Summary

Ketoconazole significantly increases fexofenadine plasma concentrations by inhibiting P-glycoprotein-mediated efflux transport. This interaction can lead to enhanced antihistamine effects and potential increased risk of side effects, requiring careful monitoring and possible dose adjustments.

Introduction

Fexofenadine is a second-generation antihistamine commonly used to treat allergic rhinitis and chronic urticaria. It belongs to the H1-receptor antagonist class and is known for its non-sedating properties. Ketoconazole is a broad-spectrum antifungal medication from the azole class, used to treat various fungal infections including candidiasis, dermatophytosis, and systemic mycoses. Both medications are frequently prescribed, making their potential interaction clinically relevant.

Mechanism of Interaction

The interaction between fexofenadine and ketoconazole occurs through inhibition of P-glycoprotein (P-gp) transport. Fexofenadine is a substrate of P-glycoprotein, an efflux transporter that limits drug absorption and facilitates elimination. Ketoconazole acts as a potent P-glycoprotein inhibitor, blocking the efflux of fexofenadine from intestinal cells and reducing its elimination. This results in increased bioavailability and elevated plasma concentrations of fexofenadine, potentially leading to enhanced pharmacological effects.

Risks and Symptoms

The primary clinical risk of this interaction is increased fexofenadine plasma levels, which may lead to enhanced antihistamine effects and potential adverse reactions. While fexofenadine is generally well-tolerated, elevated concentrations may increase the risk of headache, drowsiness, dizziness, and gastrointestinal disturbances. Although less likely than with first-generation antihistamines, there may be a slight increased risk of sedation or cognitive impairment. Patients with renal impairment may be at higher risk due to reduced fexofenadine clearance.

Management and Precautions

When concurrent use is necessary, consider reducing the fexofenadine dose by approximately 50% and monitor patients for increased antihistamine effects. Start with the lowest effective dose and titrate based on clinical response and tolerability. Patients should be advised to report any unusual drowsiness, dizziness, or other side effects. Consider alternative antifungal agents with less P-glycoprotein inhibition potential, such as fluconazole, when appropriate. If ketoconazole is discontinued, fexofenadine doses may need to be readjusted. Regular monitoring is especially important in elderly patients and those with kidney dysfunction.

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.