Drug Interactions between amoxicillin / clarithromycin / omeprazole and ketoconazole

MONITOR: Theoretically, concurrent use of two or more drugs that can cause QT interval prolongation may result in additive effects and increased risk of ventricular arrhythmias including torsade de pointes and sudden death. The risk of an individual agent or a combination of these 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: Caution and clinical monitoring are recommended if multiple agents associated with QT interval prolongation are prescribed together. 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, fainting, palpitation, irregular heart rhythm, shortness of breath, or syncope.

GENERALLY AVOID: Inhibitors of the proton pump (PPIs or potassium-competitive acid blockers [PCABs]) may decrease the gastrointestinal absorption of the azole antifungal agents, itraconazole (capsules only) and ketoconazole, both of which require an acidic environment for dissolution. By increasing gastric pH and reducing the acidity, proton pump inhibitors can decrease bioavailability of the azoles by 75% to 80%. Additionally, ketoconazole (a potent CYP450 3A4 inhibitor) may increase serum omeprazole levels. The metabolism of omeprazole includes hydroxylation catalyzed by CYP450 2C19 and, to a minor extent, sulfoxidation by CYP450 3A4. In a study involving ten subjects, ketoconazole 100 mg to 200 mg daily resulted in a marked inhibition of the formation of the omeprazole sulfone in both extensive and poor metabolizers of CYP450 2C19. In poor metabolizers, a doubling of omeprazole levels was observed. No adverse effects were reported by any of the subjects.

MANAGEMENT: In general, the concomitant use of these drugs is not recommended. If coadministration is necessary, an acidic pH may be produced with two capsules of glutamic acid hydrochloride administered 15 minutes before the azole dose. Administration with an acidic beverage such as Coca-Cola(R) may also help. Additionally, an increase of the antifungal dosage may be required. However, clinicians should still consider the possibility of a reduced or subtherapeutic antifungal effect. It may be appropriate to switch to itraconazole oral solution or an agent like fluconazole whose absorption is not affected by stomach pH.

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.