Summary

Voriconazole significantly increases fluticasone levels by inhibiting CYP3A4 metabolism, potentially leading to systemic corticosteroid effects including adrenal suppression and Cushing's syndrome. This interaction requires careful monitoring and possible dose adjustments or alternative therapy selection.

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 and immune responses. Voriconazole is a triazole antifungal medication used to treat serious fungal infections, including invasive aspergillosis and candidemia. It works by inhibiting fungal cytochrome P450 enzymes, particularly CYP51, which is essential for ergosterol synthesis in fungal cell membranes.

Mechanism of Interaction

The interaction between fluticasone and voriconazole occurs through cytochrome P450 3A4 (CYP3A4) enzyme inhibition. 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. Voriconazole is a potent inhibitor of CYP3A4, significantly reducing fluticasone metabolism and clearance. This leads to dramatically increased plasma concentrations of fluticasone, potentially resulting in systemic corticosteroid effects despite local administration routes.

Risks and Symptoms

The primary clinical risk of this interaction is the development of systemic corticosteroid toxicity, including Cushing's syndrome, adrenal suppression, and hypothalamic-pituitary-adrenal (HPA) axis dysfunction. Patients may experience symptoms such as weight gain, moon face, purple striae, muscle weakness, hyperglycemia, hypertension, and increased susceptibility to infections. Long-term exposure can lead to osteoporosis, growth retardation in children, and cardiovascular complications. The risk is particularly significant with inhaled or intranasal fluticasone, as these routes typically have minimal systemic absorption under normal circumstances.

Management and Precautions

When concurrent use is necessary, consider switching to alternative corticosteroids with less CYP3A4 dependence, such as beclomethasone or prednisolone. If fluticasone must be continued, use the lowest effective dose and monitor closely for signs of corticosteroid excess. Regular monitoring should include assessment of HPA axis function, blood glucose levels, blood pressure, and clinical signs of Cushing's syndrome. Consider temporary discontinuation of fluticasone if systemic effects develop. Patients should be educated about potential symptoms and advised to report any concerning changes. Healthcare providers should evaluate the necessity of both medications and explore alternative antifungal or anti-inflammatory options when clinically appropriate.

Voriconazole interactions with food and lifestyle

Voriconazole should be taken on an empty stomach, at least 1 hour before or 2 hours after meals, as food significantly reduces absorption and bioavailability. High-fat meals can decrease voriconazole absorption by up to 22%. Patients should avoid grapefruit and grapefruit juice during treatment, as these can increase voriconazole blood levels and risk of toxicity. Alcohol consumption should be avoided or limited, as both voriconazole and alcohol are metabolized by the liver and concurrent use may increase the risk of liver toxicity. Patients should also avoid prolonged sun exposure and use adequate sun protection, as voriconazole can cause photosensitivity reactions and increase risk of skin cancer with long-term use.