juice may delay the gastrointestinal absorption of clarithromycin but does not appear to affect the overall extent of absorption or inhibit the metabolism of clarithromycin. The mechanism of interaction is unknown but may be related to competition for intestinal CYP450 3A4 and/or absorptive sites. In an open-label, randomized, crossover study consisting of 12 healthy subjects, coadministration with grapefruit juice increased the time to reach peak plasma concentration (Tmax) of both clarithromycin and 14-hydroxyclarithromycin (the active metabolite) by 80% and 104%, respectively, compared to water. Other pharmacokinetic parameters were not significantly altered. This interaction is unlikely to be of clinical significance.