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Mechanism of Action: Fluticasone propionate is a synthetic, trifluorinated corticosteroid with anti-inflammatory activity. In vitro dose response studies on a cloned human glucocorticoid receptor system involving binding and gene expression afforded 50% responses at 1.25 and 0.17 nM concentrations, respectively. Fluticasone propionate was 3-fold to 5-fold more potent than dexamethasone in these assays. Data from the McKenzie vasoconstrictor assay in man also support its potent glucocorticoid activity.
In preclinical studies, fluticasone propionate revealed progesterone-like activity similar to the natural hormone. However, the clinical significance of these findings in relation to the low plasma levels (see Pharmacokinetics) is not known.
The precise mechanism through which fluticasone propionate affects allergic 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, and lymphocytes) and mediators (e.g., histamine, eicosanoids, leukotrienes, and cytokines) involved in inflammation. In 7 trials in adults, FLONASE (fluticasone propionate) Nasal Spray has decreased nasal mucosal eosinophils in 66% (35% for placebo) of patients and basophils in 39% (28% for placebo) of patients. The direct relationship of these findings to long-term symptom relief is not known.
FLONASE (fluticasone propionate) Nasal Spray, like other corticosteroids, is an agent that does not have an immediate effect on allergic symptoms. A decrease in nasal symptoms has been noted in some patients 12 hours after initial treatment with FLONASE (fluticasone propionate) Nasal Spray. Maximum benefit may not be reached for several days. Similarly, when corticosteroids are discontinued, symptoms may not return for several days.
Pharmacokinetics: Absorption: The activity of FLONASE (fluticasone propionate) Nasal Spray is due to the parent drug, fluticasone propionate. Indirect calculations indicate that fluticasone propionate delivered by the intranasal route has an absolute bioavailability averaging less than 2%. After intranasal treatment of patients with allergic 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. Due to the low bioavailability by the intranasal route, the majority of the pharmacokinetic data was obtained via other routes of administration. Studies using oral dosing of radiolabeled drug have demonstrated that fluticasone propionate is highly extracted from plasma and absorption is low. Oral bioavailability is negligible, and the majority of the circulating radioactivity is due to an inactive metabolite.
Distribution: 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 91% with no obvious concentration relationship. Fluticasone propionate is weakly and reversibly bound to erythrocytes and freely equilibrates between erythrocytes and plasma. Fluticasone propionate is not significantly bound to human transcortin.
Metabolism: 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. The only circulating metabolite detected in man is the 17β-carboxylic acid derivative of fluticasone propionate, which is formed through the cytochrome P450 3A4 pathway. This inactive 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.
Elimination: Following intravenous dosing, fluticasone propionate showed polyexponential kinetics and had a terminal elimination half-life of approximately 7.8 hours. 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.
Special Populations: Fluticasone propionate nasal spray was not studied in any special populations, and no gender-specific pharmacokinetic data have been obtained.
Drug Interactions: Fluticasone propionate is a substrate of cytochrome P450 3A4. Coadministration of fluticasone propionate and the highly potent cytochrome P450 3A4 inhibitor ritonavir is not recommended based upon a multiple-dose, crossover drug interaction study 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•hr/mL [range, 4.2 to 18.8 pg•hr/mL]). Fluticasone propionate Cmax and AUC(0-τ) increased to 318 pg/mL (range, 110 to 648 pg/mL) and 3,102.6 pg•hr/mL (range, 1,207.1 to 5,662.0 pg•hr/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 plasma cortisol area under the plasma concentration versus time curve (AUC).
Caution should be exercised when other potent cytochrome P450 3A4 inhibitors are coadministered with fluticasone propionate In a drug interaction study, coadministration of orally inhaled fluticasone propionate (1,000 mcg) and ketoconazole (200 mg once daily) resulted in increased fluticasone propionate exposure and reduced plasma cortisol AUC, but had no effect on urinary excretion of cortisol.
In another 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.
Pharmacodynamics: In a trial to evaluate the potential systemic and topical effects of FLONASE (fluticasone propionate) Nasal Spray on allergic rhinitis symptoms, the benefits of comparable drug blood levels produced by FLONASE (fluticasone propionate) Nasal Spray and oral fluticasone propionate were compared. The doses used were 200 mcg of FLONASE (fluticasone propionate) Nasal Spray, the nasal spray vehicle (plus oral placebo), and 5 and 10 mg of oral fluticasone propionate (plus nasal spray vehicle) per day for 14 days. Plasma levels were undetectable in the majority of patients after intranasal dosing, but present at low levels in the majority after oral dosing. FLONASE (fluticasone propionate) Nasal Spray was significantly more effective in reducing symptoms of allergic rhinitis than either the oral fluticasone propionate or the nasal vehicle. This trial demonstrated that the therapeutic effect of FLONASE (fluticasone propionate) Nasal Spray can be attributed to the topical effects of fluticasone propionate.
In another trial, the potential systemic effects of FLONASE (fluticasone propionate) Nasal Spray on the hypothalamic-pituitary-adrenal (HPA) axis were also studied in allergic patients. FLONASE (fluticasone propionate) 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 (fluticasone propionate) Nasal Spray at either dose for 4 weeks did not affect the adrenal response to 6-hour cosyntropin stimulation, while both doses of oral prednisone significantly reduced the response to cosyntropin.
Clinical Trials: A total of 13 randomized, double-blind, parallel-group, multicenter, vehicle placebo-controlled clinical trials were conducted in the United States in adults and pediatric patients (4 years of age and older) to investigate regular use of FLONASE (fluticasone propionate) Nasal Spray in patients with seasonal or perennial allergic rhinitis. The trials included 2,633 adults (1,439 men and 1,194 women) with a mean age of 37 (range, 18 to 79 years). A total of 440 adolescents (405 boys and 35 girls), mean age of 14 (range, 12 to 17 years), and 500 children (325 boys and 175 girls), mean age of 9 (range, 4 to 11 years) were also studied. The overall racial distribution was 89% white, 4% black, and 7% other. These trials evaluated the total nasal symptom scores (TNSS) that included rhinorrhea, nasal obstruction, sneezing, and nasal itching in known allergic patients who were treated for 2 to 24 weeks. Subjects treated with FLONASE (fluticasone propionate) Nasal Spray exhibited significantly greater decreases in TNSS than vehicle placebo-treated patients. Nasal mucosal basophils and eosinophils were also reduced at the end of treatment in adult studies; however, the clinical significance of this decrease is not known.
There were no significant differences between fluticasone propionate regimens whether administered as a single daily dose of 200 mcg (two 50-mcg sprays in each nostril) or as 100 mcg (one 50-mcg spray in each nostril) twice daily in 6 clinical trials. A clear dose response could not be identified in clinical trials. In 1 trial, 200 mcg/day was slightly more effective than 50 mcg/day during the first few days of treatment; thereafter, no difference was seen.
Two randomized, double-blind, parallel-group, multicenter, vehicle placebo-controlled 28-day trials were conducted in the United States in 732 patients (243 given FLONASE (fluticasone propionate nasal spray) ) 12 years of age and older to investigate “as-needed” use of FLONASE (fluticasone propionate) Nasal Spray (200 mcg) in patients with seasonal allergic rhinitis. Patients were instructed to take the study medication only on days when they thought they needed the medication for symptom control, not to exceed 2 sprays per nostril on any day, and not more than once daily. “As-needed”use was prospectively defined as average use of study medication no more than 75% of study days. Average use of study medications was 57% to 70% of days for all treatment arms. The studies demonstrated significantly greater reduction in TNSS (sum of nasal congestion, rhinorrhea, sneezing, and nasal itching) with FLONASE (fluticasone propionate) Nasal Spray 200 mcg compared to placebo. The relative difference in efficacy with as-needed use as compared to regularly administered doses was not studied.
Three randomized, double-blind, parallel-group, vehicle placebo-controlled trials were conducted in 1,191 patients to investigate regular use of FLONASE (fluticasone propionate) Nasal Spray in patients with perennial nonallergic rhinitis. These trials evaluated the patient-rated TNSS (nasal obstruction, postnasal drip, rhinorrhea) in patients treated for 28 days of double-blind therapy and in 1 of the 3 trials for 6 months of open-label treatment. Two of these trials demonstrated that patients treated with FLONASE (fluticasone propionate) Nasal Spray at a dose of 100 mcg twice daily exhibited statistically significant decreases in TNSS compared with patients treated with vehicle.
Individualization of Dosage: Patients should use FLONASE (fluticasone propionate) Nasal Spray at regular intervals for optimal effect.
Adult patients may be started on a 200-mcg once-daily regimen (two 50-mcg sprays in each nostril once daily). An alternative 200-mcg/day dosage regimen can be given as 100 mcg twice daily (one 50-mcg spray in each nostril twice daily).
Individual patients will experience a variable time to onset and different degree of symptom relief. In 4 randomized, double-blind, vehicle placebo-controlled, parallel-group allergic rhinitis studies and 2 studies of patients in an outdoor “park” setting (park studies), a decrease in nasal symptoms in treated subjects compared to placebo was shown to occur as soon as 12 hours after treatment with a 200-mcg dose of FLONASE (fluticasone propionate) Nasal Spray. Maximum effect may take several days. Regular-use patients who have responded may be able to be maintained (after 4 to 7 days) on 100 mcg/day (1 spray in each nostril once daily).
Some patients (12 years of age and older) with seasonal allergic rhinitis may find as-needed use of FLONASE (fluticasone propionate) Nasal Spray (not to exceed 200 mcg daily) effective for symptom control (see Clinical Trials). Greater symptom control may be achieved with scheduled regular use. Efficacy of as-needed use of FLONASE (fluticasone propionate) Nasal Spray has not been studied in pediatric patients under 12 years of age with seasonal allergic rhinitis, or patients with perennial allergic or nonallergic rhinitis.
Pediatric patients (4 years of age and older) should be started with 100 mcg (1 spray in each nostril once daily). Treatment with 200 mcg (2 sprays in each nostril once daily or 1 spray in each nostril twice daily) should be reserved for pediatric patients not adequately responding to 100 mcg daily. Once adequate control is achieved, the dosage should be decreased to 100 mcg (1 spray in each nostril) daily.
Maximum total daily doses should not exceed 2 sprays in each nostril (total dose, 200 mcg/day). There is no evidence that exceeding the recommended dose is more effective.
Last reviewed on RxList: 10/4/2010
This monograph has been modified to include the generic and brand name in many instances.
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