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1 New Medicines Profile November 2013 Issue No. 13/03 / Nasal Spray (Dymista ) Concise evaluated information to support the managed entry of new medicines in the NHS Summary /fluticasone nasal spray (Dymista ) combines two drugs that are currently used to treat rhinitis symptoms. The product contains 137micrograms of azelastine hydrochloride (antihistamine) and 50micrograms of fluticasone propionate (corticosteroid) per spray. The dose is one spray in each nostril twice daily. /fluticasone nasal spray is indicated for relief of symptoms of moderate to severe seasonal or perennial allergic rhinitis if monotherapy with either antihistamine or corticosteroid alone is not sufficient. It is not licensed for use in children under 12 years. Trials in patients with moderate to severe seasonal rhinitis found a greater reduction in patient-rated nasal symptom scores (primary outcome) in those using azelastine/fluticasone (28.4%) than either of the component drugs used alone (fluticasone 20.4%; azelastine 16.4%; placebo 11.2%). Ocular symptom scores (secondary outcome) were reduced similarly by 26.6%, 17.5%, 21.2% and 10.5% respectively. Quality of life scores (secondary outcome) improved with all active treatments. Differences between azelastine/fluticasone compared with either drug alone were small, but compared with placebo was considered clinically significant. No trials have compared azelastine/fluticasone with nasal steroid plus oral antihistamine, the most widely used treatment for rhinitis. /fluticasone nasal spray costs more than other nasal sprays for rhinitis, or the two drugs prescribed separately. Brand Name, (Manufacturer): Dymista (Meda) BNF Therapeutic Class: Drugs used in nasal allergy Licensed Indications: Relief of symptoms of moderate to severe seasonal and perennial allergic rhinitis if monotherapy with either intranasal antihistamine or glucocorticoid is not considered sufficient. Dosage and Administration: Adults and adolescents aged 12 years and older: one actuation in each nostril (morning and evening). Children below 12 years: not recommended for use as safety and efficacy not established in this age group. 1 Marketed: May 2013 Cost Comparisons: Cost for 28 days treatment with nasal sprays for rhinitis (prices from Drug Tariff & MIMS October 2013). Cost for fluticasone propionate based on Flixonase Aqueous; cost of budesonide based on Rhinocort Aqua. See Table 1 for details of doses and unit prices. N.B. Doses shown for general comparison & do not imply therapeutic equivalence. Introduction Allergic rhinitis is common and affects around 20% of the UK population. First line treatment is with oral antihistamines, according to British Society for Allergy and Clinical Immunology (BSACI) guidelines on allergic rhinitis. 2 Nasal sprays containing corticosteroids may be added if antihistamines fail to control symptoms and moderate to severe or persistent symptoms continue. Intranasal antihistamines are superior to oral antihistamines for rhinitis, but less effective for associated symptoms in the eye, pharynx, lower airways or skin. 2 Evidence Several randomised multicentre double-blind controlled trials have investigated the efficacy of this combination; of these one compared azelastine/fluticasone with similar doses of commercially-available formulations of fluticasone and azelastine nasal sprays as well as placebo (n=610 in total). 3 The trial lasted two weeks and relied on patients recording severity of nasal and ocular symptoms over the previous 12 hours, every morning and evening on a scale of 0 (no symptoms) to 3 (severe). For nasal symptoms the reflective total nasal symptom score (rtnss) was a composite of ratings for sneezing, congestion, itching and rhinorrhea. Daily rtnss therefore ranged from zero (no symptoms) to 24 (all four symptoms severe during the whole day). Ocular symptoms were rated in a similar way for itch, redness, and watery eyes. The primary endpoint was the reduction in rtnss from baseline (mean baseline score of 18 to 19 points in all groups), until the end of the trial.

2 / Nasal Spray (Dymista ) /fluticasone produced a greater reduction in rtnss (5.31, 28.4%), than either fluticasone (3.84), azelastine (3.25) or placebo (2.2) - see Appendix 1 for full details. A later analysis of the data from this trial found that a greater proportion (49.1%) of patients using azelastine/ fluticasone had a 50% or greater reduction in symptom score at Day 14 compared with 38.2% of those using fluticasone and 37.4% of those using azelastine alone (see Appendix 1 for details). 4 Three further trials compared azelastine/fluticasone with similar formulations that contained either one of the active drugs or placebo, intended to eliminate effects due to variation in device or excipients. Results were combined in a metaanalysis (n=3398 in total). 5 Reductions in symptom score were comparable to those in the trial described above (see Appendix 1). In this meta-analysis, time to response was analysed for each patient group. In the azelastine/ fluticasone group approximately 50% of the patients recorded a 50% or greater reduction in symptom scores after 2 weeks treatment, compared with approximately 45% who were using fluticasone alone. For azelastine alone this figure was approximately 35% and for placebo 25% (data from Figure 2 in the meta-analysis, statistical analysis not available). 5 The manufacturer of azelastine/ fluticasone claims a faster onset of symptom control, but this needs to be seen against the continuing improvement of symptom scores found with all treatments during the 2 week trials. 3,4,5 In the first trial described above 3, mean rtnss reductions were typically 2 points greater with azelastine/ fluticasone than either single agent from the second day and throughout the 14 day period. This corresponds to a reduction in one level of severity (e.g. from severe to moderate ) in one nasal symptom recorded in patients diaries. Secondary outcomes reported in the trials included changes in ocular symptom scores and Quality of Life measures. In the first trial described above 3, reductions in ocular scores (rtoss) after two weeks were 26.6% for azelastine/fluticasone, 17.5% for fluticasone, 21.2% for azelastine and 10.5% for placebo. 3 Results from a Rhinitis Quality of Life Questionnaire (RQLQ) in this trial improved over the 14 days, though these were modest. At the end of the two weeks, mean scores had fallen more in the azelastine/fluticasone group than placebo (1.6 vs 1.0) and as the difference was greater than 0.5 it was declared clinically significant by a previously validated scoring system. Other scores were 1.4 for fluticasone and 1.2 for azelastine. The difference between azelastine/fluticasone and fluticasone alone was not statistically significant. 3 Longer-term use of azelastine/ fluticasone in chronic rhinitis is supported by one open label study (n=612). 6,7 This compared azelastine/fluticasone against fluticasone alone for one year in patients with perennial or vasomotor rhinitis. The baseline figures for rtnss measured once a day (in the evening) were out of a possible 12 indicating milder symptoms than the seasonal rhinitis trials. Mean rtnss after 28 weeks was significantly more improved with azelastine/fluticasone than fluticasone (mean change from baseline 2.88 vs 2.53, p=0.048), but the difference was not statistically significant after 52 weeks. 6,7 Safety Adverse effects in trials include headache ( %), dysgeusia (bitter taste, due to the azelastine) ( %), epistaxis ( %) and nasal discomfort ( %). 3,5 The formulation contains benzalkonium as a preservative which may have a drying and irritant effect (also rarely hypersensitivity 8 ); other nasal sprays for rhinitis also contain this. 2 There is a possible risk of adrenal suppression associated with nasal sprays containing corticosteroids but BSACI guidelines consider fluticasone low risk in this context. 2 In the one year study, fasting morning serum cortisol was unchanged after 12 months. 6 NHS Impact Using a combined antihistamine/ corticosteroid nasal spray is moderately more effective than either of the two component drugs alone but the cost is greater than separate sprays of fluticasone or azelastine used alone or combined. Widespread first-line use of the combination for mild symptoms would lead to a significant increase in NHS costs. Use in moderate to severe symptoms which are not responsive to a single agent (corticosteroid or antihistamine), or where oral antihistamines (used with a nasal corticosteroid) cause unacceptable side effects would seem appropriate. Many patients treat symptoms with over-the-counter products, including oral antihistamines, fluticasone and azelastine nasal sprays. /fluticasone is a Prescription-Only Medicine (POM) and may lead to additional requests for NHS prescribing rather than self-treatment. Treatment failure with nasal sprays in rhinitis is common and often due to poor technique in use. 2 Administration using a head-down position is preferable, this treats the ostiomeatal complex; the head back position is less effective. 2 Regular treatment is required for full efficacy of nasal corticosteroids and maximal effect may not be seen until they have been used regularly for two weeks or more. 2 Risk Management Issues: None identified. Produced for the UK Medicines Information Service By Susan Carr, Trent Medicines Information Service The information contained in this document will be superseded in due course. Not to be used for commercial purposes. May be copied for use within the NHS.

3 / Nasal Spray (Dymista ) References 1. Meda Pharmaceuticals. Summary of Product Characteristics for Dymista Nasal Spray, dated 01/2013 accessed via the emc at: SPC/Dymista+Nasal+Spray/ on 25 Sept Scadding GK, Durham SR, Mirakian R et al BSACI guidelines for the management of allergic and nonallergic rhinitis. Clin Exp Allergy 2008;38:19-42 accessed via Sept Hampel F, Ratner P, Van Bavel J et al. Doubleblind placebo-controlled study of azelastine and fluticasone in a single nasal spray delivery device. Ann Allergy Asthma Immunol 2010;105: Melzer E, Ratner P, Bachert C et al. Clinically relevant effect of a new intranasal therapy (MP29-02) in allergic rhinitis assessed by responder analysis. Int Arch Allergy Immunol 2013;161: Carr W, Berstein J, Lieberman P et al. A novel intranasal therapy of azelastine with fluticasone for the treatment of allergic rhinitis. J Allergy Clin Immunol 2012;129: Price D, Bousquet J, Berger W et al. MP29-02 a novel intranasal therapy for the treatment of chronic rhinitis: safety data from a 12 month trial. Abstract no 872 from World Allergy and Asthma Congress, Milan, Price D, Shah S, Bhatia S et al. A new therapy (MP29-02) is effective for the long-term treatment of chronic rhinitis. J Investig Allergol Clin Immunol in press 8. Mezger E, Wendler O, Mayr S, et al. Anaphylactic reaction following administration of nose drops containing benzalkonium chloride. Head Face Med. 2012;8:29. Key papers are highlighted in bold. Table 1: Further cost detail for nasal sprays (Prices from MIMS October 2013) Dose Cost (unit price) Number of sprays/unit Cost per 28 days 137/ 50 (Dymista ) (Rhinolast ) propionate 50 micrograms/spray (Flixonase Aqueous ) furoate 27.5 micrograms/spray (Avamys ) Mometasone (Nasonex ) Budesonide (Rhinocort Aqua ) Beclomethasone dipropionate (Beconase ) once daily; maintenance one spray once daily once daily, maintenance one spray once daily once daily, may be reduced to one spray once daily once daily or one spray OTC preparations Retail price propionate (Pirinase ) (Rhinolast Allergy ) Beclometasone dipropionate (Beconase ) once daily sprays 50 sprays 100 sprays

4 / Nasal Spray (Dymista ) Appendix I Table 2: Seasonal allergic rhinitis: Trials comparing azelastine/fluticasone with monotherapy or placebo Ref 3: Design: Randomised multicentre double-blind controlled parallel group trial of 14 days duration with 5 days placebo treated run-in period. /fluticasone compared with commercially available sprays containing either azelastine or fluticasone propionate. Inclusion criteria: Patients aged years, in general good health with documented allergy (skin prick test) to mountain cedar pollen and seasonal allergic rhinitis for at least 2 years. Minimum score of 8 on rtnss scale (see below) and at least moderate or severe nasal congestion recorded on 3 occasions during run-in period. Symptom recording: reflective Total Nasal Symptom Score (rtnss) derived from recording of symptom severity (sneezing, congestion, itching, rhinorrhea), on a scale of 0 (no symptoms) to 3 (severe symptoms). Reflective Total Ocular Symptom Scores (rtoss) and Quality of Life scores recorded and analysed in a similar way to rtnss. Analysis of data: Treatments compared using a covariance model with baseline as a covariate. 610 patients recruited, 607 evaluable patients (ITT population). (n=152) / (n=153) Nasal symptoms (rtnss) Mean baseline 18.3 (8-24) 18.1 (10-24) 18.8 (9-24) 18.7 (10-24) rtnss (range) Primary endpoint baseline in rtnss (SD) 3.84 (4.76) 3.25 (4.16) 5.31 (5.08) 2.2 (SD not given) Reduction as % of baseline 20.4% 16.4% 28.4% 11.2% Secondary outcomes Ocular symptoms (rtoss) Mean baseline (SD)* (4.27) (4.21) (4.03) (4.35) baseline (%) 2.17 (17.5%) Rhinitis quality of life score (RQLQ) 2.62 (21.2%) 3.33 (26.6%) 1.32 (10.5%) Mean baseline (SD)* 3.82 (1.07) 3.81 (1.04) 3.90 (1.06) 3.87 (1.17) baseline * data from subsequent trial analysis ref 4 Abbreviations: SD = standard deviation, ITT = intention to treat Statistical significance /fluticasone better than other treatments, p<0.01. /fluticasone statistically superior to fluticasone and placebo, p<0.01. Not significant vs azelastine , 1.01 p=0.29 compared with fluticasone alone (not significant); p=0.005 or less compared with azelastine alone or placebo (statistically significant). clinically significant difference from placebo

5 / Nasal Spray (Dymista ) Ref 4: Further analysis of previous trial 3 : Proportion (as a percentage) of patients achieving each level of reduction in symptoms at day 14. Ref 5: Design: Meta-analysis of three randomised multicentre double-blind parallel group trials of similar design to reference days duration with 7 days placebo treated run-in period. Commercially-available azelastine/ fluticasone compared with similarly formulated sprays containing either azelastine, fluticasone propionate or placebo. Inclusion criteria: Patients aged years, in general good health with documented allergy (skin prick test) to mountain cedar pollen and moderate-severe seasonal allergic rhinitis for at least 2 years. Minimum score of 8 on rtnss scale (see reference 3) and at least moderate or severe nasal congestion recorded on 3 occasions during run-in period. Symptom recording: See reference 3. Analysis of data: Treatments were compared using a covariance model applied to primary outcome of absolute change in symptom score. % patient response (n=152) / (n=153) Statistical significance 30% reduction in rtnss 50% reduction in rtnss Figures in bold statistically different from placebo, p< % reduction in rtnss % reduction in rtnss % reduction in rtnss Nasal symptoms (rtnss) (n=846) (n=847) / (n=848) (n=857) Mean baseline (SD) 18.9 (2.8) 18.9 (3.0) 18.8 (2.9) 19.0 (2.8) Primary outcome baseline in rtnss (SD) Least squares mean difference from azelastine/fluticasone (95% confidence interval) Secondary outcomes Ocular symptoms (rtoss) Statistical significance 5.1 (4.9 ) 4.4 (4.8) 5.7 (5.3) 3.0 (4.2) Direct statistical analysis not provided -0.8 (-1.18 to -0.34) -0.9 (-1.37 to -0.52) (-2.75 to -1.95) Mean baseline (SD) 12.0 (3.9) 12.0 (4.1) 12.1 (4.0) 12.0 (4.0) baseline in rtoss (SD) Rhinitis quality of life score (RQLQ) All p compared with azelastine/ fluticasone 2.8 (3.6) 2.9 (3.8) 3.2 (4.0) 1.8 (3.4) Active treatments p vs placebo Mean baseline (SD) 3.8 (1.0) 3.9 (1.0) 3.9 (1.0) 3.9 (1.0) Reduction in score 1.5 (1.3) 1.4 (1.3) 1.6 (1.3) 1.0 (1.2) Active treatments p<0.001 vs placebo Overall response rate Overall response to treatment: complete or near-complete resolution of symptoms at day % 7.1% 12.4%* 4.2% *p<0.001 vs azelastine and placebo and p=0.033 vs fluticasone