Summary

Astemizole and fluconazole have a serious drug interaction that can lead to life-threatening cardiac arrhythmias. Fluconazole inhibits the metabolism of astemizole, resulting in elevated plasma levels and increased risk of QT prolongation and torsades de pointes.

Introduction

Astemizole is a long-acting, non-sedating H1 antihistamine that was previously used to treat allergic conditions such as allergic rhinitis and chronic urticaria. Due to serious cardiac safety concerns, astemizole has been withdrawn from most markets worldwide. Fluconazole is a triazole antifungal medication commonly prescribed for treating various fungal infections, including candidiasis, cryptococcal infections, and dermatophyte infections. It works by inhibiting fungal cytochrome P450 enzymes, particularly 14α-demethylase, which is essential for ergosterol synthesis in fungal cell membranes.

Mechanism of Interaction

The interaction between astemizole and fluconazole occurs through inhibition of hepatic cytochrome P450 enzymes, particularly CYP3A4. Fluconazole is a potent inhibitor of CYP3A4, the primary enzyme responsible for metabolizing astemizole to its active metabolite desmethylastemizole. When fluconazole blocks this metabolic pathway, astemizole accumulates in the plasma, reaching potentially toxic concentrations. Elevated astemizole levels can block cardiac potassium channels (hERG channels), leading to prolongation of the QT interval on electrocardiogram and predisposing patients to potentially fatal ventricular arrhythmias, particularly torsades de pointes.

Risks and Symptoms

The primary risk of concurrent astemizole and fluconazole use is the development of serious cardiac arrhythmias, including torsades de pointes, which can be life-threatening. Patients may experience symptoms such as dizziness, fainting, palpitations, or sudden cardiac arrest. The risk is particularly elevated in patients with pre-existing cardiac conditions, electrolyte imbalances (especially hypokalemia or hypomagnesemia), or those taking other QT-prolonging medications. This interaction is considered contraindicated due to the severity of potential outcomes and the availability of safer alternative treatments.

Management and Precautions

Due to the serious nature of this interaction, concurrent use of astemizole and fluconazole should be avoided entirely. If antifungal treatment is necessary in a patient taking astemizole, alternative antifungal agents with less CYP3A4 inhibition potential should be considered, such as terbinafine for dermatophyte infections or amphotericin B for systemic fungal infections. If antihistamine therapy is needed in a patient requiring fluconazole, safer alternatives include loratadine, cetirizine, or fexofenadine, which have better cardiac safety profiles. Healthcare providers should review all medications for potential interactions before prescribing and counsel patients about the importance of disclosing all medications, including over-the-counter drugs, to prevent dangerous interactions.

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.