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Mechanism Of Action
Fluticasone propionate is a synthetic trifluorinated corticosteroid with anti-inflammatory activity. Fluticasone propionate has been shown in vitro to exhibit a binding affinity for the human glucocorticoid receptor that is 18 times that of dexamethasone, almost twice that of beclomethasone-17-monopropionate (BMP), the active metabolite of beclomethasone dipropionate, and over 3 times that of budesonide. Data from the McKenzie vasoconstrictor assay in man are consistent with these results. The clinical significance of these findings is unknown.
The precise mechanism through which fluticasone propionate affects rhinitis symptoms is not known. Corticosteroids have been shown to have a wide range of effects on multiple cell types (e.g., mast cells, eosinophils, neutrophils, macrophages, lymphocytes) and mediators (e.g., histamine, eicosanoids, leukotrienes, cytokines) involved in inflammation. In 7 trials in adults, FLONASE Nasal Spray has decreased nasal mucosal eosinophils in 66% of patients (35% for placebo) and basophils in 39% of patients (28% for placebo). The direct relationship of these findings to long-term symptom relief is not known.
HPA Axis Effect
The potential systemic effects of FLONASE Nasal Spray on the HPA axis were evaluated. FLONASE Nasal Spray given as 200 mcg once daily or 400 mcg twice daily was compared with placebo or oral prednisone 7.5 or 15 mg given in the morning. FLONASE Nasal Spray at either dosage for 4 weeks did not affect the adrenal response to 6-hour cosyntropin stimulation, while both dosages of oral prednisone significantly reduced the response to cosyntropin.
A study specifically designed to evaluate the effect of FLONASE on the QT interval has not been conducted.
The activity of FLONASE Nasal Spray is due to the parent drug, fluticasone propionate. Due to the low bioavailability by the intranasal route, the majority of the pharmacokinetic data was obtained via other routes of administration.
Indirect calculations indicate that fluticasone propionate delivered by the intranasal route has an absolute bioavailability averaging less than 2%. Trials using oral dosing of labeled and unlabeled drug have demonstrated that the oral systemic bioavailability of fluticasone propionate is negligible ( < 1%), primarily due to incomplete absorption and presystemic metabolism in the gut and liver. After intranasal treatment of patients with rhinitis for 3 weeks, fluticasone propionate plasma concentrations were above the level of detection (50 pg/mL) only when recommended doses were exceeded and then only in occasional samples at low plasma levels.
Following intravenous administration, the initial disposition phase for fluticasone propionate was rapid and consistent with its high lipid solubility and tissue binding. The volume of distribution averaged 4.2 L/kg.
The percentage of fluticasone propionate bound to human plasma proteins averaged 99%. Fluticasone propionate is weakly and reversibly bound to erythrocytes and is not significantly bound to human transcortin.
Following intravenous dosing, fluticasone propionate showed polyexponential kinetics and had a terminal elimination half-life of approximately 7.8 hours. The total blood clearance of fluticasone propionate is high (average: 1,093 mL/min), with renal clearance accounting for less than 0.02% of the total.
Metabolism: The only circulating metabolite detected in man is the 17β-carboxylic acid derivative of fluticasone propionate, which is formed through the CYP3A4 pathway. This metabolite had less affinity (approximately 1/2,000) than the parent drug for the glucocorticoid receptor of human lung cytosol in vitro and negligible pharmacological activity in animal studies. Other metabolites detected in vitro using cultured human hepatoma cells have not been detected in man.
Excretion: Less than 5% of a radiolabeled oral dose was excreted in the urine as metabolites, with the remainder excreted in the feces as parent drug and metabolites.
Fluticasone propionate nasal spray was not studied in any special populations, and no gender-specific pharmacokinetic data have been obtained.
Inhibitors of Cytochrome P450 3A4: Ritonavir: Fluticasone propionate is a substrate of CYP3A4. Coadministration of fluticasone propionate and the strong CYP3A4 inhibitor, ritonavir, is not recommended based upon a multiple-dose, crossover drug interaction trial in 18 healthy subjects. Fluticasone propionate aqueous nasal spray (200 mcg once daily) was coadministered for 7 days with ritonavir (100 mg twice daily). Plasma fluticasone propionate concentrations following fluticasone propionate aqueous nasal spray alone were undetectable ( < 10 pg/mL) in most subjects, and when concentrations were detectable, peak levels (Cmax) averaged 11.9 pg/mL (range: 10.8 to 14.1 pg/mL) and AUC(0-τ) averaged 8.43 pg•h/mL (range: 4.2 to 18.8 pg•h/mL). Fluticasone propionate Cmax and AUC(0-τ) increased to 318 pg/mL (range: 110 to 648 pg/mL) and 3,102.6 pg•h/mL (range: 1,207.1 to 5,662.0 pg•h/mL), respectively, after coadministration of ritonavir with fluticasone propionate aqueous nasal spray. This significant increase in plasma fluticasone propionate exposure resulted in a significant decrease (86%) in serum cortisol AUC.
Ketoconazole: Coadministration of orally inhaled fluticasone propionate (1,000 mcg) and ketoconazole (200 mg once daily) resulted in a 1.9-fold increase in plasma fluticasone propionate exposure and a 45% decrease in plasma cortisol AUC, but had no effect on urinary excretion of cortisol.
Erythromycin: In a multiple-dose drug interaction study, coadministration of orally inhaled fluticasone propionate (500 mcg twice daily) and erythromycin (333 mg 3 times daily) did not affect fluticasone propionate pharmacokinetics.
Last reviewed on RxList: 11/22/2016
This monograph has been modified to include the generic and brand name in many instances.
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