Summary

The interaction between terfenadine and ketoconazole is contraindicated due to severe cardiac risks. Ketoconazole inhibits the metabolism of terfenadine, leading to dangerous accumulation and potentially fatal heart rhythm abnormalities 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 marketed for its non-sedating properties. Ketoconazole is a broad-spectrum antifungal medication belonging to the azole class of antifungals. It is used to treat various fungal infections including candidiasis, dermatophytosis, and systemic mycoses by inhibiting fungal cell membrane synthesis.

Mechanism of Interaction

The interaction occurs through ketoconazole's potent inhibition of the cytochrome P450 3A4 (CYP3A4) enzyme system. Terfenadine is extensively metabolized by CYP3A4 to its active metabolite fexofenadine. When ketoconazole blocks this metabolic pathway, terfenadine accumulates to toxic levels in the bloodstream. 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 electrocardiograms and predisposing patients to ventricular arrhythmias.

Risks and Symptoms

This drug interaction carries severe and potentially life-threatening risks. The primary concern is the development of torsades de pointes, a polymorphic ventricular tachycardia that can degenerate into ventricular fibrillation and sudden cardiac death. Patients may experience symptoms including palpitations, dizziness, syncope, or cardiac arrest. The risk is dose-dependent and increases with higher terfenadine concentrations. Additional risk factors include female gender, advanced age, electrolyte imbalances (hypokalemia, hypomagnesemia), bradycardia, and pre-existing cardiac conditions. This interaction was a major factor leading to terfenadine's withdrawal from many markets worldwide.

Management and Precautions

The concurrent use of terfenadine and ketoconazole is absolutely contraindicated and should be avoided. If antifungal therapy is necessary in patients requiring antihistamine treatment, alternative options should be considered. Safer antihistamine alternatives include fexofenadine (the active metabolite of terfenadine), loratadine, or cetirizine, which do not have the same cardiac risks. For antifungal therapy, alternatives such as fluconazole, itraconazole, or topical antifungals may be considered depending on the indication, though some azole antifungals also have CYP3A4 inhibitory effects. Healthcare providers should review all medications for potential CYP3A4 interactions and monitor patients for signs of QT prolongation if alternative combinations are used. Emergency medical attention should be sought immediately if patients experience cardiac symptoms.

Ketoconazole interactions with food and lifestyle

Ketoconazole requires an acidic environment for optimal absorption. Take ketoconazole with food or an acidic beverage to enhance absorption. Avoid taking ketoconazole with antacids, H2 blockers, or proton pump inhibitors as these medications reduce stomach acid and significantly decrease ketoconazole absorption. If antacids must be used, take them at least 2 hours after ketoconazole. Alcohol should be avoided during ketoconazole treatment as both ketoconazole and alcohol can cause liver toxicity, and concurrent use may increase the risk of hepatotoxicity. Grapefruit juice may increase ketoconazole blood levels and should be avoided to prevent increased risk of side effects.