Fluticasone furoate: A new intranasal corticosteroidR Kumar, D Kumar, A Parakh
Department of Pediatrics, Lady Hardinge Medical College and Kalawati Saran Children's Hospital, New Delhi, India
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
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. , 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.  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.
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.
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. 
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. ,, 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.  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.  It falls in Pregnancy Category C.
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.
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. 
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. 
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].
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  [Table 1].
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. 
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.  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. 
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. 
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.
There is considerable variation in the daily cost of each spray. Beclomethasone, dexamethasone and budesonide are significantly cheaper than fluticasone, mometasone or triamcinolone.  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.  No such cost analysis data is available from India.
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. ,,
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.  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. ,
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. ,
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.  The effects on growth rate and HPA axis function were not assessed in this study.
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.
[Table 1], [Table 2]