DRUG INTERACTIONS
Inhibitors of Cytochrome P450
Fluticasone propionate is a substrate of cytochrome P450 3A4. A drug interaction study with fluticasone propionate aqueous nasal spray in healthy subjects has shown that ritonavir (a highly potent cytochrome P450 3A4 inhibitor) can significantly increase plasma fluticasone propionate exposure, resulting in significantly reduced serum cortisol concentrations (see CLINICAL PHARMACOLOGY: Pharmacokinetics: Drug Interactions ). During postmarketing use, there have been reports of clinically significant drug interactions in patients receiving fluticasone propionate and ritonavir, resulting in systemic corticosteroid effects including Cushing syndrome and adrenal suppression. Therefore, coadministration of fluticasone propionate and ritonavir is not recommended unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side effects.
In a placebo-controlled crossover study in 8 healthy adult volunteers, coadministration of a single dose of orally inhaled fluticasone propionate (1,000 mcg) with multiple doses of ketoconazole (200 mg) to steady state resulted in increased systemic fluticasone propionate exposure, a reduction in plasma cortisol AUC, and no effect on urinary excretion of cortisol. Caution should be exercised when FLOVENT HFA is coadministered with ketoconazole and other known potent cytochrome P450 3A4 inhibitors.
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OVERDOSAGE
Chronic overdosage may result in signs/symptoms of hypercorticism (see PRECAUTIONS: General). Inhalation by healthy volunteers of a single dose of 1,760 or 3,520 mcg of fluticasone propionate CFC inhalation aerosol was well tolerated. Doses of 1,320 mcg administered to healthy human volunteers twice daily for 7 to 15 days were also well tolerated. Repeat oral doses up to 80 mg daily for 10 days in healthy volunteers and repeat oral doses up to 20 mg daily for 42 days in patients were well tolerated. Adverse reactions were of mild or moderate severity, and incidences were similar in active and placebo treatment groups. The oral median lethal dose in mice was >1,000 mg/kg (approximately ≥2,300 and >11,000 times the maximum human daily inhalation dose in adults and children on a mg/m2 basis, respectively), and the subcutaneous median lethal dose in rats was >1,000 mg/kg (approximately >4,600 and >22,000 times the maximum human daily inhalation dose in adults and children on a mg/m2 basis, respectively).
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