Case 1:14-cv-01453-LPS Document 48-3 Filed 11/23/15 Page 1 of 4 PageID #: 1648
`Case 1:14—cv—O1453—LPS Document 48-3 Filed 11/23/15 Page 1 of 4 PagelD #: 1648
`Azelastine nasal spray for the treatment of allergic 8: nonallergic rhinitis
`
`|
`
`nonallergic rhinitis [15]. A total of 4364 patients were treated
`with azelastine nasal spray (two sprays per nostril twice daily)
`for 2 weeks. Overall, 90% of SAR patients reported some or
`complete control of the symptom of sneezing and 78% of VMR
`patients reported an improvement in their postnasal drip. Of
`patients reporting sleep difficulties or impaired daytime activities
`owing to rhinitis symptoms, 85% experienced improvements in
`these parameters with azelastine therapy.
`
`Azelastine versus oral antihistamines
`
`Azelastine nasal spray is more effective and has a more rapid onset
`of action compared with oral antihistamines in the treatment of
`AR [16,17,24—26], and is effective in those AR patients who had an
`inadequate response to oral antihistamine therapy [13,14]. In addi—
`tion, azelastine nasal spray significantly reduces nasal congestion,
`a particularly bothersome symptom for rhinitis sufferers, without
`causing a sedative effect.
`
`Comparisons with other agents used to treat AR
`Allergic rhinitis is a disease with a complex pathophysiology.
`Therefore, several classes of drugs are available to treat it: oral
`antihistamines (e.g., desloratadine [Clarinex®, Schering Plough,
`USA] and cetirizine [Zyrtec®, Pfizer, USA]), intranasal corti—
`costeroids (e.g., fiuticasone propionate [Flonase®, GSK, USA]
`and mometasone furoate [Nasonex®, Schering Plough, USA]),
`intranasal mast cell stabilizers (e.g., nedocromil [Tilade®, King
`Pharmaceuticals, USA] and cromoglycate [Chromohexal®, Hexal
`Pharma, South Africa]), as well as other intranasal antihistamines
`
`(e.g., levocabastine [Livostin®, ]ansen—Cilag, N], USA]).
`The number needed to treat (NNT) estimates the number of
`
`patients that must be treated with a particular drug in order to
`have one positive outcome. As such, it is a useful tool to compare
`the efficacy of treatments available for the treatment of rhinitis.
`It is preferable for a drug to have a low NNT, as less patients
`would need to be treated before one positive outcome occurred.
`Limited evidence due to the usage of only a single trial for each
`drug was reported by Portnoy and colleagues, estimating the
`NNT ranges as 5-6.3 for azelastine, 3-6
`for intranasal corticosteroids and 4.6 for
`
`Azelastine versus desloratadine
`
`Desloratadine is a new, third—generation antihistamine tablet, which,
`unlike its second—generation counterparts, is thought to reduce
`nasal congestion, be nonsedating and not cause cardiac side effects.
`However, azelastine nasal spray (one spray per nostril) has been
`shown to be significantly better than desloratadine tablets (5 mg)
`in reducing the symptoms of SAR, including congestion, induced
`by allergen challenge in the Vienna Challenge Chamber (FIGURE 5)
`[18]. However, azelastine nasal spray and desloratadine tablets both
`significantly (p < 0.001) reduced nasal symptoms compared with
`placebo. Azelastine nasal spray was also superior to desloratadine
`tablets in alleviating nasal congestion, a_n unexpected result since
`second—generation antihistamines have little decongesta_nt activity.
`Furthermore, Azelastine nasal spray showed a much more
`rapid onset of action compared with desloratadine tablets (15 vs
`150 min). Almost three—quarters of patients rated azelastine as at
`least ‘satisfactory’ compared with 55.6% for desloratadine and just
`24.4% for placebo [18]. Others have confirmed this rapid onset of
`action of azelastine nasal spray [27]. The slow onset of action of
`
`20 (8.3 to ~ to 50)
`
`NNT (95% Cl)
`
`250 (9.1 to ~ to 8.3)
`
`14.3 (2.6 to ~ to 3.8)
`
`7.1 (2.7 to ~ to 12.5)
`
`10,000 (8.3 to ~ to 8.3)
`
`14.3 (4.2 to ~ to 10)
`
`5(2to~to11.1)
`
`Author
`_
`Passah
`Gambardelle
`
`C°“°'° H°'”""“°'°Z
`Gastpaf
`Gastpar
`
`Charpln
`
`Overall (95% Cl)
`
`immunotherapy, compared with 9-35 for
`oral antihistamines [23].
`
`A more recent meta—analysis system—
`atically reviewed 21 separate publications
`examining the efficacy of azelastine nasal
`spray compared with other intranasal treat—
`ments (e.g., beclomethasone [Beconase®,
`GSK, USA] and budesonide [Rhinocort®,
`AstraZeneca, USA]), and levocabastine
`and oral preparations (e.g., loratadine,
`terfenadine [Seldane®, Sanofi Avent1s,
`USA], cetirizine and ebastine [Kestine®,
`Pharmacare, USA]) [24] . The results showed
`that azelastine was more efficacious than
`
`placebo with a summary NNT of 5.0 but
`there was no statistical difference between
`
`the efficacy of azelastine nasal spray and
`any of the active comparators [24] . However,
`when the analysis was limited to studies
`in which an oral allergy treatment was
`the comparator, the point estimate of the
`pooled results favoured azelastine nasal
`spray (FIGURE 4). The results were consistent
`across SAR and nonallergic rhinitis, and
`across trials of different durations.
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`WWW.CXp Cf[—fCVlCWS. COH1
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`2
`
`5
`
`107 105
`
`2
`
`Fixed effects model; no
`significant heterogeneity
`
`NNT (favors azelastine)
`
`NNT (favors comparator)
`
`Figure 4. Number needed to treat: a global assessment of efficacy as an
`outcome for azelastine nasal spray compared with oral agents for the treatment
`of allergic rhinitis.
`~: Crossing the middle line between favoring aze|astine—tavoring comparator;
`Cl: Confidence interval; NNT: Number needed to treat.
`Reprinted with permission from [24].
`
`663
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`Case 1:14-cv-01453-LPS Document 48-3 Filed 11/23/15 Page 2 of 4 PageID #: 1649
`Case 1:14—cv—O1453—LPS Document 48-3 Filed 11/23/15 Page 2 of 4 Page|D #: 1649
`Horak 8: Zieglmayer
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`superior to oral cetirizine (10 mg) in
`terms of improvement in overall RQLQ
`score (p < 0.05) [16]. A combined analysis
`of both studies confirmed the significant
`superiority of azelastine spray both in terms
`of the overall RQLQ score (p < 0.001) as
`well as each of the RQLQ domain scores
`(p < 0.03), including the nasal symptoms
`domain (p < 0.001). Berger and colleagues
`produced similar results (FIGURE 6) [28].
`
`Nonresponders
`
`As many as 20% of all AR patients do not
`respond to oral H1 blockers at all [14]. These
`nonresponders have been shown to be sensi—
`tive to therapy with azelastine nasal spray. For
`example, patients with moderate—to—severe
`AR who had asuboptimal response to lorata—
`dine showed significant symptom improve—
`ment following treatment with azelastine
`monotherapy or azelastine plus loratadine
`compared with placebo (p < 0.001) [14].
`Another study showed similar results in
`patients who had an inadequate response
`to fexofenadine treatment for 1 week [15].
`
`
`
`5
`
`-0- Placebo
`
`-0- Azelastine
`—i:i— Desloratadine
`
`
`
`Studydrugadministration
`
`
`
`
`
`
`
`Majornasalsymptomscore
`
`0
`
`30
`
`60
`
`90
`
`120
`
`150
`
`180
`
`210
`
`240
`
`270
`
`300
`
`330
`
`360
`
`Min
`
`Figure 5. Major nasal symptom scores averaged over treatment and time for the
`per protocol population following administration of azelastine (one spray per
`nostril), desloratadine (5 mg) or placebo in patients with seasonal allergic rhinitis.
`Reprinted with permission from [18].
`
`desloratadine reported by Horak and colleagues may have been
`due to the encapsulation of the tablets for the purpose of study
`blinding, and/ or due to the fact that symptoms were allowed to
`develop for 2 h before study medication was delivered [18].
`
`Azelastine versus cetirizine
`
`Cetirizine hydrochloride is an oral, second—generation antihista—
`mine indicated for the treatment of both SAR and perennial AR.
`Corren at LIZ. examined the effectiveness and tolerability of azelas—
`tine (two sprays per nostril) and cetirizine tablets (10 mg once
`daily) over a period of 2 weeks in 307 patients with moderate—to—
`severe SAR [25]. Compared with cetirizine, azelastine nasal spray
`significantly (p = 0.015) improved nasal symptoms and patients’
`HRQOL (p = 0.049) as assessed by the RQLQ [25]. In a second
`study with identical methodology, azelastine improved the nasal
`symptoms, with a significant improvement observed for nasal
`congestion (p = 0.049) and sneezing (p = 0.01) [28], as well as
`HRQOL (p = 0.002), compared with cetirizine [28]. Pooled data of
`both trials showed significant results for all nasal symptoms [26].
`The positive effect of azelastine nasal spray on congestion was
`observed, despite the fact that the cetirizine group had the added
`benefit of daily use of a placebo saline spray [28].
`The effect on nasal congestion is an important property of
`azelastine nasal spray; in a large open—label trial of 4000 patients
`with SAR, nasal congestion was reported as the most bothersome
`rhinitis symptom by 52% of patients [15].
`Impairment of HRQOL is a major complaint of rhinitis suf—
`ferers. Results from two 2—week studies showed that azelastine
`
`nasal spray (two sprays per nostril twice daily) was significantly
`
`Therefore, monotherapy with azelastine
`nasal spray may be a useful treatment option in patients who have
`developed resistance to prior oral antihistamine therapy [20].
`
`Azelastine versus intranasal corticosteroids
`
`Azelastine nasal spray has many advantages over intranasal cor—
`ticosteroids, despite having a weaker anti—infiammatory effect. It
`has a faster onset of action [27], whereas intranasal corticosteroids
`
`develop a maximum benefit over days or even weeks [21], necessi—
`tating the need to begin treatment before the onset of symptoms
`in order to obtain optimal benefit from therapy. Furthermore,
`a better safety profile is given for local application forms [27,28].
`
`Azelastine versus fluticasone propionate
`In a study with both allergic and nonallergic rhinitis sufferers,
`azelastine nasal spray (two sprays per nostril twice daily; 1.1 mg)
`showed comparable efficacy to fiuticasone propionate nasal spray
`(two sprays per nostril daily; 200 pg) in improving patients’ RQLQ
`scores (FIGURE 7) and rhinitis symptoms [29] . Additional effects can be
`reached with a combination of azelastine and intranasal fiuticasone
`
`propionate [30,31]. Ratner, for example, reported that the combina—
`tion of both substances improved nasal symptoms by 37.9 % com—
`pared with 27.1 and 24.8% with fiuticasone and azelastine nasal
`spray, respectively (p < 0.05 vs either agent alone) [30].
`
`Azelastine versus mometasone furoate
`The fast onset of action of azelastine is also shown when com—
`
`pared with mometasone furoate, a modern nasal steroid with
`an onset of 12-72 h. An environmental exposure chamber trial
`showed no effect of the steroid on nasal symptoms within the
`
`664
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`Azelastine nasal spray for the treatment of allergic 8: nonallergic rhinitis
`
`first 8 h after intake [27], whereas the benefit of azelastine was
`
`seen within 15 min and persisted at each time point throughout
`the 8—h allergen challenge.
`
`treatment of SAR in terms ofnasal symptom relief, improvement in
`nasal inspiratory flow, global evaluation of efficacy a_nd reduction
`in eosinophil cationic protein concentration [34].
`
`Azelastine versus intranasal mast cell stabilizers
`
`Azelastine versus intranasal Ievocabastine
`
`Mast cell stabilizers (e.g., nedocromil and cromoglycate), as the
`name suggests, block the release of mediators from mast cells.
`They are most frequently used when other drugs, such as anti—
`histamines or topical corticosteroids, are ineffective or not well
`tolerated. Frequent dosing (three—to—siX—times per day) is required
`for improvement of allergy symptoms and patients need to begin
`treatment before allergen contact [32]. In general, symptoms are
`reduced within 3-7 days of daily use, but the full effect may not
`be seen for 2-4 weeks. However, owing to the favorable safety
`profile, mast cell stabilizers are recommended for young children,
`pregnant women and the elderly for the treatment of allergy symp—
`toms. Cromolyn sodium (4%) nasal solution (one spray per nostril
`every 4-6 h for 2 weeks) was superior to placebo in controlling
`allergy symptoms, providing overall symptom relief, and relieving
`sneezing and nasal congestion in self—selected patients with AR [33].
`However, disodium cromoglycate (5.6 mg four—times daily) was
`inferior to the intranasal corticosteroid mometasone furoate in the
`
`Levocabastine is a potent and selective histamine 1-l1—receptor a_ntago—
`nist. It has been shown to reduce a hyper—reactive response after nasal
`provocation with hypotonic aerosol in patients with AR [35]. The
`efficacy and tolerability of levocabastine and azelastine nasal spray
`was compared in a 4—week study in 180 patients suffering from AR.
`Azelastine nasal spray (1.12 mg, two sprays twice daily) was signifi—
`cantly superior at reducing both morning and evening nasal symp—
`toms compared with levocabastine (0.4 mg, two sprays twice daily;
`p < 0.001) [36]. Global efficacy was indicated very good or good by
`90% of doctors and 92% ofpatients, respectively, for azelastine and
`74% of doctors and 76% of patients, respectively, for levocabastine.
`
`Safety & tolerability
`Drugs delivered intranasally have a lower risk of causing sys—
`temic side effects and interacting with other drugs [37]. NDA
`studies have shown that azelastine nasal spray is safe and well
`tolerated for up to 4 weeks’ treatment in both adults and children
`
`2
`
`1-5
`
`1
`
`0.5
`
`0
`
`I Azelastine nasal spray I Cetirizine
`
`*
`
`ti
`
`t
`
`1
`
`.
`
`
`
`.2
`Eon
`cc
`.9
`
`E2
`
`‘ti
`EG.)
`
`> 21
`
`:.
`.§C
`:5
`iv
`5
`
`Overall
`RQLQ
`score
`
`Activities
`
`Sleep
`
`Non-nose,
`noneye
`symptoms
`
`Practical
`problems
`
`Nasal
`symptoms
`
`Eye
`symptoms
`
`Emotions
`
`Figure 6. Mean improvement from baseline to day 14 in overall RQLQ score and individual RQLQ domain scores
`(intention-to-treat population). *p s 0.05 vs Cetirizine; *p < 0.01 vs cetirizine.
`RQLQ: Rhinoconjunctivitis Quality of Life Questionnaire.
`Reprinted with permission from [28].
`
`WWW.CXp Cl‘[—1‘CVlCWS. COH1
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`Horak 8: Zieglmayer
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`|
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`100
`
`80
`
`60
`
`40
`
`20
`
`RQLQscore
`
`AZ
`FP
`Baseline
`
`FP
`AZ
`3 weeks
`
`AZ
`FP
`6 weeks
`
`Expert commentary
`Intranasal antihistamines are recommended
`
`as a first—line therapy for AR. The intranasal
`mode of delivery is beneficial in several ways.
`First, it deposits the drug directly onto the
`nasal mucosa, delivering medication directly
`to the site (s) ofinflammation and at concen—
`
`trations much greater than that achievable
`with systemic drugs. Second, with topical
`application, the risk of interaction with
`concomitant medication and the potential
`for systemic adverse events are minimized.
`However, the activity is reduced to the tar—
`get organ and has no input in reducing the
`general allergic inflammation.
`Azelastine nasal spray is a second—
`generation antihistamine with a complex
`anti—inflammatory mode of action. Its
`anti—inflammatory effects are widespread,
`making it particularly suitable for the treat—
`ment of a complex inflammatory disorder
`such as rhinitis. It has proven efficacy in
`treating both allergic and nonallergic rhini—
`tis, and is the only prescription antihista—
`mine approved in the USA for the treat—
`ment of both SAR (1996) and nonallergic
`rhinitis (1999).
`It has one of the fastest onsets of action
`
`Figure 7. Effect of azelastine nasal spray or fluticasone propionate nasal spray
`on Rhinitis Quality of Life Questionnaire scores in geriatric patients with either
`allergic or nonallergic rhinitis.
`AZ: Azelastine; FP: Fluticasone propionate; RQLQ: Rhinitis Quality of Life Questionnaire.
`Reprinted with permission from [29].
`
`(212 years) [38—42]. Bitter taste, headache, somnolence and nasal
`burning were the most frequently reported adverse events; how—
`ever, the vast majority of these were either mild or moderate in
`severity. It is worth noting that slightly tilting the head forward
`and not inhaling the medication too deeply prevents deposition
`of drug in the nasopharynx, so reducing the problem of bitter
`taste. Similar degrees of somnolence (~2%) have been reported
`in both local azelastine and placebo groups in postmarketing
`surveillance studies [14,1S,2S,28]. The lower incidence of azelastine—
`
`related adverse events seen in these later trials is most likely due
`to correct dosing technique (i.e., head tilted forward a_nd no deep
`inhalation), which would reduce systemic absorption, and hence
`also reduce bitter taste and somnolence. However, as the earlier
`NDA studies did show an increased incidence of somnolence
`
`whilst using azelastine nasal spray versus placebo, US prescribing
`recommendations warn against the concurrent use of alcohol and/
`or other CNS suppressants. To date, there have been no stud—
`ies designed to specifically assess the effects of azelastine nasal
`spray on the CNS in humans. Data on oral azelastine describe
`occasional tiredness, and minimal effects on performance and
`vigilance with a dose of 2 mg/day [43].
`
`(15 min for nasal spray) [is] among the cur—
`rently available rhinitis medications, and its
`effects last at least 12 h, thus allowing for a
`once— or twice—daily dosing regimen.
`Azelastine nasal spray offers flexibility of
`dosage. At a dosage of one spray per nostril
`twice daily, it has been shown to be effective, with an improved
`tolerability profile compared with two sprays per nostril twice
`daily in patients with moderate—to—severe SAR. The option ofa
`one— or two—spray azelastine dosing regimen enables physicians
`to tailor treatment regimens to the individual patient. The choice
`of azelastine nasal spray dosage should be based on the severity
`and persistence of symptoms, as well as the patient’s accept—
`ance of the nasal spray [6]. The two—spray dose could be used as
`the starting dose for patients with severe symptoms, and either
`maintained or tapered to the one—spray dose as required. The
`one—spray dose could be used as a starting dose in patients with
`mild—to—moderate symptoms, and if necessary the dose increased
`to two sprays per nostril twice daily if symptom control proved
`to be inadequate [17].
`Azelastine nasal spray can also be used on an as—needed basis
`by virtue of its rapid onset of action. Patients treated with as—
`needed azelastine nasal spray show improvement in their rhinitis
`symptoms but without the concomitant reduction in markers of
`inflammation seen with fixed dosing [19]. As—needed therapy may
`reduce the bitter taste and somnolence sometimes associated with
`
`azelastine use and may improve patient compliance.
`
`666
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`Expen‘Re1/. Clin. Immunol. 5(6), (2009)
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`APOTEX_AZFL 0130202