Safety of a novel intranasal formulation of azelastine

hydrochloride and fluticasone propionate in children:

A randomized clinical trial

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William Berger, M.D.,1 Ellen Sher, M.D.,2 Sandra Gawchik, D.O.,3 and Stanley Fineman, M.D.4

ABSTRACT

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Background: The safety of a novel intranasal formulation of azelastine hydrochloride (AZE) and fluticasone propionate (FP)
has been established in adults and adolescents with allergic rhinitis but not in children ⬍12 years old.
Objective: To evaluate the safety and tolerability of an intranasal formulation of AZE and FP in children ages 4 –11 years
with allergic rhinitis.

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Methods: The study was a randomized, 3-month, parallel-group, open-label design. Qualified patients were randomized in
a 3:1 ratio to AZE/FP (n ⫽ 304) or fluticasone propionate (FP) (n ⫽ 101), one spray per nostril twice daily, and to one of three
age groups: ⱖ4 to ⬍6 years, ⱖ6 to ⬍9 years, and ⱖ9 to ⬍12 years. Safety was assessed by child- or caregiver-reported adverse

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events, nasal examinations, vital signs, and laboratory assessments.
Results: The incidence of treatment-related adverse events (TRAEs) was low in both the AZE/FP (16%) and FP-only (12%)
groups after 90 days’ continuous use. Epistaxis was the most frequently reported TRAE in both groups (AZE/FP, 9%; FP, 9%),
followed by headache (AZE/FP, 3%; FP, 1%). All other TRAEs in the AZE/FP group were reported by ⱕ1% of the children.
The majority of TRAEs were of mild intensity and resolved spontaneously. Results of nasal examinations showed an

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improvement over time in both groups, with no cases of mucosal ulceration or nasal septal perforation. There were no unusual
or unexpected changes in laboratory parameters or vital signs.
Conclusion: The intranasal formulation of AZE and FP was safe and well tolerated after 3 months’ continuous use in
children with allergic rhinitis.

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The study was registered on ClinicalTrials.gov (NCT01794741).
(Allergy Asthma Proc 39:110 –116, 2018; doi: 10.2500/aap.2018.39.4116)

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llergic rhinitis (AR) is one of the most prevalent
chronic diseases in the general population and affects
as many as 500 million people worldwide.1–3 Its prevalence
in the United States is estimated at 60–90 million individu-
als, including as many as 40% of children.4,5 Although often
in lower quality of life (QoL).5 In addition to nasal and
ocular symptoms, many children with AR experience
headache, fatigue, cognitive impairment, and problems
with sleep,7 which affect learning and social activities.5 In
the United States, as many as 2 million school days are

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considered no more than a nuisance, the overall U.S. health lost to AR annually.8,9 Children with untreated AR often
care cost of AR is high, with annual direct costs of ⬃$7 experience psychological difficulties, including low self-
billion2 and indirect costs as high as $12 billion.2,6 esteem, anxiety, and depression.10 Also, many children

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The burden of nasal allergy symptoms has profound with AR have comorbid uncontrolled asthma.11
adverse effects on children’s overall physical and emo- There is a need for a new AR treatment option suit-
tional health, sleep quality, and daily lives, which results able for children that provides rapid and more com-
plete symptom relief than past treatments (i.e., intrana-
sal corticosteroids [INS] and antihistamines), without
From the 1Allergy and Asthma Associates of Southern California, Mission Viejo, safety repercussions. Among recent advances is Meda
California, 2Atlantic Allergy, Asthma and Immunology Associates of New Jersey, Pharma’s AzeFlu (MP-AzeFlu) (Dymista; Mylan, Inc.,
Ocean, New Jersey, 3Asthma Allergy Associates, Glen Mills, Pennsylvania, and
4
Atlanta Allergy and Asthma Clinic, Marietta, Georgia
Canonsburg, PA), a novel intranasal formulation that
Data were presented at the Paediatric Allergy and Asthma Meeting, Berlin, Germany, contains azelastine hydrochloride (AZE), fluticasone
October 15–17, 2015 propionate (FP), and excipients delivered in a single
Research and medical writing support was funded by Mylan, Inc. (Canonsburg, PA)
E. Sher is a national speaker for Mylan, Inc. and ALK Pharmaceuticals. S.
spray.12 In adults and adolescents, MP-AzeFlu pro-
Gawchik has served on the Advisory Board for Meda. The remaining authors have vides twice the nasal and ocular symptom relief as
no conflicts of interest pertaining to this article INS or intranasal antihistamine monotherapy, and
Supplemental data available at www.IngentaConnect.com
Address correspondence to William E. Berger, M.D., Allergy and Asthma Associates better long-term nasal symptom relief than FP in
of Southern California, Mission Viejo, CA 92691 adults with perennial AR (PAR) or non-AR.13,14 Its
E-mail address: weberger@uci.edu
short- and long-term safety in these populations is
Copyright © 2018, OceanSide Publications, Inc., U.S.A.
well established.13,15,16

110 March–April 2018, Vol. 39, No. 2

 The short- and long-term efficacy of MP-AzeFlu in Treatment Groups and Randomization
pediatric AR has also been assessed.17,18 Children ages The children were randomized to either MP-AzeFlu
4 –11 years with seasonal AR (SAR) treated with MP- (137 ␮g AZE and 50 ␮g FP per spray) or FP nasal spray
AzeFlu for 2 weeks experienced statistically superior (50 ␮g per spray). A centralized, age-group stratified,
and clinically relevant improvement in their QoL com- block randomization scheme using Proc Plan (SAS,
pared with children treated with placebo. Superiority Cary, NC) was used to assign subjects to treatment (3:1
of MP-AzeFlu was also observed for both overall nasal ratio). An interactive Web response system ensured

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and ocular symptom relief.17 A second study also found proper stratification. Treatments were administered as
that MP-AzeFlu provided significantly greater AR symp- one spray per nostril twice daily, morning and eve-
tom relief than FP alone.18 MP-AzeFlu has been granted ning, which provided total daily doses of 548 ␮g for

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approval for use in this age group by the U.S. Food and MP-AzeFlu and 200 ␮g for FP. Assessment of treat-
Drug Administration (FDA). The objective of this clinical ment compliance and exposure is described in the On-
trial was to evaluate the safety and tolerability of MP- line Supplement Text.
AzeFlu in children ages 4 –11 years with AR.

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Safety Variables
Safety variables included child- or caregiver-reported
METHODS adverse events (AE), nasal examinations, vital signs, and

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Study Design laboratory assessments. AEs were recorded at baseline
and each study visit, categorized by incidence, type, and
This was a prospective, randomized, multicenter, ac-
severity (see Online Supplement Text), and were coded
tive controlled, open-label, parallel-group, outpatient
by using the Medical Dictionary for Regulatory Activities
safety study (NCT01794741) conducted in children 4 –11
(MedDRA) (Version 16.0) (see Online Supplement Text).

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years of age with AR at 42 sites in the United States
Conditions already present that did not worsen were not
between March and October 2013. Ethics approval was
considered AEs. The relationship of an AE to the study
obtained (Chesapeake Research Review Inc., Columbia,
medication was assessed by study center investigators as
MD), and the study was conducted in accordance with
unlikely, possibly, or probably related (see Online Sup-

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Good Clinical Practice in compliance with the Best Phar- plement Text). The children underwent a direct visual
maceuticals for Children Act and the Pediatric Research nasal examination at baseline and each visit that included
Equity Act.19,20 The study design was based on guidance nasal mucosal grading (grade 0 – 4) (see Online Supple-

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from the FDA’s Division of Pulmonary, Allergy, and ment Text). Epistaxis, mucosal edema, nasal discharge,
Rheumatology Products. Caregiver written informed mucosal erythema, mucosal bleeding, and mucosal crust-
consent and pediatric assent (for children ⱖ7 years old) ing were also assessed and graded as none, mild, mod-
was obtained. The study consisted of a washout period erate, or severe. Vital signs were recorded at each visit.
for prohibited concomitant medications, a lead-in period Laboratory assessments were recorded at baseline and
(2–30 days), and a 3-month active-treatment period. After

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day 90.
baseline screening (day 1), clinic visits were scheduled on
study days 15, 30, 60, and 90.
Statistical Analysis
The sample size for this study was based on clinical

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considerations and discussions with the FDA. The chil-
Patients
dren were stratified into three age groups: ⱖ4 to ⬍6
Male and female children 4 –11 years old with a years, ⱖ6 to ⬍9 years, and ⱖ9 to ⬍12 years. Safety
history of AR (SAR or PAR) who, in the opinion of the analyses (SAS, version 9.2) were performed on the safety
study center investigators, could benefit from treat- population, defined as all randomized children who re-
ment with MP-AzeFlu were eligible for inclusion. Chil- ceived one or more doses of study medication. Data were
dren were required to be in generally good health, summarized for each treatment group and age stratum,
without concomitant disease or medical treatment that and were pooled across strata. Continuous data were
could interfere with interpretation of study results. summarized as mean ⫾ standard deviation. Categorical
Generally, the use of concomitant medication was dis- data were presented as number and percentage.
couraged; however, medications considered necessary
and that did not interfere with the evaluation of study
RESULTS
medications were allowed at investigator discretion.
(See the Online Supplement Text for a list of prohibited Patient Disposition
medications.) Children who were receiving immuno- A total of 405 children were randomized to treat-
therapy on a stable regimen were eligible. Exclusion ment, and 404 were included in the safety population
criteria are given in the Online Supplement Text. (Fig. 1). Completion rates were similar in both treat-

Allergy and Asthma Proceedings 111

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ment groups (MP-AzeFlu, 94%; FP, 91%) and across
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Figure 1. Subject disposition.

Epistaxis was the most common TEAE in both

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age strata (see Online Supplemental Table 1). The rate groups, followed by headache with MP-AzeFlu and
of discontinuation due to AEs was 2% with MP-AzeFlu diarrhea with FP (Table 4). Fewer than 1% of the sub-
and 4% with FP. jects experienced somnolence or dysgeusia. Epistaxis
was also the most common TRAE in both groups,

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Demographic and Baseline Characteristics followed by headache with MP-AzeFlu (Table 5). All
Of the randomized patients, 51 (12.6%) were ⱖ4 to other TRAEs in the MP-AzeFlu group occurred in ⱕ1%
⬍6 years old, 173 (42.7%) were ⱖ6 to ⬍9 years old, and of the children, for all age strata. In the FP group, the

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181 (44.7%) were ⱖ9 to ⬍12 years old. The treatment next most common TRAE was mucosal erosion (2%),
groups were comparable in demographic and baseline with all other events reported by ⱕ1% of the children.
clinical characteristics overall and for each age stratum
(Table 1). Fifteen children (all ages 6 –11 years) were on Nasal Examinations
stable immunotherapy during the study (13 MP-Aze- Children in both treatment groups had similar nasal ex-

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Flu, 2 FP). amination findings. The severity of nasal symptoms gener-
ally reduced over the course of treatment in both groups
Exposure and Treatment Compliance (Online Supplemental Table 2). There were no cases of nasal
The mean duration of exposure to the study drug mucosal ulceration or nasal septal perforation.

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and of the total and average numbers of sprays taken
were similar in both groups, in the overall population, Vital Signs and Laboratory Assessments
and by age stratum (Table 2). The rate of treatment Laboratory parameters showed no clinically relevant
compliance was high (⬎96%) and comparable in both increases or decreases in either treatment group (On-
groups across the age strata. line Supplemental Table 3), and changes were similar
between the groups and across the age strata. Simi-
AEs larly, there were no noteworthy findings in changes
The percentage of subjects with one or more treat- from baseline in vital signs in either group or for
ment-emergent AEs (TEAE) and one or more treat- different age strata (Online Supplemental Table 4).
ment-related AEs (TRAEs) over 3 months was similar
in the MP-AzeFlu and FP groups (Table 3). TEAEs and DISCUSSION
TRAEs were usually mild in severity. There were no This study showed, for the first time to our knowl-
deaths. One child in the MP-AzeFlu group reported edge, that MP-AzeFlu was safe and well tolerated dur-
two serious AEs (gastroenteritis and elevated liver ing 3 months’ continuous use in children ages 4 to 11
function tests), consistent with flu-like symptoms, years with AR. MP-AzeFlu’s good tolerability profile
which resolved within days and were considered un- was confirmed in very young children (age group ⱖ4
likely to be related to MP-AzeFlu treatment. to ⬍6 years) and older children (age groups ⱖ6 to ⬍9

112 March–April 2018, Vol. 39, No. 2

 Table 1 Demographic and baseline characteristics (safety population)
All Age Strata Ages >4 to <6 y Ages >6 to <9 y Ages >9 to <12 y
MP-AzeFlu FP MP-AzeFlu FP MP-AzeFlu FP MP-AzeFlu FP
(n ⴝ 304) (n ⴝ 100) (n ⴝ 40) (n ⴝ 11) (n ⴝ 128) (n ⴝ 44) (n ⴝ 136) (n ⴝ 45)

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Age, mean ⫾ SD, y 8.1 ⫾ 2.1 8.1 ⫾ 1.9 4.6 ⫾ 0.5 4.6 ⫾ 0.5 7.2 ⫾ 0.8 7.2 ⫾ 0.8 10.0 ⫾ 0.8 9.9 ⫾ 0.8
Boys, no. (%) 183 (60) 51 (51) 25 (63) 5 (45) 70 (55) 20 (45) 88 (65) 26 (58)
Race, no. (%)
American Indian/Alaska Native 4 (1) 1 (1) 1 (3) 0 (0) 2 (2) 1 (2) 1 (⬍1) 0 (0)
Asian 12 (4) 1 (1) 2 (5) 0 (0) 4 (3) 1 (2) 6 (4) 0 (0)

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Black/African American 62 (20) 21 (21) 12 (30) 3 (27) 24 (19) 11 (25) 26 (19) 7 (16)

Allergy and Asthma Proceedings

Native Hawaiian/other 2 (1) 1 (1) 0 (0) 0 (0) 2 (2) 1 (2) 0 (0) 0 (0)
Pacific Islander
White 237 (78) 80 (80) 26 (65) 9 (82) 100 (78) 31 (70) 111 (82) 40 (89)
Other 1 (⬍1) 1 (1) 1 (3) 0 (0) 0 (0) 0 (0) 0 (0) 1 (2)
TSS, mean ⫾ SD 1.72 ⫾ 0.76 1.77 ⫾ 0.73 1.64 ⫾ 0.76 1.50 ⫾ 0.73 1.74 ⫾ 0.73 1.76 ⫾ 0.69 1.73 ⫾ 0.81 1.84 ⫾ 0.77

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PRQLQ score, mean ⫾ SD 1.84 ⫾ 1.05 1.88 ⫾ 1.15 — — 1.84 ⫾ 1.03 2.01 ⫾ 1.23 1.84 ⫾ 1.07 1.75 ⫾ 1.06
MP-AzeFlu ⫽ Meda Pharma’s azelastine hydrochloride and fluticasone propionate; FP ⫽ fluticasone propionate; SD ⫽ standard deviation; TSS ⫽ total symptom
score; PRQLQ ⫽ Pediatric Rhinoconjunctivitis Quality of Life Questionnaire.

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All Age Strata
MP-AzeFlu
(n ⴝ 304)
FP
(n ⴝ 100)
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Table 2 Duration of exposure and compliance with medication (safety population)
Ages >4 to <6 y
MP-AzeFlu
(n ⴝ 40)
FP
(n ⴝ 11)
Ages >6 to <9 y
MP-AzeFlu
(n ⴝ 128)
FP
(n ⴝ 44)
Ages >9 to <12 y
MP-AzeFlu
(n ⴝ 136)
FP
(n ⴝ 45)
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Exposure, mean ⫾ SD, days 85.9 ⫾ 14.4 85.2 ⫾ 16.7 86.0 ⫾ 18.3 87.5 ⫾ 7.6 85.6 ⫾ 14.9 83.4 ⫾ 20.4 86.2 ⫾ 12.7 86.3 ⫾ 14.1
Total No. sprays, mean ⫾ SD 333.7 ⫾ 58.6 333.3 ⫾ 65.9 338.6 ⫾ 72.2 342.3 ⫾ 30.1 330.9 ⫾ 61.5 326.5 ⫾ 81.3 334.9 ⫾ 51.5 337.8 ⫾ 55.3
Average No. sprays/day, 3.9 ⫾ 0.2 3.9 ⫾ 0.2 3.9 ⫾ 0.1 3.9 ⫾ 0.1 3.9 ⫾ 0.3 3.9 ⫾ 0.2 3.9 ⫾ 0.2 3.9 ⫾ 0.1
mean ⫾ SD
Compliance, mean ⫾ SD, % 96.9 ⫾ 5.2 97.5 ⫾ 4.2 98.5 ⫾ 2.4 97.8 ⫾ 2.7 96.1 ⫾ 6.9 97.1 ⫾ 5.6 97.1 ⫾ 3.7 97.9 ⫾ 2.5
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Subjects with 80% compliance 300 (99) 97 (97) 38 (95) 11 (100) 126 (98) 42 (95) 136 (100) 44 (98)
overall, no. (%)
MP-AzeFlu ⫽ Meda Pharma’s azelastine hydrochloride and fluticasone propionate; FP ⫽ fluticasone propionate; SD ⫽ standard deviation.
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Table 3 Overview of adverse events (safety population)
All Age Strata Ages >4 to <6 y Ages >6 to <9 y Ages >9 to <12 y
MP-AzeFlu FP MP-AzeFlu FP MP-AzeFlu FP MP-AzeFlu FP
(n ⴝ 304) (n ⴝ 100) (n ⴝ 40) (n ⴝ 11) (n ⴝ 128) (n ⴝ 44) (n ⴝ 136) (n ⴝ 45)
ⱖ1 TEAE, no. (%) 124 (41) 37 (37) 18 (45) 5 (45) 51 (40) 15 (34) 55 (40) 17 (38)

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ⱖ1 TRAE, no. (%) 49 (16) 12 (12) 8 (20) 1 (9) 15 (12) 6 (14) 26 (19) 5 (11)
ⱖ1 SAE, no. (%) 1 (⬍1) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 1 (⬍1) 0 (0)
ⱖ1 TEAE that led to 6 (2) 4 (4) 2 (5) 1 (9) 0 (0) 1 (2) 4 (3) 2 (4)

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discontinuation,
no. (%)
Deaths, no. (%) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0)
MP-AzeFlu ⫽ Meda Pharma’s azelastine hydrochloride and fluticasone propionate; FP ⫽ fluticasone propionate; TEAE ⫽

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treatment-emergent adverse event; TRAE ⫽ treatment-related adverse event; SAE ⫽ serious adverse event.

Table 4 TEAEs (safety population)*

All Age Strata
MP-AzeFlu FP
Ages >4 to <6 y
MP-AzeFlu FP MP-AzeFlu

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Ages >6 to <9 y
FP MP-AzeFlu FP
Ages >9 to <12 y

(n ⴝ 304) (n ⴝ 100) (n ⴝ 40) (n ⴝ 11) (n ⴝ 128) (n ⴝ 44) (n ⴝ 136) (n ⴝ 45)

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Any TEAE, no. (%) 124 (41) 37 (37) 18 (45) 5 (45) 51 (40) 15 (34) 55 (40) 17 (38)
Epistaxis 30 (10) 9 (9) 4 (10) 1 (9) 12 (9) 4 (9) 14 (10) 4 (9)
Headache 20 (7) 3 (3) 2 (5) 0 (0) 10 (8) 3 (7) 8 (6) 0 (0)
Cough 11 (4) 3 (3) 3 (8) 0 (0) 4 (3) 2 (5) 4 (3) 1 (2)

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Pyrexia 10 (3) 2 (2) 2 (5) 0 (0) 4 (3) 0 (0) 4 (3) 2 (4)
Oropharyngeal pain 9 (3) 0 (0) 0 (0) 0 (0) 4 (3) 0 (0) 5 (4) 0 (0)
Otitis media 9 (3) 3 (3) 3 (8) 0 (0) 5 (4) 1 (2) 1 (⬍1) 2 (4)

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Vomiting 9 (3) 2 (2) 0 (0) 1 (9) 6 (5) 0 (0) 3 (2) 1 (2)
Upper abdominal 8 (3) 2 (2) 0 (0) 1 (9) 5 (4) 1 (2) 3 (2) 0 (0)
pain
URTI 8 (3) 1 (1) 2 (5) 1 (9) 2 (2) 0 (0) 4 (3) 0 (0)
Diarrhea 4 (1) 4 (4) 0 (0) 2 (18) 1 (⬍1) 1 (2) 3 (2) 1 (2)

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TEAE ⫽ treatment-emergent adverse event; MP-AzeFlu ⫽ Meda Pharma’s azelastine hydrochloride and fluticasone propi-
onate; FP ⫽ fluticasone propionate; URTI ⫽ upper respiratory tract infection.
*TEAEs recorded are those reported by ⱖ3% of the subjects in either treatment group.

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years and ⱖ9 to ⬍12 years), with a low incidence of
TRAEs, improvement in nasal examination findings,
and no clinically relevant changes in vital signs or
laboratory parameters. Epistaxis, headache, and cough
were the most common AEs (consistent with a diagno-
sis of AR) and were generally mild and spontaneously
resolving. The incidence of sedation or drowsiness
with MP-AzeFlu was low (⬍1%), and taste problems
tent with similar safety findings in adults, adolescents,
and children, both in randomized controlled trials and
observational studies.15–17,22 The safety and tolerability
profile of MP-AzeFlu was established in adults and ado-
lescents in a large clinical trial program that involved
⬎4000 patients with SAR13,15 and almost 3000 patients in
a real-life study.22 MP-AzeFlu was also evaluated in a
1-year safety trial in ⬎600 adult patients with chronic
were uncommon (⬍1%). Somewhat fewer children dis- rhinitis (i.e., PAR or non-AR).16 Similar to the present
continued the study due to AEs with MP-AzeFlu (2%) study, the 1-year safety trial found a low incidence of
than with FP (4%). Based on these and other study TRAEs with MP-AzeFlu (9.4%) or FP (11.1%) treatment
results,17,18 MP-AzeFlu was approved by the FDA in for 52 weeks, with no evidence of late-occurring AEs.16
February 2015 for use in children 6 to 11 years of age at Nasal examinations improved over time, no ulcerations
a dosage of one spray per nostril twice daily.21 or septal perforations occurred, ocular examination find-
The data obtained in this study were generalizable to ings were unremarkable, and hypothalamic pituitary ad-
the broad pediatric population because they were consis- renal axis suppression was not observed.16 The safety of

114 March–April 2018, Vol. 39, No. 2

Table 5 TRAEs (safety population)*
All Age Strata Ages >4 to <6 y Ages >6 to <9 y Ages >9 to <12 y
MP-AzeFlu FP MP-AzeFlu FP MP-AzeFlu FP MP-AzeFlu FP
(n ⴝ 304) (n ⴝ 100) (n ⴝ 40) (n ⴝ 11) (n ⴝ 128) (n ⴝ 44) (n ⴝ 136) (n ⴝ 45)
Any TRAE, no. (%) 49 (16) 12 (12) 8 (20) 1 (9) 15 (12) 6 (14) 26 (19) 5 (11)

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Epistaxis 27 (9) 9 (9) 4 (10) 1 (9) 10 (8) 4 (9) 13 (10) 4 (9)
Headache 10 (3) 1 (1) 1 (3) 0 (0) 5 (4) 1 (2) 4 (3) 0 (0)
TRAE ⫽ Treatment-related adverse event; MP-AzeFlu ⫽ Meda Pharma’s azelastine hydrochloride and fluticasone propionate;

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FP ⫽ fluticasone propionate.
*TRAEs recorded are those reported by ⱖ3% of the subjects in either treatment group.

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MP-AzeFlu in adults and adolescents has been compre- reflects a “high to low” preference, starting with the
hensively reviewed.23 pharmacologic treatment option with the best efficacy-
A recent randomized, double-blind, placebo con- to-safety ratio and then stepping down if tolerated.
trolled, parallel-group study confirmed the good safety First-line use of MP-AzeFlu is supported by its rapid

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and tolerability profile of MP-AzeFlu in 348 children symptom relief (within minutes) and that it causes
(ages 4 –11 years) with moderate-to-severe SAR.17 In twice the ocular and nasal symptom control as an INS
that study, 16.2% of children who received MP-AzeFlu (specifically FP),18 with comparable safety, all of which
and 13.1% who received placebo reported one or more should improve adherence. The growing evidence base

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TEAEs, and, of these, 8.7% and 3.4%, respectively, were that shows that mono and multiple AR treatment reg-
considered TRAEs. Epistaxis occurred at similar rates imens provide insufficient symptom relief for many
in the MP-AzeFlu (3.5%) and placebo (3.4%) groups. patients further supports first-line use of MP-AzeFlu.26
All TRAEs were considered mild, and no serious AEs Immunotherapy and strict environmental control mea-

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were reported.17 Similar to the current study, MP-Aze- sures are options; however, these steps are not always
Flu use for 14 days was not associated with any signif- easily implemented for pediatric patients.27
icantly focused nasal examination finding. The propor- The choice for second-line use of MP-AzeFlu reflects
tion of children with moderate or severe mucosal a “low to high” preference, starting with a lower-

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edema or nasal discharge decreased over time, and efficacy treatment and stepping up when required.
slight improvements in mucosal erythema were found This step-up approach may be particularly challenging in
with MP-AzeFlu.17 children, in whom speed of effect and the degree of
The superior symptom relief afforded by MP-AzeFlu response directly influence treatment concordance. A
in adults and adolescents13–15,22 has also been mirrored step-up approach, therefore, should be carefully weighed

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in the pediatric AR population.17,18 Children treated against the potential for reduced compliance and treat-
with MP-AzeFlu for 14 days experienced statistically ment failure, the consequent delay in achieving disease
superior and clinically relevant improvement in QoL control, and the increased medication and physician visit
by day 8 compared with those who received placebo.17 costs. For example, although second-generation oral an-

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MP-AzeFlu also provided significantly better relief tihistamines are a mainstay of AR treatment in children,
than placebo from nasal symptoms (p ⫽ 0.002) and they may not be adequate for relief of moderate-to-severe
ocular symptoms (p ⫽ 0.009).17 In addition, in efficacy symptoms, especially nasal congestion.28 Likewise, many
data from the present study (published separately), children derive insufficient symptom relief from INS,
children who received MP-AzeFlu for 3 months expe- with nasal sprays providing complete relief in only 17%
rienced significantly (p ⫽ 0.0410) better nasal symptom of respondents of the Pediatric Allergies in America sur-
reduction than those who received FP.18 Furthermore, vey.5 Adding oral antihistamines to INS therapy offers no
approximately 8 of 10 children treated with MP-Aze- benefit over INS alone,29,30 whereas use of multiple treat-
Flu in the pediatric study were symptom free or had ments (such as intranasal antihistamine and INS) is likely
mild symptoms within 1 month. This status was ob- to impair compliance and is associated with less homog-
tained up to 16 days faster with MP-AzeFlu versus enous distribution within the nasal cavity and increased
FP.18 Achieving rapid symptom control should im- runoff (both anteriorly and posteriorly) compared with
prove treatment compliance and improve school per- MP-AzeFlu.31,32
formance24 and asthma control.25 There are some inherent limitations and constraints in
How MP-AzeFlu should be used in the pediatric AR conducting clinical trials in children with AR. Efficacy
population is a matter of both physician and patient evaluations and AE reports in these studies reflected
preference. The choice for first-line use of MP-AzeFlu subjective assessments by the patient or the caregiver.

Allergy and Asthma Proceedings 115

The reporting of AEs by children may be limited by their by responder analysis. Int Arch Allergy Immunol. 2013; 161:
ability to verbalize or the parent’s or caregiver’s interpre- 369 –377.
14. Price D, Shah S, Bhatia S, et al. A new therapy (MP29 – 02) is
tation. However, in general, caregivers pay close atten-
effective for the long-term treatment of chronic rhinitis. J Inves-
tion to any event in their child that could be interpreted tig Allergol Clin Immunol. 2013; 23:495–503.
as an AE. Despite these potential limitations, the safety 15. Carr W, Bernstein J, Lieberman P, et al. A novel intranasal
profile of MP-AzeFlu in the current pediatric study was therapy of azelastine with fluticasone for the treatment of aller-
favorable and generally similar to that seen with MP- gic rhinitis. J Allergy Clin Immunol. 2012; 129:1282–1289.e10.

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16. Berger WE, Shah S, Lieberman P, et al. Long-term, randomized
AzeFlu in adults and adolescents.15,16,22
safety study of MP29 – 02 (a novel intranasal formulation of
azelastine hydrochloride and fluticasone propionate in an ad-
CONCLUSION vanced delivery system) in subjects with chronic rhinitis. J

P
Allergy Clin Immunol Pract. 2014; 2:179 –185.
MP-AzeFlu was safe and well tolerated after 3 17. Berger W, Meltzer EO, Amar N, et al. Efficacy of MP-AzeFlu in
months’ continuous use in children with AR. Analysis children with seasonal allergic rhinitis: Importance of paediatric
of these data supported the effectiveness of MP-AzeFlu symptom assessment. Pediatr Allergy Immunol. 2016; 27:126 –133.
for the treatment of moderate-to-severe AR in the pe- 18. Berger W, Bousquet J, Fox AT, et al. MP-AzeFlu is more effec-

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diatric population. tive than fluticasone propionate for the treatment of allergic
rhinitis in children. Allergy. 2016; 71:1219 –1222.
19. Guidance for Industry: How to comply with the Pediatric Re-
ACKNOWLEDGMENTS search Equity Act. [cited 13 Dec 2017]. Available from http://

C
We thank Ruth B. Murray (Medscript Ltd., Dundalk, Ireland) for bit.ly/2z9Nkzn.
critically reviewing this manuscript and for editing assistance. We 20. Best Pharmaceuticals for Children Act (BPCA). [cited 13 Dec
thank Roger Hill, Ph.D., for medical writing and Paula Stuckart for 2017]. Available from http://bit.ly/2hrLpfh.
editorial assistance in the preparation of the manuscript (Ashfield 21. Dymista approved in children 6 to 11 years of age with seasonal
Healthcare Communications, Middletown, CT). allergic rhinitis. [cited 13 Dec 2017]. Available from http://
cisn.co/2AD11JK.

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22. Klimek L, Bachert C, Stjarne P, et al. MP-AzeFlu provides rapid
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