ADIS DRUG EVALUATION
`
`Drugs 1998 Jul; 56 (1): 91-114
`0012-6667/98/0007-0091/$24.00/0
`
`© Adis International Limited. All rights reserved.
`
`Intranasal Azelastine
`A Review of its Efficacy in the Management of
`Allergic Rhinitis
`
`Wendy McNeely and Lynda R. Wiseman
`Adis International Limited, Auckland, New Zealand
`
`Various sections of the manuscript reviewed by:
`G.W. Canonica, Dipartimento di Medicina Interna, Università degli Studi di Genova, Genoa, Italy;
`S.P. Galant, Asthma and Allergy Research Center, Orange, California, USA; F. Horak, ENT University Clinic
`Vienna, Vienna, Austria; W. Kennedy, Centre de Recherche, Hôpital du Sacré Coeur de Montréal, Montreal,
`Quebec, Canada; C. LaForce, Carolina Allergy and Asthma Consultants, Radleigh, North Carolina, USA;
`V.J. Lund, Institute of Laryngology and Otology, University College, London Medical School, London,
`England.
`
`Data Selection
`Sources: Medical literature published in any language since 1966 on azelastine, identified using AdisBase (a proprietary database of Adis
`International, Auckland, New Zealand), Medline and EMBASE. 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 Bibliographical information, including contributory unpublished data, was also requested from the company developing the drug.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: AdisBase, Medline and EMBASE search terms were ‘azelastine’ and ‘allergic rhinitis’. Searches were last updated 13th
`May 1998.
`Selection: Studies in patients with allergic rhinitis who received intranasal azelastine. 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: Azelastine, allergic rhinitis, pharmacokinetics, pharmacodynamics, therapeutic use.
`
`Contents
`
` . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 92
`Summary
`1. Rationale for the Development of Intranasal Azelastine . . . . . . . . . . . . . . . . . . . . . . . . 95
`2. Pharmacodynamic Properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 96
`2.1 Antihistamine Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 96
`2.2 Antiallergic Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 97
`2.3 Anti-inflammatory Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 97
`2.3.1 Effects on Inflammatory Cell Mediators . . . . . . . . . . . . . . . . . . . . . . . . . . . 98
`2.3.2 Effects on Neutrophils . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 99
`2.3.3 Effects on Eosinophils . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 100
`2.3.4 Effects on Mast Cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 100
`2.4 CNS Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 100
`3. Pharmacokinetic Properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 100
`4. Therapeutic Efficacy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 101
`4.1 Noncomparative and Placebo-Controlled Trials . . . . . . . . . . . . . . . . . . . . . . . . . . 102
`4.1.1 Children with Allergic Rhinitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 104
`4.1.2 Nasal Spray as Adjunct Therapy to Oral Azelastine . . . . . . . . . . . . . . . . . . . . . 105
`4.2 Comparisons with Other Agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 105
`4.2.1 Antihistamine Agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 105
`4.2.2 Corticosteroid Agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 107
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`5. Tolerability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 109
`6. Dosage and Administration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 110
`7. Place of Intranasal Azelastine in the Management of Allergic Rhinitis . . . . . . . . . . . . . . . . 111
`
`Summary
`Abstract
`
`Rationale for the
`Development of
`Intranasal Azelastine
`
`Azelastine, a phthalazinone compound, is a second generation histamine H1 re-
`ceptor antagonist which has shown clinical efficacy in relieving the symptoms of
`allergic rhinitis when administered as either an oral or intranasal formulation. It
`is thought to improve both the early and late phase symptoms of rhinitis through
`a combination of antihistaminic, antiallergic and anti-inflammatory mechanisms.
`Symptom improvements are evident as early as 30 minutes after intranasal ad-
`ministration of azelastine [2 puffs per nostril (0.56mg)] and are apparent for up
`to 12 hours in patients with seasonal allergic rhinitis (SAR). The effect on nasal
`blockage is variable: in some studies objective and/or subjective assessment
`showed a reduction in blockage, whereas in other studies there was no improve-
`ment.
`Intranasal azelastine 1 puff per nostril twice daily is generally as effective as
`standard doses of other antihistamine agents including intranasal levocabastine
`and oral cetirizine, ebastine, loratadine and terfenadine at reducing the overall
`symptoms of rhinitis. The relative efficacies of azelastine and intranasal cortico-
`steroids (beclomethasone and budesonide) remain unclear. However, overall, the
`corticosteroids tended to improve rhinitis symptoms to a greater extent than the
`antihistamine.
`Azelastine was well tolerated in clinical trials and postmarketing surveys. The
`most frequently reported adverse events were bitter taste, application site irrita-
`tion and rhinitis. The incidence of sedation did not differ significantly between
`azelastine and placebo recipients and a preliminary report showed cardiovascular
`parameters were not significantly altered in patients with perennial allergic rhi-
`nitis (PAR).
`Conclusion: Twice-daily intranasal azelastine offers an effective and well
`tolerated alternative to other antihistamine agents currently recommended for the
`symptomatic relief of mild to severe SAR and PAR in adults and children (aged
`≥12 years in the US; aged ≥6 years in some European countries including the
`UK). The rapid onset, confined topical activity and reduced sedation demon-
`strated by the intranasal formulation of azelastine may offer an advantage over
`other antihistamine agents, although this has yet to be confirmed.
`Antihistamine compounds have been in use for the management of allergic rhi-
`nitis since the 1940s. The clinical value of the first generation histamine H1
`receptor antagonists, however, was marred by their ability to cross the blood-brain
`barrier and cause, among other adverse events, sedation. The second generation
`histamine H1 receptor antagonists, which include ketotifen, cetirizine, terfenad-
`ine, loratadine, ebastine and azelastine, are generally less sedative and have fewer
`nonspecific effects.
`Azelastine is a phthalazinone derivative which binds preferentially to periph-
`eral rather than central receptors; the drug has been used orally to manage the
`symptoms of bronchial and allergic asthma and allergic rhinitis. Local adminis-
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`Intranasal Azelastine: A Review
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`93
`
`Pharmacodynamic
`Properties
`
`Pharmacokinetic
`Properties
`
`tration via intranasal inhalation serves to further confine the activity of the drug
`and reduce possible adverse effects brought about by systemic exposure.
`Sneezing caused by histamine nasal challenge was significantly reduced within
`1 hour after initial application of azelastine 0.56mg (2 puffs per nostril) in patients
`and volunteers and it remained so for 10 to 12 hours thereafter. However, the
`effects of the drug on nasal blockage were varied: some studies showed improve-
`ments in either subjectively or objectively assessed nasal blockage, whereas oth-
`ers failed to show any improvements.
`After allergen-specific nasal challenge, compared with baseline, single or re-
`peated (twice daily for 2 weeks) administration of azelastine 1 puff per nostril
`significantly reduced objectively assessed nasal airway resistance (NAR) and
`increased nasal inspiration peak flowmeter values in patients with seasonal aller-
`gic rhinitis (SAR). The effects of azelastine compared with placebo on NAR,
`however, were varied. In a study which showed single-dose azelastine to have a
`significant effect compared with placebo, the mean time to onset of this effect
`was 135 minutes. Both the early (EPR) and late phase reaction (LPR) symptoms
`of allergen-induced rhinitis were significantly reduced (by up to 30%) in azelast-
`ine compared with placebo recipients. Azelastine significantly reduced allergen-
`induced sneezing within 15 minutes and was active for up to 10 hours.
`In addition to its antihistamine and antiallergic effects, azelastine also has
`anti-inflammatory properties. It reduces EPR and LPR nasal mucosal infiltration
`of eosinophils and neutrophils by up to 49% after allergen-specific nasal
`challenge. Levels of a variety of inflammatory mediators were also reduced by
`azelastine, including nasal eosinophil cationic protein, myeloperoxidase, tryptase
`and intercellular adhesion molecule-1.
`In vitro in human neutrophils, azelastine significantly and concentration-
`dependently inhibited arachidonic acid release and leukotriene B4 production. In
`neutrophils or eosinophils from nonallergic volunteers, stimulated generation of
`superoxide, a reactive oxygen species, was decreased. Furthermore, azelastine
`significantly reduced the mobilisation of intracellular calcium in N-formyl-
`methionyl-leucyl-phenylalanine (FMLP)-stimulated neutrophils, a process that
`precedes superoxide generation.
`Results from trials in rodent mast cell preparations suggest that azelastine may
`also interfere with protein kinase C activity and the release of tumour necrosis
`factor-α.
`In animal models, azelastine has poor access to the CNS. In addition, studies
`in patients with SAR found that intranasal azelastine generally increased vigi-
`lance during the medication period. Intranasal but not oral azelastine reduced the
`circadian variation in vigilance.
`Pharmacokinetic data for intranasal azelastine are scarce. Maximum plasma con-
`centrations of azelastine were achieved approximately 2.5 hours after intranasal
`administration. After daily intranasal azelastine 0.56mg, mean steady-state
`plasma concentrations of the drug were about 0.26 μg/L in healthy volunteers and
`about 0.65 μg/L in patients; the estimated systemic exposure to the drug was 6-
`to 8-fold lower than that with oral azelastine 4.4mg. The systemic bioavailability
`after intranasal administration was approximately 40%. Azelastine is metabolised
`by the cytochrome P450 enzyme system to its major active metabolite
`desmethylazelastine. At steady state, the plasma metabolite concentration ac-
`counted for 20 to 50% of the azelastine concentration.
`
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`Therapeutic Efficacy
`
`Tolerability
`
`In adults and children aged ≥5 years with SAR or perennial allergic rhinitis (PAR),
`azelastine 1 or 2 puffs per nostril (0.28 or 0.56mg) twice daily over periods of 30
`hours to ≥6 months, compared with baseline or placebo, significantly improved
`rhinitis symptoms including rhinorrhoea, itchy nose, sneezing, watery eyes, itchy
`eyes, ears or throat and postnasal drip. Compared with placebo, azelastine (2 puffs
`per nostril) significantly improved baseline rhinitis symptoms as early as 3 hours
`after drug administration in patients with SAR; significant improvement was
`apparent for up to 12 hours after initial use. Patient and physician global assess-
`ment of treatment with azelastine (1 or 2 puffs per nostril twice daily) of at least
`‘good’ was similar and ranged from 75 to 86%.
`Azelastine had varied effects on nasal blockage in clinical trials; some studies
`showed a significant improvement in azelastine compared with placebo recipi-
`ents, whereas others found no significant effects.
`In children (aged ≤12 years) with allergic rhinitis, azelastine 1 puff per nostril
`twice daily compared with placebo for up to 6 weeks significantly improved
`rhinitis symptoms. In a postmarketing survey in children aged 3 to 12 years, 85%
`of physicians evaluated the efficacy of azelastine as ‘good’/‘very good’. Rhino-
`scopic evaluation in children (aged 7 to 16 years) with PAR revealed significant
`improvement in nasal secretion, oedema and inflammation after 6 weeks’ therapy
`with intranasal azelastine (0.6 mg/day); these symptoms were further improved
`in the 62 children who completed 6 months’ treatment.
`Intranasal azelastine as an adjunct to oral azelastine therapy further improves
`rhinitis symptoms compared with the effects of oral therapy alone in patients with
`SAR.
`In comparative studies, azelastine 1 puff per nostril twice daily was generally
`as effective at reducing the overall symptoms of rhinitis as the standard doses of
`other antihistamine agents including intranasal levocabastine and oral cetirizine,
`ebastine, loratadine and terfenadine.
`Symptom relief within 30 minutes of initial drug administration occurred in
`similar numbers of patients receiving azelastine (1 puff per nostril) or levocabast-
`ine (2 puffs per nostril); the effect was maintained for up to 8 hours after initial
`drug administration in both groups. Each drug improved nasal congestion by
`about 48% and ocular symptoms by about 66% from baseline after 1 week of
`twice-daily administration.
`Results from studies that compared the effects of azelastine 1 puff per nostril
`twice daily and intranasal corticosteroids on the symptoms of rhinitis were varied,
`but overall, the corticosteroids appeared more effective. A significantly more
`rapid overall symptom relief was achieved in azelastine compared with beclo-
`methasone recipients in 1 study, but after 2 weeks’ therapy, improvements in
`overall symptom scores were significantly greater in the beclomethasone recipi-
`ents. Both beclomethasone and budesonide were superior to azelastine at redu-
`cing the nasal symptoms of rhinitis in some studies, whereas others found no
`statistically significant difference between treatments. Budesonide was associ-
`ated with greater improvements in nasal blockage than azelastine, although these
`did not reach statistical significance. In addition, patients’ global assessments of
`‘substantial’ or ‘total’ control of symptoms were significantly more common with
`budesonide (0.256mg once daily) than with azelastine (0.28mg twice daily) in a
`double-blind study (70.4 vs 44.7%).
`Results from postmarketing surveys in 7682 patients aged 3 to 85 years with
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`Intranasal Azelastine: A Review
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`95
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`allergic rhinitis who received azelastine 1 puff per nostril twice daily for up to 1
`month showed the drug to be generally well tolerated. When azelastine was given
`alone, approximately 8% of patients reported adverse events; when it was given
`in combination with other antihistamines and/or topical corticosteroids the inci-
`dence of adverse events was approximately 20%. Bitter taste and rhinitis were
`the most frequently reported adverse events.
`Where stated in clinical trials, physician and/or patient global assessment of
`tolerability was at least ‘good’ in more than 70% of patients (adults and children
`aged ≥7 years) receiving azelastine (typically 1 puff per nostril twice daily).
`Indeed, >90% of 35 azelastine recipients assessed tolerability as at least ‘good’
`during a 21-month period of medication.
`The most frequently reported adverse events were mild, transient bitter taste
`(associated with the taste of the drug) and application site irritation. Sedation did
`not differ significantly in azelastine or placebo recipients. Indeed, some study
`reports remarked on its absence and 1 trial reported an improvement in overall
`vigilance during a 2-week medication period.
`Treatment withdrawal because of drug-related adverse events was rare (1 to 3
`patients per study; ≤7%); reasons for withdrawal included mild increased nasal
`pruritus, nasal congestion, nausea and vomiting, dizziness and increased blood
`pressure.
`No significant changes in PR, QS, QT or QTc intervals were observed in
`patients with PAR who were randomised to receive azelastine (2 puffs per nostril)
`or placebo twice daily for 8 weeks. In addition, there were no changes in mean
`heart rate or blood pressure in any patient.
`The US prescribing recommendations specify 2 puffs per nostril of azelastine
`nasal spray twice daily for adults and children aged ≥12 years; each puff delivers
`approximately 0.14mg of the drug. In the UK and a number of other European
`countries, azelastine is approved as 1 puff per nostril twice daily for adults and
`children aged ≥6 years.
`Although somnolence is rare, the US prescribing information carries a caution
`regarding use of the medication and driving or operating potentially dangerous
`machinery. Concurrent use of alcohol and/or other CNS suppressants should be
`avoided.
`
`Dosage and
`Administration
`
`1. Rationale for the Development of
`Intranasal Azelastine
`
`The use of antihistamine compounds in the man-
`agement of allergic rhinitis is not new; they have
`been in use since the 1940s. However, the clinical
`value of the classical or first generation histamine
`H1 receptor antagonists was marred by their ability
`to cross the blood-brain barrier and cause sedation
`(resulting from CNS depression) and a number of
`nonspecific events (resulting from blockade of
`muscarinic-cholinergic, α-adrenergic and seroton-
`ergic receptors).[1] The newer, or second generation
`histamine H1 receptor antagonists, which include
`
`ketotifen, cetirizine, terfenadine, loratadine, ebast-
`ine and azelastine, are generally less sedative and
`have fewer nonspecific effects.
`Azelastine is a phthalazinone derivative which,
`like many of the second generation H1-receptor an-
`tagonists, binds preferentially to peripheral rather
`than central receptors.[2] Local administration via
`intranasal inhalation serves to further confine the
`activity of the drug and reduce possible adverse
`effects brought about by systemic exposure.
`Oral azelastine has been extensively used to
`manage the symptoms of bronchial and allergic
`asthma and allergic rhinitis.[3] This review focuses
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`Table I. Overview of the pharmacodynamic properties of azelastine in humans (unless stated otherwise)
`
`Antihistamine effects (after histamine nasal challenge)
`Decreases objectively assessed nasal airway resistance[4]
`Decreases sneezing[4] and nasal secretions[5]
`Significantly protects against a reduction in nasal volume (assessed by acoustic rhinometry)[6]
`
`Antiallergic effects (after allergen-specific nasal challenge)
`Decreases objectively assessed nasal airway resistance[7]
`Improves overall,[7,8] EPR and LPR rhinitis symptoms[9,10] including sneezing[4,7,11] and nasal blockage[11]
`Decreases EPR and LPR nasal neutrophil and eosinophil infiltration[9,10]
`
`Effects on inflammatory cell mediators
`Decreases ICAM-1 expression[9,10]
`Decreases nasal ECP[9,10,12,13] without affecting plasma ECP levels[12]
`Decreases nasal myeloperoxidase and tryptase levels[13]
`
`Effects on inflammatory cells
`
`Neutrophils
`Decreases stimulated superoxide generation in whole cell suspensions[14-18] but not cell-free lysate[16,17]
`Decreases mobilisation of intracellular free calcium[19]
`Decreases release of arachidonic acid[14]
`Decreases the production of LTB4[14] and LTB4 synthase[20]
`
`Eosinophils
`Decreases chemotactic activity in fresh cells[21] and EoL-1 cell cultures[22]
`Decreases mobilisation of intracellular free calcium in EoL-1 cell cultures[22]
`Decreases stimulated superoxide generation in whole cell suspensions[15,18]
`
`Central effects
`Limited access to CNS (assessed using the active avoidance response model) in mice[23]
`ECP = eosinophil cationic protein; EoL-1 = a human eosinophilic leukaemia cell line; EPR = early phase reaction; ICAM-1 = intercellular
`adhesion molecule-1; LPR = late phase reaction; LTB4 = leukotriene B4.
`
`on the newer intranasal formulation of azelastine
`and its use in the management of seasonal (SAR)
`and perennial allergic rhinitis (PAR).
`
`2. Pharmacodynamic Properties
`
`The early pharmacodynamic data for azelastine
`in animals has already been documented.[3] There-
`fore, this section focuses on human data, supple-
`mented, where necessary, with animal data.
`Table I gives an overview of the pharmacody-
`namic properties of azelastine assessed in patients,
`volunteers, human-derived cells and animals.
`Azelastine nasal spray is administered by an in-
`haler that delivers approximately 0.14mg of the
`drug per actuation.
`
`2.1 Antihistamine Effects
`
`The effect of azelastine on nasal blockage is un-
`clear, but this may be partly due to the technique
`used to assess the effects of the drug on this param-
`eter. In 27 patients with SAR, rhinomanometric
`assessment of nasal airway resistance (NAR) re-
`vealed no significant protection from nasal hista-
`mine challenge by azelastine 1 puff per nostril, but
`parallel subjective evaluation showed a 50% reduc-
`tion in nasal blockage (p = 0.005 vs placebo).[6]
`However, in another trial, objectively assessed
`blockage after histamine nasal challenge was sig-
`nificantly reduced by a higher dose of azelastine (2
`puffs per nostril) compared with placebo in 31
`evaluable patients with allergic rhinitis.[4] The
`maximum response to histamine challenge (as a
`percentage of maximum response to saline chal-
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`Intranasal Azelastine: A Review
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`lenge) was significantly reduced with azelastine
`compared with placebo at 1 hour [155 vs 210%
`(estimated from graph); p < 0.02] and 2 hours [150
`vs 250% (estimated from graph); p < 0.0001] after
`initial administration, but there was no significant
`difference between the NAR values in each group
`after 4 hours.[4]
`In a double-blind, double-dummy trial in which
`healthy volunteers received intranasal azelastine 2
`puffs per nostril, oral cetirizine 10mg or placebo,[5]
`neither azelastine nor placebo had a significant ef-
`fect on subjectively assessed histamine-induced
`nasal blockage, whereas cetirizine significantly re-
`duced nasal blockage, but only at 24 hours after
`treatment (p < 0.05).[5]
`In the same study, azelastine or cetirizine, com-
`pared with placebo, significantly reduced the num-
`ber of histamine-induced sneezes in volunteers at
`1, 9 and 12 hours after initial drug administration
`(p < 0.05 vs placebo).[5]
`Furthermore, histamine-induced nasal secretion
`in volunteers was reduced by azelastine at 1 to 12
`hours after application (p < 0.05) and by cetirizine
`at 9 (p < 0.05) and 24 hours after ingestion (p <
`0.01; all vs placebo).[5]
`In patients with allergic rhinitis (type not de-
`fined), the number of sneezes recorded in the first
`10 minutes after histamine challenge was signifi-
`cantly less in the azelastine than in the placebo
`group from 1 to 10 hours after drug administration
`(p < 0.02).[4]
`The effects of intranasal azelastine appear to be
`confined to the application site: the drug had no
`antihistaminic activity in the skin of 12 healthy
`volunteers who underwent histamine skin prick
`tests after receiving azelastine nasal spray (0.14mg
`per nostril twice daily) for 1 week.[24] This suggests
`that there is no significant systemic distribution of
`the agent after intranasal administration.
`
`2.2 Antiallergic Effects
`
`Compared with baseline values, azelastine sig-
`nificantly reduced objectively assessed NAR[8,11]
`and increased nasal inspiration peak flowmeter
`values[8] after single[11] or repeated (twice daily for
`2 weeks)[8] administration (p < 0.05). The effects
`of azelastine compared with placebo, however,
`were not clear: in 1 study the mean NAR values
`were significantly different (p < 0.01),[7] whereas
`in another there was no difference between the
`mean maximum NAR values in placebo and
`azelastine treatment groups.[4] In addition, azelast-
`ine was not significantly better than budesonide
`nasal spray twice daily (no further details)[8] or N-
`acetyl aspartyl-glutamate 8.4mg (NAAG; inhibitor
`of mast cell degranulation)[11] at reducing NAR.
`In a study which did show a significant reduc-
`tion in NAR in azelastine (single-dose 1 puff per
`nostril) compared with placebo recipients, the
`mean time to onset of effect (defined as a 20%
`difference in NAR between active drug and pla-
`cebo) was 135 (range 75 to 210) minutes.[7]
`Azelastine improved baseline scores of aller-
`gen-induced symptoms of rhinitis (typically
`sneeze, itch, rhinorrhoea and blockage).[7-10,25]
`More specifically, in patients with SAR, both the
`early (EPR) and late phase reaction (LPR) symp-
`toms were reduced[9] (by up to 30% in each phase;
`p = 0.01 for both vs placebo[10]).
`The drug significantly reduced sneezing af-
`ter,[4,11,25] or during,[7] nasal challenge (p < 0.05).
`The number of sneezes after nasal challenge was
`significantly reduced 15 minutes after azelastine
`application in 1 study (p < 0.05 vs placebo).[25] In
`another study, prechallenge treatment with azelast-
`ine reduced sneezing after the first 30 minutes of a
`4-hour challenge in a Vienna chamber.[7] In azelast-
`ine compared with placebo recipients, the number
`of sneezes after allergen nasal challenge was sig-
`nificantly reduced for up to 10 hours after drug
`administration (p < 0.05).[4]
`
`Several trials objectively assessed the effects of
`azelastine 1[6-8,11] or 2[4] puffs per nostril on NAR
`after allergen-specific nasal challenge in patients
`with SAR.
`
`2.3 Anti-inflammatory Effects
`
`It is widely accepted that allergic rhinitis is
`maintained by an inflammatory response charac-
`terised by the release of mediators, including his-
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`unclear. The following discussion, however, high-
`lights some of the important anti-inflammatory
`properties exhibited by the drug.
`
`2.3.1 Effects on Inflammatory Cell Mediators
`Eosinophil cationic protein (ECP), myeloperox-
`idase (MPO) and tryptase are, respectively, media-
`tors for eosinophils, neutrophils and mast cells.[13]
`Several studies have investigated the effects of
`azelastine on these mediators.
`In patients with allergic rhinitis[12] (or nasal
`polyposis and thus inflammation of the nasal mu-
`cosa[13]), azelastine 1 puff per nostril twice daily
`for 2[12] or 25 weeks[13] significantly reduced nasal
`levels of ECP from baseline by 57[12] or 42%[13] at
`study completion (p < 0.05 for both). Furthermore,
`compared with placebo, single-dose azelastine 1
`puff per nostril reduced ECP levels both during
`EPR (by 12%; not significant) and LPR (by 38%;
`p < 0.01) [fig. 2][10]. But in another study,[9]
`compared with baseline, ECP levels were reduced
`only during LPR (p < 0.05; no further details pro-
`vided).
`These data may explain the observed reductions
`in nasal mucosal infiltration of eosinophils in pa-
`tients (fig. 1).
`As expected, nasal but not plasma levels of ECP
`were reduced after intranasal azelastine, whereas
`both were significantly reduced after combined
`oral and nasal administration of the drug.[12] This
`provides further evidence of the localised effect of
`intranasal azelastine (see section 2.1).
`After 25 weeks of azelastine therapy (2 puffs per
`nostril twice daily) in patients with nasal inflam-
`mation resulting from polyposis, both MPO (p =
`0.0015) and tryptase (p = 0.0574) levels were re-
`duced by 41% from baseline.[13] However, in a sin-
`gle-dose study in patients with SAR, levels of MPO
`were not significantly affected by azelastine or pla-
`cebo (fig. 2).[10]
`Intercellular adhesion molecule-1 (ICAM-1) is
`expressed on epithelial cells only after allergen ex-
`posure.[10] In 2 single-dose azelastine trials (1 puff
`per nostril), both EPR and LPR ICAM-1 expres-
`sion was significantly reduced in nasal secretions
`(p < 0.05 vs placebo; fig. 2).[9,10] Furthermore,
`
`Early phase reaction
`
`**
`
`**
`
`Late phase reaction
`
`**
`
`*
`
`Azelastine
`Placebo
`
`Neutrophils
`
`Eosinophils
`
`20
`
`10
`
`0
`
`–10
`
`–20
`
`–30
`
`–40
`
`–50
`
`–60
`
`20
`
`10
`
`0
`
`–10
`
`–20
`
`–30
`
`–40
`
`–50
`
`–60
`
`98
`
`Change from baseline (%)
`
`Fig. 1. Effect of azelastine on allergen-induced nasal infiltration
`of neutrophils and eosinophils. Single-dose azelastine 1 puff per
`nostril or placebo was given to 20 patients with seasonal allergic
`rhinitis.[10] Nasal lavage was performed 30 minutes (early phase
`reaction) or 6 hours (late phase reaction) after nasal challenge.
`* p < 0.05, ** p < 0.01 vs placebo.
`
`tamine, arachidonic acid derivatives and chemo-
`tactic compounds, which precede mucosal infiltra-
`tion of inflammatory cells such as eosinophils and
`neutrophils.[10,26]
`Azelastine significantly reduced EPR and LPR
`nasal mucosal infiltration of eosinophils and neu-
`trophils (by between 35 and 49% from baseline; p
`< 0.05 vs placebo[10]) after allergen-specific nasal
`challenge in patients with SAR (fig. 1).[9,10]
`Whether or not the mechanism of action of
`azelastine in the management of allergic rhinitis
`includes an anti-inflammatory component remains
`
`© Adis International Limited. All rights reserved.
`
`Drugs 1998 Jul; 56 (1)
`
`000008
`
`

`

`Intranasal Azelastine: A Review
`
`99
`
`matory process by interfering with the mediators
`required to initiate the response.
`
`2.3.2 Effects on Neutrophils
`It is well known that arachidonic acid is re-
`quired for the production of leukotrienes, which in
`turn are involved in the inflammatory process.[28,29]
`Leukotriene B4 (LTB4), for example, is a potent
`aggregating and chemotactic agent for inflamma-
`tory cells.[30] Azelastine 100 μmol/L significantly
`inhibited arachidonic acid release (by 87%) and
`LTB4 production (by 90%; both p < 0.01 vs control)
`in human neutrophils in vitro; these effects were
`concentration-dependent over the range 20 to 100
`μmol/L.[14]
`Arachidonic acid may also be required for the
`activation of NADPH (reduced form of nicotin-
`amide-adenine dinucleotide phosphate) oxidase
`and the subsequent production of superoxide.[31,32]
`Superoxide is one of a number of reactive oxygen
`species (ROS) produced by neutrophils in response
`to immunoglobulin E (IgE)-mediated allergic reac-
`tions and is thought to help initiate and sustain
`chronic inflammation.[15,16]
`In order to assess the effects of azelastine on
`ROS generation, whole cell neutrophil suspen-
`sions prepared from blood from nonallergic volun-
`teers[14-19] were stimulated by a variety of agents
`including phorbol myristate acetate (PMA; which
`activates intracellular protein kinase C),[14,15,17,18]
`N - formyl - methionyl - leucyl - phenylalanine
`(FMLP; which stimulates a specific membrane
`receptor and leads to the activation of protein ki-
`nase C),[15,19] calcium ionophore (A23187; which
`causes the cell membrane to transport calcium in-
`tracellularly) and zymosan (which interacts with
`the C3b membrane receptor).[15,16] Cell-free lysates
`were also prepared to assess the effects of azelast-
`ine on NADPH-generated superoxide,[17,19] or xan-
`thine-oxidase generation.[16]
`Generally, stimulated superoxide generation
`was decreased in a concentration-dependent man-
`ner (p < 0.05[15]),[16-19] where stated, over the azel-
`astine concentration range 0.1 to 200 μmol/L. In-
`deed, 1 study reported significant reductions (9 to
`36%) in a variety of ROS with azelastine 0.05 to 5
`
`10
`
`Early phase reaction
`
`Late phase reaction
`
`**
`
`Azelastine
`Placebo
`
`**
`
`*
`