Drug Interactions between amoxicillin / clarithromycin / vonoprazan and itraconazole

MONITOR: Coadministration of itraconazole and the macrolide antibiotics may result in elevated plasma concentrations of itraconazole. The mechanism is decreased clearance of itraconazole due to competitive inhibition of CYP450 3A4 enzymatic activity by the macrolide agents. According to the manufacturer, the administration of a single dose of erythromycin ethyl succinate (1 gram) increased the mean peak plasma concentration and area under the concentration-time curve of itraconazole (200 mg) by 44% and 36%, respectively. Likewise, in a small number of HIV-infected patients, clarithromycin also increased the plasma levels of itraconazole. The effect of itraconazole on erythromycin and clarithromycin is uncertain, although elevated plasma clarithromycin concentrations have been reported in 3 patients treated for pulmonary Mycobacterium avium complex (MAC) and aspergillosis coinfections.

MANAGEMENT: Caution is advised if itraconazole must be used concomitantly with erythromycin or clarithromycin. Patients should be advised to notify their physician if they experience possible symptoms of itraconazole toxicity, such as nausea, vomiting, diarrhea, abdominal pain, or headache. Alternative macrolide antibiotics such as azithromycin or dirithromycin, which do not inhibit CYP450, may be appropriate.

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.