, Volume 53, Issue 5, pp 885-907
Date: 12 Oct 2012

Intranasal Fluticasone Propionate

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Summary

Synopsis

The intranasal corticosteroid fluticasone propionate is an effective agent for the treatment of rhinitis, demonstrating potent local anti-inflammatory activity and little, if any, systemic activity. Intranasal fluticasone propionate has shown clinical efficacy similar to that of other intranasal corticosteroids, including beclomethasone (administered at up to a 2- fold higher dosage than fluticasone), budesonide, flunisolide and triamcinolone acetonide, and provides greater relief from nasal symptoms (including nasal blockage) than antihistamine agents and intranasal sodium cromoglycate. Its efficacy in the treatment of seasonal allergic rhinitis and perennial allergic and nonallergic rhinitis has been demonstrated in large well-controlled studies in which the drug maintained adequate control of symptoms when administered in a once daily dose of 200µg. In addition, fluticasone propionate has shown similar efficacy to that of beclomethasone in the treatment of nasal polyps; however, its use in the postoperative setting requires further investigation.

Intranasal fluticasone propionate is well tolerated in the majority of patients, the incidence of adverse events being similar to that seen with placebo. Pharmacoeconomic analyses indicate that intranasal fluticasone propionate is significantly more cost-effective than the antihistamines terfenadine and loratadine. Overall quality of life was improved to a similar extent by fluticasone propionate and beclomethasone.

In conclusion, recent clinical experience has confirmed that intranasal fluticasone propionate is a convenient, effective and well tolerated alternative to other intranasal corticosteroids and antihistamines for the treatment of rhinitis when administered once daily.

Pharmacological Properties

Fluticasone propionate has a 3- and 1.5-fold higher affinity for the glucocorticoid receptor than budesonide and the active metabolite of beclomethasone, respectively. The anti-inflammatory activity of intranasal fluticasone propionate has been demonstrated in nasal allergen provocation tests in patients with allergic rhinitis and also in skin vasoconstriction assays, in which the potency of fluticasone propionate was at least twice that of beclomethasone and was similar to or up to 3-fold greater than that of budesonide. Fluticasone propionate reduced both the early and late responses to allergen challenge, as evidenced by reductions in the levels of inflammatory cells and mediators in nasal lavage fluid. In addition, the nasal inspiratory peak flow from 0 to 24 hours after allergen challenge was significantly improved with fluticasone propionate compared with placebo. Fluticasone propionate was more effective in improving total nasal airflow than the antihistamines terfenadine, astemizole and loratadine.

Treatment with intranasal fluticasone propionate reduced the number of eosinophils and basophils in nasal lavage fluid in patients with rhinitis, but had no effect on the levels of neutrophils, goblet cells or epithelial cells.

With regard to the hypothalamic-pituitary-adrenal (HPA) axis, well designed clinical trials have shown fluticasone to have no effect on plasma or urinary cortisol levels in patients with rhinitis.

Little is known about the pharmacokinetic properties of intranasal fluticasone propionate, as plasma concentrations are generally below the limit of detection after administration by this route (<50 ng/L). The amount of fluticasone propionate present in the systemic circulation after intranasal administration has been estimated to be <2% of the dose. As oral bioavailability is negligible (<1%), it is likely that the small systemic exposure observed after intranasal administration results from absorption of the drug through the nasal mucosa.

Studies in healthy male volunteers using intravenous and oral formulations of fluticasone propionate reported the drug to have a rapid plasma clearance rate (1.11 L/min), similar to that of hepatic blood flow. The mean volume of distribution at steady-state was 318L. Low plasma concentrations of fluticasone propionate following oral administration may be attributed to the fact that the drug is poorly absorbed and is subject to extensive hepatic metabolism. Most oral flutica-sone propionate is eliminated in the faeces; the elimination half-life after intravenous administration is about 8 hours.

Clinical Efficacy

Large, well designed multicentre clinical trials have shown intranasal fluticasone propionate to be an effective agent for the treatment of seasonal allergic rhinitis in adults, adolescents and children. The drug significantly improved nasal symptoms (including sneezing, itching, nasal blockage and rhinorrhoea), increased the number of symptom-free days and reduced the use of rescue medication compared with placebo. The efficacy of fluticasone propionate in improving nasal symptoms was similar in adults given a dosage of 100µg twice daily or 200µg once daily; however, some studies observed that the use of rescue medication was lower in patients given the 100µg twice daily dosage. Studies in adults with severe symptoms indicate that administration of a higher dosage of fluticasone propionate (200µg twice daily) may be advantageous compared with a once daily 200µg dosage. Once daily dosages of fluticasone propionate 100 or 200µg showed similar efficacy in improving symptoms in children.

In comparisons with other intranasal corticosteroids, fluticasone propionate 200 µg/day improved nasal symptoms to a similar extent to beclomethasone 336 to 400 jug/day, flunisolide 200 µg/day and triamcinolone acetonide 220 fig/day. Fluticasone propionate 200µg once daily showed similar efficacy to budesonide 128 µg/day but appeared less effective than budesonide 250 jug/day in reducing sneezing in one study. All other nasal symptom scores were improved to a similar extent. The oral antihistamines astemizole 10 mg/day, cetirizine 10 mg/day, loratadine 10 mg/day and terfenadine 120 mg/day were all less effective than fluticasone propionate in relieving nasal symptoms in patients with seasonal allergic rhinitis.

Fluticasone propionate 200µg administered once daily starting before and continuing throughout the pollen season reduced the incidence of nasal symptoms of seasonal allergic rhinitis. Fluticasone propionate prophylaxis was superior to sodium cromoglycate, and combined treatment with cetirizine did not offer any advantages over fluticasone propionate monotherapy in preventing the onset of nasal symptoms.

Intranasal fluticasone propionate was an effective agent for the treatment of perennial allergic and nonallergic rhinitis in adults, adolescents and children. Nasal symptoms were significantly improved in adults treated with fluticasone propionate (100µg twice daily or 200µg once daily) compared with placebo and the drug was as effective as intranasal beclomethasone in large double-blind studies. One study found that during prolonged therapy of up to a year, improvements in nasal blockage and discharge were significantly greater in patients with perennial allergic rhinitis treated with fluticasone propionate 200µg twice daily than in those treated with the same dosage of beclomethasone. Fluticasone propionate 100µg once or twice daily was as effective as beclomethasone 200µg twice daily in the treatment of symptoms in children with either perennial allergic or nonallergic rhinitis.

Fluticasone propionate has shown similar efficacy to beclomethasone in improving symptoms associated with the presence of nasal polyps. It has also shown efficacy in the postoperative setting in preventing the recurrence of nasal polyps following surgery; however, preliminary findings from a small nonblinded study, showing fluticasone to be associated with an increased risk of infection after surgery compared with beclomethasone (when used as an adjuvant to prevent nasal polyp recurrence), require further investigation.

Tolerability

Intranasal fluticasone propionate was well tolerated in both adults and children when administered for periods of up to 12 months in large well-controlled clinical trials. Apart from intranasal bleeding, the tolerability profile of fluticasone propionate did not differ significantly from that of placebo and, in double-blind comparative trials, fluticasone propionate was as well tolerated as intranasal beclomethasone and budesonide and the antihistamines terfenadine and lorata-dine. Adverse events were generally mild to moderate, the most common being epistaxis/blood in the nasal mucus, nasal burning, nasal dryness, sore throat and headache. The drug does not suppress adrenal function and has not been associated with oropharyngeal candidiasis or nasal septal perforation. Preliminary findings indicate that long term treatment with fluticasone propionate (up to 1 year) does not cause ocular or bone changes.

Pharmacoeconomic and Quality-of-Life Considerations

Pharmacoeconomic analysis found fluticasone propionate to be more cost-effective in the treatment of seasonal allergic rhinitis than the antihistamines terfenadine and loratadine (cost-effectiveness ratios 1: 2.5 and 1: 5.7 for fluticasone propionate versus terfenadine and loratadine, respectively). In another study, fluticasone propionate treatment was associated with a lower cost per unit of efficacy than terfenadine. Studies have shown that overall quality of life was similar during fluticasone propionate and beclomethasone treatment, whereas fluticasone propionate was more effective than astemizole in improving quality-of-life parameters.

Dosage and Administration

The recommended dosage of intranasal fluticasone propionate for the prophylaxis and treatment of nasal symptoms in adults and adolescents (>12 years) with seasonal allergic rhinitis or perennial allergic or nonallergic rhinitis is 200µg once daily. For the treatment of nasal symptoms in children (≥4 years) with seasonal or perennial allergic rhinitis, the recommended dosage is 100µg once daily. Additional therapy to control eye symptoms may be required.

Various sections of the manuscript reviewed by: J. Bousquet, Service des Maladies Respiratoires, Hôpital Arnaud de Villeneuve, Montpellier, France; J. Dolovich, McMaster University Medical Centre, Hamilton, Ontario, Canada; W.J. Fokkens, Department of Otorhinolaryngology, Dijkzigt University Hospital, Rotterdam, The Netherlands; S.P. Galant, Asthma and Allergy Research Center, Orange, California, USA; I. Garrelds, Department of Pharmacology, Erasmus University Rotterdam, Faculty of Medicine and Health Sciences, Rotterdam, The Netherlands; F. Horak, ENT University Clinic Vienna, Vienna, Austria; V.J. Lund, Institute of Laryngology and Otology, University College London Medical School, London, England; G.K. Scadding, Royal National Throat, Nose and Ear Hospital, London, England.