Summary

The interaction between terfenadine and erythromycin is considered severe and potentially life-threatening. Erythromycin inhibits the metabolism of terfenadine, leading to dangerous accumulation that can cause serious cardiac arrhythmias including 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. It belongs to the piperidine class of antihistamines and was known for being non-sedating. Erythromycin is a macrolide antibiotic commonly prescribed to treat bacterial infections including respiratory tract infections, skin infections, and sexually transmitted diseases. It works by inhibiting bacterial protein synthesis and is often used as an alternative for patients allergic to penicillin.

Mechanism of Interaction

The interaction occurs through erythromycin's potent inhibition of the CYP3A4 enzyme system in the liver. Terfenadine is normally metabolized by CYP3A4 into its active, non-cardiotoxic metabolite fexofenadine. When erythromycin blocks this metabolic pathway, terfenadine accumulates in the bloodstream at toxic levels. High concentrations of terfenadine can block cardiac potassium channels, particularly the hERG (human ether-a-go-go-related gene) channels, leading to prolongation of the QT interval on ECG and predisposing patients to potentially fatal ventricular arrhythmias.

Risks and Symptoms

The primary risk of this interaction is the development of serious cardiac arrhythmias, particularly torsades de pointes, a polymorphic ventricular tachycardia that can degenerate into ventricular fibrillation and sudden cardiac death. Patients may experience symptoms such as dizziness, fainting, palpitations, or chest pain. The risk is dose-dependent and increases with higher concentrations of terfenadine. Additional risk factors include female gender, advanced age, electrolyte imbalances (hypokalemia, hypomagnesemia), heart disease, and concomitant use of other QT-prolonging medications. This interaction was so significant that it contributed to terfenadine being withdrawn from the market in many countries.

Management and Precautions

Due to the severity of this interaction, concurrent use of terfenadine and erythromycin should be completely avoided. If both medications are deemed necessary, alternative options should be considered. For antihistamine therapy, safer alternatives include loratadine, cetirizine, or fexofenadine (the active metabolite of terfenadine). For antibiotic treatment, alternatives to erythromycin include azithromycin, clarithromycin (though this also inhibits CYP3A4), or non-macrolide antibiotics depending on the infection. If the combination cannot be avoided in exceptional circumstances, patients require intensive cardiac monitoring with frequent ECGs to monitor QT interval, electrolyte monitoring and correction, and immediate discontinuation if QT prolongation occurs. Healthcare providers should always verify current drug availability, as terfenadine has been withdrawn from many markets due to these safety concerns.

Erythromycin interactions with food and lifestyle

Erythromycin should be taken on an empty stomach (1 hour before or 2 hours after meals) for optimal absorption, as food can significantly reduce the drug's bioavailability. However, if gastrointestinal upset occurs, it may be taken with food to minimize stomach irritation, though this may reduce effectiveness. Alcohol consumption should be avoided or limited while taking erythromycin, as it may increase the risk of gastrointestinal side effects and potentially reduce the antibiotic's effectiveness. Patients should also avoid taking erythromycin with dairy products or calcium-fortified foods within 2 hours of dosing, as calcium can interfere with absorption.