Drug Interactions With Azole Antifungals: Focus on Fluconazole and Itraconazole

Azole antifungals are widelyused to treat numerousinfections. ¹ Manywell-documented, clinicallysignificant drug interactionsare associated with theseagents.^1,2

Although the focus here is onthe most commonly prescribed systemicazoles, fluconazole and itraconazole,it is important to be awareof clinically relevant drug interactionswith other systemic azoles, includingketoconazole and voriconazole.^2-4 Whenever these drugs areprescribed, assessment of potentiallyharmful interactions is essential.Many of the drug interactions describedhere for fluconazole and itraconazolealso occur with otherazoles; consult current drug interactiontexts or primary literature formore information.

In addition to systemic azoles, asmall number of case reports suggestthat topical miconazole, includingcream,⁵ oral gel,^6,7 and vaginal suppositories,⁸ can potentiate the effectsof warfarin. Although studies are requiredto establish this and possiblyother interactions, be vigilant whenpatients who take warfarin use topicalazoles.

MECHANISMS OFINTERACTIONS
Drug interactions with azole antifungalscan occur through a varietyof mechanisms. Many of these interactionsare caused by the inhibitionof the cytochrome P-450 (CYP)isoenzyme CYP3A4.² Inhibition ofCYP3A4 results in decreased hepaticmetabolism of several drugs,which increases their concentrations(Table 1).

It is highly important to notethat fluconazole inhibits CYP2C9even at low doses (100 mg/d and 200mg/d) and thus causes serum concentrationsof 2 high-risk drugs, warfarinand phenytoin, to increase.,^2,9,10At doses greater than 200 mg/d, fluconazolealso inhibits CYP3A4.,^2,11 Itraconazoleis an inhibitor of P-glycoprotein,a drug efflux transporter locatedat many sites, such as the intestines,kidneys, liver, lymphocytes, andblood-brain barrier. ^2,12

AGENTS THAT AFFECT AZOLESERUM CONCENTRATIONS
Major drug interactions are alsoseen with enzyme inducers, such asrifampin. These agents dramaticallyreduce serum concentrations of itraconazole(Table 2).^13,14 Because fluconazoleis more dependent on renalelimination, inducers of drug metabolismdo not have such a marked effecton its serum concentrations.

Finally, itraconazole and ketoconazoleare highly dependent on alow gastric pH for adequate absorption.Consequently, concurrent useof antacids, H₂ blockers, or protonpump inhibitors must be managed appropriately,or serum concentrationsof itraconazole and ketoconazole maybe greatly reduced (Table 3).^15,16