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  IN THIS Article
 ::  Abstract
 :: Introduction
 :: Pharmacology
 :: Indication
 :: Mechanism of action
 :: Drug interactions
 :: Conclusion
 ::  References
 ::  Article Tables

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  Table of Contents     
DRUG REVIEW
Year : 2012  |  Volume : 58  |  Issue : 1  |  Page : 79-83

Fluticasone furoate: A new intranasal corticosteroid


Department of Pediatrics, Lady Hardinge Medical College and Kalawati Saran Children's Hospital, New Delhi, India

Date of Submission20-Aug-2011
Date of Decision28-Sep-2011
Date of Acceptance10-Oct-2011
Date of Web Publication25-Feb-2012

Correspondence Address:
A Parakh
Department of Pediatrics, Lady Hardinge Medical College and Kalawati Saran Children's Hospital, New Delhi
India
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DOI: 10.4103/0022-3859.93260

PMID: 22387656

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 :: Abstract 

Intranasal corticosteroids are recommended as one of the first-line therapies for the treatment of allergic rhinitis (AR), especially when associated with nasal congestion and recurrent symptoms. Fluticasone furoate is a novel enhanced-affinity glucocorticoid for the treatment of AR approved by the Food and Drug Administration in 2007 and recently introduced in India. Fluticasone furoate nasal spray is indicated for the treatment of the symptoms of seasonal and perennial AR in patients aged two years and older. This review summarizes the clinical data on fluticasone furoate nasal spray and discusses its role in the management of AR. Important attributes of fluticasone furoate include low systemic bioavailability (<0.5%), 24-h symptom relief with once-daily dosing, comprehensive coverage of both nasal and ocular symptoms, safety and tolerability with daily use, and availability in a side-actuated device that makes medication delivery simple and consistent. With these properties, fluticasone furoate nasal spray has the potential to enhance patient satisfaction and compliance, thus making it a good choice amongst available intranasal steroids.


Keywords: Allergic rhinitis, children, fluticasone furoate


How to cite this article:
Kumar R, Kumar D, Parakh A. Fluticasone furoate: A new intranasal corticosteroid. J Postgrad Med 2012;58:79-83

How to cite this URL:
Kumar R, Kumar D, Parakh A. Fluticasone furoate: A new intranasal corticosteroid. J Postgrad Med [serial online] 2012 [cited 2014 Aug 29];58:79-83. Available from: http://www.jpgmonline.com/text.asp?2012/58/1/79/93260



 :: Introduction Top


Allergic rhinitis (AR) is one of the most prevalent chronic diseases affecting up to 20 to 30% of adults and up to 40% of children. [1],[2] Intranasal corticosteroids (INCS) are recommended as first-line therapy for the treatment of persistent AR by the Allergic Rhinitis and its Impact on Asthma (ARIA) guidelines. [3] Fluticasone furoate (FF) is a novel enhanced-affinity glucocorticoid approved by the Food and Drug Administration (FDA) for the treatment of symptoms of seasonal allergic rhinitis (SAR) and perennial allergic rhinitis (PAR) in adults and children two years of age and older. This article briefly highlights the clinical pharmacology, indication and therapeutic efficacy of this drug.


 :: Pharmacology Top


Pharmacodynamics

FF is a synthetic trifluorinated corticosteroid with potent anti-inflammatory activity. It has a molecular weight of 538.6. FF nasal spray is an aqueous suspension of micronized FF for topical administration by means of a metering atomizing spray pump. Each actuation delivers 27.5 μg of FF in a volume of 50 μL suspension. It is supplied commercially in a 10-g bottle containing 120 sprays. The availability of the drug in a side-actuated device makes medication delivery simple and consistent, thus improving patient compliance.

Pharmacokinetics

The onset of action of FF nasal spray is rapid and is observed 8 h after the first dose of medication. FF has greater affinity for the glucocorticoid receptor when used intranasally and demonstrates prolonged receptor binding properties resulting in prolonged action and 24-h coverage with single daily dosing. [4]

Systemic bioavailability is determined by the sum of the portion of the drug that is absorbed via the nasal mucosa plus the portion that is swallowed (approximately 40-90% of the drug administered). Following intranasal administration of FF, most of the swallowed dose undergoes incomplete absorption and extensive first-pass metabolism in the liver, by the hepatic cytochrome P450 isozyme, CYP3A4, resulting in negligible systemic exposure (oral bioavailability is <0.5%). At the highest recommended intranasal dosage, plasma concentrations of FF are typically not quantifiable despite the use of a sensitive High-performance liquid chromatography-Mass spectoscopy/MS assay in all ages. [5],[6],[7] Since FF undergoes extensive first-pass metabolism in the liver, the pharmokinetics of FF may be altered in patients with hepatic impairment and hence caution is recommended in patients with severe hepatic impairment. [7] Since FF is not detectable in the urine of healthy subjects following intranasal dosing (<1%) no dosage adjustment is required in patients with renal impairment. [5] It falls in Pregnancy Category C.


 :: Indication Top


FF nasal spray is indicated for the treatment of the symptoms of SAR and PAR in patients aged two years and older. It also demonstrated a consistent positive effect on ocular symptoms of SAR.


 :: Mechanism of action Top


The precise mechanism through which FF affects rhinitis symptoms is not known. Corticosteroids have a wide range of actions on multiple cell types (e.g., mast cells, eosinophils, neutrophils, macrophages, lymphocytes) and mediators (e.g., histamine, eicosanoids, leukotrienes, cytokines) involved in inflammation. Specific effects of FF seen in experimental sensitized rats included activation of the glucocorticoid response element, inhibition of pro-inflammatory transcription factors such as Nuclear Factor kappa-B (NFkB), and inhibition of antigen-induced lung eosinophilia. [8]


 :: Drug interactions Top


FF is cleared by extensive first-pass metabolism in the liver, hence potent inhibitors of CYP3A4 enzyme may increase exposure to FF. Caution is recommended with the co-administration of FF nasal spray and ketoconazole or other potent CYP3A4 inhibitors like ritonavir. [7]

Clinical efficacy

FF has been compared with placebo in various Randomized Control Trials (RCTs) in adults and children. FF nasal spray was observed to produce significantly greater improvements than placebo at relieving symptoms of both SAR and PAR. A few comparator studies with fluticasone propionate and fexofenadine are also available [Table 1].
Table 1: Double‑blind, placebo‑controlled, clinical trials of FF in the treatment of AR

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Nasal symptoms

Across studies, FF has been shown to offer comprehensive coverage of nasal symptoms, with significantly better results than placebo for congestion, rhinorrhea, itching and sneezing. It was also observed to improve morning, evening and daily reflective total nasal symptom score (rTNSS) and morning predose instantaneous total nasal symptom score (iTNSS). Most studies also included Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ), comprising a 28-item self-administered disease-specific instrument to assess the quality of life. Results of patient-rated overall response to therapy and RQLQ were consistent with the symptom scores in demonstrating the benefits of FF over placebo [10] [Table 1].

Ocular symptoms

Ocular symptoms of redness, itching/burning, and tearing/watery eyes were assessed using a four-point scale. FF was seen to significantly improve the reflective total ocular symptom score (rTOSS) and morning predose instantaneous total ocular symptom score (iTOSS) as compared to placebo. The efficacy of FF nasal spray for ocular symptoms has been attributed to its anti-inflammatory action and modulation of allergen-induced reflex neuronal activity from the nose to the eye. [11]

Nighttime symptoms

Nasal symptoms in AR have been strongly linked to sleeping difficulties and consequent impairment in next-day function and wellbeing. The effects of FF nasal spray on nighttime symptoms were assessed in randomized, double-blind, placebo-controlled studies in which patients received FF nasal spray 110 μg once daily, the oral antihistamine fexofenadine 180 mg daily, or placebo for two weeks. [12] FF was significantly more effective (P<0.001) than both placebo and fexofenadine with respect to mean changes from baseline in the nighttime symptoms score. Results for other efficacy endpoints are summarized in [Table 1].

Results of randomized, double-blind, placebo- and comparator-controlled studies demonstrate that FF nasal spray provides comprehensive coverage of both nasal and ocular symptoms and nighttime symptoms in AR. However, no efficacy study of duration greater than two weeks is available, hence further studies are needed to establish long-term efficacy.

Comparison of fluticasone furoate with other intranasal corticosteroids

The pharmacodynamic and pharmacokinetic profiles of available INCS are compared in [Table 2] . The onset of action for FF nasal spray was observed from the first day of treatment, whereas in the fluticasone propionate nasal spray group it was observed on the second day. Treatment with once-daily FF nasal spray was as effective and non-inferior to twice-daily fluticasone propionate nasal spray in reducing nasal symptoms. [13]

More patients (P<.001) preferred FF to fluticasone propionate based on attributes of scent or odor (58% vs. 27%), aftertaste (60% vs. 18%), leaking out of the nose and down the throat (59% vs. 21%), and mist gentleness (57% vs. 26%). No statistically significant differences were seen in preferences regarding ease of use, delivery method, or device comfort. [14]
Table 2: Comparison of available intranasal corticosteroids

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There are no head to head comparator studies available with other available INCS (mometasone, budesonide, ciclesonide) or combination of INCS with intranasal antihiataminic azelastine hydrochloride.

Cost analysis

There is considerable variation in the daily cost of each spray. Beclomethasone, dexamethasone and budesonide are significantly cheaper than fluticasone, mometasone or triamcinolone. [16] Compared with FF, all other branded INCS agents incurred statistically significant higher costs of concomitant AR drugs (6.3%, P=0.002). Mean INCS costs per patient during the 60-day follow-up period were lowest for budesonide, followed by FF, triamcinolone and mometasone. [17] No such cost analysis data is available from India.

Dose

Children 2 to 11 years of age

The recommended starting dosage in children is 55 mcg once daily administered as one spray (27.5 mcg/spray) in each nostril. Children not adequately responding to 55 mcg may use 110 mcg (two sprays in each nostril) once daily. Once symptoms have been controlled, the dosage may be decreased to 55 mcg once daily.

Adults and adolescents 12 years of age and older

The recommended starting dosage is 110 mcg once daily administered as two sprays (27.5 μg/spray) in each nostril, to be titrated to a minimum effective dosage to reduce the possibility of side-effects. When the maximum benefit has been achieved and symptoms have been controlled, reducing the dosage to 55 mcg (one spray in each nostril) once daily may be effective in maintaining control of AR symptoms. [7],[18],[19]

Adverse effects

The occurrence of systemic side-effects is limited by the targeted delivery of medication to its nasal mucosal site of action. The low potential for causing systemic side-effects has been established in both short- and long-term studies. The most common adverse drug reactions are headache, epistaxis, nasopharyngitis, pyrexia, pharyngolaryngeal pain, nasal ulceration, cough, and back pain.

The adverse event profile of FF nasal spray was assessed in older children, from 6-11 years of age, in a subanalysis of data from three randomized, double-blind, placebo-controlled, parallel-group studies. [6] The incidence of the most common adverse effects was found to be similar in both the drug and the placebo group.

In a six-week placebo-and prednisolone-controlled Hypothalamic-Pituitary-Adrenal (HPA) axis study, FF nasal spray was found to have a favorable tolerability profile in patients aged 6-11 years with PAR or SAR causing minimal HPA axis suppression as indexed by ratio from 24-h baseline serum cotisol secretion and urinary cortisol excretion. This result is consistent with low systemic bioavailability of FF. [5],[20]

Studies suggest that usual doses of INCS do not cause clinically relevant growth suppression or reduced final height in the overall majority of patients. FF nasal spray 110 μg OD for two weeks in a randomized, double-blind, placebo-controlled, crossover study was observed to have no effect on lower-leg growth rate (assessed by knemometry) in pre-pubertal children with AR. [9],[21]

Rosenblut et al., studied the adverse event profile of FF nasal spray over a 12-month period. It was well tolerated with the incidence of most adverse events similar to that of placebo, with the exception of epistaxis, which was more common with FF (20%) than placebo (8%). However, no epithelial changes were seen in nasal biopsies of patients from both the groups. [22] The effects on growth rate and HPA axis function were not assessed in this study.


 :: Conclusion Top


FF is a new topical INCS, with enhanced affinity and a unique side-actuated delivery device. It has shown good efficacy in improving nasal and also ocular symptoms of AR in all age groups (>2 years). A prolonged nasal retention time allows for a once-daily dosing regimen which would improve compliance. It has acceptable odor, aftertaste, mist gentleness and minimal leaking out of the nose and down the throat. It has minimal systemic adverse effects including minimal HPA axis suppression in children. It is a promising new agent but long-term safety and efficacy studies are still awaited.

 
 :: References Top

1.Giavina-Bianchi P, Agondi R, Stelmach R, Cukier C, Kalil J. Fluticasone furoate nasal spray in the treatment of Allergic rhinitis. Ther Clin Risk Manag 2008;4:465-72.  Back to cited text no. 1
    
2.Samolin´ski B, Sybilskia A, Raciborskia F, Tomaszewskaa A, Samel-Kowalika P, Walkiewicza A, et al. Prevalence of rhinitis in Polish population according to the ECAP (Epidemiology of Allergic Disorders in Poland) study. Otolaryngol Pol 2009;63:324-30.  Back to cited text no. 2
    
3.Bousquet J, Khaltaev N, Cruz AA, Denburg J, Fokkens WJ, Togias A, et al. Allergic Rhinitis and its Impact on Asthma (ARIA) 2008 update (in collaboration with the World Health Organization, GA(2)LEN and AllerGen). Allergy 2008;63 Suppl 86:8-160.  Back to cited text no. 3
    
4.Salter M, Biggadike K, Matthews JL, West MR, Haase MV, Farrow SN, et al. Pharmacological properties of the enhanced-affinity glucocorticoid fluticasone furoate in vitro and in an in vivo model of respiratory inflammatory disease. Am J Physiol Lung Cell Mol Physiol 2007;293:660-7.  Back to cited text no. 4
    
5.Tripathy I, Levy A, Ratner P, Clements D, Wu W, Philpot E. HPA axis safety of fluticasone furoate nasal spray once daily in children with perennial allergic rhinitis. Pediatric Allergy Immunol 2009;20:287-94.  Back to cited text no. 5
    
6.Meltzer EO, Tripathy I, Máspero JF, Wu W, Philpot E. Safety and tolerability of fluticasone furoate nasal spray once daily in paediatric patients aged 6-11 years with allergic rhinitis: Subanalysis of three randomized, double-blind, placebo-controlled, multicentre studies. Clin Drug Investig 2009;29:79-86.  Back to cited text no. 6
    
7.Martin BG, Ratner PH, Hampel FC, Andrews CP, Toler T, Wu W, et al. Optimal dose selection of fluticasone furoate nasal spray for the treatment of seasonal allergic rhinitis in adults and adolescents. Allergy Asthma Proc 2007;28:216-25.  Back to cited text no. 7
    
8.Hampel FC, Ratner PH, Van Bavel J, Amar NJ, Daftary P, Wheeler W, et al. Double-blind, placebo-controlled study of azelastine and fluticasone in a single nasal spray delivery device. Ann Allergy Asthma Immunol 2010;105:168-73.  Back to cited text no. 8
    
9.Jacobs R, Martin B, Hampel F, Toler TN, Ellsworth A, Philpot EE. Effectiveness of fluticasone furoate 110 microg once daily in the treatment of nasal and ocular symptoms of seasonal allergic rhinitis in adults and adolescents sensitized to mountain cedar pollen. Curr Med Res Opin 2009;25:1393-401.  Back to cited text no. 9
    
10.Fokkens WJ, Jogi R, Reinartz S, Sidorenko I, Sitkauskiene B, Yan Oene C, et al. Once daily fluticasone furoate nasal spray is effective in seasonal allergic rhinitis caused by grass pollen. Allergy 2007;62:1078-84.  Back to cited text no. 10
    
11.DeWester J, Philpot EE, Westlund RE, Cook CK, Rickard KA. The efficacy of intranasal fluticasone propionate in the relief of ocular symptoms associated with seasonal allergic rhinitis. Allergy Asthma Proc 2003;24:331-7.  Back to cited text no. 11
    
12.Andrews CP, Martin BG, Jacobs RL, Mohar DE, Diaz JD, Amar NJ, et al. Fluticasone furoate nasal spray is more effective than fexofenadine for nighttime symptoms of seasonal allergy. Allergy Asthma Proc 2009;30:128-38.  Back to cited text no. 12
    
13.Meltzer EO, Lee J, Tripathy I, Lim J, Ellsworth A, Philpot E. Efficacy and safety of once-daily fluticasone furoate nasal spray in children with seasonal allergic rhinitis treated for 2 wk. Pediatr Allergy Immunol 2009;20:279-86.  Back to cited text no. 13
    
14.Kaiser HB, Naclerio RM, Given J, Toler TN, Ellisworth A, Philpot EE. Fluticasone furoate nasal spray: A single treatment option for the symptoms of seasonal allergic rhinitis. J Allergy Clin Immunol 2007;119:1430-7.  Back to cited text no. 14
    
15.Hughes SC, Shardlow PC, Hollis FJ, Scott RJ, Motivaras DS, Allen A, et al. Metabolism and disposition of fluticasone furoate, an enhanced-affinity glucocorticoid, in humans. Drug Metab Dispos 2008;36:2337-44.  Back to cited text no. 15
    
16.Meltzer E, Andrews C, Journeay G, Lim J, Prillaman B, Garris C, et al. Comparison of patient preference for sensory attributes of fluticasone furoate or fluticasone propionate in adults with seasonal allergic rhinitis: A randomized, placebo-controlled, double-blind study. Ann Allergy Asthma Immunol 2010;104:331-8.  Back to cited text no. 16
    
17.Garris C, Shah M, D'Souza A, Stanford R. Comparison of corticosteroid nasal sprays in relation to concomitant use and cost of other prescription medications to treat allergic rhinitis symptoms: Retrospective cohort analysis of pharmacy claims data. Clin Drug Investig 2009;29:515-26.  Back to cited text no. 17
    
18.Okubo K, Nakashima M, Miyake N, Uchida J, Okuda M. Dose-ranging study of fluticasone furoate nasal spray for Japanese patients with perennial allergic rhinitis. Curr Med Res Opin 2008;24:3393-403.  Back to cited text no. 18
    
19.Nathan RA, Berger W, Yang W, Cheema A, Silvey M, Wu W, et al. Effect of once-daily fluticasone furoate nasal spray on nasal symptoms in adults and adolescents with perennial allergic rhinitis. Ann Allergy Asthma Immunol 2008;100:497-505.  Back to cited text no. 19
    
20.Gulliver T, Eid N. Effects of glucocort icoids on the hypothalamic-pituitary-adrenal axis in children and adults. Immunol Allergy Clin North Am 2005;25:541-55, vii.  Back to cited text no. 20
    
21.Gradman J, Caldwell MF, Wolthers OD. A 2-week, crossover study to investigate the effect of fluticasone furoate nasal spray on short-term growth in children with allergic rhinitis. Clin Ther 2007; 29:1738-47.  Back to cited text no. 21
    
22.Rosenblut A, Bardin PG, Muller B, Faris MA, Wu WW, Caldwell MF, et al. Long-term safety of fluticasone furoate nasal spray in adults and adolescents with perennial allergic rhinitis. Allergy 2007;62:1071-2.  Back to cited text no. 22
    



 
 
    Tables

  [Table 1], [Table 2]

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