Drug Interactions With Azole Antifungals: Focus on Fluconazole and Itraconazole

Azole antifungals are widely used to treat numerous infections. ¹ Many well-documented, clinically significant drug interactions are associated with these agents.^1,2

Although the focus here is on the most commonly prescribed systemic azoles, fluconazole( and itraconazole(, it is important to be aware of clinically relevant drug interactions with other systemic azoles, including ketoconazole( and voriconazole(. ^2-4 Whenever these drugs are prescribed, assessment of potentially harmful interactions is essential. Many of the drug interactions described here for fluconazole and itraconazole also occur with other azoles; consult current drug interaction texts or primary literature for more information.

In addition to systemic azoles, a small number of case reports suggest that topical miconazole, including cream,⁵ oral gel,^6,7 and vaginal suppositories,⁸ can potentiate the effects of warfarin(. Although studies are required to establish this and possibly other interactions, be vigilant when patients who take warfarin use topical azoles.

MECHANISMS OF INTERACTIONS
Drug interactions with azole antifungals can occur through a variety of mechanisms. Many of these interactions are caused by the inhibition of the cytochrome P-450 (CYP) isoenzyme CYP3A4.² Inhibition of CYP3A4 results in decreased hepatic metabolism of several drugs, which increases their concentrations (Table 1).

It is highly important to note that fluconazole inhibits CYP2C9 even at low doses (100 mg/d and 200 mg/d) and thus causes serum concentrations of 2 high-risk drugs, warfarin and phenytoin(, to increase.,^2,9,10 At doses greater than 200 mg/d, fluconazole also inhibits CYP3A4.,^2,11 Itraconazole is an inhibitor of P-glycoprotein, a drug efflux transporter located at many sites, such as the intestines, kidneys, liver, lymphocytes, and blood-brain barrier. ^2,12

AGENTS THAT AFFECT AZOLE SERUM CONCENTRATIONS
Major drug interactions are also seen with enzyme inducers, such as rifampin. These agents dramatically reduce serum concentrations of itraconazole (Table 2).^13,14 Because fluconazole is more dependent on renal elimination, inducers of drug metabolism do not have such a marked effect on its serum concentrations.

Finally, itraconazole and ketoconazole are highly dependent on a low gastric pH for adequate absorption. Consequently, concurrent use of antacids, H₂ blockers, or proton pump inhibitors must be managed appropriately, or serum concentrations of itraconazole and ketoconazole may be greatly reduced (Table 3).^15,16