Intranasal Fluticasone Propionate

Summary

Synopsis

Fluticasone propionate is a potent topical anti-inflammatory corticosteroid with low systemic activity. Available pharmacodynamic data are only preliminary; however, large placebo- and drug-controlled clinical studies involving almost 4000 patients with seasonal allergic rhinitis and 1500 with perennial allergic and nonallergic rhinitis have confirmed the efficacy of intranasal fluticasone propionate in the control of nasal symptoms. Fluticasone propionate generally demonstrated similar efficacy compared with intranasal beclomethasone dipropionate, flunisolide acetonide and oral astemizole and better or a trend towards better efficacy compared with oral loratadine, terfenadine, cetirizine and intranasal sodium cromoglycate (cromolyn sodium) against nasal symptoms.

The incidence of adverse effects in association with intranasal fluticasone propionate appears to be comparable to that observed with placebo; the most frequently reported effects are nasal dryness/burning, epistaxis and headache. Consistent with its minimal systemic availability, intranasal fluticasone propionate in a dosage of up to 4 mg/day does not cause adrenal suppression.

Thus, based on early data from large clinical trials, fluticasone propionate administered once daily offers an effective and convenient treatment option in patients with seasonal and perennial allergic rhinitis, and is distinguished by its low oral bioavailability.

Pharmacodynamic Properties

Fluticasone propionate has potent topical anti-inflammatory activity coupled with low systemic activity. It has more than 9 times the anti-inflammatory activity of fluocinolone acetonide, and twice the activity of beclomethasone dipropionate in the McKenzie skin vasoconstriction assay in humans.

After allergen challenge, 2 weeks’ pretreatment with intranasal fluticasone propionate 200 μg/ day did not significantly inhibit the immediate increase in nasal airways resistance in atopic patients; no data concerning the possible effects of fluticasone propionate on the late and rechallenge phases of the allergic response are available.

A reduction in the number of nasal eosinophils, basophils and neutrophils has been observed in patients with seasonal allergic rhinitis after treatment with intranasal fluticasone propionate 50 to 800 μg/day administered for 2 weeks to 6 months. Further investigation revealed that the number of activated eosinophils in the nasal mucosa during the immediate allergic response was reduced after treatment with fluticasone propionate 200 μg/day, suggesting that fluticasone propionate may act by preventing eosinophil activation.

Although intravenous fluticasone propionate 2mg produced a marked reduction in plasma cortisol levels, no such effects were evident after oral administration of fluticasone propionate 16mg or after intranasal fluticasone propionate 4 mg/day for 7 days. No suppression of pituitaryadrenal function was reported after up to 12 months’ treatment with intranasal fluticasone propionate 50 to 1600 μg/day in patients involved in 9 large clinical trials.

Pharmacokinetic Properties

Fluticasone propionate is poorly absorbed following oral administration. The small portion of drug which is absorbed is metabolised rapidly and has a total blood clearance (plasma clearance adjusted for packed cell volume) almost equivalent to hepatic blood flow. Thus, the hepatic extraction ratio of fluticasone propionate is almost unity, giving the drug an oral bioavailability of < 1%. For a drug intended to have only local effects, this compares favourably with budesonide (11%), flunisolide (20%) and dexamethasone and prednisolone (> 80%), as low drug bioavailability minimises systemic adverse effects. There are no investigations concerning the pharmacokinetics of intranasal fluticasone propionate.

87 to 100% of an oral dose of fluticasone propionate is excreted in the faeces, 3 to 40% as the inactive 17β-carboxylic acid metabolite.

Therapeutic Efficacy

Extensive placebo-controlled studies involving large numbers of patients have established the efficacy of intranasal fluticasone propionate 200 μg/day in both adults and children with seasonal allergic rhinitis. Further, fluticasone propionate 200 μg/day in a once daily dose has almost equal efficacy to 100μg twice daily according to the results of 5 studies involving over 1000 patients. Topical fluticasone propionate produces a significant improvement in nasal symptoms, assessed by patients and/or clinicians, although effects on ocular symptoms have been inconsistent. Improvement is evident within 1 to 3 days of initiating treatment. In an overview of 2 large studies involving over 500 patients, 54 to 66% of fluticasone propionate 200 μg/day recipients showed symptom improvement versus 25 to 36% of placebo recipients.

In comparative studies, fluticasone propionate generally showed efficacy similar to that of intranasal beclomethasone dipropionate and flunisolide acetonide. Fluticasone propionate also achieved better control of nasal symptoms compared with oral loratadine, cetirizine and intranasal sodium cromoglycate, tended to be better than oral terfenadine and had similar efficacy to oral astemizole. Oral astemizole achieved better control of ocular symptoms than intranasal fluticasone propionate.

Fluticasone propionate 200 μg/day administered for 6 or 12 months was effective in the treatment of perennial allergic rhinitis, and showed similar efficacy to intranasal beclomethasone dipropionate in 2 comparative studies in this patient group. Limited data concerning patients with perennial nonallergic rhinitis suggest that fluticasone propionate 200 μg/day is effective, but more experience in this area is required. No data concerning the use of fluticasone propionate in the treatment of nasal polyps, nonallergic rhinitis with eosinophils syndrome or rhinitis medicamentosa are available.

Tolerability

Intranasal fluticasone propionate appears to be well tolerated by both adults and children. Adverse events are restricted predominantly to local effects such as nasal dryness, burning and epistaxis, and have been reported at a rate of 0 to 6% which is comparable to that observed with placebo (2 to 4%). There have been no reports to date of oropharyngeal candidiasis, nasal septal perforation or adrenal suppression in association with intranasal fluticasone propionate. Comparative studies indicate that the incidence of adverse events is similar with intranasal beclomethasone dipropionate and fluticasone propionate. One study documented a higher incidence of stinging with intranasal flunisolide acetonide than with fluticasone propionate or placebo.

Dosage and Administration

The recommended dose of intranasal fluticasone propionate for prophylaxis and treatment of seasonal allergic rhinitis and perennial allergic and nonallergic rhinitis is 200μg once daily in adults and children over 12 years of age. Half this dose is recommended in children aged 4 to 11 years with seasonal allergic rhinitis; currently there are insufficient data to recommend the use of intranasal fluticasone propionate for perennial rhinitis in this age group. During periods of heavy allergen challenge, additional therapy may be required to control symptoms, notably eye symptoms.