U.S. patent application number 11/486454 was filed with the patent office on 2007-01-25 for compositions comprising azelastine and methods of use thereof.
This patent application is currently assigned to MedPointe Healthcare Inc.. Invention is credited to Gul Balwani, Alexander D. D'Addio, Phuong Grace Dang, Brian D. Lawrence.
Application Number | 20070020330 11/486454 |
Document ID | / |
Family ID | 46124122 |
Filed Date | 2007-01-25 |
United States Patent
Application |
20070020330 |
Kind Code |
A1 |
Dang; Phuong Grace ; et
al. |
January 25, 2007 |
Compositions comprising azelastine and methods of use thereof
Abstract
The present invention provides pharmaceutical compositions
comprising azelastine, or a pharmaceutically acceptable salt or
ester thereof including azelastine hydrochloride, and optionally
one or more additional active agents. Preferred such compositions
further comprise one or more pharmaceutically acceptable carriers
or excipients that reduce the amount of post-nasal drip, and/or
that minimize or mask the unpleasant bitter taste associated with
post-nasal drip, of the compositions into the oral cavity, upon
intranasal or ocular administration of the compositions. Especially
effective excipients used in the compositions of the present
invention are hypromellose as a viscosity modifier and sucralose as
a taste-masking agent. The invention also provides methods of
treating or preventing certain disorders, or symptomatic relief
therefrom, by administering the compositions of the invention to a
patient, e.g., for the symptomatic relief of allergic rhinitis,
non-allergic vasomotor rhinitis, allergic conjunctivitis, as well
as other disorders. The compositions and methods of the present
invention provide significant value in terms of patient
acceptability, convenience, and compliance.
Inventors: |
Dang; Phuong Grace; (Corona,
CA) ; Lawrence; Brian D.; (Somerset, NJ) ;
Balwani; Gul; (West Windsor, NJ) ; D'Addio; Alexander
D.; (Piscataway, NJ) |
Correspondence
Address: |
STERNE, KESSLER, GOLDSTEIN & FOX PLLC
1100 NEW YORK AVENUE, N.W.
WASHINGTON
DC
20005
US
|
Assignee: |
MedPointe Healthcare Inc.
Somerset
NJ
|
Family ID: |
46124122 |
Appl. No.: |
11/486454 |
Filed: |
July 14, 2006 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11284109 |
Nov 22, 2005 |
|
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11486454 |
Jul 14, 2006 |
|
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60630274 |
Nov 24, 2004 |
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Current U.S.
Class: |
424/464 ;
514/171; 514/217.05; 514/53 |
Current CPC
Class: |
A61K 9/0048 20130101;
A61K 31/573 20130101; A61K 31/58 20130101; A61K 45/06 20130101;
A61K 31/55 20130101; A61P 37/08 20180101; A61K 31/56 20130101; A61K
9/0043 20130101; A61K 31/573 20130101; A61P 11/02 20180101; A61K
9/7007 20130101; A61K 31/55 20130101; A61K 31/58 20130101; A61K
9/0073 20130101; A61K 2300/00 20130101; A61K 2300/00 20130101; A61K
2300/00 20130101; A61K 31/56 20130101; A61P 29/00 20180101; A61P
27/14 20180101; A61K 9/0056 20130101; A61K 2300/00 20130101 |
Class at
Publication: |
424/464 ;
514/053; 514/171; 514/217.05 |
International
Class: |
A61K 31/7012 20070101
A61K031/7012; A61K 31/56 20060101 A61K031/56; A61K 31/55 20060101
A61K031/55; A61K 31/573 20070101 A61K031/573 |
Claims
1. A pharmaceutical composition comprising a therapeutically
effective dose of azelastine, or a pharmaceutically acceptable salt
or ester thereof, at a concentration of from about 0.05% to about
5% by weight, one or more steroids, and one or more
pharmaceutically acceptable carriers or excipients.
2. The pharmaceutical composition of claim 1, wherein at least one
of said pharmaceutically acceptable carriers or excipients is
sucralose.
3. The pharmaceutical composition of claim 1, wherein said one or
more steroids are selected from the group consisting of
fluoromethalone, a fluticasone, mometasone, triamcinolone,
betamethasone, flunisolide, budesonide, beclomethasone, budesonide,
rimexolone, a loteprednol, beloxil, prednisone and
dexamethasone.
4. The pharmaceutical composition of claim 3, wherein said
fluticasone is fluticasone propionate.
5. The pharmaceutical composition of claim 3, wherein said
loteprednol is loteprednol etabonate.
6. The pharmaceutical composition of claim 1, further comprising
one or more additional active agents selected from the group
consisting of one or more decongestants, one or more
antihistamines, one or more non-steroidal anti-inflammatory agents
and one or more leukotriene antagonists.
7. The pharmaceutical composition of claim 1, wherein said
azelastine is present in said composition at a concentration of
from about 0.125% to about 0.15% by weight.
8. The pharmaceutical composition of claim 2, wherein said
sucralose is present in said composition at a concentration of from
about 0.05% to about 0.15% by weight.
9. The pharmaceutical composition of claim 1, wherein said
composition is formulated for intranasal administration.
10. A method of treating or preventing allergic rhinitis,
non-allergic vasomotor rhinitis or allergic conjunctivitis in an
animal suffering from or predisposed thereto, comprising
administering an effective amount of the composition of claim 1 to
the animal.
11. A method of treating or preventing allergic rhinitis,
non-allergic vasomotor rhinitis or allergic conjunctivitis in an
animal suffering from or predisposed thereto, comprising
co-administering to said animal an effective amount of azelastine
and an effective amount of one or more steroids.
12. The method of claim 11, wherein the animal is a mammal.
13. The method of claim 12, wherein the mammal is a human.
14. The method of claim 11, wherein the azelastine is azelastine
HCl.
15. The method of claim 11, wherein the steroid is selected from
the group consisting of fluoromethalone, a fluticasone, mometasone,
triamcinolone, betamethasone, flunisolide, budesonide,
beclomethasone, budesonide, rimexolone, a loteprednol, beloxil,
prednisone and dexamethasone.
16. The method of claim 15, wherein the fluticasone is fluticasone
propionate.
17. The method of claim 11, wherein said co-administration
comprises administering the azelastine and the one or more steroids
simultaneously.
18. The method of claim 11, wherein said co-administration
comprises administering azelastine and the one or more steroids
separately, within less than about 30 minutes of each other.
19. The method of claim 18, wherein said co-administration
comprises administering azelastine and the one or more steroids
separately, within less than about 20 minutes of each other.
20. The method of claim 19, wherein said co-administration
comprises administering azelastine and the one or more steroids
separately, within less than about 15 minutes of each other.
21. The method of claim 11, wherein said co-administration
comprises administering the azelastine before the one or more
steroids.
22. The method of claim 11, wherein said co-administration
comprises administering the one or more steroids before the
azelastine.
23. The method of claim 11, wherein said co-administration
comprises administering the azelastine and the one or more steroids
to the nasal passage.
24. The method of claim 11, wherein said co-administration
comprises administering the azelastine and said the or more
steroids in the form of a single pharmaceutical composition
comprising azelastine and one or more steroids.
25. The method of claim 11, wherein said co-administration
comprises administering the azelastine and the one or more steroids
separately, in the form of two separate pharmaceutical
compositions, one pharmaceutical composition comprising azelastine
and a second pharmaceutical composition comprising one or more
steroids.
26. A method of treating or preventing allergic rhinitis,
non-allergic vasomotor rhinitis or allergic conjunctivitis in an
animal suffering from or predisposed thereto, comprising
co-administering to said animal an effective amount of azelastine
and an effective amount of a fluticasone.
27. The method of claim 26, wherein the animal is a mammal.
28. The method of claim 27, wherein the mammal is a human.
29. The method of claim 26, wherein the azelastine is azelastine
HCl.
30. The method of claim 26, wherein the fluticasone is fluticasone
propionate.
31. The method of claim 26, wherein said co-administration
comprises administering the azelastine and the fluticasone
simultaneously.
32. The method of claim 26, wherein said co-administration
comprises administering the azelastine and the fluticasone
separately, within less than about 30 minutes of each other.
33. The method of claim 32, wherein said co-administration
comprises administering the azelastine and the fluticasone
separately, within less than about 20 minutes of each other.
34. The method of claim 33, wherein said co-administration
comprises administering the azelastine and the fluticasone
separately, within about 15 minutes of each other.
35. The method of claim 26, wherein said co-administration
comprises administering the azelastine before the fluticasone.
36. The method of claim 26, wherein said co-administration
comprises administering the fluticasone before the azelastine.
37. The method of claim 26, wherein said co-administration
comprises administering the azelastine and the fluticasone to the
nasal passage.
38. The method of claim 26, wherein said co-administration
comprises administering the azelastine and the fluticasone in the
form of a single pharmaceutical composition comprising azelastine
and fluticasone.
39. The method of claim 26, wherein said co-administration
comprises administering the azelastine and the fluticasone
separately, in the form of two separate pharmaceutical
compositions, one pharmaceutical composition comprising azelastine
and a second pharmaceutical composition comprising fluticasone.
40. A method of treating or preventing allergic rhinitis,
non-allergic vasomotor rhinitis or allergic conjunctivitis in an
animal suffering from or predisposed thereto, comprising
co-administering to said animal an effective amount of azelastine
HCl and an effective amount of fluticasone propionate separately,
in the form of two separate pharmaceutical compositions, one
pharmaceutical composition comprising azelastine HCl and a second
pharmaceutical composition comprising fluticasone propionate,
wherein the two pharmaceutical compositions are administered within
about 30 minutes of each other.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] The present application is a continuation-in-part of U.S.
application Ser. No. 11/284,109, filed Nov. 22, 2005, which claims
the benefit of the filing date of U.S. Provisional Patent
Application No. 60/630,274, filed Nov. 24, 2004, the disclosures of
each of which are incorporated herein by reference in their
entireties.
BACKGROUND OF THE INVENTION
[0002] 1. Field of the Invention
[0003] The present invention is in the fields of pharmaceuticals,
formulations chemistry and pharmacology. The invention generally
relates to compositions comprising azelastine or pharmaceutically
acceptable salts or esters thereof, including azelastine
hydrochloride. In certain embodiments, the invention provides
pharmaceutical compositions comprising azelastine hydrochloride
formulated for use as nasal sprays and/or ocular solutions or
drops, as well as dosage formulations for oral and pulmonary
delivery. The invention also relates to methods of use of such
compositions in treating, alleviating or preventing symptoms
associated with a variety of allergic and non-allergic
conditions.
[0004] 2. Related Art
[0005] Azelastine is a second-generation H1 antagonist
antihistamine which is used for its anti-allergic, anti-asthmatic
and antihistamine properties. Azelastine is a phthalazinone
derivative having the following structural formula: ##STR1##
[0006] Azelastine can be produced in a variety of salt forms. The
form most frequently used in pharmaceuticals is azelastine
hydrochloride, which occurs as a white, almost odorless,
crystalline powder with a strong bitter taste. The chemical name
for azelastine hydrochloride is (.+-.)-1-(2H)-phthalazinone,
4-[(4-chlorophenyl)methyl]-2-(hexahydro-1-methyl-1H-azepin-4-yl)-,
mono-hydrochloride and its molecular formula is
C.sub.22H.sub.24ClN.sub.3O.HCl. Other salt forms suitable for use
in pharmaceutical compositions include azelastine embonate, which
is reduced in bitterness compared to azelastine HCl (see U.S. Pat.
No. 5,232,919 the disclosure of which is incorporated herein by
reference), but which may also be less effective than azelastine
HCl.
[0007] Research has shown that azelastine and its physiologically
acceptable salt forms exhibit beneficial effects when the
corresponding formulations are applied directly onto the nasal
mucosa and/or the conjunctival sac of the eye (see U.S. Pat. No.
5,164,194). Elimination of symptoms or noticeable relief has thus
been achieved in allergic rhinitis (seasonal and/or nonseasonal),
vasomotor rhinitis and allergic conjunctivitis.
[0008] Despite its effectiveness, azelastine hydrochloride
possesses a strong bitter taste. This bitter taste is so intense
that it was found to be unpleasant even at a dilution of
1.times.10.sup.6 (see U.S. Pat. No. 5,164,194). The bitter taste
was not thought to be a problem in intranasal delivery of
azelastine hydrochloride (see id.). However, subsequent clinical
studies have shown that the bitter taste of azelastine
hydrochloride is, indeed, an undesired element as a portion of the
medication usually drips down into the pharynx after intranasal
administration leading to an unpleasant and undesired taste
experience by the patient. For example, MedPointe Pharmaceuticals,
Inc. (Somerset, N.J.) has reported in the ASTELIN.RTM. product
label insert that in clinical studies, the bitter taste adverse
event occurred statistically more often in patients treated with
ASTELIN.RTM. brand Nasal Spray (containing 0.10% w/v azelastine
hydrochloride) versus vehicle placebo (19.7% vs. 0.6%). Likewise,
the fluid formed by a combination of an ocularly administered
medication, and induced tears secreted by the lachrymal glands,
drains via the nasolachrymal duct into the nose and ultimately down
the pharynx (see Day, N., "Ophthalmic Dosage Forms," in:
Pharmaceutical Preformulation and Formulation, Buffalo Grove, Ill.:
Interpharm Press (2002)). Such post-nasal drip caused by the ocular
administration of compositions comprising azelastine hydrochloride
therefore can also induce a bitter and unpleasant taste experience
by the patient. Ukai et al. (U.S. Pat. No. 6,576,677) disclose the
use of polyvinylpyrrolidone and/or copolyvidone to mask the taste
of bitter medicaments, including azelastine.
[0009] There remains a need for a therapeutically effective dose of
azelastine hydrochloride, particularly for nasal, ocular, or
pulmonary delivery, which possesses a more desired taste and/or has
a reduced ability to drip down into the pharynx after intranasal or
ocular administration, thus improving patient acceptability and
compliance.
BRIEF SUMMARY OF THE INVENTION
[0010] The present invention provides compositions, particularly
stable pharmaceutical compositions, comprising azelastine and/or
one or more pharmacologically acceptable salts or esters thereof,
particularly azelastine hydrochloride. In certain embodiments, the
pharmaceutical compositions comprise one or more pharmaceutically
acceptable carriers or excipients, particularly one or more such
carriers or excipients that are useful in formulating the
composition into a form suitable for intranasal delivery, e.g., via
aerosol or spray approaches, or for ophthalmic delivery, e.g., via
ocular drops, or for pulmonary delivery, e.g., via a suitable
device.
[0011] In certain additional embodiments, the invention provides
pharmaceutical compositions comprising (or consisting essentially
of) suitable concentrations of azelastine, or a pharmaceutically
acceptable salt or ester thereof (such as azelastine hydrochloride
(HCl)) to provide a therapeutically effective dose of azelastine,
or a pharmaceutically acceptable salt or ester thereof, and one or
more pharmaceutically acceptable carriers or excipients, wherein at
least one of the pharmaceutically acceptable carriers or excipients
is a taste-masking agent that masks the bitter taste associated
with azelastine or its salts or esters such that the bitter taste
experienced by a patient, upon administration of the pharmaceutical
composition to the patient, is reduced or eliminated, thus
enhancing the organoleptic acceptance of the composition when
applied to the nasal, ocular, oral or pharyngeal mucosa. In
preferred such embodiments, the taste-masking agent is selected
from the group consisting of sucralose, thaumatin (e.g.,
Talin.RTM.) sucrose, saccharin (including the salt forms: sodium,
calcium, etc.), fructose, dextrose, corn syrup, aspartame,
acesulfame-K, xylitol, sorbitol, erythritol, ammonium
glycyrrhizinate, thaumatin, neotame, mannitol, eucalyptus oil,
camphor, and natural or artificial flavors or flavoring agents (for
example menthol, mints, vanilla, orange, etc.), or combinations of
two or more of such agents. Particularly preferred such embodiments
provide such pharmaceutical compositions in which the taste-masking
agent is sucralose, at a suitable concentration, for example, from
about 0.001% to 1%, preferably from about 0.01% to about 0.5%, more
preferably from about 0.02% to about 0.2%, or most preferably from
about 0.05% to about 0.15%, of the total composition. Additional
such embodiments may further comprise one or more additional
flavoring agents, such as menthol, mints, vanilla, orange, etc. The
compositions of the present invention preferably can be formulated
for administration via any of a variety of routes, including but
not limited to intranasal, ocular, oral, buccal, sublingual
administration and the like.
[0012] In additional embodiments, the invention provides the
intranasal or ocular pharmaceutical compositions described above,
which may further comprise one or more agents that reduce or
prevent postnasal drip of the compositions into the pharynx upon
intranasal or ocular administration of the compositions. Certain
such compositions may comprise, for example, one or more
viscosity-increasing agents that increase the viscosity of the
azelastine-containing composition. Suitable viscosity-increasing
agents for use in accordance with this aspect of the invention
include, but are not limited to, polyvinylpyrrolidones (PVP)
(preferably having a molecular weight of about 10,000 to about
360,000, as well as mixtures containing one or more grades or
molecular weight of PVP), cellulose derivatives (including, but not
limited to, hydroxyethyl cellulose, carboxymethyl cellulose or its
salts, hypromellose, and the like), carrageenan, guar gum,
alginates, carbomers, polyethylene glycols, polyvinyl alcohol,
xanthan gum, and the like. In certain preferred embodiments,
hypromellose is used as a viscosity-increasing agent in the nasal
or ocular formulations provided by the present invention.
[0013] Certain compositions of the invention may further comprise
one or more additional components or agents, including one or more
solvents, one or more preservatives, one or more stabilizers, one
or more solubility-improving agents, one or more isotonicity
agents, one or more buffers or buffering agents, one or more
synthetic, semi-synthetic or natural bioadhesives, and the
like.
[0014] The invention also provides methods of treating or
preventing a variety of allergy-related and/or vasomotor-related
conditions, or symptoms thereof, including allergic rhinitis,
vasomotor rhinitis, allergic conjunctivitis and the like. According
to this aspect of the invention, the compositions may be
administered to the patient via any suitable mode of
administration, including intranasal, ocular, oral, buccal,
sublingual, pulmonary or the like. Suitably, the compositions are
administered directly to the nasal mucosa (i.e., intranasally,
e.g., in the form of a nasal spray or drops) or to the conjunctival
sac of the eye (i.e., ocularly, e.g., in the form of ocular
drops).
[0015] The present invention also provides oral dosage
pharmaceutical compositions comprising (or consisting essentially
of) a therapeutically effective dose of azelastine, or a
pharmaceutically acceptable salt or ester thereof, at a
concentration of from about 0.05% to about 5.0% by weight, or to
provide about 0.5 mg to about 10 mg per dose, and one or more
pharmaceutically acceptable carriers or excipients, wherein at
least one of the pharmaceutically acceptable carriers or excipients
is a taste masking agent, e.g., sucralose. In certain such
embodiments, the amount of azelastine, or a pharmaceutically
acceptable salt thereof (e.g., azelastine HCl) is in the range of
about 0.05 mg to about 10 mg. Suitably the concentration of
sucralose is about 0.05% to about 0.15% by weight. Exemplary forms
of oral dosage compositions include, but are not limited to, liquid
solutions, suspensions, tablets, capsules, chewable tablets, orally
disintegrating tablets, effervescent compositions and orally
dissolving/consumable films.
[0016] The present invention also provides pharmaceutical
compositions comprising (or consisting essentially of) a
therapeutically effective dose of azelastine, or a pharmaceutically
acceptable salt or ester thereof, at a concentration of from about
0.05% to about 5.0% by weight, and one or more pharmaceutically
acceptable carriers or excipients, wherein at least one of the
pharmaceutically acceptable carriers or excipients is sucralose,
and wherein the pharmaceutical composition further comprises one or
more additional active agents. Suitable additional active agents
for use in such compositions include, but are not limited to,
antihistamines (such as cetirizine, fexofenadine, olopatadine,
terfenadine and loratadine), steroids (such as fluoromethalone,
fluticasone, mometasone, triamcinolone, betamethasone, flunisolide,
budesonide, beclomethasone, budesonide, rimexolone, loteprednol
(e.g., loteprednol etabonate), beloxil, prednisone, loteprednol
(e.g., loteprednol etabonate) and dexamethasone), leukotriene
antagonists (such as montelukast), decongestants (such as
pseudoephedrine, phenylephedrine, phenylephrine,
phenylpropanolamine, oxymetazoline, propylhexedrine,
xylometazoline, epinephrine, ephedrine, desoxyephedrine,
naphazoline, and tetrahydrozoline), expectorants (such as
guaifenesin, sodium cromoglycate, codeine phosphate, and
isoproternol hydrochloride) and non-steroidal anti-inflammatory
agents (such asibuprofen, diclofenac, aceclofenac, naproxen,
etodolac, flurbiprofen, fenoprofen, ketoprofen, suprofen, fenbufen,
fluprofen, tolmetin sodium, oxaprozin, zomepirac, sulindac
indomethacin, piroxicam, mefenamic acid, nabumetone, meclofenamate
sodium, diflunisal, flufenisal, piroxicam, ketorolac, sudoxicam and
isoxicam). Suitably the amount of sucralose in such compositions is
about 0.05% to about 0.15% by weight. The pharmaceutical
compositions can also comprise combinations of azelastine and
multiple additional active agents, for example, azelastine, one or
more steroids and one or more decongestants; or azelastine, one or
more steroids and one or more leukotriene antagonists. Such
combination compositions can also further comprise sucralose and/or
other additional carriers or excipients.
[0017] In another embodiment, the present invention provides
sustained release pharmaceutical compositions for oral delivery
comprising (or consisting essentially of) a therapeutically
effective dose of azelastine, or a pharmaceutically acceptable salt
or ester thereof, and one or more pharmaceutically acceptable
carriers or excipients, wherein at least one of the
pharmaceutically acceptable carriers or excipients is sucralose,
and wherein the azelastine, or the pharmaceutically acceptable salt
or ester thereof, is: 1) coated with one or more sustained release
components; 2) bound to a cation exchanger; 3) reacted with one or
more osmotically active substances and coated with a semi-permeable
membrane and a hole is bored into the membrane; or 4) embedded in,
or is bound to, one or more substances selected from of the group
consisting of digestible fats, indigestible fats, polymers and
swelling agents. Suitably, the amount of azelastine in such
sustained release compositions is about 0.05% to about 10.0% by
weight and the amount of sucralose in such sustained release
compositions is about 0.05% to about 0.15% by weight. In certain
such embodiments, the amount of azelastine or salt thereof (e.g.,
azelastine HCl) is about 0.5 mg to about 10 mg.
[0018] In another embodiment, the present invention provides liquid
pharmaceutical compositions for ocular administration, comprising
(or consisting essentially of) a therapeutically effective dose of
azelastine, or a pharmaceutically acceptable salt or ester thereof,
and one or more pharmaceutically acceptable carriers or excipients,
wherein at least one of the pharmaceutically acceptable carriers or
excipients is sucralose, wherein the composition is free, or
substantially free of preservatives, and wherein the composition is
provided in a single unit-dose container. Suitably, the amount of
azelastine in such liquid, unit-dose pharmaceutical compositions is
about 0.05% to about 0.15% by weight and the amount of sucralose in
such liquid, unit-dose pharmaceutical compositions is about 0.05%
to about 0.15% by weight. Suitable unit-dose containers include,
but are not limited to, high density polyethylene containers, for
example, high density polyethylene containers produced using a
blow-fill-seal manufacturing technique with a volume capacity of
about 1 mL.
[0019] In another embodiment, the present invention provides liquid
pharmaceutical compositions for nasal administration in unit-dose
or multi-dose configurations, comprising (or consisting essentially
of) a therapeutically effective dose of azelastine, or a
pharmaceutically acceptable salt or ester thereof, and one or more
pharmaceutically acceptable carriers or excipients, wherein at
least one of the pharmaceutically acceptable carriers or excipients
is sucralose, wherein the composition is free, or substantially
free of preservatives, and wherein the composition is provided in
either a unit-dose or multi-dose container. Suitably, the amount of
azelastine in such liquid, unit-dose or multi-dose pharmaceutical
compositions is about 0.05% to about 0.15% by weight and the amount
of sucralose in such liquid, unit-dose or multi-dose pharmaceutical
compositions is about 0.05% to about 0.15% by weight. Suitable
unit-dose or multi-dose containers include, but are not limited to,
high density polyethylene bottles with a volume capacity of about 1
ml to 10 mL fitted with a spray pump specifically designed for use
with preservative free formulations.
[0020] The present invention also provides inhalable powder
pharmaceutical compositions comprising (or consisting essentially
of), a therapeutically effective dose of azelastine, or a
pharmaceutically acceptable salt or ester thereof, and one or more
pharmaceutically acceptable carriers or excipients, wherein the
azelastine is in the form of micronized particles and wherein at
least one of the pharmaceutically acceptable carriers or excipients
is sucralose, for example, micronized particles of sucralose.
Suitable such inhalable powder pharmaceutical compositions comprise
micronized particles of azelastine with an average particle size of
about 1 .mu.m to about 5 .mu.m, and micronized particles of
sucralose with an average particle size of about 1 .mu.m to about
20 .mu.m. Such inhalable powder pharmaceutical compositions of the
present invention can be formulated for pulmonary delivery using,
for example, a dry powder inhaler. Suitably, the amount of
azelastine in such inhalable powder pharmaceutical compositions is
about 0.1% to about 20.0% by weight and the amount of sucralose in
such inhalable powder pharmaceutical compositions is about 0.05% to
about 20.0% by weight.
[0021] The present invention also provides inhalable spray
pharmaceutical compositions comprising (or consisting essentially
of), a suitable concentration to provide a therapeutically
effective dose of azelastine, or a pharmaceutically acceptable salt
or ester thereof, and one or more pharmaceutically acceptable
carrier, stabilizer or excipient, wherein the azelastine is in a
solution form and wherein at least one of the pharmaceutically
acceptable carriers or excipients is sucralose dissolved in the
solution. Such inhalable spray pharmaceutical compositions when
used with a suitable device provide a fine spray of the components
(including active and non-active components) having an average
particle size of about 1 .mu.m to about 5 .mu.m. Such inhalable
spray pharmaceutical compositions of the present invention can be
formulated for pulmonary delivery using, for example, a suitable
device or inhaler. Suitably the amount of azelastine in such
inhalable spray pharmaceutical compositions is about 0.1% to about
10% by weight and the amount of sucralose in such inhalable spray
pharmaceutical compositions is about 0.05% to about 0.15% by
weight.
[0022] The present invention also provides methods of treating
snoring in an animal, comprising administering to the animal a
therapeutically effective dose of azelastine, or a pharmaceutically
acceptable salt or ester thereof, and one or more pharmaceutically
acceptable carriers or excipients, wherein at least one of the
pharmaceutically acceptable carriers or excipients is sucralose.
The amount of azelastine in such compositions suitably is about
0.05% to about 0.15% by weight, and the amount of sucralose in such
compositions is suitably about 0.05% to about 0.15% by weight.
[0023] The present invention also provides methods of treating or
preventing allergic rhinitis, non-allergic vasomotor rhinitis or
allergic conjunctivitis in an animal, such as a human, suffering
from or predisposed thereto, comprising administering to said
animal a pharmaceutical composition comprising an effective amount
azelastine and a taste-masking amount of sucralose, thereby
avoiding the bitter taste associated with the azelastine.
[0024] In suitable embodiments, the present invention provides
pharmaceutical compositions comprising (or consisting essentially
of) the following:
[0025] About 0.05% to about 0.15% (w/v) azelastine hydrochloride;
and about 0.01% to about 1.0% (w/v) steroid selected from the group
consisting of fluticasone, mometasone, dexamethasone beloxil,
loteprednol (e.g., loteprednol etabonate), budesonide and
triamcinolone.
[0026] About 0.05% to about 0.15% (w/v) azelastine hydrochloride;
about 0.01% to about 1.0% (w/v) steroid selected from the group
consisting of fluticasone, mometasone, dexamethasone beloxil,
loteprednol (e.g., loteprednol etabonate), budesonide and
triamcinolone; and about 0.1% to about 0.15% (w/v) sucralose.
[0027] About 0.1% (w/v) azelastine hydrochloride; about 0.01% to
about 1.0% (w/v) steroid selected from the group consisting of
fluticasone, mometasone, dexamethasone beloxil, loteprednol (e.g.,
loteprednol etabonate), budesonide and triamcinolone; and about
0.1% (w/v) sucralose.
[0028] About 0.1% (w/v) azelastine hydrochloride; about 0.01% to
about 1.0% (w/v) steroid selected from the group consisting of
fluticasone, mometasone, dexamethasone beloxil, loteprednol (e.g.,
loteprednol etabonate), budesonide and triamcinolone; and about
0.15% (w/v) sucralose.
[0029] About 0.15% (w/v) azelastine hydrochloride; about 0.01% to
about 1.0% (w/v) steroid selected from the group consisting of
fluticasone, mometasone, dexamethasone beloxil, loteprednol (e.g.,
loteprednol etabonate), budesonide and triamcinolone; and about
0.1% (w/v) sucralose.
[0030] About 0.15% (w/v) azelastine hydrochloride; about 0.01% to
about 1.0% (w/v) steroid selected from the group consisting of
fluticasone, mometasone, dexamethasone beloxil, loteprednol (e.g.,
loteprednol etabonate), budesonide and triamcinolone; and about
0.15% (w/v) sucralose.
[0031] About 0.05% to about 0.15% (w/v) azelastine hydrochloride;
and about 0.1% to about 5.0% (w/v) montelukast.
[0032] About 0.05% to about 0.15% (w/v) azelastine hydrochloride;
about 0.1% to about 5.0% (w/v) montelukast; and about 0.1% to about
0.15% (w/v) sucralose.
[0033] About 0.1% (w/v) azelastine hydrochloride; about 0.1% to
about 5.0% (w/v) montelukast; and about 0.1% (w/v) sucralose.
[0034] About 0.1% (w/v) azelastine hydrochloride; about 0.1% to
about 5.0% (w/v) montelukast; and about 0.15% (w/v) sucralose.
[0035] About 0.15% (w/v) azelastine hydrochloride; about 0.1% to
about 5.0% (w/v) montelukast; and about 0.1% (w/v) sucralose.
[0036] About 0.15% (w/v) azelastine hydrochloride; about 0.1% to
about 5.0% (w/v) montelukast; and about 0.15% (w/v) sucralose.
[0037] About 0.05% to about 0.15% (w/v) azelastine hydrochloride;
and about 0.1% to about 1.0% (w/v) decongestant selected from the
group consisting of pseudoephedrine and phenylephrine.
[0038] About 0.05% to about 0.15% (w/v) azelastine hydrochloride;
about 0.1% to about 1.0% (w/v) decongestant selected from the group
consisting of pseudoephedrine and phenylephrine; and about 0.1% to
about 0.15% (w/v) sucralose.
[0039] About 0.1% (w/v) azelastine hydrochloride; about 0.1% to
about 1.0% (w/v) decongestant selected from the group consisting of
pseudoephedrine and phenylephrine; and about 0.1% (w/v)
sucralose.
[0040] About 0.1% (w/v) azelastine hydrochloride; about 0.1% to
about 1.0% (w/v) decongestant selected from the group consisting of
pseudoephedrine and phenylephrine; and about 0.15% (w/v)
sucralose.
[0041] About 0.15% (w/v) azelastine hydrochloride; about 0.1% to
about 1.0% (w/v) decongestant selected from the group consisting of
pseudoephedrine and phenylephrine; and about 0.1% (w/v)
sucralose.
[0042] About 0.15% (w/v) azelastine hydrochloride; about 0.1% to
about 1.0% (w/v) decongestant selected from the group consisting of
pseudoephedrine and phenylephrine; and about 0.15% (w/v)
sucralose.
[0043] About 0.05% to about 0.15% (w/v) azelastine hydrochloride;
and about 0.1% to about 10.0% (w/v) NSAID selected from the group
consisting of ibuprofen, diclofenac, aceclofenac and naproxen.
[0044] About 0.05% to about 0.15% (w/v) azelastine hydrochloride;
about 0.1% to about 10.0% (w/v) NSAID selected from the group
consisting of ibuprofen, diclofenac, aceclofenac and naproxen; and
about 0.1% to about 0.15% (w/v) sucralose.
[0045] About 0.1% (w/v) azelastine hydrochloride; about 0.1% to
about 10.0% (w/v) NSAID selected from the group consisting of
ibuprofen, diclofenac, aceclofenac and naproxen; and about 0.1%
(w/v) sucralose.
[0046] About 0.1% (w/v) azelastine hydrochloride; about 0.1% to
about 10.0% (w/v) NSAID selected from the group consisting of
ibuprofen, diclofenac, aceclofenac and naproxen; and about 0.15%
(w/v) sucralose.
[0047] About 0.15% (w/v) azelastine hydrochloride; about 0.1% to
about 10.0% (w/v) NSAID selected from the group consisting of
ibuprofen, diclofenac, aceclofenac and naproxen; and about 0.1%
(w/v) sucralose.
[0048] About 0.15% (w/v) azelastine hydrochloride; about 0.1% to
about 10.0% (w/v) NSAID selected from the group consisting of
ibuprofen, diclofenac, aceclofenac and naproxen; and about 0.15%
(w/v) sucralose.
[0049] About 0.05% to about 0.15% (w/v) azelastine hydrochloride;
about 0.01% to about 1.0% (w/v) steroid selected from the group
consisting of fluticasone, mometasone, dexamethasone beloxil,
loteprednol (e.g., loteprednol etabonate), budesonide, and
triamcinolone; and about 0.1% to about 1.0% (w/v) decongestant
selected from the group consisting of pseudoephedrine and
phenylephrine.
[0050] About 0.05% to about 0.15% (w/v) azelastine hydrochloride;
about 0.01% to about 1.0% (w/v) steroid selected from the group
consisting of fluticasone, mometasone, dexamethasone beloxil,
loteprednol (e.g., loteprednol etabonate), budesonide, and
triamcinolone; about 0.1% to about 1.0% (w/v) decongestant selected
from the group consisting of pseudoephedrine and phenylephrine; and
about 0.1% to about 0.15% (w/v) sucralose.
[0051] About 0.1% (w/v) azelastine hydrochloride; about 0.01% to
about 1.0% (w/v) steroid selected from the group consisting of
fluticasone, mometasone, dexamethasone beloxil, loteprednol (e.g.,
loteprednol etabonate), budesonide, and triamcinolone; about 0.1%
to about 1.0% (w/v) decongestant selected from the group consisting
of pseudoephedrine and phenylephrine; and about 0.1% (w/v)
sucralose.
[0052] About 0.1% (w/v) azelastine hydrochloride; about 0.01% to
about 1.0% (w/v) steroid selected from the group consisting of
fluticasone, mometasone, dexamethasone beloxil, loteprednol (e.g.,
loteprednol etabonate), budesonide, and triamcinolone; about 0.1%
to about 1.0% (w/v) decongestant selected from the group consisting
of pseudoephedrine and phenylephrine; and about 0.15% (w/v)
sucralose.
[0053] About 0.15% (w/v) azelastine hydrochloride; about 0.01% to
about 1.0% (w/v) steroid selected from the group consisting of
fluticasone, mometasone, dexamethasone beloxil, loteprednol (e.g.,
loteprednol etabonate), budesonide, and triamcinolone; about 0.1%
to about 1.0% (w/v) decongestant selected from the group consisting
of pseudoephedrine and phenylephrine; and about 0.1% (w/v)
sucralose.
[0054] About 0.15% (w/v) azelastine hydrochloride; about 0.01% to
about 1.0% (w/v) steroid selected from the group consisting of
fluticasone, mometasone, dexamethasone beloxil, loteprednol (e.g.,
loteprednol etabonate), budesonide, and triamcinolone; about 0.1%
to about 1.0% (w/v) decongestant selected from the group consisting
of pseudoephedrine and phenylephrine; and about 0.15% (w/v)
sucralose.
[0055] About 0.05% to about 0.15% (w/v) azelastine hydrochloride;
about 0.01% to about 1.0% (w/v) steroid selected from the group
consisting of fluticasone, mometasone, dexamethasone beloxil,
loteprednol (e.g., loteprednol etabonate), budesonide, and
triamcinolone; and about 0.1% to about 5.0% (w/v) montelukast.
[0056] About 0.05% to about 0.15% (w/v) azelastine hydrochloride;
about 0.01% to about 1.0% (w/v) steroid selected from the group
consisting of fluticasone, mometasone, dexamethasone beloxil,
loteprednol (e.g., loteprednol etabonate), budesonide, and
triamcinolone; about 0.1% to about 5.0% (w/v) montelukast; and
about 0.1% to about 0.15% (w/v) sucralose.
[0057] About 0.1% (w/v) azelastine hydrochloride; about 0.01% to
about 1.0% (w/v) steroid selected from the group consisting of
fluticasone, mometasone, dexamethasone beloxil, loteprednol (e.g.,
loteprednol etabonate), budesonide, and triamcinolone; about 0.1%
to about 5.0% (w/v) montelukast; and about 0.1% (w/v)
sucralose.
[0058] About 0.1% (w/v) azelastine hydrochloride; about 0.01% to
about 1.0% (w/v) steroid selected from the group consisting of
fluticasone, mometasone, dexamethasone beloxil, loteprednol (e.g.,
loteprednol etabonate), budesonide, and triamcinolone; about 0.1%
to about 5.0% (w/v) montelukast; and about 0.15% (w/v)
sucralose.
[0059] About 0.15% (w/v) azelastine hydrochloride; about 0.01% to
about 1.0% (w/v) steroid selected from the group consisting of
fluticasone, mometasone, dexamethasone beloxil, loteprednol (e.g.,
loteprednol etabonate), budesonide, and triamcinolone; about 0.1%
to about 5.0% (w/v) montelukast; and about 0.1% (w/v)
sucralose.
[0060] About 0.15% (w/v) azelastine hydrochloride; about 0.1% to
about 1.0% (w/v) steroid selected from the group consisting of
fluticasone, mometasone, dexamethasone beloxil, loteprednol (e.g.,
loteprednol etabonate), budesonide, and triamcinolone; about 0.1%
to about 5.0% (w/v) montelukast; and about 0.15% (w/v)
sucralose.
[0061] About 0.05% to about 0.15% (w/v) azelastine hydrochloride;
about 0.01% to about 1% (w/v) steroid selected from the group
consisting of fluticasone, mometasone, dexamethasone beloxil,
loteprednol (e.g., loteprednol etabonate), budesonide, and
triamcinolone; about 0.001% to about 5.00% (w/v) of a water-soluble
polymer; about 0.01% to about 2% of a suspending agent; about 0.01%
to about 0.2% of a wetting agent; about 0.01% to about 0.1% (w/v)
disodium edetate; about 0.001% to about 0.5% (w/v) of a
preservative such as benzalkonium chloride and/or phenethyl
alcohol; about 0.1% to about 0.15% sucralose; a sufficient amount
of a pharmaceutically acceptable buffer to maintain the pH of the
composition within a range of from about 4.5 to about 7.4; a
sufficient amount of an isotonicity agent to yield an osmolality of
about 220 mosmol/kg to about 350 msomol/kg; and QS water.
[0062] About 0.05% to about 0.15% (w/v) azelastine hydrochloride;
about 0.1% to about 5% (w/v) montelukast; about 0.001% to about
5.00% (w/v) of a water-soluble polymer; about 0.01% to about 0.1%
(w/v) disodium edetate; about 0.001% to about 0.5% (w/v)
benzalkonium chloride; about 0.1% to about 0.15% sucralose; a
sufficient amount of a pharmaceutically acceptable buffer to
maintain the pH of the composition within a range of from about 4.5
to about 7.4; a sufficient amount of an isotonicity agent to yield
an osmolality of about 220 mosmol/kg to about 350 msomol/kg; and QS
water.
[0063] About 0.05% to about 0.15% (w/v) azelastine hydrochloride;
about 0.1% to about 1% (w/v) decongestant selected from the group
consisting of pseudoephedrine and phenylephrine; about 0.001% to
about 5.00% (w/v) of a water-soluble polymer; about 0.01% to about
0.1% (w/v) disodium edetate; about 0.001% to about 0.5% (w/v)
benzalkonium chloride; about 0.1% to about 0.15% sucralose; a
sufficient amount of a pharmaceutically acceptable buffer to
maintain the pH of the composition within a range of from about 4.5
to about 7.4; a sufficient amount of an isotonicity agent to yield
an osmolality of about 220 mosmol/kg to about 350 msomol/kg; and QS
water.
[0064] About 0.05% to about 0.15% (w/v) azelastine hydrochloride;
about 0.1% to about 10% (w/v) NSAID selected from the group
consisting of ibuprofen, diclofenac, aceclofenac and naproxen;
about 0.001% to about 5.00% (w/v) of a water-soluble polymer; about
0.01% to about 0.1% (w/v) disodium edetate; about 0.001% to about
0.5% (w/v) benzalkonium chloride; about 0.1% to about 0.15%
sucralose; a sufficient amount of a pharmaceutically acceptable
buffer to maintain the pH of the composition within a range of from
about 4.5 to about 7.4; a sufficient amount of an isotonicity agent
to yield an osmolality of about 220 mosmol/kg to about 350
msomol/kg; and QS water.
[0065] About 0.05% to about 0.15% (w/v) azelastine hydrochloride;
about 0.01% to about 1% (w/v) steroid selected from the group
consisting of fluticasone, mometasone, dexamethasone beloxil,
loteprednol (e.g., loteprednol etabonate), budesonide and
triamcinolone; about 0.1% to about 1% (w/v) decongestant selected
from the group consisting of pseudoephedrine and phenylephrine;
about 0.001% to about 5.00% (w/v) of a water-soluble polymer; about
0.01% to about 2% of a suspending agent; about 0.01% to about 0.2%
of a wetting agent; about 0.01% to about 0.1% (w/v) disodium
edetate; about 0.001% to about 0.5% (w/v) of a preservative such as
benzalkonium chloride and/or phenylethyl alcohol; about 0.1% to
about 0.15% sucralose; a sufficient amount of a pharmaceutically
acceptable buffer to maintain the pH of the composition within a
range of from about 4.5 to about 7.4; a sufficient amount of an
isotonicity agent to yield an osmolality of about 220 mosmol/kg to
about 350 msomol/kg; and QS water.
[0066] About 0.05% to about 0.15% (w/v) azelastine hydrochloride;
about 0.01% to about 1% (w/v) steroid selected from the group
consisting of fluticasone, mometasone, dexamethasone beloxil,
loteprednol (e.g., loteprednol etabonate), budesonide and
triamcinolone; about 0.1% to about 1% (w/v) montelukast; about
0.001% to about 5.00% (w/v) of a water-soluble polymer; about 0.01%
to about 2% of a suspending agent; about 0.01% to about 0.2% of a
wetting agent; about 0.01% to about 0.1% (w/v) disodium edetate;
about 0.001% to about 0.5% (w/v) of a preservative such as
benzalkonium chloride and/or phenylethyl alcohol; about 0.1% to
about 0.15% sucralose; a sufficient amount of a pharmaceutically
acceptable buffer to maintain the pH of the composition within a
range of from about 4.5 to about 7.4; a sufficient amount of an
isotonicity agent to yield an osmolality of about 220 mosmol/kg to
about 350 msomol/kg; and QS water.
[0067] In another embodiment, the present invention provides
methods of treating or preventing a physical disorder in an animal
suffering from or predisposed thereto, comprising administering to
said animal an effective amount of any one of the pharmaceutical
compositions described herein. Suitably the animal is a human, and
the physical disorder is selected from the group consisting of
allergic rhinitis, non-allergic vasomotor rhinitis and allergic
conjunctivitis.
[0068] In an additional embodiment, the present invention provides
methods of treating or preventing allergic rhinitis, non-allergic
vasomotor rhinitis or allergic conjunctivitis in an animal (e.g., a
mammal such as a human) suffering from or predisposed thereto,
comprising co-administering to the animal an effective amount of
azelastine or a salt or ester thereof and an effective amount of
one or more steroids. Suitably, the azelastine is azelastine HCl.
Examples of steroids for co-administration include, but are not
limited to, fluoromethalone, fluticasone (e.g., fluticasone
propionate), mometasone, triamcinolone, betamethasone, flunisolide,
budesonide, beclomethasone, budesonide, rimexolone, beloxil,
prednisone, loteprednol (e.g., loteprednol etabonate), (e.g.,
loteprednol (e.g., loteprednol etabonate) etabonate) and
dexamethasone, and pharmaceutically acceptable esters, salts,
conjugates and other forms of such steroids. Suitably, the
co-administration will comprise co-administration of azelastine and
fluticasone. In certain such embodiments, the azelastine (or salt
or ester thereof) and the steroid are contained together in a
single pharmaceutical composition, for example, a single
pharmaceutical composition comprising azelastine (or a salt or
ester thereof) and a steroid. In other embodiments, the azelastine
(or a salt or ester thereof) is contained in one composition, e.g.,
a pharmaceutical composition comprising azelastine (or a salt or
ester thereof) and the steroid is contained in a different
composition, e.g., a pharmaceutical composition comprising a
steroid.
[0069] In suitable embodiments, the co-administration comprises
administering azelastine and one or more steroids (or
composition(s) comprising the agents separately or both agents
together) at the same time. In further embodiments, the
co-administration comprises administering azelastine and one or
more steroids (or composition(s) comprising the agents separately
or both agents together) within less than about 30 minutes of each
other, less than about 20 minutes of each other, or less than about
15 minutes of each other. If administered separately (e.g., in
separate compositions), the azelastine and the one or more steroids
can be co-administered in any order. Suitably, the azelastine (or a
salt or ester thereof) and the one or more steroids are
co-administered to the nasal passage.
[0070] Other features and advantages of the invention will be
apparent from the following detailed description, and from the
claims. The disclosed materials, methods, and examples are for
illustrative purposes only and are not intended to be limiting.
Skilled artisans will appreciate that methods and materials similar
or equivalent to those described herein can be used to practice the
invention.
[0071] Unless otherwise defined, all technical and scientific terms
used herein have the meaning commonly understood by one skilled in
the art to which this invention belongs. All publications, patent
applications, patents, and other references mentioned herein are
incorporated by reference in their entirety. In case of conflict,
the present specification, including definitions, will control.
BRIEF DESCRIPTION OF THE DRAWINGS/FIGURES
[0072] FIG. 1 shows the effects on the total nasal symptom score
resulting from the co-administration of azelastine HCl and
fluticasone propionate.
[0073] FIG. 2 shows the mean improvement in severity score from
baseline for the symptom of runny nose, resulting from the
co-administration of azelastine HCl and fluticasone propionate.
[0074] FIG. 3 shows the mean improvement in severity score from
baseline for the symptom of itchy nose, resulting from the
co-administration of azelastine HCl and fluticasone propionate.
[0075] FIG. 4 shows the mean improvement in severity score from
baseline for the symptom of sneezing, resulting from the
co-administration of azelastine HCl and fluticasone propionate.
[0076] FIG. 5 shows the mean improvement in severity score from
baseline for the symptom of congestion, resulting from the
co-administration of azelastine HCl and fluticasone propionate.
[0077] FIG. 6 shows the cumulative improvement in total nasal
symptom score versus baseline, resulting from the co-administration
of azelastine HCl and fluticasone propionate.
DETAILED DESCRIPTION OF THE INVENTION
Overview
[0078] As used herein when referring to any numerical value, the
term "about" means a value falling within a range that is .+-.10%
of the stated value. For example, "about 50.degree. C." encompasses
a range of temperatures from 45.degree. C. to 55.degree. C.,
inclusive; similarly, "about 100 mM" encompasses a range of
concentrations from 90 mM to 110 mM, inclusive.
[0079] As used herein, the articles "a," "an" and "one" mean "at
least one" or "one or more" of the object to which they refer,
unless otherwise specified or made clear by the context in which
they appear herein.
[0080] The present invention provides compositions, particularly
pharmaceutical compositions, comprising azelastine and/or one or
more of its pharmacologically acceptable salts or esters thereof,
particularly azelastine hydrochloride. Preferred such compositions
of the invention comprise azelastine hydrochloride as the active
ingredient, and may further comprise one or more additional
components, such as one or more solvents, one or more
preservatives, one or more stabilizers, one or more buffers or
buffering agents, one or more bioadhesives, one or more suspending
agents (e.g., microcrystalline cellulose, sodium carboxy methyl
cellulose, hypromellose carbopol and the like), one or more
surfactants or wetting agents and/or one or more isotonicity
agents. To reduce or eliminate the bitter taste associated with
azelastine (or a salt or ester thereof, such as azelastine
hydrochloride), the compositions of the present invention further
comprise one or more stable taste-masking, flavoring, or sweetening
agents, or a combination of such agents. To reduce the post-nasal
drip of the compositions of the present invention for intranasal or
ocular administration, the compositions of the present invention
may further comprise one or more stable viscosity-increasing
agents, one or more stable bioadhesive agents, and/or a combination
of viscosity-increasing agents and bioadhesive agents. In other
embodiments, the pharmaceutical compositions can comprise one or
more additional active agents, such as those described herein, in
addition to azelastine, including, but not limited to, additional
antihistamines (including H.sub.1, H.sub.3 and H.sub.4 receptor
antagonists), steroids (e.g., safe steroids), leukotriene
antagonists, prostaglandin D2 receptor antagonists, decongestants,
anti-fungal agents, triamcinolone and triamcinolone derivatives,
non-steroidal immunophilin-dependent immunosuppressants (NSIDIs),
anti-inflammatory agents, non-steroidal anti-inflammatory agents
(NSAIDs), COX-2 inhibitors, anti-infective agents, mucolytic
agents, anticholinergic agents, mast cell stabilizers,
non-antibiotic anti-microbial agents, anti-viral agents,
antiseptics, neurokinin antagonists, platelet activating factor
(PAF) and 5-lipoxygenase (5-LO) inhibitors.
[0081] In certain embodiments, the pharmaceutical compositions
comprise one or more pharmaceutically carriers or excipients,
particularly one or more such carriers or excipients that are
useful in formulating the composition into a form suitable for
delivery intranasally via aerosol or spray approaches, or for
delivery ocularly via drops. In related embodiments, the invention
provides such pharmaceutical compositions in which at least one of
the carriers or excipients is a taste-masking agent, such as
sucralose, and other compositions in which at least one of the
carriers or excipients is a viscosity-increasing agent, such as
hypromellose. In certain preferred embodiments, the pharmaceutical
compositions provided by the invention comprise at least one
taste-masking agent such as sucralose, and at least one
viscosity-increasing agent such as hypromellose. The compositions
of the invention are particularly useful in treating the symptoms
associated with a variety of conditions such as allergic rhinitis
(seasonal and/or nonseasonal), non-allergic rhinitis, vasomotor
rhinitis, allergic conjunctivitis and the like.
Compositions and Modes of Administration
[0082] In certain embodiments, the invention provides compositions,
particularly pharmaceutical compositions, comprising (or consisting
essentially of) a therapeutically or pharmacologically effective
amount of azelastine or a pharmaceutically acceptable salt or ester
thereof and one or more pharmaceutically acceptable carriers or
excipients. Particularly preferred for use in the compositions of
the invention is azelastine hydrochloride (see U.S. Pat. Nos.
3,813,384, 4,704,387 and 5,164,194, the disclosures of which are
incorporated herein by reference in their entireties). By
"pharmaceutically acceptable carrier or excipient" is meant a
non-toxic solid, semisolid or liquid filler, diluent, encapsulating
material or formulation auxiliary of any type.
[0083] The compositions of the present invention can be
administered to a patient via any suitable mode of administration,
including oral, intranasal, ocular, buccal, sublingual, pulmonary
or the like. In certain embodiments, the compositions are
administered directly to the nasal mucosa (i.e., intranasally,
e.g., in the form of a nasal spray or drops) or to the conjunctival
sac of the eye (i.e., ocularly, e.g., in the form of ocular drops).
In alternative embodiments, the compositions are administered
topically to the buccal or sublingual cavity or intrapulmonarily.
Regardless of their mode of administration, the compositions
provided by the present invention suitably comprise from about
0.0001% to about 1.0%, and more suitably from about 0.005% to about
0.5% or most suitably from about 0.05% to about 0.15% (e.g., about
0.05%, about 0.06%, about 0.07%, about 0.08%, about 0.09%, about
0.10%, about 0.11%, about 0.12%, about 0.13%, about 0.14% or about
0.15%), of pure azelastine salt based on weight (calculated as the
free azelastine base) as the active ingredient. The percentage of
azelastine in a given composition of the invention is calculated as
a percentage of the weight of the composition for solid dosage
forms (i.e., weight/weight) or as a percentage of the volume of the
composition for solution or liquid dosage forms (i.e.,
weight/volume). The amount of a given salt form of azelastine
(e.g., azelastine hydrochloride) to be included in a given
composition of the invention is calculated so that the composition
contains the amount of pure azelastine noted above. In certain
compositions of the invention, e.g., nasal spray formulations, a
solution formulated at a higher concentration of azelastine (or
salt thereof) can be delivered at a smaller volume to provide a
given dosage of azelastine (or salt thereof), thus minimizing the
possibility of postnasal drip of the solution into the pharynx
which leads to an unpleasant taste sensation by the person to whom
the azelastine-containing nasal spray is administered.
[0084] In certain embodiments, the compositions of the invention
may be formulated into forms for oral administration, including
solid dosage forms or liquid dosage forms. In alternative
embodiments, the compositions of the invention may be formulated
into forms for direct administration to the mucosa, including the
nasal mucosa (i.e., intranasal administration), ocular tissue or
conjunctival sac (i.e., ocular administration), buccal mucosa
(i.e., buccal administration) or oral mucosa under the tongue
(i.e., sublingual administration).
[0085] Solid dosage forms for oral administration include capsules,
tablets, pills, powders, particles and granules. In such solid
dosage forms, the active azelastine compound(s) are mixed with at
least one pharmaceutically acceptable excipient or carrier such as
(a) fillers or extenders such as starches, lactose, sucrose,
glucose, mannitol, dicalcium phosphate and microcrystalline
cellulose; (b) binders such as sodium carboxymethylcellulose,
alginates, gelatin, polyvinylpyrrolidone, and acacia; (c)
disintegrating agents such as agar-agar, calcium carbonate, potato
or tapioca starch, alginic acid, certain silicates, sodium
carboxymethyl cellulose, pregelatinized starch and sodium starch
glycolate; (d) lubricants such as calcium stearate, magnesium
stearate, stearic acid, solid polyethylene glycols, sodium lauryl
sulfate, and mixtures thereof, and/or (e) glidants such as talc,
silicon dioxide and starch. In the case of capsules, tablets and
pills, the dosage form may also comprise buffering agents. Solid
compositions of a similar type may also be employed as fillers in
soft and hard filled gelatin capsules using such excipients as
lactose or milk sugar as well as high molecular weight polyethylene
glycols, oils and the like. The solid dosage forms of tablets,
dragees, capsules, pills, and granules can be prepared with
coatings, which may in themselves provide taste-masking, and shells
such as enteric coatings and other coatings that are well known in
the pharmaceutical formulating art. The solid dosage forms also may
optionally contain opacifying, coloring and/or flavoring agents,
and can also be formulated such that they release the active
azelastine ingredient(s) only, or preferentially, in a certain part
of the intestinal tract, optionally in a delayed manner (see U.S.
Pat. No. 5,271,946, the disclosure of which is incorporated herein
by reference in its entirety). Examples of embedding compositions
which can be used include polymeric substances and waxes. The
active compounds can also be in micro-encapsulated form, if
appropriate, with one or more of the above-mentioned
excipients.
[0086] Liquid dosage forms for nasal, ocular or oral administration
include pharmaceutically acceptable emulsions, solutions,
suspensions, syrups and elixirs. In addition to the active
azelastine compound(s), the liquid dosage forms may contain inert
diluents and/or solvents commonly used in the art. Water is the
solvent of choice for the formulations of the invention; however,
combinations of water with other physiologically acceptable
solvents as required are also satisfactory for use. Other solvents,
solubilizing agents and emulsifiers suitable for use in place of,
or in addition to, water include but are not limited to saturated
aliphatic mono- and polyvalent alcohols which contain 2-6 carbon
atoms (including, but not limited to, ethanol, 1,2-propylene
glycol, sorbitol, and glycerine), polyglycols such as polyethylene
glycols, and surfactants/emulsifiers like the fatty acid esters of
sorbitan, and mixtures thereof. Oils, in particular, cottonseed,
peanut, or corn oils, may also be added to the compositions. The
combination of the additional solvents in the aqueous solution
should preferably not exceed about 15% (w/v) of the total
composition. Besides inert diluents, the oral compositions can also
include adjuvants such as wetting agents, emulsifying and
suspending agents (e.g., microcrystalline cellulose, sodium
carboxymethyl cellulose, hypromellose, carbopol and the like),
surfactants, sweetening, flavoring, and perfuming agents, including
those described in further detail herein below. Liquid dosage forms
that provide the active ingredient in suspension may comprise, in
addition to the active azelastine compound(s), one or more
suspending agents such as microcrystalline cellulose, magnesium
aluminum silicate, bentonite, agar-agar, hypromellose, sodium
carboxymethyl cellulose, carbopol/carbomer, pectin, acacia,
tragacanth or their mixtures.
[0087] Certain liquid compositions of the invention may further
comprise one or more preservatives and/or one or more stabilizers.
Preservatives that are suitable for use in the compositions of the
invention include, but are not limited to, edetic acid and their
alkali salts such as disodium EDTA (also referred to as "disodium
edetate" or "the disodium salt of edetic acid") and calcium EDTA
(also referred to as "calcium edetate"), benzyl alcohol,
methylparaben, propylparaben, butylparaben, chlorobutanol,
phenylethyl alcohol, benzalkonium chloride, thimerosal, propylene
glycol, sorbic acid, and benzoic acid derivatives. The
preservatives should be used at a concentration of from about
0.001% to about 0.5% (w/v) in the final composition. The
combination of benzalkonium chloride, used at a concentration of
from about 0.001% to about 0.5% or preferably from about 0.005% to
about 0.1% (w/v), and edetic acid (as a disodium salt), used at a
concentration of from about 0.005% to about 0.1% (w/v), are the
preferred preservative/stabilizer combination used in the
compositions of the present invention.
[0088] Certain compositions of the invention may further comprise
one or more solubility-enhancing agents that are used to improve
the solubility of the azelastine compound used as an active
ingredient. Solubility-enhancing agents that are suitable for use
in the compositions of the invention include, but are not limited
to, polyvinylpyrrolidone (preferably grades 25, 30, 60, or 90),
poloxamer, polysorbate 80, sorbitan monooleate 80, and polyethylene
glycols (molecular weights of 200 to 600).
[0089] Certain compositions of the invention may further comprise
one or more agents that are used to render the composition
isotonic, particularly in those compositions in which water is used
as a solvent. Such agents are particularly useful in compositions
formulated for nasal or ocular application, since they adjust the
osmotic pressure of the formulations to the same osmotic pressure
as nasal or ocular secretions. Agents that are suitable for such a
use in the compositions of the invention include, but are not
limited to, sodium chloride, sorbitol, propylene glycol, dextrose,
sucrose, and glycerine, and other isotonicity agents that are known
in the art (see, e.g., Reich et al., "Chapter 18: Tonicity,
Osmoticity, Osmolality and Osmolarity," in: Remington: The Science
and Practice of Pharmacy, 20.sup.th Edition, Lippincott Williams
and Wilkins, Philadelphia, Pa. (2000)).
[0090] It is desirable that the compositions of the present
invention that are to be administered in liquid form (including
intranasally, orally or ocularly applied formulations) have a pH of
about 4.5 to about 7.4, and preferably have a pH of about 5.5 to
7.1, for physiological reasons. Accordingly, in additional
embodiments, the compositions of the invention may further comprise
one or more buffering agents or combinations thereof, that are used
to adjust and/or maintain the compositions into the desired pH
range. Adjustment of pH or buffering agents that are suitable for
use in the compositions of the invention include, but are not
limited to, citric acid, sodium citrate, sodium phosphate (dibasic,
heptahydrate form), and boric acid or equivalent conventional
buffers, or combinations thereof. The appropriate amounts of
buffers and buffering agents, or combinations thereof, that are to
be used in the compositions of the invention are readily determined
by those of ordinary skill without undue experimentation,
particularly in view of the guidance contained herein and in
standard formularies such as the United States Pharmacopoeia,
Remington: The Science and Practice of Pharmacy, and the like, the
disclosures of which are incorporated herein by reference in their
entireties.
[0091] As noted above, azelastine salts, particularly azelastine
hydrochloride, have a strong bitter taste when the compounds or
compositions comprising them are administered intranasally,
ocularly, or orally. Thus, in certain embodiments, the liquid
formulations of the invention, particularly those that are to be
administered intranasally, ocularly, or orally, preferably further
comprise one or more taste-masking agents, one or more flavoring
agents, and/or one or more sweetening agents, or a combination of
such agents. Non-limiting examples of such substances include
sucralose (about 0.001 to about 1%), sucrose (about 0.5 to about
10%), saccharin (including the salt forms: sodium, calcium, etc.)
(about 0.01 to about 2%), fructose (about 0.5 to about 10%),
dextrose (about 0.5 to about 10%), corn syrup (about 0.5 to about
10%), aspartame (about 0.01 to about 2%), acesulfame-K (about 0.01
to about 2%), xylitol (about 0.1 to about 10%), sorbitol (about 0.1
to about 10%), erythritol (about 0.1 to about 10%), ammonium
glycyrrhizinate (about 0.01 to about 4%), thaumatin (Talin.TM.)
(about 0.01 to about 2%), neotame (about 0.01 to about 2%) mannitol
(about 0.5 to about 5%), menthol (about 0.01 to about 0.5%),
eucalyptus oil (about 0.01 to about 0.5%), camphor (about 0.01 to
about 0.5%), natural and/or artificial flavors such as Artificial
Custard Cream Flavor #36184 from International Flavors and
Fragrances, Inc. (New York, N.Y.) (about 0.01 to about 1.0%), and
the like. Sucralose, an intense sweetener marketed for food and
beverage use as SPLENDA.RTM. by McNeil Nutritionals LLP (Fort
Washington, Pa.), is especially effective as a sweetening and
taste-masking agent in the compositions of the present invention,
particularly when used at concentrations of from about 0.001% to
about 1%, preferably at concentrations of from about 0.01% to about
0.5%, and more preferably at concentrations of from about 0.02% to
about 0.2%, and most preferably from about 0.05% to about 0.15%
(e.g., about 0.05%, about 0.06%, about 0.07%, about 0.08%, about
0.09%, about 0.10%, about 0.11%, about 0.12%, about 0.13%, about
0.14%, or about 0.15%), of the total composition. Sucralose has
been shown to be useful as a taste modifying agent in oral delivery
of certain pharmaceutical compositions, for example in sore throat
spray products (see U.S. Pat. No. 6,319,513), oral suspensions (see
U.S. Pat. Nos. 5,658,919 and 5,621,005), solid dosage forms (see
U.S. Pat. No. 6,149,941), quick melt dosage forms (see U.S. Pat.
No. 6,165,512) and mucosal delivery (see U.S. Pat. No. 6,552,024),
but has not heretofore been shown to be useful in intranasally or
ocularly applied compositions such as those of the present
invention. Additional such compositions of the invention may
comprise one or more additional taste-masking or flavoring agents
such as those described herein, for example menthol at a
concentration of from about 0.01% to about 1%, preferably at a
concentration of from about 0.05% to about 0.1%. Suitable
compositions of the invention include, for example, about
0.1%-0.15% azelastine and about 0.05%-0.15% sucralose, for example,
about 0.1% azelastine and about 0.05%-0.15% sucralose, or about
0.125%-0.15% azelastine and about 0.05%-0.15% sucralose, or about
0.10% azelastine and about 0.15% sucralose, or about 0.15%
azelastine and about 0.15% sucralose.
[0092] As noted above, intranasal or ocular application of
azelastine-containing compositions, particularly those containing
azelastine hydrochloride, is often complicated by the postnasal
drip of the composition into the pharynx following intranasal or
ocular administration. Such postnasal drip can induce a very bitter
and unpleasant taste experience by the patient. Thus, to avoid,
reduce or minimize such issues arising from postnasal drip, certain
compositions of the present invention may alternatively or further
comprise one or more water-soluble viscosity-increasing agents.
Such agents are preferably used at the concentration of about 0.01%
to about 5.0% (w/v), in order to typically produce a viscosity of
the final solution between about 2 and about 300 centipoise. Use of
such viscosity-increasing agents extends the mucocilliary clearance
time, increases retention in the nasal cavity, and reduces post
nasal drip, of intranasally applied compositions (see U.S. Pat. No.
5,897,858, the disclosure of which is incorporated herein by
reference in its entirety) such as those of the present invention.
Viscosity-increasing agents that are suitable for use in accordance
with the present invention include, but are not limited to,
polyvinylpyrrolidones, cellulose derivatives including, but not
limited to, hydroxyethyl cellulose, carboxymethyl cellulose or its
salts, hypromellose, carrageenan, guar gum, alginates, carbomers,
polyethylene glycols, polyvinyl alcohol, and xanthan gum.
Particularly preferred is hypromellose, at a concentration of about
0.001% to about 5.00%, preferably at a concentration of about 0.01%
to about 1%, more preferably at a concentration of about 0.1% to
about 0.5%, and most preferably at a concentration of about 0.1% to
about 0.3%.
[0093] The compositions of the present invention that are provided
in solution form may be preserved, aseptically manufactured and/or
sterilized, for example, by filtration through a
bacterial-retaining filter.
Compositions Comprising Additional Active Agents
[0094] In addition to azelastine (e.g., azelastine HCl) and the
various excipients, taste masking agents, viscosity-increasing
agents and the like disclosed herein, the pharmaceutical
compositions of the invention can further comprise (or consist
essentially of) one or more additional active agents, such as those
disclosed throughout U.S. Patent Publication No. 2005/0148562, the
disclosure of which is herein incorporated by reference in its
entirety. Exemplary additional active agents include, but are not
limited to, additional antihistamines (including H.sub.1, H.sub.3
and H.sub.4 receptor antagonists), steroids (e.g., safe steroids),
leukotriene antagonists, prostaglandin D2 receptor antagonists,
decongestants, expectorants, anti-fungal agents, triamcinolone and
triamcinolone derivatives, non-steroidal immunophilin-dependent
immunosuppressants (NsIDIs), anti-inflammatory agents,
non-steroidal anti-inflammatory agents (NSAIDs), COX-2 inhibitors,
anti-infective agents, mucolytic agents, anticholinergic agents,
mast cell stabilizers, non-antibiotic anti-microbial agents,
anti-viral agents, antiseptics, neurokinin antagonists, platelet
activating factor (PAF) and 5-lipoxygenase (5-LO) inhibitors.
[0095] Examples of antihistamines in addition to azelastine (e.g.,
H.sub.1 receptor antagonists) suitable for inclusion in the present
compositions include, but are not limited to, acrivastine,
cyclizine, carebastine, cyproheptadine, carbinoxamine, doxylamine,
dimethindene, ebastine, epinastine, efletirizine, ketotifen,
levocabastine, mizolastine, mequitazine, mianserin, noberastine,
meclizine, norastemizole, olopatadine, picumast, tripelenamine,
temelastine, trimeprazine, triprolidine, bromopheniramine,
chlorpheniramine, dexchlorpheniramine, triprolidine, clemastine,
diphenhydramine, diphenylpyraline, tripelennamine, hydroxyzine,
methdilazine, promethazine, trimeprazine, azatadine,
cyproheptadine, antazoline, pheniramine, pyrilamine, astemizole,
terfenadine, loratadine, cetirizine, levocetirizine, fexofenadine,
descarboethoxyloratadine, desloratadine, dimenhydrinate and
hydroxyzine.
[0096] Examples of H.sub.3 receptor antagonists suitable for
inclusion in the present compositions include, but are not limited
to, thioperamide, impromidine, burimamide, clobenpropit,
impentamine, mifetidine, clozapine, S-sopromidine, R-sopromidine
and ciproxifam.
[0097] Examples of leukotriene antagonists (e.g., leukotriene D4
antagonists) suitable for inclusion in the present compositions
include, but are not limited to, albuterol sulfate, aminophylline,
amoxicillin, ampicillin, astemizole, attenuated tubercle bacillus,
azithromycin, bacampicillin, beclomethasone dipropionate,
budesonide, bupropion hydrochloride, cefaclor, cefadroxil,
cefixime, cefprozil, cefuroxime axetil, cephalexin, ciprofloxacin
hydrochloride, clarithromycin, clindamycin, cloxacillin,
doxycycline, erythromycin, ethambutol, fenoterol hydrobromide,
fluconazole, flunisolide, fluticasone propionate, formoterol
fiumarate, gatifloxacin, influenza virus vaccine, ipratropium
bromide, isoniazid, isoproterenol hydrochloride, itraconazole,
ketoconazole, ketotifen, levofloxacin, minocycline, montelukast
(e.g., montelukast sodium), moxifloxacin, nedocromil sodium,
nicotine, nystatin, ofloxacin, orciprenaline, oseltamivir,
oseltamivir sulfate, oxtriphylline, penicillin, pirbuterol acetate,
pivampicillin, pneumococcal conjugate vaccine, pneumococcal
polysaccharide vaccine, prednisone, pyrazinamide, rifampin,
salbutamol, salmeterol xinafoate, sodium cromoglycate (cromolyn
sodium), terbutaline sulfate, terfenadine, theophylline,
triamcinolone acetonide, zafirlukast and zanamivir.
[0098] Examples of decongestants suitable for inclusion in the
present compositions include, but are not limited to,
pseudoephedrine, phenylephedrine, phenylephrine,
phenylpropanolamine, oxymetazoline, propylhexedrine,
xylometazoline, epinephrine, ephedrine, desoxyephedrine,
naphazoline, and tetrahydrozoline.
[0099] Examples of expectorants suitable for inclusion in the
present compositions include, but are not limited to, guaifenesin,
codeine phosphate, and isoproternol hydrochloride.
[0100] Examples of anti-fungal agents suitable for inclusion in the
present compositions include, but are not limited to, amphotericin
B, nystatin, fluconazole, ketoconazole, terbinafine, itraconazole,
imidazole, triazole, ciclopirox, clotrimazole, and miconazole.
[0101] Examples of NSAIDs suitable for inclusion in the present
compositions include, but are not limited to, ibuprofen,
aceclofenac, diclofenac, naproxen, etodolac, flurbiprofen,
fenoprofen, ketoprofen, suprofen, fenbufen, fluprofen, tolmetin
sodium, oxaprozin, zomepirac, sulindac, indomethacin, piroxicam,
mefenamic acid, nabumetone, meclofenamate sodium, diflunisal,
flufenisal, piroxicam, ketorolac, sudoxicam and isoxicam.
[0102] By "non-steroidal immunophilin-dependent immunosuppressant"
or "NsIDI" is meant any non-steroidal agent that decreases
proinflammatory cytokine production or secretion, binds an
immunophilin, or causes a down regulation of the proinflammatory
reaction. NsIDIs suitable for inclusion in the present compositions
include, but are not limited to, calcineurin inhibitors, such as
cyclosporine, tacrolimus, ascomycin, pimecrolimus, as well as other
agents (peptides, peptide fragments, chemically modified peptides,
or peptide mimetics) that inhibit the phosphatase activity of
calcineurin. NsIDIs also include rapamycin (sirolimus) and
everolimus, which bind to an FK506-binding protein, FKBP-12, and
block antigen-induced proliferation of white blood cells and
cytokine secretion.
[0103] Examples of COX-2 inhibitors suitable for inclusion in the
present compositions include, but are not limited to, rofecoxib,
celecoxib, valdecoxib, lumiracoxib, meloxicam, and nimesulide.
[0104] Examples of steroids suitable for inclusion in the present
compositions include but are not limited to, fluoromethalone,
fluticasone (e.g., fluticasone propionate), mometasone,
triamcinolone, betamethasone, flunisolide, budesonide,
beclomethasone, budesonide, rimexolone, beloxil, prednisone,
loteprednol (e.g., loteprednol etabonate) (e.g., loteprednol (e.g.,
loteprednol etabonate) etabonate), dexamethasone and its analogues
(e.g., dexamethasone beloxil) described in U.S. Pat. Nos. 5,223,493
and 5,420,120, incorporated herein by reference in their
entireties, and other esters, salts, conjugates and analogs of such
steroids that will be familiar to one of ordinary skill in the
art.
[0105] Examples of anti-infective agents suitable for inclusion in
the present compositions include, but are not limited to,
penicillins and other beta lactam antibiotics, cephalosporins,
macrolides, ketolides, sulfonamides, quinolones, aminoglycosides,
and linezolid.
[0106] Examples of non-antibiotic antimicrobials suitable for
inclusion in the present compositions include, but are not limited
to, taurolidine.
[0107] Examples of mast cell stabilizers suitable for inclusion in
the present compositions include, but are not limited to, cromolyn
and nedcromil sodium.
[0108] Examples of mucolytic agents suitable for inclusion in the
present compositions include, but are not limited to,
acetylcysteine and domase alpha.
[0109] Examples of antibiotic agents suitable for inclusion in the
present compositions include, but are not limited to, cefuroxime,
vancomycin, amoxicillin and gentamicin.
[0110] Examples of antiseptics suitable for inclusion in the
present compositions include, but are not limited to, iodine,
chlorhexidine acetate, sodium hypochlorite, and calcium
hydroxide.
[0111] Examples of anticholinergics suitable for inclusion in the
present compositions include, but are not limited to, ipratropium,
atropine, and scopolamine.
[0112] Examples of neurokinin antagonists suitable for inclusion in
the present compositions include, but are not limited to, oximes,
hydrazones, piperidines, piperazines, aryl alkyl amines,
hydrazones, nitroalkanes, amides, isoxazolines, quinolines,
isoquinolines, azanorbornanes, naphthyridines, and benzodiazepines,
such as those disclosed in U.S. Pat. Nos. 5,798,359; 5,795,894;
5,789,422; 5,783,579; 5,719,156; 5,696,267; 5,691,362; 5,688,960;
5,654,316, incorporated by reference herein in their
entireties.
[0113] Examples of 5-lipoxygenase (5-LO) inhibitors suitable for
inclusion in the present compositions include, but are not limited
to, zileuton, docebenone, piripost and tenidap.
[0114] The concentrations, absolute amounts and relative amounts
(i.e., relative to the concentration or absolute amount of
azelastine or a salt thereof, e.g. azelastine HCl) of the
additional one or more active agents will be familiar to one of
ordinary skill in the art. For example, the amounts of additional
active agents (e.g., one or more steroid(s), leukotriene
antagonist(s), anithistaminte(s), decongestant(s), NSAIDs, etc),
can be present in any amount, for example about 0.01% to about 99%
(e.g., about 0.01%, about 0.1%, about 1%, about 10%, about 20%,
about 30%, about 40%, about 50%, about 60%, about 70%, about 80%,
or about 90%).
[0115] In one embodiment, the pharmaceutical compositions comprise
(or consisting essentially of) an effective amount of azelastine
(suitably azelastine hydrochloride) along with an effective amount
of one or more steroids. Exemplary steroids include those discussed
throughout. In certain suitable embodiments, the compositions
further comprise one or more additional ingredients, such as one or
more excipients, one or more taste-masking agents and/or one or
more viscosity-increasing agents. Such compositions can be
formulated as intranasal or ocular suspensions or solutions, with a
pH of about 6.0 to 8.0. In other embodiments, the compositions can
be formulated as oral (e.g., tablets or capsules) or topical
delivery formulations, such as those disclosed throughout. While
the amount of azelastine can be varied and adjusted appropriately
by the ordinarily skilled artisan, it is suitably contained in the
intranasal or ocular formulations in an amount of about 0.0001% to
about 1.0% by weight, and more suitably from about 0.005% to about
0.5% or most suitably from about 0.05% to about 0.15% (e.g., 0.05%,
0.06%, 0.07%, 0.08%, 0.09%. 0.10%, 0.11%, 0.12%, 0.13%, 0.14%,
0.15%), of pure azelastine (calculated as the free azelastine
base). The amount of steroid(s) present in the various formulations
can be varied and adjusted appropriately by the ordinarily skilled
artisan, and can be present in any amount, for example about 0.01%
to about 99% (e.g., about 0.01%, about 0.1%, about 1%, about 10%,
about 20%, about 30%, about 40%, about 50%, about 60%, about 70%,
about 80%, or about 90%). Suitably the amount of steroid is about
0.01% to about 1.5% by weight, more suitably about 0.01% to about
1.0% by weight, or even more suitably about 0.05% to about 0.1% by
weight (e.g., about 0.01%, about 0.02%, about 0.03%, about 0.04%,
about 0.05%, about 0.06%, about 0.07%, about 0.08%, about 0.09%, or
about 0.1% by weight). Preferred steroids for use in the
formulations of the present invention are "safe steroids." As used
herein, the term "safe steroid" means a steroid which treats
eosinophil and neurotrophil associated inflammation, reduces
papillae formation, and which is effective in treating
inflammation, without causing a clinically significant elevation in
intraocular pressure (IOP). Exemplary safe steroids that can be
used in the various formulations of the present invention,
particularly for delivery using nasal spray or ocular drop delivery
systems include, but are not limited to, any glucocorticoid which
meets the safe steroid definition, including but not limited to,
fluoromethalone, fluticasone (and its conjugates, e.g., fluticasone
propionate), rimexolone, loteprednol (e.g., loteprednol etabonate),
dexamethasone beloxil and its analogues described in U.S. Pat. Nos.
5,223,493 and 5,420,120, the disclosures of which are incorporated
by reference herein in their entireties. Additional "safe steroids"
and methods for determining appropriate amounts of such agents for
inclusion in the present compositions are disclosed in U.S. Pat.
No. 6,649,602, the disclosure of which is incorporated by reference
herein in its entirety. Exemplary compositions of the present
invention comprising azelastine and a safe steroid comprise about
0.1%-0.15% azelastine, about 0.01%-0.1% of a safe steroid, and
optionally about 0.05%-0.15% sucralose.
[0116] In one embodiment, the present invention provides
pharmaceutical compositions comprising (or consisting essentially
of) an effective amount of azelastine (suitably azelastine
hydrochloride) along with an effective amount of fluticasone,
suitably fluticaseone propionate or fluticasone dipropionate. In
certain suitable embodiments, such compositions further comprise
one or more additional ingredients, such as one or more excipients,
one or more taste-masking agents and/or one or more
viscosity-increasing agents. Such compositions can be formulated as
intranasal or ocular suspensions or solutions, with a pH of about
6.0 to 8.0. In other embodiments, the compositions can be
formulated as oral (e.g., tablets or capsules) or topical delivery
formulations, such as those disclosed throughout. While the amount
of azelastine can be varied and adjusted appropriately by the
ordinarily skilled artisan, it is suitably contained in the
intranasal or ocular formulations in an amount of about 0.0001% to
about 1.0% by weight, and more suitably from about 0.005% to about
0.5% or most suitably from about 0.05% to about 0.15% (e.g., 0.05%,
0.06%, 0.07%, 0.08%, 0.09%. 0.10%, 0.11%, 0.12%, 0.13%, 0.14%,
0.15%), of pure azelastine (calculated as the free azelastine
base). The amount of fluticasone, suitably fluticaseone propionate
or fluticasone dipropionate present in the various formulations can
be varied and adjusted appropriately by the ordinarily skilled
artisan, and can be present in any amount, for example about 0.01%
to about 99% (e.g., about 0.01%, about 0.1%, about 1%, about 10%,
about 20%, about 30%, about 40%, about 50%, about 60%, about 70%,
about 80%, or about 90%). Suitably the amount of fluticasone,
suitably fluticaseone propionate or fluticasone dipropionate is
about 0.01% to about 1.5% by weight, more suitably about 0.01% to
about 1.0% by weight, or even more suitably about 0.05% to about
0.1% by weight (e.g., about 0.01%, about 0.02%, about 0.03%, about
0.04%, about 0.05%, about 0.06%, about 0.07%, about 0.08%, about
0.09%, or about 0.1% by weight).
[0117] In another embodiment, the present invention provides
pharmaceutical compositions comprising (or consisting essentially
of) an effective amount of azelastine (suitably azelastine
hydrochloride) along with an effective amount of loteprednol (e.g.,
loteprednol etabonate), suitably loteprednol (e.g., loteprednol
etabonate) etabonate (see e.g., U.S. Pat. No. 7,022,687, the
disclosure of which is incorporated herein by reference in its
entirety) In certain suitable embodiments, such compositions
further comprise one or more additional ingredients, such as one or
more excipients, one or more taste-masking agents and/or one or
more viscosity-increasing agents. Such compositions can be
formulated as intranasal or ocular suspensions or solutions, with a
pH of about 6.0 to 8.0. In other embodiments, the compositions can
be formulated as oral (e.g., tablets or capsules) or topical
delivery formulations, such as those disclosed throughout. While
the amount of azelastine can be varied and adjusted appropriately
by the ordinarily skilled artisan, it is suitably contained in the
intranasal or ocular formulations in an amount of about 0.0001% to
about 1.0% by weight, and more suitably from about 0.005% to about
0.5% or most suitably from about 0.05% to about 0.15% (e.g., 0.05%,
0.06%, 0.07%, 0.08%, 0.09%. 0.10%, 0.11%, 0.12%, 0.13%, 0.14%,
0.15%), of pure azelastine (calculated as the free azelastine
base). The amount of loteprednol (e.g., loteprednol etabonate),
suitably loteprednol (e.g., loteprednol etabonate) etabonate,
present in the various formulations can be varied and adjusted
appropriately by the ordinarily skilled artisan, and can be present
in any amount, for example about 0.01% to about 99% (e.g., about
0.01%, about 0.1%, about 1%, about 10%, about 20%, about 30%, about
40%, about 50%, about 60%, about 70%, about 80%, or about 90%).
Suitably the amount of loteprednol (e.g., loteprednol etabonate),
suitably loteprednol (e.g., loteprednol etabonate) etabonate, is
about 0.01% to about 1.5% by weight, more suitably about 0.01% to
about 1.0% by weight, or even more suitably about 0.05% to about
0.1% by weight (e.g., about 0.01%, about 0.02%, about 0.03%, about
0.04%, about 0.05%, about 0.06%, about 0.07%, about 0.08%, about
0.09%, or about 0.1% by weight).
[0118] In another embodiment, the pharmaceutical compositions
comprise (or consist essentially of) an effective amount of
azelastine (suitably azelastine hydrochloride) along with an
effective amount of one or more steroids, and also an effective
amount of one or more decongestants. In suitable such embodiments,
the compositions further comprise one or more additional
ingredients, such as one or more excipients, one or more
taste-masking agents and/or one or more viscosity-increasing
agents. Such compositions can be formulated as intranasal or ocular
suspensions or solutions, with a pH of about 6.0 to 8.0. In other
embodiments, the compositions can be formulated as oral or topical
delivery formulations, such as those disclosed throughout. The
appropriate amounts of azelastine, steroid and decongestant can be
readily determined by those or ordinary skill in the art. Suitably,
the amount of steroid and azelastine used will be in the ranges
disclosed herein. The amount of decongestant can be present in any
amount, for example about 0.01% to about 99% (e.g., about 0.01%,
about 0.1%, about 1%, about 10%, about 20%, about 30%, about 40%,
about 50%, about 60%, about 70%, about 80%, or about 90%). Suitably
the amount of decongestiant is about 0.05% to about 1.5% by weight,
or more suitably in an amount of about 0.1% to about 1.0% by
weight. In addition, the compositions can also comprise sucralose
at about 0.05%-0.15%.
[0119] In an additional embodiment, the pharmaceutical compositions
comprise (or consist essentially of) an effective amount of
azelastine (suitably azelastine hydrochloride) along with an
effective amount of one or more additional anti-allergic and/or one
or more anti-asthmatic agents. Exemplary anti-allergics and
anti-asthmatics include those discussed herein, including, but not
limited to, H.sub.1 receptor antagonists, H.sub.3 receptor
antagonists and leukotriene antagonists (e.g., leukotriene D4
antagonists). In suitable such embodiments, the compositions
further comprise one or more additional ingredients, such as one or
more excipients, one or more taste-masking agents and/or one or
more viscosity-increasing agents. Such compositions can be
formulated as intranasal or ocular suspensions or solutions, with a
pH of about 6.0 to 8.0. In other embodiments, the compositions can
be formulated for oral or pulmonary delivery, such as those
described herein. While the amount of azelastine can be varied and
adjusted appropriately by the ordinarily skilled artisan, it is
suitably contained in the intranasal or ocular formulations in an
amount of about 0.0001% to about 1.0% by weight, and more suitably
from about 0.005% to about 0.5% or most suitably from about 0.05%
to about 0.15% (e.g., about 0.05%, 0.06%, 0.07%, 0.08%, 0.09%,
0.10%, 0.11%, 0.12%, 0.13%, 0.14%, 0.15%), of pure azelastine
(calculated as the free azelastine base). The amount of one or more
additional anti-allergic and/or anti-asthmatics present in the
various formulations can be varied and adjusted appropriately by
the ordinarily skilled artisan and can be present in any amount,
for example about 0.01% to about 99% (e.g., about 0.01%, about
0.1%, about 1%, about 10%, about 20%, about 30%, about 40%, about
50%, about 60%, about 70%, about 80%, or about 90%). Suitably the
amount of these additional compounds will be in an amount of about
0.01% to about 10% by weight, or more suitably in an amount of
about 0.1% to about 5.0% by weight. In addition, the compositions
can also comprise sucralose at about 0.05%-0.15%.
[0120] Suitable compositions of the present invention comprise (or
consist essentially of), for example (percentages of azelastine
refer to weight percentages of azelastine HCl or other suitable
salt):
[0121] About 0.05% azelastine and about 0.05% sucralose;
[0122] About 0.05% azelastine and about 0.1% sucralose;
[0123] About 0.05% azelastine and about 0.15% sucralose;
[0124] About 0.1% azelastine and about 0.05% sucralose;
[0125] About 0.1% azelastine and about 0.1% sucralose;
[0126] About 0.1% azelastine and about 0.15% sucralose;
[0127] About 0.125% azelastine and about 0.05% sucralose;
[0128] About 0.125% azelastine and about 0.1% sucralose;
[0129] About 0.125% azelastine and about 0.15% sucralose;
[0130] About 0.15% azelastine and about 0.05% sucralose;
[0131] About 0.15% azelastine and about 0.1% sucralose;
[0132] About 0.15% azelastine and about 0.15% sucralose;
[0133] About 0.05% azelastine and about 0.01% steroid;
[0134] About 0.1% azelastine and about 0.01% steroid;
[0135] About 0.125% azelastine and about 0.01% steroid;
[0136] About 0.15% azelastine and about 0.01% steroid;
[0137] About 0.05% azelastine and about 0.05% steroid;
[0138] About 0.1% azelastine and about 0.05% steroid;
[0139] About 0.125% azelastine and about 0.05% steroid;
[0140] About 0.15% azelastine and about 0.05% steroid;
[0141] About 0.05% azelastine and about 0.1% steroid;
[0142] About 0.1% azelastine and about 0.1% steroid;
[0143] About 0.125% azelastine and about 0.1% steroid;
[0144] About 0.15% azelastine and about 0.1% steroid;
[0145] About 0.05% azelastine, about 0.01% steroid and about 0.05%
sucralose;
[0146] About 0.1% azelastine, about 0.01% steroid and about 0.05%
sucralose;
[0147] About 0.125% azelastine, about 0.01% steroid and about 0.05%
sucralose;
[0148] About 0.15% azelastine, about 0.01% steroid and about 0.05%
sucralose;
[0149] About 0.05% azelastine, about 0.05% steroid and about 0.05%
sucralose;
[0150] About 0.1% azelastine, about 0.05% steroid and about 0.05%
sucralose;
[0151] About 0.125% azelastine, about 0.05% steroid and about 0.05%
sucralose;
[0152] About 0.15% azelastine, about 0.05% steroid and about 0.05%
sucralose;
[0153] About 0.05% azelastine, about 0.1% steroid and about 0.05%
sucralose;
[0154] About 0.1% azelastine, about 0.1% steroid and about 0.05%
sucralose;
[0155] About 0.125% azelastine, about 0.1% steroid and about 0.05%
sucralose;
[0156] About 0.15% azelastine, about 0.1% steroid and about 0.05%
sucralose;
[0157] About 0.05% azelastine, about 0.01% steroid and about 0.1%
sucralose;
[0158] About 0.1% azelastine, about 0.01% steroid and about 0.1%
sucralose;
[0159] About 0.125% azelastine, about 0.01% steroid and about 0.1%
sucralose;
[0160] About 0.15% azelastine, about 0.01% steroid and about 0.1%
sucralose;
[0161] About 0.05% azelastine, about 0.05% steroid and about 0.1%
sucralose;
[0162] About 0.1% azelastine, about 0.05% steroid and about 0.1%
sucralose;
[0163] About 0.125% azelastine, about 0.05% steroid and about 0.1%
sucralose;
[0164] About 0.15% azelastine, about 0.05% steroid and about 0.1%
sucralose;
[0165] About 0.05% azelastine, about 0.1% steroid and about 0.1%
sucralose;
[0166] About 0.1% azelastine, about 0.1% steroid and about 0.1%
sucralose;
[0167] About 0.125% azelastine, about 0.1% steroid and about 0.1%
sucralose;
[0168] About 0.15% azelastine, about 0.1% steroid and about 0.1%
sucralose;
[0169] About 0.05% azelastine, about 0.01% steroid and about 0.15%
sucralose;
[0170] About 0.1% azelastine, about 0.01% steroid and about 0.15%
sucralose;
[0171] About 0.125% azelastine, about 0.01% steroid and about 0.15%
sucralose;
[0172] About 0.15% azelastine, about 0.01% steroid and about 0.15%
sucralose;
[0173] About 0.05% azelastine, about 0.05% steroid and about 0.15%
sucralose;
[0174] About 0.1% azelastine, about 0.05% steroid and about 0.15%
sucralose;
[0175] About 0.125% azelastine, about 0.05% steroid and about 0.15%
sucralose;
[0176] About 0.15% azelastine, about 0.05% steroid and about 0.15%
sucralose;
[0177] About 0.05% azelastine, about 0.1% steroid and about 0.15%
sucralose;
[0178] About 0.1% azelastine, about 0.1% steroid and about 0.15%
sucralose;
[0179] About 0.125% azelastine, about 0.1% steroid and about 0.15%
sucralose;
[0180] About 0.15% azelastine, about 0.1% steroid and about 0.15%
sucralose;
[0181] About 0.05% azelastine and about 0.01% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone;
[0182] About 0.1% azelastine and about 0.01% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone;
[0183] About 0.125% azelastine and about 0.01% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone;
[0184] About 0.15% azelastine and about 0.01% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone;
[0185] About 0.05% azelastine and about 0.05% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone;
[0186] About 0.1% azelastine and about 0.05% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone;
[0187] About 0.125% azelastine and about 0.05% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone;
[0188] About 0.15% azelastine and about 0.05% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone;
[0189] About 0.05% azelastine and about 0.1% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone;
[0190] About 0.1% azelastine and about 0.1% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone;
[0191] About 0.125% azelastine and about 0.1% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone;
[0192] About 0.15% azelastine and about 0.1% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone;
[0193] About 0.05% azelastine, about 0.01% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone and about 0.05% sucralose;
[0194] About 0.1% azelastine, about 0.01% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone and about 0.05% sucralose;
[0195] About 0.125% azelastine, about 0.01% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone and about 0.05% sucralose;
[0196] About 0.15% azelastine, about 0.01% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone and about 0.05% sucralose;
[0197] About 0.05% azelastine, about 0.01% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone and about 0.1% sucralose;
[0198] About 0.1% azelastine, about 0.01% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone and about 0.1% sucralose;
[0199] About 0.125% azelastine, about 0.01% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone and about 0.1% sucralose;
[0200] About 0.15% azelastine, about 0.01% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone and about 0.1% sucralose;
[0201] About 0.05% azelastine, about 0.01% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone and about 0.15% sucralose;
[0202] About 0.1% azelastine, about 0.01% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone and about 0.15% sucralose;
[0203] About 0.125% azelastine, about 0.01% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone and about 0.15% sucralose;
[0204] About 0.15% azelastine, about 0.01% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone and about 0.15% sucralose;
[0205] About 0.05% azelastine, about 0.05% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone and about 0.05% sucralose;
[0206] About 0.1% azelastine, about 0.05% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone and about 0.05% sucralose;
[0207] About 0.125% azelastine, about 0.05% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone and about 0.05% sucralose;
[0208] About 0.15% azelastine, about 0.05% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone and about 0.05% sucralose;
[0209] About 0.05% azelastine, about 0.05% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone and about 0.1% sucralose;
[0210] About 0.1% azelastine, about 0.05% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone and about 0.1% sucralose;
[0211] About 0.125% azelastine, about 0.05% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone and about 0.1% sucralose;
[0212] About 0.15% azelastine, about 0.05% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone and about 0.1% sucralose;
[0213] About 0.05% azelastine, about 0.05% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone and about 0.15% sucralose;
[0214] About 0.1% azelastine, about 0.05% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone and about 0.15% sucralose;
[0215] About 0.125% azelastine, about 0.05% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone and about 0.15% sucralose;
[0216] About 0.15% azelastine, about 0.05% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone and about 0.15% sucralose;
[0217] About 0.05% azelastine, about 0.1% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone and about 0.05% sucralose;
[0218] About 0.1% azelastine, about 0.1% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone and about 0.05% sucralose;
[0219] About 0.125% azelastine, about 0.1% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone and about 0.05% sucralose;
[0220] About 0.15% azelastine, about 0.1% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone and about 0.05% sucralose;
[0221] About 0.05% azelastine, about 0.1% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone and about 0.1% sucralose;
[0222] About 0.1% azelastine, about 0.1% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone and about 0.1% sucralose;
[0223] About 0.125% azelastine, about 0.1% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone and about 0.1% sucralose;
[0224] About 0.15% azelastine, about 0.1% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone and about 0.1% sucralose;
[0225] About 0.05% azelastine, about 0.1% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone and about 0.15% sucralose;
[0226] About 0.1% azelastine, about 0.1% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone and about 0.15% sucralose;
[0227] About 0.125% azelastine, about 0.1% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone and about 0.15% sucralose;
[0228] About 0.15% azelastine, about 0.1% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone and about 0.15% sucralose;
[0229] About 0.05% azelastine and about 0.1% leukotriene
antagonist;
[0230] About 0.1% azelastine and about 0.1% leukotriene
antagonist;
[0231] About 0.125% azelastine and about 0.1% leukotriene
antagonist;
[0232] About 0.15% azelastine and about 0.1% leukotriene
antagonist;
[0233] About 0.05% azelastine and about 0.5% leukotriene
antagonist;
[0234] About 0.1% azelastine and about 0.5% leukotriene
antagonist;
[0235] About 0.125% azelastine and about 0.5% leukotriene
antagonist;
[0236] About 0.15% azelastine and about 0.5% leukotriene
antagonist;
[0237] About 0.05% azelastine and about 5.0% leukotriene
antagonist;
[0238] About 0.1% azelastine and about 5.0% leukotriene
antagonist;
[0239] About 0.125% azelastine and about 5.0% leukotriene
antagonist;
[0240] About 0.15% azelastine and about 5.0% leukotriene
antagonist;
[0241] About 0.05% azelastine, about 0.1% leukotriene antagonist
and about 0.05% sucralose;
[0242] About 0.1% azelastine, about 0.1% leukotriene antagonist and
about 0.05% sucralose;
[0243] About 0.125% azelastine, about 0.1% leukotriene antagonist
and about 0.05% sucralose;
[0244] About 0.15% azelastine, about 0.1% leukotriene antagonist
and about 0.05% sucralose;
[0245] About 0.05% azelastine, about 0.1% leukotriene antagonist
and about 0.1% sucralose;
[0246] About 0.1% azelastine, about 0.1% leukotriene antagonist and
about 0.1% sucralose;
[0247] About 0.125% azelastine, about 0.1% leukotriene antagonist
and about 0.1% sucralose;
[0248] About 0.15% azelastine, about 0.1% leukotriene antagonist
and about 0.1% sucralose;
[0249] About 0.05% azelastine, about 0.1% leukotriene antagonist
and about 0.15% sucralose;
[0250] About 0.1% azelastine, about 0.1% leukotriene antagonist and
about c 0.15% sucralose;
[0251] About 0.125% azelastine, about 0.1% leukotriene antagonist
and about 0.15% sucralose;
[0252] About 0.15% azelastine, about 0.1% leukotriene antagonist
and about 0.15% sucralose;
[0253] About 0.05% azelastine, about 0.5% leukotriene antagonist
and about 0.05% sucralose;
[0254] About 0.1% azelastine, about 0.5% leukotriene antagonist and
about 0.05% sucralose;
[0255] About 0.125% azelastine, about 0.5% leukotriene antagonist
and about 0.05% sucralose;
[0256] About 0.15% azelastine, about 0.5% leukotriene antagonist
and about 0.05% sucralose;
[0257] About 0.05% azelastine, about 0.5% leukotriene antagonist
and about 0.1% sucralose;
[0258] About 0.1% azelastine, about 0.5% leukotriene antagonist and
about 0.1% sucralose;
[0259] About 0.125% azelastine, about 0.5% leukotriene antagonist
and about 0.1% sucralose;
[0260] About 0.15% azelastine, about 0.5% leukotriene antagonist
and about 0.1% sucralose;
[0261] About 0.05% azelastine, about 0.5% leukotriene antagonist
and about 0.15% sucralose;
[0262] About 0.1% azelastine, about 0.5% leukotriene antagonist and
about 0.15% sucralose;
[0263] About 0.125% azelastine, about 0.5% leukotriene antagonist
and about 0.15% sucralose;
[0264] About 0.15% azelastine, about 0.5% leukotriene antagonist
and about 0.15% sucralose;
[0265] About 0.05% azelastine, about 5.0% leukotriene antagonist
and about 0.05% sucralose;
[0266] About 0.1% azelastine, about 5.0% leukotriene antagonist and
about 0.05% sucralose;
[0267] About 0.125% azelastine, about 5.0% leukotriene antagonist
and about 0.05% sucralose;
[0268] About 0.15% azelastine, about 5.0% leukotriene antagonist
and about 0.05% sucralose;
[0269] About 0.05% azelastine, about 5.0% leukotriene antagonist
and about 0.1% sucralose;
[0270] About 0.1% azelastine, about 5.0% leukotriene antagonist and
about 0.1% sucralose;
[0271] About 0.125% azelastine, about 5.0% leukotriene antagonist
and about 0.1% sucralose;
[0272] About 0.15% azelastine, about 5.0% leukotriene antagonist
and about 0.1% sucralose;
[0273] About 0.05% azelastine, about 5.0% leukotriene antagonist
and about 0.15% sucralose;
[0274] About 0.1% azelastine, about 5.0% leukotriene antagonist and
about 0.15% sucralose;
[0275] About 0.125% azelastine, about 5.0% leukotriene antagonist
and about 0.15% sucralose;
[0276] About 0.15% azelastine, about 5.0% leukotriene antagonist
and about 0.15% sucralose;
[0277] About 0.05% azelastine and about 0.1% montelukast;
[0278] About 0.1% azelastine and about 0.1% montelukast;
[0279] About 0.125% azelastine and about 0.1% montelukast;
[0280] About 0.15% azelastine and about 0.1% montelukast;
[0281] About 0.05% azelastine and about 0.5% montelukast;
[0282] About 0.1% azelastine and about 0.5% montelukast;
[0283] About 0.125% azelastine and about 0.5% montelukast;
[0284] About 0.15% azelastine and about 0.5% montelukast;
[0285] About 0.05% azelastine and about 5.0% montelukast;
[0286] About 0.1% azelastine and about 5.0% montelukast;
[0287] About 0.125% azelastine and about 5.0% montelukast;
[0288] About 0.15% azelastine and about 5.0% montelukast;
[0289] About 0.05% azelastine, about 0.1% montelukast and about
0.05% sucralose;
[0290] About 0.1% azelastine, about 0.1% montelukast and about
0.05% sucralose;
[0291] About 0.125% azelastine, about 0.1% montelukast and about
0.05% sucralose;
[0292] About 0.15% azelastine, about 0.1% montelukast and about
0.05% sucralose;
[0293] About 0.05% azelastine, about 0.1% montelukast and about
0.1% sucralose;
[0294] About 0.1% azelastine, about 0.1% montelukast and about 0.1%
sucralose;
[0295] About 0.125% azelastine, about 0.1% montelukast and about
0.1% sucralose;
[0296] About 0.15% azelastine, about 0.1% montelukast and about
0.1% sucralose;
[0297] About 0.05% azelastine, about 0.1% montelukast and about
0.15% sucralose;
[0298] About 0.1% azelastine, about 0.1% montelukast and about
0.15% sucralose;
[0299] About 0.125% azelastine, about 0.1% montelukast and about
0.15% sucralose;
[0300] About 0.15% azelastine, about 0.1% montelukast and about
0.15% sucralose;
[0301] About 0.05% azelastine, about 0.5% montelukast and about
0.05% sucralose;
[0302] About 0.1% azelastine, about 0.5% montelukast and about
0.05% sucralose;
[0303] About 0.125% azelastine, about 0.5% montelukast and about
0.05% sucralose;
[0304] About 0.15% azelastine, about 0.5% montelukast and about
0.05% sucralose;
[0305] About 0.05% azelastine, about 0.5% montelukast and about
0.1% sucralose;
[0306] About 0.1% azelastine, about 0.5% montelukast and about 0.1%
sucralose;
[0307] About 0.125% azelastine, about 0.5% montelukast and about
0.1% sucralose;
[0308] About 0.15% azelastine, about 0.5% montelukast and about
0.1% sucralose;
[0309] About 0.05% azelastine, about 0.5% montelukast and about
0.15% sucralose;
[0310] About 0.1% azelastine, about 0.5% montelukast and about
0.15% sucralose;
[0311] About 0.125% azelastine, about 0.5% montelukast and about
0.15% sucralose;
[0312] About 0.15% azelastine, about 0.5% montelukast and about
0.15% sucralose;
[0313] About 0.05% azelastine, about 5.0% montelukast and about
0.05% sucralose;
[0314] About 0.1% azelastine, about 5.0% montelukast and about
0.05% sucralose;
[0315] About 0.125% azelastine, about 5.0% montelukast and about
0.05% sucralose;
[0316] About 0.15% azelastine, about 5.0% montelukast and about
0.05% sucralose;
[0317] About 0.05% azelastine, about 5.0% montelukast and about
0.1% sucralose;
[0318] About 0.1% azelastine, about 5.0% montelukast and about 0.1%
sucralose;
[0319] About 0.125% azelastine, about 5.0% montelukast and about
0.1% sucralose;
[0320] About 0.15% azelastine, about 5.0% montelukast and about
0.1% sucralose;
[0321] About 0.05% azelastine, about 5.0% montelukast and about
0.15% sucralose;
[0322] About 0.1% azelastine, about 5.0% montelukast and about
0.15% sucralose;
[0323] About 0.125% azelastine, about 5.0% montelukast and about
0.15% sucralose;
[0324] About 0.15% azelastine, about 5.0% montelukast and about
0.15% sucralose;
[0325] About 0.05% azelastine and about 0.1% decongestant;
[0326] About 0.1% azelastine and about 0.1% decongestant;
[0327] About 0.125% azelastine and about 0.1% decongestant;
[0328] About 0.15% azelastine and about 0.1% decongestant;
[0329] About 0.05% azelastine and about 0.5% decongestant;
[0330] About 0.1% azelastine and about 0.5% decongestant;
[0331] About 0.125% azelastine and about 0.5% decongestant;
[0332] About 0.15% azelastine and about 0.5% decongestant;
[0333] About 0.05% azelastine and about 1.0% decongestant;
[0334] About 0.1% azelastine and about 1.0% decongestant;
[0335] About 0.125% azelastine and about 1.0% decongestant;
[0336] About 0.15% azelastine and about 1.0% decongestant;
[0337] About 0.05% azelastine, about 0.1% decongestant and about
0.05% sucralose;
[0338] About 0.1% azelastine, about 0.1% decongestant and about
0.05% sucralose;
[0339] About 0.125% azelastine, about 0.1% decongestant and about
0.05% sucralose;
[0340] About 0.15% azelastine, about 0.1% decongestant and about
0.05% sucralose;
[0341] About 0.05% azelastine, about 0.1% decongestant and about
0.1% sucralose;
[0342] About 0.1% azelastine, about 0.1% decongestant and about
0.1% sucralose;
[0343] About 0.125% azelastine, about 0.1% decongestant and about
0.1% sucralose;
[0344] About 0.15% azelastine, about 0.1% decongestant and about
0.1% sucralose;
[0345] About 0.05% azelastine, about 0.1% decongestant and about
0.15% sucralose;
[0346] About 0.1% azelastine, about 0.1% decongestant and about
0.15% sucralose;
[0347] About 0.125% azelastine, about 0.1% decongestant and about
0.15% sucralose;
[0348] About 0.15% azelastine, about 0.1% decongestant and about
0.15% sucralose;
[0349] About 0.05% azelastine, about 0.5% decongestant and about
0.05% sucralose;
[0350] About 0.1% azelastine, about 0.5% decongestant and about
0.05% sucralose;
[0351] About 0.125% azelastine, about 0.5% decongestant and about
0.05% sucralose;
[0352] About 0.15% azelastine, about 0.5% decongestant and about
0.05% sucralose;
[0353] About 0.05% azelastine, about 0.5% decongestant and about
0.1% sucralose;
[0354] About 0.1% azelastine, about 0.5% decongestant and about
0.1% sucralose;
[0355] About 0.125% azelastine, about 0.5% decongestant and about
0.1% sucralose;
[0356] About 0.15% azelastine, about 0.5% decongestant and about
0.1% sucralose;
[0357] About 0.05% azelastine, about 0.5% decongestant and about
0.15% sucralose;
[0358] About 0.1% azelastine, about 0.5% decongestant and about
0.15% sucralose;
[0359] About 0.125% azelastine, about 0.5% decongestant and about
0.15% sucralose;
[0360] About 0.15% azelastine, about 0.5% decongestant and about
0.15% sucralose;
[0361] About 0.05% azelastine, about 1.0% decongestant and about
0.05% sucralose;
[0362] About 0.1% azelastine, about 1.0% decongestant and about
0.05% sucralose;
[0363] About 0.125% azelastine, about 1.0% decongestant and about
0.05% sucralose;
[0364] About 0.15% azelastine, about 1.0% decongestant and about
0.05% sucralose;
[0365] About 0.05% azelastine, about 1.0% decongestant and about
0.1% sucralose;
[0366] About 0.1% azelastine, about 1.0% decongestant and about
0.1% sucralose;
[0367] About 0.125% azelastine, about 1.0% decongestant and about
0.1% sucralose;
[0368] About 0.15% azelastine, about 1.0% decongestant and about
0.1% sucralose;
[0369] About 0.05% azelastine, about 1.0% decongestant and about
0.15% sucralose;
[0370] About 0.1% azelastine, about 1.0% decongestant and about
0.15% sucralose;
[0371] About 0.125% azelastine, about 1.0% decongestant and about
0.15% sucralose;
[0372] About 0.15% azelastine, about 1.0% decongestant and about
0.15% sucralose;
[0373] About 0.05% azelastine and about 0.1% pseudoephedrine or
phenylephrine;
[0374] About 0.1% azelastine and about 0.1% pseudoephedrine or
phenylephrine;
[0375] About 0.125% azelastine and about 0.1% pseudoephedrine or
phenylephrine;
[0376] About 0.15% azelastine and about 0.1% pseudoephedrine or
phenylephrine;
[0377] About 0.05% azelastine and about 0.5% pseudoephedrine or
phenylephrine;
[0378] About 0.1% azelastine and about 0.5% pseudoephedrine or
phenylephrine;
[0379] About 0.125% azelastine and about 0.5% pseudoephedrine or
phenylephrine;
[0380] About 0.15% azelastine and about 0.5% pseudoephedrine or
phenylephrine;
[0381] About 0.05% azelastine and about 1.0% pseudoephedrine or
phenylephrine;
[0382] About 0.1% azelastine and about 1.0% pseudoephedrine or
phenylephrine;
[0383] About 0.125% azelastine and about 1.0% pseudoephedrine or
phenylephrine;
[0384] About 0.15% azelastine and about 1.0% pseudoephedrine or
phenylephrine;
[0385] About 0.05% azelastine, about 0.1% pseudoephedrine or
phenylephrine and about 0.05% sucralose;
[0386] About 0.1% azelastine, about 0.1% pseudoephedrine or
phenylephrine and about 0.05% sucralose;
[0387] About 0.125% azelastine, about 0.1% pseudoephedrine or
phenylephrine and about 0.05% sucralose;
[0388] About 0.15% azelastine, about 0.1% pseudoephedrine or
phenylephrine and about 0.05% sucralose;
[0389] About 0.05% azelastine, about 0.1% pseudoephedrine or
phenylephrine and about 0.1% sucralose;
[0390] About 0.1% azelastine, about 0.1% pseudoephedrine or
phenylephrine and about 0.1% sucralose;
[0391] About 0.125% azelastine, about 0.1% pseudoephedrine or
phenylephrine and about 0.1% sucralose;
[0392] About 0.15% azelastine, about 0.1% pseudoephedrine or
phenylephrine and about 0.1% sucralose;
[0393] About 0.05% azelastine, about 0.1% pseudoephedrine or
phenylephrine and about 0.15% sucralose;
[0394] About 0.1% azelastine, about 0.1% pseudoephedrine or
phenylephrine and about 0.15% sucralose;
[0395] About 0.125% azelastine, about 0.1% pseudoephedrine or
phenylephrine and about 0.15% sucralose;
[0396] About 0.15% azelastine, about 0.1% pseudoephedrine or
phenylephrine and about 0.15% sucralose;
[0397] About 0.05% azelastine, about 0.5% pseudoephedrine or
phenylephrine and about 0.05% sucralose;
[0398] About 0.1% azelastine, about 0.5% pseudoephedrine or
phenylephrine and about 0.05% sucralose;
[0399] About 0.125% azelastine, about 0.5% pseudoephedrine or
phenylephrine and about 0.05% sucralose;
[0400] About 0.15% azelastine, about 0.5% pseudoephedrine or
phenylephrine and about 0.05% sucralose;
[0401] About 0.05% azelastine, about 0.5% pseudoephedrine or
phenylephrine or phenylephrine and about 0.1% sucralose;
[0402] About 0.1% azelastine, about 0.5% pseudoephedrine or
phenylephrine or phenylephrine and about 0.1% sucralose;
[0403] About 0.125% azelastine, about 0.5% pseudoephedrine or
phenylephrine and about 0.1% sucralose;
[0404] About 0.15% azelastine, about 0.5% pseudoephedrine or
phenylephrine and about 0.1% sucralose;
[0405] About 0.05% azelastine, about 0.5% pseudoephedrine or
phenylephrine and about 0.15% sucralose;
[0406] About 0.1% azelastine, about 0.5% pseudoephedrine or
phenylephrine and about 0.15% sucralose;
[0407] About 0.125% azelastine, about 0.5% pseudoephedrine or
phenylephrine and about 0.15% sucralose;
[0408] About 0.15% azelastine, about 0.5% pseudoephedrine or
phenylephrine and about 0.15% sucralose;
[0409] About 0.05% azelastine, about 1.0% pseudoephedrine or
phenylephrine and about 0.05% sucralose;
[0410] About 0.1% azelastine, about 1.0% pseudoephedrine or
phenylephrine and about 0.05% sucralose;
[0411] About 0.125% azelastine, about 1.0% pseudoephedrine or
phenylephrine and about 0.05% sucralose;
[0412] About 0.15% azelastine, about 1.0% pseudoephedrine or
phenylephrine and about 0.05% sucralose;
[0413] About 0.05% azelastine, about 1.0% pseudoephedrine or
phenylephrine and about 0.1% sucralose;
[0414] About 0.1% azelastine, about 1.0% pseudoephedrine or
phenylephrine and about 0.1% sucralose;
[0415] About 0.125% azelastine, about 1.0% pseudoephedrine or
phenylephrine and about 0.1% sucralose;
[0416] About 0.15% azelastine, about 1.0% pseudoephedrine or
phenylephrine and about 0.1% sucralose;
[0417] About 0.05% azelastine, about 1.0% pseudoephedrine or
phenylephrine and about 0.15% sucralose;
[0418] About 0.1% azelastine, about 1.0% pseudoephedrine or
phenylephrine and about 0.15% sucralose;
[0419] About 0.125% azelastine, about 1.0% pseudoephedrine or
phenylephrine and about 0.15% sucralose;
[0420] About 0.15% azelastine, about 1.0% pseudoephedrine or
phenylephrine and about 0.15% sucralose;
[0421] About 0.05% azelastine and about 0.1% NSAID;
[0422] About 0.1% azelastine and about 0.1% NSAID;
[0423] About 0.125% azelastine and about 0.1% NSAID;
[0424] About 0.15% azelastine and about 0.1% NSAID;
[0425] About 0.05% azelastine and about 0.5% NSAID;
[0426] About 0.1% azelastine and about 0.5% NSAID;
[0427] About 0.125% azelastine and about 0.5% NSAID;
[0428] About 0.15% azelastine and about 0.5% NSAID;
[0429] About 0.05% azelastine and about 10.0% NSAID;
[0430] About 0.1% azelastine and about 10.0% NSAID;
[0431] About 0.125% azelastine and about 10.0% NSAID;
[0432] About 0.15% azelastine and about 10.0% NSAID;
[0433] About 0.05% azelastine, about 0.1% NSAID and about 0.05%
sucralose;
[0434] About 0.1% azelastine, about 0.1% NSAID and about 0.05%
sucralose;
[0435] About 0.125% azelastine, about 0.1% NSAID and about 0.05%
sucralose;
[0436] About 0.15% azelastine, about 0.1% NSAID and about 0.05%
sucralose;
[0437] About 0.05% azelastine, about 0.1% NSAID and about 0.1%
sucralose;
[0438] About 0.1% azelastine, about 0.1% NSAID and about 0.1%
sucralose;
[0439] About 0.125% azelastine, about 0.1% NSAID and about 0.1%
sucralose;
[0440] About 0.15% azelastine, about 0.1% NSAID and about 0.1%
sucralose;
[0441] About 0.05% azelastine, about 0.1% NSAID and about 0.15%
sucralose;
[0442] About 0.1% azelastine, about 0.1% NSAID and about 0.15%
sucralose;
[0443] About 0.125% azelastine, about 0.1% NSAID and about 0.15%
sucralose;
[0444] About 0.15% azelastine, about 0.1% NSAID and about 0.15%
sucralose;
[0445] About 0.05% azelastine, about 0.5% NSAID and about 0.05%
sucralose;
[0446] About 0.1% azelastine, about 0.5% NSAID and about 0.05%
sucralose;
[0447] About 0.125% azelastine, about 0.5% NSAID and about 0.05%
sucralose;
[0448] About 0.15% azelastine, about 0.5% NSAID and about 0.05%
sucralose;
[0449] About 0.05% azelastine, about 0.5% NSAID and about 0.1%
sucralose;
[0450] About 0.1% azelastine, about 0.5% NSAID and about 0.1%
sucralose;
[0451] About 0.125% azelastine, about 0.5% NSAID and about 0.1%
sucralose;
[0452] About 0.15% azelastine, about 0.5% NSAID and about 0.1%
sucralose;
[0453] About 0.05% azelastine, about 0.5% NSAID and about 0.15%
sucralose;
[0454] About 0.1% azelastine, about 0.5% NSAID and about 0.15%
sucralose;
[0455] About 0.125% azelastine, about 0.5% NSAID and about 0.15%
sucralose;
[0456] About 0.15% azelastine, about 0.5% NSAID and about 0.15%
sucralose;
[0457] About 0.05% azelastine, about 10.0% NSAID and about 0.05%
sucralose;
[0458] About 0.1% azelastine, about 10.0% NSAID and about 0.05%
sucralose;
[0459] About 0.125% azelastine, about 10.0% NSAID and about 0.05%
sucralose;
[0460] About 0.15% azelastine, about 1.0% NSAID and about 0.05%
sucralose;
[0461] About 0.05% azelastine, about 10.0% NSAID and about 0.1%
sucralose;
[0462] About 0.1% azelastine, about 10.0% NSAID and about 0.1%
sucralose;
[0463] About 0.125% azelastine, about 10.0% NSAID and about 0.1%
sucralose;
[0464] About 0.15% azelastine, about 10.0% NSAID and about 0.1%
sucralose;
[0465] About 0.05% azelastine, about 10.0% NSAID and about 0.15%
sucralose;
[0466] About 0.1% azelastine, about 10.0% NSAID and about 0.15%
sucralose;
[0467] About 0.125% azelastine, about 10.0% NSAID and about 0.15%
sucralose;
[0468] About 0.15% azelastine, about 10.0% NSAID and about 0.15%
sucralose;
[0469] About 0.05% azelastine and about 0.1% ibuprofen, diclofenac,
aceclofenac or naproxen;
[0470] About 0.1% azelastine and about 0.1% ibuprofen, diclofenac,
aceclofenac or naproxen;
[0471] About 0.125% azelastine and about 0.1% ibuprofen,
diclofenac, aceclofenac or naproxen;
[0472] About 0.15% azelastine and about 0.1% ibuprofen, diclofenac,
aceclofenac or naproxen;
[0473] About 0.05% azelastine and about 0.5% ibuprofen, diclofenac,
aceclofenac or naproxen;
[0474] About 0.1% azelastine and about 0.5% ibuprofen, diclofenac,
aceclofenac or naproxen;
[0475] About 0.125% azelastine and about 0.5% ibuprofen,
diclofenac, aceclofenac or naproxen;
[0476] About 0.15% azelastine and about 0.5% ibuprofen, diclofenac,
aceclofenac or naproxen;
[0477] About 0.05% azelastine and about 10.0% ibuprofen,
diclofenac, aceclofenac or naproxen;
[0478] About 0.1% azelastine and about 10.0% ibuprofen, diclofenac,
aceclofenac or naproxen;
[0479] About 0.125% azelastine and about 10.0% ibuprofen,
diclofenac, aceclofenac or naproxen;
[0480] About 0.15% azelastine and about 10.0% ibuprofen,
diclofenac, aceclofenac or naproxen;
[0481] About 0.05% azelastine, about 0.1% ibuprofen, diclofenac,
aceclofenac or naproxen and about 0.05% sucralose;
[0482] About 0.1% azelastine, about 0.1% ibuprofen, diclofenac,
aceclofenac or naproxen and about 0.05% sucralose;
[0483] About 0.125% azelastine, about 0.1% ibuprofen, diclofenac,
aceclofenac or naproxen and about 0.05% sucralose;
[0484] About 0.15% azelastine, about 0.1% ibuprofen, diclofenac,
aceclofenac or naproxen and about 0.05% sucralose;
[0485] About 0.05% azelastine, about 0.1% ibuprofen, diclofenac,
aceclofenac or naproxen and about 0.1% sucralose;
[0486] About 0.1% azelastine, about 0.1% ibuprofen, diclofenac,
aceclofenac or naproxen and about 0.1% sucralose;
[0487] About 0.125% azelastine, about 0.1% ibuprofen, diclofenac,
aceclofenac or naproxen and about 0.1% sucralose;
[0488] About 0.15% azelastine, about 0.1% ibuprofen, diclofenac,
aceclofenac or naproxen and about 0.1% sucralose;
[0489] About 0.05% azelastine, about 0.1% ibuprofen, diclofenac,
aceclofenac or naproxen and about 0.15% sucralose;
[0490] About 0.1% azelastine, about 0.1% ibuprofen, diclofenac,
aceclofenac or naproxen and about 0.15% sucralose;
[0491] About 0.125% azelastine, about 0.1% ibuprofen, diclofenac,
aceclofenac or naproxen and about 0.15% sucralose;
[0492] About 0.15% azelastine, about 0.1% ibuprofen, diclofenac,
aceclofenac or naproxen and about 0.15% sucralose;
[0493] About 0.05% azelastine, about 0.5% ibuprofen, diclofenac,
aceclofenac or naproxen and about 0.05% sucralose;
[0494] About 0.1% azelastine, about 0.5% ibuprofen, diclofenac,
aceclofenac or naproxen and about 0.05% sucralose;
[0495] About 0.125% azelastine, about 0.5% ibuprofen, diclofenac,
aceclofenac or naproxen and about 0.05% sucralose;
[0496] About 0.15% azelastine, about 0.5% ibuprofen and about 0.05%
sucralose;
[0497] About 0.05% azelastine, about 0.5% ibuprofen, diclofenac,
aceclofenac or naproxen and about 0.1% sucralose;
[0498] About 0.1% azelastine, about 0.5% ibuprofen, diclofenac,
aceclofenac or naproxen and about 0.1% sucralose;
[0499] About 0.125% azelastine, about 0.5% ibuprofen, diclofenac,
aceclofenac or naproxen and about 0.1% sucralose;
[0500] About 0.15% azelastine, about 0.5% ibuprofen, diclofenac,
aceclofenac or naproxen and about 0.1% sucralose;
[0501] About 0.05% azelastine, about 0.5% ibuprofen, diclofenac,
aceclofenac or naproxen and about 0.15% sucralose;
[0502] About 0.1% azelastine, about 0.5% ibuprofen, diclofenac,
aceclofenac or naproxen and about 0.15% sucralose;
[0503] About 0.125% azelastine, about 0.5% ibuprofen, diclofenac,
aceclofenac or naproxen and about 0.15% sucralose;
[0504] About 0.15% azelastine, about 0.5% ibuprofen, diclofenac,
aceclofenac or naproxen and about 0.15% sucralose;
[0505] About 0.05% azelastine, about 10.0% ibuprofen, diclofenac,
aceclofenac or naproxen and about 0.05% sucralose;
[0506] About 0.1% azelastine, about 10.0% ibuprofen, diclofenac,
aceclofenac or naproxen and about 0.05% sucralose;
[0507] About 0.125% azelastine, about 10.0% ibuprofen, diclofenac,
aceclofenac or naproxen and about 0.05% sucralose;
[0508] About 0.15% azelastine, about 10.0% ibuprofen, diclofenac,
aceclofenac or naproxen and about 0.05% sucralose;
[0509] About 0.05% azelastine, about 10.0% ibuprofen, diclofenac,
aceclofenac or naproxen and about 0.1% sucralose;
[0510] About 0.1% azelastine, about 10.0% ibuprofen, diclofenac,
aceclofenac or naproxen and about 0.1% sucralose;
[0511] About 0.125% azelastine, about 10.0% ibuprofen, diclofenac,
aceclofenac or naproxen and about 0.1% sucralose;
[0512] About 0.15% azelastine, about 10.0% ibuprofen, diclofenac,
aceclofenac or naproxen and about 0.1% sucralose;
[0513] About 0.05% azelastine, about 10.0% ibuprofen, diclofenac,
aceclofenac or naproxen and about 0.15% sucralose;
[0514] About 0.1% azelastine, about 10.0% ibuprofen, diclofenac,
aceclofenac or naproxen and about 0.15% sucralose;
[0515] About 0.125% azelastine, about 10.0% ibuprofen, diclofenac,
aceclofenac or naproxen and about 0.15% sucralose;
[0516] About 0.15% azelastine, about 10.0% ibuprofen, diclofenac,
aceclofenac or naproxen and about 0.15% sucralose;
[0517] About 0.05% azelastine, about 0.01% steroid and about 0.1%
decongestant;
[0518] About 0.1% azelastine, about 0.01% steroid and about 0.1%
decongestant;
[0519] About 0.125% azelastine, about 0.01% steroid and about 0.1%
decongestant;
[0520] About 0.15% azelastine, about 0.01% steroid and about 0.1%
decongestant;
[0521] About 0.05% azelastine, about 0.05% steroid and about 0.1%
decongestant;
[0522] About 0.1% azelastine, about 0.05% steroid and about 0.1%
decongestant;
[0523] About 0.125% azelastine, about 0.05% steroid and about 0.1%
decongestant;
[0524] About 0.15% azelastine, about 0.05% steroid and about 0.1%
decongestant;
[0525] About 0.05% azelastine, about 0.1% steroid and about 0.1%
decongestant;
[0526] About 0.1% azelastine, about 0.1% steroid and about 0.1%
decongestant;
[0527] About 0.125% azelastine, about 0.1% steroid and about 0.1%
decongestant;
[0528] About 0.15% azelastine, about 0.1% steroid and about 0.1%
decongestant;
[0529] About 0.05% azelastine, about 0.01% steroid and about 0.5%
decongestant;
[0530] About 0.1% azelastine, about 0.01% steroid and about 0.5%
decongestant;
[0531] About 0.125% azelastine, about 0.01% steroid and about 0.5%
decongestant;
[0532] About 0.15% azelastine, about 0.01% steroid and about 0.5%
decongestant;
[0533] About 0.05% azelastine, about 0.05% steroid and about 0.5%
decongestant;
[0534] About 0.1% azelastine, about 0.05% steroid and about 0.5%
decongestant;
[0535] About 0.125% azelastine, about 0.05% steroid and about 0.5%
decongestant;
[0536] About 0.15% azelastine, about 0.05% steroid and about 0.5%
decongestant;
[0537] About 0.05% azelastine, about 0.1% steroid and about 0.5%
decongestant;
[0538] About 0.1% azelastine, about 0.1% steroid and about 0.5%
decongestant;
[0539] About 0.125% azelastine, about 0.1% steroid and about 0.5%
decongestant;
[0540] About 0.15% azelastine, about 0.1% steroid and about 0.5%
decongestant;
[0541] About 0.05% azelastine, about 0.01% steroid and about 1.0%
decongestant;
[0542] About 0.1% azelastine, about 0.01% steroid and about 1.0%
decongestant;
[0543] About 0.125% azelastine, about 0.01% steroid and about 1.0%
decongestant;
[0544] About 0.15% azelastine, about 0.01% steroid and about 1.0%
decongestant;
[0545] About 0.05% azelastine, about 0.05% steroid and about 1.0%
decongestant;
[0546] About 0.1% azelastine, about 0.05% steroid and about 1.0%
decongestant;
[0547] About 0.125% azelastine, about 0.05% steroid and about 1.0%
decongestant;
[0548] About 0.15% azelastine, about 0.05% steroid and about 1.0%
decongestant;
[0549] About 0.05% azelastine, about 0.1% steroid and about 1.0%
decongestant;
[0550] About 0.1% azelastine, about 0.1% steroid and about 1.0%
decongestant;
[0551] About 0.125% azelastine, about 0.1% steroid and about 1.0%
decongestant;
[0552] About 0.15% azelastine, about 0.1% steroid and about 1.0%
decongestant;
[0553] About 0.05% azelastine, about 0.01% steroid, about 0.1%
decongestant and about 0.05% sucralose;
[0554] About 0.1% azelastine, about 0.01% steroid, about 0.1%
decongestant and about 0.05% sucralose;
[0555] About 0.125% azelastine, about 0.01% steroid, about 0.1%
decongestant and about 0.05% sucralose;
[0556] About 0.15% azelastine, about 0.01% steroid, about 0.1%
decongestant and about 0.05% sucralose;
[0557] About 0.05% azelastine, about 0.05% steroid, about 0.1%
decongestant and about 0.05% sucralose;
[0558] About 0.1% azelastine, about 0.05% steroid, about 0.1%
decongestant and about 0.05% sucralose;
[0559] About 0.125% azelastine, about 0.05% steroid, about 0.1%
decongestant and about 0.05% sucralose;
[0560] About 0.15% azelastine, about 0.05% steroid, about 0.1%
decongestant and about 0.05% sucralose;
[0561] About 0.05% azelastine, about 0.1% steroid, about 0.1%
decongestant and about 0.05% sucralose;
[0562] About 0.1% azelastine, about 0.1% steroid, about 0.1%
decongestant and about 0.05% sucralose;
[0563] About 0.125% azelastine, about 0.1% steroid, about 0.1%
decongestant and about 0.05% sucralose;
[0564] About 0.15% azelastine, about 0.1% steroid, about 0.1%
decongestant and about 0.05% sucralose;
[0565] About 0.05% azelastine, about 0.01% steroid, about 0.5%
decongestant and about 0.05% sucralose;
[0566] About 0.1% azelastine, about 0.01% steroid, about 0.5%
decongestant and about 0.05% sucralose;
[0567] About 0.125% azelastine, about 0.01% steroid, about 0.5%
decongestant and about 0.05% sucralose;
[0568] About 0.15% azelastine, about 0.01% steroid, about 0.5%
decongestant and about 0.05% sucralose;
[0569] About 0.05% azelastine, about 0.05% steroid, about 0.5%
decongestant and about 0.05% sucralose;
[0570] About 0.1% azelastine, about 0.05% steroid, about 0.5%
decongestant and about 0.05% sucralose;
[0571] About 0.125% azelastine, about 0.05% steroid, about 0.5%
decongestant and about 0.05% sucralose;
[0572] About 0.15% azelastine, about 0.05% steroid, about 0.5%
decongestant and about 0.05% sucralose;
[0573] About 0.05% azelastine, about 0.1% steroid, about 0.5%
decongestant and about 0.05% sucralose;
[0574] About 0.1% azelastine, about 0.1% steroid, about 0.5%
decongestant and about 0.05% sucralose;
[0575] About 0.125% azelastine, about 0.1% steroid, about 0.5%
decongestant and about 0.05% sucralose;
[0576] About 0.15% azelastine, about 0.1% steroid, about 0.5%
decongestant and about 0.05% sucralose;
[0577] About 0.05% azelastine, about 0.01% steroid, about 1.0%
decongestant and about 0.05% sucralose;
[0578] About 0.1% azelastine, about 0.01% steroid, about 1.0%
decongestant and about 0.05% sucralose;
[0579] About 0.125% azelastine, about 0.01% steroid, about 1.0%
decongestant and about 0.05% sucralose;
[0580] About 0.15% azelastine, about 0.01% steroid, about 1.0%
decongestant and about 0.05% sucralose;
[0581] About 0.05% azelastine, about 0.05% steroid, about 1.0%
decongestant and about 0.05% sucralose;
[0582] About 0.1% azelastine, about 0.05% steroid, about 1.0%
decongestant and about 0.05% sucralose;
[0583] About 0.125% azelastine, about 0.05% steroid, about 1.0%
decongestant and about 0.05% sucralose;
[0584] About 0.15% azelastine, about 0.05% steroid, about 1.0%
decongestant and about 0.05% sucralose;
[0585] About 0.05% azelastine, about 0.1% steroid, about 1.0%
decongestant and about 0.05% sucralose;
[0586] About 0.1% azelastine, about 0.1% steroid, about 1.0%
decongestant and about 0.05% sucralose;
[0587] About 0.125% azelastine, about 0.1% steroid, about 1.0%
decongestant and about 0.05% sucralose;
[0588] About 0.15% azelastine, about 0.1% steroid, about 1.0%
decongestant and about 0.05% sucralose;
[0589] About 0.05% azelastine, about 0.01% steroid, about 0.1%
decongestant and about 0.1% sucralose;
[0590] About 0.1% azelastine, about 0.01% steroid, about 0.1%
decongestant and about 0.1% sucralose;
[0591] About 0.125% azelastine, about 0.01% steroid, about 0.1%
decongestant and about 0.1% sucralose;
[0592] About 0.15% azelastine, about 0.01% steroid, about 0.1%
decongestant and about 0.1% sucralose;
[0593] About 0.05% azelastine, about 0.05% steroid, about 0.1%
decongestant and about 0.1% sucralose;
[0594] About 0.1% azelastine, about 0.05% steroid, about 0.1%
decongestant and about 0.1% sucralose;
[0595] About 0.125% azelastine, about 0.05% steroid, about 0.1%
decongestant and about 0.1% sucralose;
[0596] About 0.15% azelastine, about 0.05% steroid, about 0.1%
decongestant and about 0.1% sucralose;
[0597] About 0.05% azelastine, about 0.1% steroid, about 0.1%
decongestant and about 0.1% sucralose;
[0598] About 0.1% azelastine, about 0.1% steroid, about 0.1%
decongestant and about 0.1% sucralose;
[0599] About 0.125% azelastine, about 0.1% steroid, about 0.1%
decongestant and about 0.1% sucralose;
[0600] About 0.15% azelastine, about 0.1% steroid, about 0.1%
decongestant and about 0.1% sucralose;
[0601] About 0.05% azelastine, about 0.01% steroid, about 0.5%
decongestant and about 0.1% sucralose;
[0602] About 0.1% azelastine, about 0.01% steroid, about 0.5%
decongestant and about 0.1% sucralose;
[0603] About 0.125% azelastine, about 0.01% steroid, about 0.5%
decongestant and about 0.1% sucralose;
[0604] About 0.15% azelastine, about 0.01% steroid, about 0.5%
decongestant and about 0.1% sucralose;
[0605] About 0.05% azelastine, about 0.05% steroid, about 0.5%
decongestant and about 0.1% sucralose;
[0606] About 0.1% azelastine, about 0.05% steroid, about 0.5%
decongestant and about 0.1% sucralose;
[0607] About 0.125% azelastine, about 0.05% steroid, about 0.5%
decongestant and about 0.1% sucralose;
[0608] About 0.15% azelastine, about 0.05% steroid, about 0.5%
decongestant and about 0.1% sucralose;
[0609] About 0.05% azelastine, about 0.1% steroid, about 0.5%
decongestant and about 0.1% sucralose;
[0610] About 0.1% azelastine, about 0.1% steroid, about 0.5%
decongestant and about 0.1% sucralose;
[0611] About 0.125% azelastine, about 0.1% steroid, about 0.5%
decongestant and about 0.1% sucralose;
[0612] About 0.15% azelastine, about 0.1% steroid, about 0.5%
decongestant and about 0.1% sucralose;
[0613] About 0.05% azelastine, about 0.01% steroid, about 1.0%
decongestant and about 0.1% sucralose;
[0614] About 0.1% azelastine, about 0.01% steroid, about 1.0%
decongestant and about 0.1% sucralose;
[0615] About 0.125% azelastine, about 0.01% steroid, about 1.0%
decongestant and about 0.1% sucralose;
[0616] About 0.15% azelastine, about 0.01% steroid, about 1.0%
decongestant and about 0.1% sucralose;
[0617] About 0.05% azelastine, about 0.05% steroid, about 1.0%
decongestant and about 0.1% sucralose;
[0618] About 0.1% azelastine, about 0.05% steroid, about 1.0%
decongestant and about 0.1% sucralose;
[0619] About 0.125% azelastine, about 0.05% steroid, about 1.0%
decongestant and about 0.1% sucralose;
[0620] About 0.15% azelastine, about 0.05% steroid, about 1.0%
decongestant and about 0.1% sucralose;
[0621] About 0.05% azelastine, about 0.1% steroid, about 1.0%
decongestant and about 0.1% sucralose;
[0622] About 0.1% azelastine, about 0.1% steroid, about 1.0%
decongestant and about 0.1% sucralose; Y
[0623] About 0.125% azelastine, about 0.1% steroid, about 1.0%
decongestant and about 0.1% sucralose;
[0624] About 0.15% azelastine, about 0.1% steroid, about 1.0%
decongestant and about 0.1% sucralose;
[0625] About 0.05% azelastine, about 0.01% steroid, about 0.1%
decongestant and about 0.15% sucralose;
[0626] About 0.1% azelastine, about 0.01% steroid, about 0.1%
decongestant and about 0.15% sucralose;
[0627] About 0.125% azelastine, about 0.01% steroid, about 0.1%
decongestant and about 0.15% sucralose;
[0628] About 0.15% azelastine, about 0.01% steroid, about 0.1%
decongestant and about 0.15% sucralose;
[0629] About 0.05% azelastine, about 0.05% steroid, about 0.1%
decongestant and about 0.15% sucralose;
[0630] About 0.1% azelastine, about 0.05% steroid, about 0.1%
decongestant and about 0.15% sucralose;
[0631] About 0.125% azelastine, about 0.05% steroid, about 0.1%
decongestant and about 0.15% sucralose;
[0632] About 0.15% azelastine, about 0.05% steroid, about 0.1%
decongestant and about 0.15% sucralose;
[0633] About 0.05% azelastine, about 0.1% steroid, about 0.1%
decongestant and about 0.15% sucralose;
[0634] About 0.1% azelastine, about 0.1% steroid, about 0.1%
decongestant and about 0.15% sucralose;
[0635] About 0.125% azelastine, about 0.1% steroid, about 0.1%
decongestant and about 0.15% sucralose;
[0636] About 0.15% azelastine, about 0.1% steroid, about 0.1%
decongestant and about 0.15% sucralose;
[0637] About 0.05% azelastine, about 0.01% steroid, about 0.5%
decongestant and about 0.15% sucralose;
[0638] About 0.1% azelastine, about 0.01% steroid, about 0.5%
decongestant and about 0.15% sucralose;
[0639] About 0.125% azelastine, about 0.01% steroid, about 0.5%
decongestant and about 0.15% sucralose;
[0640] About 0.15% azelastine, about 0.01% steroid, about 0.5%
decongestant and about 0.15% sucralose;
[0641] About 0.05% azelastine, about 0.05% steroid, about 0.5%
decongestant and about 0.15% sucralose;
[0642] About 0.1% azelastine, about 0.05% steroid, about 0.5%
decongestant and about 0.15% sucralose;
[0643] About 0.125% azelastine, about 0.05% steroid, about 0.5%
decongestant and about 0.15% sucralose;
[0644] About 0.15% azelastine, about 0.05% steroid, about 0.5%
decongestant and about 0.15% sucralose;
[0645] About 0.05% azelastine, about 0.1% steroid, about 0.5%
decongestant and about 0.15% sucralose;
[0646] About 0.1% azelastine, about 0.1% steroid, about 0.5%
decongestant and about 0.15% sucralose;
[0647] About 0.125% azelastine, about 0.1% steroid, about 0.5%
decongestant and about 0.15% sucralose;
[0648] About 0.15% azelastine, about 0.1% steroid, about 0.5%
decongestant and about 0.15% sucralose;
[0649] About 0.05% azelastine, about 0.01% steroid, about 1.0%
decongestant and about 0.15% sucralose;
[0650] About 0.1% azelastine, about 0.01% steroid, about 1.0%
decongestant and about 0.15% sucralose;
[0651] About 0.125% azelastine, about 0.01% steroid, about 1.0%
decongestant and about 0.15% sucralose;
[0652] About 0.15% azelastine, about 0.01% steroid, about 1.0%
decongestant and about 0.15% sucralose;
[0653] About 0.05% azelastine, about 0.05% steroid, about 1.0%
decongestant and about 0.15% sucralose;
[0654] About 0.1% azelastine, about 0.05% steroid, about 1.0%
decongestant and about 0.15% sucralose;
[0655] About 0.125% azelastine, about 0.05% steroid, about 1.0%
decongestant and about 0.15% sucralose;
[0656] About 0.15% azelastine, about 0.05% steroid, about 1.0%
decongestant and about 0.15% sucralose;
[0657] About 0.05% azelastine, about 0.1% steroid, about 1.0%
decongestant and about 0.15% sucralose;
[0658] About 0.1% azelastine, about 0.1% steroid, about 1.0%
decongestant and about 0.15% sucralose;
[0659] About 0.125% azelastine, about 0.1% steroid, about 1.0%
decongestant and about 0.15% sucralose;
[0660] About 0.15% azelastine, about 0.1% steroid, about 1.0%
decongestant and about 0.15% sucralose;
[0661] About 0.05% azelastine, about 0.01% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone and about 0.1% pseudoephedrine or
phenylephrine;
[0662] About 0.1% azelastine, about 0.01% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone and about 0.1% pseudoephedrine or
phenylephrine;
[0663] About 0.125% azelastine, about 0.01% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone and about 0.1% pseudoephedrine or
phenylephrine;
[0664] About 0.15% azelastine, about 0.01% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone and about 0.1% pseudoephedrine or
phenylephrine;
[0665] About 0.05% azelastine, about 0.05% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone and about 0.1% pseudoephedrine or
phenylephrine;
[0666] About 0.1% azelastine, about 0.05% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone and about 0.1% pseudoephedrine or
phenylephrine;
[0667] About 0.125% azelastine, about 0.05% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone and about 0.1% pseudoephedrine or
phenylephrine;
[0668] About 0.15% azelastine, about 0.05% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone and about 0.1% pseudoephedrine or
phenylephrine;
[0669] About 0.05% azelastine, about 0.1% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone and about 0.1% pseudoephedrine or
phenylephrine;
[0670] About 0.1% azelastine, about 0.1% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone and about 0.1% pseudoephedrine or
phenylephrine;
[0671] About 0.125% azelastine, about 0.1% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone and about 0.1% pseudoephedrine or
phenylephrine;
[0672] About 0.15% azelastine, about 0.1% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone and about 0.1% pseudoephedrine or
phenylephrine;
[0673] About 0.05% azelastine, about 0.01% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone and about 0.5% pseudoephedrine or
phenylephrine;
[0674] About 0.1% azelastine, about 0.01% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone and about 0.5% pseudoephedrine or
phenylephrine;
[0675] About 0.125% azelastine, about 0.01% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone and about 0.5% pseudoephedrine or
phenylephrine;
[0676] About 0.15% azelastine, about 0.01% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone and about 0.5% pseudoephedrine or
phenylephrine;
[0677] About 0.05% azelastine, about 0.05% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone and about 0.5% pseudoephedrine or
phenylephrine;
[0678] About 0.1% azelastine, about 0.05% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone and about 0.5% pseudoephedrine or
phenylephrine;
[0679] About 0.125% azelastine, about 0.05% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone and about 0.5% pseudoephedrine or
phenylephrine;
[0680] About 0.15% azelastine, about 0.05% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone and about 0.5% pseudoephedrine or
phenylephrine;
[0681] About 0.05% azelastine, about 0.1% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone and about 0.5% pseudoephedrine or
phenylephrine;
[0682] About 0.1% azelastine, about 0.1% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone and about 0.5% pseudoephedrine or
phenylephrine;
[0683] About 0.125% azelastine, about 0.1% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone and about 0.5% pseudoephedrine or
phenylephrine;
[0684] About 0.15% azelastine, about 0.1% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone and about 0.5% pseudoephedrine or
phenylephrine;
[0685] About 0.05% azelastine, about 0.01% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone and about 1.0% pseudoephedrine or
phenylephrine;
[0686] About 0.1% azelastine, about 0.01% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone and about 1.0% pseudoephedrine or
phenylephrine;
[0687] About 0.125% azelastine, about 0.01% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone and about 1.0% pseudoephedrine or
phenylephrine;
[0688] About 0.15% azelastine, about 0.01% fluticasone, mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone and about 1.0% pseudoephedrine or
phenylephrine;
[0689] About 0.05% azelastine, about 0.05% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone and about 1.0% pseudoephedrine or
phenylephrine;
[0690] About 0.1% azelastine, about 0.05% fluticasone, mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone and about 1.0% pseudoephedrine or
phenylephrine;
[0691] About 0.125% azelastine, about 0.05% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone and about 1.0% pseudoephedrine or
phenylephrine;
[0692] About 0.15% azelastine, about 0.05% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone and about 1.0% pseudoephedrine or
phenylephrine;
[0693] About 0.05% azelastine, about 0.1% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone and about 1.0% pseudoephedrine or
phenylephrine;
[0694] About 0.1% azelastine, about 0.1% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone and about 1.0% pseudoephedrine or
phenylephrine;
[0695] About 0.125% azelastine, about 0.1% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone and about 1.0% pseudoephedrine or
phenylephrine;
[0696] About 0.15% azelastine, about 0.1% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone and about 1.0% pseudoephedrine or
phenylephrine;
[0697] About 0.05% azelastine, about 0.01% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone, about 0.1% pseudoephedrine or
phenylephrine and about 0.05% sucralose;
[0698] About 0.1% azelastine, about 0.01% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone, about 0.1% pseudoephedrine or
phenylephrine and about 0.05% sucralose;
[0699] About 0.125% azelastine, about 0.01% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone, about 0.1% pseudoephedrine or
phenylephrine and about 0.05% sucralose;
[0700] About 0.15% azelastine, about 0.01% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone, about 0.1% pseudoephedrine or
phenylephrine and about 0.05% sucralose;
[0701] About 0.05% azelastine, about 0.05% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone, about 0.1% pseudoephedrine or
phenylephrine and about 0.05% sucralose;
[0702] About 0.1% azelastine, about 0.05% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone, about 0.1% pseudoephedrine or
phenylephrine and about 0.05% sucralose;
[0703] About 0.125% azelastine, about 0.05% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone, about 0.1% pseudoephedrine or
phenylephrine and about 0.05% sucralose;
[0704] About 0.15% azelastine, about 0.05% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone, about 0.1% pseudoephedrine or
phenylephrine and about 0.05% sucralose;
[0705] About 0.05% azelastine, about 0.1% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone, about 0.1% pseudoephedrine or
phenylephrine and about 0.05% sucralose;
[0706] About 0.1% azelastine, about 0.1% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone, about 0.1% pseudoephedrine or
phenylephrine and about 0.05% sucralose;
[0707] About 0.125% azelastine, about 0.1% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone, about 0.1% pseudoephedrine or
phenylephrine and about 0.05% sucralose;
[0708] About 0.15% azelastine, about 0.1% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone, about 0.1% pseudoephedrine or
phenylephrine and about 0.05% sucralose;
[0709] About 0.05% azelastine, about 0.01% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone, about 0.5% pseudoephedrine or
phenylephrine and about 0.05% sucralose;
[0710] About 0.1% azelastine, about 0.01% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone, about 0.5% pseudoephedrine or
phenylephrine and about 0.05% sucralose;
[0711] About 0.125% azelastine, about 0.01% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone, about 0.5% pseudoephedrine or
phenylephrine and about 0.05% sucralose;
[0712] About 0.15% azelastine, about 0.01% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone, about 0.5% pseudoephedrine or
phenylephrine and about 0.05% sucralose;
[0713] About 0.05% azelastine, about 0.05% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone, about 0.5% pseudoephedrine or
phenylephrine and about 0.05% sucralose;
[0714] About 0.1% azelastine, about 0.05% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone, about 0.5% pseudoephedrine or
phenylephrine and about 0.05% sucralose;
[0715] About 0.125% azelastine, about 0.05% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone, about 0.5% pseudoephedrine or
phenylephrine and about 0.05% sucralose;
[0716] About 0.15% azelastine, about 0.05% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone, about 0.5% pseudoephedrine or
phenylephrine and about 0.05% sucralose;
[0717] About 0.05% azelastine, about 0.1% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone, about 0.5% pseudoephedrine or
phenylephrine and about 0.05% sucralose;
[0718] About 0.1% azelastine, about 0.1% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone, about 0.5% pseudoephedrine or
phenylephrine and about 0.05% sucralose;
[0719] About 0.125% azelastine, about 0.1% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone, about 0.5% pseudoephedrine or
phenylephrine and about 0.05% sucralose;
[0720] About 0.15% azelastine, about 0.1% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone, about 0.5% pseudoephedrine or
phenylephrine and about 0.05% sucralose;
[0721] About 0.05% azelastine, about 0.01% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone, about 1.0% pseudoephedrine or
phenylephrine and about 0.05% sucralose;
[0722] About 0.1% azelastine, about 0.01% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone, about 1.0% pseudoephedrine or
phenylephrine and about 0.05% sucralose;
[0723] About 0.125% azelastine, about 0.01% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone, about 1.0% pseudoephedrine or
phenylephrine and about 0.05% sucralose;
[0724] About 0.15% azelastine, about 0.01% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone, about 1.0% pseudoephedrine or
phenylephrine and about 0.05% sucralose;
[0725] About 0.05% azelastine, about 0.05% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone, about 1.0% pseudoephedrine or
phenylephrine and about 0.05% sucralose;
[0726] About 0.1% azelastine, about 0.05% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone, about 1.0% pseudoephedrine or
phenylephrine and about 0.05% sucralose;
[0727] About 0.125% azelastine, about 0.05% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone, about 1.0% pseudoephedrine or
phenylephrine and about 0.05% sucralose;
[0728] About 0.15% azelastine, about 0.05% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone, about 1.0% pseudoephedrine or
phenylephrine and about 0.05% sucralose;
[0729] About 0.05% azelastine, about 0.1% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone, about 1.0% pseudoephedrine or
phenylephrine and about 0.05% sucralose;
[0730] About 0.1% azelastine, about 0.1% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone, about 1.0% pseudoephedrine or
phenylephrine and about 0.05% sucralose;
[0731] About 0.125% azelastine, about 0.1% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone, about 1.0% pseudoephedrine or
phenylephrine and about 0.05% sucralose;
[0732] About 0.15% azelastine, about 0.1% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone, about 1.0% pseudoephedrine or
phenylephrine and about 0.05% sucralose;
[0733] About 0.05% azelastine, about 0.01% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone, about 0.1% pseudoephedrine or
phenylephrine and about 0.1% sucralose;
[0734] About 0.1% azelastine, about 0.01% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone, about 0.1% pseudoephedrine or
phenylephrine and about 0.1% sucralose;
[0735] About 0.125% azelastine, about 0.01% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone, about 0.1% pseudoephedrine or
phenylephrine and about 0.1% sucralose;
[0736] About 0.15% azelastine, about 0.01% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone, about 0.1% pseudoephedrine or
phenylephrine and about 0.1% sucralose;
[0737] About 0.05% azelastine, about 0.05% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone, about 0.1% pseudoephedrine or
phenylephrine and about 0.1% sucralose;
[0738] About 0.1% azelastine, about 0.05% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone, about 0.1% pseudoephedrine or
phenylephrine and about 0.1% sucralose;
[0739] About 0.125% azelastine, about 0.05% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone, about 0.1% pseudoephedrine or
phenylephrine and about 0.1% sucralose;
[0740] About 0.15% azelastine, about 0.05% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone, about 0.1% pseudoephedrine or
phenylephrine and about 0.1% sucralose;
[0741] About 0.05% azelastine, about 0.1% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone, about 0.1% pseudoephedrine or
phenylephrine and about 0.1% sucralose;
[0742] About 0.1% azelastine, about 0.1% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone, about 0.1% pseudoephedrine or
phenylephrine and about 0.1% sucralose;
[0743] About 0.125% azelastine, about 0.1% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone, about 0.1% pseudoephedrine or
phenylephrine and about 0.1% sucralose;
[0744] About 0.15% azelastine, about 0.1% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone, about 0.1% pseudoephedrine or
phenylephrine and about 0.1% sucralose;
[0745] About 0.05% azelastine, about 0.01% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone, about 0.5% pseudoephedrine or
phenylephrine and about 0.1% sucralose;
[0746] About 0.1% azelastine, about 0.01% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone, about 0.5% pseudoephedrine or
phenylephrine and about 0.1% sucralose;
[0747] About 0.125% azelastine, about 0.01% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone, about 0.5% pseudoephedrine or
phenylephrine or phenylephrine and about 0.1% sucralose;
[0748] About 0.15% azelastine, about 0.01% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone, about 0.5% pseudoephedrine or
phenylephrine and about 0.1% sucralose;
[0749] About 0.05% azelastine, about 0.05% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone, about 0.5% pseudoephedrine or
phenylephrine and about 0.1% sucralose;
[0750] About 0.1% azelastine, about 0.05% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone, about 0.5% pseudoephedrine or
phenylephrine and about 0.1% sucralose;
[0751] About 0.125% azelastine, about 0.05% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone, about 0.5% pseudoephedrine or
phenylephrine or phenylephrine and about 0.1% sucralose;
[0752] About 0.15% azelastine, about 0.50% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone, about 0.5% pseudoephedrine or
phenylephrine and about 0.1% sucralose;
[0753] About 0.05% azelastine, about 0.1% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone, about 0.5% pseudoephedrine or
phenylephrine and about 0.1% sucralose;
[0754] About 0.1% azelastine, about 0.1% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone, about 0.5% pseudoephedrine or
phenylephrine and about 0.1% sucralose;
[0755] About 0.125% azelastine, about 0.1% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone, about 0.5% pseudoephedrine or
phenylephrine or phenylephrine and about 0.1% sucralose;
[0756] About 0.15% azelastine, about 0.1% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone, about 0.5% pseudoephedrine or
phenylephrine and about 0.1% sucralose;
[0757] About 0.05% azelastine, about 0.01% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone, about 1.0% pseudoephedrine or
phenylephrine and about 0.1% sucralose;
[0758] About 0.1% azelastine, about 0.01% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone, about 1.0% pseudoephedrine or
phenylephrine and about 0.1% sucralose;
[0759] About 0.125% azelastine, about 0.01% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone, about 1.0% pseudoephedrine or
phenylephrine and about 0.1% sucralose;
[0760] About 0.15% azelastine, about 0.01% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone, about 1.0% pseudoephedrine or
phenylephrine and about 0.1% sucralose;
[0761] About 0.05% azelastine, about 0.05% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone, about 1.0% pseudoephedrine or
phenylephrine and about 0.1% sucralose;
[0762] About 0.1% azelastine, about 0.05% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone, about 1.0% pseudoephedrine or
phenylephrine and about 0.1% sucralose;
[0763] About 0.125% azelastine, about 0.05% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone, about 1.0% pseudoephedrine or
phenylephrine and about 0.1% sucralose;
[0764] About 0.15% azelastine, about 0.05% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone, about 1.0% pseudoephedrine or
phenylephrine and about 0.1% sucralose;
[0765] About 0.05% azelastine, about 0.1% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone, about 1.0% pseudoephedrine or
phenylephrine and about 0.1% sucralose;
[0766] About 0.1% azelastine, about 0.1% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone, about 1.0% pseudoephedrine or
phenylephrine and about 0.1% sucralose;
[0767] About 0.125% azelastine, about 0.1% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone, about 1.0% pseudoephedrine or
phenylephrine and about 0.1% sucralose;
[0768] About 0.15% azelastine, about 0.1% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone, about 1.0% pseudoephedrine or
phenylephrine and about 0.1% sucralose;
[0769] About 0.05% azelastine, about 0.01% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone, about 0.1% pseudoephedrine or
phenylephrine and about 0.15% sucralose;
[0770] About 0.1% azelastine, about 0.01% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone, about 0.1% pseudoephedrine or
phenylephrine and about 0.15% sucralose;
[0771] About 0.125% azelastine, about 0.01% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone, about 0.1% pseudoephedrine or
phenylephrine and about 0.15% sucralose;
[0772] About 0.15% azelastine, about 0.01% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone, about 0.1% pseudoephedrine or
phenylephrine and about 0.15% sucralose;
[0773] About 0.05% azelastine, about 0.05% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone, about 0.1% pseudoephedrine or
phenylephrine and about 0.15% sucralose;
[0774] About 0.1% azelastine, about 0.05% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone, about 0.1% pseudoephedrine or
phenylephrine and about 0.15% sucralose;
[0775] About 0.125% azelastine, about 0.05% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone, about 0.1% pseudoephedrine or
phenylephrine and about 0.15% sucralose;
[0776] About 0.15% azelastine, about 0.05-% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone, about 0.1% pseudoephedrine or
phenylephrine and about 0.15% sucralose;
[0777] About 0.05% azelastine, about 0.1% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone, about 0.1% pseudoephedrine or
phenylephrine and about 0.15% sucralose;
[0778] About 0.1% azelastine, about 0.1% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone, about 0.1% pseudoephedrine or
phenylephrine and about 0.15% sucralose;
[0779] About 0.125% azelastine, about 0.1% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone, about 0.1% pseudoephedrine or
phenylephrine and about 0.15% sucralose;
[0780] About 0.15% azelastine, about 0.1% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone, about 0.1% pseudoephedrine or
phenylephrine and about 0.15% sucralose;
[0781] About 0.05% azelastine, about 0.01% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone, about 0.5% pseudoephedrine or
phenylephrine and about 0.15% sucralose;
[0782] About 0.1% azelastine, about 0.01% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone, about 0.5% pseudoephedrine or
phenylephrine and about 0.15% sucralose;
[0783] About 0.125% azelastine, about 0.01% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone, about 0.5% pseudoephedrine or
phenylephrine and about 0.15% sucralose;
[0784] About 0.15% azelastine, about 0.01% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone, about 0.5% pseudoephedrine or
phenylephrine and about 0.15% sucralose;
[0785] About 0.05% azelastine, about 0.05% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone, about 0.5% pseudoephedrine or
phenylephrine and about 0.15% sucralose;
[0786] About 0.1% azelastine, about 0.05% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone, about 0.5% pseudoephedrine or
phenylephrine and about 0.15% sucralose;
[0787] About 0.125% azelastine, about 0.05% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone, about 0.5% pseudoephedrine or
phenylephrine and about 0.15% sucralose;
[0788] About 0.15% azelastine, about 0.05% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone, about 0.5% pseudoephedrine or
phenylephrine and about 0.15% sucralose;
[0789] About 0.05% azelastine, about 0.1% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone, about 0.5% pseudoephedrine or
phenylephrine and about 0.15% sucralose;
[0790] About 0.1% azelastine, about 0.1% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone, about 0.5% pseudoephedrine or
phenylephrine and about 0.15% sucralose;
[0791] About 0.125% azelastine, about 0.1% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone, about 0.5% pseudoephedrine or
phenylephrine and about 0.15% sucralose;
[0792] About 0.15% azelastine, about 0.1% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone, about 0.5% pseudoephedrine or
phenylephrine and about 0.15% sucralose;
[0793] About 0.05% azelastine, about 0.01% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone, about 1.0% pseudoephedrine or
phenylephrine and about 0.15% sucralose;
[0794] About 0.1% azelastine, about 0.01% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone, about 1.0% pseudoephedrine or
phenylephrine and about 0.15% sucralose;
[0795] About 0.125% azelastine, about 0.01% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone, about 1.0% pseudoephedrine or
phenylephrine and about 0.15% sucralose;
[0796] About 0.15% azelastine, about 0.01% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone, about 1.0% pseudoephedrine or
phenylephrine and about 0.15% sucralose;
[0797] About 0.05% azelastine, about 0.05% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone, about 1.0% pseudoephedrine or
phenylephrine and about 0.15% sucralose;
[0798] About 0.1% azelastine, about 0.05% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone, about 1.0% pseudoephedrine or
phenylephrine and about 0.15% sucralose;
[0799] About 0.125% azelastine, about 0.05% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone, about 1.0% pseudoephedrine or
phenylephrine and about 0.15% sucralose;
[0800] About 0.15% azelastine, about 0.05% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone, about 1.0% pseudoephedrine or
phenylephrine and about 0.15% sucralose;
[0801] About 0.05% azelastine, about 0.1% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone, about 1.0% pseudoephedrine or
phenylephrine and about 0.15% sucralose;
[0802] About 0.1% azelastine, about 0.1% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone, about 1.0% pseudoephedrine or
phenylephrine and about 0.15% sucralose;
[0803] About 0.125% azelastine, about 0.1% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone, about 1.0% pseudoephedrine or
phenylephrine and about 0.15% sucralose;
[0804] About 0.15% azelastine, about 0.1% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone, about 1.0% pseudoephedrine or
phenylephrine and about 0.15% sucralose;
[0805] About 0.05% azelastine, about 0.01% steroid and about 0.1%
leukotriene antagonist;
[0806] About 0.1% azelastine, about 0.01% steroid and about 0.1%
leukotriene antagonist;
[0807] About 0.125% azelastine, about 0.01% steroid and about 0.1%
leukotriene antagonist;
[0808] About 0.15% azelastine, about 0.01% steroid and about 0.1%
leukotriene antagonist;
[0809] About 0.05% azelastine, about 0.05% steroid and about 0.1%
leukotriene antagonist;
[0810] About 0.1% azelastine, about 0.05% steroid and about 0.1%
leukotriene antagonist;
[0811] About 0.125% azelastine, about 0.05% steroid and about 0.1%
leukotriene antagonist;
[0812] About 0.15% azelastine, about 0.05% steroid and about 0.1%
leukotriene antagonist;
[0813] About 0.05% azelastine, about 0.1% steroid and about 0.1%
leukotriene antagonist;
[0814] About 0.1% azelastine, about 0.1% steroid and about 0.1%
leukotriene antagonist;
[0815] About 0.125% azelastine, about 0.1% steroid and about 0.1%
leukotriene antagonist;
[0816] About 0.15% azelastine, about 0.1% steroid and about 0.1%
leukotriene antagonist;
[0817] About 0.05% azelastine, about 0.01% steroid and about 0.5%
leukotriene antagonist;
[0818] About 0.1% azelastine, about 0.01% steroid and about 0.5%
leukotriene antagonist;
[0819] About 0.125% azelastine, about 0.01% steroid and about 0.5%
leukotriene antagonist;
[0820] About 0.15% azelastine, about 0.01% steroid and about 0.5%
leukotriene antagonist;
[0821] About 0.05% azelastine, about 0.05% steroid and about 0.5%
leukotriene antagonist;
[0822] About 0.1% azelastine, about 0.05% steroid and about 0.5%
leukotriene antagonist;
[0823] About 0.125% azelastine, about 0.05% steroid and about 0.5%
leukotriene antagonist;
[0824] About 0.15% azelastine, about 0.05% steroid and about 0.5%
leukotriene antagonist;
[0825] About 0.05% azelastine, about 0.1% steroid and about 0.5%
leukotriene antagonist;
[0826] About 0.1% azelastine, about 0.1% steroid and about 0.5%
leukotriene antagonist;
[0827] About 0.125% azelastine, about 0.1% steroid and about 0.5%
leukotriene antagonist;
[0828] About 0.15% azelastine, about 0.1% steroid and about 0.5%
leukotriene antagonist;
[0829] About 0.05% azelastine, about 0.01% steroid and about 5.0%
leukotriene antagonist;
[0830] About 0.1% azelastine, about 0.01% steroid and about 5.0%
leukotriene antagonist;
[0831] About 0.125% azelastine, about 0.01% steroid and about 5.0%
leukotriene antagonist;
[0832] About 0.15% azelastine, about 0.01% steroid and about 5.0%
leukotriene antagonist;
[0833] About 0.05% azelastine, about 0.05% steroid and about 5.0%
leukotriene antagonist;
[0834] About 0.1% azelastine, about 0.05% steroid and about 5.0%
leukotriene antagonist;
[0835] About 0.125% azelastine, about 0.05% steroid and about 5.0%
leukotriene antagonist;
[0836] About 0.15% azelastine, about 0.05% steroid and about 5.0%
leukotriene antagonist;
[0837] About 0.05% azelastine, about 0.1% steroid and about 5.0%
leukotriene antagonist;
[0838] About 0.1% azelastine, about 0.1% steroid and about 5.0%
leukotriene antagonist;
[0839] About 0.125% azelastine, about 0.1% steroid and about 5.0%
leukotriene antagonist;
[0840] About 0.15% azelastine, about 0.1% steroid and about 5.0%
leukotriene antagonist;
[0841] About 0.05% azelastine, about 0.01% steroid, about 0.1%
leukotriene antagonist and about 0.05% sucralose;
[0842] About 0.1% azelastine, about 0.01% steroid, about 0.1%
leukotriene antagonist and about 0.05% sucralose;
[0843] About 0.125% azelastine, about 0.01% steroid, about 0.1%
leukotriene antagonist and about 0.05% sucralose;
[0844] About 0.15% azelastine, about 0.01% steroid, about 0.1%
leukotriene antagonist and about 0.05% sucralose;
[0845] About 0.05% azelastine, about 0.05% steroid, about 0.1%
leukotriene antagonist and about 0.05% sucralose;
[0846] About 0.1% azelastine, about 0.05% steroid, about 0.1%
leukotriene antagonist and about 0.05% sucralose;
[0847] About 0.125% azelastine, about 0.05% steroid, about 0.1%
leukotriene antagonist and about 0.05% sucralose;
[0848] About 0.15% azelastine, about 0.05% steroid, about 0.1%
leukotriene antagonist and about 0.05% sucralose;
[0849] About 0.05% azelastine, about 0.1% steroid, about 0.1%
leukotriene antagonist and about 0.05% sucralose;
[0850] About 0.1% azelastine, about 0.1% steroid, about 0.1%
leukotriene antagonist and about 0.05% sucralose;
[0851] About 0.125% azelastine, about 0.1% steroid, about 0.1%
leukotriene antagonist and about 0.05% sucralose;
[0852] About 0.15% azelastine, about 0.1% steroid, about 0.1%
leukotriene antagonist and about 0.05% sucralose;
[0853] About 0.05% azelastine, about 0.01% steroid, about 0.5%
leukotriene antagonist and about 0.05% sucralose;
[0854] About 0.1% azelastine, about 0.01% steroid, about 0.5%
leukotriene antagonist and about 0.05% sucralose;
[0855] About 0.125% azelastine, about 0.01% steroid, about 0.5%
leukotriene antagonist and about 0.05% sucralose;
[0856] About 0.15% azelastine, about 0.01% steroid, about 0.5%
leukotriene antagonist and about 0.05% sucralose;
[0857] About 0.05% azelastine, about 0.05% steroid, about 0.5%
leukotriene antagonist and about 0.05% sucralose;
[0858] About 0.1% azelastine, about 0.05% steroid, about 0.5%
leukotriene antagonist and about 0.05% sucralose;
[0859] About 0.125% azelastine, about 0.05% steroid, about 0.5%
leukotriene antagonist and about 0.05% sucralose;
[0860] About 0.15% azelastine, about 0.05% steroid, about 0.5%
leukotriene antagonist and about 0.05% sucralose;
[0861] About 0.05% azelastine, about 0.1% steroid, about 0.5%
leukotriene antagonist and about 0.05% sucralose;
[0862] About 0.1% azelastine, about 0.1% steroid, about 0.5%
leukotriene antagonist and about 0.05% sucralose;
[0863] About 0.125% azelastine, about 0.1% steroid, about 0.5%
leukotriene antagonist and about 0.05% sucralose;
[0864] About 0.15% azelastine, about 0.1% steroid, about 0.5%
leukotriene antagonist and about 0.05% sucralose;
[0865] About 0.05% azelastine, about 0.01% steroid, about 5.0%
leukotriene antagonist and about 0.05% sucralose;
[0866] About 0.1% azelastine, about 0.01% steroid, about 5.0%
leukotriene antagonist and about 0.05% sucralose;
[0867] About 0.125% azelastine, about 0.01% steroid, about 5.0%
leukotriene antagonist and about 0.05% sucralose;
[0868] About 0.15% azelastine, about 0.01% steroid, about 5.0%
leukotriene antagonist and about 0.05% sucralose;
[0869] About 0.05% azelastine, about 0.05% steroid, about 5.0%
leukotriene antagonist and about 0.05% sucralose;
[0870] About 0.1% azelastine, about 0.05% steroid, about 5.0%
leukotriene antagonist and about 0.05% sucralose;
[0871] About 0.125% azelastine, about 0.05% steroid, about 5.0%
leukotriene antagonist and about 0.05% sucralose;
[0872] About 0.15% azelastine, about 0.05% steroid, about 5.0%
leukotriene antagonist and about 0.05% sucralose;
[0873] About 0.05% azelastine, about 0.1% steroid, about 5.0%
leukotriene antagonist and about 0.05% sucralose;
[0874] About 0.1% azelastine, about 0.1% steroid, about 5.0%
leukotriene antagonist and about 0.05% sucralose;
[0875] About 0.125% azelastine, about 0.1% steroid, about 5.0%
leukotriene antagonist and about 0.05% sucralose;
[0876] About 0.15% azelastine, about 0.1% steroid, about 5.0%
leukotriene antagonist and about 0.05% sucralose;
[0877] About 0.05% azelastine, about 0.01% steroid, about 0.1%
leukotriene antagonist and about 0.1% sucralose;
[0878] About 0.1% azelastine, about 0.01% steroid, about 0.1%
leukotriene antagonist and about 0.1% sucralose;
[0879] About 0.125% azelastine, about 0.01% steroid, about 0.1%
leukotriene antagonist and about 0.1% sucralose;
[0880] About 0.15% azelastine, about 0.01% steroid, about 0.1%
leukotriene antagonist and about 0.1% sucralose;
[0881] About 0.05% azelastine, about 0.05% steroid, about 0.1%
leukotriene antagonist and about 0.1% sucralose;
[0882] About 0.1% azelastine, about 0.05% steroid, about 0.1%
leukotriene antagonist and about 0.1% sucralose;
[0883] About 0.125% azelastine, about 0.05% steroid, about 0.1%
leukotriene antagonist and about 0.1% sucralose;
[0884] About 0.15% azelastine, about 0.05% steroid, about 0.1%
leukotriene antagonist and about 0.1% sucralose;
[0885] About 0.05% azelastine, about 0.1% steroid, about 0.1%
leukotriene antagonist and about 0.1% sucralose;
[0886] About 0.1% azelastine, about 0.1% steroid, about 0.1%
leukotriene antagonist and about 0.1% sucralose;
[0887] About 0.125% azelastine, about 0.1% steroid, about 0.1%
leukotriene antagonist and about 0.1% sucralose;
[0888] About 0.15% azelastine, about 0.1% steroid, about 0.1%
leukotriene antagonist and about 0.1% sucralose;
[0889] About 0.05% azelastine, about 0.01% steroid, about 0.5%
leukotriene antagonist and about 0.1% sucralose;
[0890] About 0.1% azelastine, about 0.01% steroid, about 0.5%
leukotriene antagonist and about 0.1% sucralose;
[0891] About 0.125% azelastine, about 0.01% steroid, about 0.5%
leukotriene antagonist and about 0.1% sucralose;
[0892] About 0.15% azelastine, about 0.01% steroid, about 0.5%
leukotriene antagonist and about 0.1% sucralose;
[0893] About 0.05% azelastine, about 0.05% steroid, about 0.5%
leukotriene antagonist and about 0.1% sucralose;
[0894] About 0.1% azelastine, about 0.05% steroid, about 0.5%
leukotriene antagonist and about 0.1% sucralose;
[0895] About 0.125% azelastine, about 0.05% steroid, about 0.5%
leukotriene antagonist and about 0.1% sucralose;
[0896] About 0.15% azelastine, about 0.05% steroid, about 0.5%
leukotriene antagonist and about 0.1% sucralose;
[0897] About 0.05% azelastine, about 0.1% steroid, about 0.5%
leukotriene antagonist and about 0.1% sucralose;
[0898] About 0.1% azelastine, about 0.1% steroid, about 0.5%
leukotriene antagonist and about 0.1% sucralose;
[0899] About 0.125% azelastine, about 0.1% steroid, about 0.5%
leukotriene antagonist and about 0.1% sucralose;
[0900] About 0.15% azelastine, about 0.1% steroid, about 0.5%
leukotriene antagonist and about 0.1% sucralose;
[0901] About 0.05% azelastine, about 0.01% steroid, about 5.0%
leukotriene antagonist and about 0.1% sucralose;
[0902] About 0.1% azelastine, about 0.01% steroid, about 5.0%
leukotriene antagonist and about 0.1% sucralose;
[0903] About 0.125% azelastine, about 0.01% steroid, about 5.0%
leukotriene antagonist and about 0.1% sucralose;
[0904] About 0.15% azelastine, about 0.01% steroid, about 5.0%
leukotriene antagonist and about 0.1% sucralose;
[0905] About 0.05% azelastine, about 0.05% steroid, about 5.0%
leukotriene antagonist and about 0.1% sucralose;
[0906] About 0.1% azelastine, about 0.05% steroid, about 5.0%
leukotriene antagonist and about 0.1% sucralose;
[0907] About 0.125% azelastine, about 0.05% steroid, about 5.0%
leukotriene antagonist and about 0.1% sucralose;
[0908] About 0.15% azelastine, about 0.05% steroid, about 5.0%
leukotriene antagonist and about 0.1% sucralose;
[0909] About 0.05% azelastine, about 0.1% steroid, about 5.0%
leukotriene antagonist and about 0.1% sucralose;
[0910] About 0.1% azelastine, about 0.1% steroid, about 5.0%
leukotriene antagonist and about 0.1% sucralose;
[0911] About 0.125% azelastine, about 0.1% steroid, about 5.0%
leukotriene antagonist and about 0.1% sucralose;
[0912] About 0.15% azelastine, about 0.1% steroid, about 5.0%
leukotriene antagonist and about 0.1% sucralose;
[0913] About 0.05% azelastine, about 0.01% steroid, about 0.1%
leukotriene antagonist and about 0.15% sucralose;
[0914] About 0.1% azelastine, about 0.01% steroid, about 0.1%
leukotriene antagonist and about 0.15% sucralose;
[0915] About 0.125% azelastine, about 0.01% steroid, about 0.1%
leukotriene antagonist and about 0.15% sucralose;
[0916] About 0.15% azelastine, about 0.01% steroid, about 0.1%
leukotriene antagonist and about 0.15% sucralose;
[0917] About 0.05% azelastine, about 0.05% steroid, about 0.1%
leukotriene antagonist and about 0.15% sucralose;
[0918] About 0.1% azelastine, about 0.05% steroid, about 0.1%
leukotriene antagonist and about 0.15% sucralose;
[0919] About 0.125% azelastine, about 0.05% steroid, about 0.1%
leukotriene antagonist and about 0.15% sucralose;
[0920] About 0.15% azelastine, about 0.05% steroid, about 0.1%
leukotriene antagonist and about 0.15% sucralose;
[0921] About 0.05% azelastine, about 0.1% steroid, about 0.1%
leukotriene antagonist and about 0.15% sucralose;
[0922] About 0.1% azelastine, about 0.1% steroid, about 0.1%
leukotriene antagonist and about 0.15% sucralose;
[0923] About 0.125% azelastine, about 0.1% steroid, about 0.1%
leukotriene antagonist and about 0.15% sucralose;
[0924] About 0.15% azelastine, about 0.1% steroid, about 0.1%
leukotriene antagonist and about 0.15% sucralose;
[0925] About 0.05% azelastine, about 0.01% steroid, about 0.5%
leukotriene antagonist and about 0.15% sucralose;
[0926] About 0.1% azelastine, about 0.01% steroid, about 0.5%
leukotriene antagonist and about 0.15% sucralose;
[0927] About 0.125% azelastine, about 0.01% steroid, about 0.5%
leukotriene antagonist and about 0.15% sucralose;
[0928] About 0.15% azelastine, about 0.01% steroid, about 0.5%
leukotriene antagonist and about 0.15% sucralose;
[0929] About 0.05% azelastine, about 0.05% steroid, about 0.5%
leukotriene antagonist and about 0.15% sucralose;
[0930] About 0.1% azelastine, about 0.05% steroid, about 0.5%
leukotriene antagonist and about 0.15% sucralose;
[0931] About 0.125% azelastine, about 0.05% steroid, about 0.5%
leukotriene antagonist and about 0.15% sucralose;
[0932] About 0.15% azelastine, about 0.05% steroid, about 0.5%
leukotriene antagonist and about 0.15% sucralose;
[0933] About 0.05% azelastine, about 0.1% steroid, about 0.5%
leukotriene antagonist and about 0.15% sucralose;
[0934] About 0.1% azelastine, about 0.1% steroid, about 0.5%
leukotriene antagonist and about 0.15% sucralose;
[0935] About 0.125% azelastine, about 0.1% steroid, about 0.5%
leukotriene antagonist and about 0.15% sucralose;
[0936] About 0.15% azelastine, about 0.1% steroid, about 0.5%
leukotriene antagonist and about 0.15% sucralose;
[0937] About 0.05% azelastine, about 0.01% steroid, about 5.0%
leukotriene antagonist and about 0.15% sucralose;
[0938] About 0.1% azelastine, about 0.01% steroid, about 5.0%
leukotriene antagonist and about 0.15% sucralose;
[0939] About 0.125% azelastine, about 0.01% steroid, about 5.0%
leukotriene antagonist and about 0.15% sucralose;
[0940] About 0.15% azelastine, about 0.01% steroid, about 5.0%
leukotriene antagonist and about 0.15% sucralose;
[0941] About 0.05% azelastine, about 0.05% steroid, about 5.0%
leukotriene antagonist and about 0.15% sucralose;
[0942] About 0.1% azelastine, about 0.05% steroid, about 5.0%
leukotriene antagonist and about 0.15% sucralose;
[0943] About 0.125% azelastine, about 0.05% steroid, about 5.0%
leukotriene antagonist and about 0.15% sucralose;
[0944] About 0.15% azelastine, about 0.05% steroid, about 5.0%
leukotriene antagonist and about 0.15% sucralose;
[0945] About 0.05% azelastine, about 0.1% steroid, about 5.0%
leukotriene antagonist and about 0.15% sucralose;
[0946] About 0.1% azelastine, about 0.1% steroid, about 5.0%
leukotriene antagonist and about 0.15% sucralose;
[0947] About 0.125% azelastine, about 0.1% steroid, about 5.0%
leukotriene antagonist and about 0.15% sucralose;
[0948] About 0.15% azelastine, about 0.1% steroid, about 5.0%
leukotriene antagonist and about 0.15% sucralose;
[0949] About 0.05% azelastine, about 0.01% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone and about 0.1% montelukast;
[0950] About 0.1% azelastine, about 0.01% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone and about 0.1% montelukast;
[0951] About 0.125% azelastine, about 0.01% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone and about 0.1% montelukast;
[0952] About 0.15% azelastine, about 0.01% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone and about 0.1% montelukast;
[0953] About 0.05% azelastine, about 0.05% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone and about 0.1% montelukast;
[0954] About 0.1% azelastine, about 0.05% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone and about 0.1% montelukast;
[0955] About 0.125% azelastine, about 0.05% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone and about 0.1% montelukast;
[0956] About 0.15% azelastine, about 0.05% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone and about 0.1% montelukast;
[0957] About 0.05% azelastine, about 0.1% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone and about 0.1% montelukast;
[0958] About 0.1% azelastine, about 0.1% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone and about 0.1% montelukast;
[0959] About 0.125% azelastine, about 0.1% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone and about 0.1% montelukast;
[0960] About 0.15% azelastine, about 0.1% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone and about 0.1% montelukast;
[0961] About 0.05% azelastine, about 0.01% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone and about 0.5% montelukast;
[0962] About 0.1% azelastine, about 0.01% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone and about 0.5% montelukast;
[0963] About 0.125% azelastine, about 0.01% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone and about 0.5% montelukast;
[0964] About 0.15% azelastine, about 0.01% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone and about 0.5% montelukast;
[0965] About 0.05% azelastine, about 0.05% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone and about 0.5% montelukast;
[0966] About 0.1% azelastine, about 0.05% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone and about 0.5% montelukast;
[0967] About 0.125% azelastine, about 0.05% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone and about 0.5% montelukast;
[0968] About 0.15% azelastine, about 0.05% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone and about 0.5% montelukast;
[0969] About 0.05% azelastine, about 0.1% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone and about 0.5% montelukast;
[0970] About 0.1% azelastine, about 0.1% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone and about 0.5% montelukast;
[0971] About 0.125% azelastine, about 0.1% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone and about 0.5% montelukast;
[0972] About 0.15% azelastine, about 0.1% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone and about 0.5% montelukast;
[0973] About 0.05% azelastine, about 0.01% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone and about 5.0% montelukast;
[0974] About 0.1% azelastine, about 0.01% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone and about 5.0% montelukast;
[0975] About 0.125% azelastine, about 0.01% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone and about 5.0% montelukast;
[0976] About 0.15% azelastine, about 0.01% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone and about 5.0% montelukast;
[0977] About 0.05% azelastine, about 0.05% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone and about 5.0% montelukast;
[0978] About 0.1% azelastine, about 0.05% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone and about 5.0% montelukast;
[0979] About 0.125% azelastine, about 0.05% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone and about 5.0% montelukast;
[0980] About 0.15% azelastine, about 0.05% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone and about 5.0% montelukast;
[0981] About 0.05% azelastine, about 0.1% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone and about 5.0% montelukast;
[0982] About 0.1% azelastine, about 0.1% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone and about 5.0% montelukast;
[0983] About 0.125% azelastine, about 0.1% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone and about 5.0% montelukast;
[0984] About 0.15% azelastine, about 0.1% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone and about 5.0% montelukast;
[0985] About 0.05% azelastine, about 0.01% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone, about 0.1% montelukast and about
0.05% sucralose;
[0986] About 0.1% azelastine, about 0.01% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone, about 0.1% montelukast and about
0.05% sucralose;
[0987] About 0.125% azelastine, about 0.01% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone, about 0.1% montelukast and about
0.05% sucralose;
[0988] About 0.15% azelastine, about 0.01% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone, about 0.1% montelukast and about
0.05% sucralose;
[0989] About 0.05% azelastine, about 0.05% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone, about 0.1% montelukast and about
0.05% sucralose;
[0990] About 0.1% azelastine, about 0.05% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone, about 0.1% montelukast and about
0.05% sucralose;
[0991] About 0.125% azelastine, about 0.05% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone, about 0.1% montelukast and about
0.05% sucralose;
[0992] About 0.15% azelastine, about 0.05% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone, about 0.1% montelukast and about
0.05% sucralose;
[0993] About 0.05% azelastine, about 0.1% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone, about 0.1% montelukast and about
0.05% sucralose;
[0994] About 0.1% azelastine, about 0.1% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone, about 0.1% montelukast and about
0.05% sucralose;
[0995] About 0.125% azelastine, about 0.1% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone, about 0.1% montelukast and about
0.05% sucralose;
[0996] About 0.15% azelastine, about 0.1% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate);
budesonide, or triamcinolone, about 0.1% montelukast and about
0.05% sucralose;
[0997] About 0.05% azelastine, about 0.01% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone, about 0.5% montelukast and about
0.05% sucralose;
[0998] About 0.1% azelastine, about 0.01% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone, about 0.5% montelukast and about
0.05% sucralose;
[0999] About 0.125% azelastine, about 0.01% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone, about 0.5% montelukast and about
0.05% sucralose;
[1000] About 0.15% azelastine, about 0.01% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone, about 0.5% montelukast and about
0.05% sucralose;
[1001] About 0.05% azelastine, about 0.05% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone, about 0.5% montelukast and about
0.05% sucralose;
[1002] About 0.1% azelastine, about 0.05% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone, about 0.5% montelukast and about
0.05% sucralose;
[1003] About 0.125% azelastine, about 0.05% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone, about 0.5% montelukast and about
0.05% sucralose;
[1004] About 0.15% azelastine, about 0.05% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone, about 0.5% montelukast and about
0.05% sucralose;
[1005] About 0.05% azelastine, about 0.1% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone, about 0.5% montelukast and about
0.05% sucralose;
[1006] About 0.1% azelastine, about 0.1% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone, about 0.5% montelukast and about
0.05% sucralose;
[1007] About 0.125% azelastine, about 0.1% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone, about 0.5% montelukast and about
0.05% sucralose;
[1008] About 0.15% azelastine, about 0.1% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone, about 0.5% montelukast and about
0.05% sucralose;
[1009] About 0.05% azelastine, about 0.01% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone, about 5.0% montelukast and about
0.05% sucralose;
[1010] About 0.1% azelastine, about 0.01% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone, about 5.0% montelukast and about
0.05% sucralose;
[1011] About 0.125% azelastine, about 0.01% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone, about 5.0% montelukast and about
0.05% sucralose;
[1012] About 0.15% azelastine, about 0.01% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone, about 5.0% montelukast and about
0.05% sucralose;
[1013] About 0.05% azelastine, about 0.05% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone, about 5.0% montelukast and about
0.05% sucralose;
[1014] About 0.1% azelastine, about 0.05% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone, about 5.0% montelukast and about
0.05% sucralose;
[1015] About 0.125% azelastine, about 0.05% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone, about 5.0% montelukast and about
0.05% sucralose;
[1016] About 0.15% azelastine, about 0.05% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone, about 5.0% montelukast and about
0.05% sucralose;
[1017] About 0.05% azelastine, about 0.1% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone, about 5.0% montelukast and about
0.05% sucralose;
[1018] About 0.1% azelastine, about 0.1% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone, about 5.0% montelukast and about
0.05% sucralose;
[1019] About 0.125% azelastine, about 0.1% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone, about 5.0% montelukast and about
0.05% sucralose;
[1020] About 0.15% azelastine, about 0.1% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone, about 5.0% montelukast and about
0.05% sucralose;
[1021] About 0.05% azelastine, about 0.01% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone, about 0.1% montelukast and about 0.1%
sucralose;
[1022] About 0.1% azelastine, about 0.01% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone, about 0.1% montelukast and about 0.1%
sucralose;
[1023] About 0.125% azelastine, about 0.01% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone, about 0.1% montelukast and about 0.1%
sucralose;
[1024] About 0.15% azelastine, about 0.01% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone, about 0.1% montelukast and about 0.1%
sucralose;
[1025] About 0.05% azelastine, about 0.05% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone, about 0.1% montelukast and about 0.1%
sucralose;
[1026] About 0.1% azelastine, about 0.05% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone, about 0.1% montelukast and about 0.1%
sucralose;
[1027] About 0.125% azelastine, about 0.05% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone, about 0.1% montelukast and about 0.1%
sucralose;
[1028] About 0.15% azelastine, about 0.05% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone, about 0.1% montelukast and about 0.1%
sucralose;
[1029] About 0.05% azelastine, about 0.1% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone, about 0.1% montelukast and about 0.1%
sucralose;
[1030] About 0.1% azelastine, about 0.1% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone, about 0.1% montelukast and about 0.1%
sucralose;
[1031] About 0.125% azelastine, about 0.1% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone, about 0.1% montelukast and about 0.1%
sucralose;
[1032] About 0.15% azelastine, about 0.1% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone, about 0.1% montelukast and about 0.1%
sucralose;
[1033] About 0.05% azelastine, about 0.01% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone, about 0.5% montelukast and about 0.1%
sucralose;
[1034] About 0.1% azelastine, about 0.01% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone, about 0.5% montelukast and about 0.1%
sucralose;
[1035] About 0.125% azelastine, about 0.01% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone, about 0.5% montelukast and about 0.1%
sucralose;
[1036] About 0.15% azelastine, about 0.01% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone, about 0.5% montelukast and about 0.1%
sucralose;
[1037] About 0.05% azelastine, about 0.05% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone, about 0.5% montelukast and about 0.1%
sucralose;
[1038] About 0.1% azelastine, about 0.05% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone, about 0.5% montelukast and about 0.1%
sucralose;
[1039] About 0.125% azelastine, about 0.05% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone, about 0.5% montelukast and about 0.1%
sucralose;
[1040] About 0.15% azelastine, about 0.05% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone, about 0.5% montelukast and about 0.1%
sucralose;
[1041] About 0.05% azelastine, about 0.1% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone, about 0.5% montelukast and about 0.1%
sucralose;
[1042] About 0.1% azelastine, about 0.1% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone, about 0.5% montelukast and about 0.1%
sucralose;
[1043] About 0.125% azelastine, about 0.1% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone, about 0.5% montelukast and about 0.1%
sucralose;
[1044] About 0.15% azelastine, about 0.1% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone, about 0.5% montelukast and about 0.1%
sucralose;
[1045] About 0.05% azelastine, about 0.01% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone, about 5.0% montelukast and about 0.1%
sucralose;
[1046] About 0.1% azelastine, about 0.01% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone, about 5.0% montelukast and about 0.1%
sucralose;
[1047] About 0.125% azelastine, about 0.01% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone, about 5.0% montelukast and about 0.1%
sucralose;
[1048] About 0.15% azelastine, about 0.01% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone, about 5.0% montelukast and about 0.1%
sucralose;
[1049] About 0.05% azelastine, about 0.05% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone, about 5.0% montelukast and about 0.1%
sucralose;
[1050] About 0.1% azelastine, about 0.05% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone, about 5.0% montelukast and about 0.1%
sucralose;
[1051] About 0.125% azelastine, about 0.05% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone, about 5.0% montelukast and about 0.1%
sucralose;
[1052] About 0.15% azelastine, about 0.05% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone, about 5.0% montelukast and about 0.1%
sucralose;
[1053] About 0.05% azelastine, about 0.1% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone, about 5.0% montelukast and about 0.1%
sucralose;
[1054] About 0.1% azelastine, about 0.1% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone, about 5.0% montelukast and about 0.1%
sucralose;
[1055] About 0.125% azelastine, about 0.1% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone, about 5.0% montelukast and about 0.1%
sucralose;
[1056] About 0.15% azelastine, about 0.1% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone, about 5.0% montelukast and about 0.1%
sucralose;
[1057] About 0.05% azelastine, about 0.01% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone, about 0.1% montelukast and about
0.15% sucralose;
[1058] About 0.1% azelastine, about 0.01% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone, about 0.1% montelukast and about
0.15% sucralose;
[1059] About 0.125% azelastine, about 0.01% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone, about 0.1% montelukast and about
0.15% sucralose;
[1060] About 0.15% azelastine, about 0.01% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone, about 0.1% montelukast and about
0.15% sucralose;
[1061] About 0.05% azelastine, about 0.05% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone, about 0.1% montelukast and about
0.15% sucralose;
[1062] About 0.1% azelastine, about 0.05% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone, about 0.1% montelukast and about
0.15% sucralose;
[1063] About 0.125% azelastine, about 0.05% fluticasone,
mometasone, dexamethasone beloxil, loteprednol (e.g., loteprednol
etabonate), budesonide, or triamcinolone, about 0.1% montelukast
and about 0.15% sucralose;
[1064] About 0.15% azelastine, about 0.05% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone, about 0.1% montelukast and about
0.15% sucralose;
[1065] About 0.05% azelastine, about 0.1% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone, about 0.1% montelukast and about
0.15% sucralose;
[1066] About 0.1% azelastine, about 0.1% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone, about 0.1% montelukast and about
0.15% sucralose;
[1067] About 0.125% azelastine, about 0.1% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone, about 0.1% montelukast and about
0.15% sucralose;
[1068] About 0.15% azelastine, about 0.1% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone, about 0.1% montelukast and about
0.15% sucralose;
[1069] About 0.05% azelastine, about 0.01% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone, about 0.5% montelukast and about
0.15% sucralose;
[1070] About 0.1% azelastine, about 0.01% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone, about 0.5% montelukast and about
0.15% sucralose;
[1071] About 0.125% azelastine, about 0.01% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone, about 0.5% montelukast and about
0.15% sucralose;
[1072] About 0.15% azelastine, about 0.01% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone, about 0.5% montelukast and about
0.15% sucralose;
[1073] About 0.05% azelastine, about 0.05% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone, about 0.5% montelukast and about
0.15% sucralose;
[1074] About 0.1% azelastine, about 0.05% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone, about 0.5% montelukast and about
0.15% sucralose;
[1075] About 0.125% azelastine, about 0.05% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone, about 0.5% montelukast and about
0.15% sucralose;
[1076] About 0.15% azelastine, about 0.05% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone, about 0.5% montelukast and about
0.15% sucralose;
[1077] About 0.05% azelastine, about 0.1% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone, about 0.5% montelukast and about
0.15% sucralose;
[1078] About 0.1% azelastine, about 0.1% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone, about 0.5% montelukast and about
0.15% sucralose;
[1079] About 0.125% azelastine, about 0.1% fluticasone, mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone, about 0.5% montelukast and about
0.15% sucralose;
[1080] About 0.15% azelastine, about 0.1% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone, about 0.5% montelukast and about
0.15% sucralose;
[1081] About 0.05% azelastine, about 0.01% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone, about 5.0% montelukast and about
0.15% sucralose;
[1082] About 0.1% azelastine, about 0.01% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone, about 5.0% montelukast and about
0.15% sucralose;
[1083] About 0.125% azelastine, about 0.01% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone, about 5.0% montelukast and about
0.15% sucralose;
[1084] About 0.15% azelastine, about 0.01% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone, about 5.0% montelukast and about
0.15% sucralose;
[1085] About 0.05% azelastine, about 0.05% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone, about 5.0% montelukast and about
0.15% sucralose;
[1086] About 0.1% azelastine, about 0.05% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone, about 5.0% montelukast and about
0.15% sucralose;
[1087] About 0.125% azelastine, about 0.05% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone, about 5.0% montelukast and about
0.15% sucralose;
[1088] About 0.15% azelastine, about 0.05% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone, about 5.0% montelukast and about
0.15% sucralose;
[1089] About 0.05% azelastine, about 0.1% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone, about 5.0% montelukast and about
0.15% sucralose;
[1090] About 0.1% azelastine, about 0.1% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone, about 5.0% montelukast and about
0.15% sucralose;
[1091] About 0.125% azelastine, about 0.1% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone, about 5.0% montelukast and about
0.15% sucralose;
[1092] About 0.15% azelastine, about 0.1% fluticasone (e.g.,
fluticasone propionate or fluticasone dipropionate), mometasone,
dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate),
budesonide, or triamcinolone, about 5.0% montelukast and about
0.15% sucralose;
Chewable and/or Orally Dissolving Formulations
[1093] Chewable Formulations
[1094] In addition to the solid dosage forms disclosed throughout,
the present invention also provides chewable oral formulations. In
certain such embodiments, the formulations will comprise (or
consist essentially of) an effective amount of azelastine (e.g.,
azelastine HCl) along with suitable excipients that allow the
formulations to be chewed by the patient. In additional
embodiments, the formulations can further comprise one or more
taste-masking or sweetening agents, such as those described herein.
In one embodiment, sucralose is used in the chewable formulations.
Additional active agents, such as those described herein, can also
optionally be added to the chewable formulations. The amounts of
azelastine, other optional active agents (e.g., steroids,
decongestants, leukotriene antagonists, and combinations thereof),
and sweetening agents (e.g., sucralose) in the chewable
formulations of the present invention are readily determinable by
those of ordinary skill in the art, and include those amounts and
combinations described herein. For example, the chewable
formulations of the present invention comprise (or consist
essentially of) about 0.05% to about 5% azelastine, optionally
about 0.01% to about 10% other active agent(s) (or more as
required), and about 0.05% to about 0.15% sucralose. Such chewable
formulations are especially useful in patient populations where
compliance is an issue, such as children, the elderly, and patients
who may have difficulty swallowing or using spray/inhalable
formulations.
[1095] The formulations may also contain colorants to improve the
appearance of the chewable formulations, especially since an
attractive coloration imparted by a colorant may improve patient
compliance. The relative amounts of the colorants selected will
vary depending upon the particular hue of the individual colorants
and the resultant color desired.
[1096] Any standard pharmaceutically acceptable excipient can be
used in the chewable tablet formulations which provides adequate
compression such as diluents (e.g., mannitol, xylitol, maltitol,
lactitol, sorbitol, lactose, sucrose, and compressible sugars such
as DiPac.RTM. (dextrinized sucrose), available from Austin Products
Inc. (Holmdel, N.J.), binders, disintegrants, splitting or swelling
agents (e.g., polyvinyl polypyrrolidone, croscarmellose sodium
(e.g., Ac-Di-Sol available from FMC BioPolymer, Philadelphia, Pa.),
starches and derivatives, cellulose and derivatives,
microcrystalline celluloses, such as Avicel.TM. PH 101 or
Avicel.TM. CE-15 (a microcrystalline modified with guar gum), both
available from FMC BioPolymer, (Philadelphia, Pa.), lubricating
agents (e.g., magnesium stearate), and flow agents (e.g., colloidal
silicon dioxide, such as Cab-O-Sil M5.RTM. available from Cabot
Corporation, Kokomo, Ind.).
[1097] Suitable amounts of sweetener (e.g., sucralose) used in the
chewable formulations, will be familiar to, and can be readily
determined by, those skilled in the art. In certain embodiments,
the sweetener is present in an amount from about 0.05% to about
5.0% (e.g., about 0.05%, about 0.1%, about 0.125%, about 0.15%,
about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about
0.7%, about 0.8%, about 0.9%, about 1%, about 1.25% about 1.5%,
about 1.75%, about 2%, about 2.25%, about 2.5%, about 2.75%, about
3%, about 3.25%, about 3.5%, about 3.75%, about 4%, about 4.25%,
about 4.5%, about 4.75% or about 5%). Those or ordinary skill in
the art will appreciate that the amount of sweetener may vary
depending on the strength of the particular sweetener used and the
levels approved by the regulatory authorities for use in
pharmaceutical products.
[1098] Suitable cyclodextrins for use in the chewable formulations
of the present invention include .alpha., .beta., or .gamma.
cyclodextrins, or an alkylated or hydroxyalkylated derivatives
thereof, such as heptakis (2,6-di-o-methyl)-.beta.-cyclodextrin
(DIMEB), randomly methylated .beta.-cyclodextrin (RAMEB), and
hydroxypropyl .beta.-cyclodextrin (HPPCD). A suitable cyclodextrin
is .beta.-cyclodextrin (available from Cerestar USA, Inc., Hammond,
Ind. or from Roquette America, Inc., Keokuk. IA under the trade
name Kleptose.TM.). If desired, the complex of the active substance
with cyclodextrin can be prepared in advance, for example, by
malaxating or granulating the azelastine and any additional active
substance(s) and the cyclodextrin in the presence of water, or by
preparing an aqueous solution containing the azelastine and any
additional active substance(s) and the cyclodextrin in the desired
molar ratio. Alternatively, the azelastine and any additional
active substance(s) and the cyclodextrin can be simply mixed with
other excipients and adjuvants. The molar ratio of the azelastine
and any additional active substance(s) to cyclodextrin is suitably
from about 1.0:1.0 to about 4.0:1.0.
[1099] A typical manufacturing process for making either a single
layer or bi-layer chewable tablet generally involves blending of
the desired ingredients to form a uniform distribution of the
azelastine (and any other active agent(s)), excipients (e.g.,
colorants and flavoring agents as well as others). If desired, an
inclusion complex of the azelastine and any other active agent(s)
and cyclodextrin (e.g., .beta.-cyclodextrin) may be formed prior to
blending into the mixture by malaxating the azelastine and any
other active agent(s) and cyclodextrin in the presence of water in
a planetary mixer for about 20 minutes. The mixture is then dried
in a drying oven. After drying, the complex is mixed with any
color/flavoring blend. The blend is then compressed into a single
layer or bi-layer tablet using standard methods well-known to those
skilled in the art (e.g., Kilian T-100 tablet press or Courtoy
292/43 rotary bi-layer press). The colorants and flavoring agents
may be added to both layers to form a uniform presentation of the
tablet. Methods for preparation of chewable tablets and various
components for use in the tablets can be found throughout the
detailed description section and the Examples of U.S. Patent
Publication No. 2003/0215503, the disclosure of which is
incorporated by reference herein for all purposes. Additional
chewable/orally dissolving tablets, and methods for their
manufacture, are disclosed in U.S. Patent Publication No.
2004/0265372 and U.S. Pat. No. 6,270,790, the disclosures of each
of which are incorporated by reference herein for all purposes.
[1100] Orally Disintegrating Tablets
[1101] In another embodiment, the present invention provides orally
disintegrating/orodispersible tablets, such as those disclosed in
U.S. Pat. No. 6,723,348, the disclosure of which is incorporated
herein by reference in its entirety for all purposes. The orally
disintegrating/orodispersible tablets suitably disintegrate in the
buccal cavity upon contact with saliva forming an easy-to-swallow
suspension. Such tablets comprise (or consist essentially of)
azelastine (e.g., azelastine HCl), and optionally, one or more
additional active agents (such as those described herein), in the
form of coated granules, and a mixture of excipients comprising at
least one disintegrating agent, a soluble diluent agent, a
lubricant and optionally a swelling agent, an antistatic (fluid
flow) agent, a permeabilising agent, taste-masking
agents/sweeteners, flavoring agents and colors. In certain such
embodiments, the disintegrating/orodispersible tablets comprise the
taste-masking agent sucralose. The amounts of azelastine, other
optional active agents (e.g., steroids, decongestants, leukotriene
antagonists, and combinations thereof), and sweetening agents
(e.g., sucralose) in the orally disintegrating tablet formulations
of the present invention are readily determinable by those of
ordinary skill in the art, and include those amounts and
combinations described herein. For example, the orally
disintegrating tablet formulations of the present invention
comprise about 0.1% to about 0.15% azelastine, optionally about
0.01% to about 10% other active agent(s) (or more as required), and
about 0.05% to about 0.15% sucralose.
[1102] In suitable embodiments, the particles/granules of
azelastine (and any other optional active agents) have a particle
size such that about 100% of the particles have an average size of
less than about 50 .mu.m. In suitable such embodiments, azelastine
(and any other optional active agents) are present as coated
granules.
[1103] In one embodiment, the disintegrating tablets according to
the invention comprise coated granules of azelastine (and
optionally, one or more additional active agents) or one of its
pharmaceutically acceptable salts (such as azelastine HCl), a
taste-masking agent such as sucralose, and a mixture of excipients,
the ratio of the mixture of excipients to the coated granules
suitably is about 0.4:1 to about 9:1, more suitable about 1.5:1 to
about 5:1, or about 2 to 3 parts by weight, the mixture of
excipients suitably comprising: at least one disintegrating agent,
a soluble diluent agent, a lubricant, and optionally a
permeabilising agent, a swelling agent, an antistatic agent,
flavoring agents and one or more coloring agents.
[1104] In suitable embodiments, the disintegrating agent is
selected from the group consisting of croscarmellose, available as
e.g. Ac-di-sol.TM., crospovidone available as e.g. Kollidon CL.TM.,
sodium starch glycolate and mixtures thereof.
[1105] According to one embodiment of the invention, the soluble
diluent is a polyol having less than 13 carbon atoms and being
either in the form of a directly compressible product with an
average particle size of about 100 to 500 .mu.m, or in the form of
a powder with an average particle size of less than about 100
.mu.m, this polyol suitably being selected from the group
consisting of mannitol, xylitol, sorbitol and maltitol. The
proportion of disintegrating agent suitably is from about 3 to
about 15% by weight, e.g., about 5 to about 15% by weight, and in
the case of a mixture, each disintegrating agent being present
between about 1 and about 10% by weight, e.g., about 5 to about 10%
by weight, and the proportion of soluble diluent agent being about
30 to about 90% by weight, e.g., about 40 to about 60% by weight,
based in each case on the weight of the tablet.
[1106] Suitable lubricants for use in the disintegrating tablets
include, but are not limited to, magnesium stearate, stearic acid,
sodium stearyl fumarate, micronised polyoxyethyleneglycol
(micronised Macrogol 6000), leukine, sodium benzoate and mixtures
thereof. The amount of lubricant generally is from about 0 to about
3%, e.g., from about 1 to about 2% by weight, based on the weight
of the tablet. The lubricant can be dispersed within the mixture of
excipients, or according to one embodiment, sprayed over the outer
surface of the tablet. Thus, according to one embodiment of the
disintegrating tablets of the invention, the lubricant is in powder
form and is, at least in part, disposed on the surface of the
tablets.
[1107] The permeabilising agent allows the creation of a
hydrophilic network which facilitates the penetration of saliva and
hence assists the disintegration of the tablet. Suitable
permeabilising agent include, but are not limited to, silica with a
high affinity for aqueous solvents, such as colloidal silica
(Aerosil.TM.), precipitated silica (Syloid.TM. FP 244),
maltodextrins, .beta.-cyclodextrins and mixtures thereof. The
amount of permeabilising agent suitably is between about 0 and
about 5%, e.g., from about 0.5 to about 2% by weight, based on the
weight of the tablet.
[1108] A swelling agent can be incorporated in the mixture of
excipients. Suitable swelling agents include, but are not limited
to, starch, modified starch or microcrystalline cellulose.
[1109] An antistatic agent can also be incorporated as a flow aid.
Suitable antistatic agents include, but are not limited to,
micronised or non-micronised talc, fumed silica (Aerosil.TM. R972),
colloidal silica (Aerosil.TM. 200), precipitated silica (Syloid.TM.
FP 244), and mixtures thereof.
[1110] According to one such embodiment of the invention, the
granules of azelastine or one of its pharmaceutically acceptable
salts (and optionally, one or more additional active agents such as
those described herein) are characterized in that the granules are
coated and comprise microcrystals of azelastine or one of its
pharmaceutically acceptable salts (e.g., azelastine HCl),
sucralose, at least one binder, and optionally a diluent agent, an
antistatic agent, and a coloring agent. Furthermore, the
granulation excipients can also include disintegrating agents
and/or surfactants.
[1111] Suitable binders include, but are not limited to, cellulosic
polymers, such as ethylcellulose, hydroxypropylcellulose and
hydroxypropylmethyl cellulose, acrylic polymers, such as insoluble
acrylate ammoniomethacrylate copolymer, polyacrylate or
polymethacrylic copolymer, povidones, copovidones,
polyvinylalcohols, alginic acid, sodium alginate, starch,
pregelatinized starch, sucrose and its derivatives, guar gum,
polyethylene glycol, for example an acrylic polymer, such as
Eudragit.TM. E100, and mixtures thereof.
[1112] Optionally, in order to enhance the granulation of the
azelastine (and one or more additional active agents) or one of its
pharmaceutically acceptable salts, a diluent agent can be used.
Suitable diluent agents include, but are not limited to,
microcrystalline cellulose, sucrose, dicalcium phosphate, starches,
lactose and polyols of less than 13 carbon atoms, such as mannitol,
xylitol, sorbitol, maltitol, pharmaceutically acceptable amino
acids, such as glycin, and their mixtures.
[1113] In one embodiment, a granule of azelastine or one of its
pharmaceutically acceptable salts (as well as any additional active
agents, such as those described herein), can be in the form of a
core of granulated microcrystals of azelastine, coated with at
least one layer comprising azelastine. Such a coated core is
characterized in that the core and the layer comprise each from 70%
to 95%, preferably 80% to 95% by weight of azelastine, or one of
the pharmaceutically acceptable salts thereof, the balance to 100%
being formed with at least one binder and optionally sucralose, and
that the coated core is suitably a sphere. See e.g., French patent
application FR 00 14803, the disclosure of which is incorporated by
reference herein.
[1114] In one embodiment of the invention, the granules can
comprise (or consist essentially of): from about 10% to about 95%,
e.g., from about 50% to about 70% of azelastine or a
pharmaceutically acceptable salt thereof (e.g., azelastine HCl) and
optionally one or more additional active agents, such as those
described herein, at most about 20% by weight of the binder,
relative to the weight of azelastine, or one of the
pharmaceutically acceptable salts thereof, at most about 5%,
suitably about 2% by weight of the antistatic agent, relative to
the weight of said granules, suitably about 0.05% to about 5%
sucralose and optionally a diluent agent for the balance to
100%.
[1115] The granules can also be coated with a coating composition
comprising at least one coating polymer selected from the group
consisting of cellulosic polymers, acrylic polymers and their
mixtures. Among the cellulosic polymers, ethylcellulose,
hydroxypropylcellulose (HPC) and hydroxypropylmethylcellulose
(HPMC), can be used. Among the acrylic polymers, insoluble acrylate
ammonio-methacrylate copolymer (Eudragit.TM. RL100 or RS100 or
Eudragit.TM. RL30D or RS30D), polyacrylate (Eudragit.TM.NE30D), or
methacrylic copolymers (e.g., Eudragit.TM. L100-55 Eudragit.TM.
L30D, Eudragit.TM. E100 and Eudragit.TM. EPO) can be used, alone,
in combination, or in admixture with pH-dependent polymers.
Eudragit.TM. E100 or a mixture of Eudragit.TM. EPO and Eudragit.TM.
NE30D are suitably used. In one embodiment, the binder and the
coating polymer are the same polymer.
[1116] Optionally, permeabilising agents, plasticizers, soluble
agents, disintegrating agents and surfactants, can be added as
coating additives. Suitable plasticizers include, but are not
limited to, triacetine, triethylacetate, triethylcitrate
(Eudraflex.TM.), ethylphthalate, or mixtures thereof. The
plasticizer is used in proportions of at most about 30%, preferably
10% by weight of the coating polymers. Suitable soluble agents
include polyols having less than 13 carbon atoms. Surfactants may
be an anionic, nonionic, cationic, zwitterionic or amphoteric
surfactant. Suitable disintegrating agents include, but are not
limited to, croscarmellose, available as e.g. Ac-di-sol.TM.,
crospovidone available as e.g. Kollidon CL.TM., and mixtures
thereof.
[1117] Suitably, the coated granules according to the present
invention have a particle size distribution between about 150 .mu.m
and about 500 .mu.m, more suitably between about 150 .mu.m and
about 425 .mu.m, such that at least 50%, more suitably at least 70%
of the granules have a particle size ranging between about 150 and
about 425 .mu.m, and less than 15% of the granules have a particle
size less than about 150 .mu.m.
[1118] In one embodiment, the coated granules according to the
invention comprise: from about 10% to about 95%, preferably about
40 to about 75% of granules of azelastine or one of its
pharmaceutically acceptable salts, suitably azelastine HCl and
optionally one or more optional additional active agents, such as
those disclosed herein, sucralose from about 0.05% to about 5%,
from about 5 to about 90%, suitably about 10 to about 70% and even
more suitably from about 25 to about 55% of a coating polymer, such
as Eudragit.TM. E100, the percentages being expressed by weight
relative to the weight of the granules of azelastine, or one of its
pharmaceutically acceptable salts, from about 0 to about 10% of a
permeabilising agent, such as colloidal silica, the percentages
being expressed by weight relative to the weight of the coating
polymer.
[1119] Effervescent Formulations
[1120] In another embodiment, the present invention provides a
solid, effervescent, rapidly dissolving dosage form of azelastine
for oral administration, such as disclosed in U.S. Pat. No.
6,245,353, the disclosure of which is incorporated by reference
herein in its entirety. In such an embodiment, the effervescent
formulation comprise (or consist essentially of) (a) azelastine or
a pharmaceutically acceptable salt thereof (e.g., azelastine HCl),
and optionally one or more additional active agents such as those
disclosed herein, (b) an effervescent base comprising at least one
of (i) at least one of (1) an organic edible acid and (2) a salt
thereof, (ii) at least one of an alkali metal and an alkaline earth
metal carbonate and bicarbonate, and (c) optionally a
pharmaceutically acceptable auxiliary ingredient. In certain
suitable embodiments, the effervescent formulations further
comprise one or more taste-masking agents, such as sucralose,
and/or other taste-masking agents described herein. The amounts of
azelastine, other optional active agents (e.g., steroids,
decongestants, leukotriene antagonists, and combinations thereof),
and sweetening agents (e.g., sucralose) in the effervescent
formulations of the present invention are readily determinable by
those of ordinary skill in the art, and include those amounts and
combinations described herein. For example, the effervescent
formulations of the present invention comprise about 0.1% to about
0.15% azelastine, optionally about 0.01% to about 10% other active
agent(s) (or more if required), and about 0.05% to about 0.15%
sucralose.
[1121] A solution or suspension of azelastine or salt thereof is
formed by adding water to the soluble or dispersible effervescent
tablets or soluble granules, with evolution of CO.sub.2 gas. The
resulting effervescent solution or suspension can be ingested very
easily, even by patients who have difficulties swallowing. The
rapidly disintegrating tablet can also be administered so that it
directly disintegrates in the mouth. A rapid release of the active
ingredient is of particular importance here, to ensure a rapid
onset of action.
[1122] Effervescent agents capable of releasing CO.sub.2, which can
be used in the present invention, include alkali metal carbonates
or alkali metal bicarbonates, such as sodium carbonate or sodium
bicarbonate. Agents for inducing CO.sub.2 release which are
suitably employed are edible organic acids, or their acidic salts,
which are present in solid form and which can be formulated with
the azelastine active ingredient and the other auxiliary
ingredients (as well as any other active agents) to provide
granules or tablets, without premature evolution of CO.sub.2.
Edible organic acids which can be so used include for example,
tartaric acid, malic acid, fumaric acid, adipic acid, succinic
acid, ascorbic acid, maleic acid or citric acid. Pharmaceutically
acceptable acidic salts include, for example, salts of polybasic
acids which are present in solid form and in which at least one
acid function is still present, such as sodium dihydrogen or
disodium hydrogen phosphate or monosodium or disodium citrate.
[1123] In one embodiment, the present invention provides
effervescent azelastine formulations including the formulations and
compositions described herein, having an effervescent base
comprising (a) a mixture of calcium carbonate with an organic
edible acid; (b) a mixture of calcium carbonate, sodium carbonate,
sodium bicarbonate and an organic edible acid; or (c) a mixture of
sodium bicarbonates, sodium carbonate and an organic edible
acid.
[1124] The soluble or dispersible effervescent azelastine tablets
or the soluble granules suitably comprise (or consisting
essentially of) from about 0.5 mg to about 10 mg azelastine (or
salt thereof, e.g., azelastine HCl) and from about 50 mg to about
5000 mg, suitably from about 500 mg to about 3000 mg of an
effervescent base, optionally, along with other active agents (such
as those described herein) and excipients, including taste-masking
agents such as sucralose, suitably at about 0.05% to about 5%.
[1125] The effervescent base suitably comprises from about 100 mg
to about 500 mg calcium ions as, for example, calcium carbonate,
and from about 20 mg to about 1500 mg citric acid and/or its salts.
In another embodiment, the effervescent base comprises from about
50 mg to about 2000 mg sodium bicarbonate, from about 20 mg to
about 200 mg of sodium carbonate and from about 20 mg to about 1500
mg citric acid and/or from about 20 mg to about 500 mg tartaric
acid.
[1126] An additional suitable composition of the effervescent base
comprises from about 50 mg to about 500 mg sodium bicarbonate, from
about 20 mg to about 100 mg sodium carbonate, and from about 50 mg
to about 750 mg calcium carbonate and from about 100 mg to about
1500 mg of citric acid.
[1127] The soluble/dispersible tablets can be prepared by known
processes for preparing effervescent bases, such as those disclosed
in U.S. Pat. No. 6,245,353, the disclosure of which is incorporated
herein by reference in its entirety.
[1128] Orally Dissolving/Consumable Films
[1129] Another embodiment of the present invention is directed to a
physiologically acceptable film that is particularly well-adapted
to dissolve in the oral cavity of a warm-blooded animal including
humans, and adhere to the mucosa of the oral cavity, to allow
delivery of azelastine or a salt thereof, e.g., azelastine HCl, and
optionally one or more additional active agents such as those
described herein. Such physiologically acceptable films suitable
for use in accordance with this aspect of the present invention are
disclosed in U.S. Patent Application No. 2004/0247648, the
disclosure of which is incorporated herein by reference in its
entirety.
[1130] In one such embodiment of the present invention, an orally
dissolving/consumable film comprises a modified starch, azelastine
or a salt thereof, e.g., azelastine HCl, and optionally, one or
more additional active agents such as those described herein,
suitably, one or more taste-masking agents, such as sucralose, and
optionally, at least one water soluble polymer. The amounts of
azelastine, other optional active agents (e.g., steroids,
decongestants, leukotriene antagonists, and combinations thereof),
and sweetening agents (e.g., sucralose) in the orally
dissolving/consumable film formulations of the present invention
are readily determinable by those of ordinary skill in the art, and
include those amounts and combinations described herein. For
example, the orally dissolving/consumable film formulations of the
present invention comprise about 0.5 mg to about 10 mg azelastine,
optionally about 0.5 mg to about 10 mg other active agent(s), and
about 0.05% to about 0.15% sucralose.
[1131] The consumable films of the present invention may comprise
one or more of the following ingredients: water, antimicrobial
agents, additional film forming agents or water soluble polymers,
plasticizing agents, flavorings, sulfur precipitating agents,
saliva stimulating agents, cooling agents, surfactants, stabilizing
agents, emulsifying agents, thickening agents, binding agents,
coloring agents, triglycerides, polyethylene oxides, propylene
glycols, additional taste-masking agents or sweeteners, fragrances,
preservatives and the like, as described in U.S. Pat. No.
6,596,298, the disclosure of which is incorporated by reference
herein in its entirety.
[1132] In one such embodiment, the consumable films of the present
invention include a modified starch. The modified starches used in
accordance with the present invention can be prepared by
mechanically, chemically or thermally modifying unmodified
starches. For example, modified starches may be prepared by
chemically treating starches to produce, for example, acid
treatment starches, enzyme treatment starches, oxidized starches,
cross-bonding starches, and other starch derivatives. Starches
suitable for modification to produce modified starches may be
obtained from natural products such as corn, potatoes, tapioca as
well as genetically modified forms of the same such as high amylose
and waxy corn as well as sorghum varieties.
[1133] Examples of modified starches for use in the practice of the
present invention include, but are not limited to, modified corn
starches, modified tapioca starches, acid and enzyme hydrolyzed
corn and/or potato starches, hypochlorite-oxidized starches,
acid-thinned starches, ethylated starches, cross-bonded starches,
hydroxypropylated tapioca starches, hydroxypropylated corn
starches, pregelatinized modified starches, and the like. Preferred
modified starches are selected from pregelatinized modified corn
starches and pregelatinized modified tapioca starches.
[1134] Representative examples of commercially available modified
starches useful in the present invention include PURE-COTE.TM.
modified starches such as PURE-COTE.TM. B793 (a pregelatinized
modified corn starch) and PURE-COTE.TM. B795 (a pregelatinized
modified corn starch), for example, available from Grain Processing
Corporation, 1600 Oregon Street, Muscatine, Iowa 52761-1494
USA.
[1135] In one such embodiment of the present invention, the
modified starch is present in amounts ranging from about 1% to
about 90% by weight, in another embodiment about 10% to about 90%
by weight, and in yet another embodiment from about 35% to about
80% by weight of the film.
[1136] Modified starch may be included in the film alone or
optionally in combination with an additional water soluble film
forming polymers such as those selected from, for example,
pullulan, hydroxypropylmethyl cellulose, hydroxyethyl cellulose,
hydroxypropyl cellulose, polyvinyl pyrrolidone, carboxymethyl
cellulose, polyvinyl alcohol, sodium alginate, polyethylene glycol,
tragacanth gum, guar gum, acacia gum, arabic gum, polyacrylic acid,
methylmethacrylate copolymers, carboxyvinyl polymers, amylose, high
amylose starch, hydroxypropylated high amylose starch, pectin,
dextrin, chitin, chitosan, levan, elsinan, collagen, gelatin, zein,
gluten, soy protein isolate, whey protein isolate, casein and
combinations thereof. A preferred water soluble polymer is
pullulan. The amount of the water soluble polymer typically is up
to about 99% by weight, suitably up to about 80% by weight, more
suitably up to about 50% by weight, and most suitably up to about
40% by weight of the film.
Sustained Release Formulations
[1137] In another embodiment, the present invention provides
sustained release azelastine formulations, such as the formulations
and compositions described herein, which also comprise a
taste-masking agent, such as sucralose. In additional embodiment,
such sustained release formulations of the present invention can
further comprise one or more additional active agents, such as
those described herein.
[1138] Methods for preparing sustained release tablets, capsules,
caplets, pellets and the like, as well as excipients for use in the
sustained release formulations of the present invention, are well
known in the art, and can be found, for example, throughout the
detailed description section and the Examples of U.S. Pat. No.
5,271,946, the disclosure of which is incorporated herein by
reference in its entirety for all purposes.
[1139] As discussed in U.S. Pat. No. 5,271,946, the sustained
release formulations of the present invention can be obtained as
follows:
[1140] 1. Through binding of azelastine or a pharmaceutically
acceptable salt thereof (e.g., azelastine HCl), and optionally one
or more additional active agents such as those described herein, to
physiologically acceptable cation exchangers. The following may,
for example, be used as such cation exchangers: acrylic and
iethacrylic resins with exchangeable protons, acid groups:
COO.sup.- e.g. Amberlite.TM. IRP-64 Polystyrene resins with
exchangeable Na.sup.+, acid groups: SO.sub.3.sup.-, e.g.
Amberlite.TM. IRP-69.
[1141] 2. Coating of active ingredient particles, granulate or
pellet grains or azelastine-containing tablets with coatings of the
following substances, or mixtures of the following substances:
hydroxypropylmethyl cellulose phthalate- or acetate succinate;
cellulose-, starch-, as well as polyvinyl acetate phthalate;
carboxymethyl cellulose; hypromellose; carbopol starch acetate;
cellulose acetae; polyvinyl acetate; methylcellulose phthalate,
methylcellulose succinate, methyl cellulose phthalate succinate as
well as methyl cellulose phthalic acid half ester; zein; ethyl
cellulose as well as ethyl cellulose succinate; shellac; gluten;
ethylcarboxyethyl cellulose; ethacrylate-maleic acid anhydride
copolymer; maleic acid anhydride vinyl methyl ether copolymer;
sterol maleic acid copolymerizate; 2-ethylhexylacrylate maleic acid
anhydride; crotonic acid vinyl acetate copolymer; glutaminic
acid/glutaminic acid ester copolymer; carboxymethylethyl cellulose
glycerin mono-octanoate; cellulose acetate succinate; polyarginin;
fats, oils, waxes, fatty alcohols; anionic polymerizates of
methacrylic acid and methacrylic acid esters (Eudragit.TM.L,
Eudragit.TM.S); copolymerizates of acrylic and methacrylic acid
esters with a low ammonium group (Eudragit.TM.RS) content, as well
as copolymers of acrylic and methacrylic acid esters and trimethyl
ammonium methacrylate (Eudragit.TM.RL), copolymerizates of acrylic
acid ethyl- and methacrylic acid methyl esters 70:30
(Eudragit.TM.NE 30 D), copolymerizates of acrylic acid, methacrylic
acid as well as their esters (ratio of the free carboxyl groups to
the ester groups for example 1:1) (Eudragit.TM.L 30 D).
[1142] Such sustained release formulations may also contain
conventional softeners (e.g. dibutyl sebacate, citric and tartaric
acid esters, glycerin and glycerin esters, phthalic acid esters and
similar substances). It also is possible to add water-soluble
substances such as polyethylene glycols, polyvinylpyrrolidone,
copolymerizates of polyvinylpyrrolidone and polyvinyl acetate,
hydroxypropyl cellulose, hydroxypropylmethyl cellulose. The
addition of solids such as talcum and/or magnesium stearate to the
coating is also possible.
[1143] Organic acids (such as for example citric acid, tartaric
acid, maleic, fumaric, ascorbic acid) may also be incorporated into
the pellet grains, granulate grains or tablets.
[1144] 3. Coating of pressed disks, tablets, granulates containing
the azelastine or salt thereof, and optionally one or more
additional active agents such as those described herein, and one or
more osmotically active substances, (e.g. mannitol, sorbitol and
the like) with a semi-permeable membrane, e.g. of 70 to 90 weight %
of cellulose acetate and hydroxypropylmethyl cellulose or
hypromellose (30 to 10 weight %).
[1145] Other osmotically active substances that can be used include
organic and inorganic compounds or soluble substances which
generate an osmotic pressure gradient as compared to the outer
liquid via the semi-permeable wall. Osmotically active agents or
osmotically active compounds include magnesium sulfate, magnesium
chloride, sodium chloride, lithium chloride, potassium sulfate,
potassium hydrogen phosphate, urea, saccharose and the like. Other
osmotically active agents are disclosed in U.S. Pat. Nos.
3,854,770, 4,077,407 and 4,235,236, the disclosures of each of
which are incorporated herein by reference in their entireties.
[1146] Semi-permeable materials which can be used as polymers for
osmosis and reverse osmosis are, for example: cellulose acylate,
cellulose diacylate, cellulose triacylate, cellulose acetate,
cellulose diacetate, cellulose triacetate, .beta.-glucan acetate,
acetaldehyde dimethyl acetate, cellulose acetate ethyl carbamate,
polyamide, polyurethane, sulphonated polystyrene, cellulose acetate
phthalate, cellulose acetate methyl carbamate, cellulose acetate
succinate, cellulose acetate dimethylamino acetate, cellulose
acetate chloracetate, cellulose dipalmitate, cellulose dioctanoate,
cellulose dicaprylate, cellulose dipentanate, cellulose acetate
valerate, cellulose acetate-p-toluene sulphonate, cellulose acetate
butyrate, ethyl cellulose, selectively permeable polymers which are
formed by joint precipitation of a polycation and a polyanion as
disclosed in U.S. Pat. Nos. 3,173,876, 3,276,586, 3,541,005,
3,541,006 and 3,546,142, the disclosures of which are incorporated
by reference herein in their entireties. Coatings of this type in
semi-permeable membranes may for example also be effected according
to U.S. Pat. Nos. 4,455,143 and 4,449,983, the disclosures of which
are incorporated by reference herein.
[1147] The proportion of osmotically active substance can be from
about 10 to about 800 parts by weight, suitably about 20 to about
600, and more suitably about 50 to about 400 parts by weight, based
on 1 part by weight of azelastine. The amount of coating substances
applied is such that the semi-permeable membrane is about 50 to
about 500 .mu.m, suitably about 100 to about 300 .mu.m thick.
[1148] 4. Embedding of or binding azelastine (or salt thereof)
and/or any other optional additional active agent(s) to the
following substances or mixtures of these substances:
[1149] Digestible fats, such as triglycerides of saturated fatty
acids, C.sub.8H.sub.16O.sub.2 to C.sub.18H.sub.36O.sub.2, and
mixtures thereof, peanut oil and hydrated peanut oil, castor oil
and hydrated castor oil, olive oil, sesame oil, cottonseed oil and
hydrogenated cottonseed oil, corn oil, wheat germ oil, sunflower
seed oil, cod liver oil, mixtures of mono-, di- and triesters of
palmitic and stearic acid with glycerine, glycerine trioleate,
diglycol stearate, stearic acid.
[1150] Indigestible fats or fat-like substances, for example esters
of aliphatic saturated or unsaturated fatty acids (2 to 22 carbon
atoms, in particular 10 to 18 carbon atoms) with monovalent
aliphatic alcohols (1 to 20 carbon atoms), carnauba wax, beeswax,
fatty alcohols (straight chain or branched) of chain length
C.sub.8H.sub.17OH to C.sub.30H.sub.61 OH, in particular
C.sub.12H.sub.25OH to C.sub.24H.sub.49OH.
[1151] Polymers such as polyvinyl alcohol, polyvinyl chloride,
polyacrylic acid (Carbopol.TM.); anionic polymerizates of
methacrylic acid and methacrylic acid esters (Eudragit.TM.L,
Eudragit.TM.S), acrylic and methacrylic acid ester copolymerizates
with trimethyl ammonium methacrylate (Eudragit.TM.RL,
Eudragit.TM.RS).
[1152] Copolymerizates of ethyl acrylates and methyl methacrylates
(Eudragit.TM.NE 30 D), as well as of acrylic acid, methacrylic acid
as well as esters thereof (ratio of free carboxyl groups to ester
groups 1:1) (Eudragit.TM.L 30 D), polyethylene, polyglycolic acid,
polyhydroxybutyric acid, polylactic acid, copolymers of lactic acid
and glycolic acid (manufacturer: Boehringer Ingelheim), copolymers
of lactic acid and ethylene oxide, copolymers of glycolic acid and
ethylene oxide, copolymers of lactic acid and hydroxybutyric acid,
hydroxypropylmethyl cellulose-phthalate or -acetate succinate;
cellulose acetate phthalate, starch acetate phthalate as well as
polyvinyl acetate phthalate; carboxymethyl cellulose;
methylcellulose phthalate, -succinate, -phthalate succinate, methyl
cellulose phthalic acid half ester; zein; ethyl cellulose; shellac,
gluten; ethylcarboxyethyl cellulose; ethacrylate maleic acid
anhydride copolymer; maleic acid anhydride vinyl methyl ether
copolymer; styrene maleic acid copolymerizate; 2-ethylhexyl
acrylate maleic acid anhydride; crotonic acid vinyl acetate
copolymer; glutaminic acid/glutaminic acid ester copolymer;
carboxymethyl cellulose glycerine mono-octanoate; cellulose acetate
succinate; polyarginine; cross-linked alginate; cross-linked
gelatin.
[1153] Swelling agents such as methyl cellulose, hydroxypropyl
cellulose, hydroxypropyl methyl cellulose (Pharmacoat, Methocel E
(propylene glycol ether of methyl cellulose)), alginic acid and
their salts (Na.sup.-, Ca.sup.- salt, also mixtures of sodium
alginate and calcium salts such as CaHPO.sub.4), starch,
carboxymethyl starch, carboxymethyl cellulose and their salts (e.g.
Na.sup.- salts), galacto mannan, gum arabic, karaya rubber, ghatti
gum, agar-agar, carrageen, xanthan rubber, guar rubber and its
derivatives, carob bean flour, propylene glycol alginate, pectin,
tragacanth.
[1154] The amounts of azelastine or salt thereof, and optionally
one or more additional active agents such as those described
herein, in the formulations of the invention are about 0.1 mg to
about 50 mg, suitably about 0.2 mg to about 30 mg, and more
suitably about 0.5 mg to about 20 mg of azelastine.
[1155] Suitable exemplary sustained release components are:
[1156] a) Cation exchangers: Sodium poly(styrene,
divinylbenzene)sulphonate (e.g. Amberlite.TM.IRP 69). Suitably 3 to
10 parts of Amberlite.TM.IRP 69 are for example used per 1 part of
azelastine (base).
[1157] b) Coating substances: Hydroxypropylmethyl cellulose
phthalate, suitably at 1.5 to 3 parts of hydroxypropyl methyl
cellulose phthalate 55 are used per 1 part of azelastine. Ethyl
cellulose, suitably 0.1 to 1 part of ethyl cellulose are used per 1
part of azelastine. Eudragit resins, for example Eudragit.TM.RS
0.01 to 0.1 part of Eudragit.TM.RS per 1 part of azelastine.
[1158] c) Semi-permeable layers with osmotically acting active
substance containing core and outlet openings: Coating with 100 to
300 .mu.m thick layer of 82% cellulose acetate and 18%
hydroxypropyl methyl cellulose.
[1159] d) Embedding substances: Hydrocolloids e.g. hydroxypropyl
methyl cellulose: 2 to 10 parts of hydrocolloid per 1 part of
azelastine. Eudragit.TM.RS: 10 to 15 parts of Eudragit.TM.RS per 1
part of azelastine. Glycerineditripalmito stearate (e.g. Precirol
Ato 5) 1 to 10 parts of Precirol Ato 5 per 1 part of
azelastine.
[1160] The requisite release of azelastine (and optionally, any
additional active agents) of 0.05 to 5 mg per hour suitably occurs
within the desired range through the parameters described herein.
Should it be desired to achieve a specific release rate within this
range it is possible, for example, to proceed as follows:
[1161] 1. The preparation of the coating or embedding of the active
substance in the described manner.
[1162] 2. Testing of the release of active substance from the
dosage form using 0.1 N HCl (2 hours) and phosphate buffer pH 6.8
(subsequently) as release medium.
[1163] 3. a) Should too much substance be released: Increase of the
proportion of the sustained release component and/or reduction of
the proportion of water-soluble auxiliary substances. Reduction of
the proportion of osmotically active substance.
[1164] b) Should too little substance be released: Reduction of the
proportion of the sustained release component and/or increase of
the proportion of water soluble auxiliary substances. Increase of
the proportion of osmotically active substance.
[1165] In one embodiment, a release rate of about 0.05 mg of
azelastine per hour can be achieved.
Liquid Dosage Forms Free of Preservatives
[1166] While preservatives are useful in limiting concerns related
to chemical degradation or bacterial growth in the liquid
formulations of the present invention, the presence of these
preservatives can themselves cause stinging or irritation,
especially when administered to the oral or nasal mucosa, or to
ocular tissue or the conjunctival sac. Therefore, in order to
reduce this irritation, in one embodiment, the liquid dosage forms
disclosed herein, e.g., liquid dosage forms for nasal, ocular or
oral administration, such as pharmaceutically acceptable emulsions,
solutions, suspensions, syrups and elixirs, can be prepared free,
or substantially free, of preservatives. As used herein the phrase
"free, or substantially free, of preservatives" means that the
liquid formulations contain less than about 0.0001% (weight/volume)
of a preservative, more suitably less than about 0.00001%
(weight/volume) of a preservative, and most suitably, no
preservative.
[1167] In order to maintain the integrity of the liquid
formulations, and specifically, to protect them from bacterial
contamination transferred from the patient or external environment,
the delivery systems useful for applying the various liquid
formulations can be appropriately engineered to limit bacteria from
entering the solutions. For example, in order to limit the
introduction of bacteria or particulates that may come from the
user of a nasal spray (e.g. from the nasal passage), the spray
bottle can be fitted with a filter or other device to limit or
prevent the introduction of such bacteria into the bottle and/or
formulation. This filter can form part of the spray or dropper
nozzle, or can be located within the structure of the spray or
dropper bottle itself. The filter allows the various liquid
formulations of the present invention to pass through the filter to
the patient, but limits bacteria or particulates from the patient
or the external environment from entering the nozzle and bottle.
Suitable filters are known in the art and are commercially
available from well-known sources, and include microporous
filtration membranes made from polymers, such as, but not limited
to, poly(ethersulfone), poly(vinylidene fluoride), mixed cellulose
esters, and poly(tetrafluoroethylene). In general, the pore size of
such membranes are on the order of less than about 0.5 microns,
more suitably less than about 0.3 microns and most suitably less
than or equal to about 0.22 microns. Use of such membrane filters
eliminate the need for preservatives in the various liquid
formulations of the present invention when utilized in nasal spray
or ocular drop delivery systems.
[1168] The preservative free liquid formulations and compositions
of the present invention can also be provided in single unit-dose
containers. Such containers are acceptable to deliver the
therapeutic dose of azelastine (or salt or ester thereof, including
azelastine hydrochloride) and optionally one or more additional
active agents (such as those described herein) to the eyes, nose or
mouth. In certain such embodiments of the invention, the
compositions can be effectively contained in a package comprising a
high density polyethylene (HDPE) container produced using a
blow-fill-seal manufacturing technique with a volume capacity of
about 1 mL.
[1169] The use of single unit-dose conatiners eliminates the
concern of contamination for the user (or other outside sources),
as once the unit-dose container is opened and a single dose of the
present formulations or compositions is delivered, the container is
discarded.
[1170] The preservative-free formulations of the present invention
can also be used with multi-dose containers, such as, high density
polyethylene bottles with a volume capacity of about 10 mL fitted
with a spray pump specifically designed for use with preservative
free formulations.
Formulations for Pulmonary Delivery
[1171] In further embodiments, the present invention provides
formulations and compositions for pulmonary delivery of azelastine
or a salt thereof, and optionally, one or more additional active
agents, such as those described herein. For example, inhalable
preparations comprising azelastine or a salt thereof (e.g.,
azelastine HCl), and optionally, one or more additional active
agents such as those described herein, can be produced.
[1172] Inhalable preparations include inhalable powders,
propellant-containing metering aerosols or propellant-free
inhalable solutions. Inhalable powders according to the invention
containing, azelastine or a salt thereof, and optionally one or
more additional active ingredients including those described
herein, may comprise the active ingredients on their own, or a
mixture of the active ingredients with physiologically acceptable
excipients. In certain such embodiments, the inhalable formulas
comprise the compositions of the present invention in an inhalable
form. Within the scope of the present invention, the term
propellant-free inhalable solutions also includes concentrates or
sterile inhalable solutions ready for use. The preparations
according to the invention may comprise azelastine or a salt
thereof and optionally one or more additional active ingredients
including those described herein, in one formulation, or in two or
more separate formulations.
[1173] Physiologically acceptable excipients that may be used to
prepare the inhalable powders according to the present invention
include, but are not limited to, monosaccharides (e.g., glucose or
arabinose), disaccharides (e.g., lactose, saccharose, maltose),
oligo- and polysaccharides (e.g., dextran), polyalcohols (e.g.,
sorbitol, mannitol, xylitol), salts (e.g., sodium chloride, calcium
carbonate) or mixtures of these excipients with one another.
Suitably, mono- or disaccharides are used, for example, lactose or
glucose in the form of their hydrates. Lactose and lactose
monohydrate represent exemplary excipients. Excipients for use in
the inhalable preparations can have an average particle size of up
to about 250 .mu.m, suitably between about 10 .mu.m and about 150
.mu.m, most suitably between about 15 .mu.m and about 80 .mu.m. In
certain such embodiments, finer excipient fractions can be added
with an average particle size of about 1 .mu.m to about 9 .mu.m.
These finer excipients are also selected from the group of possible
excipients disclosed throughout. Finally, in order to prepare the
inhalable powders according to the present invention, micronised
active ingredients (e.g., azelastine and optionally one or more
additional agents described throughout), suitably with an average
particle size of about 0.5 .mu.m to about 10 .mu.m, more suitably
from about 1 .mu.m to about 5 .mu.m, are added to the excipient
mixture. Processes for producing the inhalable powders according to
the present invention by grinding and micronizing and by finally
mixing the ingredients together are routine and well known, to
those of ordinary skill in the art. The inhalable powders according
to the present invention can be prepared and administered either in
the form of a single powder mixture which contains azelastine or a
salt thereof and optionally one or more additional active agents
such as those described herein, or in the form of separate
inhalable powders, in which one powder contains only azelastine or
a salt thereof, and another powder contains one or more additional
active agents such as those described herein. Methods for preparing
the inhalable powders of the present invention, as well as devices
for their delivery, are disclosed in U.S. Pat. Nos. 6,696,042 and
6,620,438; U.S. Published Patent Application Nos. 2002/0009418,
2005/0121032, 2005/0121027 and 2005/0123486, the disclosures of
each of which are incorporated herein by reference in their
entireties.
[1174] The inhalable powders according to the present invention may
be administered using inhalers well known in the art. Inhalable
powders according to the present invention which contain a
physiologically acceptable excipient in addition to the active
agents may be administered, for example, by means of inhalers which
deliver a single dose from a supply using a measuring chamber as
described in U.S. Pat. No. 4,570,630, or by other means as
described in U.S. Pat. Nos. 5,035,237 and 4,811,731, the
disclosures of which are incorporated by reference herein in their
entireties. The inhalable powders of the present invention can also
be administered by dry powder inhalers (DPIs) or pre-metered DPIs
(see e.g., U.S. Pat. Nos. 6,779,520, 6,715,486 and 6,328,034, the
disclosures of each of which are incorporated herein by reference
in their entireties). Suitably, the inhalable powders according to
the present invention which contain physiologically acceptable
excipients in addition to the active agents are packed into
capsules (to produce so-called inhalettes) which are used in
inhalers as described, for example, in U.S. Pat. No. 5,947,118, the
disclosure of which is incorporated herein by reference in its
entirety. An additional DPI that can be used with the powder
formulations of the present invention is the Novalizer.RTM. by
Sofotec (Bad Homburg, Germany). A description of this DPI, as well
as methods to formulate powders for use in it, are disclosed in
U.S. Pat. Nos. 5,840,279; 5,881,719; 6,071,498; and 6,681,768, the
disclosures of which are incorporated herein by reference in their
entireties.
[1175] According to another embodiment of the present invention,
inhalation aerosols containing propellant gas comprising (or
consisting essentially of) azelastine or a salt thereof and
optionally, one or more additional active ingredients such as those
described herein, dissolved in a propellant gas or in dispersed
form, can be produced. Azelastine or a salt thereof, and one or
more optional active ingredients, such as those disclosed herein,
may be present in separate formulations or in a single preparation,
in which all active ingredients are each dissolved, each dispersed,
or one or more active components are dissolved and any others are
dispersed. The propellant gases which may be used to prepare the
inhalation aerosols according to the invention are known in the
art. Suitable propellant gases include, but are not limited to,
hydrocarbons such as n-propane, n-butane or isobutane and
halohydrocarbons such as fluorinated derivatives of methane,
ethane, propane, butane, cyclopropane or cyclobutane. The
propellant gases may be used on their own or in mixtures thereof.
Particularly suitable propellant gases are halogenated alkane
derivatives selected from TG134a and TG227.
[1176] The propellant-driven inhalation aerosols according to the
present invention may also contain other ingredients such as
co-solvents, stabilizers, surfactants, antioxidants, lubricants and
pH adjusters. All of these ingredients, and suitable commercial
sources thereof, are well known in the art.
[1177] The inhalation aerosols containing propellant gas according
to the present invention may contain up to about 5 wt % of active
substances (or more if required). Aerosols according to the
invention contain, for example, about 0.002 wt. % to about 5 wt. %,
about 0.01 wt. % to about 3 wt. %, about 0.015 wt. % to about 2 wt.
%, about 0.1 wt. % to about 2 wt. %, about 0.5 wt. % to about 2 wt.
%, or about 0.5 wt. % to about 1 wt. % of active substances (e.g.,
azelastine or a salt thereof and optionally one or more additional
active agents such as those described herein).
[1178] In embodiments where the active substance(s) are present in
dispersed form, the particles of active substance(s) suitably have
an average particle size of up to about 10 .mu.m, suitably from
about 0.1 .mu.m to about 5 .mu.m, more suitably from about 1 .mu.m
to about 5 .mu.m.
[1179] Propellant-driven inhalation aerosols according to certain
such embodiments of the present invention may be administered using
inhalers known in the art (e.g., MDIs: metered dose inhalers, see
e.g., U.S. Pat. Nos. 6,380,046, 6,615,826 and 6,260,549, the
disclosures of each of which are incorporated herein by reference
in their entireties). Accordingly, in another aspect, the present
invention provides pharmaceutical compositions in the form of
propellant-driven aerosols combined with one or more inhalers
suitable for administering these aerosols. In addition, the present
invention provides inhalers which are characterized in that they
contain the propellant gas-containing aerosols described
throughout. The present invention also provides cartridges which
are fitted with a suitable valve and can be used in a suitable
inhaler and which contain one or more of the propellant
gas-containing inhalation aerosols described throughout. Suitable
cartridges and methods of filling these cartridges with the
inhalable aerosols containing propellant gas according to the
invention are known in the art.
[1180] In another embodiment, the present invention provides
propellant-free inhalable formulations, such as solutions and
suspensions, comprising (or consisting essentially of) azelastine
or a salt thereof and optionally one or more additional active
agents such as those described herein. Suitable solvents for use in
such embodiments include aqueous and alcoholic solvents, suitably
an ethanolic solution. The solvents may be water on its own or a
mixture of water and ethanol. The relative proportion of ethanol
compared with water suitably is up to about 70 percent by volume,
more suitably up to about 60 percent by volume, or up to about 30
percent by volume. The remainder of the volume is made up of water.
The solutions or suspensions containing azelastine or a salt
thereof and optionally one or more additional active agents, such
as those described herein, separately or together, are adjusted to
a pH of 2 to 7, using suitable acids or bases. The pH may be
adjusted using acids selected from inorganic or organic acids.
Examples of suitable inorganic acids include hydrochloric acid,
hydrobromic acid, nitric acid, sulfuric acid and phosphoric acid.
Examples of suitable organic acids include ascorbic acid, citric
acid, malic acid, tartaric acid, maleic acid, succinic acid,
fumaric acid, acetic acid, formic acid, propionic acid, etc.
Exemplary inorganic acids include hydrochloric and sulfuric acids.
It is also possible to use the acids which have already formed an
acid addition salt with one or more of the active substances.
Exemplary organic acids include ascorbic acid, fumaric acid and
citric acid. If desired, mixtures of the above acids may be used,
particularly in the case of acids which have other properties in
addition to their acidifying qualities, e.g., as flavorings,
antioxidants or complexing agents, such as citric acid or ascorbic
acid, for example. Hydrochloric acid can be used to adjust the
pH.
[1181] Co-solvents and/or other excipients may be added to the
propellant-free inhalable formulations of the present invention.
Suitable co-solvents are those which contain hydroxyl groups or
other polar groups, e.g., alcohols--such as isopropyl alcohol,
glycols--such as propylene glycol, polyethylene glycol,
polypropylene glycol, glycol ether, glycerol, polyoxyethylene
alcohols and polyoxyethylene fatty acid esters. The terms
excipients and additives in this context denote any
pharmacologically acceptable substance which is not an active
substance but which can be formulated with the active substance or
substances in the pharmacologically suitable solvent in order to
improve the qualitative properties of the active substance
formulation. Suitably, these substances have no pharmacological
effect or, in connection with the desired therapy, no appreciable
or at least no undesirable pharmacological effect. The excipients
and additives include, for example, surfactants such as soy
lecithin, oleic acid, sorbitan esters, such as polysorbates,
polyvinylpyrrolidone, other stabilizers, complexing agents,
antioxidants and/or preservatives which prolong the shelf life of
the finished pharmaceutical formulation, flavorings, vitamins
and/or other additives known in the art. The additives also include
pharmacologically acceptable salts such as sodium chloride as
isotonic agents.
[1182] Exemplary excipients include antioxidants such as ascorbic
acid, vitamin A, vitamin E, tocopherols and similar vitamins and
provitamins occurring in the human body.
[1183] Preservatives may be used to protect the inhalable
formulations disclosed herein from contamination with pathogens.
Suitable preservatives are those which are known in the art,
particularly cetyl pyridinium chloride, benzalkonium chloride or
benzoic acid or benzoates such as sodium benzoate in the
concentration known from the prior art. The preservatives mentioned
above are suitably present in concentrations of up to about 50
mg/100 ml, more suitably between about 5 and about 20 mg/100 ml.
Alternatively, the inhalable formulations can be prepared without
preservatives, for example, in unit-dose forms, such as described
herein.
[1184] The propellant-free inhalable formulations according to the
present invention can be administered using inhalers of the kind
which are capable of nebulizing a small amount of a liquid
formulation in the therapeutic dose within a few seconds to produce
an aerosol suitable for therapeutic inhalation. Suitable inhalers
are those in which a quantity of less than about 100 .mu.L, less
than about 50 .mu.L, or between about 10 .mu.L and about 30 .mu.L
of active substance solution can be nebulized in one spray action
to form an aerosol with an average particle size of less than about
20 .mu.m, suitably less than about 10 .mu.m, in such a way that the
inhalable part of the aerosol corresponds to the therapeutically
effective quantity.
[1185] Suitable apparatuses for propellant-free delivery of a
metered quantity of a liquid pharmaceutical composition according
to the present invention are described for example in U.S. Pat.
Nos. 5,497,944; 5,662,271; 5,964,416; 6,402,055; 6,497,373;
6,726,124; and 6,918,547, the disclosures of which are incorporated
herein by reference in their entireties. In another embodiment, the
present invention provides pharmaceutical formulations in the form
of propellant-free inhalable formulations, such as solutions or
suspensions, as described herein, combined with a device suitable
for administering such formulations.
[1186] The propellant-free inhalable formulations, e.g., solutions
or suspensions, according to the present invention may take the
form of concentrates or sterile inhalable solutions or suspensions
ready for use. Formulations ready for use may be produced from the
concentrates, for example, by the addition of isotonic saline
solutions. Sterile formulations ready for use may be administered
using energy-operated fixed or portable nebulizers which produce
inhalable aerosols by means of ultrasound or compressed air by the
Venturi principle or other principles.
[1187] The present invention also provides fine particle dosages of
azelastine or a salt thereof (e.g., azelastine HCl) and optionally
one or more additional active agents such as those described
herein. A delivered fine particle dose (FPD) of azelastine or a
salt thereof (e.g., azelastine HCl) administered by inhalation
herein is not limited, and may generally be in a range from about 1
to about 50 .mu.g, including about 5, 10, 15, 20, 30 and 40 .mu.g.
The correct metered dose loaded into an inhaler to be used for the
purpose of administration can be adjusted for predicted losses such
as retention and more or less efficient de-aggregation of the
inhaled dose.
[1188] Excipient particles having a physical median particle size
larger than about 25 .mu.m and having a very narrow particle size
distribution with generally less than 5% of the particles by mass
being below 10 .mu.m generally show good flow properties, and are
suitable for use in mixtures together with azelastine or a salt
thereof (e.g., azelastine HCl) and optionally one or more
additional active agents, such as those described herein. For
inhalation purposes, carrier particles having a mass median
particle size in a range from about 10 to about 250 .mu.m are
typically selected, including about 30, 50, 70, 100, 130, 160, 190,
and 220 .mu.m. The median particle size chosen within this range
depends on many factors, e.g. type of carrier substance, degree of
powder flowability to be attained, type of inhaler and ease of
de-aggregation during inhalation of the resulting medicament.
Commercial grades of Respitos are available (lactose monohydrate
from DMV of several defined particle size distributions up to 400
.mu.m) suitable as particular excipients to be used in formulations
containing azelastine, e.g. grade SV003. Uniform homogeneous
azelastine powder formulations having a physical median particle
size down to about 10 .mu.m can also provide good flow properties
when the particles have been modified to have a very smooth
surface, thereby improving the flow properties of the
formulation.
[1189] A practical lower limit for volumetric dose forming for such
inhalable powder formulations is in a range of about 0.5 to 1 mg.
Smaller doses can be difficult to produce and still maintain a low
relative standard deviation between doses in the order of 10%.
Typically, though, dose masses range from about 1 to 10 mg.
[1190] Suitable excipients for inclusion in the azelastine powder
formulations include, but are not limited to, monosaccarides,
disaccarides, polylactides, oligo- and polysaccarides,
polyalcohols, polymers, salts or mixtures from these groups, e.g.
glucose, arabinose, lactose, lactose monohydrate, lactose anhydrous
(i.e., no crystalline water present in lactose molecule),
saccharose, maltose, dextran, sorbitol, mannitol, xylitol, sodium
chloride and calcium carbonate.
[1191] Excipients for use with azelastine or a salt thereof (e.g.,
azelastine HCl) and optionally one or more additional active
agents, such as those described herein, generally are selected from
among excipients which have good moisture qualities in the sense
that the substance will not adversely affect the active agent fine
particle dose (FPD) for the shelf life of the product regardless of
normal changes in ambient conditions during storage. Suitable "dry"
excipients are well known in the art and include those disclosed
herein. For example, lactose can be selected as a dry excipient, or
lactose monohydrate can be used in a formulation with azelastine or
a salt thereof (and optionally one or more additional active
agents, such as those described herein). Lactose has the inherent
property of having a low and constant water sorption isotherm.
Excipients having a similar or lower sorption isotherm can also be
used.
[1192] As discussed throughout, and in a further aspect of the
present invention, azelastine or a salt thereof (e.g., azelastine
HCl) may be mixed or formulated with one or more additional active
agents such as those described herein in the dry powder or other
inhalable formulations. The present invention also encompasses the
use of azelastine or a salt thereof where a combination of
azelastine or a salt thereof with other agents, such as those
described herein, constitute a formulation from which metered doses
are then produced, filled and sealed into dry, moisture-tight, high
barrier seal containers intended for insertion into a DPI to be
administered according to a particular dosing regime or as needed
by the user. Suitable additional active agents include those
disclosed throughout, for example, inhaled steroids: e.g.,
budesonid, fluticasone, rofleponide, mometasone, and/or
ciclesonide; NSAIDs, e.g., ibuprofen; leukotriene antagonists,
e.g., montelukast; additional antihistamines, e.g., epinastine,
cetirizine, fexofenadine, olopatadine, levocabastine, loratadine,
mizolastine, ketotifene, emedastine, dirnetindene, clemastine,
bamipine, cexchlorpheniramine, pheniramine, doxylamine,
chlorphenoxamine, dimenhydrinate, diphenhydramine, promethazine,
ebastine, desloratidine and/or meclozine; beta-mimetics: e.g.,
formoterol, salmeterol, salbutamol and/or terbutalinsulphate; PDE
IV inhibitors: e.g., 3',5'-cyclic nucleotide phosphodiesterases and
derivates; adenosine A2a receptor agonists: e.g.,
Ribofuranosylvanamide derivates, and/or substances described in
U.S. Published Patent Application No. 2003/013675, the disclosure
of which is incorporated by reference herein in its entirety.
[1193] A sealed, dry, high barrier container can be loaded with a
powder form azelastine or a salt thereof (e.g., azelastine HCl) and
optionally one or more additional active agents, such as those
described herein, in the form of a blister and may comprise a flat
dose bed or a formed cavity in aluminum foil or a molded cavity in
a polymer material, using a high barrier seal foil against ingress
of moisture, e.g. of aluminum or a combination of aluminum and
polymer materials. The sealed, dry, high barrier container may form
a part of an inhaler device or it may form a part of a separate
item intended for insertion into an inhaler device for
administration of pre-metered doses.
[1194] The inhalable pharmaceutical formulations of the present
invention that comprise (or consist essentially of) azelastine or a
salt thereof (e.g., azelastine HCl) and a suitable steroid (e.g., a
safe steroid) are suitably formulated as azelastine:steroid in
ratios by weight ranging from about 1:300 to about 50:1, and more
suitably from about 1:250 to about 40:1. In exemplary formulations
which contain azelastine or a salt thereof (e.g., azelastine HCl)
and a steroid selected from among budesonide, fluticasone,
mometasone, and ciclesonide, the weight ratio of azelastine (or
salt thereof):steroid are suitably in the range of about 1:150 to
about 30:1, and more suitably from about 1:50 to 20:1.
[1195] The inhalable formulations of the present invention are
especially suitable for the treatment of inflammatory (including
allergic) or obstructive diseases of the upper or lower respiratory
tract, including asthma and chronic obstructive pulmonary disease
(COPD), and complications thereof such as pulmonary hypertension,
as well as allergic and non-allergic rhinitis. In addition, the
inhalable formulations according to the present invention may be
used to treat cystic fibrosis and allergic alveolitis (Farmer's
Lung).
[1196] The present invention also provides inhalable spray
pharmaceutical compositions comprising (or consisting essentially
of), a suitable concentration to provide a therapeutically
effective dose of azelastine, or a pharmaceutically acceptable salt
or ester thereof, and one or more pharmaceutically acceptable
carrier, stabilizer or excipient, wherein the azelastine is in a
solution form and wherein at least one of the pharmaceutically
acceptable carriers or excipients is sucralose dissolved in the
solution. Such inhalable spray pharmaceutical compositions when
used with a suitable device provide a fine spray of the components
(including active and non-active components) having an average
particle size of about 1 .mu.m to about 5 .mu.m. Such inhalable
spray pharmaceutical compositions of the present invention can be
formulated for pulmonary delivery using, for example, a suitable
device or inhaler. Suitably the amount of azelastine in such
inhalable spray pharmaceutical compositions is about 0.1% to about
10% by weight and the amount of sucralose in such inhalable spray
pharmaceutical compositions is about 0.05% to about 0.15% by
weight, though other suitable amounts will readily be determined by
the ordinarily skilled artisan.
Clinical Indications
[1197] The compositions provided by the present invention are
useful in methods for the treatment of a variety of physical
disorders in animals (particularly mammals including humans) that
are predisposed to or suffering from a physical disorder that may
be delayed, prevented, cured or otherwise treated by the
administration of azelastine or a pharmaceutically acceptable salt
or ester thereof. Thus, in additional embodiments, the invention
provides methods of treating or preventing such physical disorders,
comprising administering an effective amount of one or more of the
compositions of the invention to an animal (particularly a mammal,
including a human) that is predisposed to or suffering from such a
physical disorder. As used herein, an animal that is "predisposed
to" a physical disorder is defined as an animal that does not
exhibit a plurality of overt physical symptoms of the disorder but
that is genetically, physiologically or otherwise at risk for
developing the disorder. In such situations, the compositions of
the present invention may thus be used prophylactically as
chemopreventive agents for such disorders.
[1198] According to the invention, a mammal (preferably a human)
that is predisposed to or suffering from a physical disorder may be
treated by administering to the animal an effective dose of one or
more of the pharmaceutical compositions of the present invention.
Physical disorders treatable with the compositions and methods of
the present invention include any physical disorder that is
characterized by allergic rhinitis, vasomotor rhinitis, and/or
allergic conjunctivitis, inflammatory or obstructive diseases of
the upper or lower respiratory tract, including asthma and chronic
obstructive pulmonary diseases (COPD), and complications thereof
such as pulmonary hypertension, as well as allergic and
non-allergic rhinitis, cystic fibrosis and allergic alveolitis
(Farmer's Lung), reactions to plant or insect allergens,
environmental allergens, allergic ocular conditions (e.g., hay
fever conjunctivitis, perennial allergic conjunctivitis, giant
papillary conjunctivitis, vernal keratoconjunctivitis or atopic
keratoconjunctivitis) and irritant dermatitis, as well as other
related or similar disorders. The compositions of the invention are
also useful in treating or preventing the symptoms of such
disorders, and thereby provide symptomatic relief to patients
suffering from or predisposed to such disorders.
Dosing
[1199] As noted above, by the invention, a composition comprising
an effective amount of azelastine or a pharmaceutically acceptable
salt or ester thereof (e.g., azelastine HCl), and optionally, one
or more additional active agents such as those described herein,
can be administered to a patient to provide symptomatic relief from
a variety of disorders, including allergic rhinitis, vasomotor
rhinitis, allergic conjunctivitis, as well as the various other
disorders disclosed throughout and known in the art. One of
ordinary skill will appreciate that the amount or concentration of
azelastine (or salt or ester thereof, including azelastine
hydrochloride) that constitutes "an effective amount" of azelastine
can be determined empirically. Non-limiting examples of effective
amounts of azelastine (or salt or ester thereof, including
azelastine hydrochloride) for use in the pharmaceutical
compositions of the present invention include those described in
detail herein. It also will be understood that, when administered
to a human patient, the total daily usage of the compositions of
the present invention will be decided or recommended by the
attending physician, pharmacist or other medical practitioner
within the scope of sound medical judgment.
[1200] The intranasal formulations of this invention are most
effective when proper product design is utilized. The preferred
product design includes a composition of the invention contained
within a delivery system, such as a bottle and a pump, for nasal
delivery of the formulation in a mist of spray droplets to coat the
mucosa of the nasal cavity upon administration. Preferred pumps for
use in such products of the invention are metered multi-dose pumps;
however, single unit-dose containers are also acceptable to deliver
the therapeutic dose of azelastine (or salt or ester thereof,
including azelastine hydrochloride) to the nasal cavity. The
selection of the pump is based on the desired dose/spray volume and
spray pattern appropriate for local delivery to the nasal mucosa.
In certain such embodiments of the invention, the compositions can
be effectively contained in a package comprising a high density
polyethylene bottle fitted with a screw cap, and are delivered by a
metered-dose spray pump designed for intranasal application in
volumes of 0.07 to 0.15 ml such as the VP3/140 18/415 or the
VP3/140F 18/415 Spigot 522 pumps designed by Valois Pharm, Marly le
Roi, France. In addition, the intranasal formulations can be
provided in a unit dose form, such as described herein.
[1201] The ocular formulations of this invention are also most
effective when proper product design is utilized. The preferred
product design includes a composition of the invention contained
within a delivery system, such as a bottle and a dropper, for
ocular delivery of the formulation to coat the conjunctival sac of
the eyes upon administration. Preferred packages for use in such
products of the invention are multi-dose; however, single unit-dose
containers are also acceptable to deliver the therapeutic dose of
azelastine (or salt or ester thereof, including azelastine
hydrochloride) to the eyes. In certain such embodiments of the
invention, the compositions can be effectively contained in a
package comprising a high density polyethylene bottle (HDPE) in
volume capacity of 10 mL fitted with a low density polyethylene
dropper and secured with a HDPE cap closure. In addition, the
ocular formulations can be provided in a unit dose form, such as
described herein.
[1202] Suitable compositions of the present invention include about
0.1%, about 0.125% or about 0.15% azelastine, and about 0.05%-0.15%
sucralose. Described below are non-limiting examples of the
compositions of the present invention, comprising 0.05%, 0.1% or
0.15% azelastine hydrochloride, 0.1% to 0.3% of hypromellose as a
thickener, 0.05% to 0.15% of sucralose as a sweetening and
taste-masking agent, and/or 0.05% menthol as a
taste-masking/flavoring agent. Suitable such compositions can also
comprise one or more additional active agents such as those
described herein at the various concentrations and amounts
described herein. These compositions are well-tolerated despite the
intense bitterness contributed by the presence of azelastine
hydrochloride. Thus, use of such compositions of the invention
provide symptomatic relief from allergic rhinitis, vasomotor
rhinitis, or allergic conjunctivitis, while significantly improving
patient acceptability and compliance.
Treatment of Snoring
[1203] The present invention also provides a method for treating
snoring that in some cases eliminates snoring entirely, and in
other cases reduces the intensity and frequency of snoring. The
treatment comprises administering a prescribed dosage in one or
more doses per day of azelastine or a physiologically acceptable
salt thereof along with a taste-masking agent. The azelastine is
suitably topically applied to the nasal passage, generally in the
form of a nasal spray or in other delivery forms described herein.
Azelastine is administered in an amount effective to inhibit
snoring and may be administered once or more than once a day. In a
suitable embodiment, at least one dose is administered prior to
bedtime. Published International Patent Application No. WO
02/056876, the disclosure of which is incorporated by reference
herein in its entirety, describes compositions and methods for
treatment of snoring that can be used in the practice of the
present invention.
[1204] In one embodiment, the present invention provides a sterile
and stable aqueous solution of azelastine or one or more of its
salts (e.g., azelastine HCl), along with one or more taste-masking
agents and optionally one or more additional active agents such as
those described herein, which can be used in the form of drops,
ointments, creams, gels, insufflatable powders or, in a suitable
embodiment, in the form of a spray (preferably a nasal spray). The
spray can be formed by the use of a conventional spray-squeeze
bottle or a pump vaporizer. In addition, it is also possible to use
compressed gas aerosols. For example, 0.03 to 3 mg of azelastine
base can be released per individual actuation.
[1205] In certain such embodiments, the formulations of the present
invention for use in treating snoring comprise one or more
taste-masking agents, one or more flavoring agents, and/or one or
more sweetening agents, or a combination of such agents.
Non-limiting examples of such substances include those described
herein. For example, sucralose is especially effective as a
sweetening and taste-masking agent in the compositions of the
present invention for use in treatment of snoring, particularly
when used at concentrations of from about 0.001% to about 1%,
suitably at concentrations of from about 0.01% to about 0.5%, and
more suitably at concentrations of from about 0.02% to about 0.2%,
and most suitably from about 0.05% to about 0.15%, of the total
composition.
[1206] Solvents which may be used for such formulations include,
but are not limited to, water, saturated aliphatic mono and
polyvalent alcohols which contain 2-3 carbon atoms (for example
ethanol. Isopropanol, 1,2-propylene glycol, glycerine), liquid
polyglycols (molecular weight 200 to 600). The solvent used is
suitably water or mixtures of water with other physiologically
acceptable solvents (for example those mentioned above). Suitably,
the amount of the latter solvent in the aqueous mixture should not
exceed 15% by weight.
[1207] Such solutions or formulations suitably can contain
preservatives and stabilizers, as well as other excipients
disclosed herein. Suitable excipients include, for example:
ethylene diamine tetra-acetic acid (eidetic acid) and their alkali
salts (for example dialkali salts such as disodium salt, calcium
salt, calcium-sodium salt), lower alkyl p-hydroxybenzoates,
chlorohexidine (for example in the form of the acetate or
gluconate), phenyl mercury borate. Furthermore, it is possible, for
example, to use sodium-(2-ethylmercurithio)-benzoate generally
known as "thimerosal" which may be present in an amount of 0.001 to
0.05, preferably from 0.005 to 0.02, for example 0.01%
(weight/volume in liquid formulations, otherwise weight/weight).
Other suitable preservatives are: pharmaceutically useful
quaternary ammonium compounds, for example cetylpyridinium
chloride, tetradecyltrimethyl ammonium bromide, generally known as
"cetrimide,"
benzyldimethyl-[2-[2-[p-(1,1,3,3-tetramethyl-butyl)]phenoxy]ethoxy]-ammon-
ium chloride, generally known as "benzethonium chloride" and
myristyl-:-picolinium chloride. Each of these compounds may be used
in a concentration of 0.002 to 0.05, for example 0.02%
(weight/volume in liquid formulations, otherwise weight/weight).
Preferred preservatives among the quaternary ammonium compounds are
alkylbenzyl dimethyl ammonium chloride and mixtures thereof, for
example the compounds generally known as "benzalkonium
chloride."
[1208] Such formulations of the present invention for treatment of
snoring (solutions, suspensions as well as oily solutions or
suspensions, ointments, emulsions, creams, gels, dosage aerosols)
can contain about 0.0005 to about 2, preferably about 0.001 to
about 1, or about 0.003 to about 0.5% (weight/weight) of azelastine
(related to the free azelastine base). Should azelastine be present
as a salt, the amounts should be recalculated as necessary to give
the amounts of azelastine, in the free acid form shown above. In
the case of powders, the concentration of azelastine base generally
is about 0.0005 to about 2 percent by weight relative to the solid
carrier substances.
[1209] In the case of solutions, the dosage per nostril is, for
example, 0.01 to 0.2 ml, in particular 0.05 to 0.15 ml. Such a
dosage should be applied once to several times, preferably 1 to 5
times daily (optionally also hourly).
[1210] Suitable acid components for azelastine salts are, for
example, hydrophilic acids (HCl, HBr), sulfuric acid, phosphoric
acids), nitric acid, organic mono-, di- or tricarboxylic acids of
aliphatic, alicyclic, aromatic or heterocyclic organic acids
(embonic acid, citric acid, tartaric acid), aliphatic and aromatic
sulfonic acids (for example camphorsulfonic acid).
[1211] It is also suitable to add buffer substances such as citric
acid/sodium hydrogensulphate borate buffer, phosphates (sodium
hydrogenorthophosphate, disodiumhydrogenphosphate), tromethamol or
equivalent conventional buffers in order, for example, to adjust
the formulation to a pH value of 6 to 7.5, preferably 6.5 to
7.1.
[1212] In one embodiment, snoring is treated by use of a 0.1% or a
0.15% aqueous solution of azelastine hydrochloride, suitably as a
nasal spray. The spray is metered to deliver about 137 .mu.g of
azelastine hydrochloride (equivalent to 125 .mu.g of azelastine
base).
[1213] In addition to azelastine, the compositions useful for
treating snoring can also optionally contain one or more additional
active agents such as those described herein. In addition, the
compositions for treating snoring can also further comprise one
more sedatives or sleeping aids to help assist the user in falling
asleep. Suitable sedatives and sleep aids include, but are not
limited to, melatonin (N-acetyl-5-methoxytryptamine), a melatonin
agonist, GABA (gamma-amino-butyric acid), other antihistamines (for
example, benocten and olopatadine), benzodiazepines (for example,
midazolam, diazepam), diazepines, phenobarbiturates,
diphenhydramines or methiazoles. Other suitable sleep aids include
plant extracts such as: Valeriana officinalis, Lavandula
angustifolia, Humulus lupulus, passiflora incarnate, Ocimum
basilicum, Nardostachysjatamamsi, Hypericum perforatum, Corydalis
cava, Daliva miltiorrhiza, Cyperipedium pubescens, Cymbopogon
flexuosus, Melissa officinalis, Monarda didymia, Citrus aurantii,
Psicidia piscioula, and the like.
Co-Administration of Azelastine and Steroid
[1214] In a further embodiment, the present invention provides
methods of treating a variety of disorders, including allergic
rhinitis, vasomotor rhinitis, allergic conjunctivitis, as well as
the various other disorders disclosed throughout and known in the
art, by co-administering azelastine (or a pharmaceutically
acceptable salt thereof, e.g., azelastine HCl) and one or more
steroids. Suitably, azelastine or a pharmaceutically acceptable
salt or ester thereof (e.g., azelastine HCl) is administered in the
form of a nasal spray, although additional delivery routes and
formulations as described throughout can also be used (e.g., oral,
ocular, inhalation, etc.). As described throughout, compositions
for administration of azelastine via the nasal route (as well as
other routes described throughout) can further comprise one or more
excipients, for example, a taste-masking agent such as sucralose,
as well as one or more additional active agents selected from those
described herein or otherwise known in the art, for example a
decongestant.
[1215] Examples of steroids suitable for co-administration in such
embodiments of the present invention include, but are not limited
to, fluoromethalone, fluticasone (and its conjugates, esters,
derivatives and the like, e.g., fluticasone propionate sold under
the brand name FLONASE.RTM. by GlaxoSmithKline, Research Triangle
Park, N.C., or fluticasone dipropionate), mometasone,
triamcinolone, betamethasone, flunisolide, beclomethasone,
budesonide, rimexolone, beloxil, prednisone, loteprednol (e.g.,
loteprednol etabonate), dexamethasone and its analogues (e.g.,
dexamethasone beloxil) described in U.S. Pat. Nos. 5,223,493 and
5,420,120, incorporated herein by reference in their entireties, as
well as other steroids described throughout. Preferred steroids for
use in the formulations of the present invention are "safe
steroids." As used herein, the term "safe steroid" means a steroid
which treats eosinophil and neurotrophil associated inflammation,
reduces papillae formation, and which is effective in treating
inflammation, without causing a clinically significant elevation in
intraocular pressure (IOP). Exemplary safe steroids that can be
used in the various formulations of the present invention,
particularly for delivery using nasal spray or ocular drop delivery
systems include, but are not limited to, any glucocorticoid which
meets the safe steroid definition, including but not limited to,
fluoromethalone, fluticasone (and its conjugates, esters,
derivatives and the like, e.g., fluticasone propionate sold under
the brand name FLONASE.RTM. by GlaxoSmithKline, Research Triangle
Park, N.C., or fluticasone dipropionate), rimexolone, loteprednol
(e.g., loteprednol etabonate), dexamethasone beloxil and its
analogues described in U.S. Pat. Nos. 5,223,493 and 5,420,120.
Additional "safe steroids" and methods for determining appropriate
amounts of such agents for inclusion in the present compositions
are disclosed in U.S. Pat. No. 6,649,602, the disclosure of which
is incorporated by reference herein in its entirety.
[1216] As used herein, the term "co-administration" refers to
administering azelastine or a pharmaceutically acceptable salt or
ester thereof (e.g., azelastine HCl) by any mode of administration
(e.g., intranasally, orally, ocularly, via inhalation, etc.) and
one or more steroids also by any mode of administration (e.g.,
intranasally, orally, ocularly, via inhalation, etc.)
simultaneously, i.e., at the same time, or within a suitable time
period of one another. More suitably, azelastine and one or more
steroids are administered in the form of a nasal spray formulation
within less than about 1 minute of each other (and can be
administered at the same time), or within less than about 2 minutes
of each other, within less than about 3 minutes of each other,
within less than about 4 minutes of each other, within less than
about 5 minutes of each other, within less than about 6 minutes of
each other, within less than about 7 minutes of each other, within
less than about 8 minutes of each other, within less than about 9
minutes of each other, within less than about 10 minutes of each
other, within less than about 11 minutes of each other, within less
than about 12 minutes of each other, within less than about 13
minutes of each other, within less than about 14 minutes of each
other, within less than about 15 minutes of each other, within less
than about 16 minutes of each other, within less than about 17
minutes of each other, within less than about 18 minutes of each
other, within less than about 19 minutes of each other, within less
than about 20 minutes of each other, within less than about 25
minutes of each other, within less than about 30 minutes of each
other, within less than about 35 minutes of each other, within less
than about 40 minutes of each other, within less than about 45
minutes of each other, within less than about 50 minutes of each
other, within less than about 55 minutes of each other, or within
less than about 60 minutes of each other.
[1217] In certain embodiments, azelastine or a pharmaceutically
acceptable salt or ester thereof (e.g., azelastine HCl) and one or
more steroids are administered at the same time using a spray or
dispensing device that allows for administration of both active
agents from separated storage containers at the same time. For
example, a device comprising two reservoirs, one of which contains
azelastine or a pharmaceutically acceptable salt or ester thereof
(e.g., azelastine HCl) in a suitable spray formulation, the other
of which comprises one or more steroids, also in a suitable spray
formulation. By activating the spray or dispensing devise, a dose
from each reservoir, i.e., an azelastine dose and a steroid dose,
are administered to the nasal passage of the patient at the same
time. A device in which each separate reservoir can be dispensed at
different times is also envisioned. The dosage and volume of spray
from each reservoir can also be controlled and modified as required
depending upon the agent being delivered. Additional devices and
methods are envisioned for other modes of administration, e.g., for
pulmonary delivery via inhalation as described hereinabove, for
example using dry powder inhalers (DPIs) or pre-metered DPIs.
[1218] In a further embodiment, co-administration comprises
administering azelastine or a pharmaceutically acceptable salt or
ester thereof (e.g., azelastine HCl) from a first spray or
dispensing device, and then administering one or more steroids from
a second spray or dispensing device (the devices can be attached or
joined to one another, or they can be completely separate
dispensing devices) within the time periods set forth herein. For
example, azelastine or a pharmaceutically acceptable salt or ester
thereof (e.g., azelastine HCl) can be administered by spraying a
dose (or one or more sprays can be used depending on the required
dose) of active agent into each nasal passage of the patient (or a
single nasal passage depending on the required dose). The dose
amount is determined by the configuration of the spray device and
the concentration of the agent in the spray formulation. Then,
within the time periods set forth throughout, (e.g., within less
than about 1 minute, less than about 5 minutes, less than about 10
minutes, less than about 15 minutes, less than about 20 minutes,
etc.) a dose of steroid is provided to the patient by spraying each
nasal passage with a steroid in a nasal spray formulation (or a
single nasal passage depending on the required dose). Suitably, two
sprays each of azelastine or a pharmaceutically acceptable salt or
ester thereof (e.g., azelastine HCl) and a steroid in nasal spray
formulations are given to each nasal passage, though in suitable
embodiments, a single or multiple sprays can be administered to one
or both nasal passages. In further embodiments, doses of additional
steroids and/or other agents can be co-administered before or after
the administration of azelastine and a first steroid. Similar
sequential co-administration of these active ingredients via other
modes of administration, e.g., via inhalation for pulmonary
delivery as described elsewhere herein, is also contemplated by the
present invention.
[1219] The present invention also encompasses the co-administration
of azelastine and one or more steroids, where the steroids, or both
the steroids and azelastine, are administered via a route other
than via nasal spray For example, azelastine (or a salt or ester
thereof, e.g. azelastine HCl) can be administered via nasal spray,
and one or more steroids administered via oral, inhalation,
injection, or other suitable route. Alternatively, azelastine (or a
salt or ester thereof, e.g. azelastine HCl) can be administered via
pulmonary delivery (e.g., via inhalation as described elsewhere
herein), and one or more steroids can be administered via nasal,
oral, inhalation, injection or other suitable route. In yet another
non-limiting approach, azelastine (or a salt or ester thereof, e.g.
azelastine HCl) can be administered ocularly, and one or more
steroids can be administered via nasal, oral, inhalation, injection
or other suitable route. As one of ordinary skill will be aware,
there are other examples of suitable modes of co-administration of
azelastine (or a salt or ester thereof, e.g. azelastine HCl) and a
steroid, based on the description herein and that will be familiar
to the practitioner; such other examples are also encompassed by
the present invention.
[1220] In a further embodiment, co-administration comprises
administration of azelastine (or a salt or ester thereof, e.g.
azelastine HCl) and one or more steroids in the same composition.
In certain such embodiments, the azelastine (or salt or ester
thereof) and the steroid are contained together in a single
pharmaceutical composition, for example, a single pharmaceutical
composition comprising azelastine (or a salt or ester thereof) and
a steroid (either in a solution or a suspension dosage form). Such
compositions may take any form, particularly those described herein
that are formulated for nasal administration, pulmonary
administration (e.g., via inhalation), ocular administration, oral
administration, injection and the like.
[1221] The amount of azelastine for co-administration can be varied
and adjusted appropriately by the ordinarily skilled artisan.
Suitably azelastine or a pharmaceutically acceptable salt or ester
thereof (e.g., azelastine HCl) is contained in the intranasal
formulations for co-administration in an amount of about 0.0001% to
about 1.0% by weight, and more suitably from about 0.005% to about
0.5% or most suitably from about 0.05% to about 0.20% (e.g., 0.05%,
0.06%, 0.07%, 0.08%, 0.09%. 0.10%, 0.11%, 0.12%, 0.13%, 0.14%,
0.15%, 0.16%, 0.17%, 0.18%, 0.19%, 0.20%), of pure azelastine
(calculated as the free azelastine base). The amount of steroid(s)
present in the formulations for co-administration can be varied and
adjusted appropriately by the ordinarily skilled artisan. Suitably,
one or more steroids are present in any amount in the nasal
formulations, for example about 0.01% to about 1.5% (e.g., about
0.01%, about 0.05%, about 0.1%, about 0.25%, about 0.5%, about
0.75%, about 1%, about 1.5%). Suitably the amount of steroid is
about 0.01% to about 1.5% by weight, more suitably about 0.01% to
about 1.0% by weight, or even more suitably about 0.01% to about
0.1% by weight (e.g., about 0.01%, about 0.02%, about 0.03%, about
0.04%, about 0.05%, about 0.06%, about 0.07%, about 0.08%, about
0.09%, or about 0.1% by weight). Amounts, compositions and
selection of buffers, isotonicity-adjusting agents, antioxidants,
preservatives, viscosity-increasing agents, chelating agents, and
other excipients (including taste-masking agents such as sucralose)
and other components of the formulations for use in the
co-administration embodiments of the present invention are
described herein and readily determinable by those of skill in the
art.
[1222] It has been found that co-administration of azelastine or a
pharmaceutically acceptable salt or ester thereof (e.g., azelastine
HCl) and one or more steroids provides a significant improvement in
patients suffering from allergic rhinitis, non-allergic vasomotor
rhinitis or allergic conjunctivitis, as compared to azelastine or
steroid administration alone, in symptoms such as runny nose, itchy
nose, sneezing, congestion and total nasal symptom score. (See
Example 13). Specifically, it has now been found that the
co-administration of azelastine or a pharmaceutically acceptable
salt or ester thereof (e.g., azelastine HCl) and one or more
steroids unexpectedly results in better therapeutic benefit to
patients to whom the agents have been co-administered than would be
expected, in that the effect on the symptoms of allergic rhinitis,
non-allergic vasomotor rhinitis or allergic conjunctivitis, of the
two agents co-administered (whether in the same composition or in
separate compositions) is significantly greater than the effects of
either agent administered separately.
[1223] It will be readily apparent to one of ordinary skill in the
relevant arts that other suitable modifications and adaptations to
the methods and applications described herein may be made without
departing from the scope of the invention or any embodiment
thereof. It is to be understood that while the invention has been
described in conjunction with the detailed description thereof, the
foregoing description is intended to illustrate and not limit the
scope of the invention, which is defined by the scope of the
appended claims. Other aspects, advantages, and modifications are
within the scope of the claims. Having now described the present
invention in detail, the same will be more clearly understood by
reference to the following examples, which are included herewith
for purposes of illustration only and are not intended to be
limiting of the invention.
EXAMPLES
Example 1
Azelastine Hydrochloride Nasal Solution
[1224] In one exemplary composition of the invention, a nasal spray
formulation containing azelastine hydrochloride was prepared using
hypromellose as a thickener, sorbitol as an isotonicity agent and
sweetener, and sucralose as both a sweetener and a taste-masking
agent. TABLE-US-00001 Ingredient % Azelastine Hydrochloride 0.150
Hypromellose 2900, USP 4000 0.100 Edetate Disodium, USP 0.050
Sorbitol 70%, USP 6.400 Sodium Citrate, USP, Dihydrate 0.068
Sucralose, NF 0.150 Benzalkonium Chloride 50% Solution, NF 0.025
Water Purified or Deionized Q.S. to 100%
[1225] Following preparation, the composition was filtered, and was
packaged into high density polyethylene bottles fitted with a screw
cap and comprising a VP3 metered-dose spray pump designed for
intranasal application in a volume of about 0.14 ml (Valois). For
use, one or two sprays were administered to each nostril two times
per day, or as prescribed.
Example 2
Azelastine Hydrochloride Nasal Solution
[1226] In another exemplary composition provided by the present
invention, a nasal spray formulation containing azelastine
hydrochloride was prepared using hypromellose as a thickener and
sucralose and menthol as taste-masking agents: TABLE-US-00002
Ingredient % Azelastine Hydrochloride 0.100 Hypromellose 2900, USP
4000 0.300 Edetate Disodium, USP 0.050 Sodium Citrate, USP,
Dihydrate 0.068 Sucralose, NF 0.050 Propylene Glycol, USP 1.895
Menthol, USP 0.050 Benzalkonium Chloride 50%, NF 0.025 Water
Purified or Deionized Q.S. to 100%
[1227] Following preparation, the composition was filtered, and was
packaged into high density polyethylene bottles fitted with a screw
cap and comprising a VP3 metered-dose spray pump designed for
intranasal application in a volume of about 0.14 ml (Valois). For
use, one or two sprays were administered to each nostril two times
per day, or as prescribed.
Example 3
Azelastine Hydrochloride Nasal Solution
[1228] In another exemplary composition of the invention, a nasal
spray formulation containing azelastine hydrochloride was prepared
using hypromellose as a thickener, sodium chloride as an
isotonicity agent, and sucralose as both a sweetener and a
taste-masking agent. TABLE-US-00003 Ingredient % Azelastine
Hydrochloride 0.100 Hypromellose 2900, USP 4000 0.100 Edetate
Disodium, USP 0.050 Citric Acid Anhydrous, USP 0.044 Dibasic Sodium
Phosphate Heptahydrate, USP 0.486 Sodium Chloride, USP 0.687
Sucralose, NF 0.150 Benzalkonium Chloride 50% Solution, NF 0.025
Water Purified or Deionized Q.S. to 100%
[1229] Following preparation, the composition was filtered, and was
packaged into high density polyethylene bottles fitted with a screw
cap and comprising a VP3 metered-dose spray pump designed for
intranasal application in a volume of about 0.14 ml (Valois). For
use, one or two sprays were administered to each nostril about two
times per day, or as prescribed.
Example 4
Azelastine Hydrochloride Ocular Solution
[1230] In another exemplary composition provided by the present
invention, an ocular formulation containing azelastine
hydrochloride was prepared using hypromellose as a thickener,
sorbitol as an isotonicity agent, and sucralose as a taste-masking
agent: TABLE-US-00004 Ingredient % Azelastine Hydrochloride 0.050
Hypromellose 2900, USP 4000 0.100 Edetate Disodium, USP 0.050
Sucralose, NF 0.150 Sorbitol Solution 70%, USP 6.667 Benzalkonium
Chloride 50%, NF 0.025 Water Purified or Deionized Q.S. to 100%
[1231] Following preparation, the composition was aseptically
filtered, and was packaged into high density polyethylene bottles
fitted with low density polyethylene dropper tips and a high
density polyethylene protective cap. The droppers were designed for
delivery of approximately 0.03 mL per drop. For use, one drop was
instilled into each affected eye twice a day, or as prescribed.
Example 5
Sensory Descriptive Bitterness Taste Analysis of Astelin Nasal
Spray
[1232] To determine effectiveness of masking agents in improving
the taste of Astelin.RTM.V Nasal Spray, a sensory evaluation of
various formulations was conducted. Testing was carried out via a
randomized, double-blind, placebo-controlled trial to evaluate
comparability between the currently FDA-approved Astelin.RTM. Nasal
Spray formulation and various sweetened azelastine hydrochloride
nasal spray formulations. The objective of the study was to
determine if a sweetened formulation of azelastine hydrochloride
(containing 137 .mu.g azelastine HCl), that includes 0.15%
sucralose as a taste masking agent, is equivalent in efficacy and
safety to the currently approved formulation of Astelin.RTM. Nasal
Spray (also containing 137 .mu.g of azelastine HCl).
Methodology:
[1233] Panelists: Twelve highly trained descriptive panelists led
by a panel leader.
[1234] Data Analysis: Data were entered into an Excel spreadsheet
and proofed for accuracy. An analysis was conducted with the data
using ANOVA and Duncan means separation at a confidence level of
95% using SPSS 13.0 for Windows.
[1235] Methodology: Panelists measured the bitterness, noted other
flavors perceived as well as observed the length of time the
bitterness lasted in the throat.
[1236] All solutions were prepared with Milli-Q Water
[1237] Standard Solutions [1238] 0.05% caffeine, bitter 2 [1239]
0.08% caffeine, bitter 5 [1240] 0.11% caffeine, bitter 7.5
[1241] Test samples were coded with random three-digit numbers.
Panelists scored samples on ballots individually. Samples were
evaluated by panelists using a 15-point intensity scale divided
into 0.1 point increments with zero indicating no measurable effect
and 15 indicating an extremely strong effect.
Product Identification:
[1242] (1) Astelin Nasal Spray Batch #1326 (two sprays) (azelastine
hydrochloride, 137 .mu.g azelastine HCl per two sprays)
[1243] (2) Astelin Nasal Spray Batch #1326 (four sprays)
(azelastine hydrochloride, 137 .mu.g azelastine HCl per two
sprays)
[1244] (3) Astelin Nasal Spray Batch #03-33-01c (two sprays)
(azelastine hydrochloride solution 0.1% w/v Investigational
Formulation with sorbitol and high concentration of sucralose, 137
.mu.g azelastine HCl per two sprays)
[1245] (4) Astelin Nasal Spray Batch #03-33-01c (four sprays)
(azelastine hydrochloride solution 0.1% w/v Investigational
Formulation with sorbitol and high concentration of sucralose, 137
.mu.g azelastine HCl per two sprays).
[1246] Results and Discussion
(A) Commercial Formulation (Standard Azelastine Hydrochloride
Commercial Formulation)
[1247] This sample and sample 1326 four sprays exhibited the most
bitterness with nasal discomfort that fell between mild and
moderate. The bitterness was more intense in those who experienced
more drainage. However, the bitterness dissipated within 30 minutes
for most panelists. A couple of panelists experienced some residual
bitterness for 2 to 3 hours after testing. The nasal discomfort was
predominately described as tingling, cooling or slight burning.
(B) Sample 1326 Four Sprays
[1248] This sample and the Commercial Formulation displayed the
most bitterness with nasal discomfort that fell between mild and
moderate. Several panelists described this sample as similar or
identical to the Commercial Formulation. As with the Commercial
Formulation, most panelists did not notice any bitterness after 30
minutes.
(C) Sample 1326 Two Sprays
[1249] This sample was significantly less bitter than the
Commercial Formulation using four sprays. Additionally, the nasal
discomfort was lessened and described as mild. For most, the
bitterness lasted less than 30 minutes. Some panelists questioned
the effectiveness of two sprays versus four sprays.
(D) Sample 03-33-01c Four Sprays
[1250] While this sample was also significantly less bitter than
the Commercial Formulation using four sprays, the sweetness was
notable. The nasal discomfort was described as mild and similar to
Sample 1326 two sprays and 03-33-01c two sprays. Most panelists
described this sample as more sweet than bitter. As they
experienced drainage, the sweet flavor intensified overriding any
bitterness. Both sweet and bitter flavors dissipated within an
hour.
(E) Sample 03-33-01c Two Sprays
[1251] This sample exhibited the least bitterness. Although the
panelists noted a slight sweetness in this sample, it was not
nearly as strong as when using four sprays. The sweetness did not
override the slight bitterness as it did when using four sprays.
The nasal discomfort was described as mild. Most indicated no
bitter or sweet taste after 30 minutes. The bitterness faded faster
than the sweetness. As with Sample 1326 two sprays, some panelists
questioned the effectiveness of two sprays versus four.
Panelists' Preferences
[1252] Of the four test samples, 4 of 11 panelists ranked 03-33-01c
two sprays as their first choice. Four panelists ranked it as their
second choice. They liked the slight sweetness that masked the
bitterness; however, several did question whether two sprays were
as effective as four.
[1253] Four of eleven panelists chose 03-33-01c four sprays as
their first choice with four indicating it would be their second
choice. Again, they preferred the sweet flavor that masked the
bitterness and they felt it was effective.
[1254] Three of eleven panelist chose 1326 two sprays as their
first choice, with one choosing it as a second choice. Some did not
like the sweetness and preferred a slight bitterness. Some
questioned the effectiveness of two sprays.
[1255] No panelists ranked 1326 four sprays as their first choice.
One panelist chose it as her second choice because she did not like
the sweet taste at all.
[1256] Conclusions
[1257] The panelists recognized the Commercial Formulation and
sample 1326 four sprays as the same.
[1258] Using two sprays of sample 1326 helped significantly with
the bitterness and nasal discomfort.
[1259] The 03-33-01c samples were significantly less bitter and
gave less nasal discomfort than the Commercial Formulation.
[1260] The 03-33-01c samples were equally preferred due to the
masking sweetness.
Example 6
Preservative Free Ocular Solution for Unit Dose
[1261] One exemplary composition provided by the present invention,
is a liquid dosage formulation containing azelastine hydrochloride
prepared using hypromellose as a thickener and sucralose and
menthol as a taste-masking agent in the ranges provided below:
TABLE-US-00005 Ingredient % Azelastine Hydrochloride 0.0500-.150
Hypromellose 2900, USP 4000 0.300 Edetate Disodium, USP 0.050
Sodium Citrate, USP, Dihydrate 0.068 Sucralose, NF 0.050-0.150
Propylene Glycol, USP 1.895 Water Purified or Deionized Q.S. to
100%
[1262] Following preparation, the solution is filtered, and
packaged into high density polyethylene containers. An approximate
unit dose volume of about 0.25 mL to 1 mL is filled in the
container which has a capacity of about 1 mL. The use of a single
unit-dose container eliminates the concerns of contamination and
provides the convenience of portability.
Example 7
Azelastine Hydrochloride Nasal Solution Comprising Steroid
[1263] One exemplary composition of the invention is a nasal spray
formulation containing azelastine hydrochloride prepared using
hypromellose as a thickener, a steroid, and sucralose as both a
sweetener and a taste-masking agent. TABLE-US-00006 Ingredient %
Azelastine Hydrochloride 0.05-0.150 Steroid (fluticasone,
mometasone, 0.01-2.0 dexamethasone beloxil, loteprednol (e.g.,
loteprednol etabonate), budesonide, or triamcinolone) Hypromellose
2900, USP 4000 0.100 Edetate Disodium, USP 0.050 Sorbitol 70%, USP
6.400 Sodium Citrate, USP, Dihydrate 0.068 Sucralose, NF 0.1-0.15
Benzalkonium Chloride 50% Solution, NF 0.025 Water Purified or
Deionized Q.S. to 100%
[1264] Following preparation, the solution is packaged into high
density polyethylene bottles fitted with a screw cap and comprising
a VP3 metered-dose spray pump designed for intranasal application
of about 0.14 ml (Valois). For use, one or two sprays can be
administered to each nostril two times per day, or as
prescribed.
Example 8
Azelastine Hydrochloride Nasal Solution Comprising Leukotriene
Antagonist
[1265] One exemplary composition of the invention is a nasal spray
formulation containing azelastine hydrochloride prepared using
hypromellose as a thickener, a leukotriene antagonist, and
sucralose as both a sweetener and a taste-masking agent.
TABLE-US-00007 Ingredient % Azelastine Hydrochloride 0.05-0.150
Leukotriene antagonist (montelukast) 0.1-5.0 Hypromellose 2900, USP
4000 0.100 Edetate Disodium, USP 0.050 Sorbitol 70%, USP 6.400
Sodium Citrate, USP, Dihydrate 0.068 Sucralose, NF 0.1-0.15
Benzalkonium Chloride 50% Solution, NF 0.025 Water Purified or
Deionized Q.S. to 100%
[1266] Following preparation, the solution is packaged into high
density polyethylene bottles fitted with a screw cap and comprising
a VP3 metered-dose spray pump designed for intranasal application
of about 0.14 ml (Valois). For use, one or two sprays can be
administered to each nostril two times per day, or as
prescribed.
Example 9
Azelastine Hydrochloride Nasal Solution Comprising Decongestant
[1267] One exemplary composition of the invention is a nasal spray
formulation containing azelastine hydrochloride prepared using
hypromellose as a thickener, a decongestant, and sucralose as both
a sweetener and a taste-masking agent. TABLE-US-00008 Ingredient %
Azelastine Hydrochloride 0.05-0.150 Decongestant (pseudoephedrine
or 0.1-2.0 phenylephrine) Hypromellose 2900, USP 4000 0.100 Edetate
Disodium, USP 0.050 Sorbitol 70%, USP 6.400 Sodium Citrate, USP,
Dihydrate 0.068 Optionally, Sucralose, NF 0.1-0.15 Benzalkonium
Chloride 50% Solution, NF 0.025 Water Purified or Deionized Q.S. to
100%
[1268] Following preparation, the solution is packaged into high
density polyethylene bottles fitted with a screw cap and comprising
a VP3 metered-dose spray pump designed for intranasal application
of about 0.14 ml (Valois). For use, one or two sprays can be
administered to each nostril two times per day, or as
prescribed.
Example 10
Azelastine Hydrochloride Nasal Solution Comprising NSAID
[1269] One exemplary composition of the invention is a nasal spray
formulation containing azelastine hydrochloride prepared using
hypromellose as a thickener, an NSAID, and sucralose as both a
sweetener and a taste-masking agent. TABLE-US-00009 Ingredient %
Azelastine Hydrochloride 0.05-0.150 NSAID (ibuprofen, diclofenac,
0.1-10.0 aceclofenac or naproxen) Hypromellose 2900, USP 4000 0.100
Edetate Disodium, USP 0.050 Sorbitol 70%, USP 6.400 Sodium Citrate,
USP, Dihydrate 0.068 Optionally, Sucralose, NF 0.1-0.15
Benzalkonium Chloride 50% Solution, NF 0.025 Water Purified or
Deionized Q.S. to 100%
[1270] Following preparation, the solution is packaged into high
density polyethylene bottles fitted with a screw cap and comprising
a VP3 metered-dose spray pump designed for intranasal application
of about 0.14 ml (Valois). For use, one or two sprays can be
administered to each nostril two times per day, or as
prescribed.
Example 11
Azelastine Hydrochloride Nasal Solution Comprising Steroid and
Decongestant
[1271] One exemplary composition of the invention is a nasal spray
formulation containing azelastine hydrochloride prepared using
hypromellose as a thickener, a steroid, a decongestant, and
sucralose as both a sweetener and a taste-masking agent.
TABLE-US-00010 Ingredient % Azelastine Hydrochloride 0.05-0.150
Steroid (fluticasone, mometasone, 0.01-2.0 dexamethasone beloxil,
loteprednol (e.g., loteprednol etabonate), budesonide, or
triamcinolone) Decongestant (pseudoephedrine or 0.1-1.0
phenylephrine) Hypromellose 2900, USP 4000 0.100 Edetate Disodium,
USP 0.050 Sorbitol 70%, USP 6.400 Sodium Citrate, USP, Dihydrate
0.068 Optionally, Sucralose, NF 0.1-0.15 Benzalkonium Chloride 50%
Solution, NF 0.025 Water Purified or Deionized Q.S. to 100%
[1272] Following preparation, the composition is packaged into high
density polyethylene bottles fitted with a screw cap and comprising
a VP3 metered-dose spray pump designed for intranasal application
of about 0.14 ml (Valois). For use, one or two sprays can be
administered to each nostril two times per day, or as
prescribed.
Example 12
Azelastine Hydrochloride Nasal Solution Comprising Steroid and
Leukotriene Antagonist
[1273] One exemplary composition of the invention is a nasal spray
formulation containing azelastine hydrochloride prepared using
hypromellose as a thickener, steroid, a leukotriene antagonist, and
sucralose as both a sweetener and a taste-masking agent.
TABLE-US-00011 Ingredient % Azelastine Hydrochloride 0.05-0.150
Steroid (fluticasone, mometasone, 0.01-2.0 dexamethasone beloxil,
loteprednol (e.g., loteprednol etabonate), budesonide, or
triamcinolone) Leukotriene antagonist (montelukast) 0.1-5.0
Hypromellose 2900, USP 4000 0.100 Edetate Disodium, USP 0.050
Sorbitol 70%, USP 6.400 Sodium Citrate, USP, Dihydrate 0.068
Optionally, Sucralose, NF 0.1-0.15 Benzalkonium Chloride 50%
Solution, NF 0.025 Water Purified or Deionized Q.S. to 100%
[1274] Following preparation, the solution is packaged into high
density polyethylene bottles fitted with a screw cap and comprising
a VP3 metered-dose spray pump designed for intranasal application
of about 0.14 ml (Valois). For use, one or two sprays can be
administered to each nostril two times per day, or as
prescribed.
Example 13
Co-Administration of Azelastine Hydrochloride and Fluticasone
Propionate
[1275] A two-week, randomized, double-blind study, which evaluated
the effects of the co-administration of ASTELIN.RTM. (azelastine
hydrochloride (HCl)) and FLONASE.RTM. (fluticasone propionate)
compared to either product alone in patients with seasonal allergic
rhinitis (SAR) was conducted during the 2006 Texas mountain cedar
season. After a 5-day placebo lead-in period, 151 patients with
moderate-to-severe allergic rhinitis symptoms were randomized to
either: (1) (49 total patients) ASTELIN.RTM. (azelastine
hydrochloride (HCl)) plus placebo saline nasal spray 2 sprays per
nostril, 15 minutes apart, twice daily (AM & PM); (2) (50 total
patients) FLONASE.RTM. (fluticasone propionate) plus placebo saline
nasal spray, 2 sprays per nostril, 15 minutes apart, once daily
(AM) and two sessions of placebo saline nasal spray, 2 sprays per
nostril, 15 minutes apart (PM); or (3) (52 total patients) the
co-administration of ASTELIN.RTM. (azelastine hydrochloride (HCl))
2 sprays per nostril plus FLONASE.RTM. (fluticasone propionate) 2
sprays per nostril (AM), 15 minutes apart, and ASTELIN.RTM.
(azelastine hydrochloride (HCl)) 2 sprays per nostril plus placebo
saline nasal spray, 15 minutes apart, (PM) for a 2-week
double-blind treatment period.
[1276] The primary efficacy variable was the change from baseline
in the Total Nasal Symptom Score (TNSS), which comprised sneezing,
itchy nose, runny nose, and nasal congestion (individual symptoms
scores were assigned a value between 0 and 3, where 0=no symptoms
and 3=severe symptoms). This study was not statistically designed
to assess the differences between ASTELIN.RTM. and
FLONASE.RTM..
[1277] The most common adverse events (AEs) were bitter taste (8.2%
in ASTELIN.RTM. (azelastine hydrochloride (HCl)) group, 2.0% in
FLONASE.RTM. (fluticasone propionate) group, 13.5% in
co-administration group) and headache (4.1% in ASTELIN.RTM.
(azelastine hydrochloride (HCl)) group, 4.0% in FLONASE.RTM.
(fluticasone propionate) group, 5.8% in co-administration group).
No other AE was reported by more than one patient in any treatment
group. There were no discontinuations due to AEs. The significantly
higher bitter taste AE score for the co-administration group versus
that seen in the groups receiving either agent alone indicates that
inclusion of a taste-masking agent, such as sucralose, in the
pharmaceutical formulations (whether formulations of each agent
alone, or a single formulation containing both agents) is highly
desired, to enhance patient compliance and thereby maximize
therapeutic benefit.
[1278] The results of the clinical trial are summarized and
presented in Appendix A hereinbelow and in FIGS. 1-6. FIG. 1 shows
the effect on the total nasal symptom score (TNSS) for all three
treatment groups. The co-administration of (azelastine
hydrochloride (HCl)) and (fluticasone propionate) demonstrated a
reduction in the TNSS versus either agent alone. FIGS. 2-5 show the
mean improvement in severity score (0-3 scale) from baseline for
the symptoms of runny nose, itchy nose, sneezing and congestion,
respectively. In all cases, the co-administration of (azelastine
hydrochloride (HCl)) and (fluticasone propionate) demonstrated a
reduction in the severity of the symptom versus either agent alone.
FIG. 6 shows the cumulative improvement in TNSS versus baseline
using area under the curve (AUC) units, indicating a greater than
40% improvement in TNSS versus either active agent alone. Taken
together, these results demonstrate that a significant and
unexpected therapeutic benefit is obtained by co-administration of
azelastine HCl and fluticasone propionate, beyond the response that
was expected based on therapeutic results observed by
administration of either agent alone.
[1279] A number of studies have examined the additive benefit of
combining a nasal steroid with an oral antihistamine or a
leukotriene antagonist in rhinitis (Juniper et al., J. Allergy
Clin. Immunol. 83(3):627-633 (1989); Ratner et al., J. Fam. Pract.
47(2):118-125 (1998); Simpson, R. J., Ann. Allergy 73(6):497-502
(1994); Backhouse et al., J. Int. Med. Res. 14(1):35-41 (1986);
Juniper et al., CMAJ 156(8):1123-1131 (1997); Barnes et al., Clin.
Exp. Allergy 36(5):676-684 (May 2006); Di Lorenzo et al., Clin.
Exp. Allergy 34(2):259-67 (2004)). The majority of these studies
showed that the combination of an oral rhinitis agent with a nasal
steroid was no better, with respect to improvement in symptoms and
total symptom scores, than the nasal steroid alone; a few of the
studies demonstrated only minimal improvement. For example, in a
study examining the administration of fluticasone propionate and
loratadine alone or in combination, no incremental benefit was
observed in TNSS (itchy nose, sneezing, runny nose, nasal
congestion) or Rhinitis Quality of Life Questionnaire (RQLQ) when
comparing the combination of these agents versus fluticasone
propionate alone (Ratner et al., J. Fam. Pract. 47(2):118-125
(1998)). In another study, the addition of levocetirizine to
fluticasone propionate did not provide incremental relief in TNSS,
RQLQ or peak nasal inspiratory flow relative to results with
fluticasone propionate alone (Barnes et al., Clin. Exp. Allergy
36(5):676-684 (May 2006)). In a study examining the effects of
administration of fluticasone propionate alone versus
co-administration of fluticasone with cetirizine or montelukast, no
incremental improvement in TNSS was observed with the combination
of fluticasone and cetirizine versus fluticasone alone; similarly,
there was no incremental benefit in TNSS with the combination of
fluticasone and montelukast versus fluticasone alone (Di Lorenzo et
al., Clin. Exp. Allergy 34(2):259-67 (2004)). In contrast, as shown
above, in the present studies administration of ASTELIN.RTM. brand
azelastine HCl nasal spray in combination with fluticasone
propionate demonstrated a magnitude of response that is both
clinically meaningful and statistically superior to the individual
components.
APPENDIX A
[1280] TABLE-US-00012 14.1.1 Patient Disposition All Randomized
Patients Azelastine Fluticasone Azelastine + Fluticasone Total All
Randomized Patients (N) 49 50 52 151 Number of Patients Who
Completed Study [N(%)] 49 (100.0) 48 (96.0) 50 (96.2) 147 (97.4)
Number of Patients Who Discontinued Study [N(%)] 0 (0.0) 2 (4.0) 2
(3.8) 4 (2.6) Primary Reason for Discontinuation From Study [(N(%)]
Adverse Event 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) Treatment Failure 0
(0.0) 1 (2.0) 0 (0.0) 1 (0.7) Non-Compliance 0 (0.0) 0 (0.0) 2
(3.8) 2 (1.3) Patient Withdrew Consent 0 (0.0) 1 (2.0) 0 (0.0) 1
(0.7) Lost to Follow-Up 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0)
Administrative Problems 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) Other 0
(0.0) 0 (0.0) 0 (0.0) 0 (0.0) Safety Population.sup.a [N(%)] 49
(100.0) 50 (100.0) 52 (100.0) 151 (100.0) Intent-to-Treat
Population.sup.b [N(%)] 49 (100.0) 50 (100.0) 52 (100.0) 151
(100.0) Per-Protocol Population.sup.c [N(%)] 49 (100.0) 47 (94.0)
48 (92.3) 144 (95.4) .sup.aSafety Population includes all
randomized patients who took at least one dose of the study drug.
.sup.bIntent-to-Treat Population (ITT) includes all patients who
were randomized and had at least one postbaseline observation.
.sup.cPer-Protocol Population includes all patients who completed
the 2-week treatment period per protocol. Note: all percentages are
based on all randomized patients shown in the same column.
Reference: 16.2.1
[1281] TABLE-US-00013 14.1.2.1 Patient Demographics and Baseline
Characteristics Intent-to-Treat Population Azelastine Fluticasone
Azelastine + Fluticasone Total Demographics Category/Statistics (N
= 49) (N = 50) (N = 52) (N = 151) Age (Years) N 49 50 52 151 Mean
38.4 37.4 36.0 37.2 Standard Deviation 15.36 14.78 14.75 14.89
Median 36.0 37.5 36.5 37.0 Min-Max 12-73 12-72 13-70 12-73 12 to
<18 [N(%)] 3 (6.1) 6 (12.0) 5 (9.6) 14 (9.3) 18 to <65 [N(%)]
42 (85.7) 43 (86.0) 45 (86.5) 130 (86.1) 65 or older [N(%)] 4 (8.2)
1 (2.0) 2 (3.8) 7 (4.6) Sex [N(%)] Male 22 (44.9) 15 (30.0) 19
(36.5) 56 (37.1) Female 27 (55.1) 35 (70.0) 33 (63.5) 95 (62.9)
Race [N(%)] Asian or Pacific Islander 0 (0.0) 3 (6.0) 1 (1.9) 4
(2.6) Hispanic or Latino 7 (14.3) 13 (26.0) 8 (15.4) 28 (18.5)
Black or African American 5 (10.2) 2 (4.0) 2 (3.8) 9 (6.0) American
Indian or Alaska Native 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) White or
Caucasian 36 (73.5) 32 (64.0) 41 (78.8) 109 (72.2) Other 1 (2.0) 0
(0.0) 0 (0.0) 1 (0.7) Height (in) N 49 50 52 151 Mean 65.9 65.2
65.7 65.6 Standard Deviation 4.45 4.22 4.33 4.32 Median 65.0 65.0
65.0 65.0 Min-Max 56-74 56-78 58-79 56-79 Height (in) N 3 6 5 14
(Age 12 to <18 Years) Mean 59.7 63.2 63.2 62.4 Standard
Deviation 1.53 4.45 4.06 3.91 Median 60.0 63.5 61.0 61.0 Min-Max
58-61 56-69 59-68 56-69 Height (in) N 46 44 47 137 (Age .gtoreq.18
Years) Mean 66.3 65.5 66.0 65.9 Standard Deviation 4.28 4.17 4.32
4.24 Median 65.0 65.0 65.0 65.0 Min-Max 56-74 56-78 58-79 56-79
Weight (lb) N 49 50 52 151 Mean 181.2 172.9 173.8 175.9 Standard
Deviation 47.09 40.42 51.05 46.30 Median 174.0 168.5 162.5 169.0
Min-Max 98-284 85-269 99-303 85-303 Weight (lb) N 3 6 5 14 (Age 12
to <18 Years) Mean 104.7 136.3 128.1 126.6 Standard Deviation
7.02 46.66 21.20 33.75 Median 104.0 122.5 121.4 118.0 Min-Max
98-112 85-199 108-163 85-199 Weight (lb) N 46 44 47 137 (Age
.gtoreq.18 Years) Mean 186.2 177.9 178.6 180.9 Standard Deviation
44.12 37.37 50.99 44.49 Median 177.8 169.5 169.0 171.0 Min-Max
102-284 117-269 99-303 99-303 Total Score.sup.a N 49 50 52 151 Mean
19.6 19.5 19.5 19.5 Standard Deviation 2.11 2.74 2.97 2.62 Median
19.7 19.4 19.5 19.7 Min-Max 15-24 14-24 13-24 13-24 Duration of
Texas Mountain N 49 50 52 151 Cedar Allergy (Years) Mean 19.2 15.7
16.2 17.0 Standard Deviation 13.32 9.69 9.15 10.87 Median 16.0 14.0
13.5 14.0 Min-Max 3-50 3-51 4-40 3-51 References: 16.2.4.1 and
16.2.9 .sup.aMean baseline TNSS over 5-day Lead-in Period,
including Day 1 AM. References: 16.2.4.1 and 16.2.6.1
[1282] TABLE-US-00014 14.1.1.2 Patient Demographics and Baseline
Charaeteristics Per-Protocol Population Azelastine Fluticasone
Azelastine + Fluticasone Total Demographics Category/Statistics (N
= 49) (N = 47) (N = 48) (N = 144) Age (Years) N 49 47 48 144 Mean
38.4 35.9 35.8 36.7 Standard Deviation 15.36 13.89 15.09 14.75
Median 36.0 37.0 36.0 36.0 Min-Max 12-73 12-61 13-70 12-73 12 to
<18 [N(%)] 3 (6.1) 6 (12.8) 5 (10.4) 14 (9.7) 18 to <65
[N(%)] 42 (85.7) 41 (87.2) 41 (85.4) 124 (86.1) 65 or older [N(%)]
4 (8.2) 0 (0.0) 2 (4.2) 6 (4.2) Sex [N(%)] Male 22 (44.9) 15 (31.9)
19 (39.6) 56 (38.9) Female 27 (55.1) 32 (68.1) 29 (60.4) 88 (61.1)
Race [N(%)] Asian or Pacific Islander 0 (0.0) 3 (6.4) 1 (2.1) 4
(2.8) Hispanic or Latino 7 (14.3) 13 (27.7) 6 (12.5) 26 (18.1)
Black or African American 5 (10.2) 2 (4.3) 2 (4.2) 9 (6.3) American
Indian or Alaska Native 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) White or
Caucasian 36 (73.5) 29 (61.7) 39 (81.3) 104 (72.2) Other 1 (2.0) 0
(0.0) 0 (0.0) 1 (0.7) Height (in) N 49 47 48 144 Mean 65.9 65.1
65.9 65.6 Standard Deviation 4.45 4.33 4.28 4.34 Median 65.0 65.0
65.2 65.0 Min-Max 56-74 56-78 59-79 56-79 Height (in) N 3 6 5 14
(Age 12 to <18 Years) Mean 59.7 63.2 63.2 62.4 Standard
Deviation 1.53 4.45 4.06 3.91 Median 60.0 63.5 61.0 61.0 Min-Max
58-61 56-69 59-68 56-69 Height (in) N 46 41 43 130 (Age .gtoreq.18
Years) Mean 66.3 65.4 66.2 66.0 Standard Deviation 4.28 4.30 4.25
4.26 Median 65.0 65.0 65.4 65.0 Min-Max 56-74 56-78 60-79 56-79
Weight (lb) N 49 47 48 144 Mean 181.2 173.4 174.0 176.3 Standard
Deviation 47.09 40.95 50.53 46.21 Median 174.0 169.0 162.5 169.5
Min-Max 98-284 85-269 108-303 85-303 Weight (lb) N 3 6 5 14 (Age 12
to <18 Years) Mean 104.7 136.3 128.1 126.6 Standard Deviation
7.02 46.66 21.20 33.75 Median 104.0 122.5 121.4 118.0 Min-Max
98-112 85-199 108-163 85-199 Weight (lb) N 46 41 43 130 (Age
.gtoreq.18 Years) Mean 186.2 178.9 179.3 181.6 Standard Deviation
44.12 37.68 50.34 44.23 Median 177.8 170.0 169.0 172.5 Min-Max
102-284 117-269 115-303 102-303 Total Score.sup.a N 49 47 48 144
Mean 19.6 19.5 19.3 19.5 Standard Deviation 2.11 2.74 2.97 2.62
Median 19.7 19.2 18.8 19.5 Min-Max 15-24 14-24 13-24 13-24 Duration
ofTexas Mountain N 49 47 48 144 Cedar Allergy (Years) Mean 19.2
14.5 16.5 16.8 Standard Deviation 13.32 8.14 9.38 10.65 Median 16.0
14.0 14.0 14.0 Min-Max 3-50 3-36 4-40 3-50 References: 16.2.4.1 and
16.2.9 .sup.aMean baseline TNSS over 5-day Lead-in Period,
including Day 1 AM. References: 16.2.4.1 and 16.2.6.1
[1283] TABLE-US-00015 14.1.3 Rhinitis Diagnosis Screening Results
Intent-to-Treat Population Azelastine Fluticasone Azelastine +
Fluticasone Total Category/Statistics (N = 49) (N = 50) (N = 52) (N
= 151) Background Current Age (Years) N 45 44 47 136 Mean 40.5 40.6
38.3 39.8 Standard Deviation 14.24 12.58 13.65 13.46 Median 42.0
39.0 38.0 39.0 Min-Max 18-73 18-72 18-70 18-73 Age of Symptom Onset
(Years) N 45 44 47 136 Mean 21.3 23.6 20.4 21.7 Standard Deviation
13.51 12.14 12.58 12.73 Median 17.0 23.5 20.0 19.0 Min-Max 3-57
1-50 1-51 1-57 Parental History of Allergy [N(%)] N 45 (91.8) 44
(88.0) 47 (90.4) 136 (90.1) Yes 23 (46.9) 15 (30.0) 21 (40.4) 59
(39.1) No 11 (22.4) 9 (18.0) 13 (25.0) 33 (21.9) Don't Know 11
(22.4) 20 (40.0) 13 (25.0) 44 (29.1) Parent History of Asthma
[N(%)] N 45 (91.8) 44 (88.0) 47 (90.4) 136 (90.1) Yes 6 (12.2) 4
(8.0) 9 (17.3) 19 (12.6) No 30 (61.2) 30 (60.0) 34 (65.4) 94 (62.3)
Don't Know 9 (18.4) 10 (20.0) 4 (7.7) 23 (15.2) Symptoms
Experienced [N(%)] N 45 (91.8) 44 (88.0) 47 (90.4) 136 (90.1) (All
symptoms that apply) Sneezing 43 (87.8) 39 (78.0) 46 (88.5) 128
(84.8) Stuffy Nose 41 (83.7) 43 (86.0) 47 (90.4) 131 (86.8) Runny
Nose 42 (85.7) 39 (78.0) 45 (86.5) 126 (83.4) Postnasal Drainage 41
(83.7) 40 (80.0) 42 (80.8) 123 (81.5) Itchy/watery Eyes 42 (85.7)
42 (84.0) 43 (82.7) 127 (84.1) Ear Plugging 27 (55.1) 26 (52.0) 26
(50.0) 79 (52.3) Sinus Pressure 37 (75.5) 35 (70.0) 39 (75.0) 111
(73.5) Allergic Triggers [N(%)] Cat or Cat Hair N 45 (91.8) 44
(88.0) 47 (90.4) 136 (90.1) Yes 16 (32.7) 17 (34.0) 27 (51.9) 60
(39.7) No 20 (40.8) 13 (26.0) 15 (28.8) 48 (31.8) Don't Know 9
(18.4) 14 (28.0) 5 (9.6) 28 (18.5) Dog or Dog Hair N 45 (91.8) 44
(88.0) 47 (90.4) 136 (90.1) Yes 12 (24.5) 11 (22.0) 15 (28.8) 38
(25.2) No 30 (61.2) 27 (54.0) 27 (51.9) 84 (55.6) Don't Know 3
(6.1) 6 (12.0) 5 (9.6) 14 (9.3) Other Furry Animals N 45 (91.8) 44
(88.0) 47 (90.4) 136 (90.1) Yes 6 (12.2) 9 (18.0) 13 (25.0) 28
(18.5) No 22 (44.9) 21 (42.0) 22 (42.3) 65 (43.0) Don't Know 17
(34.7) 14 (28.0) 12 (23.1) 43 (28.5) Symptoms During Spring N 45
(91.8) 44 (88.0) 47 (90.4) 136 (90.1) Summer, or Fall Yes 39 (79.6)
38 (76.0) 39 (75.0) 116 (76.8) No 5 (10.2) 3 (6.0) 6 (11.5) 14
(9.3) Don't Know 1 (2.0) 3 (6.0) 2 (3.8) 6 (4.0) Any Allergic
Triggers N 45 (91.8) 44 (88.0) 47 (90.4) 136 (90.1) Yes 42 (85.7)
41 (82.0) 44 (84.6) 127 (84.1) No 3 (6.1) 3 (6.0) 3 (5.8) 9 (6.0)
Don't Know 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) Non-allergic Triggers
[N(%)] Temperature or Humidity Changes N 45 (91.8) 44 (88.0) 47
(90.4) 136 (90.1) Yes 30 (61.2) 29 (58.0) 33 (63.5) 92 (60.9) No 7
(14.3) 9 (18.0) 5 (9.6) 21 (13.9) Don't Know 8 (16.3) 6 (12.0) 9
(17.3) 23 (15.2) Smoke N 45 (91.8) 44 (88.0) 47 (90.4) 136 (90.1)
Yes 25 (51.0) 22 (44.0) 27 (51.9) 74 (49.0) No 14 (28.6) 18 (36.0)
16 (30.8) 48 (31.8) Don't Know 6 (12.2) 4 (8.0) 4 (7.7) 14 (9.3)
Perfumes or Fragrances N 45 (91.8) 44 (88.0) 47 (90.4) 136 (90.1)
Yes 24 (49.0) 24 (48.0) 19 (36.5) 67 (44.4) No 19 (38.8) 16 (32.0)
22 (42.3) 57 (37.7) Don't Know 2 (4.1) 4 (8.0) 6 (11.5) 12 (7.9)
Incense or Candles N 45 (91.8) 44 (88.0) 47 (90.4) 136 (90.1) Yes
13 (26.5) 22 (44.0) 12 (23.1) 47 (31.1) No 28 (57.1) 18 (36.0) 29
(55.8) 75 (49.7) Don't Know 4 (8.2) 4 (8.0) 6 (11.5) 14 (9.3)
Household Cleaning Products N 45 (91.8) 44 (88.0) 47 (90.4) 136
(90.1) Yes 16 (32.7) 20 (40.0) 18 (34.6) 54 (35.8) No 23 (46.9) 22
(44.0) 24 (46.2) 69 (45.7) Don't Know 6 (12.2) 2 (4.0) 5 (9.6) 13
(8.6) Any Non-allergic Triggers N 45 (91.8) 44 (88.0) 47 (90.4) 136
(90.1) Yes 42 (85.7) 39 (78.0) 39 (75.0) 120 (79.5) No 3 (6.1) 5
(10.0) 7 (13.5) 15 (9.9) Don't Know 0 (0.0) 0 (0.0) 1 (1.9) 1 (0.7)
Drugs That Symptoms Responded Well in the Past [N(%)] Non-Sedating
Antihistamines N 45 (91.8) 44 (88.0) 47 (90.4) 136 (90.1) No Effect
1 (2.0) 0 (0.0) 0 (0.0) 1 (0.7) Small Effect 10 (20.4) 7 (14.0) 10
(19.2) 27 (17.9) Moderate Effect 18 (36.7) 19 (38.0) 21 (40.4) 58
(38.4) Big Effect 9 (18.4) 11 (22.0) 9 (17.3) 29 (19.2) Don't Know
7 (14.3) 7 (14.0) 7 (13.5) 21 (13.9) Nasal Corticosteroids N 45
(91.8) 44 (88.0) 47 (90.4) 136 (90.1) No Effect 1 (2.0) 0 (0.0) 0
(0.0) 1 (0.7) Small Effect 5 (10.2) 1 (2.0) 6 (11.5) 12 (7.9)
Moderate Effect 11 (22.4) 18 (36.0) 21 (40.4) 50 (33.1) Big Effect
9 (18.4) 7 (14.0) 8 (15.4) 24 (15.9) Don't Know 19 (38.8) 18 (36.0)
12 (23.1) 49 (32.5) Nasal Antihistamines N 45 (91.8) 44 (88.0) 47
(90.4) 136 (90.1) No Effect 1 (2.0) 2 (4.0) 0 (0.0) 3 (2.0) Small
Effect 2 (4.1) 1 (2.0) 2 (3.8) 5 (3.3) Moderate Effect 9 (18.4) 12
(24.0) 13 (25.0) 34 (22.5) Big Effect 2 (4.1) 2 (4.0) 2 (3.8) 6
(4.0) Don't Know 31 (63.3) 27 (54.0) 30 (57.7) 88 (58.3) The Best
Response From Any N 45 (91.8) 44 (88.0) 47 (90.4) 136 (90.1) of
These Drugs No Effect 2 (4.1) 0 (0.0) 0 (0.0) 2 (1.3) Small Effect
8 (16.3) 2 (4.0) 8 (15.4) 18 (11.9) Moderate Effect 16 (32.7) 23
(46.0) 22 (42.3) 61 (40.4) Big Effect 15 (30.6) 15 (30.0) 13 (25.0)
43 (28.5) Don't Know 4 (8.2) 4 (8.0) 4 (7.7) 12 (7.9) Reference:
16.2.4.3
[1284] TABLE-US-00016 14.1.4 Duration of Exposure and Compliance
With Study Drugs Intent-to-Treat Population Azelastine Fluticasone
Azelastine + Fluticasone Total Category/Statistics (N = 49) (N =
50) (N = 52) (N = 151) Duration of Exposure (Days) N 49 50 52 151
Mean 14.6 14.1 14.3 14.3 Standard Deviation 0.84 2.40 1.82 1.81
Median 15.0 14.0 15.0 15.0 Min-Max 12-16 1-18 6-19 1-19 Total
Number of Doses.sup.a Taken N 49 50 52 151 Mean 42.8 40.9 41.3 41.6
Standard Deviation 2.82 6.80 6.13 5.57 Median 44.0 42.0 42.0 42.0
Min-Max 30-47 3-51 10-47 3-51 Number of Patients With .gtoreq.80%
Compliance [N(%)] 49 (100.0) 50 (100.0) 49 (94.2) 148 (98.0)
.sup.aEach patient received 3 bottles of medication at each
treatment visit. Two bottles were for AM dosing and the 3.sup.rd
bottle is for PM doing. The patients were instructed to administer
2 sprays per nostril from each bottle once daily (3 doses total
each day) at the specified time period (AM or PM) with a 15-30
minute wait between dosings from the two AM bottles. References:
16.2.5.1 and 16.2.6.1
[1285] TABLE-US-00017 14.2.1.1 AUC of Change from Baseline in TNSS:
AM and PM Combined Intent-to-Treat Population Variable Time
Standard ANOVA Point Treatment N.sup.a Mean LS Mean.sup.b Deviation
Minimum Median Maximum Source p-value.sup.c TNSS (AM and PM
Combined) Baseline.sup.d Azelastine (A) 49 19.60 19.66 2.113 15.3
19.70 24.0 Treatment 0.957 Fluticasone (F) 49 19.53 19.56 2.771
13.7 19.17 24.0 Azelastine + Fluticasone 52 19.48 19.51 2.967 13.1
19.45 24.0 (A + F) Change from Baseline in TNSS (AM and PM
Combined) AUC.sup.e Azelastine 49 -60.38 -59.72 54.570 -184.5
-56.00 37.7 A vs A + F 0.007 Fluticasone 49 -64.53 -65.00 58.166
-231.3 -51.13 49.7 F vs A + F 0.024 Azelastine + Fluticasone 52
-92.21 -92.85 70.981 -261.5 -94.50 57.8 Treatment 0.015 .sup.aTotal
number of intent-to-treat patients with available data. .sup.bLS
Mean = Least-Square Mean obtained from analysis of variance (ANOVA)
model for baseline or analysis of covariance (ANCOVA) model for
change. .sup.cp-value for between treatment group comparison,
except Baseline, was based on an ANCOVA model containing treatment
group and site as fixed effects, and baseline as a covariate. For
Baseline, the p-value was based on an ANOVA model containing
treatment group and site as fixed effects. .sup.dMean baseline TNSS
over 5-day Lead-in Period, including Day 1 AM.
.sup.eArea-under-the-curve of change from baseline in TNSS from Day
1 to Day 14 with the change on Day 1 set to 0. The
last-observation-carried-forward method was applied for missing
TNSS scores prior to calculating the AUC. Reference: 16.2.6.1
[1286] TABLE-US-00018 14.2.1.2 AUC of Change from Baseline in TNSS:
AM and PM Combined Per-Protocol Population Variable Time Standard
ANOVA Point Treatment N.sup.a Mean LS Mean.sup.b Deviation Minimum
Median Maximum Source p-value.sup.c TNSS (AM and PM Combined)
Baseline.sup.d Azelastine (A) 49 19.60 19.66 2.113 15.3 19.70 24.0
Treatment 0.853 Fluticasone (F) 47 19.52 19.61 2.740 13.7 19.17
24.0 Azelastine + Fluticasone 48 19.27 19.40 2.973 13.1 18.80 24.0
(A + F) Change from Baseline in TNSS (AM and PM Combined) AUC.sup.e
Azelastine 49 -60.38 -59.23 54.570 -184.5 -56.00 37.7 A vs A + F
0.005 Fluticasone 47 -65.66 -65.38 58.782 -231.3 -51.13 49.7 F vs A
+ F 0.022 Azelastine + Fluticasone 48 -92.91 -94.03 69.530 -261.5
-100.42 57.8 Treatment 0.012 .sup.aTotal number of per-protocol
patients with available data. .sup.bLS Mean = Least-Square Mean
obtained from analysis of variance (ANOVA) model for baseline or
analysis of covariance (ANCOVA) model for change. .sup.cp-value for
between treatment group comparison, except Baseline, was based on
an ANCOVA model containing treatment group and site as fixed
effects, and baseline as a covariate. For Baseline, the p-value was
based on an ANOVA model containing treatment group and site as
fixed effects. .sup.dMean baseline TNSS over 5-day Lead-in Period,
including Day 1 AM. .sup.eArea-under-the-curve of change from
baseline in TNSS from Day 1 to Day 14 with the change on Day 1 set
to 0. The last-observation-carried-forward method was applied for
missing TNSS scores prior to calculating the AUC. Reference:
16.2.6.1
[1287] TABLE-US-00019 14.2.2.1 Change from Baseline in TNSS: AM and
PM Combined Intent-to-Treat Population Paired Variable Standard
t-test ANOVA Time Point Treatment N.sup.a Mean LS Mean.sup.b
Deviation Minimum Median Maximum p-value.sup.c Source p-value.sup.d
AM and PM Combined TNSS Baseline.sup.e Azelastine (A) 49 19.60
19.66 2.113 15.3 19.70 24.0 Treatment 0.958 Fluticasone (F) 50
19.53 19.57 2.742 13.7 19.38 24.0 Azelastine + Fluticasone 52 19.48
19.52 2.967 13.1 19.45 24.0 (A + F) Change from Baseline in AM and
PM Combined TNSS Overall.sup.f Azelastine 49 -4.73 -4.76 4.297
-14.4 -4.24 3.1 <0.001 A vs A + F 0.008 Fluticasone 49 -5.06
-5.24 4.582 -18.5 -3.91 3.7 <0.001 F vs A + F 0.029 Azelastine +
Fluticasone 52 -7.22 -7.40 5.586 -20.2 -7.33 4.7 <0.001
Treatment 0.018 Day <0.001 Treatment * Day 0.182 Day 2
Azelastine 49 -3.23 -3.10 4.330 -14.2 -2.67 4.1 <0.001 A vs A +
F 0.138 Fluticasone 49 -3.24 -3.12 4.331 -18.5 -2.00 2.7 <0.001
F vs A + F 0.144 Azelastine + Fluticasone 52 -4.53 -4.46 5.391
-16.1 -3.01 4.1 <0.001 Treatment 0.232 Day 3 Azelastine 49 -3.28
-3.21 4.610 -16.2 -1.67 4.1 <0.001 A vs A + F 0.009 Fluticasone
49 -4.12 -4.09 4.931 -18.5 -3.20 5.3 <0.001 F vs A + F 0.084
Azelastine + Fluticasone 52 -5.82 -5.80 5.520 -17.1 -4.68 4.3
<0.001 Treatment 0.029 Day 4 Azelastine 49 -3.93 -3.89 5.022
-17.2 -2.92 4.3 <0.001 A vs A + F 0.009 Fluticasone 49 -4.53
-4.53 4.924 -18.5 -4.17 4.5 <0.001 F vs A + F 0.045 Azelastine +
Fluticasone 52 -6.61 -6.62 5.619 -17.1 -6.62 4.1 <0.001
Treatment 0.023 Day 5 Azelastine 49 -4.48 -4.46 5.225 -17.2 -3.67
4.2 <0.001 A vs A + F 0.014 Fluticasone 49 -5.16 -5.20 5.236
-18.5 -4.40 5.3 <0.001 F vs A + F 0.072 Azelastine + Fluticasone
52 -7.19 -7.23 6.280 -21.0 -6.85 6.1 <0.001 Treatment 0.039 Day
6 Azelastine 49 -4.44 -4.40 5.147 -16.0 -3.70 5.4 <0.001 A vs A
+ F 0.003 Fluticasone 49 -5.10 -5.12 5.524 -18.5 -4.45 5.3
<0.001 F vs A + F 0.019 Azelastine + Fluticasone 52 -7.78 -7.82
6.225 -22.0 -7.99 5.1 <0.001 Treatment 0.007 Day 7 Azelastine 49
-5.09 -5.05 5.006 -16.0 -4.67 5.4 <0.001 A vs A + F 0.028
Fluticasone 49 -5.02 -5.06 4.989 -18.5 -5.00 5.5 <0.001 F vs A +
F 0.028 Azelastine + Fluticasone 52 -7.42 -7.47 6.319 -23.0 -7.07
5.1 <0.001 Treatment 0.039 Day 8 Azelastine 49 -5.38 -5.37 5.056
-17.0 -5.00 2.4 <0.001 A vs A + F 0.015 Fluticasone 49 -4.55
-4.64 4.647 -18.5 -3.70 3.7 <0.001 F vs A + F 0.002 Azelastine +
Fluticasone 52 -7.90 -7.98 6.035 -21.0 -7.11 5.1 <0.001
Treatment 0.005 Day 9 Azelastine 49 -5.38 -5.36 4.799 -18.0 -3.83
2.1 <0.001 A vs A + F 0.033 Fluticasone 49 -5.08 -5.17 5.219
-18.5 -4.58 2.7 <0.001 F vs A + F 0.021 Azelastine + Fluticasone
52 -7.59 -7.68 6.184 -23.0 -7.15 4.1 <0.001 Treatment 0.037 Day
10 Azelastine 49 -5.36 -5.29 4.976 -15.0 -5.33 4.0 <0.001 A vs A
+ F 0.018 Fluticasone 49 -5.61 -5.64 5.676 -18.5 -4.83 9.2
<0.001 F vs A + F 0.039 Azelastine + Fluticasone 52 -7.94 -8.00
6.375 -23.0 -7.14 5.1 <0.001 Treatment 0.035 Day 11 Azelastine
49 -5.77 -5.70 5.576 -18.1 -4.70 3.8 <0.001 A vs A + F 0.021
Fluticasone 49 -5.77 -5.85 5.742 -18.5 -4.83 9.2 <0.001 F vs A +
F 0.028 Azelastine + Fluticasone 52 -8.28 -8.39 6.459 -23.0 -7.72
4.3 <0.001 Treatment 0.033 Day 12 Azelastine 49 -5.54 -5.46
6.109 -19.0 -5.00 4.2 <0.001 A vs A + F 0.017 Fluticasone 49
-6.08 -6.12 5.874 -18.9 -5.17 9.2 <0.001 F vs A + F 0.062
Azelastine + Fluticasone 52 -8.32 -8.40 6.652 -24.0 -7.93 4.1
<0.001 Treatment 0.041 Day 13 Azelastine 49 -5.70 -5.65 6.060
-19.0 -5.30 5.7 <0.001 A vs A + F 0.016 Fluticasone 49 -6.83
-6.95 6.345 -18.9 -6.20 9.2 <0.001 F vs A + F 0.176 Azelastine +
Fluticasone 52 -8.48 -8.61 6.513 -24.0 -8.43 5.8 <0.001
Treatment 0.054 Day 14 Azelastine 49 -5.62 -5.56 5.890 -19.0 -5.30
6.7 <0.001 A vs A + F 0.009 Fluticasone 49 -6.91 -7.02 6.614
-18.5 -5.85 9.2 <0.001 F vs A + F 0.145 Azelastine + Fluticasone
52 -8.69 -8.82 6.517 -23.0 -9.34 5.8 <0.001 Treatment 0.031
.sup.aTotal number of intent-to-treat patients with available data.
.sup.bLS Mean = Least-Square Mean obtained from analysis of
variance (ANOVA) model for baseline or analysis of covariance
(ANCOVA) model otherwise. .sup.cp-value for the within-patient
change was based on a paired t-test. .sup.dp-value for between
treatment group comparison, except Overall and Baseline, was based
on an ANCOVA model containing treatment group and site as fixed
effects, and baseline as a covariate. For Overall, the p-value was
based on a repeated measures ANCOVA model containing study day as
the within-patient effect, treatment group and site as the
between-patient effects, treatment-by-study day interaction, and
baseline as a covariate. For Baseline, the p-value was based on an
# ANOVA model containing treatment group and site as fixed effects.
.sup.eMean baseline TNSS over 5-day Lead-in Period, including Day 1
AM. .sup.fOverall includes TNSS scores from Day 2 to Day 14.
Reference: 16.2.6.1
[1288] TABLE-US-00020 14.2.2.2 Percent Change from Baseline in
TNSS: AM and PM Combined Intent-to-Treat Population Paired Variable
Standard t-test ANOVA Time Point Treatment N.sup.a Mean LS
Mean.sup.b Deviation Minimum Median Maximum p-value.sup.c Source
p-value.sup.d AM and PM Combined TNSS Baseline.sup.e Azelastine (A)
49 19.60 19.66 2.113 15.3 19.70 24.0 Treatment 0.958 Fluticasone
(F) 50 19.53 19.57 2.742 13.7 19.38 24.0 Azelastine + Fluticasone
52 19.48 19.52 2.967 13.1 19.45 24.0 (A + F) Percent Change from
Baseline in AM and PM Combined TNSS Overall.sup.f Azelastine 49
-24.47 -24.78 22.215 -71.9 -24.26 15.4 <0.001 A vs A + F 0.011
Fluticasone 49 -26.12 -27.13 24.462 -100.0 -21.93 19.9 <0.001 F
vs A + F 0.035 Azelastine + Fluticasone 52 -36.94 -37.87 27.683
-86.9 -39.66 26.1 <0.001 Treatment 0.024 Day <0.001 Treatment
* 0.155 Day Day 2 Azelastine 49 -16.93 -16.31 22.796 -70.5 -12.31
20.8 <0.001 A vs A + F 0.207 Fluticasone 49 -16.91 -16.35 23.714
-100.0 -12.46 18.5 <0.001 F vs A + F 0.210 Azelastine +
Fluticasone 52 -22.82 -22.43 27.943 -84.7 -14.36 22.7 <0.001
Treatment 0.344 Day 3 Azelastine 49 -17.08 -16.85 24.024 -76.5
-8.11 20.8 <0.001 A vs A + F 0.014 Fluticasone 49 -22.26 -22.17
26.773 -100.0 -16.67 28.6 <0.001 F vs A + F 0.151 Azelastine +
Fluticasone 52 -29.65 -29.50 27.863 -94.1 -25.13 23.2 <0.001
Treatment 0.047 Day 4 Azelastine 49 -20.50 -20.41 26.044 -81.1
-14.29 21.8 <0.001 A vs A + F 0.011 Fluticasone 49 -23.67 -23.75
25.917 -100.0 -23.60 27.3 <0.001 F vs A + F 0.055 Azelastine +
Fluticasone 52 -33.92 -33.92 28.009 -85.1 -36.38 22.7 <0.001
Treatment 0.029 Day 5 Azelastine 49 -23.15 -23.20 26.633 -81.1
-18.64 21.0 <0.001 A vs A + F 0.016 Fluticasone 49 -26.89 -27.20
27.945 -100.0 -22.77 28.6 <0.001 F vs A + F 0.084 Azelastine +
Fluticasone 52 -37.02 -37.22 31.706 -100.0 -36.34 33.8 <0.001
Treatment 0.045 Day 6 Azelastine 49 -23.13 -23.15 26.683 -80.0
-18.78 29.0 <0.001 A vs A + F 0.003 Fluticasone 49 -26.90 -27.15
29.542 -100.0 -22.20 28.6 <0.001 F vs A + F 0.024 Azelastine +
Fluticasone 52 -40.33 -40.50 31.771 -100.0 -45.75 28.3 <0.001
Treatment 0.009 Day 7 Azelastine 49 -26.52 -26.40 26.583 -84.1
-23.31 29.0 <0.001 A vs A + F 0.037 Fluticasone 49 -25.75 -26.00
26.507 -100.0 -23.81 33.3 <0.001 F vs A + F 0.031 Azelastine +
Fluticasone 52 -38.04 -38.27 31.298 -95.8 -41.11 28.3 <0.001
Treatment 0.048 Day 8 Azelastine 49 -28.13 -28.22 26.628 -89.4
-23.73 11.2 <0.001 A vs A + F 0.020 Fluticasone 49 -23.38 -23.87
24.935 -100.0 -20.97 25.4 <0.001 F vs A + F 0.002 Azelastine +
Fluticasone 52 -40.61 -40.94 29.617 -100.0 -43.52 28.3 <0.001
Treatment 0.005 Day 9 Azelastine 49 -27.72 -27.79 24.151 -81.8
-19.35 11.1 <0.001 A vs A + F 0.038 Fluticasone 49 -25.94 -26.50
27.382 -100.0 -23.40 18.5 <0.001 F vs A + F 0.022 Azelastine +
Fluticasone 52 -38.97 -39.40 31.247 -100.0 -40.03 22.7 <0.001
Treatment 0.039 Day 10 Azelastine 49 -27.81 -27.60 25.985 -77.9
-28.93 19.7 <0.001 A vs A + F 0.025 Fluticasone 49 -28.76 -28.93
30.182 -100.0 -27.10 61.6 <0.001 F vs A + F 0.044 Azelastine +
Fluticasone 52 -40.56 -40.78 31.425 -100.0 -40.01 28.3 <0.001
Treatment 0.047 Day 11 Azelastine 49 -29.42 -29.24 27.960 -90.0
-26.11 18.6 <0.001 A vs A + F 0.027 Fluticasone 49 -29.30 -29.71
30.855 -100.0 -27.71 61.6 <0.001 F vs A + F 0.033 Azelastine +
Fluticasone 52 -42.09 -42.55 31.725 -95.8 -41.75 28.8 <0.001
Treatment 0.042 Day 12 Azelastine 49 -28.25 -27.99 31.095 -95.0
-25.86 21.0 <0.001 A vs A + F 0.018 Fluticasone 49 -31.04 -31.31
31.574 -100.0 -27.78 61.6 <0.001 F vs A + F 0.064 Azelastine +
Fluticasone 52 -42.62 -42.96 32.096 -100.0 -43.60 22.7 <0.001
Treatment 0.044 Day 13 Azelastine 49 -29.35 -29.24 31.149 -95.0
-26.15 32.7 <0.001 A vs A + F 0.024 Fluticasone 49 -34.97 -35.63
33.815 -100.0 -30.43 61.6 <0.001 F vs A + F 0.205 Azelastine +
Fluticasone 52 -43.11 -43.75 32.779 -100.0 -44.47 43.9 <0.001
Treatment 0.077 Day 14 Azelastine 49 -28.86 -28.70 30.499 -95.0
-25.00 38.5 <0.001 A vs A + F 0.013 Fluticasone 49 -35.00 -35.62
34.687 -100.0 -28.71 61.6 <0.001 F vs A + F 0.152 Azelastine +
Fluticasone 52 -44.29 -44.92 33.557 -95.8 -48.83 43.9 <0.001
Treatment 0.044 .sup.aTotal number of intent-to-treat patients with
available data. .sup.bLS Mean = Least-Square Mean obtained from
analysis of variance (ANOVA) model for baseline or analysis of
covariance (ANCOVA) model otherwise. .sup.cp-value for the
within-patient change was based on a paired t-test. .sup.dp-value
for between treatment group comparison, except Overall and
Baseline, was based on an ANCOVA model containing treatment group
and site as fixed effects, and baseline as a covariate. For
Overall, the p-value was based on a repeated measures ANCOVA model
containing study day as the within-patient effect, treatment group
and site as the between-patient effects, treatment-by-study day
interaction, and baseline as a covariate. For Baseline, the p-value
was based # on an ANOVA model containing treatment group and site
as fixed effects. .sup.eMean baseline TNSS over 5-day Lead-in
Period, including Day 1 AM. .sup.fOverall includes TNSS scores from
Day 2 to Day 14. Reference: 16.2.6.1
[1289] TABLE-US-00021 14.2.3.1 Change from Baseline in TNSS: AM and
PM Combined Per-Protocol Population Paired Variable Standard t-test
ANOVA Time Point Treatment N.sup.a Mean LS Mean.sup.b Deviation
Minimum Median Maximum p-value.sup.c Source p-value.sup.d AM and PM
Combined TNSS Baseline.sup.e Azelastine (A) 49 19.60 19.66 2.113
15.3 19.70 24.0 Treatment 0.853 Fluticasone (F) 47 19.52 19.61
2.740 13.7 19.17 24.0 Azelastine + Fluticasone 48 19.27 19.40 2.973
13.1 18.80 24.0 (A + F) Change from Baseline in AM and PM Combined
TNSS Overall.sup.f Azelastine 49 -4.73 -4.73 4.297 -14.4 -4.24 3.1
<0.001 A vs A + F 0.007 Fluticasone 47 -5.14 -5.24 4.633 -18.5
-3.91 3.7 <0.001 F vs A + F 0.030 Azelastine + Fluticasone 48
-7.28 -7.44 5.466 -20.2 -8.01 4.7 <0.001 Treatment 0.017 Day
<0.001 Treatment * Day 0.150 Day 2 Azelastine 49 -3.23 -3.08
4.330 -14.2 -2.67 4.1 <0.001 A vs A + F 0.133 Fluticasone 47
-3.27 -3.10 4.412 -18.5 -2.00 2.7 <0.001 F vs A + F 0.145
Azelastine + Fluticasone 48 -4.60 -4.48 5.326 -16.1 -3.46 4.1
<0.001 Treatment 0.232 Day 3 Azelastine 49 -3.28 -3.19 4.610
-16.2 -1.67 4.1 <0.001 A vs A + F 0.009 Fluticasone 47 -4.25
-4.18 4.977 -18.5 -3.47 5.3 <0.001 F vs A + F 0.102 Azelastine +
Fluticasone 48 -5.96 -5.86 5.526 -17.1 -4.83 4.3 <0.001
Treatment 0.031 Day 4 Azelastine 49 -3.93 -3.87 5.022 -17.2 -2.92
4.3 <0.001 A vs A + F 0.011 Fluticasone 47 -4.63 -4.61 4.961
-18.5 -4.17 4.5 <0.001 F vs A + F 0.064 Azelastine + Fluticasone
48 -6.62 -6.59 5.566 -17.1 -6.93 4.1 <0.001 Treatment 0.031 Day
5 Azelastine 49 -4.48 -4.43 5.225 -17.2 -3.67 4.2 <0.001 A vs A
+ F 0.013 Fluticasone 47 -5.23 -5.23 5.328 -18.5 -4.40 5.3
<0.001 F vs A + F 0.074 Azelastine + Fluticasone 48 -7.27 -7.31
6.212 -21.0 -7.37 6.1 <0.001 Treatment 0.037 Day 6 Azelastine 49
-4.44 -4.38 5.147 -16.0 -3.70 5.4 <0.001 A vs A + F 0.002
Fluticasone 47 -5.12 -5.11 5.632 -18.5 -4.45 5.3 <0.001 F vs A +
F 0.015 Azelastine + Fluticasone 48 -7.91 -7.97 6.076 -22.0 -8.25
5.1 <0.001 Treatment 0.006 Day 7 Azelastine 49 -5.09 -5.01 5.006
-16.0 -4.67 5.4 <0.001 A vs A + F 0.020 Fluticasone 47 -4.99
-4.98 5.093 -18.5 -5.00 5.5 <0.001 F vs A + F 0.020 Azelastine +
Fluticasone 48 -7.50 -7.60 6.147 -23.0 -7.26 5.1 <0.001
Treatment 0.028 Day 8 Azelastine 49 -5.38 -5.33 5.056 -17.0 -5.00
2.4 <0.001 A vs A + F 0.012 Fluticasone 47 -4.59 -4.61 4.683
-18.5 -3.70 3.7 <0.001 F vs A + F 0.002 Azelastine + Fluticasone
48 -7.98 -8.05 5.859 -21.0 -7.61 5.1 <0.001 Treatment 0.004 Day
9 Azelastine 49 -5.38 -5.32 4.799 -18.0 -3.83 2.1 <0.001 A vs A
+ F 0.030 Fluticasone 47 -5.18 -5.21 5.252 -18.5 -4.58 2.7
<0.001 F vs A + F 0.025 Azelastine + Fluticasone 48 -7.56 -7.69
5.978 -23.0 -7.33 4.1 <0.001 Treatment 0.039 Day 10 Azelastine
49 -5.36 -5.25 4.976 -15.0 -5.33 4.0 <0.001 A vs A + F 0.013
Fluticasone 47 -5.74 -5.70 5.713 -18.5 -4.83 9.2 <0.001 F vs A +
F 0.038 Azelastine + Fluticasone 48 -7.96 -8.10 6.172 -23.0 -7.43
5.1 <0.001 Treatment 0.029 Day 11 Azelastine 49 -5.77 -5.64
5.576 -18.1 -4.70 3.8 <0.001 A vs A + F 0.013 Fluticasone 47
-5.89 -5.89 5.775 -18.5 -4.83 9.2 <0.001 F vs A + F 0.024
Azelastine + Fluticasone 48 -8.33 -8.58 6.485 -23.0 -7.80 4.3
<0.001 Treatment 0.023 Day 12 Azelastine 49 -5.54 -5.40 6.109
-19.0 -5.00 4.2 <0.001 A vs A + F 0.013 Fluticasone 47 -6.20
-6.16 5.905 -18.9 -5.17 9.2 <0.001 F vs A + F 0.061 Azelastine +
Fluticasone 48 -8.31 -8.50 6.586 -24.0 -8.52 4.1 <0.001
Treatment 0.034 Day 13 Azelastine 49 -5.70 -5.59 6.060 -19.0 -5.30
5.7 <0.001 A vs A + F 0.010 Fluticasone 47 -7.01 -7.03 6.375
-18.9 -6.50 9.2 <0.001 F vs A + F 0.157 Azelastine + Fluticasone
48 -8.56 -8.81 6.570 -24.0 -8.57 5.8 <0.001 Treatment 0.037 Day
14 Azelastine 49 -5.62 -5.50 5.890 -19.0 -5.30 6.7 <0.001 A vs A
+ F 0.006 Fluticasone 47 -7.14 -7.15 6.638 -18.5 -6.00 9.2
<0.001 F vs A + F 0.147 Azelastine + Fluticasone 48 -8.73 -8.98
6.476 -23.0 -9.68 5.8 <0.001 Treatment 0.022 .sup.aTotal number
of per-protocol patients with available data. .sup.bLS Mean =
Least-Square Mean obtained from analysis of variance (ANOVA) model
for baseline or analysis of covariance (ANCOVA) model otherwise.
.sup.cp-value for the within-patient change was based on a paired
t-test. .sup.dp-value for between treatment group comparison,
except Overall and Baseline, was based on an ANCOVA model
containing treatment group and site as fixed effects, and baseline
as a covariate. For Overall, the p-value was based on a repeated
measures ANCOVA model containing study day as the within-patient
effect, treatment group and site as the between-patient effects,
treatment-by-study day interaction, and baseline as a covariate.
For Baseline, the p-value was based on an ANOVA # model containing
treatment group and site as fixed effects. .sup.eMean baseline TNSS
over 5-day Lead-in Period, including Day 1 AM. .sup.fOverall
includes TNSS scores from Day 2 to Day 14. Reference: 16.2.6.1
[1290] TABLE-US-00022 14.2.3.2 Percent Change from Baseline in
TNSS: AM and PM Combined Per-Protocol Population Variable Paired
Time Standard t-test ANOVA Point Treatment N.sup.a Mean LS
Mean.sup.b Deviation Minimum Median Maximum p-value.sup.c Source
p-value.sup.d AM and PM Combined TNSS Baseline.sup.e Azelastine (A)
49 19.60 19.66 2.113 15.3 19.70 24.0 Treatment 0.853 Fluticasone
(F) 47 19.52 19.61 2.740 13.7 19.17 24.0 Azelastine + Fluticasone
48 19.27 19.40 2.973 13.1 18.80 24.0 (A + F) Percent Change from
Baseline in AM and PM Combined TNSS Overall.sup.f Azelastine 49
-24.47 -24.72 22.215 -71.9 -24.26 15.4 <0.001 A vs A + F 0.010
Fluticasone 47 -26.46 -27.12 24.721 -100.0 -21.93 19.9 <0.001 F
vs A + F 0.036 Azelastine + Fluticasone 48 -37.49 -38.14 27.305
-86.9 -42.91 26.1 <0.001 Treatment 0.024 Day <0.001 Treatment
* Day 0.121 Day 2 Azelastine 49 -16.93 -16.25 22.796 -70.5 -12.31
20.8 <0.001 A vs A + F 0.206 Fluticasone 47 -17.11 -16.38 24.182
-100.0 -12.46 18.5 <0.001 F vs A + F 0.220 Azelastine +
Fluticasone 48 -23.31 -22.55 27.918 -84.7 -15.83 22.7 <0.001
Treatment 0.355 Day 3 Azelastine 49 -17.08 -16.85 24.024 -76.5
-8.11 20.8 <0.001 A vs A + F 0.015 Fluticasone 47 -22.87 -22.68
27.056 -100.0 -16.67 28.6 <0.001 F vs A + F 0.181 Azelastine +
Fluticasone 48 -30.54 -29.80 28.004 -94.1 -26.52 23.2 <0.001
Treatment 0.050 Day 4 Azelastine 49 -20.50 -20.39 26.044 -81.1
-14.29 21.8 <0.001 A vs A + F 0.013 Fluticasone 47 -24.08 -24.10
26.117 -100.0 -23.60 27.3 <0.001 F vs A + F 0.074 Azelastine +
Fluticasone 48 -34.28 -33.89 27.955 -85.1 -36.87 22.7 <0.001
Treatment 0.039 Day 5 Azelastine 49 -23.15 -23.17 26.633 -81.1
-18.64 21.0 <0.001 A vs A + F 0.015 Fluticasone 47 -27.16 -27.42
28.408 -100.0 -22.77 28.6 <0.001 F vs A + F 0.086 Azelastine +
Fluticasone 48 -37.72 -37.73 31.603 -100.0 -38.16 33.8 <0.001
Treatment 0.044 Day 6 Azelastine 49 -23.13 -23.16 26.683 -80.0
-18.78 29.0 <0.001 A vs A + F 0.003 Fluticasone 47 -26.95 -27.15
30.062 -100.0 -22.20 28.6 <0.001 F vs A + F 0.020 Azelastine +
Fluticasone 48 -41.28 -41.37 31.333 -100.0 -46.23 28.3 <0.001
Treatment 0.007 Day 7 Azelastine 49 -26.52 -26.32 26.583 -84.1
-23.31 29.0 <0.001 A vs A + F 0.029 Fluticasone 47 -25.57 -25.63
27.007 -100.0 -23.81 33.3 <0.001 F vs A + F 0.023 Azelastine +
Fluticasone 48 -38.70 -38.96 30.725 -95.8 -42.41 28.3 <0.001
Treatment 0.037 Day 8 Azelastine 49 -28.13 -28.14 26.628 -89.4
-23.73 11.2 <0.001 A vs A + F 0.017 Fluticasone 47 -23.43 -23.68
25.045 -100.0 -20.97 25.4 <0.001 F vs A + F 0.002 Azelastine +
Fluticasone 48 -41.30 -41.38 28.967 -100.0 -44.94 28.3 <0.001
Treatment 0.005 Day 9 Azelastine 49 -27.72 -27.68 24.151 -81.8
-19.35 11.1 <0.001 A vs A + F 0.036 Fluticasone 47 -26.33 -26.65
27.549 -100.0 -23.40 18.5 <0.001 F vs A + F 0.024 Azelastine +
Fluticasone 48 -39.14 -39.58 30.647 -100.0 -41.75 22.7 <0.001
Treatment 0.043 Day 10 Azelastine 49 -27.81 -27.49 25.985 -77.9
-28.93 19.7 <0.001 A vs A + F 0.020 Fluticasone 47 -29.26 -29.19
30.406 -100.0 -27.10 61.6 <0.001 F vs A + F 0.043 Azelastine +
Fluticasone 48 -40.96 -41.38 30.734 -100.0 -40.26 28.3 <0.001
Treatment 0.041 Day 11 Azelastine 49 -29.42 -29.05 27.960 -90.0
-26.11 18.6 <0.001 A vs A + F 0.018 Fluticasone 47 -29.69 -29.83
31.043 -100.0 -27.71 61.6 <0.001 F vs A + F 0.027 Azelastine +
Fluticasone 48 -42.64 -43.56 31.959 -95.8 -42.32 28.8 <0.001
Treatment 0.031 Day 12 Azelastine 49 -28.25 -27.82 31.095 -95.0
-25.86 21.0 <0.001 A vs A + F 0.014 Fluticasone 47 -31.50 -31.45
31.763 -100.0 -27.78 61.6 <0.001 F vs A + F 0.061 Azelastine +
Fluticasone 48 -42.93 -43.59 31.937 -100.0 -46.30 22.7 <0.001
Treatment 0.038 Day 13 Azelastine 49 -29.35 -29.06 31.149 -95.0
-26.15 32.7 <0.001 A vs A + F 0.017 Fluticasone 47 -35.73 -35.99
34.040 -100.0 -30.43 61.6 <0.001 F vs A + F 0.182 Azelastine +
Fluticasone 48 -43.85 -44.83 33.178 -100.0 -45.75 43.9 <0.001
Treatment 0.057 Day 14 Azelastine 49 -28.86 -28.52 30.499 -95.0
-25.00 38.5 <0.001 A vs A + F 0.010 Fluticasone 47 -36.03 -36.26
34.913 -100.0 -34.31 61.6 <0.001 F vs A + F 0.153 Azelastine +
Fluticasone 48 -44.84 -45.84 33.645 -95.8 -49.84 43.9 <0.001
Treatment 0.034 .sup.aTotal number of per-protocol patients with
available data. .sup.bLS Mean = Least-Square Mean obtained from
analysis of variance (ANOVA) model for baseline or analysis of
covariance (ANCOVA) model otherwise. .sup.cp-value for the
within-patient percent change was based on a paired t-test.
.sup.dp-value for between treatment group comparison, except
Overall and Baseline, was based on an ANCOVA model containing
treatment group and site as fixed effects, and baseline as a
covariate. For Overall, the p-value was based on a repeated
measures ANCOVA model containing study day as the within-patient
effect, treatment group and site as the between-patient effects,
treatment-by-study day interaction, and baseline as a covariate.
For Baseline, the p-value was based on an # ANOVA model containing
treatment group and site as fixed effects. .sup.eMean baseline TNSS
over 5-day Lead-in Period, including Day 1 AM. .sup.fOverall
includes TNSS scores from Day 2 to Day 14. Reference: 16.2.6.1
[1291] TABLE-US-00023 14.2.4.1 Change from Baseline in TNSS: AM
Intent-to-Treat Population Paired Variable Standard t-test ANOVA
Time Point Treatment N.sup.a Mean LS Mean.sup.b Deviation Minimum
Median Maximum p-value.sup.c Source p-value.sup.d AM TNSS
Baseline.sup.e Azelastine (A) 49 9.66 9.68 1.128 7.2 9.67 12.0
Treatment 0.725 Fluticasone (F) 50 9.79 9.81 1.369 7.2 9.78 12.0
Azelastine + Fluticasone 52 9.86 9.88 1.422 6.0 9.92 12.0 (A + F)
Change from Baseline in AM TNSS Overall.sup.f Azelastine 49 -2.21
-2.22 2.157 -7.3 -1.86 1.8 <0.001 A vs A + F 0.003 Fluticasone
49 -2.57 -2.55 2.403 -9.5 -2.14 2.5 <0.001 F vs A + F 0.021
Azelastine + Fluticasone 52 -3.76 -3.70 2.891 -10.8 -3.67 2.3
<0.001 Treatment 0.008 Day <0.001 Treatment * Day 0.065 Day 2
Azelastine 49 -1.48 -1.46 2.322 -7.3 -1.25 2.3 <0.001 A vs A + F
0.209 Fluticasone 49 -1.65 -1.58 2.266 -9.5 -1.00 1.4 <0.001 F
vs A + F 0.308 Azelastine + Fluticasone 52 -2.17 -2.07 2.908 -8.7
-1.25 2.7 <0.001 Treatment 0.406 Day 3 Azelastine 49 -1.29 -1.28
2.451 -8.0 -0.80 2.3 <0.001 A vs A + F 0.003 Fluticasone 49
-2.04 -2.01 2.667 -9.5 -1.50 3.0 <0.001 F vs A + F 0.093
Azelastine + Fluticasone 52 -2.98 -2.92 3.193 -9.0 -2.17 3.3
<0.001 Treatment 0.011 Day 4 Azelastine 49 -1.76 -1.79 2.623
-8.3 -1.33 2.5 <0.001 A vs A + F 0.007 Fluticasone 49 -2.41
-2.43 2.401 -9.5 -2.67 1.5 <0.001 F vs A + F 0.119 Azelastine +
Fluticasone 52 -3.28 -3.27 3.080 -10.3 -3.08 2.3 <0.001
Treatment 0.024 Day 5 Azelastine 49 -2.23 -2.25 2.664 -8.3 -1.67
2.3 <0.001 A vs A + F 0.030 Fluticasone 49 -2.57 -2.59 2.696
-9.8 -2.00 3.0 <0.001 F vs A + F 0.110 Azelastine + Fluticasone
52 -3.51 -3.50 3.242 -10.0 -3.25 2.7 <0.001 Treatment 0.079 Day
6 Azelastine 49 -2.01 -2.01 2.597 -9.0 -2.00 3.0 <0.001 A vs A +
F 0.001 Fluticasone 49 -2.57 -2.59 2.981 -9.8 -2.20 3.0 <0.001 F
vs A + F 0.024 Azelastine + Fluticasone 52 -3.94 -3.94 3.283 -11.0
-4.00 2.3 <0.001 Treatment 0.005 Day 7 Azelastine 49 -2.52 -2.52
2.554 -8.0 -2.20 3.0 <0.001 A vs A + F 0.018 Fluticasone 49
-2.57 -2.55 2.618 -9.5 -2.00 3.0 <0.001 F vs A + F 0.021
Azelastine + Fluticasone 52 -3.94 -3.90 3.444 -12.0 -3.58 2.7
<0.001 Treatment 0.025 Day 8 Azelastine 49 -2.62 -2.65 2.790
-9.0 -2.50 2.0 <0.001 A vs A + F 0.014 Fluticasone 49 -2.36
-2.40 2.592 -9.5 -1.67 3.0 <0.001 F vs A + F 0.004 Azelastine +
Fluticasone 52 -4.09 -4.09 3.273 -11.0 -3.63 2.3 <0.001
Treatment 0.008 Day 9 Azelastine 49 -2.52 -2.57 2.494 -9.0 -2.00
1.5 <0.001 A vs A + F 0.010 Fluticasone 49 -2.38 -2.43 2.641
-9.5 -1.83 3.0 <0.001 F vs A + F 0.005 Azelastine + Fluticasone
52 -4.01 -4.01 3.201 -12.0 -3.82 2.3 <0.001 Treatment 0.008 Day
10 Azelastine 49 -2.27 -2.29 2.620 -8.0 -2.17 2.2 <0.001 A vs A
+ F 0.004 Fluticasone 49 -2.73 -2.74 2.986 -9.5 -2.80 4.4 <0.001
F vs A + F 0.034 Azelastine + Fluticasone 52 -4.01 -3.99 3.301
-12.0 -3.70 2.7 <0.001 Treatment 0.012 Day 11 Azelastine 49
-2.48 -2.53 2.898 -9.0 -2.00 2.2 <0.001 A vs A + F 0.007
Fluticasone 49 -2.49 -2.52 3.082 -9.5 -2.00 4.4 <0.001 F vs A +
F 0.007 Azelastine + Fluticasone 52 -4.19 -4.16 3.362 -12.0 -3.63
3.3 <0.001 Treatment 0.008 Day 12 Azelastine 49 -2.58 -2.60
2.934 -9.0 -2.50 2.2 <0.001 A vs A + F 0.012 Fluticasone 49
-2.98 -2.99 3.121 -11.3 -2.75 4.4 <0.001 F vs A + F 0.059
Azelastine + Fluticasone 52 -4.17 -4.15 3.283 -12.0 -3.83 1.5
<0.001 Treatment 0.032 Day 13 Azelastine 49 -2.50 -2.55 2.992
-9.0 -1.80 3.0 <0.001 A vs A + F 0.005 Fluticasone 49 -3.32
-3.38 3.328 -10.3 -3.00 4.4 <0.001 F vs A + F 0.141 Azelastine +
Fluticasone 52 -4.28 -4.29 3.215 -12.0 -4.08 3.0 <0.001
Treatment 0.020 Day 14 Azelastine 49 -2.52 -2.56 2.982 -9.0 -2.00
3.0 <0.001 A vs A + F 0.004 Fluticasone 49 -3.28 -3.33 3.348
-9.5 -3.00 4.4 <0.001 P vs A + F 0.103 Azelastine + Fluticasone
52 -4.34 -4.34 3.245 -12.0 -4.63 3.3 <0.001 Treatment 0.017
.sup.aTotal number of intent-to-treat patients with available data.
.sup.bLS Mean = Least-Square Mean obtained from analysis of
variance (ANOVA) model for baseline of analysis of covariance
(ANCOVA) model otherwise. .sup.cp-value for the within-patient
change was based on an paired t-test. .sup.dp-value for between
treatment group comparison, except Overall and Baseline, was based
on an ANCOVA model containing treatment group and site as fixed
effects, and baseline as a covariate. For Overall, the p-value was
based on a repeated measures ANCOVA model containing study day as
the within-patient effect, treatment group and site as the
between-patient effects, treatment-by-study day interaction, and
baseline as a covariate. For Baseline, the p-value was based on an
# ANOVA model containing treatment group and site as fixed effects.
.sup.eMean baseline TNSS over 5-day Lead-in Period, including Day 1
AM. .sup.fOverall includes TNSS scores from Day 2 to Day 14.
Reference 16.2.6.1
[1292] TABLE-US-00024 14.2.4.2 Percent Change from Baseline in
TNSS: AM Intent-to-Treat Population Variable Paired Time Standard
t-test ANOVA Point Treatment N.sup.a Mean LS Mean.sup.b Deviation
Minimum Median Maximum p-value.sup.c Source p-value.sup.d AM TNSS
Baseline.sup.e Arelastine (A) 49 9.66 9.68 1.128 7.2 9.67 12.0
Treatment 0.725 Fluticasone (F) 50 9.79 9.81 1.369 7.2 9.78 12.0
Azelastine + Fluticasone 52 9.86 9.88 1.422 6.0 9.92 12.0 (A + F)
Percent Change from Baseline in AM TNSS Overall.sup.f Azelastine 49
-23.29 -23.13 22.865 -73.1 -19.23 18.6 <0.001 A vs A + F 0.006
Fluticasone 49 -26.49 -26.39 25.046 -100.0 -23.89 27.4 <0.001 F
vs A + F 0.035 Azelastine + Fluticasone 52 -37.53 -37.13 28.119
-90.4 -40.04 26.9 <0.001 Treatment 0.016 Day <0.001 Treatment
* Day 0.045 Day 2 Azelastine 49 -15.79 -15.45 25.055 -78.6 -14.29
24.1 <0.001 A vs A + F 0.403 Fluticasone 49 -17.21 -16.43 24.390
-100.0 -11.11 18.4 <0.001 F vs A + F 0.520 Azelastine +
Fluticasone 52 -20.59 -19.66 28.925 -89.7 -13.12 28.6 <0.001
Treatment 0.678 Day 3 Azelastine 49 -13.75 -13.37 26.139 -88.9
-7.89 24.1 <0.001 A vs A + F 0.007 Fluticasone 49 -22.09 -21.72
28.857 -100.0 -14.29 33.3 <0.001 F vs A + F 0.206 Azelastine +
Fluticasone 52 -29.29 -28.86 32.070 -100.0 -23.79 38.5 <0.001
Treatment 0.025 Day 4 Azelastine 49 -18.84 -18.88 27.966 -89.3
-14.89 26.3 <0.001 A vs A + F 0.011 Fluticasone 49 -25.07 -25.32
24.920 -100.0 -27.27 17.6 <0.001 F vs A + F 0.168 Azelastine +
Fluticasone 52 -32.82 -32.90 30.178 -91.1 -32.58 26.9 <0.001
Treatment 0.040 Day 5 Azelastine 49 -23.62 -23.57 27.972 -89.3
-15.79 24.1 <0.001 A vs A + F 0.041 Fluticasone 49 -26.62 -26.91
28.378 -100.0 -19.23 33.3 <0.001 F vs A + F 0.138 Azelastine +
Fluticasone 52 -35.41 -35.63 32.170 -100.0 -33.23 28.6 <0.001
Treatment 0.106 Day 6 Azelastine 49 -21.35 -21.14 27.405 -90.0
-16.67 33.3 <0.001 A vs A + F 0.002 Fluticasone 49 -27.12 -27.42
31.284 -100.0 -23.81 33.3 <0.001 F vs A + F 0.040 Azelastine +
Fluticasone 52 -39.68 -40.06 32.703 -100.0 -40.66 26.9 <0.001
Treatment 0.008 Day 7 Azelastine 49 -26.58 -26.26 27.521 -80.0
-25.00 33.3 <0.001 A vs A + F 0.027 Fluticasone 49 -26.29 -26.16
27.454 -100.0 -22.22 33.3 <0.001 F vs A + F 0.026 Azelastine +
Fluticasone 52 -39.62 -39.49 33.817 -100.0 -40.65 28.6 <0.001
Treatment 0.036 Day 8 Azelastine 49 -27.83 -27.73 29.736 -90.0
-25.00 20.0 <0.001 A vs A + F 0.021 Fluticasone 49 -24.67 -25.01
26.795 -100.0 -19.23 33.3 <0.001 F vs A + F 0.006 Azelastine +
Fluticasone 52 -41.25 -41.56 31.878 -100.0 -43.02 26.9 <0.001
Treatment 0.012 Day 9 Azelastine 49 -26.20 -26.38 25.942 -81.8
-22.22 18.4 <0.001 A vs A + F 0.015 Fluticasone 49 -24.52 -24.94
27.327 -100.0 -21.95 33.3 <0.001 F vs A + F 0.007 Azelastine +
Fluticasone 52 -40.21 -40.39 31.450 -100.0 -38.98 26.9 <0.001
Treatment 0.012 Day 10 Azelastine 49 -23.81 -23.62 28.124 -80.0
-23.64 25.0 <0.001 A vs A + F 0.008 Fluticasone 49 -28.06 -28.09
31.748 -100.0 -28.36 57.9 <0.001 F vs A + F 0.052 Azelastine +
Fluticasone 52 -40.09 -40.04 32.464 -100.0 -39.49 33.3 <0.001
Treatment 0.022 Day 11 Azelastine 49 -25.65 -25.86 29.971 -90.0
-19.40 22.0 <0.001 A vs A + F 0.016 Fluticasone 49 -25.02 -25.25
32.944 -100.0 -18.37 57.9 <0.001 F vs A + F 0.012 Azelastine +
Fluticasone 52 -41.35 -41.23 32.948 -100.0 -43.25 38.5 <0.001
Treatment 0.017 Day 12 Azelastine 49 -26.72 -26.61 30.825 -90.0
-26.32 25.0 <0.001 A vs A + F 0.016 Fluticasone 49 -30.49 -30.64
32.747 -100.0 -26.83 57.9 <0.001 F vs A + F 0.073 Azelastine +
Fluticasone 52 -41.84 -41.89 31.114 -100.0 -38.98 15.4 <0.001
Treatment 0.042 Day 13 Azelastine 49 -26.20 -26.36 31.095 -90.0
-18.37 33.3 <0.001 A vs A + F 0.011 Fluticasone 49 -34.03 -34.62
34.647 -100.0 -28.36 57.9 <0.001 F vs A + F 0.203 Azelastine +
Fluticasone 52 -42.46 -42.77 32.117 -100.0 -43.92 50.0 <0.001
Treatment 0.040 Day 14 Azelastine 49 -26.44 -26.51 31.727 -90.0
-20.00 33.3 <0.001 A vs A + F 0.010 Fluticasone 49 -33.12 -33.54
34.789 -100.0 -31.03 57.9 <0.001 F vs A + F 0.126 Azelastine +
Fluticasone 52 -43.30 -43.48 32.821 -100.0 -46.19 38.5 <0.001
Treatment 0.033 .sup.aTotal number of intent-to-treat patients with
available data. .sup.bLS Mean = Least-Square Mean obtained from
analysis of variance (ANOVA) model for baseline or analysis of
covariance (ANCOVA) model otherwise. .sup.cp-value for the
within-patient percent change was based on a paired t-test.
.sup.dp-value for between treatment group comparison, except
Overall and Baseline, was based on an ANCOVA model containing
treatment group and site as fixed effects, and baseline as a
covariate. For Overall, the p-value was based on a repeated
measures ANCOVA model containing study day as the within-patient
effect, treatment group and site as the between-patient effects,
treatment-by-study day interaction, and baseline as a covariate.
For Baseline, the p-value was based on an # ANOVA model containing
treatment group and site as fixed effects. .sup.eMean baseline TNSS
over 5-day Lead-in Period, including Day 1 AM. .sup.fOverall
includes TNSS scores from Day 2 to Day 14. Reference: 16.2.6.1
[1293] TABLE-US-00025 14.2.5.1 Change from Baseline in TNSS: PM
Intent-to-Treat Population Paired Variable Standard t-test ANOVA
Time Point Treatment N.sup.a Mean LS Mean.sup.b Deviation Minimum
Median Maximum p-value.sup.c Source p-value.sup.d PM TNSS
Baseline.sup.e Azelastine (A) 49 9.94 9.97 1.126 7.3 10.00 12.0
Treatment 0.456 Fluticasone (F) 50 9.74 9.77 1.436 6.5 9.63 12.0
Azelastine + Fluticasone 52 9.62 9.64 1.725 3.4 9.80 12.0 (A + F)
Change from Baseline in PM TNSS Overall.sup.f Azelastine 49 -2.51
-2.57 2.253 -7.1 -2.38 1.8 <0.001 A vs A + F 0.023 Fluticasone
50 -2.43 -2.71 2.288 -9.0 -1.86 1.5 <0.001 F vs A + F 0.042
Azelastine + Fluticasone 52 -3.46 -3.73 2.791 -9.4 -3.52 2.8
<0.001 Treatment 0.043 Day <0.001 Treatment * Day 0.563 Day 2
Azelastine 49 -1.76 -1.65 2.490 -8.2 -1.00 2.0 <0.001 A vs A + F
0.155 Fluticasone 49 -1.59 -1.54 2.465 -9.0 -1.00 2.3 <0.001 F
vs A + F 0.098 Azelastine + Fluticasone 52 -2.37 -2.37 2.732 -8.8
-1.67 1.4 <0.001 Treatment 0.198 Day 3 Azelastine 49 -1.98 -1.91
2.535 -8.2 -1.50 2.0 <0.001 A vs A + F 0.060 Fluticasone 49
-2.08 -2.08 2.560 -9.6 -1.80 2.7 <0.001 F vs A + F 0.118
Azelastine + Fluticasone 52 -2.85 -2.88 2.680 -8.8 -2.63 2.4
<0.001 Treatment 0.129 Day 4 Azelastine 49 -2.17 -2.09 2.774
-9.2 -2.20 2.0 <0.001 A vs A + F 0.026 Fluticasone 49 -2.12
-2.10 2.842 -9.6 -1.80 3.0 <0.001 F vs A + F 0.028 Azelastine +
Fluticasone 52 -3.33 -3.35 2.886 -8.8 -3.47 3.4 <0.001 Treatment
0.037 Day 5 Azelastine 49 -2.25 -2.19 3.062 -9.2 -1.20 2.5
<0.001 A vs A + F 0.014 Fluticasone 49 -2.59 -2.61 2.675 -9.0
-2.00 2.3 <0.001 F vs A + F 0.071 Azelastine + Fluticasone 52
-3.67 -3.73 3.392 -11.0 -3.60 3.4 <0.001 Treatment 0.038 Day 6
Azelastine 49 -2.43 -2.38 2.763 -9.0 -2.00 2.4 <0.001 A vs A + F
0.011 Fluticasone 49 -2.53 -2.53 2.751 -9.0 -2.00 2.3 <0.001 F
vs A + F 0.022 Azelastine + Fluticasone 52 -3.85 -3.88 3.144 -11.0
-3.63 3.4 <0.001 Treatment 0.019 Day 7 Azelastine 49 -2.57 -2.54
2.705 -8.4 -2.25 2.4 <0.001 A vs A + F 0.074 Fluticasone 49
-2.45 -2.50 2.632 -9.0 -2.00 3.0 <0.001 F vs A + F 0.064
Azelastine + Fluticasone 52 -3.48 -3.57 3.178 -11.0 -3.13 2.4
<0.001 Treatment 0.107 Day 8 Azelastine 49 -2.76 -2.69 2.584
-8.5 -2.75 1.8 <0.001 A vs A + F 0.027 Fluticasone 49 -2.18
-2.24 2.575 -9.0 -2.00 4.3 <0.001 F vs A + F 0.003 Azelastine +
Fluticasone 52 -3.81 -3.91 3.062 -10.0 -3.43 3.4 <0.001
Treatment 0.007 Day 9 Azelastine 49 -2.86 -2.78 2.675 -9.0 -2.33
1.2 <0.001 A vs A + F 0.128 Fluticasone 49 -2.69 -2.73 2.852
-9.0 -2.00 3.3 <0.001 F vs A + F 0.107 Azelastine + Fluticasone
52 -3.58 -3.67 3.226 -11.0 -3.50 3.4 <0.001 Treatment 0.191 Day
10 Azelastine 49 -3.08 -3.01 2.812 -9.0 -3.00 2.8 <0.001 A vs A
+ F 0.102 Fluticasone 49 -2.88 -2.90 2.900 -9.0 -2.60 4.8 <0.001
F vs A + F 0.067 Azelastine + Fluticasone 52 -3.92 -4.00 3.265
-11.0 -3.43 2.4 <0.001 Treatment 0.130 Day 11 Azelastine 49
-3.29 -3.20 3.122 -9.5 -3.33 2.4 <0.001 A vs A + F 0.099
Fluticasone 49 -3.29 -3.33 2.862 -9.7 -3.00 4.8 <0.001 F vs A +
F 0.148 Azelastine + Fluticasone 52 -4.10 -4.21 3.338 -11.0 -3.50
1.8 <0.001 Treatment 0.195 Day 12 Azelastine 49 -2.96 -2.85
3.340 -10.0 -2.40 2.8 <0.001 A vs A + F 0.031 Fluticasone 49
-3.10 -3.13 3.029 -9.0 -3.00 4.8 <0.001 F vs A + F 0.081
Azelastine + Fluticasone 52 -4.15 -4.26 3.553 -12.0 -3.63 3.4
<0.001 Treatment 0.071 Day 13 Azelastine 49 -3.21 -3.11 3.248
-10.0 -3.00 3.7 <0.001 A vs A + F 0.062 Fluticasone 49 -3.51
-3.57 3.187 -9.3 -3.00 4.8 <0.001 F vs A + F 0.244 Azelastine +
Fluticasone 52 -4.19 -4.32 3.505 -12.0 -3.90 2.8 <0.001
Treatment 0.167 Day 14 Azelastine 49 -3.10 -3.00 3.142 -10.0 -2.80
3.7 <0.001 A vs A + F 0.025 Fluticasone 49 -3.63 -3.70 3.473
-9.3 -3.00 4.8 <0.001 F vs A + F 0.228 Azelastine + Fluticasone
52 -4.35 -4.48 3.448 -11.0 -4.10 3.8 <0.001 Treatment 0.079
.sup.aTotal number of intent-to-treat patients with available data.
.sup.bLS Mean = Least-Square Mean obtained from analysis of
variance (ANOVA) model for baseline or analysis of covariance
(ANCOVA) model otherwise. .sup.cp-value for the within-patient
change was based on a paired t-test. .sup.dp-value for between
treatment group comparison, except Overall and Baseline, was based
on an ANCOVA model containing treatment group and site as fixed
effects, and baseline as a covariate. For Overall, the p-value was
based on a repeated measures ANCOVA model containing study day as
the within-patient effect, treatment group and site as the
between-patient effects, treatment-by-study day interaction, and
baseline as a covariate. For Baseline, the p-value was based on an
# ANOVA model containing treatment group and site as fixed effects.
.sup.eMean baseline TNSS over 5-day Lead-in Period, including Day 1
AM. .sup.fOverall includes TNSS scores from Day 2 to Day 14.
Reference: 16.2.6.1
[1294] TABLE-US-00026 14.2.5.2 Percent Change from Baseline in
TNSS: PM Intent-to-Treat Population Variable Paired Time Standard
t-test ANOVA Point Treatment N.sup.a Mean LS Mean.sup.b Deviation
Minimum Median Maximum p-value.sup.c Source p-value.sup.d PM TNSS
Baseline.sup.e Azelastine (A) 49 9.94 9.97 1.126 7.3 10.00 12.0
Treatment 0.456 Fluticasone (F) 50 9.74 9.77 1.436 6.5 9.63 12.0
Azelastine + Fluticasone 52 9.62 9.64 1.725 3.4 9.80 12.0 (A + F)
Percent Change from Baseline in PM TNSS Overall.sup.f Azelastine 49
-25.39 -26.45 22.390 -70.8 -21.68 18.9 <0.001 A vs A + F 0.020
Fluticasone 50 -24.98 -27.75 24.983 -100.0 -20.34 21.9 <0.001 F
vs A + F 0.037 Azelastine + Fluticasone 52 -36.18 -38.67 27.800
-86.3 -35.94 32.4 <0.001 Treatment 0.037 Day <0.001 Treatment
* Day 0.575 Day 2 Azelastine 49 -17.76 -17.15 24.989 -73.2 -10.00
20.0 <0.001 A vs A + F 0.166 Fluticasone 49 -16.52 -16.05 26.828
-100.0 -11.11 25.0 <0.001 F vs A + F 0.110 Azelastine +
Fluticasone 52 -24.74 -24.49 28.552 -89.8 -16.15 16.3 <0.001
Treatment 0.219 Day 3 Azelastine 49 -20.01 -19.66 25.506 -73.2
-15.15 20.0 <0.001 A vs A + F 0.074 Fluticasone 49 -22.28 -22.22
27.434 -100.0 -20.00 28.6 <0.001 F vs A + F 0.190 Azelastine +
Fluticasone 52 -29.10 -29.08 26.759 -89.8 -28.08 27.9 <0.001
Treatment 0.178 Day 4 Azelastine 49 -21.99 -21.42 27.647 -82.1
-23.08 20.0 <0.001 A vs A + F 0.034 Fluticasone 49 -22.22 -21.91
30.751 -100.0 -20.00 37.5 <0.001 F vs A + F 0.040 Azelastine +
Fluticasone 52 -34.16 -34.05 30.123 -89.8 -36.04 39.5 <0.001
Treatment 0.054 Day 5 Azelastine 49 -22.50 -22.87 30.099 -82.1
-13.04 26.3 <0.001 A vs A + F 0.012 Fluticasone 49 -27.06 -27.51
29.028 -100.0 -22.22 33.3 <0.001 F vs A + F 0.072 Azelastine +
Fluticasone 52 -38.96 -39.10 35.621 -100.0 -41.86 39.5 <0.001
Treatment 0.035 Day 6 Azelastine 49 -24.82 -25.18 28.081 -81.8
-20.45 25.0 <0.001 A vs A + F 0.011 Fluticasone 49 -26.62 -26.81
29.839 -100.0 -22.22 25.0 <0.001 F vs A + F 0.022 Azelastine +
Fluticasone 52 -40.94 -40.78 32.866 -100.0 -41.86 39.5 <0.001
Treatment 0.019 Day 7 Azelastine 49 -26.20 -26.39 28.186 -89.4
-23.81 25.0 <0.001 A vs A + F 0.085 Fluticasone 49 -25.18 -25.72
28.316 -100.0 -20.45 37.5 <0.001 F vs A + F 0.066 Azelastine +
Fluticasone 52 -36.25 -36.65 31.573 -91.7 -36.50 27.9 <0.001
Treatment 0.117 Day 8 Azelastine 49 -28.17 -27.94 26.451 -89.4
-27.27 18.9 <0.001 A vs A + F 0.036 Fluticasone 49 -21.91 -22.44
28.831 -100.0 -21.95 63.0 <0.001 F vs A + F 0.002 Azelastine +
Fluticasone 52 -39.45 -40.02 29.932 -100.0 -36.70 39.5 <0.001
Treatment 0.008 Day 9 Azelastine 49 -28.91 -28.94 25.922 -81.8
-25.00 12.2 <0.001 A vs A + F 0.127 Fluticasone 49 -27.18 -27.82
30.627 -100.0 -22.22 48.1 <0.001 F vs A + F 0.086 Azelastine +
Fluticasone 52 -37.64 -38.21 33.093 -100.0 -39.83 39.5 <0.001
Treatment 0.167 Day 10 Azelastine 49 -31.29 -31.30 28.433 -88.6
-33.33 29.7 <0.001 A vs A + F 0.109 Fluticasone 49 -29.48 -29.73
31.092 -100.0 -27.27 65.5 <0.001 F vs A + F 0.063 Azelastine +
Fluticasone 52 -41.03 -41.24 32.243 -100.0 -41.86 27.9 <0.001
Treatment 0.129 Day 11 Azelastine 49 -32.77 -32.80 30.202 -90.0
-33.96 25.0 <0.001 A vs A + F 0.084 Fluticasone 49 -33.54 -34.15
30.853 -100.0 -33.33 65.5 <0.001 F vs A + F 0.128 Azelastine +
Fluticasone 52 -43.12 -43.71 33.524 -100.0 -39.11 25.0 <0.001
Treatment 0.166 Day 12 Azelastine 49 -29.44 -29.18 32.936 -100.0
-25.00 29.7 <0.001 A vs A + F 0.027 Fluticasone 49 -31.52 -32.00
33.300 -100.0 -31.82 65.5 <0.001 F vs A + F 0.071 Azelastine +
Fluticasone 52 -43.65 -44.26 35.487 -100.0 -44.95 39.5 <0.001
Treatment 0.062 Day 13 Azelastine 49 -32.27 -32.19 33.207 -100.0
-33.33 44.0 <0.001 A vs A + F 0.067 Fluticasone 49 -35.75 -36.56
34.708 -100.0 -33.33 65.5 <0.001 F vs A + F 0.227 Azelastine +
Fluticasone 52 -44.03 -44.83 36.109 -100.0 -43.68 38.9 <0.001
Treatment 0.174 Day 14 Azelastine 49 -31.14 -31.07 31.947 -100.0
-28.57 44.0 <0.001 A vs A + F 0.028 Fluticasone 49 -36.79 -37.70
37.211 -100.0 -33.33 65.5 <0.001 F vs A + F 0.206 Azelastine +
Fluticasone 52 -45.57 -46.50 36.136 -100.0 -44.51 52.8 <0.001
Treatment 0.087 .sup.aTotal number of intent-to-treat patients with
available data. .sup.bLS Mean = Least-Square Mean obtained from
analysis of variance (ANOVA) model for baseline or analysis of
covariance (ANCOVA) model otherwise. .sup.cp-value for the
within-patient percent change was based on a paired t-test.
.sup.dp-value for between treatment group comparison, except
Overall and Baseline, was based on an ANCOVA model containing
treatment group and site as fixed effects, and baseline as a
covariate. For Overall, the p-value was based on a repeated
measures ANCOVA model containing study day as the within-patient
effect, treatment group and site as the between-patient effects,
treatment-by-study day interaction, and baseline as a covariate.
For Baseline, the p-value was based on an # ANOVA model containing
treatment group and site as fixed effects. .sup.eMean baseline TNSS
over 5-day Lead-in Period, including Day 1 AM. .sup.fOverall
includes TNSS scores from Day 2 to Day 14, Reference: 16.2.6.1
[1295] TABLE-US-00027 14.2.6.1 Change from Baseline in Individual
Nasal Symptom Score (AM and PM Combined): Itchy Nose
Intent-to-Treat Population Paired Variable Standard t-test ANOVA
Time Point Treatment N.sup.a Mean LS Mean.sup.b Deviation Minimum
Median Maximum p-value.sup.c Source p-value.sup.d AM and PM
Combined Nasal Symptom Score: Itchy Nose Baseline.sup.e Azelastine
(A) 49 4.74 4.76 0.807 2.9 4.73 6.0 Treatment 0.982 Fluticasone (F)
50 4.76 4.78 1.309 0.0 5.16 6.0 Azelastine + Fluticasone 52 4.72
4.74 1.047 1.5 4.76 6.0 (A + F) Change from Baseline in AM and PM
Combined Nasal Symptom Score: Itchy Nose Overall.sup.f Azelastine
49 -1.16 -1.14 1.358 -4.5 -0.98 1.1 <0.001 A vs A + F 0.009
Fluticasone 49 -1.24 -1.25 1.464 -5.4 -0.95 2.2 <0.001 F vs A +
F 0.023 Azelastine + Fluticasone 52 -1.94 -1.94 1.730 -5.8 -1.89
2.3 <0.001 Treatment 0.017 Day <0.001 Treatment * Day 0.889
Day 2 Azelastine 49 -0.61 -0.58 1.245 -4.2 -0.50 1.8 0.001 A vs A +
F 0.022 Fluticasone 49 -0.66 -0.61 1.600 -5.4 -0.40 3.2 0.006 F vs
A + F 0.027 Azelastine + Fluticasone 52 -1.28 -1.25 1.742 -5.1
-1.00 2.0 <0.001 Treatment 0.033 Day 3 Azelastine 49 -0.84 -0.85
1.364 -4.2 -0.75 1.3 <0.001 A vs A + F 0.020 Fluticasone 49
-0.97 -0.99 1.533 -5.4 -0.67 2.2 <0.001 F vs A + F 0.061
Azelastine + Fluticasone 52 -1.53 -1.55 1.770 -6.0 -1.38 1.9
<0.001 Treatment 0.046 Day 4 Azelastine 49 -1.00 -1.01 1.606
-4.8 -0.73 2.2 <0.001 A vs A + F 0.030 Fluticasone 49 -0.97
-0.98 1.638 -5.4 -0.90 2.3 <0.001 F vs A + F 0.024 Azelastine +
Fluticasone 52 -1.69 -1.71 1.683 -6.0 -1.67 1.0 <0.001 Treatment
0.037 Day 5 Azelastine 49 -1.10 -1.11 1.690 -4.8 -0.75 1.3
<0.001 A vs A + F 0.031 Fluticasone 49 -1.15 -1.16 1.650 -5.4
-1.00 2.3 <0.001 F vs A + F 0.042 Azelastine + Fluticasone 52
-1.86 -1.88 1.998 -6.0 -1.81 1.9 <0.001 Treatment 0.052 Day 6
Azelastine 49 -1.14 -1.14 1.650 -4.8 -0.73 1.4 <0.001 A vs A + F
0.019 Fluticasone 49 -1.21 -1.21 1.630 -5.4 -1.00 1.6 <0.001 F
vs A + F 0.032 Azelastine + Fluticasone 52 -1.94 -1.95 1.923 -6.0
-2.00 1.9 <0.001 Treatment 0.033 Day 7 Azelastine 49 -1.17 -1.18
1.464 -4.8 -0.90 1.3 <0.001 A vs A + F 0.009 Fluticasone 49
-1.27 -1.30 1.580 -5.4 -1.00 2.3 <0.001 F vs A + F 0.024
Azelastine + Fluticasone 52 -2.03 -2.06 1.993 -6.0 -2.00 2.9
<0.001 Treatment 0.017 Day 8 Azelastine 49 -1.12 -1.15 1.497
-4.8 -0.83 1.4 <0.001 A vs A + F 0.004 Fluticasone 49 -1.29
-1.33 1.643 -5.4 -1.15 3.2 <0.001 F vs A + F 0.018 Azelastine +
Fluticasone 52 -2.11 -2.15 2.059 -6.0 -1.95 2.9 <0.001 Treatment
0.009 Day 9 Azelastine 49 -1.27 -1.29 1.472 -5.4 -0.93 1.3
<0.001 A vs A + F 0.019 Fluticasone 49 -1.35 -1.40 1.624 -5.4
-1.30 2.2 <0.001 F vs A + F 0.040 Azelastine + Fluticasone 52
-2.05 -2.10 2.025 -6.0 -2.00 2.9 <0.001 Treatment 0.037 Day 10
Azelastine 49 -1.35 -1.35 1.743 -5.0 -1.10 1.3 <0.001 A vs A + F
0.041 Fluticasone 49 -1.19 -1.21 1.817 -5.4 -1.00 3.4 <0.001 F
vs A + F 0.015 Azelastine + Fluticasone 52 -2.05 -2.08 1.904 -6.0
-2.00 2.0 <0.001 Treatment 0.032 Day 11 Azelastine 49 -1.37
-1.39 1.803 -5.0 -1.10 1.4 <0.001 A vs A + F 0.028 Fluticasone
49 -1.29 -1.33 1.810 -5.4 -1.08 3.4 <0.001 F vs A + F 0.019
Azelastine + Fluticasone 52 -2.13 -2.18 1.908 -6.0 -2.12 2.9
<0.001 Treatment 0.030 Day 12 Azelastine 49 -1.33 -1.33 1.930
-6.0 -1.00 1.3 <0.001 A vs A + F 0.017 Fluticasone 49 -1.48
-1.50 1.945 -5.4 -1.17 3.4 <0.001 F vs A + F 0.051 Azelastine +
Fluticasone 52 -2.19 -2.23 1.883 -6.0 -2.23 2.0 <0.001 Treatment
0.039 Day 13 Azelastine 49 -1.43 -1.44 1.842 -5.4 -1.15 1.8
<0.001 A vs A + F 0.078 Fluticasone 49 -1.62 -1.64 2.031 -6.0
-1.42 3.4 <0.001 F vs A + F 0.224 Azelastine + Fluticasone 52
-2.05 -2.10 1.978 -6.0 -2.25 2.9 <0.001 Treatment 0.194 Day 14
Azelastine 49 -1.39 -1.39 1.903 -6.0 -1.15 1.8 <0.001 A vs A + F
0.017 Fluticasone 49 -1.74 -1.76 2.052 -6.0 -1.57 3.4 <0.001 F
vs A + F 0.146 Azelastine + Fluticasone 52 -2.26 -2.30 1.946 -6.0
-2.56 2.9 <0.001 Treatment 0.053 .sup.aTotal number of
intent-to-treat patients with available data. .sup.bLS Mean =
Least-Square Mean obtained from analysis of variance (ANOVA) model
for baseline or analysis of covariance (ANCOVA) model otherwise.
.sup.cp-value for the within-patient change was based on a paired
t-test. .sup.dp-value for between treatment group comparison,
except Overall and Baseline, was based on an ANCOVA model
containing treatment group and site as fixed effects, and baseline
as a covariate. For Overall, the p-value was based on a repeated
measures ANCOVA model containing study day as the within-patient
effect, treatment group and site as the between-patient effects,
treatment-by-study day interaction, and baseline as a covariate.
For Baseline, the p-value was based on an # ANOVA model containing
treatment group and site as fixed effects. .sup.eMean baseline TNSS
over 5-day Lead-in Period, including Day 1 AM. .sup.fOverall
includes TNSS scores from Day 2 to Day 14, Reference: 16.2.6.1
[1296] TABLE-US-00028 14.2.6.2 Change from Baseline in Individual
Nasal Symptom Score (AM and PM Combined): Congestion
Intent-to-Treat Population Paired Variable Standard t-test ANOVA
Time Point Treatment N.sup.a Mean LS Mean.sup.b Deviation Minimum
Median Maximum p-value.sup.c Source p-value.sup.d AM and PM
Combined Nasal Symptom Score: Congestion Baseline.sup.e Azelastine
(A) 49 5.48 5.48 0.511 4.5 5.47 6.0 Treatment 0.505 Fluticasone (F)
50 5.51 5.51 0.388 4.5 5.55 6.0 Azelastine + Fluticasone 52 5.40
5.40 0.578 3.8 5.45 6.0 (A + F) Change from Baseline in AM and PM
Combined Nasal Symptom Score: Congestion Overall.sup.f Azelastine
49 -1.12 -1.08 1.452 -5.0 -0.77 1.5 <0.001 A vs A + F 0.019
Fluticasone 49 -1.19 -1.14 1.243 -5.2 -0.99 0.9 <0.001 F vs A +
F 0.035 Azelastine + Fluticasone 52 -1.70 -1.70 1.349 -4.6 -1.54
1.2 <0.001 Treatment 0.034 Day <0.001 Treatment * Day 0.220
Day 2 Azelastine 49 -0.78 -0.73 1.386 -4.1 -0.17 1.5 <0.001 A vs
A + F 0.717 Fluticasone 49 -0.65 -0.59 1.380 -5.4 -0.30 1.2 0.002 F
vs A + F 0.349 Azelastine + Fluticasone 52 -0.84 -0.83 1.243 -3.7
-0.88 1.9 <0.001 Treatment 0.641 Day 3 Azelastine 49 -0.68 -0.62
1.701 -5.8 0.00 1.5 0.007 A vs A + F 0.011 Fluticasone 49 -0.90
-0.81 1.457 -5.4 -0.67 1.1 <0.001 F vs A + F 0.059 Azelastine +
Fluticasone 52 -1.38 -1.37 1.511 -5.4 -1.43 1.9 <0.001 Treatment
0.030 Day 4 Azelastine 49 -0.82 -0.78 1.533 -5.1 -0.92 1.5
<0.001 A vs A + F 0.010 Fluticasone 49 -1.06 -1.00 1.388 -5.2
-1.00 1.4 <0.001 F vs A + F 0.070 Azelastine + Fluticasone 52
-1.53 -1.53 1.497 -5.0 -1.48 1.8 <0.001 Treatment 0.031 Day 5
Azelastine 49 -1.07 -1.02 1.680 -5.1 -0.90 1.5 <0.001 A vs A + F
0.110 Fluticasone 49 -1.06 -1.00 1.462 -5.4 -0.83 1.1 <0.001 F
vs A + F 0.099 Azelastine + Fluticasone 52 -1.53 -1.53 1.679 -5.4
-1.55 1.8 <0.001 Treatment 0.169 Day 6 Azelastine 49 -1.09 -1.04
1.771 -5.8 -0.92 1.5 <0.001 A vs A + F 0.044 Fluticasone 49
-1.10 -1.03 1.563 -5.4 -0.83 1.1 <0.001 F vs A + F 0.042
Azelastine + Fluticasone 52 -1.69 -1.69 1.569 -5.0 -1.57 1.8
<0.001 Treatment 0.064 Day 7 Azelastine 49 -1.23 -1.17 1.791
-5.8 -1.00 1.5 <0.001 A vs A + F 0.102 Fluticasone 49 -1.10
-1.03 1.392 -5.2 -1.08 1.1 <0.001 F vs A + F 0.040 Azelastine +
Fluticasone 52 -1.71 -1.69 1.663 -6.0 -1.67 1.8 <0.001 Treatment
0.093 Day 8 Azelastine 49 -1.27 -1.24 1.670 -5.8 -1.00 1.5
<0.001 A vs A + F 0.079 Fluticasone 49 -0.98 -0.94 1.361 -5.2
-0.83 1.1 <0.001 F vs A + F 0.006 Azelastine + Fluticasone 52
-1.74 -1.76 1.495 -4.8 -1.70 1.8 <0.001 Treatment 0.021 Day 9
Azelastine 49 -1.23 -1.20 1.515 -5.8 -1.00 1.5 <0.001 A vs A + F
0.023 Fluticasone 49 -1.22 -1.19 1.311 -5.2 -1.27 0.9 <0.001 F
vs A + F 0.021 Azelastine + Fluticasone 52 -1.84 -1.86 1.569 -6.0
-1.73 0.9 <0.001 Treatment 0.030 Day 10 Azelastine 49 -1.17
-1.12 1.574 -5.3 -1.00 1.5 <0.001 A vs A + F 0.010 Fluticasone
49 -1.39 -1.34 1.463 -5.2 -1.50 1.4 <0.001 F vs A + F 0.061
Azelastine + Fluticasone 52 -1.90 -1.92 1.701 -5.1 -1.67 1.8
<0.001 Treatment 0.028 Day 11 Azelastine 49 -1.23 -1.18 1.762
-6.0 -0.92 1.5 <0.001 A vs A + F 0.009 Fluticasone 49 -1.28
-1.22 1.367 -5.2 -1.27 1.4 <0.001 F vs A + F 0.013 Azelastine +
Fluticasone 52 -1.96 -1.98 1.599 -5.0 -1.74 0.8 <0.001 Treatment
0.013 Day 12 Azelastine 49 -1.27 -1.21 1.844 -6.0 -1.00 1.5
<0.001 A vs A + F 0.045 Fluticasone 49 -1.49 -1.41 1.579 -5.2
-1.55 1.4 <0.001 F vs A + F 0.157 Azelastine + Fluticasone 52
-1.88 -1.88 1.707 -6.0 -1.90 1.1 <0.001 Treatment 0.119 Day 13
Azelastine 49 -1.29 -1.25 1.690 -5.0 -1.00 1.5 <0.001 A vs A + F
0.009 Fluticasone 49 -1.59 -1.55 1.648 -5.2 -1.43 1.4 <0.001 F
vs A + F 0.080 Azelastine + Fluticasone 52 -2.11 -2.14 1.791 -6.0
-2.00 1.8 <0.001 Treatment 0.028 Day 14 Azelastine 49 -1.39
-1.33 1.827 -6.0 -1.05 1.5 <0.001 A vs A + F 0.032 Fluticasone
49 -1.59 -1.53 1.749 -5.4 -1.30 1.4 <0.001 F vs A + F 0.116
Azelastine + Fluticasone 52 -2.05 -2.06 1.671 -5.1 -2.00 0.8
<0.001 Treatment 0.084 .sup.aTotal number of intent-to-treat
patients with available data. .sup.bLS Mean = Least-Square Mean
obtained from analysis of variance (ANOVA) model for baseline or
analysis of covariance (ANCOVA) model otherwise. .sup.cp-value for
the within-patient change was based on a paired t-test.
.sup.dp-value for between treatment group comparison, except
Overall and Baseline, was based on an ANCOVA model containing
treatment group and site as fixed effects, and baseline as a
covariate. For Overall, the p-value was based on a repeated
measures ANCOVA model containing study day as the within-patient
effect, treatment group and site as the between-patient effects,
treatment-by-study day interaction, and baseline as a covariate.
For Baseline, the p-value was based on an ANOVA # model containing
treatment group and site as fixed effects. .sup.eMean baseline TNSS
over 5-day Lead-in Period, including Day 1 AM. .sup.fOverall
includes TNSS scores from Day 2 to Day 14. Reference: 16.2.6.1
[1297] TABLE-US-00029 14.2.6.3 Change from Baseline in Individual
Nasal Symptom Score (AM and PM Combined): Runny Nose
Intent-to-Treat Population Paired Variable Standard t-test ANOVA
Time Point Treatment N.sup.a Mean LS Mean.sup.b Deviation Minimum
Median Maximum p-value.sup.c Source p-value.sup.d AM and PM
Combined Nasal Symptom Score: Runny Nose Baseline.sup.e Azelastine
(A) 49 4.91 4.92 0.780 2.1 4.92 6.0 Treatment 0.843 Fluticasone (F)
50 4.96 4.97 0.950 0.7 5.16 6.0 Azelastine + Fluticasone 52 4.86
4.87 0.961 1.5 4.92 6.0 (A + F) Change from Baseline in AM and PM
Combined Nasal Symptom Score: Runny Nose Overall.sup.f Azelastine
49 -1.08 -1.06 1.409 -4.4 -0.67 1.6 <0.001 A vs A + F 0.019
Fluticasone 49 -1.36 -1.34 1.244 -4.3 -1.04 2.1 <0.001 F vs A +
F 0.187 Azelastine + Fluticasone 52 -1.73 -1.71 1.563 -5.5 -1.35
1.7 <0.001 Treatment 0.063 Day <0.001 Treatment * Day 0.084
Day 2 Azelastine 49 -0.72 -0.70 1.513 -4.7 -0.42 1.8 0.002 A vs A +
F 0.354 Fluticasone 49 -0.90 -0.86 1.300 -4.3 -1.00 2.3 <0.001 F
vs A + F 0.708 Azelastine + Fluticasone 52 -0.98 -0.97 1.639 -4.5
-0.53 2.2 <0.001 Treatment 0.647 Day 3 Azelastine 49 -0.79 -0.74
1.583 -5.7 -1.00 1.8 0.001 A vs A + F 0.074 Fluticasone 49 -1.05
-0.96 1.421 -5.0 -0.80 2.0 <0.001 F vs A + F 0.302 Azelastine +
Fluticasone 52 -1.30 -1.27 1.646 -5.2 -1.21 2.2 <0.001 Treatment
0.199 Day 4 Azelastine 49 -0.79 -0.76 1.402 -4.8 -0.43 1.6
<0.001 A vs A + F 0.018 Fluticasone 49 -1.17 -1.12 1.534 -6.0
-1.15 2.3 <0.001 F vs A + F 0.237 Azelastine + Fluticasone 52
-1.49 -1.48 1.611 -5.2 -1.27 2.4 <0.001 Treatment 0.061 Day 5
Azelastine 49 -0.97 -0.96 1.450 -4.0 -0.67 1.6 <0.001 A vs A + F
0.025 Fluticasone 49 -1.43 -1.42 1.660 -5.0 -1.05 3.3 <0.001 F
vs A + F 0.391 Azelastine + Fluticasone 52 -1.69 -1.70 1.818 -6.0
-1.53 2.2 <0.001 Treatment 0.079 Day 6 Azelastine 49 -0.95 -0.94
1.406 -4.1 -1.00 1.8 <0.001 A vs A + F 0.003 Fluticasone 49
-1.35 -1.35 1.630 -5.0 -1.00 2.3 <0.001 F vs A + F 0.083
Azelastine + Fluticasone 52 -1.90 -1.92 1.859 -6.0 -1.38 1.2
<0.001 Treatment 0.012 Day 7 Azelastine 49 -0.95 -0.93 1.601
-4.1 -1.07 1.8 <0.001 A vs A + F 0.017 Fluticasone 49 -1.31
-1.28 1.553 -4.3 -1.45 3.3 <0.001 F vs A + F 0.189 Azelastine +
Fluticasone 52 -1.71 -1.72 1.804 -6.0 -1.53 2.2 <0.001 Treatment
0.058 Day 8 Azelastine 49 -1.25 -1.23 1.711 -5.1 -1.00 1.8
<0.001 A vs A + F 0.065 Fluticasone 49 -0.98 -0.95 1.430 -4.3
-0.73 3.3 <0.001 F vs A + F 0.007 Azelastine + Fluticasone 52
-1.84 -1.84 1.776 -6.0 -1.70 1.6 <0.001 Treatment 0.023 Day 9
Azelastine 49 -1.15 -1.14 1.637 -4.8 -0.90 1.8 <0.001 A vs A + F
0.101 Fluticasone 49 -1.21 -1.18 1.674 -5.5 -1.00 2.3 <0.001 F
vs A + F 0.133 Azelastine + Fluticasone 52 -1.69 -1.69 1.744 -6.0
-1.38 1.2 <0.001 Treatment 0.188 Day 10 Azelastine 49 -1.13
-1.11 1.843 -5.1 -0.83 1.8 <0.001 A vs A + F 0.038 Fluticasone
49 -1.54 -1.52 1.672 -4.5 -1.45 2.3 <0.001 F vs A + F 0.343
Azelastine + Fluticasone 52 -1.84 -1.85 1.764 -6.0 -1.68 1.2
<0.001 Treatment 0.115 Day 11 Azelastine 49 -1.38 -1.35 2.018
-6.0 -1.10 1.8 <0.001 A vs A + F 0.062 Fluticasone 49 -1.54
-1.51 1.656 -5.5 -1.42 1.6 <0.001 F vs A + F 0.151 Azelastine +
Fluticasone 52 -2.03 -2.05 1.956 -6.0 -1.90 1.2 <0.001 Treatment
0.145 Day 12 Azelastine 49 -1.25 -1.22 2.133 -6.0 -0.43 2.0
<0.001 A vs A + F 0.043 Fluticasone 49 -1.58 -1.54 1.434 -4.3
-1.35 1.6 <0.001 F vs A + F 0.244 Azelastine + Fluticasone 52
-1.96 -1.97 2.008 -6.0 -1.58 2.2 <0.001 Treatment 0.126 Day 13
Azelastine 49 -1.38 -1.36 1.949 -5.4 -1.07 1.8 <0.001 A vs A + F
0.061 Fluticasone 49 -1.78 -1.78 1.677 -4.5 -2.00 2.3 <0.001 F
vs A + F 0.478 Azelastine + Fluticasone 52 -1.99 -2.03 1.893 -6.0
-1.90 2.2 <0.001 Treatment 0.168 Day 14 Azelastine 49 -1.34
-1.32 1.829 -5.4 -1.43 1.9 <0.001 A vs A + F 0.037 Fluticasone
49 -1.88 -1.89 1.791 -5.8 -2.15 1.6 <0.001 F vs A + F 0.604
Azelastine + Fluticasone 52 -2.03 -2.07 1.894 -6.0 -2.22 2.2
<0.001 Treatment 0.096 .sup.aTotal number of intent-to-treat
patients with available data. .sup.bLS Mean = Least-Square Mean
obtained from analysis of variance (ANOVA) model for baseline or
analysis of covariance (ANCOVA) model otherwise. .sup.cp-value for
the within-patient change was based on a paired t-test.
.sup.dp-value for between treatment group comparison, except
Overall and Baseline, was based on an ANCOVA model containing
treatment group and site as fixed effects, and baseline as a
covariate. For Overall, the p-value was based on a repeated
measures ANCOVA model containing study day as the within-patient
effect, treatment group and site as the between-patient effects,
treatment-by-study day interaction, and baseline as a covariate.
For Baseline, the p-value was based on an ANOVA # model containing
treatment group and site as fixed effects. .sup.eMean baseline TNSS
over 5-day Lead-in Period, including Day 1 AM. .sup.fOverall
includes TNSS scores from Day 2 to Day 14. Reference: 16.2.6.1
[1298] TABLE-US-00030 14.2.6.4 Change from Baseline in Individual
Nasal Symptom Score (AM and PM Combined): Sneezing Intent-to-Treat
Population Paired Variable Standard t-test ANOVA Time Point
Treatment N.sup.a Mean LS Mean.sup.b Deviation Minimum Median
Maximum p-value.sup.c Source p-value.sup.d AM and PM Combined Nasal
Symptom Score: Sneezing Baseline.sup.a Azelastine (A) 49 4.48 4.51
1.102 1.2 4.42 6.0 Treatment 0.625 Fluticasone (F) 50 4.29 4.31
1.283 0.0 4.34 6.0 Azelastine + Fluticasone 52 4.49 4.51 1.199 2.2
4.58 6.0 (A + F) Change from Baseline in AM and PM Combined Nasal
Symptom Score: Sneezing Overall.sup.f Azelastine 49 -1.49 -1.48
1.029 -4.0 -1.31 0.4 <0.001 A vs A + F 0.039 Fluticasone 49
-1.44 -1.52 1.500 -5.0 -1.34 1.3 <0.001 F vs A + F 0.053
Azelastine + Fluticasone 52 -2.06 -2.06 1.712 -5.7 -2.12 1.2
<0.001 Treatment 0.067 Day <0.001 Treatment * Day 0.092 Day 2
Azelastine 49 -1.11 -1.09 1.275 -4.3 -0.90 1.0 <0.001 A vs A + F
0.255 Fluticasone 49 -1.03 -1.06 1.280 -4.4 -1.00 1.6 <0.001 F
vs A + F 0.218 Azelastine + Fluticasone 52 -1.44 -1.42 1.777 -5.0
-1.21 1.9 <0.001 Treatment 0.386 Day 3 Azelastine 49 -0.97 -0.99
1.363 -4.8 -0.77 2.0 <0.001 A vs A + F 0.040 Fluticasone 49
-1.21 -1.29 1.484 -4.0 -1.00 1.5 <0.001 F vs A + F 0.282
Azelastine + Fluticasone 52 -1.61 -1.63 1.793 -5.0 -1.36 2.0
<0.001 Treatment 0.119 Day 4 Azelastine 49 -1.32 -1.34 1.668
-5.8 -1.00 2.0 <0.001 A vs A + F 0.097 Fluticasone 49 -1.33
-1.42 1.579 -5.4 -1.10 2.0 <0.001 F vs A + F 0.159 Azelastine +
Fluticasone 52 -1.90 -1.92 2.007 -6.0 -2.00 2.0 <0.001 Treatment
0.199 Day 5 Azelastine 49 -1.34 -1.36 1.431 -4.3 -1.03 0.9
<0.001 A vs A + F 0.023 Fluticasone 49 -1.52 -1.61 1.649 -5.4
-1.33 1.5 <0.001 F vs A + F 0.121 Azelastine + Fluticasone 52
-2.11 -2.14 2.017 -6.0 -2.18 1.1 <0.001 Treatment 0.066 Day 6
Azelastine 49 -1.26 -1.27 1.352 -4.3 -1.30 1.6 <0.001 A vs A + F
0.003 Fluticasone 49 -1.44 -1.51 1.769 -5.4 -1.27 2.0 <0.001 F
vs A + F 0.024 Azelastine + Fluticasone 52 -2.26 -2.28 1.892 -6.0
-2.38 1.0 <0.001 Treatment 0.009 Day 7 Azelastine 49 -1.75 -1.76
1.501 -4.3 -1.55 1.6 <0.001 A vs A + F 0.491 Fluticasone 49
-1.33 -1.44 1.751 -5.4 -1.20 2.0 <0.001 F vs A + F 0.111
Azelastine + Fluticasone 52 -1.97 -2.00 2.029 -6.0 -2.13 2.9
<0.001 Treatment 0.278 Days 8 Azelastine 49 -1.73 -1.74 1.465
-4.3 -1.55 2.8 <0.001 A vs A + F 0.124 Fluticasone 49 -1.29
-1.41 1.677 -5.4 -1.25 3.0 <0.001 F vs A + F 0.011 Azelastine +
Fluticasone 52 -2.21 -2.23 1.750 -5.3 -2.00 1.0 <0.001 Treatment
0.037 Day 9 Azelastine 49 -1.73 -1.72 1.598 -5.8 -1.67 1.8
<0.001 A vs A + F 0.382 Fluticasone 49 -1.29 -1.40 1.831 -5.4
-1.40 2.0 <0.001 F vs A + F 0.071 Azelastine + Fluticasone 52
-2.01 -2.02 1.852 -6.0 -2.10 2.0 <0.001 Treatment 0.196 Day 10
Azelastine 49 -1.71 -1.70 1.309 -4.2 -1.75 0.7 <0.001 A vs A + F
0.176 Fluticasone 49 -1.50 -1.57 1.833 -5.4 -1.58 3.0 <0.001 F
vs A + F 0.081 Azelastine + Fluticasone 52 -2.15 -2.15 1.904 -6.0
-2.18 1.4 <0.001 Treatment 0.183 Day 11 Azelastine 49 -1.79
-1.79 1.590 -6.0 -1.55 0.8 <0.001 A vs A + F 0.259 Fluticasone
49 -1.66 -1.78 1.966 -5.4 -1.83 3.0 <0.001 F vs A + F 0.243
Azelastine + Fluticasone 52 -2.17 -2.19 1.946 -6.0 -2.10 2.0
<0.001 Treatment 0.410 Day 12 Azelastine 49 -1.63 -1.63 1.589
-5.3 -1.73 2.8 <0.001 A vs A + F 0.046 Fluticasone 49 -1.54
-1.68 1.982 -5.4 -1.80 2.8 <0.001 F vs A + F 0.064 Azelastine +
Fluticasone 52 -2.30 -2.33 1.917 -6.0 -2.20 1.0 <0.001 Treatment
0.082 Day 13 Azelastine 49 -1.60 -1.60 1.682 -5.1 -1.75 2.5
<0.001 A vs A + F 0.033 Fluticasone 49 -1.84 -1.98 1.963 -5.4
-1.83 2.8 <0.001 F vs A + F 0.293 Azelastine + Fluticasone 52
-2.32 -2.34 1.854 -6.0 -2.18 2.0 <0.001 Treatment 0.102 Day 14
Azelastine 49 -1.50 -1.51 1.794 -5.8 -1.35 3.5 <0.001 A vs A + F
0.020 Fluticasone 49 -1.70 -1.87 2.046 -5.4 -1.83 3.6 <0.001 F
vs A + F 0.181 Azelastine + Fluticasone 52 -2.34 -2.37 2.108 -6.0
-2.28 3.4 <0.001 Treatment 0.065 .sup.aTotal number of
intent-to-treat patients with available data. .sup.bLS Mean =
Least-Square Mean obtained from analysis of variance (ANOVA) model
for baseline or analysis of covariance (ANCOVA) model otherwise.
.sup.cp-value for the within-patient change was based on a paired
t-test. .sup.dp-value for between treatment group comparison,
except Overall and Baseline, was based on an ANCOVA model
containing treatment group and site as fixed effects, and baseline
as a covariate. For Overall, the p-value was based on a repeated
measures ANCOVA model containing study day as the within-patient
effect, treatment group and site as the between-patient effects,
treatment-by-study day interaction, and baseline as a covariate.
For Baseline, the p-value was based on an ANOVA # model containing
treatment group and site as fixed effects. .sup.eMean baseline TNSS
over 5-day Lead-in Period, including Day 1 AM. .sup.fOverall
includes TNSS scores from Day 2 to Day 14. Reference: 16.2.6.1
[1299] TABLE-US-00031 14.2.7.1 Percent Change from Baseline in
Individual Nasal Symptom Score (AM and PM Combined): Itchy Nose
Intent-to-Treat Population Paired Variable LS Standard t-test ANOVA
Time Point Treatment N.sup.a Mean Mean.sup.b Deviation Minimum
Median Maximum p-value.sup.c Source p-value.sup.d AM and PM
Combined Nasal Symptom Score: Itchy Nose Baseline.sup.e Azelastine
(A) 49 4.74 4.76 0.807 2.9 4.73 6.0 Treatment 0.982 Fluticasone (F)
50 4.76 4.78 1.309 0.0 5.16 6.0 Azelastine + Fluticasone 52 4.72
4.74 1.047 1.5 4.76 6.0 (A + F) Percent Change from Baseline in AM
and PM Combined Nasal Symptom Score: Itchy Nose Overall.sup.f
Azelastine 49 -25.53 -25.36 29.667 -100.0 -19.66 24.4 <0.001 A
vs A + F 0.033 Fluticasone 48 -25.67 -25.54 32.846 -100.0 -18.89
78.1 <0.001 F vs A + F 0.037 Azelastine + Fluticasone 52 -39.65
-39.86 38.963 -98.0 -41.67 73.7 <0.001 Treatment 0.050 Day
<0.001 Treatment * Day 0.912 Day 2 Azelastine 49 -13.55 -13.14
28.296 -100.0 -11.11 44.0 0.002 A vs A + F 0.101 Fluticasone 48
-14.27 -12.72 39.625 -100.0 -8.39 110.5 0.016 F vs A + F 0.092
Azelastine + Fluticasone 52 -25.04 -24.76 41.506 -100.0 -16.67 96.7
<0.001 Treatment 0.154 Day 3 Azelastine 49 -18.60 -19.04 31.661
-100.0 -16.67 27.7 <0.001 A vs A + F 0.111 Fluticasone 48 -22.41
-22.88 36.902 -100.0 -15.32 75.4 <0.001 F vs A + F 0.289
Azelastine + Fluticasone 52 -29.89 -30.63 42.602 -100.0 -28.99
104.5 <0.001 Treatment 0.265 Day 4 Azelastine 49 -22.23 -22.54
37.258 -100.0 -13.79 56.5 <0.001 A vs A + F 0.072 Fluticasone 48
-20.31 -20.59 38.528 -100.0 -16.67 75.4 <0.001 F vs A + F 0.041
Azelastine + Fluticasone 52 -35.17 -35.72 36.235 -100.0 -33.94 36.4
<0.001 Treatment 0.080 Day 5 Azelastine 49 -24.24 -24.75 37.297
-100.0 -15.49 27.7 <0.001 A vs A + F 0.100 Fluticasone 48 -24.64
-25.02 38.416 -100.0 -25.00 75.4 <0.001 F vs A + F 0.109
Azelastine + Fluticasone 52 -37.54 -38.19 45.751 -100.0 -33.33
104.5 <0.001 Treatment 0.168 Day 6 Azelastine 49 -25.00 -24.98
35.189 -100.0 -15.49 30.9 <0.001 A vs A + F 0.047 Fluticasone 48
-26.87 -27.12 37.321 -100.0 -24.76 40.4 <0.001 F vs A + F 0.089
Azelastine + Fluticasone 52 -39.77 -40.13 41.232 -100.0 -46.22 61.3
<0.001 Treatment 0.097 Day 7 Azelastine 49 -25.83 -26.35 32.567
-100.0 -21.57 27.7 <0.001 A vs A + F 0.033 Fluticasone 48 -26.92
-27.79 36.738 -100.0 -23.55 75.4 <0.001 F vs A + F 0.053
Azelastine + Fluticasone 52 -41.85 -42.66 43.566 -100.0 -50.00 93.5
<0.001 Treatment 0.060 Day 8 Azelastine 49 -24.80 -25.37 32.681
-100.0 -18.92 30.9 <0.001 A vs A + F 0.018 Fluticasone 48 -27.33
-28.16 39.760 -100.0 -30.22 110.5 <0.001 F vs A + F 0.045
Azelastine + Fluticasone 52 -43.28 -44.15 44.339 -100.0 -47.47 93.5
<0.001 Treatment 0.037 Day 9 Azelastine 49 -26.97 -27.69 30.150
-100.0 -21.57 27.7 <0.001 A vs A + F 0.033 Fluticasone 48 -28.73
-29.96 35.790 -100.0 -31.23 75.4 <0.001 F vs A + F 0.069
Azelastine + Fluticasone 52 -42.78 -43.85 45.194 -100.0 -43.46 93.5
<0.001 Treatment 0.069 Day 10 Azelastine 49 -29.56 -29.83 38.926
-100.0 -21.57 30.4 <0.001 A vs A + F 0.083 Fluticasone 48 -22.79
-23.04 41.732 -100.0 -18.99 126.4 <0.001 F vs A + F 0.012
Azelastine + Fluticasone 52 -43.11 -43.96 41.925 -100.0 -44.14 61.3
<0.001 Treatment 0.035 Day 11 Azelastine 49 -29.59 -30.38 39.232
-100.0 -22.33 31.4 <0.001 A vs A + F 0.080 Fluticasone 48 -25.70
-26.56 41.558 -100.0 -27.36 126.4 <0.001 F vs A + F 0.029
Azelastine + Fluticasone 52 -43.70 -45.12 45.931 -100.0 -50.00
104.5 <0.001 Treatment 0.067 Day 12 Azelastine 49 -28.74 -29.11
41.037 -100.0 -16.67 27.7 <0.001 A vs A + F 0.037 Fluticasone 48
-29.58 -29.96 45.257 -100.0 -30.22 126.4 <0.001 F vs A + F 0.048
Azelastine + Fluticasone 52 -45.74 -46.77 41.579 -100.0 -50.00 61.3
<0.001 Treatment 0.061 Day 13 Azelastine 49 -31.63 -32.25 40.192
-100.0 -22.33 44.0 <0.001 A vs A + F 0.209 Fluticasone 48 -30.81
-31.14 45.786 -100.0 -31.23 126.4 <0.001 F vs A + F 0.170
Azelastine + Fluticasone 52 -41.85 -43.24 47.158 -100.0 -52.66
104.5 <0.001 Treatment 0.309 Day 14 Azelastine 49 -31.14 -31.60
41.995 -100.0 -25.00 44.0 <0.001 A vs A + F 0.085 Fluticasone 48
-33.38 -33.39 46.398 -100.0 -33.33 126.4 <0.001 F vs A + F 0.130
Azelastine + Fluticasone 52 -45.77 -46.96 46.575 -100.0 -56.91
104.5 <0.001 Treatment 0.167 .sup.aTotal number of
intent-to-treat patients with available data. .sup.bLS Mean =
Least-Square Mean obtained from analysis of variance (ANOVA) model
for baseline or analysis of covariance (ANCOVA) model otherwise.
.sup.cp-value for the within-patient percent change was based on a
paired t-test. .sup.dp-value for between treatment group
comparison, except Overall and Baseline, was based on an ANCOVA
model containing treatment group and site as fixed effects, and
baseline as a covariate. For Overall, the p-value was based on a
repeated measures ANCOVA model containing study day as the
within-patient effect, treatment group and site as the
between-patient effects, treatment-by-study day interaction, and
baseline as a covariate. For Baseline, the p-value was based on an
ANOVA # model containing treatment group and site as fixed effects.
.sup.eMean baseline TNSS over 5-day Lead-in Period, including Day 1
AM. .sup.fOverall includes TNSS scores from Day 2 to Day 14.
Reference: 16.2.6.1
[1300] TABLE-US-00032 14.2.7.2 Percent Change from Baseline in
Individual Nasal Symptom Score (AM and PM Combined): Congestion
Intent-to-Treat Population Paired Variable LS Standard t-test ANOVA
Time Point Treatment N.sup.a Mean Mean.sup.b Deviation Minimum
Median Maximum p-value.sup.c Source p-value.sup.d AM and PM
Combined Nasal Symptom Score: Congestion Baseline.sup.e Azelastine
(A) 49 5.48 5.48 0.511 4.5 5.47 6.0 Treatment 0.505 Fluticasone (F)
50 5.51 5.51 0.388 4.5 5.55 6.0 Azelastine + Fluticasone 52 5.40
5.40 0.578 3.8 5.45 6.0 (A + F) Percent Change from Baseline in AM
and PM Combined Nasal Symptom Score: Congestion Overall.sup.f
Azelastine 49 -19.82 -19.23 26.640 -85.5 -12.82 32.4 <0.001 A vs
A + F 0.016 Fluticasone 49 -21.68 -21.11 23.391 -100.0 -18.72 17.3
<0.001 F vs A + F 0.042 Azelastine + Fluticasone 52 -31.49
-31.19 25.710 -91.8 -26.01 29.2 <0.001 Treatment 0.034 Day
<0.001 Treatment * Day 0.197 Day 2 Azelastine 49 -14.05 -13.19
26.251 -80.4 -3.23 32.4 <0.001 A vs A + F 0.740 Fluticasone 49
-11.97 -10.84 26.153 -100.0 -5.66 24.1 0.002 F vs A + F 0.418
Azelastine + Fluticasone 52 -15.18 -14.81 23.853 -64.7 -16.67 45.2
<0.001 Treatment 0.718 Day 3 Azelastine 49 -11.70 -10.71 31.360
-100.0 0.00 32.4 0.012 A vs A + F 0.012 Fluticasone 49 -16.63
-15.34 27.665 -100.0 -11.76 22.0 <0.001 F vs A + F 0.089
Azelastine + Fluticasone 52 -25.04 -24.87 28.329 -100.0 -26.38 45.2
<0.001 Treatment 0.036 Day 4 Azelastine 49 -14.44 -13.79 28.821
-100.0 -16.67 32.4 <0.001 A vs A + F 0.010 Fluticasone 49 -19.51
-18.75 26.344 -100.0 -16.67 30.4 <0.001 F vs A + F 0.090
Azelastine + Fluticasone 52 -28.34 -28.13 28.168 -83.3 -27.90 44.0
<0.001 Treatment 0.031 Day 5 Azelastine 49 -18.92 -18.24 31.108
-100.0 -16.67 32.4 <0.001 A vs A + F 0.094 Fluticasone 49 -19.38
-18.74 27.542 -100.0 -14.29 23.3 <0.001 F vs A + F 0.112
Azelastine + Fluticasone 52 -28.54 -28.40 32.252 -100.0 -28.42 44.0
<0.001 Treatment 0.166 Day 6 Azelastine 49 -18.97 -18.26 32.497
-100.0 -18.37 32.4 <0.001 A vs A + F 0.035 Fluticasone 49 -20.16
-19.32 29.269 -100.0 -14.29 22.0 <0.001 F vs A + F 0.053
Azelastine + Fluticasone 52 -31.14 -31.21 29.999 -100.0 -28.12 44.0
<0.001 Treatment 0.063 Day 7 Azelastine 49 -22.02 -21.14 33.150
-100.0 -18.37 32.4 <0.001 A vs A + F 0.086 Fluticasone 49 -20.17
-19.42 25.842 -100.0 -21.31 22.0 <0.001 F vs A + F 0.046
Azelastine + Fluticasone 52 -31.85 -31.47 32.137 -100.0 -29.41 44.0
<0.001 Treatment 0.096 Day 8 Azelastine 49 -22.68 -22.22 30.873
-100.0 -18.64 32.4 <0.001 A vs A + F 0.070 Fluticasone 49 -17.88
-17.55 25.284 -100.0 -14.29 23.3 <0.001 F vs A + F 0.009
Azelastine + Fluticasone 52 -32.28 -32.46 29.026 -100.0 -29.92 44.0
<0.001 Treatment 0.027 Day 9 Azelastine 49 -22.05 -21.68 27.567
-100.0 -18.64 32.4 <0.001 A vs A + F 0.020 Fluticasone 49 -22.28
-22.17 24.501 -100.0 -24.05 18.0 <0.001 F vs A + F 0.026
Azelastine + Fluticasone 52 -34.18 -34.36 29.937 -100.0 -30.22 20.0
<0.001 Treatment 0.031 Day 10 Azelastine 49 -20.94 -20.32 29.482
-100.0 -16.67 32.4 <0.001 A vs A + F 0.011 Fluticasone 49 -25.31
-24.97 27.721 -100.0 -27.27 30.4 <0.001 F vs A + F 0.080
Azelastine + Fluticasone 52 -35.02 -35.22 32.451 -100.0 -29.92 44.0
<0.001 Treatment 0.034 Day 11 Azelastine 49 -21.53 -20.72 31.552
-100.0 -16.67 32.4 <0.001 A vs A + F 0.007 Fluticasone 49 -23.45
-22.54 25.792 -100.0 -24.05 30.4 <0.001 F vs A + F 0.017
Azelastine + Fluticasone 52 -35.97 -36.20 29.653 -100.0 -31.03 20.0
<0.001 Treatment 0.013 Day 12 Azelastine 49 -22.63 -21.71 33.872
-100.0 -16.67 32.4 <0.001 A vs A + F 0.041 Fluticasone 49 -27.05
-26.02 29.299 -100.0 -27.93 30.4 <0.001 F vs A + F 0.173
Azelastine + Fluticasone 52 -34.65 -34.57 31.613 -100.0 -33.33 22.4
<0.001 Treatment 0.112 Day 13 Azelastine 49 -23.01 -22.44 31.203
-83.3 -18.64 32.4 <0.001 A vs A + F 0.009 Fluticasone 49 -28.95
-28.59 30.706 -100.0 -26.38 30.4 <0.001 F vs A + F 0.093
Azelastine + Fluticasone 52 -38.96 -39.28 33.996 -100.0 -33.33 42.9
<0.001 Treatment 0.028 Day 14 Azelastine 49 -24.78 -23.87 33.330
-100.0 -20.79 32.4 <0.001 A vs A + F 0.027 Fluticasone 49 -29.09
-28.37 32.768 -100.0 -24.53 30.4 <0.001 F vs A + F 0.129
Azelastine + Fluticasone 52 -38.15 -38.04 32.039 -100.0 -33.33 19.0
<0.001 Treatment 0.075 .sup.aTotal number of intent-to-treat
patients with available data. .sup.bLS Mean = Least-Square Mean
obtained from analysis of variance (ANOVA) model for baseline or
analysis of covariance (ANCOVA) model otherwise. .sup.cp-value for
the within-patient percent change was based on a paired t-test.
.sup.dp-value for between treatment group comparison, except
Overall and Baseline, was based on an ANCOVA model containing
treatment group and site as fixed effects, and baseline as a
covariate. For Overall, the p-value was based on a repeated
measures ANCOVA model containing study day as the within-patient
effect, treatment group and site as the between-patient effects,
treatment-by-study day interaction, and baseline as a covariate.
For Baseline, the p-value was based on an ANOVA # model containing
treatment group and site as fixed effects. .sup.eMean baseline TNSS
over 5-day Lead-in Period, including Day 1 AM. .sup.fOverall
includes TNSS scores from Day 2 to Day 14. Reference: 16.2.6.1
[1301] TABLE-US-00033 14.2.7.3 Percent Change from Baseline in
Individual Nasal Symptom Score (AM and PM Combined): Runny Nose
Intent-to-Treat Population Paired Variable LS Standard t-test ANOVA
Time Point Treatment N.sup.a Mean Mean.sup.b Deviation Minimum
Median Maximum p-value.sup.c Source p-value.sup.d AM and PM
Combined Nasal Symptom Score: Runny Nose Baseline.sup.e Azelastine
(A) 49 4.91 4.92 0.780 2.1 4.92 6.0 Treatment 0.843 Fluticasone (F)
50 4.96 4.97 0.950 0.7 5.16 6.0 Azelastine + Fluticasone 52 4.86
4.87 0.961 1.5 4.92 6.0 (A + F) Percent Change from Baseline in AM
and PM Combined Nasal Symptom Score: Runny Nose Overall.sup.f
Azelastine 49 -21.06 -20.47 27.637 -77.3 -15.44 37.4 <0.001 A vs
A + F 0.045 Fluticasone 49 -23.19 -23.02 53.352 -100.0 -21.99 295.6
0.004 F vs A + F 0.091 Azelastine + Fluticasone 52 -36.87 -36.40
32.928 -100.0 -31.06 45.7 <0.001 Treatment 0.096 Day <0.001
Treatment * Day 0.064 Day 2 Azelastine 49 -14.08 -13.68 30.566
-100.0 -7.98 41.2 0.002 A vs A + F 0.394 Fluticasone 49 -12.95
-12.11 57.175 -100.0 -16.67 328.6 0.119 F vs A + F 0.300 Azelastine
+ Fluticasone 52 -20.64 -20.90 37.053 -100.0 -12.73 57.9 <0.001
Treatment 0.539 Day 3 Azelastine 49 -14.69 -13.72 31.227 -100.0
-16.67 41.2 0.002 A vs A + F 0.079 Fluticasone 49 -18.81 -17.15
43.046 -100.0 -13.79 185.7 0.004 F vs A + F 0.198 Azelastine +
Fluticasone 52 -26.99 -26.42 35.215 -100.0 -23.93 57.9 <0.001
Treatment 0.188 Day 4 Azelastine 49 -16.23 -15.76 30.087 -100.0
-7.98 37.4 <0.001 A vs A + F 0.063 Fluticasone 49 -18.21 -17.17
59.211 -100.0 -22.33 328.6 0.036 F vs A + F 0.090 Azelastine +
Fluticasone 52 -32.13 -31.97 35.962 -100.0 -24.29 66.7 <0.001
Treatment 0.118 Day 5 Azelastine 49 -18.42 -18.46 28.691 -76.0
-11.76 37.4 <0.001 A vs A + F 0.084 Fluticasone 49 -22.31 -22.06
79.601 -100.0 -21.31 471.4 0.056 F vs A + F 0.164 Azelastine +
Fluticasone 52 -36.01 -36.84 39.297 -100.0 -33.33 57.9 <0.001
Treatment 0.184 Day 6 Azelastine 49 -18.89 -18.89 28.555 -80.4
-21.74 42.9 <0.001 A vs A + F 0.014 Fluticasone 49 -22.47 -22.60
61.486 -100.0 -18.64 328.6 0.014 F vs A + F 0.039 Azelastine +
Fluticasone 52 -40.73 -41.46 40.234 -100.0 -28.93 31.6 <0.001
Treatment 0.030 Day 7 Azelastine 49 -18.92 -18.66 32.863 -80.4
-25.00 42.9 <0.001 A vs A + F 0.082 Fluticasone 49 -18.63 -18.01
78.054 -100.0 -28.99 471.4 0.101 F vs A + F 0.072 Azelastine +
Fluticasone 52 -36.57 -37.21 39.658 -100.0 -35.36 57.9 <0.001
Treatment 0.121 Day 8 Azelastine 49 -24.97 -24.85 34.586 -100.0
-25.00 42.9 <0.001 A vs A + F 0.153 Fluticasone 49 -12.38 -11.82
76.230 -100.0 -14.29 471.4 0.261 F vs A + F 0.008 Azelastine +
Fluticasone 52 -39.04 -39.68 37.171 -100.0 -36.17 36.4 <0.001
Treatment 0.029 Day 9 Azelastine 49 -23.25 -23.07 34.072 -100.0
-21.74 42.9 <0.001 A vs A + F 0.140 Fluticasone 49 -19.22 -18.79
61.104 -100.0 -16.67 328.6 0.033 F vs A + F 0.053 Azelastine +
Fluticasone 52 -36.32 -36.62 37.348 -100.0 -34.41 31.6 <0.001
Treatment 0.127 Day 10 Azelastine 49 -22.22 -22.00 37.229 -100.0
-16.67 42.9 <0.001 A vs A + F 0.056 Fluticasone 49 -26.39 -26.05
62.505 -100.0 -29.13 328.6 0.005 F vs A + F 0.138 Azelastine +
Fluticasone 52 -39.75 -40.12 37.259 -100.0 -34.41 31.6 <0.001
Treatment 0.132 Day 11 Azelastine 49 -25.83 -25.36 39.046 -100.0
-21.57 42.9 <0.001 A vs A + F 0.020 Fluticasone 49 -31.74 -31.56
37.692 -100.0 -33.33 42.9 <0.001 F vs A + F 0.121 Azelastine +
Fluticasone 52 -43.68 -43.71 40.451 -100.0 -40.29 31.6 <0.001
Treatment 0.059 Day 12 Azelastine 49 -23.43 -22.75 41.313 -100.0
-8.40 50.0 <0.001 A vs A + F 0.014 Fluticasone 49 -31.86 -31.33
32.712 -100.0 -25.62 42.9 <0.001 F vs A + F 0.175 Azelastine +
Fluticasone 52 -41.90 -41.82 41.487 -100.0 -37.47 57.9 <0.001
Treatment 0.049 Day 13 Azelastine 49 -27.57 -27.36 39.121 -100.0
-24.05 42.9 <0.001 A vs A + F 0.094 Fluticasone 49 -30.84 -30.96
62.521 -100.0 -33.33 328.6 0.001 F vs A + F 0.195 Azelastine +
Fluticasone 52 -42.30 -43.25 39.438 -100.0 -42.11 57.9 <0.001
Treatment 0.211 Day 14 Azelastine 49 -25.22 -25.17 39.838 -100.0
-29.41 93.5 <0.001 A vs A + F 0.027 Fluticasone 49 -35.65 -36.10
49.133 -100.0 -41.75 185.7 <0.001 F vs A + F 0.344 Azelastine +
Fluticasone 52 -43.18 -44.15 40.256 -100.0 -47.22 57.9 <0.001
Treatment 0.084 .sup.aTotal number of intent-to-treat patients with
available data. .sup.bLS Mean = Least-Square Mean obtained from
analysis of variance (ANOVA) model for baseline or analysis of
covariance (ANCOVA) model otherwise. .sup.cp-value for the
within-patient percent change was based on a paired t-test.
.sup.dp-value for between treatment group comparison, except
Overall and Baseline, was based on an ANCOVA model containing
treatment group and site as fixed effects, and baseline as a
covariate. For Overall, the p-value was based on a repeated
measures ANCOVA model containing study day as the within-patient
effect, treatment group and site as the between-patient effects,
treatment-by-study day interaction, and baseline as a covariate.
For Baseline, the p-value was based on an ANOVA # model containing
treatment group and site as fixed effects. .sup.eMean baseline TNSS
over 5-day Lead-in Period, including Day 1 AM. .sup.fOverall
includes TNSS scores from Day 2 to Day 14. Reference: 16.2.6.1
[1302] TABLE-US-00034 14.2.7.4 Percent Change from Baseline in
Individual Nasal Symptom Score (AM and PM Combined): Sneezing
Intent-to-Treat Population Paired Variable LS Standard t-test ANOVA
Time Point Treatment N.sup.a Mean Mean.sup.b Deviation Minimum
Median Maximum p-value.sup.c Source p-value.sup.d AM and PM
Combined Nasal Symptom Score: Sneezing Baseline.sup.e Azelastine
(A) 49 4.48 4.51 1.102 1.2 4.42 6.0 Treatment 0.625 Fluticasone (F)
50 4.29 4.31 1.283 0.0 4.34 6.0 Azelastine + Fluticasone 52 4.49
4.51 1.199 2.2 4.58 6.0 (A + F) Percent Change from Baseline in AM
and PM Combined Nasal Symptom Score: Sneezing Overall.sup.f
Azelastine 49 -33.98 -34.20 25.752 -92.9 -33.20 31.9 <0.001 A vs
A + F 0.077 Fluticasone 48 -31.11 -31.80 38.116 -100.0 -33.13 83.6
<0.001 F vs A + F 0.036 Azelastine + Fluticasone 52 -45.98
-46.38 37.157 -94.9 -52.92 28.8 <0.001 Treatment 0.077 Day
<0.001 Treatment * Day 0.166 Day 2 Azelastine 49 -26.94 -26.72
32.849 -100.0 -21.05 28.6 <0.001 A vs A + F 0.476 Fluticasone 48
-22.69 -22.64 32.208 -100.0 -16.67 63.3 <0.001 F vs A + F 0.201
Azelastine + Fluticasone 52 -31.69 -31.74 39.544 -100.0 -29.41 61.3
<0.001 Treatment 0.438 Day 3 Azelastine 49 -22.81 -23.56 32.550
-100.0 -16.08 50.0 <0.001 A vs A + F 0.071 Fluticasone 48 -28.44
-29.62 39.779 -100.0 -30.09 93.5 <0.001 F vs A + F 0.322
Azelastine + Fluticasone 52 -36.24 -37.05 39.298 -100.0 -33.33 50.0
<0.001 Treatment 0.194 Day 4 Azelastine 49 -31.90 -32.76 41.004
-100.0 -25.00 48.8 <0.001 A vs A + F 0.177 Fluticasone 48 -30.67
-31.80 36.729 -100.0 -27.36 50.0 <0.001 F vs A + F 0.146
Azelastine + Fluticasone 52 -42.90 -43.88 44.936 -100.0 -43.42 61.3
<0.001 Treatment 0.264 Day 5 Azelastine 49 -32.23 -33.21 33.600
-100.0 -25.23 17.6 <0.001 A vs A + F 0.048 Fluticasone 48 -34.14
-35.40 40.666 -100.0 -33.33 93.5 <0.001 F vs A + F 0.090
Azelastine + Fluticasone 52 -47.78 -48.95 44.067 -100.0 -50.00 29.0
<0.001 Treatment 0.099 Day 6 Azelastine 49 -31.52 -32.36 34.306
-100.0 -28.00 37.4 <0.001 A vs A + F 0.012 Fluticasone 48 -31.22
-32.10 46.825 -100.0 -32.77 100.0 <0.001 F vs A + F 0.012
Azelastine + Fluticasone 52 -52.55 -53.59 43.193 -100.0 -56.28 28.6
<0.001 Treatment 0.014 Day 7 Azelastine 49 -39.73 -40.66 40.109
-100.0 -38.78 71.4 <0.001 A vs A + F 0.623 Fluticasone 48 -30.14
-31.86 39.516 -100.0 -31.32 50.0 <0.001 F vs A + F 0.133
Azelastine + Fluticasone 52 -43.58 -44.87 47.974 -100.0 -51.00 93.5
<0.001 Treatment 0.310 Day 8 Azelastine 49 -37.78 -38.54 53.003
-100.0 -33.33 242.9 <0.001 A vs A + F 0.152 Fluticasone 48
-26.04 -28.16 46.403 -100.0 -31.03 150.0 <0.001 F vs A + F 0.012
Azelastine + Fluticasone 52 -50.63 -51.74 38.420 -100.0 -51.00 25.0
<0.001 Treatment 0.040 Day 9 Azelastine 49 -36.04 -36.31 46.303
-100.0 -35.48 157.1 <0.001 A vs A + F 0.256 Fluticasone 48
-28.22 -29.73 44.136 -100.0 -32.58 93.5 <0.001 F vs A + F 0.060
Azelastine + Fluticasone 52 -45.43 -46.13 39.919 -100.0 -50.00 50.0
<0.001 Treatment 0.165 Day 10 Azelastine 49 -40.82 -41.13 32.513
-100.0 -38.78 16.3 <0.001 A vs A + F 0.377 Fluticasone 48 -31.17
-31.65 49.076 -100.0 -33.33 150.0 <0.001 F vs A + F 0.046
Azelastine + Fluticasone 52 -47.87 -48.50 42.235 -100.0 -50.00 53.8
<0.001 Treatment 0.135 Day 11 Azelastine 49 -42.70 -43.40 37.450
-100.0 -38.78 28.6 <0.001 A vs A + F 0.598 Fluticasone 48 -33.52
-35.11 58.224 -100.0 -36.05 158.1 <0.001 F vs A + F 0.158
Azelastine + Fluticasone 52 -47.10 -48.26 41.763 -100.0 -50.00 53.8
<0.001 Treatment 0.362 Day 12 Azelastine 49 -34.06 -34.92 53.768
-100.0 -33.33 242.9 <0.001 A vs A + F 0.076 Fluticasone 48
-31.18 -33.86 56.246 -100.0 -35.69 158.1 <0.001 F vs A + F 0.062
Azelastine + Fluticasone 52 -51.04 -52.43 40.279 -100.0 -52.19 28.6
<0.001 Treatment 0.107 Day 13 Azelastine 49 -35.28 -35.90 44.192
-100.0 -30.43 100.0 <0.001 A vs A + F 0.057 Fluticasone 48
-40.87 -42.84 48.895 -100.0 -35.42 93.5 <0.001 F vs A + F 0.267
Azelastine + Fluticasone 52 -51.26 -52.60 40.496 -100.0 -51.00 53.8
<0.001 Treatment 0.159 Day 14 Azelastine 49 -29.95 -30.86 58.715
-100.0 -27.93 242.9 <0.001 A vs A + F 0.054 Fluticasone 48
-36.07 -39.31 52.487 -100.0 -33.94 144.9 <0.001 F vs A + F 0.262
Azelastine + Fluticasone 52 -49.62 -51.14 51.854 -100.0 -57.14
130.8 <0.001 Treatment 0.152 .sup.aTotal number of
intent-to-treat patients with available data. .sup.bLS Mean =
Least-Square Mean obtained from analysis of variance (ANOVA) model
for baseline or analysis of covariance (ANCOVA) model otherwise.
.sup.cp-value for within-patient percent change was based on a
paired t-test. .sup.dp-value for between treatment group
comparison, except Overall and Baseline, was based on an ANCOVA
model containing treatment group and site as fixed effects, and
baseline as a covariate. For Overall, the p-value was based on a
repeated measures ANCOVA model containing study day as the
within-patient efffect, treatment group and site as the
between-patient effects, treatment-by-study day interaction, and
baseline as a covariate. For Baseline, the p-value was based on an
ANOVA # model containing treatment group and site as fixed effects.
.sup.eMean baseline TNSS over 5-day Lead-in Period, including Day 1
AM. .sup.fOverall includes TNSS scores from Day 2 to Day 14.
Reference 16.2.6.1
[1303] TABLE-US-00035 14.2.8 Adult Rhinoconjunctivitis Quality of
Life Questionnaire Outcomes Intent-to-Treat Population Domain
Standard Paired t-test ANOVA Time Point Treatment N.sup.a Mean LS
Mean.sup.b Deviation Minimum Median Maximum p-value.sup.c Source
p-value.sup.d Activity Baseline Azelastine (A) 44 4.17 4.17 1.180
1.3 4.33 6.0 Treatment 0.216 Fluticasone (F) 41 4.49 4.45 0.966 2.3
4.67 6.0 Azelastine + Fluticasone 47 4.55 4.55 1.104 1.3 4.67 6.0
(A + F) Change From Baseline in Activity Day 14/ET Azelastine 43
-1.25 -1.37 1.386 -5.0 -1.00 1.3 <0.001 A vs A + F 0.041
Fluticasone 41 -1.50 -1.52 1.638 -4.3 -1.33 1.7 <0.001 F vs A +
F 0.116 Azelastine + Fluticasone 47 -2.07 -2.03 1.702 -6.0 -2.00
1.0 <0.001 Treatment 0.098 Sleep Baseline Azelastine 45 3.23
3.25 1.241 0.0 3.33 5.7 Treatment 0.024 Fluticasone 44 3.93 3.91
1.397 0.0 4.17 6.0 Azelastine + Fluticasone 47 3.78 3.81 1.265 0.7
4.00 6.0 Change From Baseline in Sleep Day 14/ET Azelastine 44
-1.02 -1.23 1.081 -3.0 -1.00 1.0 <0.001 A vs A + F 0.024
Fluticasone 43 -1.26 -1.23 1.558 -4.3 -1.33 1.7 <0.001 F vs A +
F 0.023 Azelastine + Fluticasone 47 -1.90 -1.88 1.658 -6.0 -1.33
1.0 <0.001 Treatment 0.031 Non-nose/eye Symptoms Baseline
Azelastine 44 3.22 3.22 1.281 0.3 3.21 5.9 Treatment 0.598
Fluticasone 44 3.53 3.48 1.299 0.3 3.57 5.6 Azelastine +
Fluticasone 47 3.39 3.40 1.375 0.6 3.71 5.7 Change From Baseline in
Non-nose/eye Symptoms Day 14/ET Azelastine 43 -0.82 -0.88 1.226
-3.4 -0.86 1.7 <0.001 A vs A + F 0.014 Fluticasone 43 -1.23
-1.19 1.355 -4.4 -1.14 2.3 <0.001 F vs A + F 0.203 Azelastine +
Fluticasone 47 -1.52 -1.52 1.462 -4.6 -1.29 1.1 <0.001 Treatment
0.048 Practical Problems Baseline Azelastine 44 4.27 4.28 1.297 0.3
4.33 6.0 Treatment 0.555 Fluticasone 44 4.59 4.55 1.325 1.3 5.00
6.0 Azelastine + Fluticasone 46 4.48 4.48 1.231 1.7 4.33 6.0 Change
From Baseline in Practical Problems Day 14/ET Azelastine 43 -1.50
-1.59 1.581 -5.7 -1.33 2.7 <0.001 A vs A + F 0.024 Fluticasone
43 -1.76 -1.74 1.511 -4.7 -1.67 0.7 <0.001 F vs A + F 0.073
Azelastine + Fluticasone 46 -2.29 -2.29 1.622 -5.7 -2.33 0.3
<0.001 Treatment 0.056 Nasal Symptoms Baseline Azelastine 44
4.29 4.31 1.251 1.3 4.50 6.0 Treatment 0.290 Fluticasone 44 4.69
4.65 1.190 1.3 5.00 6.0 Azelastine + Fluticasone 47 4.59 4.62 1.242
1.8 5.00 6.0 Change From Baseline in Nasal Symptoms Day 14/ET
Azelastine 43 -1.31 -1.46 1.309 -4.3 -1.25 1.8 <0.001 A vs A + F
0.006 Fluticasone 43 -1.74 -1.72 1.377 -4.8 -1.50 0.3 <0.001 F
vs A + F 0.075 Azelastine + Fluticasone 47 -2.21 -2.19 1.512 -5.0
-1.75 0.3 <0.001 Treatment 0.020 Eye Symptoms Baseline
Azelastine 44 3.77 3.78 1.550 0.0 4.00 6.0 Treatment 0.627
Fluticasone 44 4.11 4.02 1.558 0.0 4.25 6.0 Azelastine +
Fluticasone 47 4.03 4.04 1.583 0.5 4.25 6.0 Change From Baseline in
Eye Symptoms Day 14/ET Azelastine 43 -1.49 -1.64 1.555 -6.0 -1.25
2.5 <0.001 A vs A + F 0.069 Fluticasone 43 -1.53 -1.51 1.372
-4.5 -1.75 1.0 <0.001 F vs A + F 0.025 Azelastine + Fluticasone
47 -2.18 -2.18 1.862 -6.0 -2.25 1.0 <0.001 Treatment 0.056
Emotional Baseline Azelastine 44 3.19 3.20 1.597 0.0 3.25 6.0
Treatment 0.516 Fluticasone 44 3.61 3.55 1.507 0.0 4.00 6.0
Azelastine + Fluticasone 47 3.41 3.43 1.474 0.5 3.25 6.0 Change
From Baseline in Emotional Day 14/ET Azelastine 43 -1.13 -1.26
1.189 -3.5 -1.00 1.8 <0.001 A vs A + F 0.149 Fluticasone 43
-1.50 -1.42 1.534 -5.5 -1.25 1.5 <0.001 F vs A + F 0.397
Azelastine + Fluticasone 47 -1.64 -1.66 1.722 -5.8 -1.00 1.5
<0.001 Treatment 0.345 Overall Score Baseline Azelastine 43 3.65
3.66 1.126 0.5 3.75 5.5 Treatment 0.335 Fluticasone 41 3.99 3.95
1.138 0.9 4.26 5.6 Azelastine + Fluticasone 46 3.93 3.93 1.092 1.6
4.23 5.5 Change From Baseline in Overall Score Day 14/ET Azelastine
42 -1.11 -1.21 1.018 -3.9 -1.13 1.5 <0.001 A vs A + F 0.005
Fluticasone 41 -1.49 -1.47 1.214 -4.4 -1.37 0.6 <0.001 F vs A +
F 0.075 Azelastine + Fluticasone 46 -1.93 -1.92 1.464 -5.1 -1.55
0.2 <0.001 Treatment 0.018 .sup.aTotal number of intent-to-treat
patients with available data. .sup.bLS Mean = Least-Square Mean
obtained from analysis of variance (ANOVA) model for baseline or
analysis of covariance (ANCOVA) model otherwise. .sup.cp-value for
the within-patient change was based on a paired t-test.
.sup.dp-value for between treatment group comparison, except
Baseline, was based on an ANCOVA model containing treatment group
and site as fixed effects, and baseline as a covariate. For
Baseline, the p-value was based on an ANOVA model containing
treatment group and site as fixed effects. Reference: 16.2.6.2
[1304] TABLE-US-00036 14.3.1.1 Overview of Adverse Events Safety
Population Azelastine Fluticasone Azelastine + Fluticasone Total (N
= 49) (N = 50) (N = 52) (N = 151) Number of Adverse Events (AE)
Reported All Treatment-Emergent.sup.a AEs 9 5 17 31 All
Treatment-Related.sup.b AEs 4 4 13 21 Number (%) Patients With Any
AEs All Treatment-Emergent AEs 8 (16.3) 5 (10.0) 12 (23.1) 25
(16.6) All Treatment-Related AEs 4 (8.2) 4 (8.0) 10 (19.2) 18
(11.9) Number (%) of Patients With Serious AEs 0 (0.0) 0 (0.0) 0
(0.0) 0 (0.0) Number (%) of Deaths 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0)
Number (%) Patients With AEs by Maximum Severity All
Treatment-Emergent AEs Mild 3 (6.1) 4 (8.0) 5 (9.6) 12 (7.9)
Moderate 2 (4.1) 1 (2.0) 2 (3.8) 5 (3.3) Severe 3 (6.1) 0 (0.0) 5
(9.6) 8 (5.3) All Treatment-Related AEs Mild 1 (2.0) 3 (6.0) 4
(7.7) 8 (5.3) Moderate 0 (0.0) 1 (2.0) 1 (1.9) 2 (1.3) Severe 3
(6.1) 0 (0.0) 5 (9.6) 8 (5.3) .sup.aTreatment-emergent adverse
event was an adverse event (AE) with an onset date on or after the
first dose of study drug (Azelastine or Fluticasone), or an AE that
is worsened (increased in severity) after taking the study drug.
.sup.bTreatment-related adverse event was a treatment-emergent
adverse event considered possibly or probably related to the study
drug by an investigator. Reference: 16.2.7
[1305] TABLE-US-00037 14.3.1.2 Treatment-Emergent Adverse Events by
System Organ Class, Preferred Term, and Maximum Severity Safety
Population Azelastine Fluticasone (N = 49) (N = 50) System Organ
Class No. of Patients (%) No. of Patients (%) Preferred Term Mild
Moderate Severe Total Mild Moderate Severe Total Any Adverse Event
3 (6.1) 2 (4.1) 3 (6.1) 8 (16.3) 4 (8.0) 1 (2.0) 0 (0.0) 5 (10.0)
EAR AND LABYRINTH DISORDERS Any Preferred Term 0 (0.0) 1 (2.0) 0
(0.0) 1 (2.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) EAR PAIN 0 (0.0) 1
(2.0) 0 (0.0) 1 (2.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0)
GASTROINTESTINAL DISORDERS Any Preferred Term 1 (2.0) 0 (0.0) 3
(6.1) 4 (8.2) 2 (4.0) 1 (2.0) 0 (0.0) 3 (6.0) DRY MOUTH 0 (0.0) 0
(0.0) 0 (0.0) 0 (0.0) 1 (2.0) 0 (0.0) 0 (0.0) 1 (2.0) DYSGEUSIA 1
(2.0) 0 (0.0) 3 (6.1) 4 (8.2) 1 (2.0) 0 (0.0) 0 (0.0) 1 (2.0)
STOMACH DISCOMFORT 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 1 (2.0)
0 (0.0) 1 (2.0) MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS Any
Preferred Term 1 (2.0) 0 (0.0) 0 (0.0) 1 (2.0) 0 (0.0) 0 (0.0) 0
(0.0) 0 (0.0) MYALGIA 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0
(0.0) 0 (0.0) 0 (0.0) NECK PAIN 1 (2.0) 0 (0.0) 0 (0.0) 1 (2.0) 0
(0.0) 0 (0.0) 0 (0.0) 0 (0.0) Azelastine + Fluticasone (N = 52)
System Organ Class No. of Patients (%) Preferred Term Mild Moderate
Severe Total Any Adverse Event 5 (9.6) 2 (3.8) 5 (9.6) 12 (23.1)
EAR AND LABYRINTH DISORDERS Any Preferred Term 0 (0.0) 0 (0.0) 0
(0.0) 0 (0.0) EAR PAIN 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0)
GASTROINTESTINAL DISORDERS Any Preferred Term 1 (1.9) 1 (1.9) 5
(9.6) 7 (13.5) DRY MOUTH 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) DYSGEUSIA
1 (1.9) 1 (1.9) 5 (9.6) 7 (13.5) STOMACH DISCOMFORT 0 (0.0) 0 (0.0)
0 (0.0) 0 (0.0) MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS Any
Preferred Term 0 (0.0) 1 (1.9) 0 (0.0) 1 (1.9) MYALGIA 0 (0.0) 1
(1.9) 0 (0.0) 1 (1.9) NECK PAIN 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0)
Azelastine Fluticasone (N = 49) (N = 50) System Organ Class No. of
Patients (%) No. of Patients (%) Preferred Term Mild Moderate
Severe Total Mild Moderate Severe Total NERVOUS SYSTEM DISORDERS
Any Preferred Term 1 (2.0) 1 (2.0) 0 (0.0) 2 (4.1) 2 (4.0) 0 (0.0)
0 (0.0) 2 (4.0) HEADACHE 1 (2.0) 1 (2.0) 0 (0.0) 2 (4.1) 2 (4.0) 0
(0.0) 0 (0.0) 2 (4.0) RESPIRATORY, THORACIC AND MEDIASTINAL
DISORDERS Any Preferred Term 0 (0.0) 1 (2.0) 0 (0.0) 1 (2.0) 0
(0.0) 0 (0.0) 0 (0.0) 0 (0.0) EPISTAXIS 0 (0.0) 0 (0.0) 0 (0.0) 0
(0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) NASAL DISCOMFORT 0 (0.0) 0
(0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0)
PHARYNGOLARYNGEAL PAIN 0 (0.0) 1 (2.0) 0 (0.0) 1 (2.0) 0 (0.0) 0
(0.0) 0 (0.0) 0 (0.0) Azelastine + Fluticasone (N = 52) System
Organ Class No. of Patients (%) Preferred Term Mild Moderate Severe
Total NERVOUS SYSTEM DISORDERS Any Preferred Term 2 (3.8) 1 (1.9) 0
(0.0) 3 (5.8) HEADACHE 2 (3.8) 1 (1.9) 0 (0.0) 3 (5.8) RESPIRATORY,
THORACIC AND MEDIASTINAL DISORDERS Any Preferred Term 3 (5.8) 0
(0.0) 0 (0.0) 3 (5.8) EPISTAXIS 1 (1.9) 0 (0.0) 0 (0.0) 1 (1.9)
NASAL DISCOMFORT 1 (1.9) 0 (0.0) 0 (0.0) 1 (1.9) PHARYNGOLARYNGEAL
PAIN 1 (1.9) 0 (0.0) 0 (0.0) 1 (1.9) Note: Adverse Events (AEs)
coded using the MedDRA dictionary. A patient with multiple AEs is
counted only once under the maximum severity experienced and once
under the Total in any AE row. Reference: 16.2.7
[1306] TABLE-US-00038 14.3.1.3 Treatment-Related Adverse Events by
System Organ Class, Preferred Term, and Relationship to Study Drug
Safety Population Azelastine Fluticasone (N = 49) (N = 50) System
Organ Class No. of Patients (%) No. of Patients (%) Preferred Term
Possibly Probably Total Possibly Probably Total Any Adverse Event 1
(2.0) 3 (6.1) 4 (8.2) 4 (8.0) 0 (0.0) 4 (8.0) GASTROINTESTINAL
DISORDERS Any Preferred Term 1 (2.0) 3 (6.1) 4 (8.2) 3 (6.0) 0
(0.0) 3 (6.0) DRY MOUTH 0 (0.0) 0 (0.0) 0 (0.0) 1 (2.0) 0 (0.0) 1
(2.0) DYSGEUSIA 1 (2.0) 3 (6.1) 4 (8.2) 1 (2.0) 0 (0.0) 1 (2.0)
STOMACH DISCOMFORT 0 (0.0) 0 (0.0) 0 (0.0) 1 (2.0) 0 (0.0) 1 (2.0)
NERVOUS SYSTEM DISORDERS Any Preferred Term 0 (0.0) 0 (0.0) 0 (0.0)
1 (2.0) 0 (0.0) 1 (2.0) HEADACHE 0 (0.0) 0 (0.0) 0 (0.0) 1 (2.0) 0
(0.0) 1 (2.0) RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS Any
Preferred Term 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0)
EPISTAXIS 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) NASAL
DISCOMFORT 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0)
Azelastine + Fluticasone (N = 52) System Organ Class No. of
Patients (%) Preferred Term Possibly Probably Total Any Adverse
Event 1 (1.9) 9 (17.3) 10 (19.2) GASTROINTESTINAL DISORDERS Any
Preferred Term 0 (0.0) 7 (13.5) 7 (13.5) DRY MOUTH 0 (0.0) 0 (0.0)
0 (0.0) DYSGEUSIA 0 (0.0) 7 (13.5) 7 (13.5) STOMACH DISCOMFORT 0
(0.0) 0 (0.0) 0 (0.0) NERVOUS SYSTEM DISORDERS Any Preferred Term 0
(0.0) 2 (3.8) 2 (3.8) HEADACHE 0 (0.0) 2 (3.8) 2 (3.8) RESPIRATORY,
THORACIC AND MEDIASTINAL DISORDERS Any Preferred Term 1 (1.9) 1
(1.9) 2 (3.8) EPISTAXIS 1 (1.9) 0 (0.0) 1 (1.9) NASAL DISCOMFORT 0
(0.0) 1 (1.9) 1 (1.9) Note: Adverse Events (AEs) coded using the
MedDRA dictionary. Treatment-related adverse event was a
treatment-emergent adverse event considered possibly or probably
related to the study drug by an investigator. A patient with
multiple AEs is counted only once under the closest relationship to
the study drug and under the Total in any AE row. Reference:
16.2.7
[1307] TABLE-US-00039 14.3.1.4 Treatment-Emergent Adverse Events by
Decreasing Order of Frequency Safety Population Azelastine
Fluticasone Azelastine + Fluticasone (N = 49) (N = 50) (N = 52)
Preferred Term No. of Patients (%) No. of Patients (%) No. of
Patients (%) Any Adverse Event 8 (16.3) 5 (10.0) 12 (23.1)
DYSGEUSIA 4 (8.2) 1 (2.0) 7 (13.5) HEADACHE 2 (4.1) 2 (4.0) 3 (5.8)
PHARYNGOLARYNGEAL PAIN 1 (2.0) 0 (0.0) 1 (1.9) EAR PAIN 1 (2.0) 0
(0.0) 0 (0.0) NECK PAIN 1 (2.0) 0 (0.0) 0 (0.0) DRY MOUTH 0 (0.0) 1
(2.0) 0 (0.0) STOMACH DISCOMFORT 0 (0.0) 1 (2.0) 0 (0.0) EPISTAXIS
0 (0.0) 0 (0.0) 1 (1.9) MYALGIA 0 (0.0) 0 (0.0) 1 (1.9) NASAL
DISCOMFORT 0 (0.0) 0 (0.0) 1 (1.9) Note: Adverse Events (AEs) coded
using the MedDRA dictionary. A patient with multiple AEs is counted
only once in any row. Reference: 16.2.7
[1308] TABLE-US-00040 14.3.2.1 Listing of Adverse Events Resulting
in Death Treatment Group: Sex Investigator Term Start Date (Day)
Site- Age (years) Preferred Term Stop Date (Day) Serious AE?/
Relationship/ Patient Race System Organ Class Duration of AE
Severity Treatment for AE Action NO OBSERVATIONS IN THE DATABASE +
Treatment-Emergent Adverse Event. Reference: CRF Pages 1 and 10
[1309] TABLE-US-00041 14.3.2.2 Listing of Serious Adverse Events
Treatment Group: Sex Investigator Term Start Date (Day) Site- Age
(years) Preferred Term Stop Date (Day) Relationship/ Action/
Patient Race System Organ Class Duration of AE Severity Treatment
for AE Outcome NO OBSERVATIONS IN THE DATABASE + Treatment-Emergent
Adverse Event. Reference: CRF Pages 1 and 10
[1310] TABLE-US-00042 14.3.2.3 Listing of Adverse Events Resulting
in Discontinuation Treatment Group: Sex Investigator Term Start
Date (Day) Site- Age (years) Preferred Term Stop Date (Day) Serious
AE?/ Relationship/ Patient Race System Organ Class Duration of AE
Severity Treatment for AE Outcome NO OBSERVATIONS IN THE DATABASE +
Treatment-Emergent Adverse Event. Reference: CRF Pages 1 and 10
[1311] TABLE-US-00043 14.3.5 Vital Sign Assessments Safety
Population Azelastine + Azelastine Fluticasone Fluticasone (N = 49)
(N = 50) (N = 52) Visit Statistics Actual Change.sup.a Actual
Change.sup.a Actual Change.sup.a Systolic Blood Pressure (mmHg)
Screening N 49 50 52 Mean 124.0 121.2 120.5 Standard Deviation
14.06 13.96 13.25 Median 123.0 119.5 119.5 Min-Max 96-162 96-156
97-154 Day 1 N 49 50 52 Mean 120.2 117.9 119.7 Standard Deviation
13.90 12.82 13.29 Median 120.0 118.5 120.0 Min-Max 96-156 93-142
80-147 Day 7 N 49 49 48 48 50 50 Mean 121.9 1.7 116.7 -1.4 118.3
-1.8 Standard Deviation 13.66 10.20 11.99 9.26 14.13 9.86 Median
120.0 2.0 116.0 -0.5 118.0 -2.5 Min-Max 96-156 -23-28 95-142 -21-15
90-144 -23-20 Day 14 N 49 49 50 50 52 52 Mean 122.6 2.4 118.9 1.0
119.0 -0.7 Standard Deviation 12.38 10.50 13.81 11.69 14.40 10.98
Median 121.0 3.0 117.0 1.5 117.5 -0.5 Min-Max 98-150 -20-22 98-170
-20-40 93-154 -33-24 Diastolic Blood Pressure (mmHg) Screening N 49
50 52 Mean 75.9 75.6 75.2 Standard Deviation 8.47 9.76 8.88 Median
75.0 78.0 73.5 Min-Max 50-96 50-95 60-95 Day 1 N 49 50 52 Mean 74.6
74.0 74.4 Standard Deviation 8.57 9.75 7.92 Median 74.0 76.0 74.0
Min-Max 54-90 41-89 50-90 Day 7 N 49 49 48 48 50 50 Mean 75.5 0.8
72.7 -1.5 72.4 -2.1 Standard Deviation 8.39 7.50 7.37 6.97 9.51
7.94 Median 76.0 1.0 74.0 -1.5 72.0 -1.0 Min-Max 56-90 -16-20 58-86
-15-19 52-90 -21-16 Day 14 N 49 49 50 50 52 52 Mean 75.9 1.3 73.6
-0.4 72.8 -1.5 Standard Deviation 7.93 6.39 9.01 7.52 8.28 7.16
Median 78.0 0.0 74.0 0.0 72.0 0.0 Min-Max 60-90 -13-18 54-90 -24-22
56-90 -18-15 Pulse Rate (bpm) Screening N 49 50 52 Mean 73.7 75.5
76.0 Standard Deviation 9.95 10.47 7.94 Median 74.0 78.0 75.0
Min-Max 52-100 50-103 59-94 Day 1 N 49 50 52 Mean 73.4 75.0 76.8
Standard Deviation 10.38 8.87 9.45 Median 73.0 75.0 74.0 Min-Max
56-98 57-92 60-107 Day 7 N 49 49 48 48 50 50 Mean 75.7 2.3 75.5 0.5
74.7 -1.7 Standard Deviation 9.09 8.78 10.85 10.77 9.95 10.69
Median 75.0 3.0 74.0 -2.0 74.0 -3.5 Min-Max 60-95 -18-22 52-102
-29-38 60-104 -25-30 Day 14 N 49 49 50 50 52 52 Mean 75.4 2.0 75.3
0.3 75.9 -0.9 Standard Deviation 8.51 9.57 9.38 8.77 10.44 10.46
Median 76.0 1.0 74.0 1.0 74.0 -2.0 Min-Max 60-96 -23-24 53-95
-22-23 60-102 -26-22 Respiration (bpm) Screening N 49 50 52 Mean
16.1 15.7 16.2 Standard Deviation 2.14 2.29 2.58 Median 16.0 16.0
16.0 Min-Max 12-20 12-20 12-24 Day 1 N 49 50 52 Mean 15.8 15.8 15.5
Standard Deviation 2.00 1.43 1.99 Median 16.0 16.0 16.0 Min-Max
12-20 12-18 12-18 Day 7 N 49 49 48 48 50 50 Mean 15.9 0.1 16.0 0.2
16.0 0.4 Standard Deviation 1.67 1.93 1.62 1.73 1.59 2.18 Median
16.0 0.0 16.0 0.0 16.0 0.0 Min-Max 12-18 -4-4 12-20 -4-4 12-20 -4-6
Day 14 N 49 49 50 50 52 52 Mean 15.9 0.2 15.8 0.0 15.9 0.3 Standard
Deviation 1.64 1.89 1.56 1.76 1.70 1.89 Median 16.0 0.0 16.0 0.0
16.0 0.0 Min-Max 12-18 -4-4 12-20 -4-4 12-20 -4-4 Temperature
(.degree. F.) Screening N 49 50 52 Mean 97.91 98.04 97.75 Standard
Deviation 0.623 0.646 0.623 Median 98.00 98.00 97.80 Min-Max
96.2-99.3 96.9-99.3 96.2-99.3 Day 1 N 49 50 52 Mean 97.73 97.89
97.81 Standard Deviation 0.583 0.667 0.541 Median 97.80 97.85 97.70
Min-Max 96.5-99.4 97.0-99.8 96.8-99.0 Day 7 N 49 49 48 48 50 50
Mean 97.82 0.09 97.90 -0.03 97.85 0.02 Standard Deviation 0.621
0.642 0.567 0.743 0.526 0.642 Median 97.80 0.10 97.95 0.00 97.80
0.00 Min-Max 96.3-99.0 -2.0-1.3 96.0-98.9 -1.8-1.8 96.5-98.9
-1.6-1.4 Day 14 N 49 49 50 50 52 52 Mean 97.94 0.21 97.86 -0.03
97.89 0.09 Standard Deviation 0.630 0.750 0.578 0.765 0.536 0.683
Median 98.00 0.30 97.90 0.10 97.90 0.10 Min-Max 96.0-99.5 -1.1-1.8
96.2-99.1 -1.6-2.0 96.8-99.0 -1.3-1.7 Body Weight (lb) Screening N
49 50 52 Mean 181.2 172.9 173.8 Standard Deviation 47.09 40.42
51.05 Median 174.0 168.5 162.5 Min-Max 98-284 85-269 99-303 Day 14
N 49 49 49 49 52 52 Mean 180.9 -0.3 173.0 -0.5 174.2 0.4 Standard
Deviation 46.60 2.18 40.04 2.35 50.14 3.42 Median 174.0 -1.0 168.0
0.0 162.0 0.0 Min-Max 98-282 -5-7 87-265 -6-7 103-302 -8-15 Body
Weight (lb) for Patients of Age 12 to 17 Screening N 3 6 5 Mean
104.7 136.3 128.1 Standard Deviation 7.02 46.66 21.20 Median 104.0
122.5 121.4 Min-Max 98-112 85-199 108-163 Day 14 N 3 3 6 6 5 5 Mean
105.7 1.0 135.8 -0.5 130.6 2.5 Standard Deviation 9.29 2.65 45.95
1.52 21.09 7.29 Median 103.0 0.0 121.5 -0.5 131.0 0.0 Min-Max
98-116 -1-4 87-197 -2-2 108-162 -2-15 Body Weight (lb) for Patients
of Age 18 and Beyond Screening N 46 44 47 Mean 186.2 177.9 178.6
Standard Deviation 44.12 37.37 50.99 Median 177.8 169.5 169.0
Min-Max 102-284 117-269 99-303 Day 14 N 46 46 43 43 47 47 Mean
185.8 -0.4 178.2 -0.5 178.8 0.2 Standard Deviation 43.70 2.15 36.83
2.46 50.20 2.80 Median 176.2 -1.0 172.0 0.0 169.0 0.0 Min-Max
102-282 -5-7 115-265 -6-7 103-302 -8-7 .sup.aChange from baseline
where baseline was measured at Screening. Reference: 16.2.9
[1312] TABLE-US-00044 14.3.6 Concomitant Medications
Intent-to-Treat Population Azelastine Fluticasone Azelastine +
Fluticasone Total Anatomical Therapeutic Class (N = 49) (N = 50) (N
= 52) (N = 151) Preferred Term No. of Patients (%) No. of Patients
(%) No. of Patients (%) No. of Patients (%) Any Concomitant
Medications 44 (89.8) 40 (80.0) 41 (78.8) 125 (82.8) ACE INHIBITORS
AND DIURETICS Any Preferred Term 0 (0.0) 0 (0.0) 1 (1.9) 1 (0.7)
PRINZIDE /00977901/ 0 (0.0) 0 (0.0) 1 (1.9) 1 (0.7) ACE INHIBITORS,
PLAIN Any Preferred Term 3 (6.1) 4 (8.0) 1 (1.9) 8 (5.3) BENAZEPRIL
HYDROCHLORIDE 0 (0.0) 1 (2.0) 0 (0.0) 1 (0.7) LISINOPRIL 2 (4.1) 3
(6.0) 1 (1.9) 6 (4.0) QUINAPRIL HYDROCHLORIDE 1 (2.0) 0 (0.0) 0
(0.0) 1 (0.7) ALLERGEN EXTRACTS Any Preferred Term 1 (2.0) 0 (0.0)
2 (3.8) 3 (2.0) ALLERGENS NOS 1 (2.0) 0 (0.0) 2 (3.8) 3 (2.0) AMINO
ACIDS AND DERIVATIVES Any Preferred Term 1 (2.0) 0 (0.0) 0 (0.0) 1
(0.7) LEVOGLUTAMIDE 1 (2.0) 0 (0.0) 0 (0.0) 1 (0.7) AMINOALKYL
ETHERS Any Preferred Term 2 (4.1) 3 (6.0) 2 (3.8) 7 (4.6)
CLEMASTINE FUMARATE 0 (0.0) 2 (4.0) 0 (0.0) 2 (1.3) DIPHENHYDRAMINE
0 (0.0) 1 (2.0) 0 (0.0) 1 (0.7) DIPHENHYDRAMINE HYDROCHLORIDE 2
(4.1) 0 (0.0) 2 (3.8) 4 (2.6) AMINOSALICYLIC ACID AND SIMILAR
AGENTS Any Preferred Term 0 (0.0) 0 (0.0) 1 (1.9) 1 (0.7)
SULFASALAZINE 0 (0.0) 0 (0.0) 1 (1.9) 1 (0.7) ANDROGENS AND
ESTROGENS Any Preferred Term 0 (0.0) 1 (2.0) 1 (1.9) 2 (1.3)
ESTRATEST HS 0 (0.0) 1 (2.0) 1 (1.9) 2 (1.3) ANGIOTENSIN II
ANTAGONISTS AND DIURETICS Any Preferred Term 1 (2.0) 0 (0.0) 1
(1.9) 2 (1.3) CO-DIOVAN 0 (0.0) 0 (0.0) 1 (1.9) 1 (0.7) PRITOR
/01506701/ 1 (2.0) 0 (0.0) 0 (0.0) 1 (0.7) ANGIOTENSIN II
ANTAGONISTS, PLAIN Any Preferred Term 1 (2.0) 1 (2.0) 0 (0.0) 2
(1.3) OLMESARTAN MEDOXOMIL 0 (0.0) 1 (2.0) 0 (0.0) 1 (0.7)
VALSARTAN 1 (2.0) 0 (0.0) 0 (0.0) 1 (0.7) ANILIDES Any Preferred
Term 9 (18.4) 12 (24.0) 9 (17.3) 30 (19.9) AXOTAL /00727001/ 0
(0.0) 1 (2.0) 1 (1.9) 2 (1.3) CO-TYLENOL 0 (0.0) 0 (0.0) 1 (1.9) 1
(0.7) MEDINITE 0 (0.0) 1 (2.0) 0 (0.0) 1 (0.7) MIDOL /00095101/ 0
(0.0) 1 (2.0) 0 (0.0) 1 (0.7) PAMPRIN 0 (0.0) 0 (0.0) 1 (1.9) 1
(0.7) PARACETAMOL 9 (18.4) 8 (16.0) 9 (17.3) 26 (17.2) THOMAPYRIN N
0 (0.0) 2 (4.0) 0 (0.0) 2 (1.3) ANTACIDS WITH ANTIFLATULENTS Any
Preferred Term 0 (0.0) 1 (2.0) 0 (0.0) 1 (0.7) MYLANTA /0036701/ 0
(0.0) 1 (2.0) 0 (0.0) 1 (0.7) ANTIALLERGIC AGENTS, EXCL.
CORTICOSTEROIDS Any Preferred Term 1 (2.0) 0 (0.0) 0 (0.0) 1 (0.7)
AZELASTINE HYDROCHLORIDE 1 (2.0) 0 (0.0) 0 (0.0) 1 (0.7)
ANTIINFLAMMATORY/ANTIRHEUMATIC PROD., NON-STEROIDS Any Preferred
Term 1 (2.0) 0 (0.0) 0 (0.0) 1 (0.7) GLUCOSAMINE W/CHONDROITIN 1
(2.0) 0 (0.0) 0 (0.0) 1 (0.7) ANTIPROPULSIVES Any Preferred Term 1
(2.0) 0 (0.0) 0 (0.0) 1 (0.7) LOPERAMIDE HYDROCHLORIDE 1 (2.0) 0
(0.0) 0 (0.0) 1 (0.7) ASCORBIC ACID (VITAMIN C), PLAIN Any
Preferred Term 1 (2.0) 1 (2.0) 2 (3.8) 4 (2.6) ASCORBIC ACID 1
(2.0) 1 (2.0) 2 (3.8) 4 (2.6) BETA BLOCKING AGENTS, SELECTIVE Any
Preferred Term 0 (0.0) 0 (0.0) 1 (1.9) 1 (0.7) METOPROLOL TARTRATE
0 (0.0) 0 (0.0) 1 (1.9) 1 (0.7) BIGUANIDES Any Preferred Term 2
(4.1) 0 (0.0) 0 (0.0) 2 (1.3) METFORMIN 1 (2.0) 0 (0.0) 0 (0.0) 1
(0.7) METFORMIN HYDROCHLORIDE 1 (2.0) 0 (0.0) 0 (0.0) 1 (0.7)
BISMUTH PREPARATIONS Any Preferred Term 1 (2.0) 0 (0.0) 0 (0.0) 1
(0.7) BISMUTH SUBSALICYLATE 1 (2.0) 0 (0.0) 0 (0.0) 1 (0.7)
BISPHOSPHONATES Any Preferred Term 0 (0.0) 1 (2.0) 0 (0.0) 1 (0.7)
ALENDRONATE SODIUM 0 (0.0) 1 (2.0) 0 (0.0) 1 (0.7) CALCIUM Any
Preferred Term 4 (8.2) 2 (4.0) 3 (5.8) 9 (6.0) CALCIUM 3 (6.1) 2
(4.0) 3 (5.8) 8 (5.3) CALCIUM CARBONATE 1 (2.0) 0 (0.0) 0 (0.0) 1
(0.7) CARBAMIC ACID ESTERS Any Preferred Term 0 (0.0) 1 (2.0) 0
(0.0) 1 (0.7) METHOCARBAMOL 0 (0.0) 1 (2.0) 0 (0.0) 1 (0.7) COMB
AND COMPL OF ALUMIN., CALC AND MAGNES COMP Any Preferred Term 0
(0.0) 0 (0.0) 1 (1.9) 1 (0.7) MAALOX /00091001/ 0 (0.0) 0 (0.0) 1
(1.9) 1 (0.7) DIHYDROPYRIDINE DERIVATIVES Any Preferred Term 0
(0.0) 1 (2.0) 0 (0.0) 1 (0.7) AMLODIPINE BESILATE 0 (0.0) 1 (2.0) 0
(0.0) 1 (0.7) DIPHENYLPROPYLAMINE DERIVATIVES Any Preferred Term 0
(0.0) 0 (0.0) 1 (1.9) 1 (0.7) PROPACET 0 (0.0) 0 (0.0) 1 (1.9) 1
(0.7) DRUGS USED IN ERECTILE DYSFUNCTION Any Preferred Term 0 (0.0)
1 (2.0) 0 (0.0) 1 (0.7) TADALAFIL 0 (0.0) 1 (2.0) 0 (0.0) 1 (0.7)
DRUGS USED IN NICOTINE DEPENDENCE Any Preferred Term 0 (0.0) 1
(2.0) 1 (1.9) 2 (1.3) BUPROPION HYDROCHLORIDE 0 (0.0) 1 (2.0) 1
(1.9) 2 (1.3) ESTREN DERIVATIVES Any Preferred Term 0 (0.0) 0 (0.0)
1 (1.9) 1 (0.7) NORETHISTERONE ACETATE 0 (0.0) 0 (0.0) 1 (1.9) 1
(0.7) FLUOROQUINOLONES Any Preferred Term 0 (0.0) 0 (0.0) 1 (1.9) 1
(0.7) LEVOFLOXACIN 0 (0.0) 0 (0.0) 1 (1.9) 1 (0.7) FOLIC ACID AND
DERIVATIVES Any Preferred Term 1 (2.0) 0 (0.0) 0 (0.0) 1 (0.7)
FOLIC ACID 1 (2.0) 0 (0.0) 0 (0.0) 1 (0.7) GLUCOCORTICOIDS Any
Preferred Term 2 (4.1) 0 (0.0) 0 (0.0) 2 (1.3) FLUTICASONE
PROPIONATE 1 (2.0) 0 (0.0) 0 (0.0) 1 (0.7) GLUCOCORTICOIDS
TRIAMCINOLONE ACETONIDE 1 (2.0) 0 (0.0) 0 (0.0) 1 (0.7) H2-RECEPTOR
ANTAGONISTS Any Preferred Term 0 (0.0) 0 (0.0) 1 (1.9) 1 (0.7)
RANITIDINE HYDROCHLORIDE 0 (0.0) 0 (0.0) 1 (1.9) 1 (0.7) HMG COA
REDUCTASE INHIBITORS Any Preferred Term 3 (6.1) 3 (6.0) 4 (7.7) 10
(6.6) ATORVASTATIN CALCIUM 1 (2.0) 2 (4.0) 2 (3.8) 5 (3.3) INEGY 1
(2.0) 0 (0.0) 0 (0.0) 1 (0.7) LOVASTATIN 0 (0.0) 1 (2.0) 0 (0.0) 1
(0.7) PRAVASTATIN SODIUM 0 (0.0) 0 (0.0) 1 (1.9) 1 (0.7)
SIMYASTATIN 1 (2.0) 0 (0.0) 1 (1.9) 2 (1.3) INTRAUTERINE
CONTRACEPTIVES Any Preferred Term 1 (2.0) 0 (0.0) 0 (0.0) 1 (0.7)
INTRAUTERINE CONTRACEPTIVE DEVICE 1 (2.0) 0 (0.0) 0 (0.0) 1 (0.7)
LOW-CEILING DIURETICS AND POTASSIUM- SPARING AGENTS Any Preferred
Term 0 (0.0) 1 (2.0) 1 (1.9) 2 (1.3) ALDACTAZIDE A 0 (0.0) 1 (2.0)
0 (0.0) 1 (0.7) DYAZIDE 0 (0.0) 0 (0.0) 1 (1.9) 1 (0.7)
MULTIVITAMINS WITH MINERALS Any Preferred Term 1 (2.0) 0 (0.0) 0
(0.0) 1 (0.7) CENTRUM /00554501/ 1 (2.0) 0 (0.0) 0 (0.0) 1 (0.7)
MULTIVITAMINS, PLAIN Any Preferred Term 5 (10.2) 2 (4.0) 5 (9.6) 12
(7.9) MULTIVITAMINS, PLAIN 5 (10.2) 2 (4.0) 5 (9.6) 12 (7.9)
NATURAL AND SEMISYNTHETIC ESTROGENS, PLAIN Any Preferred Term 2
(4.1) 1 (2.0) 3 (5.8) 6 (4.0) ESTRADIOL 0 (0.0) 0 (0.0) 1 (1.9) 1
(0.7) ESTROGENS CONJUGATED 2 (4.1) 1 (2.0) 2 (3.8) 5 (3.3) NATURAL
OPIUM ALKALOIDS Any Preferred Term 1 (2.0) 0 (0.0) 0 (0.0) 1 (0.7)
VICODIN 1 (2.0) 0 (0.0) 0 (0.0) 1 (0.7) NUCLEOSIDES AND NUCLEOTIDES
EXCL REV.TRANSCRINHIB Any Preferred Term 0 (0.0) 0 (0.0) 1 (1.9) 1
(0.7) ACICLOVIR 0 (0.0) 0 (0.0) 1 (1.9) 1 (0.7) OPIUM ALKALOIDS AND
DERIVATIVES Any Preferred Term 0 (0.0) 1 (2.0) 0 (0.0) 1 (0.7)
HYDROCODONE 0 (0.0) 1 (2.0) 0 (0.0) 1 (0.7) OTHER ANTIALLERGICS Any
Preferred Term 1 (2.0) 1 (2.0) 0 (0.0) 2 (1.3) OLOPATADINE
HYDROCHLORIDE 1 (2.0) 1 (2.0) 0 (0.0) 2 (1.3) OTHER ANTIDEPRESSANTS
Any Preferred Term 0 (0.0) 1 (2.0) 0 (0.0) 1 (0.7) VENLAFAXINE
HYDROCHLORIDE 0 (0.0) 1 (2.0) 0 (0.0) 1 (0.7) OTHER ANTIEPILEPTICS
Any Preferred Term 1 (2.0) 1 (2.0) 1 (1.9) 3 (2.0) GABAPENTIN 0
(0.0) 1 (2.0) 1 (1.9) 2 (1.3) TOPIRAMATE 1 (2.0) 0 (0.0) 0 (0.0) 1
(0.7) OTHER ANTIHISTAMINES FOR SYSTEMIC USE Any Preferred Term 6
(12.2) 4 (8.0) 5 (9.6) 15 (9.9) ALLEGRA-D /01413301/ 0 (0.0) 1
(2.0) 2 (3.8) 3 (2.0) DESLORATADINE 0 (0.0) 0 (0.0) 1 (1.9) 1 (0.7)
FEXOFENADINE HYDROCHLORIDE 4 (8.2) 1 (2.0) 0 (0.0) 5 (3.3)
LORATADINE 2 (4.1) 3 (6.0) 2 (3.8) 7 (4.6) OTHER
ANTIINFL/ANTIRHEUMATIC AGENTS, NON-STEROIDS Any Preferred Term 1
(2.0) 0 (0.0) 1 (1.9) 2 (1.3) GLUCOSAMINE 1 (2.0) 0 (0.0) 1 (1.9) 2
(1.3) OTHER CHOLESTEROL AND TRIGLYCERIDE REDUCERS Any Preferred
Term 2 (4.1) 1 (2.0) 1 (1.9) 4 (2.6) EZETIMIBE 0 (0.0) 1 (2.0) 0
(0.0) 1 (0.7) FISH OIL 2 (4.1) 0 (0.0) 1 (1.9) 3 (2.0) OTHER
OPHTHALMOLOGICALS Any Preferred Term 1 (2.0) 0 (0.0) 0 (0.0) 1
(0.7) OTHER OPHTHALMOLOGICALS 1 (2.0) 0 (0.0) 0 (0.0) 1 (0.7) OTHER
PLAIN VITAMIN PREPARATIONS Any Preferred Term 3 (6.1) 1 (2.0) 1
(1.9) 5 (3.3) PYRIDOXINE HYDROCHLORIDE 2 (4.1) 0 (0.0) 0 (0.0) 2
(1.3) TOCOPHERYL ACETATE 1 (2.0) 1 (2.0) 1 (1.9) 3 (2.0) OTHER
POTASSIUM-SPARING AGENTS Any Preferred Term 1 (2.0) 0 (0.0) 0 (0.0)
1 (0.7) TRIAMTERENE 1 (2.0) 0 (0.0) 0 (0.0) 1 (0.7) OXAZOL,
THIAZINE, AND TRIAZINE DERIVATIVES Any Preferred Term 0 (0.0) 1
(2.0) 0 (0.0) 1 (0.7) METAXALONE 0 (0.0) 1 (2.0) 0 (0.0) 1 (0.7)
OXICAMS Any Preferred Term 2 (4.1) 1 (2.0) 0 (0.0) 3 (2.0)
MELOXICAM 2 (4.1) 1 (2.0) 0 (0.0) 3 (2.0) PHENYLALKYLAMINE
DERIVATIVES Any Preferred Term 1 (2.0) 0 (0.0) 0 (0.0) 1 (0.7)
VERAPAMIL 1 (2.0) 0 (0.0) 0 (0.0) 1 (0.7) PIPERAZINIE DERIVATIVES
Any Preferred Term 1 (2.0) 4 (8.0) 6 (11.5) 11 (7.3) CETIRIZINE
HYDROCHLORIDE 1 (2.0) 4 (8.0) 6 (11.5) 11 (7.3) POTASSIUM Any
Preferred Term 0 (0.0) 1 (2.0) 1 (1.9) 2 (1.3) POTASSIUM 0 (0.0) 1
(2.0) 1 (1.9) 2 (1.3) PREGNEN (4) DERIVATIVES Any Preferred Term 1
(2.0) 2 (4.0) 1 (1.9) 4 (2.6) MEDROXYPROGESTERONE ACETATE 1 (2.0) 2
(4.0) 1 (1.9) 4 (2.6) PROGESTOGENS AND ESTROGENS, FIXED
COMBINATIONS Any Preferred Term 2 (4.1) 2 (4.0) 6 (11.5) 10 (6.6)
ANOVLAR 1 (2.0) 1 (2.0) 1 (1.9) 3 (2.0) CILEST 1 (2.0) 0 (0.0) 2
(3.8) 3 (2.0) CONLUNETT 0 (0.0) 1 (2.0) 0 (0.0) 1 (0.7) BUGYNON
/00022701/ 0 (0.0) 0 (0.0) 1 (1.9) 1 (0.7) EVRA 0 (0.0) 0 (0.0) 1
(1.9) 1 (0.7) NORMENSAL 0 (0.0) 0 (0.0) 1 (1.9) 1 (0.7) PROPIONIC
ACID DERIVATIVES Any Preferred Term 14 (28.6) 12 (24.0) 14 (26.9)
40 (26.5) CO-ADVIL 2 (4.1) 0 (0.0) 0 (0.0) 2 (1.3) IBUPROFEN 13
(26.5) 11 (22.0) 11 (21.2) 35 (23.2) NAPROXEN 0 (0.0) 0 (0.0) 1
(1.9) 1 (0.7) NAPROXEN SODIUM 1 (2.0) 1 (2.0) 3 (5.8) 5 (3.3)
PROTEIN SUPPLEMENTS Any Preferred Term 1 (2.0) 0 (0.0) 0 (0.0) 1
(0.7) PROTEIN SUPPLEMENTS 1 (2.0) 0 (0.0) 0 (0.0) 1 (0.7) PROTON
PUMP INHIBITORS Any Preferred Term 2 (4.1) 5 (10.0) 2 (3.8) 9 (6.0)
ESOMEPRAZOLE MAGNESIUM 2 (4.1) 0 (0.0) 1 (1.9) 3 (2.0) OMEPRAZOLE 0
(0.0) 3 (6.0) 1 (1.9) 4 (2.6) PANTOPRAZOLE SODIUM 0 (0.0) 1 (2.0) 0
(0.0) 1 (0.7) RABEPRAZOLE SODIUM 0 (0.0) 1 (2.0) 0 (0.0) 1 (0.7)
PYRAZOLONES Any Preferred Term 1 (2.0) 1 (2.0) 2 (3.8) 4 (2.6)
TYLENOL SINUS MEDICATION 1 (2.0) 1 (2.0) 2 (3.8) 4 (2.6) SALICYLIC
ACID AND DERIVATIVES Any Preferred Term 7 (14.3) 5 (10.0) 3 (5.8)
15 (9.9) ACETYLSALICYLIC ACID 7 (14.3) 5 (10.0) 3 (5.8) 15 (9.9)
SELECTIVE BETA-2-ADRENORECEPTOR AGONISTS Any Preferred Term 1 (2.0)
2 (4.0) 1 (1.9) 4 (2.6) SALBUTAMOL 1 (2.0) 1 (2.0) 1 (1.9) 3 (2.0)
SALBUTAMOL SULFATE 0 (0.0) 1 (2.0) 0 (0.0) 1 (0.7) SELECTIVE
SEROTONIN REUPTAKE INHIBITORS Any Preferred Term 2 (4.1) 4 (8.0) 2
(3.8) 8 (5.3) ESCITALOPRAM OXALATE 0 (0.0) 4 (8.0) 0 (0.0) 4 (2.6)
FLUOXETINE HYDROCHLORIDE 0 (0.0) 0 (0.0) 1 (1.9) 1 (0.7) PAROXETINE
HYDROCHLORIDE 1 (2.0) 0 (0.0) 0 (0.0) 1 (0.7)
SERTRALINE HYDROCHLORIDE 1 (2.0) 0 (0.0) 1 (1.9) 2 (1.3) SELENIUM
Any Preferred Term 1 (2.0) 0 (0.0) 0 (0.0) 1 (0.7) SELENIUM 1 (2.0)
0 (0.0) 0 (0.0) 1 (0.7) SYMPATHOMIMETICS Any Preferred Term 2 (4.1)
3 (6.0) 2 (3.8) 7 (4.6) ADVIL /1717101/ 0 (0.0) 0 (0.0) 1 (1.9) 1
(0.7) PSEUDOEPHEDRINE 1 (2.0) 1 (2.0) 0 (0.0) 2 (1.3)
PSEUDOEPHEDRINE HYDROCHLORIDE 1 (2.0) 2 (4.0) 0 (0.0) 3 (2.0)
PSEUDOEPHEDRINE, COMBINATIONS 0 (0.0) 0 (0.0) 1 (1.9) 1 (0.7)
SYMPATHOMIMETICS USED AS DECONGESTANTS Any Preferred Term 0 (0.0) 0
(0.0) 1 (1.9) 1 (0.7) TETRYZOLINE HYDROCHLORIDE 0 (0.0) 0 (0.0) 1
(1.9) 1 (0.7) SYMPATHOMIMETICS, PLAIN Any Preferred Term 0 (0.0) 0
(0.0) 1 (1.9) 1 (0.7) OXYMETAZOLINE HYDROCHLORIDE 0 (0.0) 0 (0.0) 1
(1.9) 1 (0.7) TESTOSTERONE-5-ALPHA REDUCTASE INHIBITORS Any
Preferred Term 2 (4.1) 0 (0.0) 0 (0.0) 2 (1.3) FINASTERIDE 2 (4.1)
0 (0.0) 0 (0.0) 2 (1.3) THIAZIDES, PLAIN Any Preferred Term 1 (2.0)
0 (0.0) 0 (0.0) 1 (0.7) HYDROCHLOROTHIAZIDE 1 (2.0) 0 (0.0) 0 (0.0)
1 (0.7) THYROID HORMONES Any Preferred Term 3 (6.1) 1 (2.0) 2 (3.8)
6 (4.0) LEVOTHYROXINE SODIUM 2 (4.1) 0 (0.0) 2 (3.8) 4 (2.6)
THYROID HORMONES NOVOTHYRAL 1 (2.0) 0 (0.0) 0 (0.0) 1 (0.7) THYROID
0 (0.0) 1 (2.0) 0 (0.0) 1 (0.7) TONICS Any Preferred Term 1 (2.0) 0
(0.0) 0 (0.0) 1 (0.7) ROYAL JELLY 1 (2.0) 0 (0.0) 0 (0.0) 1 (0.7)
UNSPECIFIED HERBAL Any Preferred Term 2 (4.1) 1 (2.0) 0 (0.0) 3
(2.0) GINKGO BILOBA 1 (2.0) 0 (0.0) 0 (0.0) 1 (0.7) GLYCINE MAX
EXTRACT 0 (0.0) 1 (2.0) 0 (0.0) 1 (0.7) LINUM USITATISSIMUM SEED
OIL 2 (4.1) 0 (0.0) 0 (0.0) 2 (1.3) OENOTHERA BIENNIS OIL 1 (2.0) 0
(0.0) 0 (0.0) 1 (0.7) URINARY ANTISPASMODICS Any Preferred Term 0
(0.0) 1 (2.0) 0 (0.0) 1 (0.7) TOLTERODINE L-TARTRATE 0 (0.0) 1
(2.0) 0 (0.0) 1 (0.7) VITAMIN B-COMPLEX, PLAIN Any Preferred Term 0
(0.0) 1 (2.0) 0 (0.0) 1 (0.7) B-COMPLEX 0 (0.0) 1 (2.0) 0 (0.0) 1
(0.7) VITAMIN B12 (CYANOCOBALAMIN AND ANALOGUES) Any Preferred Term
2 (4.1) 0 (0.0) 0 (0.0) 2 (1.3) CYANOCOBALAMIN 1 (2.0) 0 (0.0) 0
(0.0) 1 (0.7) CYANOCOBALAMIN-TANNIN COMPLEX 1 (2.0) 0 (0.0) 0 (0.0)
1 (0.7) Note: Concomitant medications were coded using the WHO Drug
dictionary. A patient who took multiple medications is counted only
once in each row. Reference: 16.2.5.2
[1313] The present invention has been described with reference to
certain embodiments thereof. However, the scope of the invention is
not limited to the embodiments described or exemplified. Workers of
ordinary skill in the relevant arts will readily appreciate that
other embodiments and examples can be practiced without departing
from the scope of the present invention. All such variations are
considered to be part of, and therefore encompassed by, the present
invention.
[1314] All publications, patents and patent applications mentioned
or referenced in this specification are herein incorporated by
reference to the same extent as if each individual publication,
patent or patent application was specifically and individually
indicated to be incorporated by reference.
* * * * *