Summary

Fluconazole significantly increases repaglinide blood levels through CYP2C8 enzyme inhibition, leading to a high risk of severe and prolonged hypoglycemia. This interaction is considered clinically significant and requires careful management or alternative therapy selection.

Introduction

Fluconazole is a triazole antifungal medication commonly used to treat yeast infections, including vaginal candidiasis, oral thrush, and systemic fungal infections. Repaglinide is a meglitinide antidiabetic drug used to control blood sugar levels in patients with type 2 diabetes by stimulating insulin release from pancreatic beta cells. Both medications are metabolized through the cytochrome P450 enzyme system, which creates the potential for significant drug interactions.

Mechanism of Interaction

The interaction between fluconazole and repaglinide occurs through inhibition of the CYP2C8 enzyme pathway. Fluconazole is a potent inhibitor of CYP2C8, which is the primary enzyme responsible for metabolizing repaglinide. When fluconazole blocks this metabolic pathway, repaglinide clearance is significantly reduced, leading to increased plasma concentrations and prolonged half-life. Studies have shown that fluconazole can increase repaglinide exposure by up to 40-fold, dramatically enhancing its glucose-lowering effects.

Risks and Symptoms

The primary risk of this drug interaction is severe, prolonged hypoglycemia that can be life-threatening. Patients may experience symptoms including dizziness, confusion, sweating, rapid heartbeat, seizures, and loss of consciousness. The hypoglycemic episodes may be more severe and longer-lasting than typical repaglinide-induced hypoglycemia due to the dramatically increased drug exposure. This interaction is particularly dangerous because the hypoglycemia may not respond adequately to standard treatment measures and can persist for extended periods, potentially requiring hospitalization and intensive monitoring.

Management and Precautions

Concurrent use of fluconazole and repaglinide should generally be avoided due to the high risk of severe hypoglycemia. If fluconazole treatment is absolutely necessary in a patient taking repaglinide, consider temporarily discontinuing repaglinide and using alternative diabetes management strategies. If both medications must be used together, repaglinide should be discontinued or the dose significantly reduced under close medical supervision. Patients should be counseled about hypoglycemia symptoms and have glucose monitoring supplies readily available. Healthcare providers should consider alternative antifungal agents with less CYP2C8 inhibition potential, such as terbinafine for appropriate indications. Close blood glucose monitoring is essential if concurrent therapy cannot be avoided.

Fluconazole interactions with food and lifestyle

Fluconazole can be taken with or without food as food does not significantly affect its absorption. However, patients should avoid excessive alcohol consumption while taking fluconazole, as both substances can potentially affect liver function. While moderate alcohol intake is generally considered acceptable, patients with liver conditions or those taking fluconazole for extended periods should discuss alcohol use with their healthcare provider. No specific dietary restrictions are required with fluconazole therapy.

Repaglinide interactions with food and lifestyle

Repaglinide should be taken with meals to optimize blood glucose control and reduce the risk of hypoglycemia. The timing of repaglinide administration is important - it should be taken within 30 minutes before each meal, and if a meal is skipped, the corresponding dose should also be skipped. Alcohol consumption may increase the risk of hypoglycemia when used with repaglinide, and patients should be counseled to monitor blood glucose levels closely if consuming alcohol. Grapefruit juice may potentially increase repaglinide levels and should be consumed with caution, though this interaction is not as well-established as with some other medications.