CLINICAL PHARMACOLOGY

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 threefold to fivefold 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 seven trials in adults, 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.

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 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 fluticasone propionate nasal spray is due to the parent drug, fluticasone propionate. Indirect calculations indicate that fluticasone propionate delivered by the intranasal route has 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 dispostion 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, 1093 ml/min), with renal clearance accounting for less than 0.02% of the total. The only circulating metabolite detected in man is the 17b-carboxylic acid derivative of fluticasone propionate, which is formed through the cytochrome P450 3A4 pathway. This inactive metabolite had approximately 2000 times less affinity than the parent drug for the clucocorticoid 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.

In a multiple-dose drug interaction study, coadministration of orally inhaled fluticasone propionate (500 mcg twice daily) and erythromycin (333 mg three times daily) did not affect fluticasone propionate pharmacokinetics.

In a drug interaction study, coadministration of orally inhaled fluticasone propionate (1000 mcg, 5 times the maximum daily intranasal dose) and ketoconazole (200 mg once daily) resulted in increased fluticasone propionate concentrations, a reduction in plasma cortisol AUC, and no effect on urinary excretion of cortisol.

Excretion: 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 was not studied in any special populations, and no gender-specific pharmacokinetic data have been obtained.

Pharmacodynamics

In a trial to evaluate the potential systemic and topical effects of fluticasone propionate nasal spray on allergic rhinitis symptoms, the benefits of comparable drug blood levels produced by fluticasone propionate nasal spray and oral fluticasone propionate were compared. The doses used were 200 mcg of 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. 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 fluticasone propionate nasal spray can be attributed to the topical effects of fluticasone propionate.

In another trial, the potential systemic effects of fluticasone propionate nasal spray on the hypothalamic-pituitary-adrenal (HPA) axis were also studied in allergic patients. 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. 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.

Individualization of Dosage

Adult patients may be started on 200-mcg once-a-day regimen (two 50-mcg sprays in each nostril once a day). An alternative 200-mcg/day dosage regimen can be given as 100 mcg twice daily (one 50-mcg spray in each nostril twice a day).

Individual patients will experience a variable time to onset and different degree of symptom relief. In 4 randomized, double-blind, 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 fluticasone propionate nasal spray. Maximum effect may take several days. Patients who have responded may be able to be maintained (after 4 to 7 days) on 100 mcg per day (one spray in each nostril once daily).

Pediatric patients 4 years of age and older should be started with 100 mcg (one spray in each nostril once-a-day). Treatment with 200 mcg (two sprays in each nostril once daily or one 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 may be decreased to 100 mcg (one spray in each nostril) daily.

Maximum total daily doses should not exceed two sprays in each nostril (total dose, 200 mcg per day). There is no evidence that exceeding the recommended dose is more effective.

CLINICAL STUDIES

A total of 13, randomized, double-blind, parallel, multicenter, vehicle-controlled clinical trials were conducted in the United States in adults and pediatric patients (4 years of age and older) with seasonal of perennial allergic rhinitis. The trials included 2633 adults (1439 men and 1194 women) with mean age of 37 years (range, 18 to 79). A total of 440 adolescents (405 boys and 35 girls), mean age of 14 (range, 12 to 17), and 500 children (325 boys and 175 girls), mean age of 9 (range, 4 to 11) were also studied. The overall racial distribution was 89% white, 4% black, and 7% other. These trials evaluated the total nasal symptoms 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 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 six clinical trials. A clear dose response could not be identified in clinical trials. In one trial, 200 mcg/day was slightly more effective than 50 mcg/day during the first few days of treatment, thereafter, no difference was seen.

Three randomized, double-blind, parallel, vehicle-controlled trials were conducted in 1191 patients with perennial nonallergic rhinitis. These trials evaluated the patient-rated total nasal symptom scores (nasal obstruction, postnasal drip, rhinorrhea) in patients treated for 28 days of double-blind therapy and in one of the three trials for 6 months of open-label treatment. Two of these trials demonstrated that patients treated with fluticasone propionate nasal spray at a dose of 100 mcg twice daily exhibited statistically significant decreases in total nasal symptom scores compared with patients treated with vehicle.