Combination therapy with azelastine
`hydrochloride nasal spray and fluticasone
`propionate nasal spray in the treatment of
`patients with seasonal allergic rhinitis
`Paul H. Ratner, MD*; Frank Hampel, MD†; Julius Van Bavel, MD‡; N. J. Amar, MD§;
`Pramila Daftary, MD¶; William Wheeler, PhD储; and Harry Sacks, MD储
`
`Background: To our knowledge, there are no published studies that evaluated the efficacy of azelastine hydrochloride nasal
`spray in combination with an intranasal corticosteroid, although anecdotal reports of the use of these agents in combination are
`common.
`Objective: To determine if greater efficacy could be achieved with the intranasal antihistamine azelastine and the intranasal
`corticosteroid fluticasone propionate used concurrently compared with the efficacy of each agent alone.
`Methods: This randomized, 2-week, multicenter, double-blind trial was conducted during the Texas mountain cedar season.
`After a 5-day placebo lead-in period, 151 patients with moderate to severe nasal symptoms were randomized to treatment with
`the following: (1) azelastine nasal spray, 2 sprays per nostril twice daily; (2) fluticasone nasal spray, 2 sprays per nostril once
`daily; or (3) azelastine nasal spray, 2 sprays per nostril twice daily, plus fluticasone nasal spray, 2 sprays per nostril once daily.
`The primary efficacy variable was the change from baseline in the total nasal symptom score (TNSS), consisting of sneezing,
`itchy nose, runny nose, and nasal congestion.
`Results: All 3 groups had statistically significant (P ⬍ .001) improvements from their baseline TNSS after 2 weeks of
`treatment. The TNSS improved 27.1% with fluticasone nasal spray, 24.8% with azelastine nasal spray, and 37.9% with the 2
`agents in combination (P ⬍ .05 vs either agent alone). All 3 treatments were well tolerated.
`Conclusions: The significant improvement in the TNSS with combination therapy relative to the individual agents alone is in
`contrast to previously published studies that found no advantage with an oral antihistamine and an intranasal corticosteroid in
`combination. Azelastine nasal spray and fluticasone nasal spray in combination may provide a substantial therapeutic benefit for
`patients with seasonal allergic rhinitis compared with therapy with either agent alone.
`Ann Allergy Asthma Immunol. 2008;100:74–81.
`
`INTRODUCTION
`The most commonly used agents in the treatment of seasonal
`allergic rhinitis (SAR) are oral antihistamines and intranasal
`corticosteroids. Clinical studies1,2 have shown that the sec-
`ond-generation antihistamines, cetirizine and fexofenadine,
`provide approximately equal therapeutic efficacy, whereas
`the efficacy of cetirizine seems to exceed that of loratadine.3–5
`Reviews6,7 of well-controlled clinical trials that directly com-
`pared an intranasal corticosteroid with an oral antihistamine
`
`Affiliations: * Sylvana Research, San Antonio, Texas; † Central Texas
`Health Research, New Braunfels, Texas; ‡ Allergy and Asthma Associates
`Research, Austin, Texas; § Allergy and Asthma Research Institute, Waco,
`Texas; ¶ Allergy and Asthma Care of Waco, Waco, Texas; 储 MedPointe
`Pharmaceuticals, Somerset, New Jersey.
`Disclosures: Drs Ratner, Hampel, Van Bavel, Amar, and Daftary re-
`ceived research grants for conducting this study, and Drs Wheeler and Sacks
`are employees of MedPointe Pharmaceuticals.
`Sources of Funding: This study was supported by MedPointe Pharma-
`ceuticals.
`Received for publication December 20, 2006; Received in revised form
`July 26, 2007; Accepted for publication August 23, 2007.
`
`concluded that intranasal corticosteroids are superior to oral
`antihistamines for the relief of allergic rhinitis symptoms.
`Azelastine hydrochloride nasal spray is the only second-
`generation antihistamine recommended for the treatment of
`SAR and nonallergic vasomotor rhinitis.8,9 Compared with
`oral antihistamines, azelastine nasal spray significantly im-
`proved rhinitis symptom scores in placebo-controlled studies
`in patients with SAR who remained symptomatic after treat-
`ment with loratadine or fexofenadine. In these studies,10,11
`patients treated with azelastine nasal spray who received
`loratadine or fexofenadine concomitantly had no additional
`improvement when compared with treatment with azelastine
`nasal spray alone. In 2 direct comparative trials vs cetirizine
`in patients with SAR, azelastine nasal spray was significantly
`better than cetirizine for treating nasal symptoms in one
`trial,12 numerically better than cetirizine in the second trial,13
`and significantly better than cetirizine in both trials for im-
`proving quality-of-life variables using the Rhinoconjunctivi-
`tis Quality of Life Questionnaire (RQLQ).
`In 2-week, double-blind studies with intranasal corticoste-
`roids in patients with SAR, azelastine nasal spray at a dosage
`of 1 spray per nostril twice daily showed comparable efficacy
`
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`

`to budesonide, 2 sprays per nostril twice daily (400 ␮g/d),14,15
`and beclomethasone (0.2 mg twice daily).16 In a 6-week
`double-blind trial in patients with SAR, azelastine, 1 spray
`per nostril twice daily, and loratadine, 10-mg tablets once
`daily, significantly (P ⬍ .05) improved symptom scores
`compared with baseline, and the physician global evaluation
`of efficacy rated similar numbers of patients in each group
`with either “good” or “very good” improvement.17 In a
`2-week, double-blind trial in patients with SAR, azelastine, 1
`spray per nostril twice daily, and cetirizine, 10 mg/d, pro-
`duced total symptom score improvements of 61% and 67%,
`respectively.18 In a 6-week, placebo-controlled study19 in
`patients with perennial allergic rhinitis, a once-daily dose of
`256 ␮g of budesonide aqueous suspension was significantly
`(P ⬍ .01) more effective than azelastine nasal spray, 1 spray
`per nostril twice daily, in improving the total nasal symptom
`score (TNSS). In a double-blind, placebo-controlled study20
`of flunisolide nasal spray and azelastine nasal spray in pa-
`tients with perennial allergic rhinitis, the researchers reported
`little difference between the 2 treatments for the overall
`summary score; however,
`the
`topical
`corticosteroid
`showed a greater decrease in symptom severity compared
`with placebo than the antihistamine spray for all symp-
`toms, except rhinorrhea.
`Unfortunately, many patients with SAR do not achieve
`optimal symptom relief with single-agent therapy. In a survey
`conducted by the American College of Allergy, Asthma &
`Immunology, more than 75% of allergists and primary care
`physicians surveyed cited inadequate symptom relief as the
`reason for changing medications or prescribing combination
`therapy.21 Although oral antihistamines and intranasal corti-
`costeroids routinely are prescribed together, the weight of
`clinical evidence indicates that combination therapy with
`these agents is no more effective than the corticosteroid
`alone.7,22,23 To our knowledge, there have been no published
`studies that evaluated the efficacy of azelastine nasal spray
`used in combination with an intranasal corticosteroid. We
`hypothesized that 2 agents with different mechanisms of
`action could have the potential for a greater effect when used
`in combination than separately. The antihistaminic effect of
`azelastine would be evident quickly after initial administra-
`tion and sustained with regular use. The primary antihista-
`minic activity of azelastine could be augmented by anti-
`inflammatory effects of the intranasal corticosteroid during
`the 2-week study period. Therefore, this study was conducted
`to determine if greater efficacy could be achieved with the
`combination of intranasal azelastine and intranasal flutica-
`sone propionate when compared with the efficacy of either
`agent alone in patients with SAR.
`
`METHODS
`
`Patients
`The study population consisted of patients 12 years and older
`with a minimum 2-year history of allergy to Texas mountain
`cedar (Juniperus ashei) pollen, as confirmed by a positive
`
`allergy skin test result within the past year. Use of concom-
`itant medications was discontinued for specified times, based
`on the elimination half-life of each drug, before patients
`began the double-blind treatment period. All patients or their
`guardians (if the patient was aged ⬍18 years) signed an
`institutional review board–approved informed consent agree-
`ment (Sterling institutional review board, Atlanta, Georgia)
`before participation.
`
`Study Design
`This randomized, double-blind, double-dummy, parallel-
`group study was conducted between December 27, 2005, and
`February 17, 2006, at 5 investigational sites during the Texas
`mountain cedar season. Pollen counts were conducted at each
`study site to confirm the presence of mountain cedar pollen
`during the investigation. The objective was to determine if
`greater efficacy could be achieved with the combination of
`azelastine hydrochloride nasal spray (Astelin; MedPointe
`Pharmaceuticals, Somerset, New Jersey) and fluticasone pro-
`pionate nasal spray (Flonase; GlaxoSmithKline, Research
`Triangle Park, North Carolina) compared with the efficacy of
`each agent alone.
`The primary efficacy variable was the change from base-
`line to day 14 for the entire double-blind treatment period in
`the TNSS, consisting of rhinorrhea, sneezing, itchy nose, and
`nasal congestion. Secondary efficacy variables included the
`following: (1) change from baseline for each individual treat-
`ment day, (2) change from baseline to day 14 in individual
`symptom scores, and (3) change from baseline to day 14 in
`the RQLQ, including overall score and individual domains.
`Safety was evaluated by patient reports of adverse experi-
`ences and vital sign assessments, including body temperature,
`blood pressure, pulse rate, and respiration rate, performed at
`baseline and at the end of the study.
`There were 10 symptom assessments (in the morning and
`evening each day) during the 5-day placebo lead-in period.
`To qualify for randomization to the double-blind treatment
`period, patients must have recorded a 12-hour reflective
`TNSS of at least 8 at 3 evaluation times either in the morning
`or in the evening (1 of which was within 48 hours of study
`day 1) during the lead-in period. In addition, a morning or
`evening nasal congestion score of 3 must have been recorded
`at 3 assessments (1 of which was within 48 hours of day 1).
`Patients randomized to the azelastine nasal spray group
`received azelastine nasal spray, 2 sprays per nostril twice
`daily, in the morning and evening (1.1-mg azelastine) and
`placebo spray once daily in the morning. Patients randomized
`to the fluticasone group received fluticasone, 2 sprays per
`nostril once daily, in the morning (200-␮g fluticasone) and
`placebo spray twice daily in the morning and evening. Pa-
`tients randomized to the combination group received azelas-
`tine nasal spray, 2 sprays per nostril twice daily, in the
`morning and evening and fluticasone nasal spray, 2 sprays
`per nostril once daily, in the morning. The kits containing
`study drugs were assembled so that blinded azelastine nasal
`spray was administered before blinded fluticasone nasal
`
`VOLUME 100, JANUARY, 2008
`
`75
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`

`

`Table 1. Demographic and Baseline Characteristics
`
`Characteristic
`
`Age, y
`Mean
`Range
`Sex, No. (%)
`Males
`Females
`Race/ethnicity, No. (%)a
`White
`Black
`Asian
`Hispanic
`Other
`Baseline TNSS
`Mean
`SD
`Range
`Duration of allergy, y
`Mean
`Range
`
`Azelastine hydrochloride
`nasal spray group
`(n ⴝ 49)
`
`Fluticasone propionate nasal
`spray group (n ⴝ 50)
`
`Combination azelastine
`nasal spray and fluticasone
`nasal spray group (n ⴝ 52)
`
`Total
`(N ⴝ 151)
`
`38.4
`12–73
`
`22 (44.9)
`27 (55.1)
`
`36 (73.5)
`5 (10.2)
`0
`7 (14.3)
`1 (2.0)
`
`19.6
`2.11
`15–24
`
`19.2
`3–50
`
`37.4
`12–72
`
`15 (30.0)
`35 (70.0)
`
`32 (64.0)
`2 (4.0)
`3 (6.0)
`13 (26.0)
`0
`
`19.5
`2.74
`14–24
`
`15.7
`3–51
`
`36.0
`13–70
`
`19 (36.5)
`33 (63.5)
`
`41 (78.8)
`2 (3.8)
`1 (1.9)
`8 (15.4)
`0
`
`19.5
`2.97
`13–24
`
`16.2
`4–40
`
`37.2
`12–73
`
`56 (37.1)
`95 (62.9)
`
`109 (72.2)
`9 (6.0)
`4 (2.6)
`28 (18.5)
`1 (0.7)
`
`19.5
`2.62
`13–24
`
`17.0
`3–51
`
`Abbreviation: TNSS, total nasal symptom score.
`a Percentages may not total 100 because of rounding.
`
`spray. Patients were instructed to administer the morning
`doses of each study drug 15 to 30 minutes apart. Instruction
`on proper technique for administering the nasal sprays was
`given before starting the lead-in period and again before the
`double-blind treatment period, and patients were observed
`taking their initial dose of study medications before leaving
`the clinic at these visits.
`The identity of the study medications was concealed
`through use of a device (Pharmask Inc, Medfield, Massachu-
`setts) that prevented identification of the product but allowed
`for the proper administration of the nasal sprays.
`During the 2-week, double-blind treatment period, the pa-
`tients recorded symptom scores twice daily (morning and
`evening) on diary cards. Symptoms were recorded before the
`morning and evening doses of study medications as an eval-
`uation of symptom severity during the previous 12 hours
`(12-hour reflective TNSS). Individual symptoms of the TNSS
`were scored on a 4-point scale, where 0 indicates no symp-
`toms; 1, mild symptoms; 2, moderate symptoms; and 3,
`severe symptoms (such that the maximum combined morning
`and evening TNSS was 24).
`
`Statistical Analysis
`Patients were randomized to treatment by a computer-
`generated randomization schedule, which was accessible
`only to authorized persons who were not involved in the
`study. The primary efficacy analyses were performed on
`an intent-to-treat population consisting of all randomized
`patients with at least 1 postbaseline observation. Missing
`TNSS values were imputed using the last-observation-
`carried-forward method. Safety analyses were performed
`
`on all randomized patients who received at least 1 dose of
`study medication.
`The effects of treatment were determined at each day of
`the study and after 14 days based on change from baseline
`in the TNSS. Baseline TNSS was defined as the average of
`all TNSS scores during the 5-day placebo lead-in-period.
`The treatment groups were compared using an analysis of
`variance model with baseline as a covariate. The data from
`this study were tested for homogeneity and were normally
`distributed. No site-related effects were identified. The
`TNSS was analyzed as the mean change from baseline
`during the entire 14-day study period. Additional analyses
`included the mean change from baseline in TNSS for
`individual study days and individual symptoms and the
`mean percentage change from baseline during the entire
`14-day study period.
`The quality-of-life evaluation was performed using the
`self-administered RQLQ, which evaluated the following 7
`domains: (1) activities, (2) sleep, (3) non–nose/eye symp-
`toms, (4) practical problems, (5) nasal symptoms, (6) eye
`symptoms, and (7) emotional factors. The change from base-
`line to day 14 in the RQLQ domains and overall score was
`calculated and analyzed according to the method described by
`Juniper at al.24
`The incidence of adverse events was summarized by
`body system, severity, and relationship to study drug. Vital
`sign measurements, including oral body temperature, sys-
`tolic and diastolic blood pressure, pulse rate, and respira-
`tion rate, were examined for abnormal values and changes
`from baseline.
`
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`

`

`Table 2. Data for the TNSS
`
`Variablea
`
`Baseline data
`
`Change from baseline
`TNSS data
`
`% Change from baseline
`TNSS data
`
`LS Mean
`
`SD
`
`LS Mean
`
`SD
`
`P valueb
`
`% change
`LS mean
`
`SD
`
`P valueb
`
`19.5
`
`19.7
`19.6
`
`4.7
`
`4.8
`4.8
`
`3.0
`
`2.1
`2.7
`
`1.0
`
`0.8
`1.3
`
`7.4
`
`4.8
`5.2
`
`1.9
`
`1.1
`1.3
`
`1.7
`
`5.6
`
`4.3
`4.6
`
`1.7
`
`1.4
`1.5
`
`1.4
`
`NA
`
`.008
`.03
`
`NA
`
`.009
`.02
`
`NA
`
`37.9
`
`24.8
`27.1
`
`39.9
`
`25.4
`25.5
`
`31.2
`
`27.7
`
`22.2
`24.5
`
`39.0
`
`29.7
`32.9
`
`25.7
`
`NA
`
`.01
`.04
`
`NA
`
`.03
`.04
`
`NA
`
`TNSS
`Azelastine hydrochloride nasal spray plus
`fluticasone propionate nasal spray
`Azelastine nasal spray alone
`Fluticasone nasal spray alonec
`Itchy nose
`Azelastine nasal spray plus fluticasone
`nasal spray
`Azelastine nasal spray alone
`Fluticasone nasal spray alone
`Congestion
`Azelastine nasal spray plus fluticasone
`nasal spray
`Azelastine nasal spray alone
`Fluticasone nasal spray alone
`Runny nose
`Azelastine nasal spray plus fluticasone
`nasal spray
`Azelastine nasal spray alone
`Fluticasone nasal spray alone
`Sneezing
`Azelastine nasal spray plus fluticasone
`nasal spray
`Azelastine nasal spray alone
`Fluticasone nasal spray alone
`
`5.4
`
`5.5
`5.5
`
`4.9
`
`4.9
`5.0
`
`4.5
`
`4.5
`4.3
`
`0.6
`
`0.5
`0.4
`
`1.0
`
`0.8
`1.0
`
`1.2
`
`1.1
`1.3
`
`1.1
`1.1
`
`1.7
`
`1.1
`1.3
`
`2.1
`
`1.5
`1.5
`
`1.5
`1.2
`
`1.6
`
`1.4
`1.2
`
`1.7
`
`1.0
`1.5
`
`.02
`.04
`
`NA
`
`.02
`.19
`
`NA
`
`.04
`.05
`
`19.2
`21.1
`
`36.4
`
`20.5
`23.0
`
`46.4
`
`34.2
`31.8
`
`26.6
`23.4
`
`32.9
`
`27.6
`53.4
`
`37.2
`
`25.8
`38.1
`
`.02
`.04
`
`NA
`
`.05
`.09
`
`NA
`
`.08
`.04
`
`Abbreviations: LS, least squares; NA, data not applicable; TNSS, total nasal symptom score.
`a Data were available for 52 patients in the combination therapy group, 49 in the azelastine nasal spray group, and 49 in the fluticasone nasal spray
`group.
`b Statistical significance of azelastine nasal spray plus fluticasone nasal spray vs the individual agent.
`c One patient had no postbaseline efficacy assessment and was not included in the analysis.
`
`RESULTS
`
`Primary Efficacy
`
`Disposition of Patients
`A total of 151 patients were randomized to double-blind
`treatment at 5 study centers. Of the 151 randomized patients,
`150 had postbaseline diary data and were included in the
`efficacy analysis. Data for all 151 randomized patients were
`included in the safety analysis. A total of 147 patients com-
`pleted all 14 days of the double-blind treatment period. All of
`the patients in the azelastine nasal spray group completed 14
`study days. In the fluticasone group, 1 patient withdrew
`consent and 1 withdrew for lack of efficacy. In the combina-
`tion group, 2 patients were withdrawn for noncompliance
`with the protocol.
`
`Demographic Characteristics
`The treatment groups were comparable for baseline demo-
`graphic and clinical characteristics (Table 1). The patients
`were a mean age of 37.2 years (range, 12–73 years), most
`were female, and the average duration of allergy to Texas
`mountain cedar was 17 years.
`
`Primary efficacy was change from baseline to day 14 in
`TNSS. Table 2 provides the mean improvements in the TNSS
`and individual symptoms for the 3 treatment groups. The
`treatment groups were comparable for baseline symptom
`scores, and all 3 treatments resulted in statistically significant
`(P ⬍ .001) improvements from baseline. The mean ⫾ SD
`improvement from the baseline TNSS was 4.8 ⫾ 4.3 with
`azelastine nasal spray, 5.2 ⫾ 4.6 with fluticasone nasal spray,
`and 7.4 ⫾ 5.6 with the 2 agents in combination. The TNSS
`improved from baseline by 27.1% with intranasal fluticasone,
`by 24.8% with azelastine nasal spray, and by 37.9% with the
`2 agents in combination (P ⬍ .05 vs either agent alone); there
`were absolute improvements of 11% and 13% with combi-
`nation therapy compared with intranasal azelastine and fluti-
`casone, respectively. These absolute improvements represent
`greater than 40% relative improvement compared with either
`agent alone (P ⫽ .007 vs azelastine and P ⫽ .02 vs flutica-
`sone).
`
`VOLUME 100, JANUARY, 2008
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`77
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`

`

`Secondary Efficacy
`Change from baseline to day 14 in individual symptoms.
`Combination therapy improved all individual TNSS symp-
`toms compared with the individual agents (Fig 1). Combina-
`tion therapy provided 48% more relief from nasal congestion
`and 56% more relief from nasal itching than fluticasone
`alone, and the combination was statistically superior to both
`azelastine and fluticasone. Combination therapy provided
`58% more relief from runny nose than fluticasone alone, and
`the combination was statically superior to azelastine. Com-
`bination therapy provided 46% more relief from sneezing
`than fluticasone alone, and the combination was statistically
`superior to fluticasone.
`Change from baseline to day 14 in TNSS on individual
`study days. Figure 2 shows the improvement in the 3 treat-
`ment groups on each individual day of the study. The com-
`bination of azelastine and fluticasone was statistically supe-
`rior to azelastine alone on study days 3 through 14, and the
`combination was statistically superior to fluticasone alone on
`days 4 and 6 through 11.
`Change from baseline to day 14 in RQLQ scores. All 3
`treatments produced statistically significant (P ⬍ .001) im-
`provements from their respective baseline RQLQ scores for
`overall score and for each individual domain of the RQLQ
`(Table 3). The mean change from baseline in the overall
`RQLQ score was 1.21 in the azelastine nasal spray group,
`1.47 in the fluticasone group, and 1.92 in the combination
`group, which was statistically significant compared with
`azelastine and approached significance compared with fluti-
`casone.
`
`Figure 1. Total nasal symptom score (TNSS) and individual symptoms.
`The asterisk indicates P ⬍ .05 for azelastine hydrochloride plus fluticasone
`propionate vs fluticasone alone; dagger, P ⬍ .05 for azelastine plus flutica-
`sone vs azelastine alone.
`
`Figure 2. Total nasal symptom score (TNSS) daily improvements. The
`asterisk indicates P ⬍ .05 for azelastine hydrochloride plus fluticasone
`propionate vs azelastine alone; dagger, P ⬍ .05 for azelastine plus flutica-
`sone vs fluticasone alone.
`
`Safety
`All 3 treatments were well tolerated. The most common
`adverse event was the bitter taste associated with azelastine
`(8.2% in the azelastine group, 2.0% in the fluticasone group,
`and 13.5% in the combination group). Headache was reported
`by 4.1% of patients in the azelastine group, by 4.0% of
`patients in the fluticasone group, and by 5.8% of patients in
`the combination group. No other adverse event was reported
`by more than 1 patient. There were no significant changes
`from baseline to the end of the study in vital sign assess-
`ments.
`
`DISCUSSION
`In this study, significantly greater efficacy was achieved by
`combination therapy with an antihistamine nasal spray and an
`intranasal corticosteroid spray, when compared with either
`agent alone.
`Azelastine nasal spray plus fluticasone nasal spray pro-
`vided greater than 40% relief of the TNSS relative to fluti-
`casone alone and greater than 48% relief of nasal congestion
`relative to fluticasone alone. All of the individual symptoms
`of the TNSS were improved with combination therapy when
`compared with either fluticasone or azelastine alone. This
`improvement reached statistical significance compared with
`azelastine on day 3 and compared with both fluticasone and
`azelastine on day 4, and the improvement in TNSS steadily
`increased with combination therapy during the 14-day study
`period.
`The combination regimen was well tolerated by the pa-
`tients in this study. Compliance was evaluated by patient
`diary entries and confirmed by bottle weights measured be-
`fore and after the double-blind treatment period. Compliance
`
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`

`Table 3. Overall RQLQ and Individual Domain Scoresa
`
`RQLQ score by treatment
`group
`
`Baseline LS value,
`mean (SD)
`
`LS change from
`baseline, mean (SD)
`
`P value
`
`Compared with
`azelastine
`hydrochloride alone
`
`Compared with
`fluticasone
`propionate alone
`
`Overall score
`Azelastine group
`Fluticasone group
`Azelastine plus fluticasone
`group
`Activities
`Azelastine group
`Fluticasone group
`Azelastine plus fluticasone
`group
`Sleep
`Azelastine group
`Fluticasone group
`Azelastine plus fluticasone
`group
`Non–nose/eye symptoms
`Azelastine group
`Fluticasone group
`Azelastine plus fluticasone
`group
`Practical problems
`Azelastine group
`Fluticasone group
`Azelastine plus fluticasone
`group
`Nasal symptoms
`Azelastine group
`Fluticasone group
`Azelastine plus fluticasone
`group
`Eye symptoms
`Azelastine group
`Fluticasone group
`Azelastine plus fluticasone
`group
`Emotions
`Azelastine group
`Fluticasone group
`Azelastine plus fluticasone
`group
`
`3.66 (1.13)
`3.95 (1.14)
`3.93 (1.09)
`
`4.17 (1.18)
`4.45 (0.97)
`4.55 (1.10)
`
`3.25 (1.24)
`3.91 (1.40)
`3.81 (1.27)
`
`3.22 (1.28)
`3.48 (1.30)
`3.40 (1.38)
`
`4.28 (1.30)
`4.55 (1.33)
`4.48 (1.23)
`
`4.31 (1.25)
`4.65 (1.19)
`4.62 (1.24)
`
`3.78 (1.55)
`4.02 (1.56)
`4.04 (1.58)
`
`3.20 (1.60)
`3.55 (1.51)
`3.43 (1.47)
`
`1.21 (1.02)
`1.47 (1.21)
`1.92 (1.46)
`
`1.37 (1.39)
`1.52 (1.64)
`2.03 (1.70)
`
`1.23 (1.08)
`1.23 (1.56)
`1.88 (1.66)
`
`0.88 (1.23)
`1.19 (1.36)
`1.52 (1.46)
`
`1.59 (1.58)
`1.74 (1.51)
`2.29 (1.62)
`
`1.46 (1.31)
`1.72 (1.38)
`2.19 (1.51)
`
`1.64 (1.56)
`1.51 (1.37)
`2.18 (1.86)
`
`1.26 (1.19)
`1.42 (1.53)
`1.66 (1.72)
`
`NA
`NA
`.005
`
`NA
`NA
`.04
`
`NA
`NA
`.02
`
`NA
`NA
`.01
`
`NA
`NA
`.02
`
`NA
`NA
`.006
`
`NA
`NA
`.07
`
`NA
`NA
`.15
`
`NA
`NA
`.08
`
`NA
`NA
`.12
`
`NA
`NA
`.02
`
`NA
`NA
`.20
`
`NA
`NA
`.07
`
`NA
`NA
`.08
`
`NA
`NA
`.02
`
`NA
`NA
`.40
`
`Abbreviations: LS, least squares; NA, data not applicable; RQLQ, Rhinoconjunctivitis Quality of Life Questionnaire.
`a Data are given for patients 18 years and older. An analysis of variance model was used.
`
`was greater than 98% in each treatment group. Other than a
`small increase in the incidence of bitter taste and headache in
`the combination group, no other adverse event was reported
`by more than 1 patient. In particular, there was no increase in
`the incidence of nasal irritation or epistaxis with azelastine
`nasal spray and fluticasone nasal spray in combination. As
`expected, there were no significant changes from baseline to
`the end of the study in vital sign assessments.
`Virtually all of the patients seen in allergy specialty prac-
`tice have tried at least 1 allergy medication without success,
`
`and many patients require more than 1 medication to achieve
`a satisfactory degree of symptom control. Although combi-
`nation therapy frequently is prescribed, there are relatively
`few published clinical studies that have evaluated combina-
`tion therapies for allergic rhinitis. Nielsen and Dahl7 analyzed
`pertinent medical literature published between 1966 and 2001
`and reported no striking differences in efficacy among the
`intranasal corticosteroids for treating allergic rhinitis and no
`clinical evidence to support the practice of combining an
`intranasal corticosteroid with an oral antihistamine. Review
`
`VOLUME 100, JANUARY, 2008
`
`79
`
`

`

`articles by Akerlund et al22 and Howarth23 also reported no
`evidence to suggest that a clinical benefit can be achieved by
`combining an intranasal corticosteroid and an oral antihista-
`mine in the treatment of allergic rhinitis.
`The substantial improvements with combination therapy in
`the present study suggest that in addition to differences in
`mechanism of action between antihistamines and corticoste-
`roids, the ability to direct the medication to the target tissue
`is an important determinant of the effectiveness of this com-
`bination. In contrast to oral antihistamines, intranasal delivery
`targets the nasal mucosa, the site of allergic inflammation;
`reduces the risk of systemic adverse effects and drug inter-
`actions25; and possibly enhances antiallergic and anti-inflam-
`matory effects by increasing local tissue concentrations.26
`There are no known contraindications regarding concom-
`itant use of azelastine nasal spray and an intranasal cortico-
`steroid. If azelastine nasal spray and intranasal fluticasone are
`used together, the dosage and administration of each agent
`can be tailored to individual needs with regard to the total
`number of sprays per day and the timing of the doses. Patients
`with moderate to severe symptoms can receive the highest
`recommended dosages when therapy begins and then the
`dosage can be adjusted downward if symptoms improve,
`whereas patients with less severe symptoms can receive
`lower dosages when therapy begins, with dosage increases if
`adequate symptom relief is not achieved.
`The economic burden of allergic rhinitis is substantial and
`includes the direct medical costs of physician visits and
`medications and the indirect costs related to reductions in
`productivity because of rhinitis symptoms or the effects of
`treatment. Although methods vary, the annual direct cost of
`rhinitis has been estimated to be as much as $5 billion
`(updated to 2003 US dollars) and annual indirect costs as
`much as $9.7 billion.27 With allergic, nonallergic, and mixed
`rhinitis affecting up to 60 million persons in the United States
`annually,9,28 the costs of treatment must be viewed in light of
`the potential clinical benefit. Ineffective treatment leads to
`patient frustration, dissatisfaction, and poor compliance. Phy-
`sicians may likewise become frustrated that patients do not
`adhere to their prescribed treatment regimens despite their
`efforts to educate them.
`Considering the efficacy of combination therapy that was
`demonstrated in this trial, the lower cost associated with
`generic fluticasone, and the widespread preferred formulary
`status of azelastine nasal spray, which entails lower out-of-
`pocket cost to the patient compared with second-generation
`oral antihistamines, the combination of azelastine nasal spray
`and fluticasone nasal spray may be cost-effective for patients
`with moderate to severe or persistent seasonal allergies.
`The high baseline symptom scores reported by the patients
`are indicative of the severity of rhinitis symptoms that can be
`caused by Texas mountain cedar pollen. In this patient pop-
`ulation, azelastine nasal spray in combination with flutica-
`sone nasal spray provided 40% or more relief of nasal SAR
`symptoms relative to fluticasone nasal spray alone. Combi-
`nation therapy began to improve symptoms within 24 hours
`
`compared with the individual agents, and increasing improve-
`ment was observed throughout the 14-day study period. The
`combination was well tolerated; only bitter taste and head-
`ache were reported as adverse events by more than 1 patient.
`The use of intranasal azelastine in combination with intra-
`nasal fluticasone produced an unanticipated magnitude of
`improvement in rhinitis symptoms among patients with al-
`lergy to Texas mountain cedar pollen. The 40% or greater
`improvement in the TNSS relative to the individual agents is
`in contrast to previously published studies that showed no
`appreciable benefit with an oral antihistamine and an intra-
`nasal corticosteroid in combination. Azelastine nasal spray
`and fluticasone nasal spray used in combination may provide
`a substantial clinical benefit for patients with SAR compared
`with therapy with either agent alone.
`
`ACKNOWLEDGMENTS
`We thank Carrie D’Andrea, MS, MedPointe Pharmaceuticals,
`Somerset, New Jersey, for clinical trial management; and i3
`Statprobe, Ann Arbor, Michigan, for statistical analysis of the
`data.
`
`REFERENCES
`1. Howarth PH, Stern MA, Roi L, et al. Double-blind, placebo-controlled
`study comparing the efficacy and safety of fexofenadine hydrochloride
`(120 and 180 mg once daily) and cetirizine in seasonal allergic rhinitis.
`J Allergy Clin Immunol. 1999;104:927–933.
`2. Hampel F, Ratner P, Mansfield L, et al. Fexofenadine hydrochloride,
`180 mg, exhibits equivalent efficacy to cetirizine, 10 mg, with less
`drowsiness in patients with moderate-to-severe seasonal allergic rhinitis.
`Ann Allergy Asthma Immunol. 2003;91:354 –361.
`3. Day JH, Briscoe M, Widlitz MD. Cetirizine, loratadine, or placebo in
`subjects with seasonal allergic rhinitis: effects after controlled ragweed
`pollen challenge in an environmental exposure unit. J Allergy Clin
`Immunol. 1998;101:638 – 645.
`4. Day JH, Briscoe M, Rafeiro E, et al. Comparative onset of action and
`symptom relief with cetirizine, loratadine, or placebo in an environmen-
`tal exposure unit in subjects with seasonal allergic rhinitis: confirmation
`of a test system. Ann Allergy Asthma Immunol. 2001;87:474 – 481.
`5. Meltzer EO, Weiler JM, Widlitz MD. Comparative outdoor study of the
`efficacy, onset and duration of action, and safety of cetirizine, loratadine,
`and placebo for seasonal allergic rhinitis. J Allergy Clin Immunol.
`1996;97:617– 626.
`6. Weiner JM, Abramson MJ, Puy RM. Intranasal corticosteroids versus
`oral H1 receptor antagonists in allergic rhinitis: systematic review of
`randomized controlled trials. BMJ. 1998;317:1624 –1629.
`7. Nielsen LP, Dahl R. Comparison of intranasal corticosteroids and anti-
`histamines in allergic rhinitis. Am J Respir Med. 2003;2:55– 65.
`8. Bousquet J, van Cauwenberge P, Khaltaev N. Allergic rhinitis and its
`impact on asthma. J Allergy Clin Immunol. 2001;108(suppl 5):
`S147–S334.
`9. Dykewicz MS, Fineman S, Skoner DP, et al. Diagnosis and management
`of rhinitis: complete guidelines of the Joint Task Force on practice
`parameters in allergy, asthma and immunology. Ann Allergy Asthma
`Immunol. 1998;81:478 –518.
`10. Berger WE, White MV; Rhinitis Study Group. Efficacy of azelastine
`nasal spray in patients with an unsatisfactory response to loratadine. Ann
`Allergy Asthma Immunol. 2003;91:205–211.
`11. LaForce CF, Corren J, Wheeler WJ, Berger WE. Efficacy of azelastine
`nasal spray in seasonal allergic rhinitis patients remaining symptomatic
`after treatment with fexofenadine. Ann Allergy Asthma Immunol. 2004