Summary

The combination of terfenadine and fluconazole represents a serious drug interaction that can lead to life-threatening cardiac arrhythmias. This interaction is considered contraindicated due to the risk of QT prolongation and torsades de pointes.

Introduction

Terfenadine is a second-generation H1 antihistamine that was previously used to treat allergic conditions such as hay fever and urticaria. However, it has been withdrawn from many markets due to serious cardiac safety concerns. Fluconazole is a triazole antifungal medication commonly prescribed to treat various fungal infections, including candidiasis, cryptococcal meningitis, 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 terfenadine and fluconazole occurs through inhibition of the cytochrome P450 3A4 (CYP3A4) enzyme system. Fluconazole is a potent inhibitor of CYP3A4, which is the primary enzyme responsible for metabolizing terfenadine to its active, non-cardiotoxic metabolite fexofenadine. When fluconazole blocks this metabolic pathway, terfenadine accumulates in the plasma at toxic concentrations. High levels of terfenadine can block cardiac potassium channels, particularly the hERG (human ether-a-go-go-related gene) channel, leading to prolongation of the QT interval on electrocardiogram and potentially triggering the dangerous arrhythmia torsades de pointes.

Risks and Symptoms

The primary risk of this drug interaction is the development of serious cardiac arrhythmias, particularly torsades de pointes, which can be fatal. Patients may experience symptoms such as dizziness, fainting, palpitations, or sudden cardiac arrest. The risk is dose-dependent and increases with higher concentrations of terfenadine in the blood. Additional risk factors include female gender, advanced age, electrolyte imbalances (particularly hypokalemia and hypomagnesemia), bradycardia, and pre-existing cardiac conditions. Even therapeutic doses of both medications can result in clinically significant QT prolongation when used concurrently. This interaction has led to several documented cases of sudden cardiac death, which ultimately resulted in terfenadine's withdrawal from many international markets.

Management and Precautions

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.