Summary

Itraconazole significantly increases fluticasone levels by inhibiting CYP3A4 metabolism, potentially leading to systemic corticosteroid effects including adrenal suppression. This interaction is considered clinically significant and requires careful monitoring or alternative therapy consideration.

Introduction

Fluticasone is a synthetic corticosteroid commonly used as an inhaled medication for asthma and allergic rhinitis, and as a topical treatment for inflammatory skin conditions. It belongs to the glucocorticoid class and works by reducing inflammation in the airways and tissues. Itraconazole is a triazole antifungal medication used to treat various fungal infections, including aspergillosis, candidiasis, and dermatophyte infections. It works by inhibiting fungal cell membrane synthesis and is known to be a potent inhibitor of the cytochrome P450 3A4 (CYP3A4) enzyme system.

Mechanism of Interaction

The interaction between fluticasone and itraconazole occurs through inhibition of the CYP3A4 enzyme system. Fluticasone is extensively metabolized by CYP3A4 in the liver, which normally results in rapid clearance and minimal systemic exposure when used topically or by inhalation. Itraconazole is a potent CYP3A4 inhibitor that significantly reduces fluticasone metabolism, leading to increased plasma concentrations and prolonged half-life. This results in enhanced systemic corticosteroid activity, even when fluticasone is administered locally (inhaled or topical routes).

Risks and Symptoms

The primary risk of this interaction is the development of systemic corticosteroid effects due to elevated fluticasone levels. These may include Cushing's syndrome, adrenal suppression, growth retardation in children, osteoporosis, hyperglycemia, hypertension, and increased susceptibility to infections. Case reports have documented severe adrenal insufficiency and Cushing's syndrome in patients receiving concurrent fluticasone and itraconazole therapy. The risk is particularly elevated with inhaled or intranasal fluticasone, as patients and healthcare providers may not anticipate systemic effects from these "local" routes of administration.

Management and Precautions

When concurrent use is necessary, consider using alternative corticosteroids with less CYP3A4 dependence, such as beclomethasone or prednisolone. If fluticasone must be continued with itraconazole, use the lowest effective dose and monitor closely for signs of corticosteroid excess, including weight gain, moon face, purple striae, muscle weakness, and mood changes. Regular monitoring should include blood pressure, blood glucose, bone density assessments, and adrenal function tests. Consider temporary discontinuation of fluticasone during short-term itraconazole therapy when clinically appropriate. Patients should be educated about the signs and symptoms of corticosteroid excess and advised to seek medical attention if these develop.

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.