Drug Interactions between amoxicillin / clarithromycin / omeprazole and trazodone

ADJUST DOSE: Coadministration with potent inhibitors of CYP450 3A4 may increase the plasma concentrations and pharmacologic effects of trazodone, which is primarily metabolized by the isoenzyme. In ten healthy volunteers, administration of a single 50 mg dose of trazodone in combination with the potent CYP450 3A4 inhibitor ritonavir (200 mg orally for 4 doses) increased mean trazodone peak plasma concentration (Cmax) by 34% and systemic exposure (AUC) by 137% compared to administration with placebo. Trazodone elimination half-life was prolonged 122% by ritonavir, while apparent oral clearance decreased 52%. Sedation, fatigue, and performance impairment were also increased during coadministration with ritonavir, and three subjects experienced nausea, dizziness, and hypotension. Although not reported in the study, the potential for increased risk of QT interval prolongation and ventricular arrhythmias including torsade de pointes should also be considered. There have been postmarketing reports of torsade de pointes associated with immediate-release trazodone following overdose and in the presence of multiple confounding factors, even at dosages of 100 mg/day or less. Moreover, some of the potent CYP450 3A4 inhibitors such as clarithromycin, erythromycin, telithromycin, lopinavir-ritonavir, saquinavir, and azole antifungal agents have also been reported to prolong the QT interval, thus additive effects may occur when used with trazodone.

MANAGEMENT: If concomitant use cannot be avoided, a lower dosage of trazodone should be considered during coadministration with a potent CYP450 3A4 inhibitor. Pharmacologic response to trazodone should be monitored more closely whenever a CYP450 3A4 inhibitor is added to or withdrawn from therapy, and the trazodone dosage adjusted as necessary. Patients should seek prompt medical attention if they experience symptoms that could indicate the occurrence of torsade de pointes such as dizziness, lightheadedness, fainting, palpitations, irregular heartbeat, 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.

An interaction with omeprazole was suggested as the cause of trazodone toxicity in a patient who experienced lightheadedness and syncope while receiving the combination. In an isolated case report, a 54-year-old patient receiving trazodone (50 mg/day), omeprazole (20 mg/day), and simvastatin (20 mg/day) developed second degree Mobitz type 1 atrioventricular block, which the authors speculated was due to trazodone toxicity stemming from inhibition of its metabolism by omeprazole. However, causality is difficult to establish in this particular case due to potential confounding factors and lack of details. Trazodone is primarily metabolized by CYP450 3A4, yet omeprazole is not known to be a significant in vivo inhibitor of the isoenzyme. In addition, the patient had doubled the dose of trazodone on his own the night before presentation to the emergency room. There were also no rechallenge or dechallenge information provided in the report, nor blood levels of trazodone indicating toxicity. The patient recovered following discontinuation of both omeprazole and trazodone.