APC/DTC Briefing Document

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1 London New Drugs Group Page 1 APC/DTC Briefing Document Intranasal corticosteroids for allergic rhinitis SUMMARY Contents Summary 1 Recommendations 2 Background 2 Treatment 3 Intranasal corticosteroids 3 Effects on growth 4 Clinical efficacy 7 Seasonal allergic rhinitis 7 Perennial allergic rhinitis 10 Patient preferences 14 Cost 20 Reference list 21 Produced for the London New Drugs Group by: Alexandra Denby, Regional MI Manager (Projects & New Products) Contact: Alexandra Denby Regional MI Manager (Projects & New Products) London New Drugs Group Medicines Information Service Northwick Park Hospital Middlesex HA1 3UJ Tel: alexandra.denby@nwlh.nhs.uk Further copies of this document are available from URL: Allergic rhinitis is defined as intermittent (or seasonal) or persistent (or perennial), according to symptom duration and frequency. Intranasal corticosteroids are the most effective treatment option for moderate-severe symptoms and reduce sneezing, rhinorrhea, itching, post-nasal drip and nasal blockage, and total nasal symptom scores better than antihistamines. There are currently six intranasal corticosteroids sprays available in the UK: beclometasone, budesonide, flunisolide, fluticasone, mometasone and triamcinolone. Administration is either once or twice a day, depending on the preparation used. Although the six have not been directly compared in a single trial, there have been a number of comparison studies. Results show that they are all equally effective in controlling the symptoms of allergic rhinitis, both intermittent and persistent. Corticosteroids are known to be potent inhibitors of nearly every component of the growth axis. There are no long-term comparative studies of once-daily intranasal corticosteroids on growth rate in children and the data from short- and intermittent-term studies is very limited. From one-year studies it appears that twice daily beclometasone can slow growth velocity in prepubertal children, whilst once daily mometasone, triamcinolone, fluticasone and budesonide do not affect growth velocity. It is possible that detectable growth suppression may only be seen with twice daily administration. The effects of inhaled corticosteroids on growth velocity cannot be extrapolated to intranasal corticosteroids. It is questionable whether the effects on childhood growth seen in intermediate-term studies of intranasal corticosteroids for allergic rhinitis result in reduced adult height. When agents in a given treatment class have similar efficacy and safety profiles, other product attributes can play a pivotal role in choosing a product. Sensory perception questionnaires have evaluated patient s preferences and acceptability of the intranasal corticosteroids with respect to factors such as overall comfort during administration, medication run-off, odour and taste. There has not been a direct comparison of all six intranasal corticosteroids with regard to patient preference. Triamcinolone was preferred by patients when compared with beclometasone, fluticasone and mometasone in two studies. Other studies showed that mometasone was preferred over budesonide, fluticasone and beclometasone (in that order), whilst budesonide was preferred over fluticasone. PRODUCED TO INFORM LOCAL DECISION-MAKING USING THE BEST AVAILABLE EVIDENCE AT THE TIME OF PUBLICATION.

2 Page 2 The recommended starting and maintenance doses of the intranasal corticosteroid preparations vary and there may be an economical advantage of certain products over others. The prescription duration of the individual preparations varies because the prescribed daily dosage varies as well as the pack size. Factors such as taste, odour, irritation and moistness, must be taken into account when choosing a preparation. A lack of adherence may result in sub-optimal control of allergic rhinitis, potentially leading to increases in both indirect (absenteeism, reduced quality of life) and direct (drug, GP visits) costs. RECOMMENDATION As they are all equally effective, the least expensive product that suits the patient should be prescribed. Currently (January 2008) the Beconase 200 dose intranasal spray (POM pack) is the most cost effective intranasal corticosteroid. BACKGROUND The true prevalence of allergic rhinitis (AR) is difficult to assess, as many patients self diagnose and treat themselves, as there are products that are available to buy over-thecounter. A recent telephone survey of adults estimated that the lifetime prevalence of AR is at least 20%, but may be over 30%. 1 The most common symptoms are sneezing, nasal blockage, runny nose (rhinorrhea) and an itchy nose. They are usually bilateral, and in 70% of sufferers are worse in the morning. Additional symptoms are itchy eyes and throat, impaired sense of smell, headache and facial pain. 1 Allergic rhinitis is classified as intermittent or persistent, based on symptom duration and frequency. 1 If the symptoms are present for either less than four days a week, or for less than four weeks, AR is classified as intermittent. Persistent AR is classified as symptoms for more than four days a week and for more than four weeks. 1 Both are then subdivided according to the severity of patient s symptoms into mild or moderate-severe. In mild AR none of the following are present, whilst in moderate-severe at least one is present: sleep disturbance, impairment of daily activities, leisure and/or sport, impairment of school or work, troublesome symptoms. The symptoms of AR are not life threatening but they can significantly impact on a patients quality of life, reducing productivity at work, impairing concentration and affecting learning in children. 2 Allergic rhinitis often coexists with other respiratory conditions, such as sinusitis, otitis media, nasal polyposis and asthma. 3 Epidemiologic studies indicate that as many as 78% of patients with asthma have symptoms of AR, and that as many as 38% of patients with AR have symptoms of asthma. 3` The pathology of AR can be divided into early and late phase reactions. 2;3 The early phase symptoms (rhinorrhea, nasal obstruction, sneezing and pruritis) are caused by immunoglobulin E-mediated activation of mast cells and basophil release mediators (histamine, tryptase and leukotriene), which activate their respective receptors and induce the symptoms of AR. The late phase reaction occurs 4-5 hours after the early phase and affects 30-40% of patients. Inflammatory cells, such as eosinophils, are activated by cytokines, chemokines, (such as interleukin-8) histamine and leukotrienes, and they themselves release mediators. Symptoms are perpetuated with sufferers existing in a continual state of eosinophilia and increased mediator release. 2

3 Page 3 TREATMENT The first step is allergen avoidance. 1 Intermittent AR (seasonal allergic rhinitis or hayfever) is most commonly due to hypersensitivity to pollens and occasionally mould spores. Persistent AR is commonly due to hypersensitivity to house-dust mite and domestic pets. 1 The most effective pharmacological treatments for allergic rhinitis are intranasal corticosteroids (INSs), oral antihistamines and leukotriene receptor antagonists. 4 Intranasal corticosteroids are the most effective treatment option and reduce sneezing, rhinorrhea, itching, post-nasal drip and nasal blockage, and total nasal symptom score more than antihistamines. 3;4 Antihistamines can treat the early phase allergic reaction by inhibiting the release of histamine, whereas corticosteroids also treat the late-phase inflammatory response caused by infiltration of the nasal mucosa with activated eosinophils and lymphocytes. 3 Leukotriene receptor antagonists are no more effective than antihistamines and are less effective than intranasal corticosteroids. 3;4 Table 1 shows the relative effectiveness of available treatments for specific symptoms of allergic rhinitis. Pharmacological treatment options depend upon the type of AR: 1 MILD INTERMITTENT AR Antihistamine as required. Intranasal preparations have a faster onset of action but require more frequent administration. If using an oral product, a non-sedating oral antihistamine is preferable. Intranasal decongestants should be used if nasal blockage is a problem. These should not be used for more than seven days continuously. Intranasal corticosteroids are not usually necessary in patients with mild intermittent symptoms. MILD PERSISTENT OR MODERATE-SEVERE INTERMITTENT AR Antihistamine or intranasal corticosteroid. Individual preference and response to previous treatments should direct choice. Corticosteroids are preferred if nasal blockage is a problem. Intranasal decongestants can be used in the short term to relieve congestion and allow penetration of intranasal corticosteroids. Intranasal sodium cromoglicate is a suitable alternative if other drugs are contraindicated, or as an add-on if symptoms are troublesome despite other treatments. MODERATE-SEVERE PERSISTENT AR Intranasal corticosteroid. Intranasal decongestants can be used in the short term to relieve congestion and allow penetration of intranasal corticosteroids. Alternative or add-on treatment may be required: antihistamines, intranasal sodium cromoglicate, intranasal ipratropium bromide, leukotriene antagonists. AR WITH EYE SYMPTOMS Non-sedating oral antihistamines. Intranasal corticosteroids are as effective as antihistamines and are preferred if there are more persistent symptoms. Eye drops if oral antihistamines and intranasal corticosteroids are not appropriate. INTRANASAL CORTICOSTEROIDS (INSS) Corticosteroids have a profound effect on the inflammatory response and suppress many elements of the allergic inflammatory cascade. 2 They reduce eosinophil infiltration and suppress cytokines, dramatically reducing the infiltration of inflammatory cells into the nasal mucosa. Corticosteroids also reduce the release of histamine and leukotrienes, though this may be due to a reduction in the overall number of inflammatory cells in the epithelium. Despite the potential differences between the preparations of INSs, they are all considered equally efficacious in the treatment of allergic rhinitis. 1;2;4;5 No randomised controlled trials have consistently identified any particular product having superior efficacy or improved safety over another. It should not be assumed that more potent corticosteroids have greater efficacy. 1 INSs have been shown to improve health-related quality of life, as assessed using the Rhinoconjunctivitis Quality of Life Questionnaire, the Nocturnal Rhinoconjunctivitis Quality of Life Questionnaire and the Pittsburgh Sleep Quality index. 2 Table 2 shows the INSs which

4 Page 4 Table 1: Relative effectiveness of available treatments for specific symptoms of allergic rhinitis 3 Symptom Ocular Sneezing Rhinorrhea (nasal discharge) Congestion (nasal blockage) Itching Treatment Oral antihistamines ++ Intranasal corticosteroids ++ Oral antihistamines ++ Nasal antihistamines ++ Intranasal corticosteroids +++ Intranasal mast cell stabilisers + Oral antihistamines ++ Nasal antihistamines ++ Intranasal corticosteroids +++ Intranasal mast cell stabilisers + Topical anticholinergics ++ Oral antihistamines + Nasal antihistamines + Intranasal corticosteroids +++ Oral decongestants + Intranasal decongestants ++++ Intranasal mast cell stabilisers + Oral antihistamines ++ Nasal antihistamines ++ Intranasal corticosteroids +++ Intranasal mast cell stabilisers = substantial effect + = marginal effect are currently licensed in the UK for the treatment of allergic rhinitis. When agents in a given treatment class have similar efficacy and safety profiles, other product attributes can play a pivotal role in choosing a product. Comparisons of the sensory attributes of INSs (such as taste, smell, feel) are warranted because patients may be less inclined to use the prescribed treatment if the sensory attributes are perceived to be unfavourable. 6;7 Adherence is important for treating the symptoms of AR in order to achieve long-term symptom management. 7 INSs should be regarded as preventative rather than relieving treatment; they take time to work and ideally should be started one week before exposure to allergens (such as the pollen season for patients with severe SAR). 1 It is advisable to use the lowest corticosteroid dose to control AR, especially if the patient is using inhaled corticosteroids as well. 2 ADVERSE EFFECTS Local adverse events are generally minor and easily managed, and include irritation of the nasal epithelium, minor nosebleeds and headaches. 2 There is no evidence that proper use of INSs leads to nasal mucosal atrophy. 4 EFFECTS ON GROWTH Corticosteroids are known to be potent inhibitors of nearly every component of the growth axis. 9 When they are used at the recommended doses, INSs do not affect the hypothalamic-pituitary-adrenal (HPA) axis. 2;4;10 Concerns have been raised over the effect of long-term use of INSs on linear growth in children 2, which may be an indication of systemic absorption. 4 Studies have investigated the effects of inhaled corticosteroids in children with asthma, but these results cannot necessarily be extrapolated to children with AR who use INSs. 11

5 Page 5 Table 2: Intranasal corticosteroids and licensed doses 8 Drug / Tradenames Beclometasone diproprionate Beconase (50mcg/spray) Nasobec Aqueous (50mcg/spray) Budesonide Rhinocort Aqua (64mcg/spray) Budesonide (100mcg/spray) Flunisolide Syntaris (25mcg/spray) Fluticasone propionate Flixonase (50mcg/spray) Nasofan (50mcg/spray) Mometasone furoate Nasonex (50mcg/spray) Triamcinolone acetonide Nasacort (55mcg/spray) Dose for treatment of allergic rhinitis Adult and Child over 6 years, 100 micrograms (mcg) (2 sprays) into each nostril twice daily; max. total 400 mcg (8 sprays) daily; when symptoms controlled, dose reduced to 50 mcg (1 spray) into each nostril twice daily Adult and Child over 12 years,2 sprays into each nostril once daily in the morning or 1 spray into each nostril twice daily; when control achieved reduce to 1 spray into each nostril once daily Adult, 50 mcg (2 sprays) into each nostril twice daily, increased if necessary to max. 3 times daily then reduced for maintenance Child 5 14 years initially 25 mcg (1 spray) into each nostril up to 3 times daily ADULT: 100mcg (2 sprays) into each nostril once daily, preferably in the morning, increased to max. twice daily if required; when control achieved reduce to 50 mcg (1 spray) into each nostril once daily Child 4 11 years, 50 mcg (1 spray) into each nostril once daily, preferably in the morning, increased to max. twice daily if required Adult and Child over 12 years, 100 mcg (2 sprays) into each nostril once daily, increased if necessary to max. 200 mcg (4 sprays) into each nostril once daily; when control achieved reduce to 50 mcg (1 spray) into each nostril once daily Child 6 11 years, 50 mcg (1 spray) into each nostril once daily Adult and Child over 12 years 110 mcg (2 sprays) into each nostril once daily; when control achieved, reduce to 55 mcg (1 spray) into each nostril once daily Child 6 12 years, 55 mcg (1 spray) into each nostril once daily Patient characteristics affect susceptibility to growth suppression and include age and growth pattern of the child, underlying disease severity and timing of drug administration. 12 There are three distinct phases of growth in children: a period of rapidly decelerating growth during the first 2-3 years of life, primarily controlled by nutrition; a childhood growth phase from approximately 3-11 years of age, governed by the action of the endocrine system, especially growth hormone, and the pubertal growth phase, reliant on a combination of growth hormone and sex steroids. 9;12 In some children susceptibility to growth suppression is increased during transitions from one growth phase to the next, especially in the 2-3 years before puberty when growth rates are lower. 12 Conclusions on the growth effects of drugs from one age group cannot be generalised to the other age groups. An effect on growth found from short- or intermediate-term studies is not necessarily equivalent to an effect on final adult height, which, in relation to expected height, is the most important outcome measure of human growth. The correlation between two consecutive annual height velocity values for normal pre-pubertal children is very small: a low gain in one year is not necessarily followed by a low gain the next year, and vice versa. In addition, one-month lower-leg length velocity does not adequately predict the variation in annual statural height velocity. 9

6 Page 6 Chronic disease during childhood is known to affect growth, as seen in children with asthma who may have delayed pubertal development and attainment of (normal) adult height. 12 Allergic rhinitis does not appear to have an important effect on growth. Growth hormone secretion in prepubertal children is pulsatile and primarily nocturnal; absorption of exogenous corticosteroid at that time might be expected to have a more pronounced suppressive effect on growth hormone release than a morning dose. 12 A few studies have monitored the effects of INSs on growth velocity. Short-term studies Knemometry measures changes in the linear growth of the lower leg over a period of weeks. 9 One month lower leg growth velocity and steroid-induced changes in short-term lower leg growth rate do not account for the variation in annual statural height velocity. Knemometry studies have been performed with intranasal mometasone and budesonide. In one six-week study budesonide (via a metered dose inhaler) significantly reduced lower leg growth by 0.54mm/week (p<0.001), whilst in a similar study (using a Turbohaler), velocity was reduced by 0.18mm/week (not statistically significant). In a two-week cross-over study with intranasal mometasone and budesonide, there was no significant difference between lower leg growth during placebo or active treatments. Conclusions from one drug or formulation should not be extrapolated to other drugs or devices. Intermediate-term studies A year long study in children aged 6-9 years compared intranasal beclometasone 168mcg bd (n=51) with placebo (n=49) with respect to growth rates. 11 After one year the rate of growth was found to be significantly lower in the beclometasone group than the placebo group (0.013cm/day vs cm/day, p<0.01). After 12 months the beclometasone group had grown 5cm and the placebo group 5.9cm (p<0.01). No significant differences were seen between the groups for either early morning plasma cortisol concentrations or HPA-axis function. In another year long study children aged between 3 and 9 years were randomised to treatment with either intranasal mometasone 100mcg daily (n=49) or placebo. 13 After 52 weeks of treatment, the mean increase in height was 6.95cm in the mometasone group compared with 6.35cm in the placebo group (p=0.02). Additional analyses found that mometasone did not retard growth in any specific sex or age group of patients. There was no evidence of suppression of the HPA-axis in either group at any time point. Treatment for one year with intranasal triamcinolone acetonide has also not demonstrated any significant effects on growth or HPA function. In a small study 24 patients aged 6-14 years using intranasal triamcinolone followed their age-appropriate growth velocities. 14 A year long placebo-controlled study of intranasal fluticasone (200mcg daily) in children aged 3.5 to 9 years (n=150) also demonstrated equivalent growth velocity between the groups. 15 Height increases from baseline were 6.4cm in both groups. Intranasal budesonide, 64mcg/day (n=155) or placebo (n=74) were administered for one year in 229 children, aged 4-8 years. 16 The mean growth velocity during the treatment period was 5.91cm/year for patients on budesonide compared with 6.19cm/year for those on placebo. The mean difference (0.27cm) was not statistically significant. Mean growth velocity during the three-month follow-up was similar for the two treatment groups. There were also no significant differences between the groups in the percentages of patients who growth velocity was below the third percentile or whose quartile for growth velocity increased or remained unchanged. Long-term studies There are no long-term comparative studies of once-daily INSs on growth rate in children. From the intermediate studies outlined it appears that twice daily beclometasone can slow growth velocity in prepubertal children, whilst once daily mometasone, triamcinolone, fluticasone and budesonide do not affect growth velocity. It is possible that twice daily administration is needed in order to cause detectable growth suppression. 12 It is questionable whether the effects on childhood growth seen in intermediate-term studies of INSs for allergic rhinitis result in reduced adult height. 11 Growth study results should not be generalised to all patients because individ-

7 Page 7 ual patients may be susceptible to growth suppression during treatment with corticosteroids. The growth of children receiving such treatment should be monitored routinely. 16 If growth is slowed then the dose should be reviewed with the aim of reducing it to the lowest (once daily) dose that controls symptoms. 1;12 CLINICAL EFFICACY Clinical trials use the terms seasonal allergic rhinitis (SAR) and perennial allergic rhinitis (PAR), rather than intermittent or persistent allergic rhinitis. SAR occurs seasonally due to outdoor allergens such as pollen; PAR occurs perennially due to indoor allergens such as dust mites and pet dander. 2 In vitro and pre-clinical studies have demonstrated differences in the pharmacologic attributes of available intranasal steroids, such as lipophilicity, systemic bioavailability and molecular potency. 17 Topical potencies of glucocorticoids are compared using a variety of techniques, including the McKenzie assay. 17 These techniques show that fluticasone propionate is the most potent, followed by mometasone furoate, budesonide, beclometasone dipropionate and triamcinolone acetonide. 18 This section is divided into seasonal allergic rhinitis, perennial allergic rhinitis and patient preferences. In the following trials the beclometasone doses of 168mcg and 336mcg are equivalent to 200mcg and 400mcg, as the actual dose delivered is lower than the dose in each actuation. Similarly, the budesonide doses of 128mcg and 256mcg are equivalent to 200mcg and 400mcg. 19 SEASONAL ALLERGIC RHINITIS Triamcinolone 220mcg daily/ Fluticasone 200mcg daily A number of studies have confirmed the similar efficacy of triamcinolone and fluticasone. Small et al carried out a single blind, randomised, two-parallel-group, multicentre three-week study in 223 patients (12-70 years) with a Rhinitis Index Score (RIS) of at least 24 points (out of a maximum of 48). 20 The RIS was scored on 4 variables: congestion, rhinorrhea, sneezing and nasal itch. The primary efficacy variables were changes from baseline in the mean RIS and the change from baseline in the mean scores of each of the four individual rhinitis symptoms. The secondary efficacy variables were global evaluations and patient acceptance of study medication. Acceptance was based on medication runs down throat/out of nose, tastes bad, causes sore throat / bleeding nose / dry nostril / bloody mucus and stuffed-up nose. Both drugs produced a reduction of the RIS (-4.20 (-55%) with triamcinolone and (-60%) with fluticasone, p=0.23) and individual symptom scores. The only significant difference between the two drugs was the acceptability of the drugs. Fluticasone scored less favourably with respect to medication running down the throat (score of 6.77 vs. 0.70, p<0.01) and medication running out of the nose (score of 6.26 vs. 1.19, p=0.01). Triamcinolone was more likely to cause dry nostrils (score of 4.88 vs. 2.15, p<0.01) and a stuffed-up nose (score of vs. 5.31, p<0.01). These differences were expected because of the different formulations used: triamcinolone has more thixotropic properties (which reduces the amount running down the throat) but the irritating properties of the aerosol spray explain the dry nose and stuffed up nostrils. Gross et al carried out an investigatorblinded, randomised, parallel-group, active controlled, multicentre, three-week study in 352 patients, aged years. 18 All patients filled out the Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ) at both baseline and endpoint. Total nasal symptoms scores (TNSS) were required to be at least 42 on the morning of the randomisation visit plus 3 of the 4 previous days (out of a possible 84). Twelve-hour reflective symptom assessments were performed on waking and before going to bed (0=absent, 3=severe). The primary efficacy parameter was the mean TNSS for triamcinolone versus fluticasone. Secondary parameters included the mean score for each nasal symptom and each ocular symptom, and patient discontinuations due to lack of efficacy. The primary analysis of the health related quality of life (HRQL) data was differences between the two groups at study endpoint. No patients withdrew from the study because

8 Page 8 of lack of efficacy. There were no significant differences between the triamcinolone and fluticasone groups in the mean change from baseline for daily TNSS overall (49.4% and 52.7%, p=0.3323) or at any weekly timepoint. There were also no significant differences between the two groups in any individual symptom score at any time period, except for a greater reduction in sneezing score at week 2 with fluticasone (p=0.046). There was no significant difference in the incidence of side effects between the groups. Significantly more patients in the triamcinolone group complained of medication running out of the nose (though this would not be expected because of its thixotropic properties) and sneezing (p and p respectively), while more patients in the fluticasone group complained of medication smelling bad (p ) and burning and stinging (p ). RQLQ scores fell from 3 to 4.5 (moderately to very troubled) at baseline to 1 to 2 (hardly to somewhat troubled) at week 3. There were no significant differences between triamcinolone and fluticasone with regard to safety and efficacy. This reinforces the need to distinguish drug potency from clinical efficacy. Berger et al compared triamcinolone with fluticasone in a randomised, parallel-group, multicentre, single-blinded, active controlled study in 295 patients aged 12 to 70 years. 17 The RQLQ was filled out before enrolment and after the three week treatment period. The RQLQ comprised 28 items in 7 dimensions (activities, emotions, eye symptoms, nasal symptoms, non-hay fever problems, practical problems, sleep). All patients submitted nasal symptom diary cards on which they assessed their nasal symptoms twice a day. A sensory attributes questionnaire (SAQ) was used to evaluated medication attributes such as odour, taste and comfort associated with each product (0=none at all, 100=extreme amount). The primary efficacy parameter was the mean TNSS for triamcinolone versus fluticasone. Secondary efficacy parameters included the mean score for each individual nasal symptom, and the patient dropout rate due to lack of therapeutic effects. No patient discontinued because of either adverse events or lack of efficacy. Both drugs were equally as effective in improving all nasal symptoms, and TNSS were significantly reduced from baseline (p<0.05). There were no significant differences between the treatments during any week or overall. Baseline RQLQ scores ranged from 2.3 to 4.4 ( somewhat troubled to quite a bit troubled ), compared with end-of-study scores ranging from 1.1 to 2.2 ( hardly troubled to somewhat troubled ). There were no significant differences in mean overall RQLQ scores (p=0.54) or in individual domain scores between treatments. All changes were statistically significant compared with baseline (p<0.001). The only difference in the SAQ was significantly less odour with triamcinolone compared with fluticasone (12.3 vs. 40.7, p<0.0001). Both treatments were well tolerated, with headache as the most frequently reported adverse event (6.8% in the triamcinolone group, 4.1% in the fluticasone group). There were no statistically significant differences between treatments for incidence or severity of adverse events. Scores for nose bleeds and nasal irritation were higher with fluticasone than with triamcinolone (20.1 and 4.0, compared with 16.6 and 1.6). Fluticasone 200mcg daily / Beclometasone 168 mcg twice daily Ratner et al carried out a multicentre, randomised, double-blind, placebo-controlled, parallel-group, two-week study in 313 adults. 21 Chlorphenamine 4mg tablets were provided as rescue medication. Adults with a two-year history of SAR and a total score of four nasal symptoms (nasal obstruction, rhinorrhoea, sneezing, nasal itching) of 200 out of 400 on at least four of the seven days preceding treatment, were eligible for trial inclusion. Symptoms were recorded on a visual analogue scale, where 0= no symptoms and 100 = severe symptoms. Total nasal symptom scores were evaluated similarly by patients and clinicians. The scores were significantly improved (i.e. decreased) after seven days of treatment with fluticasone or beclometasone compared with placebo (clinician-rated, p<0.001; patientrated, p<0.01). The scores increased after stopping treatment but still remained significantly lower than those seen with placebo treatment. The differences in scores between the beclometasone and fluticasone groups were minimal and not statistically significant. Overall response to treatment was signifi-

9 Page 9 cantly better in the active treatment groups compared with placebo (p<0.001). During the final week of treatment rescue medication was used by 32% to 36% of patients receiving fluticasone or beclometasone compared with approximately 50% of patients in the placebo group (active vs. placebo, p<0.05; no statistically significant difference between the active groups). No significant differences in adverse events were seen between the treatment groups, though more patients using fluticasone had blood in their mucus or nasal burning. Fluticasone and beclometasone were equally effective as judged by no statistically significant differences for any clinician- or patientrated efficacy variable during the study. Total nasal symptoms scores improved after two doses of either study medication, compared with placebo. Budesonide 128mcg or 256mcg daily / Fluticasone 200mcg daily Stern et al 22 compared the efficacy of budesonide with fluticasone in 602 adults in a two-centre, blinded, placebo-controlled, parallel-group, randomised 4-6 week study. Terfenadine (60mg -120mg daily) and sodium cromoglicate eye drops were allowed as rescue medication. Daily diary records were kept to record symptoms, number of puffs of nasal spray and use of rescue medication. The study was powered to detect a treatment difference between active treatment groups of 0.2 on individual symptom scores. Analysis was carried out on an all patients treated approach. The primary efficacy variables were individual treatment scores and the patients overall assessment of treatment efficacy. Compliance was comparable across all four treatment groups ( puffs/day). Withdrawals were mainly for reasons unrelated to disease deterioration or adverse events. The use of eye drops increased in all treatment groups, with no significant difference between the groups, and the use of antihistamine tablets fell by approximately 50% in the active treatment groups, compared with an approximate doubling in the placebo group. Significant reductions from baseline in all individual nasal symptoms (blocked nose, runny nose and sneezing) were seen in the active treatment groups (p<0.001 vs. placebo) whilst patients in the placebo group experienced an increase in all symptom scores. The only significant difference between the active treatment groups was seen in the reduction of sneezing scores with budesonide 256mcg (-0.54) and fluticasone (- 0.45), in favour of budesonide (p=0.04). The differences between the active and placebo groups in the changes in combined nasal symptoms scores from baseline (-1.29 with budesonide 128mcg, with budesonide 256mcg, with fluticasone, and with placebo) and in the amount of symptom control (85%, 88%, 82% and 31% respectively) were statistically significant (p<0.001 for both). There was a trend towards a greater reduction with budesonide 256mcg (p=0.06). On days when the pollen count was higher (>10 grains/m 3 ) significantly greater reductions were seen with budesonide 256mcg with respect to combined nasal symptom scores (p=0.04 vs. fluticasone), runny nose (p=0.04 vs. fluticasone and p=0.05 vs. budesonide 128mcg) and sneezing (p=0.02 vs. both fluticasone and budesonide 128mcg). The results showed a trend towards greater combined symptom control with the higher dose of budesonide, whilst the lower dose was as efficacious as fluticasone 200mcg/day. Beclometasone 336mcg daily / Flunisolide 200mcg daily The relative effectiveness and safety of beclometasone, flunisolide and cromolyn sodium were compared in 120 patients in a placebocontrolled, blinded, randomised two month study. 23 Beclometasone, flunisolide and placebo were administered as two puffs in each nostril twice a day; cromolyn was given four times a day. Beclometasone and placebo were administered in a double-blind manner, whilst flunisolide and cromolyn were administered in a single-blind manner. Daily symptoms and supplemental antihistamine use were recorded in a diary. Of the 13 patients that withdrew from the study, two each were in the flunisolide and beclometasone groups. Diary data was used to calculate symptom scores, which were augmented when supplemental antihistamine

10 Page 10 or decongestants were used; additional therapy was used by 6/30 in the flunisolide group and 9/28 in the beclometasone group, compared with 17/27 in the placebo group (and 14/28 in the cromolyn group). All active treatments were superior to placebo in controlling hay fever symptoms (p<0.001) according to patient diaries. Flunisolide and beclometasone were also superior to cromolyn in controlling symptoms (p<0.001). The flunisolide-treated patients reported fewer symptoms than those treated with beclometasone, but the differences were not statistically significant. On physical examination by a clinician, those patients treated with corticosteroids had less severe symptoms than the placebo- (p<0.001) and the cromolyn- (p<0.05) treated patients. No difference in symptom control was found between the two corticosteroids. Flunisolide was significantly more effective than placebo in alleviating eye symptoms (p<0.05). Significantly more patients in the flunisolide group (10/30) reported nasal burning (p<0.001). The authors consider the results reliable despite the differences in blinding. Strict double blinding would have required triple-dummy design: this would be impractical as the patient would have had to administer more than one nasal spray several times a day. PERENNIAL ALLERGIC RHINITIS Mometasone 200mcg daily/ Fluticasone 200mcg daily Mandl et al carried out a randomised, doubleblind, placebo-controlled, double-dummy, parallel group multicentre 12 week study in 548 patients aged 12 years. 24 Patients must have demonstrated at least moderate (score of 2 on a 4 point scale 0-3, none severe) rhinorrhea and/or congestion, and a total nasal symptom score of at least 5. Loratadine 10mg once daily could be used as rescue medication for intolerable symptoms. The primary efficacy variable was the patients average change from baseline in total AM plus PM diary nasal symptom score over the first 15 days of treatment. The secondary efficacy variables were total diary nasal symptoms scores averaged over 15-day intervals beyond day 15, all other composite total and individual diary symptoms scores, number of symptomfree days, physician evaluated perennial rhinitis symptoms at visits, evaluation of overall condition, and use of rescue medication. Nasal symptoms assessed were discharge, congestion, sneezing and itch. Both active treatments were significantly better than placebo (p<0.01) in improving symptoms at all time points. Differences in the changes in symptoms between the mometasone and fluticasone groups were not statistically significant at any time period (p 0.43). The mean reductions from baseline in physician-rated overall condition at the end of the study were 55% (mometasone) and 47% (fluticasone). The overall condition in mometasone-treated patients was significantly better than that for fluticasone at weeks 8 and 12 (p=0.04). Both active treatments maintained statistically significant effectiveness during the offset period. There were no statistically significant differences between the groups with respect to rescue medication used and side effects (epistaxis, headache, nasal burning or irritation). The rates of rescue medication were similar between the treatment groups (54% for mometasone and 57% for fluticasone) and lower than that in the placebo group (71%).

11 Page 11 Fluticasone 200mcg daily, or 100mcg twice daily / Beclometasone 168mcg (equivalent to 100mcg) twice daily Van As et al carried out a randomised, multicentre, double-blind, placebo-controlled, parallel-group, six-month study in patients years of age. 25 The severity of nasal symptoms was scored by clinicians at each visit and by patients at the end of each day, on a numerical scale. Effectiveness of treatment was assessed on an 8-point scale (significant/ moderate/ mild improvement, no change, mildly/ moderately/ significantly worse, un-evaluable). Before treatment clinician-rated mean total nasal symptoms scores were similar among all four treatment groups and ranged from , indicating moderate to severe nasal symptoms. After seven days of treatment mean scores had improved by points in the active treatment groups, compared with only 18 points in patients on placebo (p<0.05). After 24 weeks of treatment at least a 45% improvement in symptoms was seen in patients on active treatment compared with 30% in those on placebo. With the exception of one time point, mean total nasal symptom scores were significantly lower in patients receiving active treatment compared with placebo. Clinician-rated individual scores for obstruction, rhinorrhea, sneezing and itching were improved in patients on active treatment compared with placebo. There were no significant differences in any clinician-rated nasal symptom score between the fluticasone and beclometasone groups. For patient-rated nasal symptom scores, the mean scores fell from ~200 to 110 points at week 24, a reduction of 45%, compared with 29% in the placebo group. Patterns of change with individual symptoms were similar to those seen in the clinician-rated scores. Fewer patients in the fluticasone or beclometasone treatment groups used rescue medication, compared with placebo, but the differences were not statistically significant. More patients in the fluticasone twice daily and beclometasone groups suffered from blood in nasal mucus (p<0.05). There were no significant differences between the once and twice daily fluticasone dosing regimens for any efficacy evaluation. Fluticasone was as effective as beclometasone for treating perennial allergic rhinitis. Triamcinolone 220mcg daily / Beclometasone 168mcg twice daily Grubbe et al 26 carried out a multicentre, single-blind, randomised, parallel-group 4 week study in 313 patients aged years. Five rhinitis symptoms were evaluated each evening on a 4 point scale (0=none, 3 = severe) before and during the study. Patients with 24 points at the end of the baseline period were eligible for study entry. After two and four weeks a global evaluation of treatment effectiveness relative to the drug-free baseline period was made. The primary efficacy variable was the change from baseline in the mean total nasal symptom score. Secondary efficacy variables included the change from baseline for each nasal symptom and the results of the physician global evaluation of symptom relief. Onset of action was assessed by the changes from baseline in the scores during the first seven days. One patient (in the triamcinolone group) discontinued due to lack of efficacy. There were no statistically significant differences between the two treatments in changes in mean total nasal symptom scores (-4.3 with triamcinolone and -3.9 with beclometasone) or in the individual symptom scores or in the physicians rating of the relief of rhinitis symptoms. Significantly more patients in the beclometasone group than the triamcinolone group complained of medication running down the throat or out of nose (54% and 33% vs. 16% and 6% respectively, p=0.001 for both). Severity scores for three specific treatment-related side effects (medication running out of nose and running down throat and bad medication taste) were significantly higher in the beclometasone group (p=0.0024). Adverse events related to the study medication occurred more frequently in the beclometasone group (22% of patients) compared with the triamcinolone group (16%). Only two adverse events were considered to be remotely related to the medication. Both drugs were effective and well tolerated, though some specific treatment-related side effects occurred more frequently or were more bothersome with the beclometasone spray.

12 Page 12 Budesonide 256mcg daily / Fluticasone 200mcg daily Day et al compared the efficacy of the two corticosteroids in 273 adult patients with at least a one-year history of PAR. 27 The sixweek study was of a parallel-group, randomised, placebo-controlled and blinded design. Loratadine 10mg could be used as rescue medication if symptoms became intolerable. Patients recorded symptoms every evening, scored on a 4-point scale (0=no symptoms, 3=severe symptoms). The primary efficacy variable was the score of 3 individual nasal symptoms (blocked nose, runny nose and sneezing). After three and six weeks patients were asked to evaluate the efficacy of their medication, and asked if they had experienced any adverse events. The reduction from baseline in mean nasal symptom scores were for budesonide (p< vs. placebo and p=0.03 vs. fluticasone) and for fluticasone (p= vs. placebo). However, the patients overall evaluation of the treatment efficacy did not differ significantly between the budesonide and fluticasone groups and both active treatment groups were better than placebo. A similar incidence of adverse events were seen in both treatment groups though budesonide use was associated with a higher rate of bloody nasal discharge (18% of patients compared with 7%). Budesonide was more effective at controlling nasal blockage (score reduced by 0.75 compared with 0.5 with fluticasone, p=0.009), and the study suggests that it has a faster onset of action than fluticasone, though it was not designed to determine this. There were no statistically significant differences between the rates of adverse events. Two patients in the budesonide group and one in the fluticasone group withdrew because of symptom progression. The use of rescue medication fell from 1.14 to 0.40 tablets/week in the budesonide group, from 1.16 to 0.42 tablets/week in the fluticasone group and from 1.05 to 0.83 tablets/week in the placebo group. The reductions from baseline were statistically significant but there was no statistically significant difference between the active treatment groups. Budesonide 128mcg or 256mcg daily / Mometasone 200mcg daily Adults (n=438) over the age of 18 years were enrolled into a randomised, multicentre, placebo-controlled, parallel-group four-week study. 28 Loratadine 10mg daily could be used as rescue medication. Symptoms were recorded on a 4 point scale (0=no symptoms, 3=severe symptoms) every morning and evening, and individual scores were summed to produce a Nasal Index Score (NIS). The primary efficacy variable was the NIS, the secondary efficacy variables were the individual nasal symptoms scores. All three treatments significantly reduced the NIS and each individual symptom score compared with placebo, but there were no significant differences between the active treatments. Statistically significant improvements in NIS, compared with placebo, were measurable 4 hours after the first dose (p=0.046, budesonide 256mcg, p=0.01, budesonide 128mcg and p=0.014, mometasone). Significantly better symptom control was achieved with active treatment (p<0.002). The proportion of patients experiencing no symptom control was 25% in the placebo group, compared with 5.9% (budesonide 256mcg), 10.1% (budesonide 128mcg) and 7.6% (mometasone). There was no significant difference between the active treatments in terms of symptom control. Mean weekly consumption of rescue medication was 0.93 tablets (budesonide 256mcg), 1.18 (budesonide 128mcg), 1.31 (mometasone) and 1.23 (placebo). Peak nasal inspiratory flow rates (PNIF) were significantly (p<0.01) improved with active treatment compared with placebo. The effects of budesonide 256mcg on PNIF were significantly greater than the other two (p<0.05) and, during the first 10 days, were approximately twice those of the other two. PNIF provide a convenient and reproducible measure of nasal patency during therapeutic interventions. Eleven patients withdrew because of adverse events (mainly infections). The adverse events were mainly mild or moderate. A higher incidence in epistaxis was seen in the active treatment groups, but this was not statistically significant.

13 Page 13 Budesonide 256mcg daily/ Beclometasone 336mcg daily A 12 month, open-label, parallel-group study was carried out to evaluate the efficacy and safety of intranasal budesonide and beclometasone in 24 patients (>15 years). 19 Budesonide was administered twice a day and beclometasone was administered four times a day, which precluded the use of a doubleblind design. Nasal blockage, runny nose and sneezing were graded according to a 4 point scale (0=none, 3=severe). At study entry all of the patients had at least one nasal symptom (blockage, runny nose or sneezing) and regarded them as moderate-severe. The mean total symptom score at baseline was 4.67 in the budesonide group and 4.42 in the beclometasone group. Patients in both treatment groups experienced a reduction in the severity of nasal symptoms. This was statistically significant at all visits for all symptoms in the budesonide group and in the beclometasone group for nasal blockage and runny nose at most visits. The total nasal symptom score showed a statistically significant decrease from baseline at all visits in both groups, but at 6 and 12 months was significantly greater in the budesonide group (p<0.05). No significant changes in mean plasma cortisol levels were seen between study entry and subsequent visits. Both drugs were effective in the long term treatment of PAR but only budesonide provided a significant reduction in the sneezing score throughout the one-year treatment period; in the beclometasone group this was only significantly reduced at the 6 month visit. Compliance was not measured in this trial. It is possible that the four-times a day administration of beclometasone may have affected compliance and the efficacy results. A more objective comparison would have been achieved if a twice-daily dosing regimen was used. Mometasone 200mcg daily / Beclometasone 400mcg daily This was a randomised, double-blind, placebo-controlled, parallel group, multicentre 12 week study comparing once daily mometasone with twice daily beclometasone in 427 patients aged 12 years. 29 In order to qualify for randomisation patients must have demonstrated at least moderate rhinorrhoea and/or congestion (score of 2 on a 4-point scale of 0-3) and a total nasal symptoms score of at least 5. Loratadine 10mg was used as rescue medication. Individual daily symptom and rescue medication usage diaries were kept. The primary efficacy comparison was comparing mometasone to placebo, with respect to the primary efficacy variable, which was the patient s average change from baseline in total nasal symptom scores over the first 15 days of treatment. Secondary efficacy variables consisted of total daily nasal symptom scores averaged over 15 days intervals after the first 15 days. Pairwise comparisons between mometasone and beclometasone were also conducted. The use of rescue medication was taken into account when calculating the symptoms scores. A total of 55 patients withdrew from the study because of treatment failure, 26 in the placebo group and 15 and 14 patients in the mometasone and beclometasone groups. Adverse events related to the study drug led to the withdrawal of 16 patients; 8 in the mometasone group, 6 in the beclometasone group and 2 in the placebo group. The most frequently reported adverse event was epistaxis (19% in the mometasone group and 23% in the beclometasone group). The mean total nasal symptom diary score at baseline was approximately 7 out of a possible maximum score of 12. The mean percentage reductions from baseline for each 15-day period ranged from 25%-52% for mometasone, 30%-56% for beclometasone and 15%-38% for placebo. Mometasone and beclometasone produced a significantly greater (p 0.01) improvement in total nasal symptoms compared with placebo. The physicians-rated reductions in nasal symptoms scores ranged from 34%- 58% with mometasone, 40%-60% with beclometasone and 20% to 47% with placebo. Both active treatments were statistically significantly superior to placebo. The use of rescue medication was not statistically different between the groups (48% in the mometasone group, 46% in the loratadine group and 56% in the placebo group).

14 Page 14 The difference between mometasone and beclometasone in nasal symptoms scores was not statistically different at any time point (p 0.32). Patients demonstrating complete or marked relief of symptoms were similar at week 12 (54% for mometasone and 53% for beclometasone). The highest percentage of patients in the placebo group with marked/ complete relief was 37% at 1 month. There was also no difference in 24 hour control between the two active treatments, demonstrating that once daily mometasone was comparable to twice daily beclometasone. PATIENT PREFERENCES When agents in a given treatment class have similar efficacy and safety profiles, other product attributes can play a pivotal role in choosing a product. Measurement of sensory perceptions can distinguish a drug from a group of equally effective drugs belonging to the same class. 30 Comparisons of the sensory attributes of INSs are warranted because patients are less inclined to use the prescribed treatment if the sensory attributes are deemed unfavourable. 6 Currently available INSs contain additives and preservatives that prevent bacterial growth, absorb extra water and maintain appropriate moisture levels. Some can irritate or dry nasal tissue, and /or lead to hypersensitivity. 31 The different formulations of INSs can vary in composition and concentration of additives and preservatives and will have varying degrees of effect on the nasal mucosa. Benzalkonium chloride is a surfactant used as a preservative. 31 It is a skin irritant, though the effects on the nasal mucosa are unclear, and has an unpleasant bitter taste. It may affect ciliary movement, though reports from in vitro and in vivo studies are mixed. The nasal toxicity of benzalkonium chloride may be neutralised by nasal secretions. Long term use of nasal sprays that contain benzalkonium chloride appears to increase the susceptibility to rhinitis medicamentosa (inflammation of the nasal mucosa caused by rebound vasodilation subsequent to long-term use of intranasal vasostricting agents). Potassium sorbate inhibits microbial growth and is used as a preservative. 31 It is physiologically inert and has a neutral taste. No adverse effects have been associated with its use in INSs in humans. Alcohols are used to enhance the sensory attributes of nasal sprays. 31 Alcohol may irritate and cause drying of the mucosa. Polysorbates Table 3: Excipients in intranasal corticosteroid formulations 32 Beclometasone Beconase Budesonide Rhinocort Aqua Flunisolide Syntaris Fluticasone propionate Flixonase Fluticasone propionate Nasofan Mometasone furoate Nasonex Triamcinolone acetonide Nasacort Benzalkonium chloride - Potassium sorbate Phenylethyl alcohol Polysorbate 80 Propylene glycol Polyethylene glycol Carboxymethylcellulose Microcrystalline cellulose - -

15 Page 15 are surfactants and emulsifying agents which can cause contact allergy or hypersensitivity. 31 Propylene glycol is used with polyethylene glycol as wetting agents. 31 Contact dermatitis can be caused by propylene glycol; a new formulation of flunisolide which contained a lower percentage of propylene glycol was associated with reduced nasal burning and stinging (though still higher than with other INSs). Thixotropic agents, such as carboxymethylcellulose, confer high viscocity to the suspension, but as they have a drying effect, may contribute to the increased rates of epistaxis. 31 The Nasal Spray Evaluation Questionnaire (NSEQ) was used in a number of the following studies. This questionnaire was used to evaluate the acceptability of the drug and associated sensory perceptions immediately after drug administration (10 items) and 2 minutes later (4 items). The attributes were scored on a 100 point scale (0=not at all comfortable/none at all to 100 = extremely comfortable/an extreme amount). In the following studies before and in between each drug administration all patients were asked to rinse their mouth thoroughly with water, chew unsalted crackers and smell a swatch of wool cloth in order to cleanse their palates. The following trials were the observations of a one-time administration of the medications, and there were no follow-ups on symptom control or compliance after the trials. There appears to be no clearly preferred INS: in the first two studies triamcinolone was preferred over fluticasone, which was preferred over mometasone (TAA>FLU>MOM), in the third study budesonide was preferred over fluticasone (BUD>FLU), and the preferences in others studies were MOM>BUD>FLU>BEC, TAA>BEC>FLU and BEC=FLUNIS. No study has compared all available INSs. Triamcinolone, fluticasone and mometasone Stokes et al 6 compared product attributes, preferences and expected compliance of triamcinolone acetonide aqueous 220mcg/day or fluticasone propionate 200mcg/day or mometasone furoate 200mcg/day using pooled data from two identical multicentre, randomised, double-blind, crossover studies (n=215). There were six possible drug administration sequences. There was a 30 minute waiting period between the administrations of each corticosteroid, where patients were advised to cleanse their palates. The primary study measures were the questions on the NSEQ. The Overall NSEQ (ONSEQ) was used to evaluate overall patient preference and expected treatment compliance. Triamcinolone was rated more favourably than fluticasone for many of the sensory attributes and more favourably than mometasone for nearly all of them (see table 3). Mean scores for the overall index differed significantly for triamcinolone (78.6) versus fluticasone (72.3) and mometasone (69.3), (p<0.001). Twice as many patients (50%) preferred triamcinolone to be prescribed compared with fluticasone and mometasone (25.0% for each, p<0.001 vs. triamcinolone). More patients reported that they would definitely comply with taking triamcinolone (62.5%) than fluticasone (49.0%) or mometasone (51.0%), p<0.01. Bunnag et al 33 also compared medication preferences and sensory perceptions of triamcinolone, fluticasone and mometasone nasal sprays in a multicentre, double-blind, randomised, crossover study in 364 adult patients. Between test medications patients cleansed their palates and rested for 30 minutes before the next application. The drugs were rated on the NSEQ. Triamcinolone acetonide was perceived to be significantly more comfortable than fluticasone and mometasone (p=0.0406) and had a significantly lower and preferable odour (p<0.0001). Although no significant differences in the taste detection, strength of taste and liking the taste were seen, triamcinolone was preferred more. The patients overall liking was with triamcinolone (58.8%, p=0.0008) compared with fluticasone (53.2%) and mometasone (52.6%), and it was also the one that patients would prefer to have prescribed (38.2% compared with 36.8% and 24.9% respectively, p<0.0001). Mometasone was the nasal spray that the largest number of patients would least want prescribed (35.2%). When the preferred nasal spray was prescribed, 82.3% said that they would comply with a prescription for triamcinolone, compared with 39.6% for fluticasone and 20.5% for mometasone. There

16 Page 16 Table 3: Nasal spray evaluation questionnaire results for the Stokes et al study 6 Sensory attribute Triamcinolone Fluticasone Mometasone P value * Immediately after administration: (0=not at all comfortable/none at all, 100 = extremely comfortable/an extreme amount) Overall comfort during administration ** Amount of medication run-off Amount of irritation ** Strength of urge to sneeze Odour strength <0.001 Liking of odour <0.001 Strength of taste <0.001 Bitter taste ** Liking taste ** 63.9 <0.001 Moist nose and throat 60.0 ** minutes after administration Strength of aftertaste <0.001 Amount of irritation ** 21.3 <0.001 Amount of medication run-off Overall liking of product ** 57.5 <0.001 p value for overall treatment difference higher score more favourable significantly different from mometasone, p<0.01 significantly different from fluticasone, p<0.01 significantly different from fluticasone, p<0.05 ** significantly different from mometasone, p<0.05 was no difference with regard to the order of the administration of the nasal sprays. Triamcinolone acetonide has been developed to have unscented, odourless and thixotropic properties, and it has been reported to be less likely than other aqueous formulations to run out of the nose and/or down the back of the throat. Patient preference for this product is reflected in the sensory perceptions of the studies by Stokes et al and Bunnag et al. Budesonide and fluticasone In two multicentre, randomised, single-blind, single-dose crossover studies Shah et al 7 compared the attributes of budesonide aqueous nasal spray (64mcg/day, 2 sprays of the 32mcg study medication) with fluticasone propionate (200mcg/day, 4 sprays, in study 1 and 100mcg/day, 2 sprays, in study 2). In each study the primary endpoint was patient preference. Patients over the age of 18, with at least a one-year history of SAR or PAR were assigned to one of two treatment sequences. Before receiving study medication patients in study 1 (n=181) rinsed their mouth out with a small cup of water, and in study 2 (n=190) they cleansed their palates as stated in previously described studies. Study 1 had a one-hour washout period between dosings; in study 2 it was a two-hour washout period. Immediately after dosing, patients completed the two-part 23-item Sensory Perceptions Questionnaire (SPQ). Part I recorded the perceptions of specific sensory attributes of the treatment and was completed after the first treatment. After a washout period (1-2 hours) and administration of the second treatment, Part I was com-

17 Page 17 pleted again to record their perceptions of the second treatment, and Part II was completed to determine their overall (global) preference of the sprays. Part I questions were either yes/no answers or rated on a scale of 1 (strongest perception or greatest dislike) to 5 (weakest perception or greatest like). In study 1, patients were less likely to perceive any scent, taste, aftertaste, medicine run-down into nose and throat (p<0.001 for all) or medicine run-out of nostrils (p<0.019) when using budesonide compared with fluticasone. The lower spray volume of budesonide may have contributed to the significant difference in medicine run-down and run-out. The licensed dose of Rhinocort is one or two 64mcg-sprays in both nostrils, daily. In study 2, patients were also significantly less likely to perceive any scent or taste (p<0.001) when using budesonide compared with fluticasone; no differences were found between products for aftertaste, medicine run-down or medicine run-out. In both studies more patients perceived the budesonide spray to be less wet in both their nose and throat and preferred the feel of it in both the nose and throat compared with fluticasone (see table 4). The budesonide spray was perceived to be less forceful than that of fluticasone, and was preferred. Not all the patients expressed a preference for 1 of the 2 treatments, but budesonide was the preferred treatment for those who did. Fluticasone propionate contains benzalkonium chloride, a preservative with a bitter taste, and phenylelthyl alcohol, an additive with a floral scent; budesonide does not contain either of these and may influence patient preference. 7 Beclometasone, budesonide, fluticasone and mometasone In this study by Khanna et al 34 the preference and acceptability of four INSs (beclometasone, budesonide, fluticasone and mometasone) was compared in 125 adults. Sensory attributes were assessed using the NSEQ. Each patient was randomly assigned to one of the 24 possible drug sequences of budesonide 400mcg (BUD), beclometasone 200mcg (BDP), fluticasone 200mcg (FP) and mometasone 200 mcg (MF). Before and in between each drug administration all patients cleansed their palates. They were then administered two actuations of the drug in each nostril in the designated sequence, with 30 minutes between each drug. Patients were asked to rate 10 sensory attributes immediately after drug administration. Two minutes Table 4: Sensory Perceptions Questionnaire results for the Shah et al study 7 Budesonide Fluticasone P value Attribute Study 1 Study 2 Study 1 Study 2 Study 1 Study 2 Degree of perception of sensory attribute (mean score, rated 1-5) Feel in throat P<0.004 P<0.002 Feel in nose P<0.001 P<0.001 Spray force P<0.001 P<0.001 Like/dislike of sensory attribute (mean score) Feel in throat P<0.001 P<0.006 Feel in nose P<0.001 P<0.001 Spray force P<0.002 P<0.001 Overall satisfaction based on the sensory features Mean score P<0.001 P<0.015 Global preference all patients including those who did not express a preference Percentage 54.4% 47.4% 37.8% 41.1% P<0.022 NS Global preference patients who expressed a preference Percentage 59% 53.6% 41% 46.4% P=0.021 NS

18 Page 18 later patients were then asked a second set of questions regarding their overall preference, if they could distinguish differences between the nasal sprays, the strongest attribute affecting their choice and whether this would affect their compliance. Patients were classified as sneezers and runners (63%, sneezing and rhinorrhea as main symptoms) or blockers (37%, nasal blockage and postnasal drip as main symptoms). Significant differences between the INSs were seen in 6 of the 14 sensory attributes (see table 5). Overall comfort was similar for all 4 drugs but mometasone was considered most comfortable. The taste of mometasone was the weakest and most preferred. Overall and also when comparing sneezers and runners with blockers, a significant preference was shown for mometasone (54%, 56% and 50% respectively) because of superior moistness, less irritation, liking of odour and less aftertaste. Liking the odour was the strongest attribute that affected choice in the sneezers and runners group, whilst strength of aftertaste was the strongest attribute affecting choice in the blockers group. Fluticasone was less liked because of significantly more Table 5: Nasal Spray Evaluation Questionnaire results for the Khanna et al study 34 NSEQ attribute BDP BUD FP MF Significance Immediately after administration: mean attribute rating (0=not at all comfortable/none at all, 100 = extremely comfortable/an extreme amount) Overall comfort during administration NS Amount of medication run-off NS Amount of irritation MF<FP* MF<BDP* MF<BUD** Strength of urge to sneeze NS Odour strength Liking of odour FP>BUD** FP>BDP** FP>MF** MF>BDP** MF>BUD** MF>FP** Strength of taste NS Bitter taste NS Liking taste NS Dry vs. moist sensation MF>BDP** MF>BUD** MF>FP** 2-5 minutes after administration: mean attribute rating Strength of aftertaste Amount of medication run-off NS Amount of irritation NS Overall liking of product Most preferred drug 9% 22% 16% 54%** *p<0.01, **p<0.05, NS = not significant MF<BDP* MF<BUD** MF<FP** MF>BDP** MF>FP* MF>BUD*

19 Page 19 irritation and strength of odour. The majority of patients (72%) could appreciate the difference in the attributes of the four nasal sprays and 80% predicted a better compliance with their preferred drug. Triamcinolone, beclometasone and fluticasone Gerson et al 30 et al conducted a randomised, cross-over trial to evaluate the acceptability of triamcinolone, beclometasone and fluticasone nasal sprays. Patients (n=94) were randomly assigned to one of six drug sequences. Prior to administration of the test drug patients cleansed their palates. A 30 minute interval separated out the drug administrations. Sensory attributes were assessed using the NSEQ. The odour of triamcinolone was preferred over the other two sprays and although the taste intensities were not significantly different, the patients preferred the taste of triamcinolone. The overall liking of triamcinolone was higher than that of fluticasone (p<0.05) and beclometasone (not significant). Results are shown in table 6. The order that the drugs were administered did not affect the mean ratings for each product. Beclometasone and flunisolide Flunisolide has been shown to be equally as effective as aqueous beclometasone nasal spray in relieving symptoms of allergic rhinitis. Conley 35 compared the nasal irritation of the two products in a double-blind, crossover study in 100 adults. Two puffs of the study drug were administered in the specified nostril, after which a visual analog scale indicating the degree of nasal burning/stinging experienced was completed (0=none, 99=severe). There were four medication sequences, e.g. Group 1: 1 st beclometasone in the right nostril, 2 nd flunisolide in the left nostril; Group 2: 1 st beclometasone in the left nostril, 2 nd flunisolide in the right nostril. An interview with an investigator Table 6: Nasal Spray Evaluation Questionnaire results for the Gerson et al study 30 NSEQ Beclomethasone Triamcinolone Fluticasone P value Immediately after administration: mean attribute rating (0=not at all comfortable/none at all, 100 = extremely comfortable/an extreme amount) Overall comfort during administration NS Amount of medication run-off NS Amount of irritation NS Strength of urge to sneeze NS Odour strength Liking of odour Strength of taste NS Bitter taste NS TAA<BDP, p<0.001 TAA<FP, p<0.001 TAA<BDP, p<0.001 TAA<FP, p<0.001 Liking taste TAA<FP, p<0.04 Moist nose and throat TAA<BDP, p< minutes after administration: mean attribute rating Amount of irritation NS Amount of medication run-off Overall liking of product NS TAA>FP, p<0.05

20 Page 20 querying for any other problems followed. After 15 minutes (no nasal cleansing was performed as only one drug was administered per nostril), the other study drug was administered. An overall preference evaluation was performed at the end of the study. The order of drug administration did not affect the results. No significant difference between the degree of nasal airway irritation caused by either drug was found. Study drug acceptance was not affected by sequence or spray. Both sprays were highly acceptable to 64% of patients, whilst 12% found flunisolide acceptable and beclometasone unacceptable, and 18% found beclometasone acceptable but not flunisolide. Cost Studies and comparison trials have found that intranasal corticosteroid demonstrate approximately the same level of efficacy for treating the symptoms of AR. They are also safe and generally well tolerated. They do differ on sensory attributes (taste, smell etc), which influence patient preference for one product above another. The recommended starting and maintenance doses of the preparations vary and there may be an economical advantage of certain products over others. The prescription duration of the individual preparations varies because the prescribed daily dosage varies as well as the pack size. In table 7 below the prescription duration and the approximate price/day relate to the maintenance dose. Table 7: Doses and costs of intranasal corticosteroids Strength / adult dose 8 Sprays/ day Pack size Rx Duration Price Approx price/day Beclometasone Beconase (prescription pack) Beclometasone Non-proprietary Beconase hayfever (OTC product) 2 x50mcg sprays into each nostril bd, reduce to 1 spray in each nostril bd once control achieved 8 reduced to dose 50 days 200 dose 50 days 100 dose 25 days sprays = 4p (category M) 4 sprays = 9p sprays = 24p Budesonide Rhinocort Aqua 2 x64mcg sprays into each nostril od, or 1 spray into each nostril bd, reduce to 1 spray into each nostril od once control achieved 4 reduced to dose 60 days sprays = 7.5p Budesonide Non-proprietary 2 x100mcg sprays into each nostril od, or 1 spray into each nostril bd, reduce to 1 spray into each nostril od once control achieved 4 reduced to dose 100 days sprays =6p Flunisolide Syntaris 2 x25mcg sprays into each nostril bd, increased to tds if necessary, then reduced for maintenance max 24mls (240 doses) 30 days sprays = 17p Fluticasone Flixonase Fluticasone Nasofan 2 x50mcg sprays into each nostril od, increased to bd if required, reduced to 1 spray into each nostril od when control achieved 4 8, reduced to dose 75 days 150 dose 75 days sprays = 15p sprays = 14p Mometasone Nasonex 2 x50mcg sprays into each nostril od, increased to 4 sprays if necessary, reduced to 1 spray into each nostril od when control achieved 4 8, reduced to dose 70 days sprays = 11p Triamcinolone - Nasacort 2 x55mcg sprays into each nostril od, reduce to 1 spray into each nostril od when control achieved 4 reduced to dose 60 days sprays = 12p