Sign Out
Therapeutic Classification: Corticosteroid for nasal use.
Pharmacology: Pharmacodynamics: Mode of Action: Fluticasone propionate has potent anti-inflammatory activity but when used topically on the nasal mucosa has no detectable systemic activity.
Fluticasone propionate causes little or no hypothalamic-pituitary-adrenal axis suppression following intranasal administration.
Following intranasal dosing of fluticasone propionate, (200 micrograms/day) no significant change in 24 h serum cortisol AUC was found compared to placebo (ratio: 1.01, 90% CI 0.9 to 1.14).
Clinical Trials: Rhinitis: Clinical trials aimed to establish the efficacy of fluticasone propionate aqueous nasal spray (FPANS) 200 micrograms once daily (od) in adults and 100 micrograms od in children with seasonal or perennial rhinitis. To determine that these dosages were optimal for treating adults and children respectively, and to compare the efficacy of FPANS 200 micrograms od and 100 micrograms od with that of the standard therapy, beclomethasone dipropionate aqueous nasal spray (BDPANS) 200 micrograms was used twice daily (bd). Clinical trial data is available from over 4000 patients. Efficacy determination included daily symptom assessments.
Dose-ranging studies showed FPANS to be significantly superior to placebo in the relief of symptoms of rhinitis, even at very low doses (25 micrograms twice daily), although higher doses (eg 200 micrograms daily) provided significant improvements more rapidly.
Once daily doses of 200 micrograms FPANS have been shown to be efficacious in patients with seasonal rhinitis. For the relief of adult perennial rhinitis, 200 micrograms once daily was as effective as 100 micrograms twice daily.
Paediatric studies showed that FPANS 100 micrograms od was as effective as 200 micrograms od for the treatment of both seasonal and perennial rhinitis. The maximum treatment duration in children was 12 weeks.
Sinus pain and pressure: In patients with allergic rhinitis, fluticasone propionate aqueous nasal spray has also been shown to be of benefit for the management of associated sinus pain and pressure.
Two 14 days, randomized, double blind, parallel group clinical studies were performed in 401 adult and adolescent patients aged ≥ 12 years. Both studies compared fluticasone propionate nasal spray 200 micrograms once daily, administered as two 50 micrograms sprays per nostril, with placebo. The primary endpoint for both studies was the mean change from baseline in the patient-rated sinus pain and pressure score at week 2. In both studies, fluticasone propionate nasal spray provided significantly greater improvement compared with placebo for the primary endpoint (p<0.05). The magnitude of the improvement was 10 points compared to placebo and approximately 35 points from baseline (baseline score for this symptom was 75 on a 0-100 scale). The sinus pain and pressure score was also significantly decreased in the fluticasone propionate nasal spray treated group over the entire 2 week study period (p<0.05).
Treatment with fluticasone propionate nasal spray provided significantly greater improvement in symptoms of nasal congestion during week 1, 2 and overall during the 2 week study period (p<0.05). The overall improvement in congestion compared to placebo was 10 points and approximately 37 points from baseline (baseline score for this symptom was 78 on a 0-100 scale).
Pharmacokinetics: Absorption: Following intranasal dosing of fluticasone propionate (200 micrograms/day), steady-state maximum plasma concentrations were not quantifiable in most subjects (less than 0.01 nanograms/ml). The highest Cmax observed was 0.017 nanograms/ml. Direct absorption in the nose is negligible due to the low aqueous solubility with the majority of the dose being eventually swallowed. Absolute oral bioavailability is negligible (less than absorption arising from both nasal and oral absorption of the swallowed dose is therefore negligible).
Distribution: Fluticasone propionate has a large volume of distribution at steady-state (approximately 318 L). Plasma protein binding is moderately high (91%).
Metabolism: Fluticasone propionate is cleared rapidly from the systemic circulation, principally by hepatic metabolism to an inactive carboxylic acid metabolite, by the cytochrome P450 enzyme CYP3A4. Swallowed fluticasone propionate is also subject to extensive first pass metabolism. Care should be taken when co-administering potent CYP3A4 inhibitors such as ketoconazole and ritonavir as there is potential for increased systemic exposure to fluticasone propionate.
Elimination: The elimination rate of i.v. administered fluticasone propionate is linear over the 250 to 1000 micrograms dose range and is characterized by a high plasma clearance (CL=1.1 L/min). Peak plasma concentrations are reduced by approximately 98% within 3 to 4 h and only low plasma concentrations were associated with the 7.8 h terminal half-life. The renal clearance of fluticasone propionate is negligible (less than 0.2%) and less than 5% as the carboxylic acid metabolite. The major route of elimination is the excretion of fluticasone propionate and its metabolites in the bile.
