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`|
`EXPERT
`I REVIEWS
`
`Azelastine nasal spray for the
`treatment of allergic and
`nonallergic rhinitis
`
`Expert Rev. Clin. Immunol. 5(6), 659-669 (2009)
`
`Friedrich Hora k’‘ and
`U rs u I a Petra
`
`Zi eg I maye r
`[Author for Correspondence
`HNO — Un/versitats/</in/'/< W/"en,
`Wahringer GL'Jrte/ 78-20,
`A—7090 Vienna, Austria
`Te/..' ——43 740 400 3336
`FaX.' ——43 7789 7676
`friedr/"ch.hora/<@vienna.at
`
`Rhinitis affects millions of people around the world, places a huge burden on the economy and
`reduces patients’ health—related quality of life. Azelastine nasal spray is a second—generation
`antihistamine, indicated for the treatment of allergic and nonallergic rhinitis in both adults and
`children. It offers a rapid onset of action (15 min) and flexibility of both dose (ie, one or two
`sprays/nostril twice daily) as well as dosage (i.e., fixed or as needed). Compared with other
`agents used to treat allergic rhinitis, azelastine nasal spray exhibits superior efficacy to oral
`antihistamines (e.g., desloratadine and cetirizine), other intranasal antihistamines (e.g.,
`levocabastine) and the intranasal corticosteroid mometasone furoate, and comparable efficacy
`to the potent intranasal corticosteroid fluticasone propionate (FP). Combination therapy with
`intranasal FP has the potential to enhance clinical benefit, as the combination of azelastine and
`FP nasal sprays reduce symptoms in allergic rhinitis patients more than either agent alone.
`Azelastine nasal spray has an excellent safety profile.
`
`KEYWORDS: allergic rhinitis 0 azelastine nasal spray 0 intranasal corticosteroid 0 nonallergic rhinitis
`0 oral antihistamine
`
`Rhinitis is an inflammatory disease of the nasal
`mucosa affecting approximately 10-30% of adults
`and 40% of children, making it the sixth most
`common chronic illness in the USA. Over the
`
`past 30 years, the prevalence of this condition has
`risen dramatically in industrialized countries, with
`England, Sweden and Australia reporting a dou—
`bling in rates, a trend similar to that seen with other
`atopic conditions such as asthma. Rhinitis places
`a huge burden on the economy, being responsible
`for between US$2 and 5 billion annually in both
`direct and indirect costs [1], and approximately
`3.5 million lost work days per year [2].
`Traditionally, rhinitis has been classified as
`allergic, nonallergic and mixed. Definitions of
`these rhinitis classifications are discussed later.
`
`Patients with seasonal allergic rhinitis (SAR)
`present with a huge range of symptoms, includ—
`ing nasal congestion, runny nose, nasal and
`nasopharyngeal itching, ear symptoms, sneez—
`ing, and ocular symptoms in many patients,
`including itchy and watery eyes [3]. The symp—
`toms of sneezing, itching and rhinorrhea are less
`common with perennial rhinitis (PR).
`Rhinitis symptoms have a major negative
`impact on patients’ health—related quality of
`life (HRQOL). They impair not only patients’
`
`daily activities, but furthermore disturb qual—
`ity of sleep, which causes fatigue during the day
`and impairs cognitive function [4]. An inability
`to concentrate is a frequent complaint made by
`rhinitis sufferers, and in the case of SAR, patients
`often avoid outdoor activities to avoid allergen
`exposure. The Joint Task Force on Allergy
`Practice and Parameters mentions that improv—
`ing the negative impact on daily life in rhinitis
`patients defines successful treatment as much as
`providing symptom relief.
`A recent survey investigated symptom percep—
`tion and the impact of allergic rhinitis (AR)
`in 447 patients and their doctors on HRQOL
`[S]. The results highlighted the high symptom
`burden and impaired HRQOL associated with
`AR. Interestingly, patients rated their disease as
`more severe than physicians did. At the time of
`the consultation, 44% of patients were suffer—
`ing from nasal and ocular symptoms, 23.7% of
`patients reported that their current nasal and
`ocular symptoms were moderate or severe in
`nature, and approximately two—thirds of patients
`with intermittent disease reported some impair—
`ment of their professional or daily life as a result
`of AR [5]. HRQOL correlated negatively with
`the number of symptoms, with AR having a
`
`www.expert- reviews.com
`
`10.1586/ECI.09.38
`
`© 2009 Expert Reviews Ltd
`
`ISSN 1744-666X
`
`659
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`APOTEX_AZFL 0130195
`
`

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`significantly greater impact on patients with more persistent dis—
`ease compared with those with intermittent disease. Finally,
`more than 50% of patients surveyed were using two or more
`medications for their AR [5]. AR seems to be a disease that is
`
`poorly controlled and whose effects are underestimated.
`
`Traditional classification of rhinitis
`
`Traditionally, rhinitis has been classified as allergic, nonallergic
`or mixed (FIGURE 1) [6]. With AR, symptoms occur in association
`with a specific IgE—mediated response. With nonallergic rhinitis,
`symptoms are induced by irritant triggers but without an IgE—
`mediated response. AR is further classified as seasonal or peren—
`nial. SAR symptoms are induced by exposure to pollens, whilst
`PR is associated with environmental allergens that are generally
`present on a year—round basis.
`As many as half of all patients diagnosed with rhinitis have
`nonallergic disease. Nonallergic rhinitis includes infectious rhi—
`nitis (also known as rhinosinusitis), occupational rhinitis, drug—
`induced rhinitis (e.g., rhinitis induced by aspirin and nonsteroidal
`anti—infiammatory drugs [NSAIDs]), hormonal rhinitis (e.g., dur—
`ing pregnancy), rhinitis in smokers, food—induced rhinitis (very
`rare), nonallergic rhinitis with eosinophilia and eosinophilic rhini—
`tis, senilic rhinitis, atrophic rhinitis (often infected with K13/rsiella
`azaemze) and finally idiopathic rhinitis. Details of diagnosis a_nd
`management of rhinitis are provided in the Allergic Rhinitis
`and its Impact on Asthma (ARIA) report [101], and the updated
`American Association of Allergy, Asthma and Immunology/
`American College of Allergy, Asthma and Immunology practice
`parameter [7].
`
`New AR classification
`
`The classification ofAR into ‘seasonal’ and ‘perennial’ categories
`is not entirely satisfactory. The majority of AR patients are sen—
`sitized to many different allergens and are exposed throughout
`the year [8—10]. In many patients, perennial symptoms are often
`present, and patients experience seasonal exacerbations when
`exposed to pollens or molds. Therefore, the old classification of
`
`AR into seasonal and perennial categories is not indicative of the
`real—life situation. A major change in the subdivision of AR was
`proposed by ARIA (FIGURE 2). AR is subdivided into ‘intermittent’
`and ‘persistent’ disease, and the severity classified as either ‘mild’
`or ‘moderate/severe’. However, it is important to remember that
`indications for treatment and clinical studies investigating the
`efficacy of azelastine still refer to the older rhinitis classification.
`
`Treatment guidelines
`As many as 66% of adult allergy sufferers are dissatisfied with
`their current allergy medication due to a lack of effectiveness [11].
`Clearly, effective and convenient therapies with a good safety
`profile are needed to treat patients with AR. The ARIA guide—
`lines recommend a stepwise approach to therapy based upon the
`frequency and severity of symptoms (TABLE 1). Intranasal antihista—
`mines are recommended for all severities of intermittent rhinitis
`
`symptoms and mild persistent symptoms. Treatment guidelines
`from the Joint Task Force and the WHO agree with ARIA,
`and recommend antihistamines (both topical and oral second—
`generation) be used as a first—line therapy for AR. Intranasal
`corticosteroids may also be considered as initial therapy for AR
`patients with more severe or persistent symptoms, particularly
`nasal congestion.
`
`Azelastine
`
`Azelastine hydrochloride nasal spray is a topically administered
`second—generation antihistamine, marketed as Allergodil®
`(Meda AB, Stockholm, Sweden) in Europe and Astelin® (Meda
`Pharmaceuticals Inc., N], USA) in the USA. It is indicated for
`the treatment of the symptoms of SAR (approved in 1996) such
`as rhinorrhea, sneezing, and nasal pruritus in adults and chil—
`dren 5 years of age and older. It is also indicated for the treat—
`ment of the symptoms of vasomotor rhinitis (VMR; approved
`in 1999) such as rhinorrhea, nasal congestion and postnasal
`drip in adults and children aged 12 years or older. The recom—
`mended dose of azelastine nasal spray depends on patient age.
`For those aged 12 years or older, two sprays per nostril twice
`daily is recommended, which reduces to
`one spray per nostril twice daily in chil—
`dren aged 5-11 years. A new formulation
`of azelastine nasal spray with sucralose
`as a taste—masking agent (Astepro®) was
`approved in the USA in October 2008 for
`the treatment of SAR in patients 12 years
`of age and older.
`Applying azelastine topically to the nasal
`mucosa means that the drug is delivered
`directly to the site of inflammation, where
`it is needed most. Compared with sys—
`temic treatments, higher concentrations of
`azelastine can be applied topically, which
`should enhance its anti—allergic and anti—
`inflammatory effects. In addition, the risk
`of interaction with concomitant medica—
`
`tion, and the potential for systemic adverse
`
`Expen‘Re1/. Clin. Immunol. 5(6), (2009)
`
`APOTEX_AZFL 0130196
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`
`
`I Nonallergic
`‘"7"’
`
`itis (aka VMR,
`
`‘
`
`
`
`Perennial
`‘asonal allergic
`
`rhinitis
`largic rhinitis
`
`
`
`
`Figure 1. Traditional classification of rhinitis.
`Vl\/IR: Vasomotor rhinitis.
`
`660
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`Azelastine nasal spray for the treatment of allergic 8: nonallergic rhinitis
`
`|
`
`Intermittent
`Symptoms occur:
`- <4 days/week, or
`- <4 consecutive weeks
`
`Mild
`- No sleep disturbance
`- No impairment of schooll
`work, daily activities, leisure
`and/or sport
`- No troublesome symptoms
`
`
`
`Moderatelsevere
`>1 of the following:
`- Sleep disturbance
`- Impairment of school/work,
`daily activities, leisure
`and/or sport
`- Troublesome symptoms
`
`Persistent
`Symptoms occur:
`- >4 days/week, and
`- >4 consecutive weeks
`
`Figure 2. New Allergic Rhinitis and its Impact on Asthma classification of allergic rhinitis.
`
`events is minimized. The efficacy and safety of azelastine nasal
`spray in treating AR and nonallergic rhintis have been deter—
`mined in a number of US multicenter, randomized, double—blind,
`
`symptomatic after therapy with either oral loratadine (Claritin®,
`Schering Plough, USA) or fexofenadine (Allegra®, Sanofi Aventis,
`USA) [13,14].
`
`placebo—controlled trials. In all trials, azelastine Was associated
`with a rapid onset of action, and a sustained improvement over
`time in rhinitis, congestion, and other symptoms [12]. The topical
`application of azelastine nasal spray has been shown to be effec—
`tive in treating rhinitis patients who remained at least moderately
`
`Dosage
`
`A dosage of two sprays per nostril twicy daily improves not only all
`symptoms of allergic and nonallergic rhinitis, as shown in an open
`trial with 4000 patients [15], but also HRQOL [16] immediately.
`
`
`
`Table 1. Summary of ARIA allergic rhinitis management guidelines.
`
`l\/lild intermittent
`
`l\/loderate/severe intermittent
`
`Oral/intranasal antihistamines and/or decongestants
`
`Oral antihistamines and/or decongestants, intranasal antihistamines, intranasal corticosteroids
`or cromones
`
`l\/lild persistent
`
`Oral antihistamines and/or decongestants, intranasal antihistamines, intranasal corticosteroids
`or cromones
`
`A step—wise approach is advised with reassessment after 2 weeks. If symptoms are controlled and the
`patient is receiving a intranasal corticosteroid, the dose should be reduced, but otherwise treatment
`continued. If symptoms persist and the patient is receiving antihistamines or cromones, a change
`should be made to an intranasal corticosteroid
`
`l\/loderate/severe persistent
`
`lntranasal corticosteroid (tirst—line treatment)
`If symptoms are uncontrolled after 2-4 weeks, medication should be added depending on the
`persistent symptom. For example, add an antihistamine it the major symptom is rhinorrhea, pruitis or
`sneezing, double the dose of intranasal steroid for persistent nasal blockage and add ipratropium for
`prominent complaint of rhinorrhea
`ARIA: Allergic Rhinitis and its Impact on Asthma.
`
`WWW.CXp Cf[—fCVlCWS. COH1
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`661
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`APOTEX_AZFL 0130197
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`CH2
`
`\N
`i
`
`O
`
`CI
`
` N—CH3 HCI
`
`Figure 3. Azelastine hydrochloride.
`
`Azelastine nasal spray at a dosage of one spray per nostril twice
`daily is also effective and has an improved tolerability profile
`compared with two sprays per nostril twice daily in patients
`(212 years; n = 554) with moderate—to—severe SAR [17].
`In addition, one spray per nostril twice daily ofazelastine was asso—
`ciated with significant improvements in the Rhinoconjunctivitis
`Quality of Life Questionnaire (RQLQ) daily activity a_nd nasal
`symptoms domains and patient global evaluations compared with
`placebo. The incidence of a bitter aftertaste following azelastine
`application more than halved, and the incidence of somnolence
`was decreased almost 30—times in the one—spray group versus the
`labeled incidence with the two—spray regimen.
`
`As needed
`
`Azelastine nasal spray can also be used on an as—needed basis
`by virtue of its rapid onset of action, just 15 min after appli—
`cation [18]. Ciprandi and colleagues carried out a randomized,
`controlled study in 30 patients sensitized to Parietaria pollen and
`grass and treated them with azelastine (0.56 or 0.28 mg/day), or
`as needed [19]. Patients who received the 0.56— or 0.28—mg/day
`dose had a marked improvement in their rhinitis symptoms,
`and a concomitant reduction in markers of inflammation, most
`
`notably neutrophil and eosinophil counts and intracellular adhe—
`sion molecule (1CAM)—1 expression in nasal scrapings. Although
`this anti—inflammatory effect was absent in patients treated with
`azelastine nasal spray on an as—needed basis, these patients did
`show an improvement in their rhinitis symptoms [19]. Therefore,
`although patients derive maximum benefit from regular treatment
`with azelastine, as—needed therapy may be useful in the treatment
`of clinical symptoms and would be expected to improve drug
`tolerability and patient compliance.
`
`Chemistry
`The chemical name of azelastine hydrochloride is
`(:)—1—(2H)—phthalazinone,4—[(4—chlorophenyl) methyl]—2—
`(hexahydro—1—methyl—1H—azepin—4—yl)—monohydrochloride. Its
`empirical formula and molecular weight are C22H24ClN3O~HCl
`and 418.37, respectively, and structurally it is arranged as a
`seven—membered ring (FIGURE 3).
`Azelastine is a white, almost odorless crystal with a bitter taste.
`It is soluble in dichloromethane and chloroform, sparingly soluble
`in propylene glycol and methanol, slightly soluble in glycerin,
`octanol and ethanol, and almost insoluble in hexane.
`
`Pharmacokinetics & metabolism
`
`The systemic bioavailability of intranasally administered azelas—
`tine hydrochloride is approximately 40%, with maximum plasma
`concentrations (Cmx) observed within 2-3 h. Based on intravenous
`and oral administration, the elimination half—life is 22 h, steady—
`state volume of distribution is 14.5 l/kg and plasma clearance is
`0.5 l/h/kg, respectively. In z1z'tr0 studies with human plasma indicate
`plasma protein binding of azelastine and desmethylazelastine of
`approximately 88 and 97%, respectively. Azelastine is oxidatively
`metabolized by the cytochrome P450 enzyme system into a princi—
`pally active metabolite, desmethylazelastine and two inactive car—
`boxylic acid metabolites. When azelastine is administered orally,
`desmethylazelastine has an elimination half—life ranging from 22 to
`54 h. Approximately 75% of an oral dose of radiolabeled azelastine
`is excreted with feces, with less than 10% excreted unchanged.
`Following oral administration, pharmacokinetic parameters
`of azelastine are not influenced by age, gender or hepatic impair—
`ment. However, oral, single—dose studies show that patients with
`renal insufficiency (i.e., creatinine clearance <50 ml/min) had a
`70-75% higher Cm” and AUC compared with normal subjects,
`but time to Cm” remained the same.
`
`Mode of action
`
`Azelastine has a fast a_nd long—lasting effect due to its complex
`anti—inflammatory mode of action [6,20]. It is a high—affinity his—
`tamine H1—receptor antagonist, being ten—times more potent than
`chlorpheniramine, and also has some affinity for H2 receptors. In
`aVCC trial, azelastine showed one of the fastest onsets of action
`
`(15 min with nasal spray) [18] among the currently available rhi—
`nitis medications, and its effect lasts at least 12 h, thus allowing
`for a once— or twice—daily dosing regimen.
`Azelastine’s anti—inflammatory activity is widespread. Azelastine
`inhibits TNF—(X release, gra_nulocyte macrophage colony—stimulating
`factor generation and reduces the number of a range ofinflammatory
`cytokines, including IL—1[_’), IL—4, IL—6 and IL—8 [6,20]. These cyto—
`kines perpetuate the inflammatory response [21]. In 2/itro azelastine
`decreases free—radical production by human eosinophils and neutro—
`phils, and calcium influx induced by platelet—activating factor. It
`reduces inflammatory cell migration in patients with rhinitis, most
`likely as a consequence of the downregulation of ICAM—1 expres—
`sion [6,20], and inhibits kinin (e.g., bradykinin and substance P),
`platelet—activating factor and leukotriene release in z1z'tr0 and in viva.
`Leukotrienes are associated with dilation of vessels, increased vas—
`
`cular permeability and edema, which results in nasal congestion,
`mucus production and recruitment ofinflammatory cells in yitro [22]
`and in viva [21] . Clinically, substance P and bradykinin are associated
`with the AR symptoms of nasal itching and sneezing, but may also
`contribute to the onset of nonallergic rhinitis symptoms.
`The widespread anti—inflammatory effects of azelastine ensure
`that it is a highly effective treatment, combating the broad range
`of clinical symptoms associated with rhinitis.
`
`Clinical efficacy of azelastine
`The clinical efficacy of azelastine nasal spray has been confirmed
`in a real—world setting for the treatment of allergic, mixed and
`
`662
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`Expen‘Re1/. Clin. Immunol. 5(6), (2009)
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`APOTEX_AZFL 0130198