Drugs 2008; 68 (12): 1723-1739 0012-6667/08/0012-1723/$53.45/0

ADIS DRUG EVALUATION

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Mometasone Furoate A Review of its Intranasal Use in Allergic Rhinitis Claudine M. Baldwin and Lesley J. Scott Wolters Kluwer Health | Adis, Auckland, New Zealand, an editorial office of Wolters Kluwer Health, Conshohocken, Pennsylvania, USA Various sections of the manuscript reviewed by: L. Bielory, Division of Allergy and Immunology, New Jersey Medical School, Newark, New Jersey, USA; G.W. Canonica, Department of Internal Medicine, University of Genoa, Genoa, Italy; L.M. DuBuske, Immunology Research Institute of New England, Gardener, Massachusettes, USA; G. Hochhaus, Department of Pharmaceutics, University of Florida, Gainesville, Florida, USA. Data Selection Sources: Medical literature published in any language since 1980 on ‘mometasone furoate’, identified using MEDLINE and EMBASE, supplemented by AdisBase (a proprietary database of Wolters Kluwer Health | Adis). Additional references were identified from the reference lists of published articles. Bibliographical information, including contributory unpublished data, was also requested from the company developing the drug. Search strategy: MEDLINE, EMBASE or AdisBase search terms were ‘mometasone furoate’ and ‘allergic rhinitis’. Searches were last updated 18 July 2008. Selection: Studies in patients with allergic rhinitis who received mometasone furoate. Inclusion of studies was based mainly on the methods section of the trials. When available, large, well controlled trials with appropriate statistical methodology were preferred. Relevant pharmacodynamic and pharmacokinetic data are also included. Index terms: Mometasone furoate, allergic rhinitis, pharmacodynamics, pharmacokinetics, therapeutic use, pharmacoeconomics, tolerability.

Contents Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1724 1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1725 2. Pharmacodynamic Properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1725 2.1 Mechanism of Action . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1725 2.1.1 Glucocorticosteroid Receptor Affinity and Effects on Soluble Mediator Expression and Inflammatory Cell Infiltration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1726 2.2 Onset of Action . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1727 2.3 Effects on Hypothalamic-Pituitary-Adrenal Axis Function . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1727 3. Pharmacokinetic Properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1727 4. Therapeutic Use in Allergic Rhinitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1728 4.1 Perennial Allergic Rhinitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1730 4.1.1 In Adolescents and Adults . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1730 4.1.2 In Children . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1731 4.2 Seasonal Allergic Rhinitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1731 4.2.1 In Adolescents and Adults . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1731 4.2.2 In Children . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1732 4.2.3 Post-Marketing Surveillance Study . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1732 4.3 Prophylaxis of Seasonal Allergic Rhinitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1732 4.4 Patient Preference . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1733

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4.5 Pharmacoeconomic Considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1733 5. Tolerability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1733 6. Dosage and Administration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1734 7. Place of Mometasone Furoate in the Management of Allergic Rhinitis . . . . . . . . . . . . . . . . . . . . . . . . 1735

Summary Abstract

Mometasone furoate (Nasonex®) is a high-potency intranasal corticosteroid available for the treatment and/or prophylaxis of the nasal symptoms of seasonal allergic rhinitis (SAR) and perennial allergic rhinitis (PAR). In the EU, it is approved for use in patients aged ≥6 years and, in the US, it is approved as a treatment in patients aged ≥2 years and as prophylaxis in those ≥12 years of age. Extensive experience in both clinical trials and the clinical practice setting has firmly established the efficacy and good tolerability profile of intranasal mometasone furoate in children and adults with PAR or SAR. Thus, intranasal mometasone furoate is a useful first-line option for the treatment and prophylactic management of these conditions, including in children as young as 2 years of age in some countries and 6 years of age in others.

Pharmacological Properties

Intranasal mometasone furoate is a synthetic glucocorticosteroid that inhibits the early- and late-phase allergic response. It acts by preventing the influx of inflammatory cells into the nasal mucosa, and inhibits the expression of soluble mediators such as histamine, interleukin (IL)-1, IL-4, IL-5, IL-6, IL-8, interferonγ, leukotrienes and tumour necrosis factor-α. Intranasal mometasone furoate has no suppressive activity on hypothalamicpituitary-adrenal axis function, nor on growth, in volunteers or children and adults with allergic rhinitis when administered at recommended therapeutic dosages. No atrophy or alterations in epithelial thickness were observed in patients undergoing nasal biopsies before and after 1 year of treatment with intranasal mometasone furoate. Systemic absorption of mometasone furoate after intranasal administration is negligible and has been estimated to be <1%. Mometasone furoate is ≈99% protein bound at clinically relevant plasma concentrations. Any part of the intranasal dose swallowed and absorbed undergoes extensive first-pass metabolism to multiple metabolites, which are excreted predominantly in the bile and, to a lesser extent, in the urine.

Therapeutic Efficacy

Intranasal mometasone furoate improved the nasal symptoms of SAR and PAR to a significantly greater extent than placebo as determined by reductions from baseline in patient- and/or investigator-assessed total nasal symptom scores (TNSS). There were no significant differences between mometasone furoate and active comparators (budesonide, beclomethasone dipropionate, fluticasone propionate) in this regard in well designed clinical trials. Intranasal mometasone furoate also improved individual nasal symptom scores, non-nasal symptom scores and ocular symptoms, with significantly greater effects than placebo at the majority of timepoints. Overall assessments of treatment response (patient- or investigator-rated) also demonstrated the significant therapeutic benefits of mometasone furoate (and other active treatments) over placebo.

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Mometasone Furoate: A Review

Tolerability

In trials evaluating mometasone furoate as prophylaxis for SAR, a significantly greater proportion of minimal symptom days and significantly lower TNSS during the pollination period were recorded in patients treated with mometasone furoate than placebo or nedocromil recipients; there were no significant differences between the prophylactic benefits of mometasone furoate and beclomethasone dipropionate. In a large, randomized, double-blind, multicentre, crossover study that used questionnaires to assess the patient’s perceptions of product efficacy and sensory features of intranasal spays, a scent-free formulation of intranasal mometasone furoate was preferred by significantly more patients than intranasal fluticasone propionate. Intranasal mometasone furoate is generally well tolerated in patients with PAR or SAR and is associated with an incidence of adverse events not dissimilar to that of placebo or other comparator intranasal corticosteroids. In clinical trials, treatmentemergent adverse events reported in ≥5% of mometasone furoate recipients and with a ≥2% higher incidence than placebo recipients included headache, viral infection, pharyngitis, epistaxis, coughing, upper respiratory tract infection, dysmenorrhoea, musculoskeletal pain and sinusitis. Most events were mild to moderate in severity and of short duration.

1. Introduction Allergic rhinitis can be seasonal (triggered by inhaled allergens such as pollen) or perennial (triggered by allergens including dust mites and animal dander), with symptoms principally consisting of nasal congestion, rhinorrhoea, sneezing and nasal itching.[1] Non-nasal symptoms may include itching/ burning eyes, watering and redness of the eyes and itching of the ear or palate. The intranasal formulation of mometasone furoate (Nasonex®)1 is approved in the EU for the prophylaxis and treatment of the nasal symptoms of seasonal allergic rhinitis (SAR) and perennial allergic rhinitis (PAR) in patients aged ≥6 years,[2] and in the US as a treatment for the same indications in patients aged ≥2 years or as prophylaxis in those aged ≥12 years.[3] Mometasone furoate, a glucocorticosteroid, can also be applied topically for inflammatory skin disorders, inhaled for lower respiratory tract disorders (such as asthma) or administered intranasally for nasal polyps. The topical,[4] intranasal[1] and inhaled[5] uses of mometasone furoate have been re1

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viewed previously in Drugs. This review focuses on the efficacy and tolerability of intranasal mometasone furoate for the prophylaxis and treatment of allergic rhinitis, with a brief overview of its pharmacological properties. 2. Pharmacodynamic Properties 2.1 Mechanism of Action

The mechanism by which corticosteroids, including mometasone furoate, act to relieve the symptoms of allergic rhinitis remains incompletely understood. It is apparent that these agents inhibit several aspects of the allergic response.[1,3] Mometasone furoate binds to and activates cytosolic glucocorticosteroid receptors to form a complex that enters the cell nucleus and acts to regulate the expression of numerous pro-inflammatory and antiinflammatory genes.[6] Mometasone furoate inhibits the early- and late-phase allergic response, preventing inflammatory cell influx into the nasal mucosa and inhibiting expression of soluble mediators such as histamine, interleukin (IL)-1, IL-4, IL-5, IL-6,

The use of trade names is for identification purposes only and does not imply endorsement.

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IL-8, interferon (IFN)-γ, leukotrienes and tumour necrosis factor (TNF)-α.[1] In allergic rhinitis, the hypersensitivity response is initiated with binding of an inhaled allergen to specific IgE molecules attached to high-affinity IgE receptors of nasal mucosal mast cells.[1] This binding activates the associated mast cells, causing rapid release of soluble biochemical mediators (including histamine, arachidonic acid metabolites, eosinophil chemotactic factor and cytokines), which have various effects on local cells, blood vessels and nerves. The arachidonic acid metabolites (leukotrienes, thromboxanes and prostaglandins), plus histamine, are largely responsible for this early phase of the allergic response (such as afferent nerve ending stimulation and vasodilation) that result in the cardinal nasal symptoms of allergic rhinitis that typically develop within minutes of allergen exposure. Corticosteroid pretreatment may reduce the number of nasal epithelial mast cells or the tissue response to histamine, thereby inhibiting this early-phase response.[1] The subsequent late-phase response, occurring 6–12 hours after allergen exposure, involves basophil, eosinophil, monocyte and T-lymphocyte recruitment to the nasal mucosa.[1] These inflammatory cells, and their associated soluble mediators (including IL-1, IL-4, IL-5, IL-6 and IL-8, TNFα and IFNγ), plus the ongoing leukotriene release from mast cells, are responsible for the continuing symptoms associated with the early-phase response. Repeated allergen exposure leads to chronic nasal inflammation, which is dominated by the late-phase response, during which corticosteroids inhibit both the influx of inflammatory cells and their expression of pro-inflammatory mediators.[1] 2.1.1 Glucocorticosteroid Receptor Affinity and Effects on Soluble Mediator Expression and Inflammatory Cell Infiltration

The rank order of in vitro relative receptor affinities for four glucocorticosteroids has been reported as mometasone furoate > fluticasone propionate > budesonide > triamcinolone acetonide, despite considerable variability in the study methodologies utilized.[6] © 2008 Adis Data Information BV. All rights reserved.

Baldwin & Scott

Mometasone furoate inhibits the expression of inflammatory mediators by cells involved in the early- and late-phase allergic responses (reviewed by Onrust and Lamb[1]). In in vitro and in vivo studies, mometasone furoate decreased histamine, leukotriene, IL-1, IL-4, IL-5, IL-6, IL-8, TNFα and IFNγ secreted by mast cells, T-helper lymphocytes and macrophages. When compared with other corticosteroids in vitro, mometasone furoate inhibited IL-1 synthesis with a potency greater than that of betamethasone or dexamethasone, and was a more potent inhibitor of IL-4 and IL-5 synthesis than betamethasone, beclomethasone dipropionate, budesonide or triamcinolone acetonide. Furthermore, mometasone furoate inhibited IL-6 and TNFα synthesis with greater potency than betamethasone, dexamethasone, beclomethasone dipropionate or hydrocortisone, and was a more potent inhibitor of leukotriene release than beclomethasone dipropionate. Mometasone furoate and fluticasone propionate displayed similar potencies with regard to the inhibition of IL-4 and IL-5 synthesis.[1] Mometasone furoate reduced early-phase histamine levels[7,8] and late-phase inflammatory cell infiltration[8,9] in patients treated for allergic rhinitis,[10] and in asymptomatic patients undergoing antigen challenge.[7-9] Mometasone furoate 200 μg/day significantly reduced late-phase events in a study of 42 subjects with allergic rhinitis undergoing experimental nasal allergen challenge.[9] After evaluation at baseline and 6 hours, mometasone furoate pretreatment was associated with significant decreases in nasal mucosal eosinophil and neutrophil infiltration, eosinophil cationic protein and TNFα in the nasal lavage, and intercellular adhesion molecule-1 expression on nasal epithelial cells (all p ≤ 0.03 vs baseline).[9] In a 1-year study, 69 patients with PAR were treated with mometasone furoate 200 μg/day and underwent nasal biopsy at baseline and at study end.[10] Long-term treatment with mometasone furoate reduced inflammatory cell infiltration (particularly mast cells and eosinophils). No atrophy or alterations in epithelial thickness were observed. Drugs 2008; 68 (12)

Mometasone Furoate: A Review

2.2 Onset of Action

Maximal therapeutic benefits of intranasal mometasone furoate are usually achieved within 1–2 weeks of treatment initiation.[1,3] However, improvements in nasal symptoms have been observed as soon as 7 hours after an intranasal dose of mometasone furoate in patients with SAR, and within 4 hours in one study enrolling patients with PAR (section 4.1).[11] The onset of action of intranasal mometasone furoate was specifically investigated in two studies,[12,13] and was examined in a pooled analysis of four randomized, double-blind trials in patients with SAR.[14] In one 12-hour study in which symptomatic patients were given single doses of intranasal mometasone furoate 200 μg or placebo in a park setting, decreases in total nasal symptom scores (TNSS) were significantly different from placebo by 7 hours post-dose, having changed from baseline by –3.3 and –2.3 in the two respective groups (p < 0.05).[13] In a 2-week study, 28% of mometasone furoatetreated patients experienced at least moderate relief from the symptoms of SAR within 12 hours of the first dose (p < 0.02 vs placebo).[12] Sixty-four percent of mometasone furoate recipients achieved at least moderate symptom relief within 72 hours (compared with 40% of placebo recipients; p < 0.01).[12] In a retrospective pooled analysis of four randomized, double-blind trials, the improvements in congestion and TNSS were significantly greater in mometasone furoate (n = 492) than placebo (n = 497) recipients on day 2 of treatment (–13.6% vs –7.7% and –16.5% vs –8.1%; both p < 0.001).[14] At day 15, corresponding changes in congestion and TNSS were –34.5% versus –17.2% and –41.6% versus –21.8% (both p < 0.001 vs placebo).[14] 2.3 Effects on Hypothalamic-Pituitary-Adrenal Axis Function

Control mechanisms of the hypothalamic-pituitary-adrenal (HPA) axis respond to exogenously administered corticosteroids by decreasing cortisol secretion, with possible long-term consequences of © 2008 Adis Data Information BV. All rights reserved.

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HPA axis suppression, and impairment of bone growth and maintenance.[6] In adults[15] and children[16,17] with allergic rhinitis, mometasone furoate at recommended dosages for up to 42 days had little or no effect on the HPA axis with no detectable systemic exposure to the drug. For example, after 42 days’ treatment with intranasal mometasone furoate 100 μg once daily, there were no significant changes from baseline in serum cortisol or urinary free cortisol levels and no effects on the HPA axis in 56 children (aged 2–6 years) in a randomized, partially blinded, placebocontrolled trial.[16] No growth retardation has been seen in children with allergic rhinitis treated with intranasal mometasone furoate 200 μg once daily for 2 weeks[18] or 100 μg once daily for 1 year.[19] 3. Pharmacokinetic Properties The pharmacokinetic properties of mometasone furoate in intranasal[1] and inhaled[5] forms have been previously reviewed in Drugs. This section provides a brief overview of the pharmacokinetic profile of intranasal mometasone furoate, using studies performed in healthy adult volunteers[20] and in children with allergic rhinitis.[17] There are few relevant pharmacokinetic data available as mometasone furoate is generally undetectable in the plasma following intranasal administration.[2] In children with allergic rhinitis[17] and healthy adult volunteers[20] receiving recommended[17] and supratherapeutic[20] dosages, there was virtually no systemic exposure to mometasone furoate after administration via intranasal routes. For example, in a 4-day, crossover study in 12 healthy adult volunteers, mean plasma area under the concentrationtime curve values were 123 and 112 pmol • h/L after intranasal mometasone furoate or fluticasone propionate 800 μg three times daily.[20] Respective estimated bioavailability values were 0.46% and 0.42%; neither drug caused a significant decrease in 24-hour serum cortisol levels. Mometasone furoate is 98–99% protein bound in vitro over the concentration range of 5–500 ng/ mL.[3] The drug has an effective elimination half-life Drugs 2008; 68 (12)

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Table I. Comparative efficacy of mometasone furoate (MF) in patients (pts) with perennial allergic rhinitis. Results from randomized, doubleblind, placebo-controlled, double-dummy,[11,29,30] multicentre trials. All study treatments were administered as intranasal sprays, with rescue medication (loratadine [LOR]) given orally. One trial included a 2-wk run-in period prior to treatment initiation[11] Reference

Study

No. of pts

(age; y)

duration

randomized [evaluated]

Treatment regimen

TNSSa baseline

Rescue LOR % change [range]

use (% ptsb [mean no. of tablets/wk])

–1.45; –1.41; –1.26; –0.44;

[1.31] [1.18] [0.93] [1.23]

Adolescents and adults Bende et al.[11] (>18)

4 wk

106 110 107 114

[103] [107] [99] [104]

MF 200 μg od BUD 128 μg od BUD 256 μg od PL

3.72; 4.08; 3.86; 3.98;

Drouin et al.[29] (12–67)

3 mo

143 [129] 146 [134] 138 [124]

MF 200 μg od BDP 200 μg bid PL

7.1 7.1 7.0

25** [25–52] 30** [30–56] 15 [15–38]

48 46 56

Mandl et al.[30] (12–77)

3 mo

181 [166] 183 [162] 184 [146]

MF 200 μg od FP 200 μg od PL

7.0 7.0 7.1

37** [37–63] 39** [39–60] 22 [22–39]

54 57 71

≤28 wk

190 [NR] 191 [NR]

MF 100 μg od PL

NR NR

39* 32

3.75c 3.94c 3.95c 4.02c

–1.59c* –1.50c* –1.44c* –0.58c

Children Patel[27]d (3–11) a

Where specified, this was the primary endpoint;[29,30] results at the primary timepoint of 15 days[27,29,30] or study end.[11] Investigatoror patient-assessed[11,29,30] scores. The range is the average from each 15-day interval during the entire study period.[29,30]

[27]

b

Proportion who used rescue medication on at least one occasion during the study.

c

Primary endpoint was the mean change from baseline in patient-assessed NIS, adjusted for centre and treatment, at study end. Results are reported as NIS morning; NIS evening. Total daily NIS was not reported.

d

Abstract presentation. 4-wk double-blind period followed by open-label MF treatment for ≤24 wk. No further design details reported.

BDP = beclomethasone dipropionate; bid = twice daily; BUD = budesonide; od = once daily; FP = fluticasone propionate; NIS = nasal index score; NR = not reported; PL = placebo; TNSS = total nasal symptom scores. * p ≤ 0.05; ** p ≤ 0.01 vs PL.

of 5.8 hours following intravenous administration.[3] While the systemic clearance of mometasone furoate is not readily available, it has been reported as being not dissimilar to that of other inhaled glucocorticosteroid agents.[21] Any part of the intranasal dose swallowed and absorbed undergoes extensive first-pass metabolism to multiple metabolites, which are excreted predominantly in the bile and, to a lesser extent, in the urine.[3] The potential main metabolites of mometasone furoate are mometasone (the free alcohol), 6βhydroxy-mometasone furoate, 21-hydroxy-mometasone furoate, 6β-hydroxymometasone and 21-hydroxymometasone, all of which have high binding affinities for the glucocorticoid receptor (0.15–0.44 nmol/L vs 0.18–1.19 nmol/L for mometasone furoate).[22] No bioactive glucocorticoid metabolites have been seen in humans.[6] To date, adequate investigations of the pharmacokinetic profile of mometasone furoate in patients © 2008 Adis Data Information BV. All rights reserved.

with renal or hepatic impairment, in the elderly, or addressing the possible effects of gender are lacking.[3] 4. Therapeutic Use in Allergic Rhinitis The efficacy of mometasone furoate in the treatment of PAR (section 4.1) and SAR (section 4.2), and as prophylaxis for the latter (section 4.3), has been assessed in numerous studies enrolling adults,[11,23,24] children[25-27] and patient groups of mixed ages,[28-32] most of which are published in full (see table I and table II for dosage and design details). Trial participants generally had a ≥1- or 2year history of allergy to at least one allergen (such as dust mite, moulds and animal dander in patients with PAR,[11,29,30] and prevalent local aeroallergens in patients with SAR)[23-25] confirmed by positive skin tests. Disease severity was moderate to severe at study entry (where stated, with baseline TNSS ≥5,[29,30] ≥6[23,25,28] or ≥10,[24] or baseline nasal index Drugs 2008; 68 (12)

Mometasone Furoate: A Review

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scores [NIS] ≥3 on 4 of the last 7 days of the run-in period, plus blocked nose symptoms of at least moderate severity).[11] Patients participating in studies evaluating mometasone furoate for the prophylaxis of SAR were required to be clinically asymptomatic at baseline, but were confirmed as being allergic to the relevant local allergens (ragweed[31] or Parietaria, olive or grass pollens).[32] Efficacy measures in trials evaluating mometasone furoate for the treatment of PAR or SAR were primarily changes from baseline in patient- or investigator-rated average daily TNSS or NIS. NIS were the sum of patient-rated individual scores on a scale from 0 to 3 (3 indicating highest severity) for the symptoms of blocked nose, runny nose, and the

worst of itchy nose or sneezing, recorded in the morning and evening.[11] TNSS were generally defined as the sum of severity scores for four nasal symptoms (rhinorrhoea, congestion, sneezing and nasal itch), rated on a 4-[23,25,28-32] or 7-point[24] scale (from 0 to 3 or 6 [3 or 6 indicating highest severity]). Corresponding scales were generally used in studies where non-nasal symptoms were also recorded (itching/burning eyes, redness of eyes, watering/ tearing eyes, itching ear or palate). Where combined, the sum of nasal and non-nasal symptom scores was reported as a total symptom score (TSS). Patients recorded symptom scores in the morning and evening prior to scheduled treatments, and investigators scored symptoms at scheduled visits. Across trials, investigator-rated scores tended to re-

Table II. Comparative efficacy of mometasone furoate (MF) in patients (pts) with seasonal allergic rhinitis. Results from randomized, doubleblind, double-dummy,[23,28] multicentre trials[23-25,28] conducted when pts were likely to be exposed to the relevant allergens. Corticosteroids were administered as intranasal sprays and loratadine (LOR) was administered orally Reference

Study

No. of pts

(age; y)

duration (wk)

randomized

Treatment regimen

TNSSa baseline

Investigatormean % decrease from baseline

evaluated response to treatment (% of pts)b

35**† 32**† 22* 15

47**† 38**† 27 23

13.3 13.4 13.5 13.4 13.3

54* 47* 55* 55* 32

49c 62c 65c 69c 33c

Adolescents and adults MF 200 μg od + LOR 10 mg od MF 200 μg od LOR 10 mg od PL

Anolik et al.[28] (11–71)

2

169 176 181 176

Bronsky et al.[24] (18–65)

4

96 95 98 95 95

Hebert et al.[23] (≥18)

4

126 126 126 123

MF 100 μg od MF 200 μg od BDP 200 μg bid PL

8.1 8.1 7.9 8.0

53** 59** 59** 34

77** 79** 74** 54

4

137 135 133 138 136

MF 25 μg od MF 100 μg od MF 200 μg od BDP 84 μg bid PL

NR NR NR NR NR

2.8*d 2.8d* 2.8d* 2.8d* 1.9d

69* 71* 74* 70* 57

MF MF MF MF PL

50 μg od 100 μg od 200 μg od 800 μg od

7.9 7.8 7.9 8.0

Children Meltzer et al.[25] (5–12)

a

Where specified, this was the primary endpoint; results at the primary timepoints of 8 days[23,25] or study end.[24,28] Investigator-[23-25] or patient-assessed[28] scores.

b

Defined as ‘good’ or ‘excellent’ response,[24] complete or marked symptom relief,[23,28] or complete, marked or moderate symptom relief.[25]

c

No statistical data reported.

d

Absolute decrease from baseline; estimated from a graph.

BDP = beclomethasone dipropionate; bid = twice daily; NR = not reported; od = once daily; PL = placebo; TNSS = total nasal symptom scores; * p ≤0.05, ** p ≤ 0.01 vs PL; † p ≤ 0.03 vs LOR.

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flect patient-rated scores. A number of trials also reported global evaluations of overall condition using scales from 1 (complete relief) to 5 (treatment failure). The primary efficacy variable in the two trials evaluating mometasone furoate as prophylaxis for SAR was the proportion of minimal symptom days (defined as days where TNSS were ≤2 out of a total maximum score of 12) after the start of the pollen season.[31,32] Mometasone furoate was administered intranasally once daily, with half of each dose administered into each nostril. Comparator intranasal corticosteroids, including budesonide,[11] fluticasone propionate[30] and beclomethasone propionate,[23,25,26,29] and oral loratadine[28] or desloratadine (in an open-label post-marketing study),[33] were administered once or twice daily at dosages recommended by the manufacturer. Loratadine (10 mg once daily) was also permitted in some trials as rescue medication, and its use recorded as a secondary indicator of efficacy in these studies.[11,23,29,30] 4.1 Perennial Allergic Rhinitis 4.1.1 In Adolescents and Adults

Intranasal mometasone furoate improved nasal symptoms to a significantly greater extent than placebo, as determined by reductions from baseline in patient-assessed TNSS[29,30] and NIS[11] at study end[11] or 15 days[29,30] (primary endpoint and timepoint) [see table I for dosage and design details]. Furthermore, there were no significant differences between mometasone furoate and beclomethasone dipropionate[29] or fluticasone propionate[30] groups in terms of improvements in TNSS at any timepoint during the two 3-month studies, including the primary timepoint (table I), with all active treatments improving nasal symptoms to a greater extent than placebo at all timepoints.[29,30] Corresponding investigator-rated TNSS and NIS were generally similar to patient-assessed scores in all trials.[11,29,30] In one 3-month study, mometasone furoate and fluticasone propionate recipients had more symptom-free days than placebo recipients (10 and 11 vs 4 days; both p < 0.01).[30] © 2008 Adis Data Information BV. All rights reserved.

Baldwin & Scott

Overall assessments of treatment response also showed mometasone furoate and other active treatments were better than placebo in the two 3-month trials.[29,30] Investigator-rated ‘response to treatment’ was significantly (p ≤ 0.05) better in mometasone furoate than placebo recipients at days 8 and 15 and at week 12, whereas beclomethasone dipropionate treatment was better than placebo at days 8, 15 and 29 (all p < 0.01) [no quantitative data provided], with no significant differences between the active treatments at any timepoint.[29] In the other study, investigator-rated overall improvement in the patient’s condition was significantly higher in the mometasone furoate and fluticasone propionate than in the placebo group at study end (55% and 45% vs 36%; both p < 0.01), with the response rate in the mometasone furoate group being significantly (p < 0.04) higher than that in the fluticasone group.[30] Where evaluated, the beneficial effects of mometasone furoate and beclomethasone dipropionate in adolescent and adult patients with perennial allergic rhinitis were sustained throughout the 24-hour dosage interval, as assessed using morning TNSS.[29] In addition, there was no difference between the active treatment groups for improvements in morning and evening TNSS, with improvements in both active treatment groups being better than those in the placebo group at almost all timepoints throughout the study (where significant p < 0.05).[29] Improvements in morning and evening peak nasal inspiratory flow (PNIF) were significantly greater in the mometasone furoate 200 μg and budesonide 128 and 256 μg groups than in the placebo group in a 3-month study in adults (see table I for details of dosage regimen).[11] For example, the mean adjusted increase from baseline in morning PNIF at study end in the mometasone furoate 200 μg (baseline 103.8 L/min), budesonide 128 μg (109.2 L/min), budesonide 256 μg (108.9 L/min) and placebo group (107.1 L/min) was 16.1, 18.6, 24.0 and 7.7 L/min, respectively (all p < 0.01 vs placebo). In addition, the budesonide 256 μg group experienced significantly (p < 0.05) greater imDrugs 2008; 68 (12)

Mometasone Furoate: A Review

provements in morning PNIF than patients in the mometasone furoate or budesonide 128 μg groups. There were no significant differences between any of the treatment groups in terms of rescue medication used (table I).[11,29,30] 4.1.2 In Children

These data are only available as abstract presentations.[26,27] Mometasone furoate provided better relief of nasal symptoms than placebo in a shorter-term (≤28 weeks) study in children (aged 3–11 years), based on the investigator-rated primary efficacy endpoint and timepoint (see table I for dosage and design details).[27] In addition, significant (p = 0.02) improvements in TNSS scores were seen at 15 days (39% vs 32% reduction), with a numerical improvement during the subsequent 6-month open-label extension phase in all patients, irrespective of whether they had received mometasone furoate or placebo during the double-blind phase (45% and 49% reduction, respectively). In a 1-year, randomized, partially-blinded, multicentre study in 251 children aged 6–11 years, the mean percentage reduction at study end in investigator-rated overall scores in the once-daily mometasone furoate 100 μg (n = 166) and beclomethasone propionate 168 μg (n = 88) groups was 42.1% and 44.0%; corresponding reductions in patient-rated overall scores were 39.7% and 39.0%.[26] Of evaluable patients, 59.4% of mometasone furoate recipients (n = 138 evaluable) experienced complete/ marked symptom relief by study end versus 54.3% (n = 70) in the comparator group. No statistical data were reported in the abstract presentation. 4.2 Seasonal Allergic Rhinitis 4.2.1 In Adolescents and Adults

In a dose-finding trial, the optimal dosage of intranasal mometasone furoate in the treatment of adults with SAR was 200 μg once daily, with no additional benefits shown at the higher dosage of 800 μg once daily.[24] Intranasal mometasone furoate improved nasal symptoms to a significantly greater extent than pla© 2008 Adis Data Information BV. All rights reserved.

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cebo, as determined by reductions from baseline in investigator and/or patient-assessed TNSS at 8 days[23] or study end[24,28] (primary endpoint and timepoints) [see table II for dosage and design details]. There were no significant differences between mometasone furoate monotherapy,[23,28] mometasone furoate plus loratadine,[28] or beclomethasone dipropionate[23] treatment groups for improvements in TNSS at any timepoint during the two active comparator trials, including the primary timepoint (table II), with all active treatments improving nasal symptoms to a greater extent than placebo at the majority of timepoints. Beneficial effects of treatment were sustained for the durations of the two 4-week trials.[23,24] For example, in one study, reductions in TNSS from baseline at day 29 were 80%, 75% and 73% for mometasone furoate 100 and 200 μg/day, and beclomethasone dipropionate 400 μg/day, respectively (all p < 0.01 vs placebo).[23] Improvements in individual nasal symptoms (rhinorrhoea, nasal stuffiness/congestion, nasal itching and sneezing) were also significantly greater in mometasone furoate recipients than in patients who were administered placebo (p ≤ 0.05).[23] In one study, mometasone furoate and beclomethasone dipropionate relieved nasal stuffiness at day 8 to a significantly (p ≤ 0.05) greater extent than placebo, with congestion scores improving by 41–52% in active treatment recipients versus 28% of placebo recipients; similar results were recorded for the other three nasal symptoms.[23] Mometasone furoate (with or without loratadine) also reduced the non-nasal symptoms of SAR to a significantly (p < 0.05) greater extent than placebo, as reflected by patient ratings of ocular itching, tearing and redness, and ear/palate itching in a 2-week study.[28] These data are supported by a pooled analysis of four randomized trials in patients with SAR, in which intranasal mometasone furoate 200 μg/day effectively relieved total ocular symptom scores (OSS) and individual OSS.[34] Total OSS decreased from baseline over days 1–15 of treatment by 1.33 in mometasone furoate recipients versus 0.93 in placebo recipients (p < 0.001). CorrespondDrugs 2008; 68 (12)

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ing decreases in total OSS from baseline were 1.97 and 1.51 (p = 0.002 vs placebo) in the subgroup of patients with total OSS ≥4 at baseline.[34] Individual symptoms of eye tearing, eye itching and eye redness were improved in mometasone furoate recipients to a significantly (p ≤ 0.002) greater extent than placebo at most timepoints during the 15-day treatment period. Across trials, improvements in TSS (TNSS and non-nasal symptom scores combined) tended to mirror those of TNSS, with active treatments reducing TSS from baseline to a significantly greater extent than placebo.[23,24,28] Investigator-assessments of overall response to treatment (of ‘good’ or ‘excellent’ response, or complete, marked or moderate symptom relief) were recorded in significantly higher proportions of patients treated with mometasone furoate (with or without loratadine) or beclomethasone dipropionate than in those given placebo (table II).[23,28] In one comparative trial in patients with moderate to severe SAR, 66% and 71% of individuals treated with mometasone furoate 100 and 200 μg/ day, 75% of beclomethasone dipropionate recipients and 43% of placebo recipients, had no or mild symptoms according to investigator assessment at day 8.[23] At study end, all active treatments were significantly superior to placebo in terms of the proportions of patients with complete or marked relief (table II).[23] The use of rescue loratadine did not significantly differ between mometasone furoate 100 and 200 μg/ day recipients (41% and 34%) and beclomethasone dipropionate recipients (35%), but was significantly less than that in placebo recipients (55% of patients; p ≤ 0.05 vs active comparators).[23] 4.2.2 In Children

In children aged 5–12 years, the optimal dosage of intranasal mometasone furoate was 100 μg/day, based on reductions from baseline in investigatorassessed TNSS at the primary timepoint of 8 days.[25] Both 100 or 200 μg/day dosages effectively relieved the symptoms of SAR, although the higher 200 μg/day dosage provided no additional treatment benefits over the 100 μg/day dosage. © 2008 Adis Data Information BV. All rights reserved.

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There were no significant differences between mometasone furoate and beclomethasone dipropionate in terms of decreases in investigator-assessed TNSS from baseline at 8 days (primary efficacy variable; table II) or after 29 days’ treatment (except mometasone furoate 25 μg/day), and all active treatments decreased TNSS to a significantly greater extent than placebo (p ≤ 0.02).[25] Similar trends were seen with the patient-assessed TNSS, as well as patient- and investigator-assessed TSS and individual symptom scores. Significantly more mometasone furoate and beclomethasone dipropionate than placebo recipients demonstrated complete, marked or moderate symptom relief according to the investigator’s evaluation at study end (p ≤ 0.05); there were no significant differences between active treatments or mometasone furoate dosages in terms of the investigators’ assessment of overall response.[25] 4.2.3 Post-Marketing Surveillance Study

A combination of mometasone furoate (200 μg/ day) plus desloratadine (5 mg/day) significantly improved nasal symptoms in an open-label, multicentre, German, post-marketing study in 3752 patients with moderate or severe SAR (available as an abstract).[33] After a mean treatment duration of ≈31 days, TNSS were significantly (p < 0.0001) reduced from 8.54 at baseline to 2.10 at the endpoint assessment (co-primary endpoint).[33] The combination of mometasone furoate and desloratadine significantly reduced total non-nasal symptom scores (from 4.64 to 0.97; p < 0.0001) and overall sleep disturbance scores (from 6.27 to 1.61; p < 0.0001) compared with baseline.[33] Total OSS (the other coprimary endpoint) significantly decreased from 4.64 at baseline to 0.97 at study end (p < 0.0001), with overall assessments of treatment as ‘excellent’ or ‘very good’ reported by ≈75% of investigators and ≈71% of patients.[33,35] 4.3 Prophylaxis of Seasonal Allergic Rhinitis

Intranasal mometasone furoate was an effective prophylaxis in adults and adolescents with confirmed SAR, based on the proportion of minimal symptom days from the start of the pollen season to Drugs 2008; 68 (12)

Mometasone Furoate: A Review

study completion (after a total of 2[31] or ≤4[32] months of treatment) when initiated 2–4 weeks prior to the pollen season in two randomized, comparative trials.[31,32] In a double-blind, multicentre study enrolling 349 patients, the proportion of minimal symptom days was significantly greater in patients receiving prophylactic treatment with mometasone furoate 200 μg once daily or beclomethasone dipropionate 168 μg twice daily, than in those receiving placebo (83% vs 77% vs 64%; both active treatments p < 0.01 vs placebo).[31] Both investigator- and patient-assessed TNSS were decreased from baseline to a significantly greater extent than placebo for both active treatments at all timepoints (up to day 50). Furthermore, mometasone furoate and beclomethasone dipropionate significantly (p < 0.01 logrank test) delayed the time to first occurrence of a ‘nonminimal symptom’ day and evening TNSS (median duartion of 27 days in active treatemetn groups vs 10.5 days with placebo).[31] In an open-label, multicentre, ‘real-life’ study (n = 61) comparing the efficacy of mometasone furoate and nedocromil sodium nasal sprays as prophylactic antiallergic therapy, patients randomized to mometasone furoate had significantly more days without symptoms (75% vs 55%; p < 0.001 vs nedocromil), and significantly lower TNSS during the pollination period (means 1.4 vs 2.9; p < 0.001).[32] Furthermore, significantly more individuals in the mometasone furoate-treated group reported satisfaction with treatment at the final visit (93% vs 44%; p < 0.001).[32] 4.4 Patient Preference

Discussion in this section focuses on a recent randomized, double-blind, multicentre, crossover study in 100 adult patients with symptomatic allergic rhinitis that evaluated patient preference for the scent-free formulation of mometasone furoate versus that for fluticasone propionate nasal spray.[36] Patients received mometasone furoate 200 μg followed 30 minutes later by fluticasone propionate nasal spray or vice versa, with a washout between treatments. Based on questionnaires assessing the © 2008 Adis Data Information BV. All rights reserved.

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patient’s perception of product efficacy and sensory features, a significantly greater proportion of patients preferred the scent-free formulation of mometasone furoate over fluticasone propionate for several of the individual sensory attributes (assessed immediately after administration), including whether the product had a scent (p < 0.0001), whether it had an immediate taste (p = 0.0002), whether the product ran out of the nose (p < 0.05) and whether the product felt soothing (p = 0.03). Results for sensory attributes 2 minutes after drug administration correlated with these data.[36] 4.5 Pharmacoeconomic Considerations

In a US-based cost-minimization analysis of intranasal corticosteroid prescribing patterns in the management of allergic rhinitis, one prescription of budesonide aqueous nasal spray provided more days of treatment at a lower daily cost than mometasone furoate, fluticasone propionate and triamcinolone acetonide.[37] The mean respective treatment costs per day for the four leading intranasal corticosteroids (mometasone furoate, fluticasone propionate, triamcinolone acetonide and budesonide) based on the mean prescribed daily dosage were $US1.80, $US1.88, $US1.97 and $US1.54. Data for the year 2002 were obtained from the National Disease and Therapeutic Index (NDTI) database, a centralized database containing physician-reported patient data including information about prescribing practice. In this study, the two key model assumptions were that NDTI results could be generalized to the target population and that product utilization was equal to the prescribed dosages; the average wholesale price utilized was that as at January 2003.[37] 5. Tolerability Intranasal mometasone furoate was generally well tolerated in adolescents, adults and children with allergic rhinitis participating in clinical trials discussed in section 4, with no significant differences in the incidence or nature of adverse events between active comparator groups or placebo.[11,23-25,29-31] Discussion in this section focuses on pooled data reported in the US prescribing informaDrugs 2008; 68 (12)

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25

MF 200 (n = 2103) PL (n = 1671)

20 15 10 5

TI rh oe lo a sk el et p a al in Si nu si tis

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Incidence (% of patients)

tion,[3] supplemented with data from the European summary of product characteristics.[2] In the pooled analysis, mometasone furoate was generally well tolerated in 3210 adult and adolescent (aged ≥12 years) patients receiving 50–80 μg/day (mostly 200 μg/day; n = 2103) and in 990 children (aged 3–11 years) receiving 25–200 μg/day; n = 720); in the overall population, 513 patients were treated for ≥1 year.[3] Very few (≤3%) patients discontinued treatment because of an adverse event, with the nature and incidence of treatment-emergent adverse events, and the rate of treatment discontinuation being similar between active treatment groups and also between mometasone furoate and placebo. In addition, the tolerability profile of mometasone furoate was not affected by age, gender or race.[3] Treatment-emergent adverse events that occurred with an incidence of ≥5% and in numerically more mometasone furoate (200 μg/day) than placebo recipients in the pooled analysis of adults and children are summarized in figure 1.[3] In children, vomiting (5% vs 4%) and upper respiratory tract infections (5% vs 4%) were the only treatment-emergent adverse events that met these criteria for occurrence in mometasone furoate

Fig. 1. Comparative tolerability profile of intranasal mometasone furoate (MF) in adolescent and adult patients (aged ≥12 years) with seasonal or perennial allergic rhinitis. Incidence of treatment-emergent adverse events that occurred in ≥5% of MF (200 μg/day) recipients and with a ≥2% higher incidence in MF than in placebo (PL) groups in a pooled analysis of US and international studies, as reported in the US prescribing information.[3] The duration of treatment was not reported, although the overall analysis included 513 adults, adolescents and children who were treated for ≥1 year. No statistical data reported. URTI = upper respiratory tract infection.

© 2008 Adis Data Information BV. All rights reserved.

(100 μg/day; n = 374) and placebo recipients (n = 376).[3] Where reported, the majority of adverse events were of mild or moderate severity and of short duration.[23,30,31] In general, intranasal mometasone furoate was not associated with any changes in vital signs, electrocardiography or laboratory test results.[23-25,29-31] Nasal mucosal atrophy has not been observed with mometasone furoate use.[38] In one study no atrophy or alterations in epithelial thickness were observed in nasal biopsies of patients treated with intranasal mometasone furoate 200 μg/day for 1 year (section 2.1.1).[10] Mometasone furoate has no demonstrable effects on the HPA axis in adults or children, nor suppressive activity on growth in the latter (section 2.3). No significant changes in intraocular pressure or posterior subcapsular cataracts have been observed with the long-term (up to 1 year) use of intranasal mometasone furoate in children and adults with PAR.[26,39] Post-marketing surveillance has revealed very rare cases of anaphylaxis and angioedema, plus rare occurrences of nasal septal perforation and olfactory disturbance, associated with intranasal mometasone furoate use.[3] 6. Dosage and Administration Mometasone furoate is a high-potency corticosteroid available as a nasal spray for the treatment and/or prophylaxis of the nasal symptoms of SAR and PAR. In the EU, it is approved for use in patients aged ≥6 years and, in the US, it is approved as a treatment in patients aged ≥2 years and as prophylaxis in those aged ≥12 years. Mometasone furoate is presented as a metered-dose (50 μg) manual pump spray unit containing an aqueous suspension of mometasone furoate monohydrate (0.05% w/ w).[2,3] In adults and children aged ≥12 years, the recommended total daily dosage is 200 μg administered as two sprays into each nostril once daily, increased to 400 μg once daily in the event of inadequate symptom control.[2,3] Once symptom control is achieved, dosage reduction is recommended; a total daily dose Drugs 2008; 68 (12)

Mometasone Furoate: A Review

of 100 μg may be effective as maintenance treatment. The initiation of mometasone furoate as prophylaxis for SAR is recommended 2–4 weeks prior to the anticipated start of the pollen season.[2,3] In children aged 2–[3] or 6–[2]11 years, the recommended total daily mometasone furoate dosage is 100 μg administered as one actuation into each nostril once daily. The efficacy and tolerability of mometasone furoate have not been established in patients younger than 2 years. While mometasone furoate may have a clinically significant onset of action within 12 hours of administration, full benefits may take up to 48 hours to be achieved.[2,3] Thus, patients are advised to continue regular use of mometasone furoate in order to obtain full therapeutic benefits. Mometasone furoate should not be used until after wound healing in patients with recent nasal trauma, and should be used with caution in patients with untreated fungal, bacterial or systemic viral infections.[2,3] Local prescribing information should be consulted for full details such as warnings, contraindications and precautions. 7. Place of Mometasone Furoate in the Management of Allergic Rhinitis The worldwide prevalence of allergic rhinitis is difficult to ascertain, as it depends on the definition of the disease itself and is complicated by underreporting, underdiagnosis[40] and the large number of individuals who self-medicate with over-the-counter treatments.[41] However, across a broad body of literature, the incidence of allergic rhinitis is estimated to be approximately 10–30% in adults and up to 40% in children,[40,42] with evidence that these rates may be increasing.[43,44] The sheer number of affected individuals contributes to the high economic burden of the disease.[41] For the individual, allergic rhinitis can have significant detrimental effects on quality of life as well as a substantial economic impact, with co-morbid conditions (such as sinusitis, otitis media, respiratory infections and asthma) contributing additional burden.[43] While there has been a tendency to trivialize the disease,[40] allergic rhinitis can lead to more © 2008 Adis Data Information BV. All rights reserved.

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serious co-morbidities, and has been established as a risk factor for asthma[45,46] and a contributor to the development of sleep-disordered breathing and sleep apnoea.[44] Recommendations for the management of allergic rhinitis generally consist of a four-stage approach: (i) allergen avoidance; (ii) pharmacotherapy; (iii) immunotherapy; and (iv) education.[44] Usually, it is impossible to completely avoid the triggering allergens, and pharmacotherapy is required and aimed at symptom reduction or prevention. Immunotherapy is generally reserved for those in whom other approaches have failed. Education of the patient and/or caregiver is essential and should include information about the disease and its proper management. International Primary Care Respiratory Group (IPCRG) guidelines for the management of allergic rhinitis list treatment goals as the following: (i) unimpaired sleep; (ii) unimpaired ability to perform normal daily activities; (iii) no troublesome symptoms; and (iv) no or minimal treatment-related adverse events.[47] The highly individualistic nature of patient presentation, type and severity of disease, and response to treatment are factors that complicate the management of allergic rhinitis.[44] The appropriate pharmacotherapy must be matched to the patient’s symptoms to ensure an optimal outcome. Pharmacological options for the management of allergic rhinitis include antihistamines (such as azelastine and loratadine), corticosteroids (such as mometasone furoate, beclomethasone dipropionate and budesonide), leukotriene receptor antagonists (such as montelukast), mast cell stabilizers (such as nedocromil), anticholinergics (such as ipratropium bromide) and decongestants (such as phenylephrine).[47,48] Intranasal corticosteroids and antihistamines are the cornerstones of therapy for allergic rhinitis, with the other agents utilized to a lesser extent.[43] The Allergic Rhinitis and its Impact on Asthma (ARIA) guidelines recommend intranasal corticosteroids as first-line treatment for moderate to severe allergic rhinitis.[45] The British Society of Allergy and Clinical Immunology (BSACI) guidelines for Drugs 2008; 68 (12)

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allergic and non-allergic rhinitis recommend intranasal corticosteroids and antihistamines as firstline treatments, specifically recommending for children, the use of long-acting oral antihistamines (to increase compliance) and intranasal corticosteroids with a low systemic availability.[48] Although no one agent is specifically recommended in the IPCRG guidelines, corticosteroids are considered the most effective agents.[47] US allergic rhinitis treatment guidelines recommend second-generation antihistamines for mild to moderate disease, in combination with intranasal corticosteroids (as the primary agent) for severe disease.[49] First-generation antihistamines (such as diphenhydramine) are generally not recommended due to their sedative effects. Antihistamine agents are effective in relieving the histamine-mediated symptoms of allergic rhinitis (sneezing, nasal itch, rhinorrhoea and ocular symptoms) but are less effective against nasal congestion.[47] However, antihistamines are an appropriate choice for patients with mild or intermittent disease, or for those requiring an ‘as needed’ therapy owing to their fast and effective actions.[50] The topical corticosteroids have well established efficacy in the suppression of both histamine-mediated and nasal symptoms of allergic rhinitis, and with their rapid onset of action, are considered the most effective agents available for the treatment of allergic rhinitis according to IPCRG[47] and BSACI[48] guidelines. In particular, intranasal corticosteroids are the first-line choice in patients with moderate to severe disease or persistent symptoms.[47,48] It has been a common perception, particularly with the older agents of this class, that topical corticosteroids may cause local histopathological changes, have a propensity to suppress the HPA axis, have potential systemic adverse effects and have a slow onset of action.[38] The intranasal corticosteroids currently available for use in the treatment of allergic rhinitis (mometasone furoate, beclomethasone dipropionate, budesonide, flunisolide, fluticasone propionate, fluticasone furoate and triamcinolone acetonide) have less association with such characteristics.[38] When used within the recommended dosage, modern intranasal corticoster© 2008 Adis Data Information BV. All rights reserved.

Baldwin & Scott

oids are safe for long-term use, although the lowest symptom-controlling dosage should be used in children, particularly when other corticosteroid agents are being used for co-morbid conditions such as asthma.[51] In fact, the step-down approach, to achieve the lowest possible effective maintenance dosage, is recommended for all patients being treated with both intranasal and inhaled corticosteroids. Mometasone furoate is a high-potency corticosteroid that is effective in the treatment of the symptoms of allergic rhinitis, without damaging the nasal mucosa,[10] causing HPA axis suppression,[16,17] or suppression of childhood growth (section 2.3).[18] In clinical trials, mometasone furoate reduced TNSS in adults, adolescents and children with SAR or PAR to a significantly greater extent than placebo, although there were no significant differences between mometasone furoate and other active comparator intranasal corticosteroids (section 4). In patients aged ≥12 years, 2–4 weeks of intranasal mometasone furoate pretreatment prior to the anticipated start of the pollen season provided effective prophylaxis in patients with SAR. As with other intranasal corticosteroids, the most common adverse events associated with the use of mometasone furoate include headache, viral infection, pharyngitis and epistaxis (section 5). In general, adverse events were mild to moderate in severity, of short duration, and did not occur with any significantly different frequency in mometasone furoate recipients than in placebo recipients in clinical trials. Septal perforation has been rarely seen with mometasone furoate use and may be prevented by correct administration technique (avoiding nasal trauma with the device tip and directing the spray away from the septum).[3] Literature review has found no clear evidence supporting the suggestion that any one of the currently available intranasal corticosteroids is more safe or effective than another,[52,53] although budesonide is the only corticosteroid with a US FDA Pregnancy Category rating of B, having been shown to be safe for use during pregnancy.[53] While the possibility cannot be entirely ruled out, there is little evidence that any of the intranasal corticosteroids Drugs 2008; 68 (12)

Mometasone Furoate: A Review

restrict skeletal growth or suppress adrenal activity, apart from fluticasone, which can reduce endogenous cortisol secretion.[52] In addition, mometasone furoate, budesonide, fluticasone propionate, fluticasone furoate and triamcinolone acetonide are all available as once-daily dosage regimens.[53,54] However, mometasone furoate and fluticasone furoate are the only agents of their class to be available for use in children as young as 2 years (for which they are approved in the US).[3,54] Improvements in nasal symptoms have been observed as soon as 7 hours after an intranasal dose of mometasone furoate (section 2.2). As with other currently available intranasal corticosteroids, maximum therapeutic benefits of intranasal mometasone furoate are usually achieved within 1–2 weeks of treatment initiation;[1] alleviation of the ocular symptoms of allergic rhinitis (section 4)[33,34] and a reduction in asthma exacerbations in patients with co-morbid allergic rhinitis and asthma may occur.[53] The apparent lack of marked differences between the currently available intranasal corticosteroids for the alleviation of the symptoms of SAR and PAR suggests that, at least in part, treatment selection is likely to be influenced by patient preference and cost. In the only study to date that evaluated the scent-free formulation of mometasone furoate, significantly more patients preferred the scent-free formulation of mometasone furoate than fluticasone propionate nasal spray (section 4.4). The mometasone furoate delivery device is also the first nasal allergy spray to receive the Ease-of-Use Commendation from the Arthritis Foundation.[55] To date, robust pharmacoeconomic data regarding mometasone furoate are lacking and are required to fully determine the relative cost-effectiveness of this intranasal corticosteroid to that of other intranasal corticosteroids. In conclusion, extensive experience in both clinical trials and the clinical practice setting has firmly established the efficacy and good tolerability profile of intranasal mometasone furoate in children and adults with PAR or SAR. Thus, intranasal mometasone furoate is a useful first-line option for the treatment and prophylactic management of these © 2008 Adis Data Information BV. All rights reserved.

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conditions, including in children as young as 2 years of age in some countries and 6 years of age in others. Disclosure The preparation of this review was not supported by any external funding. During the peer review process, the manufacturer of the agent under review was offered an opportunity to comment on this article. Changes resulting from comments received were made on the basis of scientific and editorial merit.

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Correspondence: Claudine M. Baldwin, Wolters Kluwer Health | Adis, 41 Centorian Drive, Private Bag 65901, Mairangi Bay, North Shore 0754, Auckland, New Zealand. E-mail: [email protected]

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