Utah Medicaid Pharmacy and Therapeutics Committee Drug

Home , Beclometasone, Ciclesonide, Dexbudesonide, Flunisolide, Fluticasone furoate, Fluticasone propionate

Utah Medicaid Pharmacy and Therapeutics Committee

Drug Class Review

Single Ingredient Nasal Corticosteroids

Beclomethasone dipropionate (Qnasl) Beclomethasone dipropionate monohydrate (Beconase AQ) Budesonide (Rhinocort) Ciclesonide (Omnaris, Zetonna) Flunisolide (Generic) Fluticasone Furoate (Flonase Sensimist) Fluticasone Propionate (Flonase, Xhance) Mometasone Furoate (Nasonex) Triamcinolone Acetonide (Nasacort)

AHFS Classification: 52.08.08 Corticosteroids (EENT)

Final Report February 2018

Review prepared by: Valerie Gonzales, Pharm.D., Clinical Pharmacist Elena Martinez Alonso, B.Pharm., MSc MTSI, Medical Writer Vicki Frydrych, Pharm.D., Clinical Pharmacist Joanita Lake, B.Pharm., MSc EBHC (Oxon), Research Assistant Professor Joanne LaFleur, Pharm.D., MSPH, Associate Professor University of Utah College of Pharmacy

Abbreviations ...... 2 Executive Summary ...... 3 Introduction ...... 5 Table 1. Nasal corticosteroid products ...... 6 Disease Overview & Treatment Guidelines ...... 9 Table 2. Guidelines for the use of nasal corticosteroids in rhinitis conditions ...... 10 Pharmacology & Special Populations ...... 14 Table 3. Pharmacokinetics of nasal corticosteroid products ...... 15 Table 4. Drug interactions per product labeling ...... 16 Table 5. Special population considerations for nasal corticosteroids ...... 17 Methods ...... 18 Figure 1. PRISMA Data ...... 19 Efficacy ...... 20 Systematic Reviews ...... 20 Randomized Controlled Trials ...... 23 Safety...... 25 Table 6. General warnings for INCS drug class ...... 25 Summary ...... 26 Table 1. Indication comparisons for nasal corticosteroids ...... 27 Appendix A: INCS Indication Comparison ...... 27 Appendix B: Search Strategies ...... 28 Table 1. Ovid Medline Literature Search Strategy ...... 28 Table 2. EMBASE Literature Search Strategy ...... 29 Appendix C: Excluded Studies ...... 33 Appendix D: Randomized Controlled Trials ...... 36 Table 1. Randomized Controlled Trials ...... 36 References ...... 43

Abbreviations

AAOHNS – American Academy of Otolaryngology Head and Neck Surgery

AQ – aqueous

AR – allergic rhinitis

CRS – chronic rhinosinusitis

CRSsNP – chronic rhinosinusitis without nasal polyps

CRSwNP - chronic rhinosinusitis with nasal polyps

FDA - U.S. Food & Drug Administration

INCS - intranasal corticosteroids

NAR – non-allergic rhinitis

OTC – over the counter

RCT - randomized control trial

Rx – formulation available by prescription

SR - systematic review

Executive Summary Intranasal corticosteroids (INCS) are indicated and widely used for seasonal and perennial allergic rhinitis (AR). Mometasone furoate also has specific indications for nasal congestion and prophylaxis of seasonal AR symptoms. Three products are indicated for the management of nasal polyps (e.g. Beconase AQ [beclomethasone dipropionate monohydrate], Nasonex [mometasone furoate], and Xhance [fluticasone propionate]). Beconase AQ is indicated following surgical removal of polyps once healing has occurred, whereas Nasonex and Xhance can additionally be used prior to surgery. Several INCSs are available over-the-counter (budesonide, fluticasone furoate, fluticasone propionate, and triamcinolone), and others only by prescription (beclomethasone, ciclesonide, flunisolide, fluticasone propionate as the Xhance product, and mometasone). Two products are approved for non-allergic rhinitis, Beconase AQ and fluticasone propionate. The majority of products are formulated as aqueous sprays. Upon administration, aqueous formulations tend to run down the back of the throat and have sensory attributes (scent, taste) which may influence patient compliance. Two products employ a hydrofluoroalkane (HFA) device to propel medication as an aerosol: Qnasl (beclomethasone dipropionate) and Zetonna (ciclesonide). When using INCSs for allergic rhinitis, products are to be administered once daily with the exception of beclomethasone dipropionate monohydrate (Beconase AQ) and generic flunisolide nasal sprays with twice daily dosing. The 3 products indicated for the management of nasal polyps (e.g. Beconase AQ, Nasonex, and Xhance) are dosed twice daily. Several agents have little systemic bioavailability (<2% bioavailable: ciclesonide, fluticasone furoate, fluticasone propionate, and mometasone furoate), considerably lower than that for beclomethasone, budesonide, flunisolide, and triamcinolone nasal sprays. During rhinitis exacerbations, INCS treatment significantly improves nasal symptoms (itching, discharge, congestion, and sneezing) in adults and children, while also improving quality of life. Recommendation for the use of one INCS over another is not specified in guidelines for the treatment of allergic rhinitis, chronic rhinosinusitis (CRS), or for nasal polyps. Following a systematic search we screened 313 systematic reviews (SR) and 634 randomized controlled trials (RCT) published from 2007 onward. A total of 5 systematic reviews were identified that addressed treatment-effect differences between INCSs. Three of these SRs found no available head-to-head RCTs for the following conditions: CRS without nasal polyps (Chong et al, Cochrane 2016), CRS following post-surgical intervention for nasal polyps (Fandino et al, 2013), and persistent AR in children (Al Sayyad et al, Cochrane 2007). One SR (Chong et al, Cochrane 2016) also investigated INCS treatment for CRS with nasal polyps and concluded that change in disease severity was not significantly different after treatment with fluticasone propionate versus beclomethasone or mometasone; no evidence was found for other head-to-head comparisons in the CRS setting. Based on evidence from a high quality SR by Selover et al. (2008) comparing nasal corticosteroids for patients with allergic rhinitis or non-allergic rhinitis, there were few differences between agents. One head-to-head comparison stands out in particular (budesonide versus fluticasone propionate). An RCT (Day et al. 1998) reported a significant difference in the

reduction of the patient-rated total nasal symptom score (primary endpoint) in favor of budesonide 256 mcg/day versus fluticasone propionate 200 mcg/day for treatment of adults with perennial AR. In the setting of adult seasonal AR, one study (Stern et al. 1997) suggested budesonide 256 mcg/day improves patient-rated nasal symptoms better than fluticasone propionate 200 mcg/day only for days when the pollen count was greater than 10 grains/m3. Products performed similarly when total nasal symptom scores were evaluated over all treatment days regardless of pollen count. It should be noted that the dosage form used in these studies was a budesonide 64mcg/actuation product; this strength is no longer available in the US. There is conflicting evidence for the comparison of mometasone versus fluticasone propionate. In an RCT (Mandl et al. 1997) in patients older than 12 years, with perennial AR, the primary outcome of patient-rated total nasal symptom score reduction did not differ between the two treatment groups at any time period, yet a significantly greater reduction in physician-rated secondary outcomes of nasal congestion (at day 29 and week 8), nasal discharge (at week 8 and 12), and improved overall condition (at week 8 and 12) was observed in favor of the mometasone group. Another study assessing this comparison (Mak et al. 2013) in children 6 to 12 years of age with moderate to severe perennial AR found no differences in patient quality of life scores after 4 weeks of treatment. Four additional RCTs published in the last 10 years, reported no significant differences in primary efficacy endpoints between certain treatment comparisons: fluticasone furoate versus mometasone furoate, and beclomethasone dipropionate monohydrate versus mometasone for perennial AR; fluticasone propionate versus mometasone for child dust mite AR; fluticasone furoate versus fluticasone propionate for seasonal AR. Regarding safety comparisons, one RCT was identified (Fokkens et al, 2012) that assessed long-term treatment with fluticasone furoate 110 mcg once daily versus mometasone furoate 200 mcg once daily over 1 year on nasal epithelium. After 52 weeks, there was no difference in epithelial thickening (per nasal biopsy) between active treatment groups and respective placebo control groups, nor between each active arm. The authors concluded that long-term treatment with these agents does not induce nasal epithelium atrophy. Intranasal corticosteroids are well tolerated with common mild adverse effects being headache, epistaxis, dizziness, and nasopharyngeal irritation. Serious, yet infrequent, adverse effects include fungal infection, growth inhibition, hypothalamic pituitary adrenal axis suppression, cataracts, increased intraocular pressure, nasal mucosal ulceration, and changes in taste and smell. Patients should be cautioned about possible brief lightheadedness/dizziness upon administration. In summary, there is little RCT evidence suggesting that any one INCS agent is more efficacious than another. Moreover, the treatment guidelines reviewed recommend the INCS drug class as a whole, not specifying preference of one product over another. There are some product differences with respect to dosing frequency, delivery device, and systemic bioavailability that may be considered as previously discussed.

Introduction

Intranasal corticosteroids (INCS) are indicated and widely used for seasonal and perennial allergic rhinitis (AR). Mometasone furoate also has specific indications for nasal congestion and prophylaxis of seasonal AR symptoms.1 Three products are indicated for the management of nasal polyps (e.g. Beconase AQ [beclomethasone dipropionate monohydrate], Nasonex [mometasone furoate], and Xhance [fluticasone propionate]). Beconase AQ is indicated following surgical removal of polyps once healing has occurred, whereas Nasonex and Xhance can additionally be used prior to surgery.1-3 Several INCSs are available over-the-counter (budesonide, fluticasone furoate, fluticasone propionate, and triamcinolone), and others only by prescription (beclomethasone, ciclesonide, flunisolide, fluticasone propionate as the Xhance product, and mometasone). Two products are approved for non-allergic rhinitis, Beconase AQ and fluticasone propionate.2,4 The majority of products are available as aqueous sprays. Aqueous formulations tend to run down the back of the throat and have sensory attributes (scent, taste) which may influence patient compliance and the likelihood of systemic absorption via the stomach.5,6 Two products employ a hydrofluoroalkane (HFA) device to propel medication as an aerosol: Qnasl (beclomethasone) and Zetonna (ciclesonide).7,8 This report will discuss the head-to-head comparative evidence, following a systematic review methodology, available for the INCS products used within the FDA-approved dosing as listed in Table 1. Table 1 details the indications, and dosing for the eleven intranasal corticosteroid preparations available in the United States (US). The Utah Medicaid Preferred Drug List classifies Beconase AQ (beclomethasone dipropionate monohydrate), Omnaris (ciclesonide), generic flunisolide, generic fluticasone propionate, and generic mometasone furoate as preferred agents. Table 1 of Appendix A provides a shorter summary table of the approved indications for these products.

Table 1. Nasal corticosteroid products Available Generic Name Indication & Dosage Formulations Rhinitis Qnasl7 [Aerosol; 24Hr] (Rx) Qnasl: Relief of nasal symptoms from seasonal or perennial AR in patients ≥ 4yrs. Patients >12 years, using the 80mcg/actuation product: 2 actuations in each • 40mcg/actuation nostril once daily (320mcg total daily dose; this is also the maximum • 80mcg/actuation recommended dose • HFA device Patients 4 to < 12 years of age using the 40mcg/actuation product: 1 actuation in

each nostril once daily (80mcg total daily dose; this is also the maximum

recommended daily dose)

Beclomethasone Beconase AQ: Relief of symptoms of seasonal or perennial AR and non-allergic Beclomethasone (vasomotor) rhinitis in patients 6 years and older dipropionate dipropionate Patients > 12 years of age: 1 to 2 sprays per nostril twice daily (max 336 monohydrate mcg/day) Beconase AQ2 [Spray] Patients 4 to 12 years of age: initial dose is 1 actuation in each nostril twice daily; (Rx) may increase dose to 2 actuations per nostril for inadequate responders, • 42mcg/actuation however, dose should be reduced back to 1 actuation per nostril once control of • Aqueous; symptoms is achieved 0.25%v/w phenylethyl Nasal polyps alcohol, pH 5 to Beconase AQ only: Nasal polyps recurrence prevention following surgical 6.8) removal. Same dosing as specified above

Allergic rhinitis Old Rx*10 [DISC]11: for the management of symptoms of seasonal or perennial Rhinocort Allergy9 allergic rhinitis in adults and children ≥6 years [Spray, 24Hr] Patients 6 to 12 years of age: 64mcg/day to up to 128mcg/d (OTC) Patients 12 years and older: 64mcg/day to up to 256mcg/d Budesonide • 32mcg/actuation • Aqueous; old Rx OTC9: For the relief of upper respiratory symptoms associated with hay fever or formulation had other respiratory allergies (e.g. nasal congestion, runny nose, itchy nose, pH adjusted to sneezing) in adults and children ≥6 years of age 4.5*10 Patients > 12 years of age: initially 2 sprays into each nostril once daily; decrease to 1 spray/nostril/day once allergy symptoms improve (generic available) Patients 6 to <12 years of age: initially 1 spray into each nostril once daily; inadequate responders may increase to 2 sprays/nostril/day, however, should decrease back to 1 spray/nostril/day once allergy symptoms improve OTC max dose is 128mcg/day Omnaris12 [Spray; 24Hr] (Rx) Allergic rhinitis • 50mcg/actuation Omnaris: for treatment of nasal symptoms associated with seasonal allergic • Aqueous; pH rhinitis for patients > 6 years of age and for perennial allergic rhinitis in patients > adjusted to 4.5 Ciclesonide 12 years of age. For all ages/indications: 2 sprays per nostril once daily (max of 200mcg/day) 8 Zetonna [Aerosol; 24Hr] Zetonna: for treatment of nasal symptoms associated with seasonal or perennial (Rx) allergic rhinitis in patients > 12 years of age • 37mcg/actuation For all ages/indications: 1 spray per nostril once daily (max of 74mcg/day) • HFA device

Table 1. Nasal corticosteroid products Available Generic Name Indication & Dosage Formulations Allergic rhinitis For treatment of nasal symptoms associated with seasonal or perennial allergic rhinitis in patients >6 years of age

Adults: 2 sprays per nostril twice daily; may increase to 2 sprays per nostril 3 Generic13 [Spray] times/ day; after obtaining desired clinical effect, reduce maintenance dose to (Rx) lowest amount necessary for symptom control Flunisolide • 25mcg/actuation Patients 6 to 14 years: 1 spray per nostril 3 times/day or 2 sprays per nostril 2 • Aqueous; pH times/day; after obtaining desired clinical effect, use dose to lowest amount adjusted to 5.1-5.4 necessary for symptom control • Do not exceed 8 sprays in each nostril for adults (max 400mcg/day) and 4 sprays in each nostril for patients under 14 years (max 200mcg/day). Approximately 15% of patients with perennial rhinitis may be maintained on as little as 1 spray in each nostril per day Allergic rhinitis OTC: for the relief of upper respiratory symptoms associated with hay fever or other respiratory allergies (e.g. nasal congestion, runny nose, itchy nose, sneezing) in adults and children ≥ 2 years of age 14 Flonase Sensimist Patients > 12 years of age: For week 1, use 2 sprays in each nostril once daily. For [Spray; 24Hr] week 2 to 6, use 1 to 2 spray(s)/nostril/day as needed per symptom response. Fluticasone (OTC) After 6 weeks, ask your doctor if you can keep using this medication Furoate • 27.5mcg/actuation Patients 2 to 11 years of age: 1 spray in each nostril once daily; use for shortest • Aqueous; old Rx duration necessary to achieve symptom relief. Consult a doctor if child needs the product had a pH spray for longer than two months a year near 6*15 Veramyst15 [DISC]16: for treatment of seasonal & perennial allergic rhinitis Patients ≥12 years: 110 mcg (2 sprays per nostril) once daily Children 2-11 years: 55 mcg (1 spray per nostril) once daily Allergic rhinitis OTC Flonase: for relief of upper respiratory symptoms due to hay fever or other respiratory allergies in adults and children ≥ 4 years of age Generic4 [Spray; 24Hr] Patients > 12 years of age: Week 1, use 2 sprays in each nostril once daily. Week (Rx) 2 through 6 months, use 1 to 2 spray(s)/nostril/day as needed per symptom • 50mcg/actuation response. After 6 months, ask your doctor if you can keep using this medication • Aqueous; pH 5-7 Patients 4 to 11 years of age: 1 spray in each nostril once daily; only use for the shortest duration necessary to achieve symptom relief. Consult a doctor if the Flonase Allergy child seems to need the spray for longer than two months a year Relief17 [Spray; 24Hr] Non-allergic rhinitis: Fluticasone (OTC) Rx Generic Flonase: For the management of nasal symptoms of perennial non- Propionate • 50mcg/actuation allergic rhinitis in adult and pediatric patients aged 4 years and older • Aqueous Adult Dose: Initially, 2 sprays per nostril once daily; alternatively, the same total daily dosage may be divided for twice daily administration. After the first few days and with symptom control, dosage may be reduced to 1 spray per nostril Xhance3 [Spray] once daily for maintenance therapy. (max 2 sprays per nostril [200 mcg]/day) (Rx) Children 4 years and older: 1 spray per nostril once daily; may increase to • 93mcg/actuation 2sprays/nostril/day if initial response is inadequate, however the dosage should • Aqueous; pH 5-7 be decreased to 1spray/nostril/day upon symptom control. Nasal polyps Xhance: for treatment of nasal polyps in patients ≥18 years of age Dose: 1 spray per nostril twice daily; some patients may benefit from an increase in dose up to 2 sprays per nostril twice daily

Table 1. Nasal corticosteroid products Available Generic Name Indication & Dosage Formulations Allergic rhinitis: for the treatment of nasal symptoms of seasonal allergic and perennial allergic rhinitis in adults and pediatric patients ≥2 years Patients 12 years of age and older: 2 sprays into each nostril once daily Patients 2 to 11 years of age: 1 spray in each nostril once daily 1 Nasonex Nasal congestion: for relief of nasal congestion associated with seasonal allergic [Spray, 24Hr] rhinitis in adults and pediatric patients ≥2 years Mometasone (Rx) Patients 12 years of age and older: 2 sprays into each nostril once daily. Furoate • 50 mcg/actuation Patients 2 to 11 years of age: 1 spray in each nostril once daily • Aqueous; pH 4.3- Prophylaxis of seasonal allergic rhinitis: Prophylaxis of nasal symptoms of 4.9 seasonal allergic rhinitis in adults and pediatric patients ≥12 years (generics available) Patients 12 years of age and older: 2 sprays into each nostril once daily Nasal polyps: Treatment of nasal polyps in patients ≥18 years old Patients 18 years of age and older: 2 sprays into each nostril twice daily; 2 sprays into each nostril once daily may also be effective for some patients

Allergic rhinitis OTC: For the relief of upper respiratory symptoms associated with hay fever or other respiratory allergies in adults and children ≥ 4 years of age Nasacort Allergy18 Patients > 12 years of age: Initially use 2 sprays in each nostril once daily. Once [Spray, 24Hr] symptoms improve, reduce to 1 spray/nostril/day. If allergy symptoms don’t Triamcinolone (OTC) improve after one week, consult a doctor Patients 6 to < 12 years of age: 1 spray per nostril once daily; increase to 2 • 55 mcg/actuation Acetonide sprays/nostril/day if symptoms do not improve. Should reduce back to 1 • Aqueous; pH spray/nostril/day upon symptom control unknown Patients 2 to < 6 years of age: 1 spray in each nostril once daily (generics available) Old Rx Aerosol19[DISC]20: Management of seasonal and perennial allergic rhinitis in adults and children 2 years and older

* Some prescription brand products have been discontinued as the comparable OTC product was marketed. Old Rx dosing and information on product characteristics (e.g. pH) is provided where available. Abbreviations: 24Hr, [DISC], discontinued, signifies once daily dosing; AR, allergic rhinitis; HFA, hydrofluoroalkane; OTC, over the counter; Rx, prescription only

Disease Overview & Treatment Guidelines Allergic rhinitis (AR) is an inflammatory response, mediated by immunoglobulin E (IgE), following inhalation of allergens.6 The prevalence of AR, based on self-reporting, is estimated to be 10 to 30% of adults and up to 40% of children in the US.21,22 Hallmark symptoms include anterior and posterior nasal drip (rhinorrhea), nasal congestion, nasal itching, nasal polyps, and sneezing (in addition to cough and fatigue particularly in children). Allergic rhinitis may be accompanied by ocular symptoms including watery eye, itching, redness, conjunctiva swelling, and puffiness of the lower eyelids. This condition can exacerbate other chronic/recurrent respiratory conditions such as asthma and can lead to sleep and behavior disturbance, fatigue, and reduced learning performance. Other conditions such as viral/bacterial sinusitis, vasomortor rhinitis, and granulomatous diseases may present with similar symptoms, so must be ruled out (considering symptoms such as fever, myalgia, etc. that are not typically present in allergic rhinitis).6 Exposure to the allergen may be seasonal (typically from plant pollens), perennial (e.g. from dust mites, animal dander, molds), or episodic (when not normally encountered) and ultimately determines the patient’s temporary or ongoing need for pharmacotherapy.6 Depending on geographic location, pollens and molds may be classified as perennial allergens. Some patients may suffer from concurrent AR to both perennial and seasonal influences or may have comorbidities that are directly exacerbated by the inflammatory reaction (e.g. asthma, sleep disturbances).6 In 2015, the Centers for Disease Control and Prevention estimated that 20 million adults and 6.1 million children were diagnosed with hay fever in the prior year.23 The American Academy of Otolaryngology Head and Neck Surgery (AAOHNS) describes that while symptoms can be classified by frequency (intermittent and persistent) and severity (mild or more severe), the classification system has limitations. They propose determining which category the patient falls into without use of the strict definitions, using a case-by-case consideration approach.6 Physicians can advise allergen avoidance, environmental controls, pharmacologic therapies, and immunotherapy desensitization.6,24 Table 2 lists recent guidelines regarding the treatment of allergic rhinitis and their recommendations for the use of INCS agents in particular. There are five drug classes approved for the treatment of allergic rhinitis that are available as nasal sprays including the INCS products. Other classes include decongestants (e.g. phenylephrine, oxymetolazone); the anticholinergic, ipratropium; the mast cell stabilizer, cromolyn; and antihistamines (e.g. azelastine, olopatadine).25 Intranasal corticosteroids are considered to be the most effective for the management of nasal symptoms associated with allergic rhinitis compared to oral antihistamines and leukotriene receptor antagonists.24 Oral antihistamines, decongestants, and intranasal antihistamines, may be advantageous when a faster onset of action is desired. Intranasal corticosteroids are generally recommended for moderate to severe symptoms of allergic rhinitis (“defined as rhinitis accompanied by other troublesome symptoms and/or that affects quality of life”26).6,26 The guidelines do not recommend one INCS over another for the treatment of allergic rhinits.6,24,26,27 Nasal polyps can occur with chronic allergic rhinitis or chronic rhinosinusitis.6,28-30 Chronic rhinosinusitis (CRS) is defined as inflammation of the nose and paranasal sinuses with 2 9

or more symptoms present, with at least one being nasal blockage or nasal discharge lasting more than 12 weeks; other symptoms may include facial pain and dysosmia.30 There are different underlying pathologies in chronic rhinosinusitis, however, the disease is characterized by inflammation and treatment with INCSs is recommended.31,32 Chronic rhinosinusitis is subtyped into CRS with nasal polyps (CRSwNP) and without nasal polyps (CRSsNP).33,34 An estimated 4% of patients with CRS have nasal polyps.28 Intranasal corticosteroids are recommended as a first line therapy for the treatment of nasal polyps and to reduce the risk of recurrence following polypectomy.35 There is ongoing research to better characterize the disease-causing pathology and potential treatment targets. Non-allergic rhinitis (NAR) is characterized by an absence of IgE and has diverse etiologies, which may have some overlapping biological mechanism involved in chronic rhinosinusitis.36 Subtypes of this disease include NAR rhinopathy (previously known as vasomotor rhinitis), NAR with eosinophilia, drug-induced rhinitis, hormonal-induced rhinitis, atrophic rhinitis, senile rhinitis, gustatory rhinitis, and cerebral spinal fluid leak manifesting rhinorrhea.21 NAR triggers may include changes in the environment (temperature, humidity, and pressure), odors/fumes, and pollutants/chemicals. NAR is characterized by nasal obstruction and rhinorrhea; in contrast, AR is generally associated with more sneezing/conjunctivitis/nasal pruritis, and higher blood/nasal eosinophil counts. A detailed discussion pertaining to the complexity of diagnosing this disease state is addressed by Greiwe et al.21

Table 2. Guidelines for the use of nasal corticosteroids in rhinitis conditions Guideline Recommendation Allergic Rhinitis Pharmacologic Treatment of Seasonal Allergic Initial treatment of seasonal allergic rhinitis: Rhinitis: Synopsis of • “The 2008 update of the Joint Task Force's rhinitis practice parameter (26) Guidance From the 2017 recommended intranasal corticosteroids as the most effective medication class Joint Task Force on for controlling symptoms, as did the original practice parameter from 1998 (27). Practice Parameters24 • For persons aged 12 years or older, use monotherapy with an intranasal corticosteroid rather than the combination of an intranasal corticosteroid in American Academy of combination with an oral antihistamine. (Strong recommendation) Allergy, Asthma and • For patients over 15, recommend an intranasal corticosteroid over a Immunology (AAAAI) and leukotriene receptor antagonist. (Strong recommendation) the American College of Moderate to severe seasonal allergic rhinitis: • Allergy, Asthma and For patients over 12 years of age, consider a combination of an intranasal corticosteroid and an intranasal antihistamine for initial treatment. (Weak Immunology (ACAAI) recommendation)

Table 2. Guidelines for the use of nasal corticosteroids in rhinitis conditions Guideline Recommendation Allergic Rhinitis and its Impact on Asthma (ARIA) Choosing an intranasal corticosteroid: guidelines—2016 “ARIA guideline panel acknowledged that the choice of treatment would depend mostly revision27 on patient preferences and local availability and cost of treatment. Panel members assumed that in the majority of situations, potential net benefit would not justify spending additional resources.”

Recommendations for intranasal corticosteroids regarding choosing one drug class over another and combination therapy:

For patients with Seasonal Allergic Rhinitis: • Use an INCS rather than an inhaled antihistamine (conditional recommendation | moderate certainty of evidence). • Use either a combination of an INCS with an intranasal antihistamine or an INCS alone (conditional recommendation | moderate certainty of evidence). • Use either a combination therapy with an oral antihistamine + INCS or an INCS alone (conditional recommendation | low certainty of evidence) For patients with Perennial Allergic Rhinitis: • Use either an INAH or OAH (conditional recommendation | very low certainty of evidence). • Use an INCS rather than an INAH (conditional recommendation | low certainty of evidence). • Use an INCS alone rather than a combination of an INCS with an oral antihistamine (conditional recommendation | very low certainty of evidence) • Use either a combination of an INCS with an inhaled antihistamine or an INCS alone (conditional recommendation | very low certainty of evidence)

Clinical Practice Guideline: Classifications Allergic Rhinitis 20156 Intermittent: exposure or symptoms that occur <4 days per week or <4 weeks per year American Academy of Persistent: ongoing symptoms >4 days per week and >4 weeks per year Otolaryngology Head and Episodic: exposure that is not normally part of the individual’s environment Neck Surgery (AAO-HNS) Mild: symptoms don’t interfere with quality of life More severe: symptoms are bad enough to interfere with quality of life

Recommendation definitions: • “Less frequent variation in practice is expected for a “strong recommendation” than might be expected with a “recommendation.” “Options” offer the most opportunity for practice variability.” • Strong recommendation: benefits clearly exceed the harms; quality of supporting evidence is excellent (Grade A or B) • Recommendation: benefits exceed the harms, but quality of evidence is not as strong (Grade B or C) • Option: either the quality of evidence that exists is suspect (Grade D) or that well- done studies (Grade A, B, or C) show little clear advantage to one approach versus another • Recommendation against: based on RCTs and systematic reviews, with a preponderance of benefit over harm

Table 2. Guidelines for the use of nasal corticosteroids in rhinitis conditions Guideline Recommendation Pharmacotherapy for Patients with Allergic Rhinitis Topical steroids: “Clinicians should recommend intranasal steroids for patients with a clinical diagnosis of AR whose symptoms affect their quality of life.” (Strong recommendation) • Onset: “… it is reasonable to assume that efficacy would be reached after 1 week of therapy at the most and, if none is observed, the treatment might be considered ineffective.” Oral antihistamines: use oral second-generation/less sedating antihistamines for primary complaints of sneezing and itching. (Strong recommendation) Intranasal antihistamines: may consider for patients with seasonal, perennial, or episodic AR. (Option) Oral leukotriene: Do not offer oral leukotriene receptor antagonists as primary therapy for patients with AR (Recommendation against) Combination therapy: consider for those who have inadequate response to pharmacologic monotherapy. (Option) Allergy testing an immunotherapy: can be considered for patients with inadequate response to above pharmacotherapies (an adequate trial of medications is consider to be 2 to 4 weeks in duration), when the diagnosis is uncertain, or when knowing the culprit allergen will affect treatment decision making. (Recommendation)

Sinusitis

Clinical Practice Guideline Topical intranasal therapy for chronic rhinosinusitis: (Update): Adult Sinusitis: “Clinicians should recommend saline nasal irrigation, topical intranasal 201528 corticosteroids, or both for symptom relief of CRS. Recommendation based on a preponderance of benefit over harm”

AAO-HNS Symptomatic relief of viral rhinosinusitis: “Clinicians may recommend analgesics, topical intranasal steroids, and/or nasal saline irrigation for symptomatic relief of VRS. Option based on randomized controlled trials with limitations and cohort studies with an unclear balance of benefit and harm that varies by patient.”

Table 2. Guidelines for the use of nasal corticosteroids in rhinitis conditions Guideline Recommendation Diagnosis and Statements that apply to the use of intranasal corticosteroids: Management of • Summary Statement 13: Treat allergic fungal rhinosinusitis with a combination of Rhinosinusitis: A Practice surgery and systemic and/or topical corticosteroids for optimal disease control. Parameter Update; 201434 (Recommendation, B) • Summary Statement 22: Use intranasal steroids for treatment of acute Joint Task Force on rhinosinusitis as monotherapy or with antibiotics. (Recommendation, B) Practice Parameters, • Summary Statement 28: Use intranasal corticosteroid (sprays and aerosols) for the representing the treatment of CRSwNP and CRSsNP. (Strong Recommendation, A) American Academy of • Summary Statement 41: Use an intranasal steroids as a potentially useful adjunct Allergy, Asthma and to antibiotics in the treatment of acute bacterial rhinosinusitis in children. (Strong Immunology, the Recommendation, A) American College of • Summary Statement 45: Use intranasal steroids in the treatment of chronic Allergy, Asthma and rhinosinusitis in children. (Recommendation, C) Immunology, and the Joint Council of Allergy, Recommendation definitions: Asthma and Immunology • Strong recommendation: benefits clearly exceed the harms; quality of supporting evidence is excellent (Grade A or B). • Recommendation: benefits exceed the harms, but quality of evidence is not as strong (Grade B or C). • Option: either the quality of evidence that exists is suspect (Grade D) or that well- done studies (Grade A, B, or C) show little clear advantage to one approach versus another. Topical Therapies in the “There is overwhelming evidence from 5 meta-analyses that standard topical steroid Management of Chronic therapy results in both patient based and objective clinical improvements in CRSwNP Rhinosinusitis: An and CRSsNP. When combining an aggregate grade A of evidence with a preponderance Evidence-based Review of benefit over harm, we have produced a strong recommendation for the use of with Recommendations; standard topical steroid therapy in patients with CRS. To optimize treatment effect, the 201332 evidence suggests that the delivery technique should focus on improving sinus penetration rather than simple nasal application.”32

Clinical Practice Guideline No recommendation is given for INCS for the treatment of bacterial sinusitis. “No for the Diagnosis and recommendation indicates that there is a lack of pertinent published evidence and that Management of Acute the anticipated balance of benefits and harms is presently unclear.”37 Bacterial Sinusitis in Children Aged 1 to 18 Years; 201337

American Academy of Pediatrics Clinical Practice Guideline “Intranasal corticosteroids (INCSs) are recommended as an adjunct to antibiotics in the for Acute Bacterial empiric treatment of ABRS, primarily in patients with a history of allergic rhinitis (weak, Rhinosinusitis in Children moderate).”38 and Adults; 201238

Infectious Disease Society of America (IDSA) Abbreviations: CRS, chronic rhinosinusitis; CRSsNP, chronic rhinosinusitis without nasal polyps; CRSwNP, chronic rhinosinusitis with nasal polyps; INAH, inhaled antihistamine; INCS, intranasal corticosteroid; OAH, oral antihistamine

Pharmacology & Special Populations

Administration of corticosteroids reduces inflammatory mediators including T- lymphocytes, basophils, eosinophils, neutrophils, mononuclear cells, cytokines (e.g. IL-2, IL-4, interferon-gamma, and TNF-alpha), and histamine realease.5,6 Topical INCS administration to the nasal epithelium exerts anti-inflammatory/vasoconstrictor effects and reduces vascular permeability.2,5 During rhinitis exacerbations, INCS treatment significantly improves nasal symptoms (itching, discharge, congestion, and sneezing) in adults and children, while also improving quality of life.6 They are most commonly used continuously during seasonal or perennial allergen exposure. On demand use is also being studied and has been shown to be as effective as regular use in some situations.39,40 Guideline authors highlight, “studies of as-needed use of intranasal fluticasone have shown that intermittent use is better than placebo,” in the setting of seasonal allergic rhinitis.6 When using INCS for allergic rhinitis, most products are to be administered once daily with the exception of beclomethasone dipropionate monohydrate (Beconase AQ) and generic flunisolide nasal sprays requiring twice daily dosing. The 3 products indicated for the management of nasal polyps (e.g. Beconase AQ, Nasonex, and Xhance) are each dosed twice daily. Several agents have little systemic bioavailability (<2% bioavailable: ciclesonide, fluticasone furoate, fluticasone propionate, and mometasone furoate), lower than reported for beclomethasone, budesonide, flunisolide, and triamcinolone.41,42 The majority of these products are available as aqueous sprays. Aqueous formulations tend to run down the back of the throat and have sensory qualities (e.g. odor, nasal irritation), especially if formulated with alcohol, which can influence patient compliance.5 Two products employ a hydrofluoroalkane (HFA) device to propel medication as an aerosol: Qnasl (beclomethasone) and Zetonna (ciclesonide).7,8 Table 3 provides pharmacokinetic information the products. Table 4 summarizes drug interaction warnings in product labeling for the intranasal corticosteroids. Since systemic exposure of INCSs is relatively low (especially with ciclesonide, fluticasone furoate, fluticasone propionate, and mometasone furoate), drug interactions are expected to be minimal. The first generation agents (beclomethasone, budesonide, and flunisolide), with higher bioavailabilities and metabolism pathways via cytochrome P450 3A4 enzyme (CYP3A4), are the most concerning with regard to potential systemic drug interactions with other molecules affecting CYP3A4 metabolism. In addition, drug monographs in Lexicomp cite a major interaction with INCS agents and desmopressin (may enhance hyponatremic effect of desmopressin exposure).16 Table 5 summarizes special population information for these products.

Table 3. Pharmacokinetics of nasal corticosteroid products Bio- Half-life Generic Name Brand Name Metabolism Excretion availability (hours)

Qnasl7 (Rx) 27.5% 2.8 (mean) CYP3A4; Esterases Mainly excreted through feces; Beclomethasone <15% excreted in urine Beclomethasone (hydrolyze the dipropionate dipropionate prodrug) monohydrate 44% 0.5 to 2.7 Beconase AQ2 (Rx)

10 Mostly excreted through the Budesonide16 Rhinocort Allergy* 34% 2 to 3 CYP3A4 (OTC available) urine ( ̴66%)

Omnaris12 (Rx) Esterases Predominantly excreted Ciclesonide <1% NR (hydrolysis); through the feces; <20% Zetonna8 (Rx) CYP3A4 & 2D6 through the urine

CYP3A4 minor Half of the dose excreted in Flunisolide 13 50% 1 to 2 (per Lexicomp Generic (Rx) the urine and other half monograph)16 through the feces Fluticasone Flonase Sensimist*43 Primarily excreted via bile; <1% 15.1 CYP3A4 Furoate (OTC available) <1% excreted through urine

Fluticasone Generic (Rx)4 <2% (OTC available) Primarily excreted in the feces; Propionate 7.9 CYP3A4 <5% excreted in the urine Xhance3 (Rx) NR

Mometasone Nasonex1 (Rx)

Furoate (generics available) <1% 5.8 CYP3A4 Primarily excreted via bile

19 Triamcinolone Nasacort Allergy* CYP3A4 minor 34-49%42 4 (per Lexicomp Feces ( ̴60%); Urine ( ̴40%)16 Acetonide (OTCs available) monograph)16 Abbreviations: AQ, aqueous; CYP3A4, cytochrome P450 3A4; NR, not reported; OTC, over the counter; Rx, available by prescription only *Pharmacokinetic information is from a product label with a different brand name, since PK data is not provided in OTC labeling

Table 4. Drug interactions per product labeling Generic Name Brand Name Drug Interaction

Qnasal labeling states that drug interaction studies have not been Qnasl7 (Rx) performed. Beclomethasone Beconase AQ labeling does not discuss drug interactions. Beclomethasone

dipropionate dipropionate monohydrate Note: drug interaction considerations should be taken into account since beclomethasone is a CYP3A4 substrate and has some systemic Beconase AQ2 (Rx) bioavailability

10 Prescription labeling for Rhinocort states that caution is advised when used Budesonide16 Rhinocort Allergy* (OTC available) with strong CYP3A4 inhibitors.

Omnaris12 (Rx) Ciclesonide No drug interactions are expected8,12 Zetonna8 (Rx)

Flunisolide Generic13 (Rx) Labeling dose not discuss drug interactions.13 Prescription labeling for Veramyst states that concomitant administration Fluticasone Flonase Sensimist*43 with ritanovir should be avoided and caution is advised with potent Furoate (OTC available) CYP3A4 inhibitor. 15

Generic (Rx)4 Since fluticasone propionate is a substrate of CYP3A4, the use of strong Fluticasone (OTC available) CYP3A4 inhibitors (e.g., ritonavir, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, saquinavir, ketoconazole, Propionate Xhance3 (Rx) telithromycin, conivaptan, lopinavir, voriconazole) with Xhance of Flonase is not recommended, as systemic corticosteroid adverse effect risk may be increased.3,4 Mometasone Nasonex1 (Rx) Labeling states that drug interaction studies have not been performed.1 Furoate (generics available)

Triamcinolone Nasacort Allergy*19 Drug interactions are not discussed in prescription product labeling.19 Acetonide (OTCs available) Abbreviations: AQ, aqueous; CYP3A4, cytochrome P450 3A4; OTC, over the counter; Rx, available by prescription only

Table 5. Special population considerations for nasal corticosteroids Generic Name Pediatric Indication Age Hepatic & Renal Impairment Pregnancy & Nursing

Pregnancy Category C Qnasl7: indicated for patients ≥ 4 No formal PK studies have been years old for AR (seasonal/perennial) conducted in any special population May be excreted into breast milk Beclomethasone Beconase AQ2 : indicated for patients Potential teratogenic and dipropionate ≥ 6 years old for AR No dosing adjustment embryocidal effects; May (seasonal/perennial), non-allergic recommendation provided in the be excreted into breast rhinitis, and prevention of nasal polyp prescribing information milk recurrence Rhinocort Allergy: OTC indicated for PK studies have not been conducted seasonal AR in patients ≥ 6 year;9 in renal impairment. Reduced liver function may affect the elimination of Pregnancy Category B Budesonide Rx formulation was indicated for corticosteroids however, dosing May be excreted into 10 seasonal and perennial AR for patients adjustment recommendations are not breast milk* ≥ 6 years old10 provided*10 Omnaris12: labeled to treat seasonal AR in patients ≥ 6 years old and for No adjustment for liver impairment the treatment of perennial AR in necessary; trials in renal impairment Pregnancy Category C Ciclesonide patients ≥ 12 years were not conducted since renal May be excreted Zetonna8: labeled to treat AR elimination is a minor excretion route into breast milk (perennial/seasonal) in patients ≥ 12 per labeling years No dosing adjustment Potential teratogenic and 13 Flunisolide Generic : for AR (seasonal/perennial) recommendation provided in the fetotoxic effects; May be in patients ≥6 years prescribing information excreted into breast milk Flonase Sensimist: OTC product 15 labeled for seasonal AR in patients ≥ 2 Pregnancy Category C * Fluticasone No dosing adjustment years;14 Rx product was labeled to recommendation provided in the There are no adequate Furoate treat AR (perennial/seasonal) in European prescribing information*43 studies conducted in pregnant women patients ≥ 2 years15 Flonase: OTC product labeled for seasonal AR in patients ≥ 4 years old;17 Fluticasone Rx product is labeled for age ≥4 to Pregnancy Category C Propionate treat perennial nonallergic rhinitis4 PK studies have not been conducted in renal and hepatic impairment May be excreted into breast milk Xhance3: only for use in patients ≥18 years of age to treat nasal polyps Mometasone PK studies have not been conducted Nasonex1 : indicated for patients ≥ 2 in renal impairment. Reduced liver Furoate years old for allergic rhinitis and nasal function may increase exposure of congestion; for those ≥ 12 years for corticosteroids however, the levels Pregnancy Category C remain hardly detectable; dosing seasonal AR prophylaxis; and for those May be excreted into ≥ 18 years old to treat nasal polyps adjustment recommendations are not breast milk provided10 Nasacort: OTC product is indicated for seasonal AR in patients ≥2 years;18 Rx Triamcinolone No dosing adjustment Pregnancy Category C formulation was approved for recommendation provided in the Acetonide May be excreted into perennial and seasonal AR in patients prescribing information*19 breast milk*19 over 6 years of age Abbreviations: AR, allergic rhinitis; AQ, aqueous; OTC, over the counter; Rx, prescription only product *Information is from a product label with a different brand name, since data is not provided in OTC labeling

Methods

Literature Search

Search strategies were developed by an Informational Scientist for OVID Medline and EMBASE. Strategies consisted of controlled vocabulary, such as MeSH, and keyword phrases. Two methodological filters were used, one for systematic reviews (ad hoc) and another for randomized controlled trials44 (RCT) developed by the Cochrane Collaboration. Results were limited to English language. Databases were searched from date of inception forward. In EMBASE, we excluded conference abstracts. Searches were conducted in December, 2017. Articles were transferred to EndNote for deduplication and to limit the publication date from 2007 onward. The complete search strategies and terms are available in Appendix B.

We also screened the reference lists and other relevant websites for further information: I. For guidelines addressing the treatment of rhinitis: websites of American Academy of Allergy, Asthma and Immunology (AAAAI) and the American College of Allergy, Asthma and Immunology, guidelins.gov; American Academy of Otolaryngology Head and Neck Surgery (AAO-HNS) II. For prescribing information package inserts: The Food and Drug Administration website (Drugs@FDA: FDA Approved Drug Products: https://www.accessdata.fda.gov/scripts/cder/daf/) III. Evidence-based drug information databases (Micromedex and Lexicomp)

Screening Two reviewers screened titles and abstracts for articles identified with publications dates from 2007 onward. Full text for all citations receiving at least one inclusion or maybe vote were retrieved and reviewed; inclusion was determined by the lead author. Figure 1 shows the PRISMA flow chart for the review process. Inclusion and Exclusion Criteria Systematic reviews and RCTs providing head-to-head efficacy and safety comparisons (for the approved indications) among the intranasal corticosteroids sprays listed in Table 1 were included. For product comparisons where a systematic review provided robust data, we examined trials published after the search date of that systematic review. A list containing the excluded references is provided in Appendix C.

Figure 1. PRISMA Data

Records after duplicates removed (n = 947) This represents RCTs and SRs published since 2007 • SRs 313

Identification • RCTs 634

Screening Records screened Records excluded (n = 947) (n =904)

Full-text articles assessed for eligibility (n = 51)

Eligibility Full-text articles excluded, with reasons (n = 41) Wrong intervention (2) Wrong patient population (1) Wrong comparator (15) Wrong study design (16)

Studies included in Wrong outcome (5) qualitative synthesis Article withdrawn (2) (n = 10) Included

Notes: (a) 3 of the 947 records in box 1 were found outside of the search strategy, (b) for the 10 studies included in the qualitative synthesis, 9 address efficacy and 1 addresses safety. Abbreviations: RCT, randomized controlled trial; SR, systematic review

Efficacy

Systematic Reviews

Upon screening 313 systematic reviews (restricted to 2007 through 2017), a total of 5 systematic reviews (SR) were identified that addressed treatment effect differences between intranasal corticosteroids. Three of these SRs identified head-to-head RCT evidence: 2 publications for allergic rhinitis indications (Selover et al. and Herman et al.)45,46 and the other (Chong et al.)47 reviewed use in the setting of CRSwNP. Although searches were conducted by authors for head-to-head comparative evidence, none was identified for INCS treatment in the setting of CRSsNP (Chong et al.)47, CRS following post-surgical intervention for nasal polyps (Fandino et al)48, and persistent allergic rhinitis in children (Al Sayyad et al)49. Findings from these systematic reviews are described below.

Allergic rhinitis Selover et al, (2008) was a high quality systematic review searching Cochrane Central and Medline to September 2007 for controlled trials and systematic reviews comparing intranasal corticosteroids for patients with allergic rhinitis or non-allergic rhinitis.45 • Adults with seasonal allergic rhinitis: No significant differences were found between agents with respect to total rhinitis symptom primary endpoints based on physician assessment, or when outcomes were assessed by patient-reported composite nasal symptom scores.45 Few selective secondary endpoint differences were found for budesonide versus fluticasone propionate. Head-to-head RCTs identified ranged between 2 and 8 weeks duration and included the following comparisons. a) Beclomethasone vs. triamcinolone (1 trial), fluticasone propionate (2 trials), mometasone (1 trial), budesonide (1 trial) and flunisolide (as the old chlorofluorocarbon formulation, 3 trials): no differences found in composite nasal symptom primary endpoints. b) Triamcinolone vs. fluticasone propionate (2 trials using aqueous forms): no differences found in composite nasal symptom primary endpoints. c) Budesonide vs. fluticasone propionate (1 trial): No differences found in composite nasal symptom endpoint over the whole time period. • Note secondary endpoint differences: While this trial found no difference in physician-rated global nasal symptom improvement between the budesonide and flunisolide treatment groups, there were significant differences found in secondary endpoints in favor of budesonide 256 mcg/day over fluticasone 200 mcg/day for the days analyzed when the pollen count was greater than 10grains/m3 and for the individual sneezing score.50

Three trials were identified that assessed Rhinoconjunctivitis Quality of Life after 3 weeks of treatment comparing triamcinolone to beclomethasone and fluticasone propionate (2 trials). Similar mean reductions were found between the treatment groups.45

• Adults with perennial allergic rhinitis: Head-to-head RCTs ranged between 3 weeks to 1 year duration and included the following comparisons: a) Beclomethasone vs. flunisolide (3 trials), triamcinolone (1 trial) fluticasone propionate (2 trials), and budesonide (1 trial) b) Budesonide vs. fluticasone propionate (1 trial) c) Mometasone vs. fluticasone propionate (1 trial); and budesonide (1 trial)

An RCT by Day et al., assessed the efficacy difference between budesonide versus fluticasone propionate over 6-weeks and including 273 adults. A significant difference was found in favor of budesonide 256 mcg per day versus fluticasone propionate 200 mcg daily based on a combined patient-rated nasal score (-2.11 vs -0.65, p=0.031). Primary efficacy nasal symptoms included blocked nose, runny nose, and sneezing rated by patients using a 4 point scale.51 It should be noted that the dosage form used in the study was a 64 mcg/actuation product; this strength is no longer available in the US. A study by Mandl et al, assessed the efficacy difference between mometasone 200 mcg versus fluticasone propionate 200 mcg administer daily. 52 This study reported conflicting results between the primary patient-rated endpoint and the secondary physician rated endpoint. This was a 12 week, multicenter study including 550 adults and adolescents over 12 years old. The primary outcome of patient-rated total nasal symptom score reduction did not differ between the two groups at any time period, yet a significantly greater reduction in physician-rated secondary outcomes of nasal congestion (at day 29 and week 8), nasal discharge (at week 8 and 12), and overall condition (at week 8, and 12) was reported for the mometasone group. Primary efficacy nasal symptoms included sneezing, rhinorrhea, nasal itch, and congestion rated by patients using a 4 point scale. 52 No other significant differences were found between agents when used at FDA- approved doses with respect to composite rhinitis symptoms.45

• Children with seasonal allergic rhinitis: Only 1 RCT was found for the pediatric population, which included children ages 6 to 11 years old (n=679).45 No significant differences were found with respect to physician-rated composite nasal symptom score reductions between groups treated with mometasone 100 or 200 mcg daily and beclomethasone 84 mcg twice daily after 4 weeks.53

• Children with perennial allergic rhinitis: One publication was found comparing beclomethasone 200 mcg twice daily to fluticasone 100 or 200 mcg once daily, including

children ages 4 to 11 years old (n=120). No significant differences were reported.45 In addition, the previous RCT by Mandl et al, discussed previously fits for this population.

Herman (2007) reviewed evidence from 1966 to January 2004 for RCTs in patients with allergic rhinitis comparing the once daily intranasal corticosteroid products. Findings are largely consistent with those by Selover et al.46 • Several head-to-head studies were identified assessing once daily dosed INCSs for the treatment of seasonal allergic rhinitis: (a) triamcinolone vs. fluticasone propionate (2 trials), (b) budesonide vs. fluticasone propionate (1 trial), and mometasone (1 trial). No significant differences were found in terms of total nasal symptom score reduction for comparisons. • Several head-to-head studies were identified assessing once daily dosed INCSs for the treatment of perennial allergic rhinitis: (a) budesonide vs. fluticasone propionate (1 trial), and mometasone (1 trial); and (b) mometasone vs. fluticasone propionate (1 trial). Similar to the SR by Selover et al, the head-to-head study showing a significant difference in favor of budesonide 256 mcg per day versus fluticasone propionate 200 mcg daily was identified.51 No significant differences were found in terms of total nasal symptom score reduction for other comparisons.46

Chronic rhinosinusitis with nasal polyps Chong et al, (Cochrane Review 2016) searched (up to August 11, 2015) for RCTs with a follow-up period of at least three months comparing different types of nasal corticosteroids for treatment of patients with or without nasal polyps.47 This SR included 3 RCTs evaluating head- to-head comparisons for the treatment of CRSwNP. No differences were reported for fluticasone propionate versus beclomethasone or mometasone furoate based on very low quality evidence.47

• Fluticasone propionate nasal spray (400 mcg/day) versus beclomethasone dipropionate nasal spray (400mcg/day): 2 small studies (totaling 56 participants with polyps) evaluated disease severity and epistaxis which reported no differences between the two steroids. The evidence was graded as very low quality.47 • Fluticasone propionate nasal spray (200 mcg/day) versus mometasone furoate nasal spray (200 mcg/day): 1 study was identified (including 100 participants with polyps) that evaluated disease severity by nasal symptoms scores, and reported no difference between the two steroids. The evidence was graded as very low quality.47

No Head-to-head studies found for the following subpopulations & indications CRSsNP Chong et al, (Cochrane Review 2016) searched (up to August 11, 2015) for RCTs with a follow-up period of at least three months comparing different types of nasal corticosteroids used for patients with or without nasal polyps. No studies were found for the patient population without nasal polyps.47 22

CRSwNP in adults post endoscopic sinus surgery and polypectomy Fandino et al, (2013) searched (up to May 2012) for RCTs comparing INCSs with each other, versus placebo, or no treatment during the immediate postoperative period of endoscopic sinus surgery for at least 6 to 8 weeks continuously. No trial comparing INCs head-to-head were identified. Based on several placebo comparative studies, the authors concluded “INCS showed significant improvement in polyp score, patients’ symptoms and significant decrease in polyp recurrence in the first year postoperatively.”54

Persistent allergic rhinitis in children Al Sayyad et al, (Cochrane Review 2007) searched (up to September 5th, 2005) for randomized controlled trials comparing topical nasal steroid preparations against each other or placebo for the treatment of allergic rhinitis in children. No head-to-head trials were identified, only placebo controlled trials. The authors concluded that the three placebo controlled trials, “provided some weak and unreliable evidence for the effectiveness of Beconase AQ and flunisolide used topically intranasally for the treatment of intermittent and persistent allergic rhinitis in children.”49

Randomized Controlled Trials Following a systematic review of RCTs (published from 2007 through 2017), 4 additional RCTs were identified that addressed efficacy differences between intranasal corticosteroids. One trial was in regard to the indication for seasonal allergic rhinitis and the other 3 were conducted in the setting of perennial allergic rhinitis. Appendix D includes a table summarizing information from these trials described below.

Seasonal allergic rhinitis Okubu et al, (2009), was a multicenter RCT taking place in Japan, comparing fluticasone furoate 110 mcg once daily versus fluticasone proprionate 100 mcg twice daily (200mcg/day) in patients ≥16 year of age with a history of seasonal allergic rhinitis to Japanese ceder pollen for greater than 2 years. After treating patients for 2 weeks while symptoms were present during an active pollen season, no significant differences in primary or secondary endpoints were found at any time point between the treatment group. The primary efficacy end point was mean change from baseline over the entire treatment period in 3TNSS, defined as the sum (0 to 9) of three patient rated symptom scores for sneezing, rhinorrhea, and nasal congestion scored on a scale of 0 to 3 in the allergy diary. Secondary efficacy end points included (a) mean change from baseline over the entire treatment period in 4TNSS (sum of scores for sneezing, rhinorrhea, nasal congestion, and nasal itching), (b) mean change in the 3TNSS and 4TNSS in weeks 1 and 2; and over the entire treatment period in individual nasal symptom scores, (c) change from baseline in the individual nasal examination (rhinoscopy) score were also assessed,

(d) patients’ impression of the treatment effect, (e) change in the mean activities of daily living interference scores over the treatment period were also evaluated in this study. With regard to safety, the authors conclude that incidence of overall adverse events was comparable between treatment groups (17% for FFNS, and 18% for FPNS; 21% for placebo FFNS and 19% for placebo FPNS) Perennial Allergic Rhinitis Aneeza et al, (2013)55 was a single center RCT taking place in Malaysia, comparing fluticasone furoate NS 110 mcg once daily versus mometasone furoate NS 200 mcg once daily in patient ≥ 12 years of age (n=63), who had both nasal and ocular symptoms of allergic rhinoconjunctivitis for 2 years or more. Both groups had significant improvement in patient rated nasal and ocular total symptom scores compared to baseline after 1 week of treatment, in addition to rhinoconjunctivitis quality of life scores after 1 month of treatment. No statistically significant differences between treatment groups were found for primary endpoints assessed at 4 and 8 weeks. Daily documentation of nasal (rhinorrhea, congestion, sneezing, and itching) and ocular (watering, itching, and redness) symptoms severity was based on a patient rated 4-point categorical scale from 0 to 3 for how patient felt at that moment.55

Mak et al, (2013)56 was a single center RCT in Taiwan, comparing fluticasone propionate 100 mcg/day versus mometasone furoate 100 mcg/day in children 6 to 12 years of age (n=83), diagnosed with moderate to severe perennial allergic rhinitis for at least 1 year, with a positive skin prick test response to house dust mites. After 4 weeks of treatment, there was no statistical difference found with respect to patient quality of life scores (based on 23 questions in five categories such as nasal symptoms, eye symptoms, practical problems, activity limitations, and other, recalled for the previous week, using a 7-point scale).56

Ratner et al, (2009)57 compared an old product of beclomethasone aqueous nasal spray 0.084mg per actuation under the brand name Vancenase AQ, manufactured by Schering-Plough Corp, which has since been discontinued. This is a more concentrated form than the comparable beclomethasone aqueous product now on the market. This was a multicenter US study comparing the beclomethasone dipropionate monohydrate 168 mcg/day (n=85) versus mometasone furoate 100 mcg/day (n=166) in children 6 to less than 12 years old with established moderately severe perennial rhinitis at baseline. No efficacy difference was found between treatment groups over 8 to 52 weeks based on physician or subject rated condition scores using a 5 point rating scale to assessing nasal symptom severity (rhinorrhea, nasal congestions, nasal itch, and sneezing) and non-nasal symptom severity (itching/burning eyes, watery eye, eye redness, itching ears/or palate).57

Safety

An RCT was identified (Fokkens et al, 2012) that assessed nasal epithelial atrophy following long-term treatment (for 1 year) of adults with perennial AR with fluticasone furoate 110 mcg versus mometasone furoate 200 mcg, each administered once daily.58 After 52 weeks, there was no difference in epithelial thickening (per nasal biopsy) between active treatment groups and their respective placebo control groups, nor between each active arm. The authors concluded that long-term treatment of fluticasone furoate and mometasone does not induce nasal epithelium atrophy.58 More recently, in 2015, Verkerk et al, concluded that “The concept of nasal mucosal atrophy is poorly defined and there is no histological evidence for deleterious effects from INCS use on human nasal mucosa,” upon performing a systematic review.59 Intranasal corticosteroids are well tolerated with common mild adverse effects being headache, epistaxis, dizziness, and nasopharyngeal irritation.1,2,10,12,19 Serious, yet infrequent, adverse effects include fungal infection, growth inhibition, hypothalamic pituitary adrenal axis suppression, cataracts, increased intraocular pressure, nasal mucosal ulceration, and loss of taste and smell.2,3 Patients should be cautioned about possible brief lightheadedness/dizziness upon administration. Table 6 provides general warning considerations for all nasal corticosteroids.

Table 6. General warnings for INCS drug class 1-3,7,8,10,12,13

. Nasal discomfort, epistaxis, nasal ulceration, Candida albicans infection, nasal septal perforation, impaired wound healing: monitor for possible changes in the nasal mucosa with long-term use and avoid use in patients with recent nasal ulcers, nasal surgery, or nasal trauma. . Eye Disorders: monitor for change in vision, increased intraocular pressure, blurred vision, glaucoma, and cataracts. . Hypersensitivity . Potential worsening of existing tuberculosis; fungal, bacterial, viral, or parasitic infections; or ocular herpes simplex. More serious or even fatal course of chickenpox or measles in susceptible patients. . Adrenal insufficiency and hypercorticism with very high dosages or at the regular dosage in susceptible individuals. . Potential reduction in growth velocity in pediatric patients: monitor growth routinely

* Refer to prescribing information for full details and recommended monitoring with respect to warnings/precautions

Summary

Intranasal corticosteroids are recommended and widely used for the management of allergic rhinitis and for nasal polyps. When using approved INCSs for allergic rhinitis, most products are administered once daily with the exception of beclomethasone dipropionate monohydrate (Beconase AQ) and generic flunisolide nasal sprays, dosed twice daily. The 3 products indicated for the management of nasal polyps (e.g. Beconase AQ, Nasonex, and Xhance) are dosed twice daily. Preference for the use of one INCS over another is not specified in guidelines identified for the treatment of allergic rhinitis, chronic rhinosinusitis, or for nasal polyps. Following a systematic search, we screened 313 systematic reviews and 634 randomized controlled trials published from 2007 onward. Where head-to-head studies were available, (a) no difference was reported in the change of CRSwNP disease severity comparing fluticasone propionate with beclomethasone or mometasone furoate47; and (b) there was no difference in epithelial thickening after 52 weeks of treatment with fluticasone furoate versus mometasone (safety endpoint).58 No head-to-head studies were found in systematic reviews designed to address INCS- head-to-head comparative evidence in the settings of CRS without nasal polyps (Chong et al, Cochrane 201647); CRS following post-surgical intervention for nasal polyps (Fandino et al, 201348); and persistent allergic rhinitis in children (Al Sayyad et al, Cochrane 200749). Additional RCTs published since 2007, reported no significant differences in primary efficacy endpoints between certain treatment comparisons: fluticasone furoate versus mometasone furoate and beclomethasone versus mometasone for perennial AR; fluticasone propionate versus mometasone for child dust mite AR; fluticasone furoate versus fluticasone propionate for seasonal AR.55-57,60 The majority of evidence suggests that these products have similar efficacy profiles, with one head-to-head comparison standing out in particular (budesonide vs. fluticasone propionate). One RCT (Day et al.) reported a significant difference the reduction of the patient-rated total nasal symptom score (primary endpoint) in favor of budesonide 256 mcg/day versus fluticasone propionate 200 mcg/day for treatment of adults with perennial allergic rhinitis.51 In the setting of adult seasonal allergic rhinitis, one study (Stern et al.) suggested budesonide 256 mcg/day improves patient-rated nasal symptoms better than fluticasone propionate 200 mcg/day only for days when the pollen count was greater than 10 grains/m3; products performed similarly when total nasal symptom scores were evaluated over all treatment days regardless of pollen count.50

Appendix A: INCS Indication Comparison

Table 1. Indication comparisons for nasal corticosteroids1-3,8,10,12,13,15,19,61 Generic name Non-allergic (available brand Allergic Rhinitis Nasal Polyps Rhinitis/or names) Perennial Seasonal Vasomotor Beclomethasone diproprionate X X (Qnasl Rx) Beclomethasone diproprionate X X X X monohydrate (Beconase AQ Rx) Budesonide X (Rx) X (OTC/Rx) (Rhinocort OTC) Ciclesonide X X (Omnaris, Zetonna) Flunisolide X X (Generic Rx) Fluticasone Furoate X (per old Rx Veramyst labeling) X (OTC) (Flonase Sensimist OTC) Fluticasone Proprionate (Generic Rx; Flonase X (Xhance product only) X (Flonase OTC) X (Rx) OTC; Xhance Rx) X; also has specific nasal Mometasone Furoate X X congestion and (Nasonex Rx) prophylaxis indications Triamcinolone Acetonide X (per old Rx Nasacort labeling) X (OTC) (Nasacort OTC) *Note that the indication is specified for the drug moiety in general, however, depends on the specific product formulation/strength/age group. Refer to table 1 in text for the specific product that the indication applies to. Abbreviations: OTC, over the counter formulation; Rx, prescription formulation

Appendix B: Search Strategies

Table 1. Ovid Medline Literature Search Strategy • Ovid MEDLINE(R) Epub Ahead of Print, In-Process & Other Non-Indexed Citations, Ovid MEDLINE(R) Daily, Ovid MEDLINE and Versions(R) 1 Beclomethasone/ or ("beclomethasone dipropionate" or aerobec or afifon or alanas? or aldecin? or anceron or "asmabec clickhaler" or atomase or atomide or beceze or beclamet or beclat? or beclazon? or "beclo siozwo nasenspray" or beclo-asma or "beclo-asma cfc free" or beclo-rhino or becloasma or "beclocort nasel" or beclofort? or beclojet or beclomet or "beclometasone dipropionate monohydrate" or "beclomethasone dipropionate" or "beclomethasone dipropionate monohydrate" or "beclomethazone dipropionate" or beclon? or beclorhinol or beclosol or "beclosol aquoso" or beclotaide or becloturmant or becloturmat or beclovent or becodisk? or beconas? or "beconase aq" or beconasol or becotid? or belax or "bemedrex easyhaler" or bronconox or "bronconox forte" or "chf 1514" or chf1514 or clenil or decomit or ecobec or filair or miflason? or "nasobec aqueous" or nexxair or nobec or orbec or propaderm or "propaderm forte" or "q var" or qnasl or qvar or "qvar 40" or "qvar 80" or "qvar autohaler" or "qvar inhaler" or ratioallerg or respocort or rhinivict or "rhino clenil" or rinaz? or rino-clenil or rynconox or sanasthmax or sanasthmyl or "sbn 024" or sbn024 or "sch 18020w" or vancenas? or vanceril or viarex or viarox or xiten).ti,ab,kw,kf,rn. (3578) 2 Budesonide/ or (acorspray or aerox or allercort or aquacort or "b cort" or bidien or budecol or budecort or budefat or budeflam or budelin or "budenase aq" or budeno or budenofalk or budenoside or budes or budeson or budiair or budo-san or budon or budosan or bunase or buparid or butacort or clebudan or coramen or cortiment or cycortide or "desona nasal" or desonix or dexbudesonide or duasma or eltair or entocir or entocort or esonide or "giona easyhaler" or inflammide or inflanaze or intesticort or intestifalk or larbex or "map 0010" or map0010 or miflo or miflonid or miflonide or miflonil or mikicort or nebbud or neo-rinactive or novopulmon or numark or olfex or preferid or pulmaxan or "pulmicon susp for nebuliser" or "pulmicon susp for nebulizer" or pulmicort or pulmoliseflam or pulmotide or respicort or rhinocort or ribujet or ribuspir or ribuvent or "s 1320" or s1320 or spirocort or tafen nasal or uceris).ti,ab,kw,kf,rn. (4432) 3 (ciclesonide or alvesco or "b 9207 015" or "b 9207015" or "b9207 015" or b9207015 or "by 9010" or by9010 or omnaris or zetonna).ti,ab,kw,kf,rn. (371) 4 (flunisolide or aerobid or aerobid-m or aerospan or bronalide or bronilide or cyntaris or flunisolide hemihydrate or flunitec or gibiflu or inhacort or locasyn or lokilan or lunis or nasalide or nasarel or rhinalar or "rs 3999" or rs3999 or sanergal or synaclyn or syntaris or "val 679" or val679).ti,ab,kw,kf,rn. (406) 5 ("fluticasone furoate" or alisade or allermist or arnuity or arnuity ellipta or avamys or "fluticasone 17 furoate" or "fluticasone furoate gsk" or "gsk 685698" or gsk685698 or "gw 685698" or "gw 685698x" or gw685698 or gw685698x or veramyst).ti,ab,kw,kf,rn. (328) 6 Fluticasone/ or ("fluticasone propionate" or "armonair respiclick" or atemur or axotide or "beconase allergy 24 hour" or "cci 18781" or cci18781 or cutivat or cutivate or flixonase or flixotide or flixovate or flonase or flovent or flunase or fluspiral or "fluticasone 17 propionate" or flutide or flutinase or flutivate or fluxonal or "gr 18781" or gr18781 or zoflut).ti,ab,kw,kf,rn. (3670) 7 Mometasone furoate/ or ("allermax aqueous" or asmanex or dermotasone or dermovel or ecural or elica or elocom or elocon or elocyn or elomet or eloson or flumeta or mefurosan or metaspray or momate or mometasone or monovel or morecort or motaderm or nasonex or novasone or rinelon or rivelon or "sch 32088" or sch32088 or uniclar).ti,ab,kw,kf,rn. (1038) 8 Triamcinolone Acetonide/ or ("adcortyl in orabase" or aftab or ahbina or albicort or aquatain or "aristocort a" or "aristocort acetonide" or aristogel or azmacort or centocort or cinolar or "denkacort forte" or facort or "fluoxiprednisolone acetonide" or flutex or flutone or fougera or ftorocort or gemicort or generlog or "invert plaster" or kemzid or "kena log" or kenac or "kenacort a" or "kenacort e" or "kenacort im" or "kenacort t" or kenacort-a or kenalog* or kenalone or kenlog or "kortikoid ratiopharm" or "ledercort a" or "ledercort d" or manolone or metoral or nasacort or "nasocor aq" or nincort or oracort or oralog or oralone or oramedy or orrepaste or panalog or pokkortolon or shincort or solodelf or "steronase aq" or tibicorten or tibiocorten or tramacin or "tri anemul" or tri-nasal or triacet or triacort or triaderm or triam or triam-denk or triamalone or "triamcinolide acetonide" or "triamcinolon acetonide" or "triamcinolone acetamide" or "triamcinolone acetonamide" or "triamcinolone acetonid" or "triamcinolone acetonide in absorbase" or "triamcinolone acetonide potassium phosphate" or "triamcinolone acetonide tincture" or "triamcinolone benetonide" or trianide or triatex or tricort or tricortone or triderm or tridez or triesence or trigon or trikort or trinolone or trivaris or trymex or vetalog or vistrec or "volon a" or "volon a 10" or "volon a 40" or "volon a 80" or "volon a antibiotikafrei" or "volon a spray" or "volon a tincture" or volonimat or yn 102 or yn102).ti,ab,kw,kf,rn. (10076) 9 1 or 2 or 3 or 4 or 5 or 6 or 7 or 8 (21842) 10 (((systematic adj2 review) or (overview adj3 review?)).ti. or (metaanaly$ or meta-analy$).ti,ab,pt. or

Table 1. Ovid Medline Literature Search Strategy • Ovid MEDLINE(R) Epub Ahead of Print, In-Process & Other Non-Indexed Citations, Ovid MEDLINE(R) Daily, Ovid MEDLINE and Versions(R) ((systematic adj2 review) or (metaanaly$ or meta-analy$)).kw,kf.) not ((exp animals/ not humans.sh.) or (animal? or beaver? or beef or bovine or breeding or bull or canine or castoris or cat or cattle or cats or chicken? or chimp$ or cow or dog or dogs or equine or foal or foals or fish or insect? horse or horses or livestock or mice or monkey? or mouse or murine or plant or plants or pork or porcine or protozoa? or purebred or rat or rats or rodent? or sheep or thoroughbred).ti. or veterinar$.ti,ab,kw,kf,hw.) (204944) 11 9 and 10 (359) 12 limit 11 to english (348) 13 limit 12 to yr="2007 -Current" (254) 14 remove duplicates from 13 [ total SRs for all drugs, Eng, Not animals ] (215) 15 ((randomized controlled trial or controlled clinical trial).pt. or randomized.ab. or placebo.ab. or clinical trials as topic.sh. or randomly.ab. or trial.ti.) not ((exp animals/ not humans.sh.) or (animal? or beaver? or beef or bovine or breeding or bull or canine or castoris or cat or cattle or cats or chicken? or chimp$ or cow or dog or dogs or equine or foal or foals or fish or insect? horse or horses or livestock or mice or monkey? or mouse or murine or plant or plants or pork or porcine or protozoa? or purebred or rat or rats or rodent? or sheep or thoroughbred).ti. or veterinar$.ti,ab,kw,kf,hw.) (1143416) 16 9 and 15 (6327) 17 limit 16 to english language [ RCTs ] (5876) 18 limit 17 to yr="2011 -Current" [ RCTs, date from 2011 (1530) 19 18 not 14 (1423) 20 remove duplicates from 19 [total RCTs for all drugs, Eng, Not animals, 2011 - present] (1167) 21 exp Rhinitis/ or exp Sinusitis/ or Nasal Polyps/ or Rhinitis, Allergic, Seasonal/ or (((rhinitis or rhinosinusitis or nasosinusitis or sinusnitis or pansinusitis or sphenoiditis or 'nasal polyp*' or 'nose polyp*' or 'nasal papilloma*' or (papilloma adj2 nasi) or 'polyposis nasi' or 'hay fever' or hayfever* or 'pollen allerg*' or pollensos* or pollinos* or (Pollen* or season* or summer)) adj2 (allerg* or hypersensitivity* or bronchitis* or rhinoconjunctivitis)) or catarrh).ti,ab,kw,kf. (60688) 22 17 and 21 [ RCT plus Indications ] (973) 23 limit 22 to yr="2011 -Current" [ RCTplus Indications, date from 2011 ] (209) 24 Administration, Intranasal/ or (intranasal* or "intra nasal*" or nasal* or nose or transnasal* or "' trans nasl*").ti,ab,kw,kf. (159348) 25 17 and 24 [RCTs plus nasal ] (1075) 26 limit 25 to yr="2011 -Current" [RCTs plus nasal - 2011 to present] (235) 27 22 or 25 [ RCT plus (indications or nasal admin) No date limit ] (1122) 28 23 or 26 [ RCTs plus (indications or nasal) 2011 - present ] (247) 29 28 not 14 [ RCTs not SR results ] (228) 30 remove duplicates from 29 [ Final RCTs plus (indications or nasal) 2011 - present ] (212)

Table 2. EMBASE Literature Search Strategy • EMBASE.com #1 'beclometasone dipropionate '/mj OR aerobec:ti ,ab,dn,mn,rn,t n OR afi fon:ti ,ab,dn,mn,rn,tn OR alanas?:ti,ab,dn,mn,rn,tn OR aldecin?:ti,ab,dn,mn, rn,tn OR anceron:ti ,ab,dn,mn,rn,tn OR 'asmabec clickhaler' :ti,ab,dn,mn,rn,tn OR atomase :ti,ab,dn,mn, rn,tn OR atomide:ti ,ab,dn,mn,rn,tn OR b eceze:ti,ab,dn,mn,rn,tn OR becl amet: ti,ab,dn,mn,rn,tn OR b eclat?:ti,ab,dn,mn,rn,tn OR becl azon?:ti,ab,dn,mn,rn,tn OR 'beclo siozwo nasenspray':ti ,ab,dn,mn,rn,tn OR 'beclo asma':t i,ab,dn,mn,rn,tn OR 'beclo-asma cfc free':ti,ab,dn,mn,rn,tn OR 'beclo rhino':ti, ab,dn,mn,rn,tn OR b ecloasma:ti ,ab,dn,mn,rn,tn OR 'beclocort nasel':ti, ab,dn,mn,rn,tn OR beclo fort?:ti ,ab,dn,mn,rn,tn OR beclojet :ti,ab,dn,mn, rn,tn OR beclomet :ti,ab,dn,mn, rn,tn OR 'beclometasone dipropionate monohydrate':ti, ab,dn, mn,rn,tn OR 'beclomethasone dipropionate':ti ,ab,dn,mn,rn,tn OR 'beclo methasonedipropionate monohydrate' :ti,ab,dn,mn,rn,tn OR 'beclomethazone dipropionate' :ti,ab,dn,mn,rn,tn OR beclon?:t i,ab,dn,mn,rn,tn OR beclorhinol:ti ,ab,d n,mn,rn,tn OR b eclosol:t i,ab,dn,mn, rn,tn OR 'beclosol aquoso':t i,ab,dn,mn, rn,tn OR beclot aide:ti,ab,dn,mn,rn,tn OR becloturm ant :ti,ab,dn,mn,rn,tn OR becloturm at:ti, ab,dn,mn,rn,tn OR b eclovent :ti,ab,dn,mn,rn,tn OR becodisk? :ti,ab,dn,mn, rn,tn OR becon as?:ti,ab,dn,mn,rn,tn OR 'beconase aq':ti ,ab,dn,mn, rn,tn OR becon asol:ti,ab,dn,mn, rn,tn OR becotid?: ti,ab,dn,mn,rn,tn OR bel ax:ti,ab,dn,mn,rn,tn OR 'bemedrex easyhaler'

Table 2. EMBASE Literature Search Strategy • EMBASE.com :ti,ab,dn,mn,rn,tn OR bron conox:ti ,ab,dn,mn,rn,tn OR 'bronconox forte':ti ,ab,dn,mn, rn,tn OR 'chf 1514':ti,ab,dn,mn,rn,tn OR chf1514:ti ,ab,dn,mn,rn,tn OR clenil:ti,ab,dn ,mn,rn,tn OR decomit:ti,ab,dn, mn,rn,tn OR ecob ec:ti,ab,dn,mn, rn,tn OR fil air:ti ,ab,dn,mn, rn,tn OR mifl ason?:ti,ab,dn,mn, rn,tn OR 'nasobec aqueous':ti ,ab,dn,mn,rn,tn OR nexxair:ti,ab,dn,mn,rn,tn OR nobec:ti ,ab,dn,m n,rn,tn OR orb ec:ti,ab,dn,mn, rn,tn OR prop aderm:t i,ab,dn,mn,rn,tn OR 'propaderm forte' :ti,ab,dn,mn,rn,tn OR 'q v ar' :ti,ab,dn,mn,rn,tn OR qn asl:ti,ab,dn,mn, rn,tn OR qv ar:ti,ab,dn,mn,rn,tn OR 'qvar 40':ti,ab,dn, mn,rn,tn OR 'qvar 80':ti ,ab,dn,mn,rn ,tn OR 'qvar autohaler':ti,ab ,dn,mn ,rn,tn OR 'qvar inhaler':ti ,ab,dn,mn,rn,tn OR r atioallerg:ti,ab ,dn, mn,rn,tn OR respocort :ti,ab,dn,mn,rn,tn OR rhinivict:ti,ab,dn,mn,rn,tn OR 'rhino clenil ':ti,ab,dn,mn,rn,tn OR rinaz?:ti,ab,dn,mn,rn,tn OR 'rino clenil':ti ,ab,d n,mn ,rn,tn OR ryn conox:ti ,ab,dn,mn,rn,tn OR sanasthmax:ti ,ab,dn,mn,rn,tn OR sanasthmyl:ti ,ab,dn,mn, rn,tn OR 'sbn 024':ti,ab,dn,mn,rn,tnOR sbn024 :ti,ab,dn,mn,rn,tnOR 'sch 18020w':ti ,ab,dn,mn,rn,tn OR v ancenas?:ti,ab,dn,mn, rn,tn OR vanceril:ti,ab ,dn,mn,rn,tn OR vi arex:ti, ab,dn,m n,rn,tn OR vi arox:ti,ab ,dn, mn,rn,tn OR xiten: ti,ab,dn,mn,rn,tn (5,344) #2 'budesonide'/mj OR ((acorspray:t i,ab,dn,mn,rn,tn OR aerox:ti, ab,dn,mn, rn,tn OR all ercort:t i,ab,dn,mn,rn,tn OR aquacort :t i,ab,dn,mn, rn,tn OR 'b cort':ti,ab,dn,mn,rn,tn OR bidien :ti,ab,dn, mn,rn,tn OR budecol :ti,ab,dn,mn, rn,tn OR budecort: t i,ab,d n,mn,rn,tn OR budef at :ti,ab,dn,mn,rn, tn OR budefl am:ti,ab,dn,mn,rn,tn OR budelin:ti ,ab,dn, mn,rn,tn OR 'budenase aq':ti, ab,dn, mn,rn,tn OR budeno:ti ,ab,dn, mn,rn,tn OR bud enofalk :ti,ab,dn,mn,rn,tn OR budenoside: ti,ab,dn,mn, rn,tn OR budes:ti ,ab,dn,mn,rn,tn OR budeson:ti, ab,dn,mn,rn,tn OR budi air :ti,ab,dn,mn,rn,tn OR 'budo san':ti,ab,dn,mn,rn,tn OR budon:ti,ab ,dn,mn,rn,tn OR budos an:ti,ab,dn,mn,rn,tn OR bun ase:ti,ab,dn,mn,rn,t n OR bup arid:ti ,ab,dn,mn,rn,tn OR but acort:ti ,ab,d n,mn, rn,tn OR clebudan :ti,ab,dn,mn,rn,tn OR coramen :ti,ab,dn,mn,rn,tn OR cortiment:t i,ab,dn,mn,rn,tn OR cycortide :ti,ab,dn,mn, rn,tn OR 'desona nasal':ti ,ab,dn,mn,rn,tn OR desonix:t i,ab,dn,mn,rn,tn OR dexbudesonide:ti ,ab,dn,mn,rn,t n OR du asma:ti,ab,dn,mn,rn,tn OR elt air:ti ,ab,dn,mn,rn,tn OR entocir:ti, ab,dn,mn,rn,tn OR entocort:ti, ab,dn,mn,rn,tn OR esonide :ti,ab,dn,mn, rn,tn OR 'giona easyhaler': ti,ab,dn,mn ,rn,tn OR infl ammide:ti ,ab,dn,mn,rn,t n OR infl anaze:ti,ab,dn, mn,rn,tn OR intesticort:ti ,ab,dn,mn,rn,tn OR intestifalk:ti,ab,dn,mn,rn,tn OR larbex :ti,ab,dn,mn,rn,tn OR 'map 0010':ti,ab,dn, mn,rn,tn OR m ap0010:ti,ab,dn,mn,rn,tn OR mifl o:t i,ab, dn,mn,rn,tn OR mifl onid:ti ,ab,d n,mn,rn,tn OR mifl onid e:ti,ab,dn,mn,rn,tn OR mifl onil:ti ,ab,dn, mn,rn,tn OR mikicort:ti ,ab,dn,mn, rn,tn OR nebbud:ti ,a b,dn,mn,rn,tn OR 'neo rinactive':ti ,ab,dn,mn,rn, tn OR novopulmon:ti ,a b,dn,mn,rn,tn OR num ark :ti,ab,dn,mn,rn,tn OR olfex :t i,a b,dn,mn,rn,tn OR preferid:ti ,ab, dn,mn,rn,tn OR pulmax an:ti,ab,dn,mn,rn,tn OR 'pulmicon susp for nebuliser':t i,ab,dn,mn, rn,tn OR 'pulmicon susp for nebulizer' :ti,ab,dn,mn,rn,tn OR pulmi cort:ti, ab,dn,mn,rn,tn OR pulmolise fl am:ti,ab,dn,mn,rn,tn OR pulmotid e:ti,ab,dn,mn,rn,tn OR respicort:ti ,ab,dn,mn,rn,tn OR rhinocort :t i,ab,dn,mn, rn,tn OR ribujet:t i,ab, dn,mn,rn,tn OR ribuspir:ti, ab,dn,mn,rn,tn OR ribuv ent :ti,ab,dn,mn,rn,tn OR 's 1320' :ti,ab,dn,mn,rn,tn OR s1320:ti,ab,dn,mn,rn,tn OR spirocort:ti ,ab,dn,mn, rn,tn OR t afen:t i,ab,dn,mn,rn,tn) AND nasal:ti ,ab,dn,mn,rn,tn) OR uc eris:ti ,ab,dn,mn, rn,tn (4,887) #3 'ciclesonide'/d e OR ((ciclesonide:ti,ab,dn,mn,rn,tn OR alvesco:ti,ab,dn,mn, rn,tn OR 'b 9207 015':ti,ab,dn,mn,rn,tn OR 'b 207015':ti,ab,dn, mn,rn,tn OR b 9207:ti,ab,dn,mn,rn,t n) AND 015:ti,ab,dn,mn,rn,tn) OR b 9207015:ti,ab,dn, mn,rn,tn OR 'by 9010':ti,ab,dn,mn,rn,tn OR by9 010:ti,ab,dn, mn,rn,tn OR omn aris:ti,ab,dn,mn,rn,tn OR zetonna :ti,ab,dn,mn,rn,tn (1,359) #4 ('flunisolide'/mj OR aerobid OR 'aerobid m' OR aerospan OR bronalide OR bronilide OR cyntaris OR flunisolide) AND hemihydrate OR flunitec OR gibiflu OR inhacort OR locasyn OR lokilan OR lunis OR nasalide OR nasarel OR rhinalar OR 'rs 3999' OR rs3999 OR sanergal OR synaclyn OR syntaris OR 'val 679' OR v al679:ti,ab,dn,mn,rn,tn (303) #5 'fluticasone furoate' /mj OR ((alisade:ti,ab,dn,mn,rn,tn OR allermist:t i,ab,dn, mn,rn,tn OR arn uity:ti ,ab,dn,mn,rn,tn) AND ellipta:ti,ab ,dn,mn,rn,tn) OR avamys:ti,ab,dn,mn,rn,tn OR 'fluticasone 17 furoate' :ti,ab,dn,mn,rn,tn OR 'fluticasone furoate gsk':ti,ab,dn,mn, rn,tn OR 'gsk 685698':ti,ab,dn,mn,rn,tnOR gsk 685698:ti,ab,dn,mn,rn,tn OR 'gw 68 5698':ti,ab,dn,mn,rn,tn OR 'gw 685698x':ti,ab,dn,mn, rn,tn OR gw68 5698:ti,ab,dn, mn,rn,tn OR gw 685698x:ti,ab,dn, mn,rn,tn OR ver amyst:ti,ab,dn,mn,rn,tn (339) #6 'fluticasone propionate'/mj OR 'armonair respiclick':ti,ab,dn,mn,rn,tn OR atemur:ti,ab,dn,mn,rn,tn OR axotide:ti,ab,dn,mn,rn,tn OR 'beconase allergy 24 hour':ti,ab,dn,mn,rn,tn OR 'cci 18781':ti,ab,dn,mn,rn,tn OR cci18781:ti,ab,dn,mn,rn,tn OR cutivat:ti,ab,dn,mn,rn,tn OR cutivate:ti,ab,dn,mn,rn,tn OR flixonase:ti,ab,dn,mn,rn,tn OR flixotide:ti,ab,dn,mn,rn,tn OR flixovate:ti,ab,dn,mn,rn,tn OR flonase:ti,ab,dn,mn,rn,tn OR flovent:ti,ab,dn,mn,rn,tn OR flunase:ti,ab,dn,mn,rn,tn OR fluspiral:ti,ab,dn,mn,rn,tn OR 'fluticasone 17 propionate':ti,ab,dn,mn,rn,tn OR flutide:ti,ab,dn,mn,rn,tn OR flutinase:ti,ab,dn,mn,rn,tn OR flutivate:ti,ab,dn,mn,rn,tn OR fluxonal:ti,ab,dn,mn,rn,tn OR 'gr 18781':ti,ab,dn,mn,rn,tn OR gr18781:ti,ab,dn,mn,rn,tn OR zoflut:ti,ab,dn,mn,rn,tn #7 'mometasone furoate' /mj OR 'allermax aqueous' :ti,ab,dn,mn, rn,tn OR asmanex:ti ,ab,dn,mn,rn,tn OR d ermotasone :ti,ab,dn,mn, rn,tn OR dermovel:ti ,ab, dn,mn,rn,tn OR ecur al:ti,ab,dn,mn,rn,tn OR elic a:ti,ab,dn,mn,rn,tn OR elocom:ti ,ab,dn,mn, rn,tn OR elocon:ti, ab,dn ,mn,rn ,tn OR elocyn :ti,ab,dn,mn,rn,tn OR elomet :ti,ab,dn,mn,rn,tn OR eloson :ti,ab,dn,mn, rn,tn OR flum eta :ti,ab,dn,mn,rn,tn OR

Table 2. EMBASE Literature Search Strategy • EMBASE.com mefuros an:ti,ab,dn,mn,rn,tn OR m etaspray:ti ,ab,dn,mn,rn,tn OR mom ate:ti,ab,dn,mn, rn,tn OR momet asone:ti,ab,dn,mn, rn,tn OR monovel:ti,ab,dn,mn,rn,tn OR morecort :ti,ab,dn,mn, rn,tn OR mot aderm: ti,ab,dn,mn,rn,tn OR nasonex:ti,ab,dn,mn,rn,tn OR no vasone:ti,ab,dn,mn, rn,tn OR rin elon: ti,ab,dn,mn,rn,tn OR rivelon:ti ,a b,dn,mn,rn,tn OR 'sch 32088':ti,ab,dn, mn,rn,tn OR sch32088:ti,ab,dn, mn,rn,tn OR unicl ar:ti,ab,dn,mn,rn,tn (2043) 'triamcinolone acetonide'/mj OR (('adcortyl in orabase':ti ,ab,dn,mn, rn,tn OR aft ab:ti,ab,dn,mn,rn,tn OR ahbina:t i,ab,dn,mn,rn,tn OR albicort :ti,ab,dn,mn,rn,tn OR aquatain:t i,ab,dn,mn,rn,tn OR 'aristocort a':ti,ab,dn,mn,rn,tn OR 'aristocort acetonide' :ti,ab,dn,mn,rn,tn OR aristogel:ti ,ab,dn,mn, rn,tn OR azmacort:ti ,ab,dn,mn, rn,tn OR centocort:ti,ab,dn,mn,rn,tn OR cinolar:t i,ab,dn,mn,rn,tn OR 'denkacort forte' :ti,ab,dn,mn,rn,tn OR f acort :ti,ab,dn,mn, rn,tn OR 'fluoxiprednisolone acetonide' :ti,ab,dn,mn,rn,tn OR flutex:ti,ab,dn,mn,rn,tn OR fluton e:ti,ab,dn,mn,rn,tn OR foug era:t i,ab,dn,mn,rn,tn OR ftorocort:ti,ab ,dn,mn, rn,tn OR gemicort:ti,ab ,dn,mn, rn,tn OR generlog:t i,ab,dn, mn,rn,tn OR 'invert plaster' :ti,ab,dn, mn,rn,tn OR kemzid:ti,ab,dn,mn,rn,tn OR 'kena log':ti ,ab,dn,mn,rn,tn OR k enac:ti,ab,dn,mn, rn,tn OR 'kenacort e':ti,ab,dn,mn,rn,tn OR 'kenacort im':ti, ab,dn,mn,rn,tn OR 'kenacort t ':ti,ab,dn,mn,rn,tn OR 'kenacort a':t i,ab,dn,mn,rn,tn OR ken alog* :ti,ab,dn,mn,rn,tn OR ken alone :ti,ab,dn,mn,rn,tn OR k enlog:ti,ab,dn,mn,rn,tn OR 'kortikoid ratiopharm':ti,ab ,dn, mn,rn,tn OR 'ledercort a':ti,ab,dn,mn,rn,tn OR 'ledercort d':ti ,ab,dn,mn,rn,tn OR manolon e:ti,ab,dn,mn,rn,tn OR metor al:ti,ab,dn,mn,rn,tn OR n asacort :ti,ab,dn,mn, rn,tn OR 'nasocor aq':ti,ab,dn,mn,rn,tn OR nin cort :ti,ab,dn,mn,rn,tn OR or acort:ti ,ab,dn,mn, rn,tn OR or alog:ti,ab,dn,mn,rn,tn OR or alone:ti, ab,dn ,mn,rn ,tn OR or amedy:ti ,ab,dn,mn,rn,tn OR orr epaste:ti,ab,dn,mn,rn,tn OR p analog:t i,ab,dn,mn,rn,tn OR pokkortolon:t i,ab,dn, mn,rn,tn OR shincort:t i,ab,dn,mn,rn,tn OR solodelf:ti ,ab,dn,mn, rn,tn OR 'steronase aq':ti ,ab,dn,mn,rn,tn OR tibicorten:ti,ab,dn,mn,rn,tn OR tibiocorten:ti,ab,dn,mn,rn,tn OR tr amacin :ti,ab,dn,mn, rn,tn OR 'tri anemul' :ti,ab,dn,mn,rn,tn OR 'tri nasal':t i,ab,dn,mn,rn,tn OR triacet :ti,ab,dn,mn, rn,tn OR triacort:ti,ab,dn,mn,rn,tn OR tri aderm: ti,ab,dn,mn,rn,tn OR triam:ti,ab,dn,mn,rn,tn OR 'triam denk':ti ,ab,dn,mn,rn,tn OR tri amalone:ti ,ab,dn,mn,rn,tn OR 'triamcinolide acetonide':ti ,ab,dn,mn,rn,tn OR 'triamcinolon acetonide' :ti,ab,dn,mn,rn,tn OR 'triamcinolone acetamide':ti,ab ,dn, mn,rn,tn OR 'triamcinolone acetonamide':ti ,ab,dn,mn,rn,tn OR 'triamcinolone acetonid' :ti,ab,dn,mn ,rn,tn OR 'triamcinolone acetonide in absorbase' :ti,ab,dn,mn, rn,tn OR 'triamcinolone acetonide potassium phosphate':ti,ab,dn,mn,rn,tn OR 'triamcinolone acetonide tincture':ti ,ab,d n,mn,rn,t n OR 'tria mcinolone benetonide':ti ,ab,dn,mn,rn,tn OR tri anide :ti,ab,dn,mn,rn,tn OR triatex:ti,ab,dn,mn,rn,tn OR tricort :ti,ab,dn,mn, rn,tn OR tri cortone:ti ,ab,dn,mn,rn,tn OR triderm:ti,ab,dn,mn,rn,tn OR tridez:ti ,ab,dn,mn, rn,tn OR tri esence:ti,ab,dn,mn,rn,tn OR trigon:ti,ab,dn,mn,rn,tn OR trikort:t i,ab,dn, mn,rn,tn OR trinolon e:ti,ab,dn,mn,rn,tn OR triv aris:t i,ab,dn,mn, rn,tn OR trym ex:ti,ab,dn,mn,rn,tn OR vetalog:ti ,ab,dn,mn,rn,tn OR vistrec:ti ,ab,dn,mn,rn,tn OR 'volon a':ti,ab,dn,mn,rn,tn OR 'volon a 10':ti,ab,dn,mn,rn,tn OR 'volon a 40':ti,ab,dn, mn,rn,tn OR 'volon a 80':ti,ab,dn,mn,rn,tn OR 'volon a antibiotikafrei':ti ,ab,dn,mn,rn,tn OR 'volon a spray':t i,ab,dn,mn,rn,tn OR 'volon a tincture':t i,ab,dn,mn,rn,tn OR volonimat:ti ,ab,dn,mn,rn,tn OR yn:ti,ab ,dn,mn, rn,tn) AND 102:ti ,ab,dn, mn,rn,tn) OR yn1 02:ti,ab,dn,mn,rn,tn (6356) #8 'triamcinolone acetonide'/mj OR (('adcortyl in orabase':ti ,ab,dn,mn, rn,tn OR aft ab:ti,ab,dn,mn,rn,tn OR ahbina:t i,ab,dn,mn,rn,tn OR albicort :ti,ab,dn,mn,rn,tn OR aquatain:t i,ab,dn,mn,rn,tn OR 'aristocort a':ti,ab,dn,mn,rn,tn OR 'aristocort acetonide' :ti,ab,dn,mn,rn,tn OR aristogel:ti ,ab,dn,mn, rn,tn OR azmacort:ti ,ab,dn,mn, rn,tn OR centocort:ti,ab,dn,mn,rn,tn OR cinolar:t i,ab,dn,mn,rn,tn OR 'denkacort forte' :ti,ab,dn,mn,rn,tn OR f acort :ti,ab,dn,mn, rn,tn OR 'fluoxiprednisolone acetonide' :ti,ab,dn,mn,rn,tn OR flutex:ti,ab,dn,mn,rn,tn OR fluton e:ti,ab,dn,mn,rn,tn OR foug era:t i,ab,dn,mn,rn,tn OR ftorocort:ti,ab ,dn,mn, rn,tn OR gemicort:ti,ab ,dn,mn, rn,tn OR generlog:t i,ab,dn, mn,rn,tn OR 'invert plaster' :ti,ab,dn, mn,rn,tn OR kemzid:ti,ab,dn,mn,rn,tn OR 'kena log':ti ,ab,dn,mn,rn,tn OR k enac:ti,ab,dn,mn, rn,tn OR 'kenacort e':ti,ab,dn,mn,rn,tn OR 'kenacort im':ti, ab,dn,mn,rn,tn OR 'kenacort t ':ti,ab,dn,mn,rn,tn OR 'kenacort a':t i,ab,dn,mn,rn,tn OR ken alog* :ti,ab,dn,mn,rn,tn OR ken alone :ti,ab,dn,mn,rn,tn OR k enlog:ti,ab,dn,mn,rn,tn OR 'kortikoid ratiopharm':ti,ab ,dn, mn,rn,tn OR 'ledercort a':ti,ab,dn,mn,rn,tn OR 'ledercort d':ti ,ab,dn,mn,rn,tn OR manolon e:ti,ab,dn,mn,rn,tn OR metor al:ti,ab,dn,mn,rn,tn OR n asacort :ti,ab,dn,mn, rn,tn OR 'nasocor aq':ti,ab,dn,mn,rn,tn OR nin cort :ti,ab,dn,mn,rn,tn OR or acort:ti ,ab,dn,mn, rn,tn OR or alog:ti,ab,dn,mn,rn,tn OR or alone:ti, ab,dn ,mn,rn ,tn OR or amedy:ti ,ab,dn,mn,rn,tn ORorr epaste:ti,ab,dn,mn,rn,tn OR p analog:t i,ab,dn,mn,rn,tn OR pokkortolon:t i,ab,dn, mn,rn,tn OR shincort:t i,ab,dn,mn,rn,tn OR solodelf:ti ,ab,dn,mn, rn,tn OR 'steronase aq':ti ,ab,dn,mn,rn,tn OR tibicorten:ti,ab,dn,mn,rn,tn OR tibiocorten:ti,ab,dn,mn,rn,tn OR tr amacin :ti,ab,dn,mn, rn,tn OR 'tri anemul' :ti,ab,dn,mn,rn,tn OR 'tri nasal':t i,ab,dn,mn,rn,tn OR triacet :ti,ab,dn,mn, rn,tn OR triacort:ti,ab,dn,mn,rn,tn OR tri aderm: ti,ab,dn,mn,rn,tn OR triam:ti,ab,dn,mn,rn,tn OR 'triam denk':ti ,ab,dn,mn,rn,tn OR tri amalone:ti ,ab,dn,mn,rn,tn OR 'triamcinolide acetonide':ti ,ab,dn,mn,rn,tn OR 'triamcinolon acetonide' :ti,ab,dn,mn,rn,tn OR 'triamcinolone acetamide':ti,ab ,dn, mn,rn,tn OR 'triamcinolone

Table 2. EMBASE Literature Search Strategy • EMBASE.com acetonamide':ti ,ab,dn,mn,rn,tn OR 'triamcinolone acetonid' :ti,ab,dn,mn ,rn,tn OR 'triamcinolone acetonide in absorbase' :ti,ab,dn,mn, rn,tn OR 'triamcinolone acetonide potassium phosphate':ti,ab,dn,mn,rn,tn OR 'triamcinolone acetonide tincture':ti ,ab,d n,mn,rn,t n OR 'tria mcinolone benetonide':ti ,ab,dn,mn,rn,tn OR tri anide :ti,ab,dn,mn,rn,tn OR riatex:ti,ab,dn,mn,rn,tn OR tricort :ti,ab,dn,mn, rn,tn OR tri cortone:ti ,ab,dn,mn,rn,tn OR triderm:ti,ab,dn,mn,rn,tn OR tridez:ti ,ab,dn,mn, rn,tn OR tri esence:ti,ab,dn,mn,rn,tn OR trigon:ti,ab,dn,mn,rn,tn OR trikort:t i,ab,dn, mn,rn,tn OR trinolon e:ti,ab,dn,mn,rn,tn OR triv aris:t i,ab,dn,mn, rn,tn OR trym ex:ti,ab,dn,mn,rn,tn OR vetalog:ti ,ab,dn,mn,rn,tn OR vistrec:ti ,ab,dn,mn,rn,tn OR 'volon a':ti,ab,dn,mn,rn,tn OR 'volon a 10':ti,ab,dn,mn,rn,tn OR 'volon a 40':ti,ab,dn, mn,rn,tn OR 'volon a 80':ti,ab,dn,mn,rn,tn OR 'volon a antibiotikafrei':ti ,ab,dn,mn,rn,tn OR 'volon a spray':t i,ab,dn,mn,rn,tn OR 'volon a tincture':t i,ab,dn,mn,rn,tn OR volonimat:ti ,ab,dn,mn,rn,tn OR yn:ti,ab ,dn,mn, rn,tn) AND 102:ti ,ab,dn, mn,rn,tn) OR yn1 02:ti,ab,dn,mn,rn,tn (6,356) #9 #1 OR #2 OR #3 OR #4 OR #5 OR #6 OR #7 OR #8 (20,843) #10 'corticosteroid' /mj/exp (323,195) #11 'intranasal drug administration' /de OR intranasal*:ti,ab,dn,mn,rn,tn OR 'intra nasal*':t i,ab,dn,mn,rn,tn OR n asal* :ti,ab,dn,mn,rn,tn OR nose:ti ,ab,dn,mn,rn,t n OR tr ansnasal*: ti,ab,dn,mn,rn,tn OR 'trans nasl* ':ti ,ab,dn,mn, rn,tn (185,068) #12 #10AND#11 (5,044) #13 #9 OR #12 (23,574) #14 ('meta analysis' /mj OR 'systematic review' /de OR (((systematic OR integrative OR drug OR therapeutic*) NEAR/2 review):ti) OR 'meta analys* ':ti,ab OR m etaanaly* :ti,ab) NOT ('conference abstract '/it OR 'conference paper'/it OR (('animal'/exp OR 'invertebrate'/exp OR 'animal experiment'/exp OR 'animal model'/exp OR 'animal tissue'/exp OR 'animal cell' /exp OR 'nonhuman'/de) NOT (('animal'/exp OR 'invert ebrate' /exp OR 'animal experiment '/exp OR 'animal model'/exp OR 'animal tissue'/exp OR 'animal cell' /exp OR 'nonhuman' /de) AND ('human'/exp OR 'human cell '/de)))) AND [englis h] / li m (194,150) #15 #13 AND #14 (325) #16 #13 AND #14 AND [2012-2017]/py (134) #17 ('clinical study' /m j OR 'clinical trial' /mj OR 'controlled clinical trial' /mj OR 'controlled study' /m j OR 'major clinical study'/mj OR 'randomized controlled trial'/mj OR 'control group'/mj OR (((clinical OR comparative OR efficacy OR effectiveness OR randomi* OR controlled OR multicentre OR multicenter OR ' multi centre' OR 'multi center') NEAR/3 (study OR tri al)):a b) OR pl acebo:ab,ti OR controlled:ti OR trial:ti OR multicent*:t i OR 'multi cent*':ti OR study:t i OR r andomly :ab OR 'head to head':ti,ab) NOT ('conference abstract '/it OR conference paper'/it OR (('animal'/exp OR 'invertebrate'/exp OR 'animal experiment'/exp OR 'animal model'/exp OR 'animal tissue'/exp OR 'animal cell' /exp OR 'nonhum an' /de) NOT (('animal' /exp OR 'invertebr ate' /exp OR 'animal experiment'/exp OR 'animal model'/exp OR 'animal tissue'/exp OR 'animal cell '/e xp OR 'nonhuman'/de) AND ('human'/exp OR 'human cell' /de)))) AND [english]/lim (1,509,002) #18 #9 OR #10 (326,425) #19 'rhinitis' /exp/m j OR 'rhinosinusitis'/exp/mj OR 'sinusitis'/exp/m j OR 'nose polyp' /mj OR 'pollen all ergy' /mj OR rhinitis :ti,ab,de,lnk OR 100,392 rhinosinusitis: ti,ab,de,lnk OR naso sinusitis :ti,ab,de,ln k OR inusnitis:ti ,ab,de,lnk OR p ansinusitis:ti ,ab,de,lnk OR sphenoiditis :ti,ab,de,lnk OR 'nasal polyp*':ti ,ab,de,lnk OR 'nose polyp*' :t i,ab,de,lnk OR 'nasal papi ll oma*':t i,ab,de,lnk OR ((papilloma NEAR/2 nasi):t i,ab,de, lnk) OR 'polyposis nasi' :ti,ab,de,lnk OR 'hay fever':t i,ab,de,lnk OR h ayfever* :ti,ab,de,lnk OR 'pollen allerg* ':ti,ab,de,lnk OR poll ensos* :ti,ab,de,lnk OR polli nos*:ti,ab ,de,lnk OR (((pollen* OR season* OR summer) NEAR/2 (allerg* OR hypersensitivity* OR bronchitis* OR rhinoconjunctivitis)):ti,ab,de,lnk ) OR catarrh: ti,ab,de,lnk #20 #18 AND #11 [ Drugs + Drug class plus Nasal] (5,102) #21 #18 AND #19 [ Drugs + Drug class plus Indications] (5,567) #22 #20 AND #17 [ RCTs for Drugs + Drug class plus Nasal] (1,151) #23 #21 AND #17 [ RCTs for Drugs + Drug class plus Indications] (1,204) #24 #22 OR #23 (1,432) #25 #24 NOT #16 [RCTs (Indication OR Nasal) not SR for last 5 yrs] (1,406)

Appendix C: Excluded Studies

Wrong intervention 1. Poetker DM, Jakubowski LA, Lal D, Hwang PH, Wright ED, Smith TL. Oral corticosteroids in the management of adult chronic rhinosinusitis with and without nasal polyps: an evidence-based review with recommendations. International forum of allergy & rhinology. 2013;3(2):104-120. 2. Varshney J, Varshney H, Dutta S, Hazra A. Comparison of sensory attributes and immediate efficacy of intranasal ciclesonide and fluticasone propionate in allergic rhinitis: A randomized controlled trial. Indian Journal of Pharmacology. 2012;44(5):550-554. • Patient preference study (not efficacy study) that appears to use products not available in the US Wrong patient population 3. Chadha NK, Zhang L, Mendoza-Sassi RA, Cesar JA. Using nasal steroids to treat nasal obstruction caused by adenoid hypertrophy: does it work? 2009;140(2):139-147. Wrong comparator 4. Bachert C. Evidence-based management of nasal polyposis by intranasal corticosteroids: from the cause to the clinic. International archives of allergy and immunology. 2011;155(4):309-321. 5. Berger WE, Meltzer EO. Intranasal spray medications for maintenance therapy of allergic rhinitis. American journal of rhinology & allergy. 2015;29(4):273-282. 6. Benninger M, Farrar JR, Blaiss M, et al. Evaluating approved medications to treat allergic rhinitis in the United States: an evidence-based review of efficacy for nasal symptoms by class. Annals of allergy, asthma & immunology : official publication of the American College of Allergy, Asthma, & Immunology. 2010;104(1):13-29. 7. Broersen LH, Pereira AM, Jorgensen JO, Dekkers OM. Adrenal Insufficiency in Corticosteroids Use: Systematic Review and Meta-Analysis. The Journal of clinical endocrinology and metabolism. 2015;100(6):2171-2180. 8. Grossman J, Gates D. Mometasone furoate nasal spray for the treatment of elderly patients with perennial allergic rhinitis. Annals of Allergy, Asthma, and Immunology. 2010;104(5):452-453. 9. Hayward G, Heneghan C, Perera R, Thompson M. Intranasal corticosteroids in management of acute sinusitis: a systematic review and meta-analysis. Annals of family medicine. 2012;10(3):241-249. 10. Mener DJ, Shargorodsky J, Varadhan R, Lin SY. Topical intranasal corticosteroids and growth velocity in children: a meta-analysis. International forum of allergy & rhinology. 2015;5(2):95-103. 11. Mirmoezzi MS, Yazdi MS, Gholami O. Comparative study on the efficacy of mometasone and fluticasone nasal sprays for treatment of allergic rhinitis. International Journal of Pharmacy and Pharmaceutical Sciences. 2017;9(3):211-214 • Study used a fluticasone propionate product not available in the US (100 mcg/actuation) 12. Rudmik L, Soler ZM. Medical Therapies for Adult Chronic Sinusitis: A Systematic Review. Jama. 2015;314(9):926-939. 13. Rudmik L, Schlosser RJ, Smith TL, Soler ZM. Impact of topical nasal steroid therapy on symptoms of nasal polyposis: a meta-analysis. The Laryngoscope. 2012;122(7):1431-1437 14. Rudmik L, Hoy M, Schlosser RJ, et al. Topical therapies in the management of chronic rhinosinusitis: an evidence-based review with recommendations. International forum of allergy & rhinology. 2013;3(4):281- 298. 15. Wei CC, Adappa ND, Cohen NA. Use of topical nasal therapies in the management of chronic rhinosinusitis. The Laryngoscope. 2013;123(10):2347-2359 16. Zalmanovici Trestioreanu A, Yaphe J. Intranasal steroids for acute sinusitis. The Cochrane database of systematic reviews. 2013(12):Cd005149. 17. Zalmanovici A, Yaphe J. Intranasal steroids for acute sinusitis. Cochrane Database of Systematic Reviews. 2009(4). 18. Zalmanovici A, Yaphe J. Steroids for acute sinusitis. Cochrane Database of Systematic Reviews. 2007(2).

Wrong study design 19. Anonymous. Seasonal allergic rhinitis: limited effectiveness of treatments. Prescrire International. 2008;17(93):28-32. 20. Benninger M. Diagnosis and management of nasal congestion: The role of intranasal corticosteroids. Postgraduate Medicine. 2009;121(1):122-131. 21. Berger WE, Prenner B, Turner R, Meltzer EO. A patient preference and satisfaction study of ciclesonide nasal aerosol and mometasone furoate aqueous nasal spray in patients with perennial allergic rhinitis. Allergy and asthma proceedings. 2013;34(6):542-550. 22. Braido F, Sclifo F, Ferrando M, Canonica GW. New therapies for allergic rhinitis. Current allergy and asthma reports. 2014;14(4):422. • Literature search dates were too limited, only searching 1 years’ worth of studies 23. Keith PK, Scadding GK. Are intranasal corticosteroids all equally consistent in managing ocular symptoms of seasonal allergic rhinitis? Current Medical Research and Opinion. 2009;25(8):2021-2041. 24. Kowalski ML. Oral and nasal steroids for nasal polyps. Current allergy and asthma reports. 2011;11(3):187- 188. 25. Kubavat AH, Pawar P, Mittal R, et al. An open label, active controlled, multicentric clinical trial to assess the efficacy and safety of fluticasone furoate nasal spray in adult Indian patients suffering from allergic rhinitis. Journal of the Association of Physicians of India. 2011;59:424-428. • Randomization unclear 26. Meltzer EO. Formulation considerations of intranasal corticosteroids for the treatment of allergic rhinitis. Annals of allergy, asthma & immunology : official publication of the American College of Allergy, Asthma, & Immunology. 2007;98(1):12-21. 27. Meltzer EO, Teper A, Danzig M. Intranasal corticosteroids in the treatment of acute rhinosinusitis. Current allergy and asthma reports. 2008;8(2):133-138. 28. Meltzer EO, Bensch GW, Storms WW. New intranasal formulations for the treatment of allergic rhinitis. Allergy and asthma proceedings. 2014;35 Suppl 1:S11-19. • This is a descriptive review article without a systematic search methodology 29. Nayak A, Langdon RB. Montelukast in the treatment of allergic rhinitis: an evidence-based review. Drugs. 2007;67(6):887-901 30. Passali D, Spinosi MC, Crisanti A, Bellussi LM. Mometasone furoate nasal spray: a systematic review. Multidisciplinary respiratory medicine. 2016;11:18. 31. Ratner PH, Stoloff S, Meltzer EO, Hadley JA. Intranasal corticosteroids in the treatment of allergic rhinitis. Allergy and asthma proceedings. 2007;28 Suppl 1:S25-32. • This is a descriptive review article without a systematic search methodology 32. Rodriguez-Martinez CE, Sossa-Briceno MP, Vladimir Lemos E. Cost-effectiveness analysis of mometasone furoate versus beclomethasone dipropionate for the treatment of pediatric allergic rhinitis in Colombia. Advances in therapy. 2015;32(3):254-269. 33. Schafer T, Schnoor M, Wagenmann M, Klimek L, Bachert C. Therapeutic Index (TIX) for intranasal corticosteroids in the treatment of allergic rhinitis. Rhinology. 2011;49(3):272-280. 34. Villa E, Magnoni MS, Micheli D, Canonica GW. A review of the use of fluticasone furoate since its launch. Expert Opinion on Pharmacotherapy. 2011;12(13):2107-2117. • This is a descriptive review article without a systematic search methodology Wrong outcome 35. Lohia S, Schlosser RJ, Soler ZM. Impact of intranasal corticosteroids on asthma outcomes in allergic rhinitis: a meta-analysis. Allergy. 2013;68(5):569-579 36. Meltzer EO, Stahlman JE, Leflein J, et al. Preferences of adult patients with allergic rhinitis for the sensory attributes of fluticasone furoate versus fluticasone propionate nasal sprays: A randomized, multicenter, double-blind, single-dose, crossover study. Clinical Therapeutics. 2008;30(2):271-279. 37. Meltzer EO, Andrews C, Journeay GE, et al. Comparison of patient preference for sensory attributes of fluticasone furoate or fluticasone propionate in adults with seasonal allergic rhinitis: a randomized, placebo-controlled, double-blind study. Annals of Allergy, Asthma and Immunology. 2010;104(4):331-338.

38. Yanez A, Dimitroff A, Bremner P, et al. A patient preference study that evaluated fluticasone furoate and mometasone furoate nasal sprays for allergic rhinitis. Allergy & Rhinology. 2016;7(4):183-192. 39. Yonezaki M, Akiyama K, Karaki M, et al. Preference evaluation and perceived sensory comparison of fluticasone furoate and mometasone furoate intranasal sprays in allergic rhinitis. Auris, Nasus, Larynx. 2016;43(3):292-297. Other 40. Kalish L, Snidvongs K, Sivasubramaniam R, Cope D, Harvey RJ. Topical steroids for nasal polyps. Cochrane database of systematic reviews (Online). 2012;12:CD006549. • Article withdrawn by Cochrane and updated to publication by Chong et al. 2016 41. Snidvongs K, Kalish L, Sacks R, Craig JC, Harvey RJ. Topical steroid for chronic rhinosinusitis without polyps. Cochrane Database of Systematic Reviews. 2011;2011(8). • Article withdrawn by Cochrane and updated to publication by Chong et al. 2016

Appendix D: Randomized Controlled Trials

Table 1. Randomized Controlled Trials Study Interventions & Population Results

Informational: excluded due to A) FFNS 27.5 mcg/actuation (Avamys GlaxoSmithKline, US trade “Overall, 56% of patients stated a preference for FFNS versus 32% for wrong outcome name, Veramyst) with excipients (glucose anhydrous, MFNS (p < 0.001); the remaining 12% stated no preference. More dispersible cellulose, polysorbate 80, benzalkonium chloride, patients stated a preference for FFNS versus MFNS for the attributes of Yanez et al 2016: A disodium edetate, and purified water): “less drip down the throat” (p < 0.001), “less run out of the nose” (p < patient preference Dose: 2 sprays per nostril, 110mcg total dose 0.05), “more soothing” (p < 0.05), and “less irritating” (p < 0.001). More study that B) MFNS 50 mcg/actuation (Nasonex Merck Sharp & Dohme patients responded in favor of FFNS versus MFNS for the immediate evaluated Limited) with excipients (benzalkonium chloride, dispersible attributes, “run down the throat” (p < 0.001), and “run out of the nose” fluticasone furoate cellulose, glycerol, sodium citrate, citric acid monohydrate, (p < 0.001), and, in the delayed attributes, “run down the throat” (p < and mometasone polysorbate 80, and purified water) 0.001), “run out of the nose” (p < 0.01), “presence of aftertaste” (p < furoate nasal Dose: 2 sprays per nostril, 200mcg total dose 0.01), and “no nasal irritation” (p < 0.001).” sprays for allergic Author’s conclusion: “Patients with allergic rhinitis preferred FFNS versus rhinitis Patients (n=300): adults, 18 – 65 years of age, with either MFNS overall and based on a number of individual attributes, including seasonal or perennial allergic rhinitis confirmed by a positive “less drip down the throat,” “less run out of the nose,” and “less allergen skin test result within 12 months of study treatment. irritating.” Greater preference may improve patient adherence and Multicenter, Excluded women who were pregnant or breast-feeding; patients thereby improve symptom management of the patient's allergic rhinitis.” double blind with an infection or structural abnormality of the respiratory Single dose cross- system; patients who used an intranasal corticosteroid within 4 over study weeks of study participation, other intranasal medications within 1 week of study participation, or medications that could disturb taste or smell

Table 1. Randomized Controlled Trials Study Interventions & Population Results

Informational: Patients were randomized to 2 weeks of treatment, then crossed excluded due to over the next 2 weeks of treatment “FNS was significantly preferred over MFNS. Significantly, fewer subjects wrong outcome A) FFNS (Allermist; GlaxoSmithKline K.K, Tokyo, Japan): Dose: 2 perceived a bitter taste (p = 0.01), medication running down their throat sprays per nostril, 110mcg total dose (p = 0.033), and medication running out of their nose (p = 0.002) with Yonezaki et al B) MFNS (Nasonex; MSD K.K, Tokyo, Japan): Dose: 2 sprays per FFNS. MFNS was more frequently reported to induce nasal irritation (p = 2016: nostril, 200mcg total dose 0.012), sneezing (p = 0.017), and rhinorrhea (p = 0.007) compared to Preference FFNS. Interestingly, these findings were markedly observed in females. evaluation and Patients (n=48): adult patients diagnosed with seasonal allergic Medicine dripping out of the nose and nasal shooting were the most perceived sensory rhinitis as defined by a clinical history of nasal allergic symptoms common problems reported for MFNS with a higher proportion of comparison of (e.g., nasal congestion, rhinorrhea, sneezing, nasal irritation, and subjects who felt moderate-to-severe discomfort. Overall, 52.5% of fluticasone furoate ocular symptoms) for a minimum of 2 years with scores of 2 or patients expressed a preference for FFNS compared with 22.5% for and mometasone more on the CAP radio-allergosorbent test corresponding to MFNS.” furoate intranasal individuals. Specific IgE against house dust mites, Japanese cedar Author’s Conclusion: “Several perceived sensory attributes of FFNS were sprays in allergic pollen, grass pollen (sweet vernal and orchard), and fall weed rated significantly superior to MFNS. FFNS may contribute to enhanced rhinitis pollens (ragweed and wormwood) were measured in the present treatment outcomes in AR patients due to improved treatment study. adherence” Excluded patients with history of treatment with oral, inhalation, Multicenter, (not or topical steroid therapy within 2 months of study enrollment; blinded) cross-over pregnant or breast feeding women; or presence of severe study (2 weeks of systemic diseases such as severe diabetes, uncontrolled asthma, treatment per and immunodeficiency intervention)

Table 1. Randomized Controlled Trials Study Interventions & Population Results

Mak et al, 2013: Patients randomized to 4 weeks of treatment: The only between group differences that were tested for significance Comparison of A) FPNS (Flixonase): 1 spray per nostril, 100mcg total daily dose (with p values provided) include the finding for: Mometasone B) MFNS (Nasonex): 1 spray per nostril, 100mcg total daily dose 1) Patient quality of life scores (based on 23 questions in five Furoate categories such as nasal symptoms, eye symptoms, practical Monohydrate Patients (n= 94): patients age 6 to 12 years old diagnosed with the problems, activity limitations, and other, recalled for the previous (Nasonex) and following (a) moderate to severe (defined per ARIA classification as week, on a 7-point scale): there was not a significant difference Fluticasone AR that occurs throughout the year) perennial allergic rhinitis for at between treatment groups at week 4 Propionate least 1 year, (b) a positive reaction to mite-specific IgE, and (c) (Flixonase) allergy to house dust mites confirmed by a skin-prick test response. • Although the authors concluded that the total symptom score Nasal Sprays in the Excluded individuals with a positive response to other allergens; analysis showed MFNS to be more effective for relieving nasal Treatment of Dust deformities of the ear, nose, or throat, or infection in the 2 weeks symptoms, and FPNS more effective for relieving non-nasal Mite-sensitive preceding the initial visit; medications that may affect allergy symptoms, a statistical significance test for the difference in baseline Children with symptoms (e.g oral antihistamines, decongestants, steroids, or change between treatment groups was not performed (rather Perennial Allergic leukotriene antagonists) within 2 weeks prior to the study or during significance was only tested against baseline score) and there is clear Rhinitis the study period; respiratory-tract infection within 2 weeks prior to overlap in the result intervals provided suggesting that differences the study; intranasal corticosteroid use within 2 weeks prior to the between treatment groups were not significant. Thus one should not Single center study study; or with nasal polyp disease. conclude that one agent is better than the other with this evidence. in Taiwan *Flixonase produced by GlaxoSmithKine

Aneeza et al, Patients were randomized to 8 weeks of treatment: • Endpoints assessed at 4 and 8 weeks 2013: Efficacy of A) FFNS (Avamys; GlaxoSmithKline): 110mcg total daily dose 1. Rhinoconjunctivitis QOLQ mometasone B) MFNS (Nasonex; Merck Sharp & Dohme Corp): 200mcg total 2. Daily documentation of nasal and ocular symptoms severity furoate and daily dose using a 4-point categorical scale from 0 to 3 (for how patient fluticasone furoate • Patients allowed rescue medication (loratadine 10mg/day) felt at that moment) on persistent Patients (n=78) 12 to 59 years old who had both nasal and ocular • Total nasal symptom score (TNSS): tally of nasal allergic symptoms of allergic rhinoconjunctivitis for 2 years or more. symptoms (rhinorrhea, congestion, sneezing, and rhinoconjunctivitis Excluded patients pregnant; with other nasal obstructive conditions itching) or nasal polyps; smokers; users of INCS or oral steroids for 4 weeks • Total ocular symptoms score: tally of ocular investigator before the baseline period. symptoms TOSS(watering, itching, and redness) blinded, Patients were dropped from the study if they • 63 patients who were randomized completed the study: (MFNS 8 week study did not complete 80% of their symptom scores in their diary or were n=36 and FFNS n =27); there was a 19.2% drop out rate mainly due noncompliant to treatment. to medication non-compliance and default of follow-up (per Single center in protocol assessments) Malaysia Results: Both groups had significant improvement in nasal and ocular total symptom scores compared to baseline after 1 week of treatment, in addition to QOLQ scores after 1 month. No statistically significant differences between groups were found for these scores.

Table 1. Randomized Controlled Trials Study Interventions & Population Results

Fokkens et al, A) FFNS 110mcg total daily dose administered for 1 yr (n=56) “Results: The nasal biopsy population comprised 96 participants (37 using 2012 B) MFNS 200mcg total daily dose administered for 1 yr (n=60) FFNS, 42 using MFNS, and 17 healthy controls). Epithelial thickness did not change appreciably from baseline to week 52 in any of the groups No mucosal and mean change from baseline did not differ between FFNS and MFNS atrophy and Male or female subjects 18 years and older. The active treatment (least square mean difference, <0.001 mm, 95% confidence interval, reduced group (FFNS and MFNS) required a physician-confirmed greater -0.007, 0.006).” inflammatory cells: than 2-year clinical history of treated perennial allergic Active-controlled rhinitis trial with yearlong Excluded: pregnant adults; persons with severe physical obstruction fluticasone furoate of the nose, nasal injury or surgery in the past 3 months, asthma nasal spray unless it was mild intermittent asthma, rhinitis medicamentosa, upper respiratory bacterial or viral infection within 4 weeks before open label, screening, acute sinusitis or significant chronic sinusitis, and current multinational or recent tobacco use, presence of glaucoma and/or cataracts or study ocular herpes simplex, and use of the following medications within the following time periods before screening: subcutaneous omalizumab within 5 months; corticosteroids(intranasal form within 4 weeks and inhaled, intramuscular, i.v.,and/or dermatologic forms, except ≤1% hydrocortisone cream/ointment,within 8 weeks); short-acting prescription or over-the-counter antihistamines, oral or intranasal decongestants, anticholinergics, or oral antileukotrienes within 3 days; long-acting antihistamines within 10 days (except astemizole, within 12 weeks); and intranasal antihistamines or intranasal or ocular cromolyn within 14 days. Informational: A) FFNS (Veramyst; GlaxoSmithKline): 110mcg total daily dose • 58% vs 27% (P<0.001) preferred fluticasone furoate compared with excluded due to administered for 7 days, then off (washed out) for 7 days fluticasone propionate based on scent or odor; 15% of patients had wrong outcome prior to crossing over to FPNS (n=166) no preference for either product based on scent or odor. B) FPNS (Flonase; GlaxoSmithKline): 200mcg total daily dose • Significantly more patients preferred fluticasone furoate compared Meltzer et al, administered for 7 days (n=159) with fluticasone propionate “because less medication leaked out of 2010: C) Placebo FFNS for 7 days the nose or down the throat (59% vs 21%), because of the Comparison of D) Placebo FPNS for 7 days gentleness of the mist (57% vs 26%), and because of less aftertaste patient preference Included adults with a history of seasonal AR and nasal symptoms (60% vs 18%).” for sensory during the 2 previous fall seasons (with a positive skin test to fall • “No statistically significant differences were found in preferences for attributes of allergens appropriate to their region). Patient had to have an fluticasone furoate and fluticasone propionate with respect to fluticasone furoate average 12-hour rTNSS of 6 or higher. attributes related to ease of use, consistency of medication or fluticasone delivered, the delivery method, or device comfort. Between 17%

Table 1. Randomized Controlled Trials Study Interventions & Population Results propionate in Excluded pregnant adults, clinically significant uncontrolled medical and 31% of patients had no preference for either fluticasone furoate adults with disorder, infection, or structural abnormality of the respiratory or fluticasone propionate with respect to the secondary and other seasonal allergic system, recent use of allergy or other medications, use of intranasal attributes.” rhinitis: a corticosteroids within 4 weeks of the study, use of oral or randomized, parenteral corticosteroids within 8 weeks of the study, and use of placebo intranasal fluticasone propionate or fluticasone furoate within 1 controlled, double- year before the study. blind study

Okubo, et al. Patients randomized to 2 weeks’ treatment of: No significant differences found 2009: A) FFNS 110mcg once daily (n=147, 21% with PAR) Primary efficacy end point: mean change from baseline over the entire Comparison of B) FPNS 200mcg twice daily (n=144, 17% with PAR) treatment period in 3TNSS, defined as the sum (0 –9) of three individual fluticasone furoate C) Placebo FFNS once daily (n=70, 20% with PAR) symptom scores for sneezing, rhinorrhea, and nasal congestion scored and fluticasone D) Placebo FPNS twice daily (n=72; 24% with PAR) on a scale of 0–3 in the allergy diary. propionate for the • Mean change from baseline in each active treatment group was treatment of Patients aged 16 and older with a history of more than 2years of similar and within the non-inferiority margin (mean difference Japanese cedar seasonal allergic rhinitis with positive skinprick test to Japanese upper limit 95% CI 0.17) pollinosis cedar pollen or a positive in vitro test for specific IgE antibody; Secondary efficacy end points: diagnosis confirmed by either nasal challenge test or nasal (a) mean change from baseline over the entire treatment period in Non-inferiority eosinophil counting; required to be symptomatic at baseline during 4TNSS (sum of scores for sneezing, rhinorrhea, nasal study using 0.75 the Japanese cedar pollen season; with or without perennial allergic congestion, and nasal itching) margin; rhinitis • Mean change from baseline in each active treatment group was multicenter study Excluded pregnant/lactating women; patients who had an similar for all treatment periods and within the non-inferiority in Japan; interfering existing nasal disorder (e.g. acute/chronic sinusitis, nasal margin for FFNS and FPNS treatment groups (difference of adjusted investigator polyposis, vasomotor rhinitis, or drug-induced rhinitis) or a means; week 1, -0.245; week 2, -0.279; over the entire treatment blinded; using per coexisting disease (e.g., serious hepatic/renal, cardiac, or pulmonary period, -0.249, 95% CI not reported) protocol dysfunction; tuberculous diseases; systemic mycosis; hypertension; (b) mean change in the 3TNSS and 4TNSS in weeks 1 and 2; and over the assessment diabetes mellitus; nasal or oropharynx candidiasis; asthma [except entire treatment period in individual nasal symptom scores

Table 1. Randomized Controlled Trials Study Interventions & Population Results

mild intermittent asthma]; glaucoma; cataract; herpes simplex • Similar mean changes were found for symptom scores (sneezing, ophthalmic; or recurrent epistaxis);patients who received a rhinorrhea, nasal congestion, and nasal itching) in the FFNS and corticosteroid within 8 FPNS groups at each of the treatment period and the entire weeks of the screening period or any other medication treatment period that could affect efficacy assessment (c) change from baseline in the individual nasal examination (rhinoscopy) score were also assessed. • No significant difference between active treatment groups (d) patients’ impression of the treatment effect • Statistical significance testing not reported to assess difference between active treatment groups (e) the number of days until onset of action, based on the significant change in 3TNSS compared with placebo (f) change in the mean activities of daily living interference scores over the treatment period were also evaluated in this study • No significant difference between active treatment groups

Safety: Authors conclude that incidence of overall adverse events was comparable between treatment groups (17% for FFNS, and 18% for FPNS; 21% for placebo FFNS and 19% for placebo FPNS) Ratner et al, A) BDPM: 84mcg (1 spray) per nostril (168mcg total daily dose); No efficacy difference between treatments over 8 to 52 weeks 2009: the authors do not specify the product details, however it is based on physician or subject rated condition scores using a 5 Mometasone likely Vancenase AQ 0.84mcg/actuation was used to achieve point rating scale (in which 1 = complete relief and 5 = treatment furoate nasal spray this dosing and funding sponsor [n=166] failure) is safe and B) MFNS: 50mcg per nostril once daily (100mcg total daily effective for 1-year dose) [n=168] (product was most likely Nasonex; Merk Sharp treatment of & Dohme Corp) children with perennial allergic Patients 6 to less than 12 years old were required to be have rhinitis perennial rhinitis of at least moderately severe at baseline. Excluded patients with asthma managed by inhaled or systemic corticosteroids; current condition or a history of clinically significant Randomized, sinusitis or chronic purulent postnasal drip; rhinitis medicamentosa; active control multiple drug allergies or allergy to corticosteroids; nasal structural study, evaluator abnormalities affecting nasal air flow; upper respiratory infection or blinded sinus infection requiring antibiotic therapy during the 2 weeks prior Study took place in to screening; viral upper respiratory infection during the 7 days 18 centers in the before screening; or receiving immunotherapy (desensitization)

Table 1. Randomized Controlled Trials Study Interventions & Population Results

US between 1996 were excluded unless they had been on a stable maintenance to 1998 schedule for at least 1 month prior to screening.

Funded by Scheing-Plough

Abbreviations: AR, allergic rhinitis; BDPM, beclomethasone dipropionate monohydrate; FF, fluticasone furoate; FFNS, fluticasone furoate nasal spray; FPNS, fluticasone propionate nasal spray; INCS, intranasal corticosteroids; MF, mometasone furoate; MFNS, mometasone Furoate nasal spray; PAR, perennial allergic rhinitis; QOLQ, quality of life questionaire

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