Summary

Ketoconazole significantly increases loratadine plasma concentrations by inhibiting CYP3A4 metabolism, potentially leading to elevated antihistamine levels. This interaction may increase the risk of cardiac arrhythmias and other adverse effects associated with higher loratadine exposure.

Introduction

Loratadine is a second-generation antihistamine commonly used to treat allergic rhinitis, urticaria, and other allergic conditions. It belongs to the class of non-sedating antihistamines and is metabolized primarily by the cytochrome P450 enzyme CYP3A4. Ketoconazole is a potent antifungal medication from the azole class, used to treat serious systemic fungal infections. Ketoconazole is a strong inhibitor of CYP3A4 and several other cytochrome P450 enzymes, making it prone to numerous drug interactions.

Mechanism of Interaction

The interaction between loratadine and ketoconazole occurs through competitive inhibition of the CYP3A4 enzyme system. Loratadine undergoes extensive first-pass metabolism via CYP3A4 to form its active metabolite, desloratadine. When ketoconazole is co-administered, it potently inhibits CYP3A4, significantly reducing loratadine's metabolism and clearance. This results in substantially increased plasma concentrations of loratadine, with studies showing up to 10-fold increases in loratadine AUC (area under the curve) when combined with ketoconazole.

Risks and Symptoms

The primary clinical concern with this interaction is the potential for cardiac toxicity due to elevated loratadine levels. Higher concentrations of loratadine may lead to QT interval prolongation and increased risk of serious cardiac arrhythmias, including torsades de pointes. Patients may also experience enhanced antihistaminic effects, including increased sedation, dizziness, and anticholinergic effects such as dry mouth and constipation. The interaction is considered clinically significant and may require dosage modifications or alternative therapy selection.

Management and Precautions

When concurrent use of loratadine and ketoconazole is necessary, consider reducing the loratadine dose by 50-75% and monitor patients closely for signs of cardiac toxicity and enhanced antihistaminic effects. Obtain baseline and periodic ECGs to monitor QT interval, especially in patients with pre-existing cardiac conditions or other risk factors for arrhythmias. Alternative antihistamines that are not significantly metabolized by CYP3A4, such as fexofenadine or cetirizine, may be preferred options. If possible, consider alternative antifungal agents with less CYP3A4 inhibition potential, such as fluconazole or terbinafine, depending on the indication.

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.