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`
`Azelastine nasal spray as adjunctive therapy to
`azelastine tablets in the management of seasonal
`allergic rhinitis
`EXHIBIT
`g~ (A It' 1'met1
`John M:Weiler, MD* and Eli 0 Meltzer, MDt
`(3
`
`Background: Azelastine rhinitis medications (nasal spray and tablets) have been
`shown to relieve the symptoms of allergic rhinitis. Nevertheless, many rhinitic
`subjects suffer from acute exacerbations of symptoms that sometimes require
`additional treatment.
`Objective: To assess the efficacy and safety of azelastine nasal spray as adjunc(cid:173)
`tive therapy to azelastine tablets in the management of symptomatic seasonal
`allergic rhinitis in subjects who remain symptomatic despite the oral medication.
`Methods: A 2-day, randomized, multicenter, double-blind, placebo-controlled,
`parallel-group study. Two hundred thirty-three subjects with symptomatic allergic
`rhinitis received azelastine tablets (0.5 mg bid) for a minimum of seven days prior
`to receiving either azelastine nasal spray (2 sprays per nostril bid) or placebo nasal
`spray as adjunctive therapy. Efficacy was determined by improvement in rhinitis
`symptoms that were grouped according to total and major symptom complex
`severity scores.
`Results: Mean percent improvements in the total symptom complex severity
`scores for azelastine were statistically significant (P :5 .05) or showed a trend
`toward statisticf!,l significance (.05 :5 P < .1 0) versus placebo from the second
`through the first ten hours after the initial dose and for each of the last five hours of
`the second day, demonstrating a rapid onset of action and sustained efficacy over the
`2-day study period. Azelastine was well tolerated, and no subject discontinued
`therapy with azelastine due to an adverse experience.
`Conclusion: Azelastine nasal spray can be effectively administered as adjunctive
`therapy, in an outdoor environment in which subjects are exposed to pollen and
`other aeroallergens.
`
`Ann Allergy Asthma Immunol 1997;79:327-32.
`
`INTRODUCTION
`Allergic rhinitis can be a debilitating
`disease when acute exacerbations of
`symptoms over a short period of time
`are not adequately controlled with rou(cid:173)
`tine daily oral medication. During pe(cid:173)
`riods of intense pollen exposure, many
`subjects require supplemental antial(cid:173)
`lergy therapy to alleviate symptoms
`befor:e they become severe. Adjunctive
`
`• Department of Internal Medicine, Iowa
`City, Iowa;
`tAilergy and Asthma Medical
`Group and Research Center, San Diego, Califor(cid:173)
`nia.
`Financial support for this project provided by
`Wallace Laboratories, Cranbury, NJ.
`Received for publication November 6, 1996.
`Accepted for publication in revised fonn Feb(cid:173)
`ruary 13, )997.
`
`therapy can be problematic if the sub(cid:173)
`ject is exposed to different classes of
`drugs, increasing the risk of adverse
`experiences, especially when the med(cid:173)
`ications are given systemically. In ad(cid:173)
`dition, adjunctive therapy with intrana(cid:173)
`sal steroids 1 or cromolyn2 may take
`days to weeks to be effective, and pro(cid:173)
`longed treatment with topical decon(cid:173)
`gestants may result in rebound conges(cid:173)
`tion.
`Azelastine, a phthalazinone deriva(cid:173)
`tive with a chemical structure unlike
`other antirhinitis drugs, is a multifunc(cid:173)
`tional antiallergic compound that an(cid:173)
`tagonizes the effects of chemical me(cid:173)
`diators released during the early-phase
`and late-phase allergic responses in the
`upper and lower airways.3•4 Oral and
`
`VOLUME 79, OCTOBER, 1997
`
`PLAINTIFFS'
`TRIAL EXHIBIT
`PTX0329
`
`topical formulations of azelastine have
`been evaluated in worldwide clinical
`trials for the treatment of allergic rhi(cid:173)
`nitis.
`In controlled clinical
`trials,
`azelastine administered topically as a
`0.1% nasal solution was well tolerated
`and effectively relieved rhinitis symp(cid:173)
`toms in subjects with allergic rhini(cid:173)
`tis. s-9 The results of the controlled tri(cid:173)
`als with
`azelastine
`tablets
`also
`demonstrate effective long-lasting re(cid:173)
`lief of symptoms of both seasonal and
`perennial allergic rhinitis. 10- 13
`This 2-day multicenter study was
`conducted in an outdoor environment
`(park) during the . falVautunin pollen
`season
`to maximize exposUre
`to
`aeroallergens and standardize as many
`variables as possible that could influ(cid:173)
`ence the outcome of the study. The
`objective of the study was to assess the
`efficacy and safety of azelastine nasal
`spray as adjunctive therapy to oral
`azelastine in the management of sub(cid:173)
`jects with symptomatic seasonal aller(cid:173)
`gic rhinitis who remain symptomatic
`despite treatment with 0.5 mg oral
`azelastine.
`
`METHODS
`Subjects
`All subjects were 12 years of age and
`older, had a history and diagnosis of
`seasonal allergic rhinitis, were symp(cid:173)
`tomatic to allergens prevalent at the
`time. the study was conducted; and re(cid:173)
`quired pharmacologic therapy each
`year for at least the preceding 2 years
`prior to enrollment in the study. Each
`subject demonstrated a significant re(cid:173)
`sponse to one or more of the common
`prevalent seasonal (grass in San Diego
`or ragweed in Iowa) allergens as con(cid:173)
`firmed by a recognized epicutaneous
`
`327
`
`PTX0329-0000 1
`
`1
`
`CIP2046
`Argentum Pharmaceuticals LLC v. Cipla Ltd.
`IPR2017-00807
`
`

`

`scratch or prick test within the past
`year.
`Subjects with histories of asthma
`were enrolled· if no chronic antiasthma
`medication had been taken within the
`past 24 months. Subjects with a history
`of exercise-induced asthma could be
`enrolled if only inhaled {3 agonists
`were used to treat their asthma. Fe(cid:173)
`males were postmenopausal, were doc(cid:173)
`umented as surgically incapable of
`conception or, if of childbearing poten(cid:173)
`tial, agreed not to become pregnant
`durmg·.the sttidy.
`·
`Subjects with a clinically significant
`nasal anatomical defonnity (ie, septal
`defects, polyps), an episode of acute
`sinusitis within 30 days of study entry,
`or subjects starting or changing an im(cid:173)
`munotherapy
`regimen during
`the
`course of the sttidy were excluded
`from participation. Additionally, sub(cid:173)
`jects were excluded for any abnormal
`prestudy laboratory test value or phys(cid:173)
`ical examination measurement that
`was considered to be clinically signif(cid:173)
`icant by the investigator and limiting to
`the conduct of the study.
`Prior to the screening visit, subjects
`were not permitted to use intranasal or
`ophthalmic steroids for 14 days or sys(cid:173)
`temic steroids for 30 days; intranasal
`or ophthalmi~ cromolyn, monoamine
`oxidase inhibitors, reserpine, or {3
`blockers for 14 days; decongestants for
`48 hours; or astemizole for 60 days.
`All subjects or their parents or
`guardians signed infonned consent
`statements, and the study protocol was
`approved by
`institutional
`review
`boards.
`Study Design
`This was a randomized, multicenter,
`double-blind, placebo-controlled, par(cid:173)
`allel-group study conducted in parks
`on two consecutive days during the
`fall/autumn grass season in California
`and ragweed season in Iowa. Subjects
`received azelastine tablets (0.5 mg bid)
`for a minimum of seven days prior to
`the double-blind
`treatment period.
`Aeroallergen data, obtained using a
`volumetric sampler, were recorded by
`the principal investigator during all
`evaluations conducted in the park.
`
`Table 1. Symptom Scoring Scale for the Individual Rhinitis Symptoms
`Symptom
`Scoring Scale
`
`Runny nose, left side
`R'unny nose, right side
`Sniffles
`Itchy nose, left side
`Itchy nose, right side
`Watery eyes
`Itchy eyes and ears
`Itchy throat
`Cough
`Postnasal drip
`Dry nose
`
`Nose blows
`Sneezes
`
`Stuffiness
`
`0 =None
`1 = A little, mild
`2 =Moderate
`3 = Quite a bit
`4 =Severe
`5 = Very severe
`
`G-5 = Actual number
`6 = 6 through 9
`7 = 10 through 15
`8 = Greater than 15
`
`0 = Clear, fully open
`1 = Slight block
`2 =Stuffy
`3 = Very stuffy
`4 =Blocked
`
`On the morning of the first study
`day, all subjects were instructed to take
`one tablet of azelastine at home at 7
`AM. Subjects arrived at the park before
`8 AM and recorded their baseline symp(cid:173)
`tom severity in diaries at 8 AM, 9 AM,
`and 10 AM prior to treatment. Subjects
`qualified for randomization to study
`treatment if the sum of the three hourly
`prestudy evaluations for the combined
`symptom-rated scores for nose blows,
`sneezes, itchy nose left side, itchy nose
`right side, runny nose left side, runny
`nose right side, dry nose, sniffles, post(cid:173)
`nasal drip, watery eyes, itchy eyes and
`ears, itchy throat, and cough was 12 or
`more (based on the scoring scale de(cid:173)
`scribed in Table 1 ).
`Qualified subjects were randomized
`to receive either azelastine nasal spray
`(2 sprays each nostril bid) or placebo
`(saline) nasal spray (2 sprays each nos(cid:173)
`tril bid) as adjunctive therapy to their
`low-dose azelastine tablet regimen.
`The total daily dose of azelastine ad(cid:173)
`ministered (in 2 sprays per nostril
`twice a day) was 1.10 mg. Subjects
`took the first dose of study medication
`at 10 AM: (Fig 1).
`After the initial dose of study med(cid:173)
`ication, symptom scoring diary cards
`
`were completed by each subject for the
`next six hours (11 AM to 4 PM) while in
`the park. Subjects were allowed to
`leave the park after recording symp(cid:173)
`toms on the 4 PM diary card. They
`continued to complete the symptom
`scoring diary cards at 6 PM, 8 PM, and
`10 PM at home. At 7 PM, each subject
`took the second dose of oral aielastirie
`and, at 10 PM, subjects took their sec(cid:173)
`ond intranasal dose of study medica(cid:173)
`tion immediately after completing the
`diary card for that hour.
`On the second day, each subject
`took the first dose of oral azelastine at
`7 AM at home and returned to the park
`between 7:30AM and 8 AM, where they
`resumed rating their symptoms l).ourly
`on the symptom scoring diarY cards.
`Following the 10 AM evaluation, sub(cid:173)
`jects took the third and fmal intranasal
`dose of study medication and contin(cid:173)
`ued to rate symptoms on their diary
`cards until 4 PM. Subjects received a
`follow-up physical examination and
`laboratory evaluation within seven
`days of the second study day.
`Response Measurements
`The primary efficacy variables were
`the total and major symptom complex
`
`328
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`ANNALS OF ALLERGY, ASTHMA, & IMMUNOLOGY
`
`PTX0329-00002
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`2
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`

`

`DAY 1
`
`BASELINE 1 PERIOD 1
`,L,
`or--.-..1..1 --.1
`<·-·········PARK·············>
`I I i i i i i i i i
`
`123456
`11 12 ;1 2 3 4
`i
`· 1st Dose of
`Nasal Spray
`
`STUDY HOUR -3 ·2 ·1 0
`TIME OF DAY .t7 6 9 10
`
`DOUBLE-BLIND
`I
`PERIOD2
`I
`I
`I
`<····HOME····>
`
`DAY2
`
`PERIOD 4 1
`
`•
`
`•
`
`t
`
`•
`
`I
`
`o
`
`I i I i I i
`1 2nd Dose of 1
`
`7 6
`5 6
`
`9 10 11 12
`7 6 9 10i
`
`Nasal Spray
`
`PERIOD 3
`r--1---1
`<············PARK·············>
`I i i i
`I I I I I I
`
`21 22 23 24
`.t 7 8 9 10
`
`25 26 27 28 29 30
`11 12 *1 2 3 4
`i
`Srd Dose of
`Nasal Spray
`
`treatment at each evaluation period,
`and an endpoint analysis, based on
`each subject's last observation period
`during double-blind treatment, were
`performed. For each of the evaluation
`periods, the symptom complex sever(cid:173)
`ity scores were calculated based on the
`sum of the hourly severity scores. Im(cid:173)
`provements in the total and major
`symptom complex severity scores
`were analyzed in terms of percent
`change from baseline, and the individ(cid:173)
`ual symptoms were analyzed in terms
`of absolute change from baseline.
`The
`improvements
`in
`the
`total
`symptom complex, major symptom
`complex, and individual rhinitis symp(cid:173)
`tom scores during double-blind treat(cid:173)
`ment were evaluated by an analysis of
`covariance (ANCOV A) model, incor(cid:173)
`porating terms for treatment and cen(cid:173)
`ter, with the baseline value as the co(cid:173)
`variate. Treatment differences for the
`global evaluation were analyzed by the
`Cochran-Mantel-Haenszel test (adjust(cid:173)
`ing for investigator effect).
`The proportions of subjects with the
`most frequently reported adverse.expe(cid:173)
`riences across the treatment groups
`were analyzed by chi-square tests. The
`changes from baseline to the end of
`treatment for each clinical laboratory
`test and the mean change from baseline
`for vital sign measurements and body
`weight were analyzed by the two-fac(cid:173)
`tor ANOV A model,
`incorporating
`
`Dose of
`Doseol
`Dose of
`Oral Azelastine
`Oral Azelastine
`Oral Azelas1ine
`Figure 1. Schematic design of the study. "' = symptom scoring, tAM, and tPM.
`
`severity scores. Scores for eight rhini(cid:173)
`tis symptoms (runny nose left side,
`runny nose right side, sniffles, itchy
`nose left side, itChy nose right side,
`sneezes, nose blows, and watery eyes)
`were summed to form the major symp(cid:173)
`tom complex severity score and scores
`for five additional rhinitis symptoms
`(postnasal drip, cough, dry nose, itchy
`throat, and itchy eyes and ears) were
`summed with the major symptom com(cid:173)
`plex severity score to form the total
`symptom complex severity score (Ta(cid:173)
`ble 1). The secondary efficacy vari(cid:173)
`ables were the total symptom complex
`severity score with
`the additional
`symptom of stuffmess, the individual
`rhinitis symptom scores, and subject
`global evaluations. Safety evaluations
`consisted of vital sign measurements,
`physical examination fmdings, clinical
`laboratory test values, and adverse ex-
`perience . reports.
`. .
`·
`. .
`.·
`For the purpose of the efficacy anal(cid:173)
`yses, the 2-day, double-blind, treat(cid:173)
`ment period was divided into five sep(cid:173)
`arate periods including baseline (Fig
`1 ). The total duration of the double(cid:173)
`blind period was 30 hours. The base(cid:173)
`line period is the average of the three
`hours prior to the first intranasal dose
`taken at the park. Period 1 is the aver(cid:173)
`age qf the first six hours (11 AM to 4
`PM) after the first intranasal dose. Pe(cid:173)
`riod 2 is the average of the three hourly
`evaluations at 6 PM, 8 PM, and 1 0 PM, 8
`to 12 hours after the first intranasal
`dose and prior to receiving the second
`intranasal dose. Period 3, the following
`morning, is the average of the three
`hourly evaluations at 8 AM, 9 AM, and
`
`10 AM just prior to the third dose of
`study medication (at 10 AM). Period 4
`is the average of the six hours (11 AM
`to 4 PM) following the third dose of
`study medication. All periods, except
`period 2, were conducted in a park.
`
`Statistical Methods
`Pretreatment baseline comparability of
`the treatment groups for each efficacy
`variable was determined by a two-way
`analysis of variance (ANOV A) model,
`incorporating terms for treatment, cen(cid:173)
`ter, and their respective interaction.
`The treatment effect at each evalua(cid:173)
`tion period and at each of the 18 spec(cid:173)
`ified assessment points was analyzed
`for each of the efficacy variables. In
`addition, an overall
`intent-to-treat
`analysis, based on averages of all
`available subject-response data during
`
`Table 2. Demographic and Baseline Characteristics
`
`Treatment
`(Azelastine, 0.5 mg PLUS)
`
`Age, yr
`Mean
`Range
`Sex,%
`Male
`Female
`Race,%
`White
`Other
`Weight, lb
`Mean
`Range
`Mean baseline scores
`Total symptom complex
`Major symptom complex
`
`Azelastine
`Nasal Spray
`N = 116
`
`Placebo
`Nasal Spray
`N::: 117
`
`27.4
`12-73
`
`53
`47
`
`91
`9
`
`157.9
`92-272
`
`16.9
`10.7
`
`30.5
`12-64
`
`54
`46
`
`89
`11
`
`163.4
`91-259
`
`18.2
`11.2
`
`VOLUME 79, OCTOBER, 1997
`
`329
`
`PTX0329-00003
`
`3
`
`

`

`3Sr-------------------------------------------.
`AzelasUne 0.5 mg + AzelllBtine 2 sprays b.l.d.
`-
`~ AulOBtinc 0.5 mg + Plllcebc 2 spmys b.ld.
`* P<.OS
`
`Period 1
`
`Period 2
`
`Period 3
`
`Perlod4
`
`Endpoint
`
`Figure 2. The mean percent improvement from baseline in the total symptom complex severity scores
`at each period and at endpoint.
`
`ward statistical significance (P = .061)
`in favor of azelastine.
`The mean percent improvements in
`the total symptom complex severity
`scores for each treatment group at the
`18 specified hourly evaluations during
`the double-blind treatment period are
`shown in Figure 3. At hours 2 through
`6 and hours 27 and 30; the· differences
`in
`the
`improvement between
`the
`
`azelastine group and the placebo group
`were statistically significant (P :5 .05)
`in favor of azelastine and showed a
`trend toward statistical significance
`(P :5 .10) at hours 8, 10, 24, 26, 28,
`and 29. The azelastine group had clin(cid:173)
`ically significant mean per~ent im(cid:173)
`provements in the total symptom com(cid:173)
`plex severitY scores at hours 2 through
`10 and hours 23 through 30.
`
`40 -Aulattlne 0.5 m,g + AulasijJIO 2 opmy1 b.i:d.
`
`IS.:SI AuluUne O.S mg +Placebo 2 opmy• b.Ld.
`*
`•
`
`*
`
`•
`
`tl
`II
`
`I
`
`*
`
`+
`
`t
`
`~
`
`~
`
`I I
`
`I
`
`~5
`
`35
`
`30
`
`1:
`CD
`E
`~
`
`2S K 20
`
`IS
`
`.§
`1:
`~
`~ 10
`fii
`s
`CD
`~ 0
`-s
`
`-lO
`
`•
`
`t
`
`P< .OS
`.M< PSI
`+ •
`
`t
`
`•
`
`+
`
`t
`
`L .,
`
`"ti
`L__jl
`Period 3
`PARK
`
`od4 Peri
`
`PARK
`
`I
`)21 22 23 24 25 26 27 28 29 30
`
`Buclino
`PARK
`
`- 15
`) - 3 -2 - 1 0
`(HoursF
`
`Azelasle O.S mg t
`
`Period 2
`Period I
`HOME
`PARK
`I
`I 2 3 4 s 6 7 8 9 10 11 121
`
`M.elaadt.e O.S mg t M.elao~o 0.!1 mg f
`
`terms for treatment, center, and center(cid:173)
`by-treatment interaction. The level of
`significance for all statistical tests was
`set at .05. All treatment comparisons
`utilized two-sided tests. A clinically
`significant improvement was defined
`as a mean improvement with azelastine
`nasal spray that was at least 50%
`greater than that observed with placebo
`nasal spray.
`
`RESULTS
`thirty-three subjects
`Two hundred
`were randomized to the double-blind
`phase of the study, and 228 completed
`the study. Treatment groups were sim(cid:173)
`ilar at baseline with regard to demo(cid:173)
`graphic characteristics and the total
`and major. symptom complex severity
`scores (Table 2). Of the five subjects
`who did not complete the study, two in
`the placebo group developed intercur(cid:173)
`rent illness, one in each group failed to
`return to the park on the second day,
`and one in the azelastine group failed
`to take the medicine in the evening of
`the first study day. All 233 subjects
`were included in the intent-to-treat
`analyses . .
`Pollen counts, temperature, and hu(cid:173)
`midity were typical for the fall allergen
`season during the 2-day study at each
`site.
`Primary Efficacy Variables
`In this study, the azelastine group had
`improvements in the total symptom
`complex severity score that were supe(cid:173)
`rior to thos~ for the placebo group at
`every evaiuation period (Fig 2). At pe(cid:173)
`riods 1 and 4, the mean percent im(cid:173)
`provements for the azelastine group
`were clinically and statistically signif(cid:173)
`icant (P :5 .041) versus placebo. In
`addition, the results of the endpoint
`analyses showed statistically signifi(cid:173)
`cant (P ==
`.043) mean percent im(cid:173)
`provement for the azelastine group
`when comp·ared· with
`the placebo
`group. The difference in the overall
`mean percent improvement in the total
`symptom complex severity score and
`the total symptom complex severity
`score including the additional symp(cid:173)
`tom of stuffiness showed a trend to-
`
`Sludy Medication
`
`Study Medication
`
`Sludy Medlcotlnn
`
`Figure 3. The mean percent improvement from baseline in the total symptom complex severity scores
`at each hour during the double-blind treatment period.
`
`330
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`ANNALS OF ALLERGY, ASTHMA, & IMMUNOLOGY
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`PTX0329-00004
`
`4
`
`

`

`Azclasllne o.s ma + Azcwlloo 2 sprays b.i.d.
`•
`~ Azclastlne 0.5 mg + Plucebo 2 aprays b.i.d.
`
`Figure 4. The mean percent improvement from baseline in the major symptom complex severity
`scores at e.a~h period and at endpoint.
`
`For the major symptom complex se(cid:173)
`verity score, the mean percent im(cid:173)
`provements for the azelastine group
`were clinically significant compared
`with those for the placebo group at
`each period (Fig 4). At periods I and 4,
`the azelastine group had the highest
`mean percent improvements (27 .I%
`and 27.4%, respectively) compared
`with those for the placebo group
`(-0.7% and -3.9%, respectively). In
`addition, at each of the specified
`hourly evaluations during the 30-hour,
`double-blind,
`treatment period,
`the
`azelastine group had mean percent im(cid:173)
`provements in the major symptom
`complex severity score that were greater
`than the improvements for the placebo
`group. These differences from placebo
`showed a trend toward statistical signif-
`
`icance (P ~ .095) at hours 3, 4, 5, 27,
`and 30 and were clinically significant at
`each hour, except hour 12.
`
`Secondary Efficacy Variables
`The overall improvements for the in(cid:173)
`dividual rhinitis symptoms of nose
`blows, sneezes, sniffles, postnasal drip,
`itchy eyes and ears, itchy nose, and
`runny nose for the azelastine group
`were superior to those for the placebo
`group. For sniffles and itchy eyes and
`ears, the differences from placebo
`were statistically significant (P < .05)
`and showed a trend toward statistical
`significance (P = .07) for postnasal
`drip. The subject global evaluations of
`the overall drug effect showed that
`64% of the subjects in the azelastine
`group rated their response as improved
`versus 59% in the placebo group.
`
`Table 3. Number and Percentage of Patients Who Reported Adverse Experiences During the
`Double-Blind Phase of the Study (.5% Incidence in Any Treatment Group)
`
`Adva.-'se Experience
`
`Number (%} of Patients
`
`Azelastlne Nasal Spray
`
`Placebo Nasal Spray
`
`18 (15.5)
`Headache
`15 (12.9)
`Taste perversion
`8 (6.9)
`Nasal burning
`6 (5.2)
`Somnolence
`• P < .05: placebo versus azelastine groups.
`
`19 (16.2)
`1 (0.9)*
`2 (1.7)*
`3 (2.6}
`
`Safety
`The most frequently reported adverse
`experiences during the double-blind
`phase of the study are presented in
`Table 3. Subjects in the azelastine
`group reported taste perversion and na(cid:173)
`sal burning significantly more fre(cid:173)
`quently than those in the placebo
`group. For the majority of the subjects,
`the altered taste sensation was· due to
`the bitter taste of the medication itself
`and was of very short duration. The
`episodes of nasal burning were mild
`and transient, were related to the use of
`the nasal spray, and began immedi(cid:173)
`ately after administration. In addition,
`they did not affect the ability of the
`subject to complete the study. No sub(cid:173)
`je(,:t in the azelastine group discontin(cid:173)
`ued therapy due to an adverse experi(cid:173)
`ence. There were no .· clili.ically
`meaningful mean changes in .labora(cid:173)
`tory test values, vital sign measure(cid:173)
`ments, or physical examination find(cid:173)
`ings associated with
`the use of
`azelastine.
`
`DISCUSSION
`Adjunctive
`therapy with different
`classes of drugs is often used ' in the
`management of allergic rhinitis, when
`routine medication does not satisfacto(cid:173)
`rily control symptoms. In this study,
`adjunctive therapy with azelastine 2
`sprays twice a day demonstrated clin(cid:173)
`ically significant improvements in the
`severity of rhinitis symptoms during
`each treatment period and statistically
`significant improvements during the
`periods immediately followitig admin(cid:173)
`istration of azelastine nasal spray (pe(cid:173)
`riods 1 and 4). Because both treatment
`groups received a dose of azelastine
`tablets during the second and third pe(cid:173)
`riods, the lack of statistical signifi(cid:173)
`cance versus placebo at these evalua(cid:173)
`tion points may have been due to the
`timing that the treatment groups re(cid:173)
`ceived the oral . medication, ·Although
`not statistically significant at periods2
`and 3, subjects treated with adjunctive
`azelastine nasal spray experienced
`greater improvements in their rhinitis
`symptoms than subjects treated with
`placebo.
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`Th~ addition of azelastine nasal
`spray to oral azelastine resulted in a
`more rapid relief of symptoms than
`would be expected with the addition of
`topical steroid or cromolyn nasal prep(cid:173)
`arations. 1•2 This was demonstrated by
`the clinically and statistically signifi(cid:173)
`cant differences from placebo that
`were achieved by the second hour after
`nasal spray administration. In contrast,
`the clinical response to .corticosteroids
`or croniolyn would not be expected for
`many hours and sometimes for days.
`Additionally, treatment with intranasal
`azelastine would not be expected to
`cause rebound congestion that is com(cid:173)
`mon with topical nasal decongestants
`when used for a prolonged time. The
`additional benefit of azelastine nasal
`spray would be expected to continue
`for even a longer duration than this
`study because the nasal spray has dem(cid:173)
`onstrated efficacy in studies of up to 4
`weeks. 9
`Superimposed on a background of
`active
`antirhinitis
`treatment
`(oral
`azelastine ), intranasal azelastine dem(cid:173)
`onstrated an overall improvement in
`the total and major symptom complex
`severity scores that was supported by
`improvements in · in<;iividual symptom
`scores. It should be noted that this
`study was not designed to determine if
`azelastine nasal spray is more effica(cid:173)
`cious than azelastine, 0.5-mg tablets,
`or the efficacy of azelastine mono(cid:173)
`therapy for seasonal allergic rhinitis.
`In this study, both oral and intrana(cid:173)
`sal azelastine were well tolerated. The
`most frequently reported adverse expe(cid:173)
`riences were headache and taste per(cid:173)
`version, probably caused 'by the bitter
`taste of the medication.
`
`In conclusion, this study demon(cid:173)
`strates that even in an outdoor environ(cid:173)
`ment, in which subjects are exposed to
`pollen and other aeroallergens, azelas(cid:173)
`tine nasal spray can be effectively ad(cid:173)
`ministered as adjunctive therapy for
`patients with seasonal allergic rhinitis.
`
`REFERENCES
`I. Orgel HA, Meltzer EO, Kemp JP, eta!.
`Comparison of intranasal cromolyn so(cid:173)
`dium, 4%, and oral terfenadine for al(cid:173)
`lergic rhinitis: symptoms, nasal cytol(cid:173)
`ogy, nasal ciliary clearance and
`rhinomanometry. Ann Allergy 1991;
`66:237-44.
`2. Meltzer EO, Orgel HA, Bronsky EA,
`et a!. A dose-ranging study of flutica(cid:173)
`sone propionate aqueous nasal spray
`for seasonal allergic rhinitis assessed
`by symptoms, rhinomanometry, and
`nasal cytology. J Allergy Clin Immu(cid:173)
`nol 1990;86:221-30.
`3. Perhach JL, Chand N, Diamantis W, et
`a!. Azelastine: a novel oral anti-asthma
`compound with several modes of ac(cid:173)
`tion. In: Kay AB, ed. Allergy and
`asthma: new trends and approaches to
`therapy. Oxford: Blackwell Scientific
`Publications 1989:230-48.
`4. Perhach JL, Connell JT, Kemp JP.
`Treatment of upper and lower airway
`disease with azelastine. N Eng! Reg
`Allergy Proc 1987;8:121-4.
`5. Meltzer EO, Weiler JM, Dockhorn RJ,
`et a!. Azelastine nasal spray in the
`management of seasonal allergic rhini(cid:173)
`tis. Ann Allergy 1994;72:354-9.
`6. Storms WW, Pearlman DS, Chervin(cid:173)
`sky P, et a!. Effectiveness of azelastine
`nasal solution in seasonal allergic rhi(cid:173)
`nitis. Ear Nose Throat J 1994;73:
`382-94.
`7. Weiler JM, Meltzer EO, Benson PM,
`
`et a!. A dose-ranging study of the ef(cid:173)
`ficacy and . safety of azelastine nasal
`spray in the treatment of seasonal ai(cid:173)
`lergic rhinitis with an acute model. J
`Allergy Clin Immunol 1994;94:
`972-80.
`8. Ratner PH, Findlay SR, Hampel F Jr,
`et al. A double-blind, controlled trial to
`assess the safety and efficacy of
`azelastine nasal spray in seasonal aller(cid:173)
`gic rhinitis. J Allergy Clin Immunol
`1994·94:818-25.
`. ..
`9. Laforce C, Dockhom RJ,.Pre.rtnerBM,
`et aJ. Safety and efFicacy of azelastirie
`nasal spray (Astelin NS) for seasonal
`allergic rhinitis: a 4-week comparative
`multicenter trial. Ann Allergy Asthma
`Immunol 1996;76:181-8.
`10. Weiler JM, Donnelly A, Campbell BH,
`et a!. Multicenter, double-blind, multi(cid:173)
`ple-dose, parallel-groups efficacy and
`safety trial of azelastine, chlorphenira(cid:173)
`mine, and placebo in the treatment of
`spring allergic rhinitis. J Allergy Clin
`Immunol 1988;82:801:-"11.
`11. Meltzer EO, Storms WW, Pierson WE,
`et al. Efficacy of azelastine in peren(cid:173)
`nial allergic rhinitis: clinical and rhi(cid:173)
`nomanometric evaluation. J Allergy
`Clin Immunol 1988;82:447-55.
`12. Grossman J, Halverson PC, Meltzer
`EO, et al. Double-blind assessment of
`azelastine in the treatment of perennial
`allergic rhinitis. Ann Allergy 1994;73:
`141-6.
`.
`.
`.
`13. Meltzer EO, Halverson PC, Banov
`CH, et a!. The effectiveness of oral
`azelastine in the management of peren(cid:173)
`nial allergic rhinitis. Am J Rhino!
`1994;8:323-8.
`
`Request for reprints should be addressed to:
`John M Weiler, MD
`Department of Internal Medicine
`200 Hawkins Drive
`Iowa City, Iowa 52242-1081
`
`332
`
`ANNALS OF ALLERGY, ASTHMA, & IMMUNOLOGY
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