Medicine Review. Medicine / Trade name Azelastine and fluticasone / Dymista Manufacturer

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1 East & South East England Specialist Pharmacy Services East of England, London, South Central & South East Coast East Anglia Medicines Information Service Medicine Review Medicine / Trade name Azelastine and fluticasone / Dymista Manufacturer Meda Document status Reviewed at Suffolk CCGs D&TC 16 th July 2013 and CPG 12 th August 2013 Date of last revision 9/7/2013 Traffic light decision Double red Prescribers rating Nothing new Mechanism of action Licensed indication Dosage Treatment alternatives Place in therapy Future alternatives Evidence for use Azelastine is potent long-acting anti-allergic compound with selective H 1 anatgaonist, mast-cell stabilising and anti-inflammatory action. Fluticasone is synthetic corticosteroid that possesses a very high affinity for the glucocorticoid receptor and has a potent anti-inflammatory action. (1) Relief of symptoms of moderate to severe seasonal and perennial allergic rhinitis if monotherapy with either intranasal antihistamine or glucocorticoid is not considered sufficient. (1) Adults and adolescents (12 years and older), one actuation in each nostril twice daily (morning and evening). (1) Oral or intranasal steroids and antihistamines. Leukotriene receptor antagonists. (2) Relief of symptoms of moderate to severe seasonal and perennial allergic rhinitis if monotherapy with either intranasal antihistamine or glucocorticoid is not considered sufficient. (1) None known There have been 4 main clinical studies see appendix 1 for more detail. (1) Hampel; et al (2010) compared Dymista with the separate ingredients and placebo using commercially available products. (3) The other 3 clinical trials compared Dymista with the separate ingredients and placebo using the same formulation/delivery device, as requested by the regulators. The results of these 3 studies have been combined in a meta- analysis and published by Carr et al in (4) In all 4 clinical studies in adults and adolescents with allergic rhinitis Dymista nasal spray, one spray in each nostril twice daily, significantly improved nasal symptoms (comprising rhinorrhoea, nasal congestion, sneezing and nasal itching) compared with placebo, azelastine hydrochloride alone and fluticasone propionate alone. It significantly improved ocular symptoms (comprising itching, tearing/watering and redness of the eyes) and the patients' disease-related quality of life (Rhinoconjunctivitis Quality of Life Questionnaire RQLQ) in all 4 studies. (1) In comparison to a marketed fluticasone propionate nasal spray substantial symptom improvement (50% reduction in nasal symptoms

2 Cautions severity) was achieved significantly earlier (3 days and more) with Dymista. The superior effect of Dymista nasal spray to fluticasone propionate nasal spray was maintained throughout a one-year study in patients with chronic persistent allergic rhinitis and non-allergic / vasomotor rhinitis. (1) Systemic effects of nasal corticosteroids may occur, particularly when prescribed at high doses for prolonged periods. These effects are much less likely to occur than with oral corticosteroids and may vary in individual patients and between different corticosteroid preparations. Potential systemic effects may include Cushing's syndrome, Cushingoid features, adrenal suppression, growth retardation in children and adolescents, cataract, glaucoma and more rarely, a range of psychological or behavioural effects including psychomotor hyperactivity, sleep disorders, anxiety, depression or aggression (particularly in children). (1) NB these are standard warnings for steroids. Systemic exposure of intranasal fluticasone propionate in patients with severe liver disease is likely to be increased. Caution is advised when treating these patients. (1) Close monitoring is warranted in patients with a change in vision or with a history of increased ocular pressure, glaucoma and/or cataracts. If there is any reason to believe that adrenal function is impaired, care must be taken when transferring patients from systemic steroid treatment to Dymista nasal spray. (1) In patients who have tuberculosis, any type of untreated infection, or have had a recent surgical operation or injury to the nose or mouth, the possible benefits of the treatment with Dymista nasal spray should be weighed against possible risk. (1) Infections of the nasal airways should be treated with antibacterial or antimycotical therapy, but do not constitute a specific contraindication to treatment with Dymista nasal spray. (1) Drug Interactions Dymista contains benzalkonium chloride. It may cause irritation of the nasal mucosa and bronchospasm. (1) Fluticasone During post-marketing use, there have been reports of clinically significant drug interactions in patients receiving fluticasone propionate and ritonavir, resulting in systemic corticosteroid effects including Cushing's syndrome and adrenal suppression. Therefore, concomitant use of fluticasone propionate and ritonavir should be avoided, unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side-effects. (1) Azelastine No specific interaction studies with azelastine hydrochloride nasal spray have been performed. Interaction studies at high oral doses have been performed. However, they bear no relevance to azelastine nasal spray because recommended nasal doses result in much lower systemic exposure. Nevertheless, care should be taken when administering azelastine hydrochloride in patients taking concurrent sedative or central nervous medications because sedative effect may

3 be enhanced. Alcohol may also enhance this effect. (1) Side effects Common side effects include dysgeusia (unpleasant taste) may occur after administration and often due to incorrect administration See SPC for further details. (1) NNT/NNH Not calculated Cost (MIMS July 2013) Dymista (age 12 and over) for 120 sprays Costs of alternatives Drug / dose Cost (BNF 65) Fluticasone (age 4 and over) 8.04 for 150 sprays Beclometasone (age 6 and over) 2.19 for 200 sprays Azelastine (age 5 and over) for 157 sprays Potential number of patients per 100,000 population Allergic rhinitis affects 30% of people globally, and 20% of the UK population, and is increasing in incidence. The incidence of the type and severity of allergic rhinitis is related to age: children of school age and adolescents are most commonly affected by seasonal allergic rhinitis. Adults are more likely to have perennial allergic rhinitis. (5) Points for consideration This is the first clinical development program that has demonstrated additional benefit over 2 currently recommended first line allergic rhinitis therapies in patients with moderate to severe disease. Dymista has shown superiority over intranasal fluticasone and intranasal azelastine monotherapy in patients with allergic rhinitis in a set of 3 randomised, double-blind, placebo controlled clinical studies with active controls using the same device and formulation. Results were consistent across the 3 trials. Many patient seen in primary care, i.e. those with milder symptoms were not included in the study. Dymista is more expensive ( for 120 doses) relative to single-component corticosteroid nasal sprays and single component azelastine. A potential disadvantage of the combination treatment is that there may be reduced flexibility in dosing, e.g. the as needed antihistamine. Only licensed in over 12s, the separate components are licensed in younger children. Comments sought from Decisions sought from other bodies Decision review date ENT consultants and specialists; Ipswich Hospital and the West Suffolk Hospital NICE not reviewed Norfolk TAG not reviewed Cambridgeshire JPG not reviewed Scottish Medicines Consortium not reviewed All Wales Medicines Strategy Group not reviewed TBC References 1. Summary of Product Characteristics. Dymista, Meda. Date last updated 01/13. Accessed 29/05/13 via 2. Hampel F et al. Double blind, placebo controlled study of Azelastine and fluticasone in a single nasal spray delivery device. Annals of Allergy, Asthma, & Immunology, 2010;105: Carr W et al. A novel intranasal therapy of Azelastine with fluticasone for the treatment of allergic rhinitis. J Allergy Clin Immunol 2012;129(5): Clinical Knowledge Summaries. Allergic Rhinitis. Accessed 29/05/13. Available via

4 Comments Mahmoud Salam Consultant Otolaryngologist - Head & Neck Surgeon Lead Clinician for ENT, IHT) Thank you for your . The following are the views of ENT consultants in Ipswich: 1. The current evidence from clinical trials in UK and Europe suggest that Dymista is superior to using Monotherapy (Steroid spray or antihistamine) for treatment of moderate to severe allergic rhinitis (Presented in EAACI conference, March 2013, Bergen) which I have attended. 2. The availability of this drug to be used in cases where other steroidal sprays do not work either alone or with antihistamine, will be useful and I support that (as second line of management) 3. Dymista is much more expensive than other steroidal spray but again it is a combination medicine (containing both steroid and antihistamine) in one preparation. Therefore, ideally used in cases not responsive to standard monotherapy. I hope the above views are useful. Kind regards Mr Mahmoud

5 Appendix 1: Key Clinical Trials Trial Trial Design Trial Population Treatment Primary Outcomes Hampel et al 2010 N=610 total 12 years old. One spray per nostril twice per day for 14 days following a 5 day placebo lead in. Carr at al 2012 Metaanalysis of 3 trials; MP4002, MP 4004 and MP4006 Multicentre, randomised, double blind study conducted in the US during the Texas mountain cedar season. Patients with a 2 year history of moderate to severe SAR were enrolled into 3 multicentre, randomized, double-blind, placebo and active controlled, parallel -group trials (4002, 4004 and 4006). Each trial was conducted for 14 days during different allergy seasons in the US. Patients with moderate to severe nasal symptoms. N=3,398 total 12 years old. Patients had significant current clinical rhinitis symptomology, and a positive skin prick test response to relevant pollen. All had moderate-tosevere seasonal allergic rhinits defined by a reflective total nasal symptom score (rtnss) of at least 8 out of 12, with a congestion score of 2 or 3 during screening. Combination intranasal azelastine (137µg) and fluticasone (50µg) vs. placebo or vs. commercially available azelastine 137µg or vs. fluticasone 50µg One spray per nostril twice per day for 14 days following a 7 day single blind placebo lead in. Combination intranasal azelastine (137µg) and fluticasone (50µg) vs. placebo* or vs. azelastine* 137µg or vs. fluticasone* 50µg * same vehicle / formulation. 3 study visits at days 1,7 and 14. On visit 2 (day 1), eligible patients werer andomised to 14 days of treatment (1 spray per nostril twice daily). Review prepared by Sarah Cavanagh, East Anglia Medicines Information Service May be freely copied by NHS agencies Not to be used for promotional purposes The primary outcome was the change from baseline in total nasal symptom score (TNSS) (consisting of nasal congestion, itching, runny nose, and sneezing). Results: All 3 active groups were statistically superior ( 0.02) to placebo and the combination was statistically superior ( 0.03) to either agent alone. The TNSS improved by: 28.4% with Dymista, 20.4% with fluticasone and 16.4% with azelastine and 11.2% with placebo. All 3 treatments were well tolerated. Patients recorded application times and symptom scores in a diary. Compliance with treatment was assessed. The primary outcome was the sum of morning and evening overall change from baseline in 12 hour reflective total nasal symptoms score (rtnsss) (range 0-24) over the entire 14 days treatment period. (sum of the individual nasal symptoms of congestion, itching, rhinorrhoea, and sneezing). All nasal and ocular symptoms were scored by patients twice daily on each treatment according to a 4 point scale. Results: Dymista reduced the mean reflective total nasal score from baseline (-5.7 [SD, 5.3]), more than fluticasone (-5.1 [SD 4.9], p<0.001), azelastine (-4.4 [SD, 4.8], p<0.001), or placebo (-3.0 [SD 4.2], p<0.001). Study completion rates were high (approximately 95%) and similar across all treatment groups.

6 Grids used to assist the NHS Suffolk PCT Drug & Therapeutics Committee in reaching a decision about new medications For many years scientists have recognised two types of research: Primary: original studies, based on observation or experimentation on subjects. Secondary: reviews of published research, drawing together the findings of two or more primary studies. In biomedical science there is general agreement over a hierarchy: the higher up a methodology is ranked, the more robust and closer to objective truth it is assumed to be. The orthodox hierarchy looks something like this- Rank: Methodology Description 1 Systematic reviews and meta-analyses Systematic review: review of a body of data that uses explicit methods to locate primary studies, and explicit criteria to assess their quality. Meta-analysis: A statistical analysis that combines or integrates the results of several independent clinical trials considered by the analyst to be "combinable" usually to the level of re-analysing the original data, also sometimes called: pooling, quantitative synthesis. Both are sometimes called "overviews." 2 Randomised controlled trials (finer distinctions may be drawn within this group based on statistical parameters like the confidence intervals) Individuals are randomly allocated to a control group and a group who receive a specific intervention. Otherwise the two groups are identical for any significant variables. They are followed up for specific end points. 3 Cohort studies Groups of people are selected on the basis of their exposure to a particular agent and followed up for specific outcomes. 4 Case-control studies "Cases" with the condition are matched with "controls" without, and a retrospective analysis used to look for differences between the two groups. 5 Cross sectional surveys Survey or interview of a sample of the population of interest at one point in time 6 Case reports. A report based on a single patient or subject; sometimes collected together into a short series 7 Expert opinion A consensus of experience from the good and the great. 8 Anecdotal Something a bloke told you after a meeting or in the bar. Adapted from Systematic reviews, What are they and why are they useful? ScHARR 2008 Review prepared by Sarah Cavanagh, East Anglia Medicines Information Service May be freely copied by NHS agencies Not to be used for promotional purposes

7 To Decide if a Medication Is To Be Used In Suffolk Criterion to be measured Tends to poor Medium Tends to good Quality of evidence in the papers reviewed Low Medium High Magnitude of effect inferred from trials reviewed Low Medium High Are trial end-points surrogate markers or clinical outcomes? Clinical usefulness of trial end-points Low Medium High Known Side Effect Profile High Medium Low Known Interactions High Medium Low Concern re Possible Side Effects Not Yet Uncovered High Medium Low Balance of Benefit To Harm (side effects toxicity interactions etc) Poor Medium Good NNT High Medium Low Comparison Of Effectiveness With Other Medicines In Use For The Poor Medium Good Same Condition Severity of Condition to be Treated Severe Medium Trivial Novel drug or member of existing class Uptake (estimated proportion of people with this condition likely to be prescribed the medication under consideration maximum and minimum uptake) Is the drug to be used in Suffolk? Prescriber s Rating Definitions 1. Bravo! -The drug is a major therapeutic advance in an area where previously no treatment was available. 2. A real advance - The product is an important therapeutic innovation but has certain limitations. 3. Offers an advantage - The product has some value but does not fundamentally change present therapeutic practice. 4. Possibly Helpful - The product has minimal additional value, and should not change prescribing habits except in rare circumstances. 5. Judgement reserved - The Committee postpones its judgement until better data and a more thorough evaluation of the drug are available. 6. Nothing New - The product may be a new substance but is superfluous because it does not add to the clinical possibilities offered by previous products available. In most cases these are me-too products. 7. Not acceptable - Product without evident benefit over others but with potential or real disadvantages. (With acknowledgement to Prescrire) Review prepared by Sarah Cavanagh, East Anglia Medicines Information Service May be freely copied by NHS agencies Not to be used for promotional purposes

8 To Decide Where A Medication Is To Be Used In Suffolk Skills of the prescriber Criterion Red Amber Green Blue Experience Of The Condition Specific Specific Specific General Diagnosis Specific Specific Specific General Monitoring Progress Of Treatment Difficult Specific General General Therapy Patient Selection Difficult Specific Specific Easy Initiation Of Treatment Difficult Difficult Easy Easy Dose Titration Difficult Specific Easy Easy Monitoring Of Side Effects Complex Easy Easy Easy Method Of Administration Complex Normal Normal Normal Discontinuation Of Treatment Complex Complex Easy Easy References Jonsen A. Bentham in a box: Technology assessment and health care allocation. Law Med. Health Care. 1986;14: Suffolk Drug & Therapeutics Committee Responsibility for prescribing, Hospital Trust or GP Review prepared by Sarah Cavanagh, East Anglia Medicines Information Service May be freely copied by NHS agencies Not to be used for promotional purposes