Summary

The combination of itraconazole and amiodarone represents a significant drug interaction with increased risk of cardiac arrhythmias and QT prolongation. This interaction occurs through CYP3A4 inhibition by itraconazole, leading to elevated amiodarone levels and enhanced cardiotoxic effects.

Introduction

Itraconazole is a triazole antifungal medication commonly used to treat systemic fungal infections, including aspergillosis, histoplasmosis, and onychomycosis. It works by inhibiting fungal cytochrome P450 enzymes, particularly CYP3A4. Amiodarone is a class III antiarrhythmic agent used for treating life-threatening ventricular arrhythmias and maintaining normal sinus rhythm in atrial fibrillation. Both medications have the potential to prolong the QT interval and affect cardiac conduction.

Mechanism of Interaction

The interaction between itraconazole and amiodarone occurs primarily through cytochrome P450 enzyme inhibition. Itraconazole is a potent inhibitor of CYP3A4, the primary enzyme responsible for amiodarone metabolism. When co-administered, itraconazole significantly reduces amiodarone clearance, leading to increased plasma concentrations of both amiodarone and its active metabolite, desethylamiodarone. Additionally, both drugs independently possess QT-prolonging properties, creating an additive effect on cardiac repolarization that increases the risk of torsades de pointes and other serious arrhythmias.

Risks and Symptoms

The concurrent use of itraconazole and amiodarone poses several significant clinical risks. The primary concern is severe QT interval prolongation, which can lead to life-threatening ventricular arrhythmias, including torsades de pointes. Patients may experience increased amiodarone-related side effects such as bradycardia, heart block, hypotension, and pulmonary toxicity due to elevated drug levels. The interaction may also increase the risk of hepatotoxicity, thyroid dysfunction, and neurological effects. Elderly patients and those with pre-existing cardiac conditions, electrolyte imbalances, or hepatic impairment are at particularly high risk for adverse outcomes.

Management and Precautions

When this combination cannot be avoided, intensive monitoring is essential. Obtain baseline and frequent ECGs to monitor QT interval changes, with immediate discontinuation if QTc exceeds 500 milliseconds or increases by more than 60 milliseconds from baseline. Monitor serum electrolytes (potassium, magnesium, calcium) and correct any imbalances promptly. Consider reducing amiodarone dose by 30-50% when initiating itraconazole therapy. Regular monitoring of liver function, thyroid function, and pulmonary status is recommended. Alternative antifungal agents with less CYP3A4 inhibition potential, such as fluconazole or micafungin, should be considered when clinically appropriate. Patients should be counseled on symptoms of arrhythmias and advised to seek immediate medical attention for palpitations, dizziness, or syncope.

Itraconazole interactions with food and lifestyle

Itraconazole should be taken with food to enhance absorption and bioavailability. The capsule formulation requires an acidic environment for optimal absorption, so it should be taken with a full meal or acidic beverage. Avoid taking itraconazole with antacids, H2 blockers, or proton pump inhibitors as these reduce stomach acid and significantly decrease drug absorption. Grapefruit juice should be avoided as it can increase itraconazole levels and risk of side effects. Alcohol should be used with caution as both itraconazole and alcohol can affect liver function.

Amiodarone interactions with food and lifestyle

Grapefruit and grapefruit juice should be avoided as they can significantly increase amiodarone blood levels and risk of toxicity. Alcohol consumption should be limited or avoided as it may increase the risk of liver toxicity when combined with amiodarone. Patients should maintain consistent dietary habits and avoid excessive sun exposure, as amiodarone can cause photosensitivity reactions and skin discoloration with prolonged sun exposure.