Case 1:14-cv-01453-LPS Document 43-16 Filed 10/22/15 Page 1 of 119 PageID #: 1181
`Case 1:14—cv—O1453—LPS Document 43-16 Filed 10/22/15 Page 1 of 119 Page|D #: 1181
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`EXHIBIT 56
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`EXHIBIT 56
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`Case 1:14-cv-01453-LPS Document 43-16 Filed 10/22/15 Page 2 of 119 PageID #: 1182
`Case 1:14—cv—O1453—LPS Document 43-16 Filed 10/22/15 Page 2 of 119 Page|D #: 1182
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`This materiai may be protected by Copyright law (Titie 17 U.S. Code)
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`Drugs 211)): 61 (11):1563—'l579
`0012-6667/Ollmi 1-1563/527.50/D
`REVIEW ARTICLE
`0 Adis International Limited. All rights reserved.
`
`rlntraniasal Corticosteroids for '9
`AllergictRhinitis i
`
`6
`Superior Relief?
`Lars Peter Nielsen,” Niels Mygindz and Ronald Dahlz
`1 Department of Clinical Pharmacology, University of Aarhus, Aarhus, Denmark
`2 Department of Respiratory Diseases, Aarhus University Hospital, Aarhus, Denmark
`
`I
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`Contents
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`Abstract’
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`1. Antihistamines p
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`1.1 Gene'"rdiCon'sid‘e‘ra"f|6'ns
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`1.2 Oral Antihistamines .
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`1.3 Topical Antihistamines .
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`-1.4 Comparative Effect ofAntihistamines .
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`1.4.1 Singie Dose Studies .
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`1.4.2 PerenniaiAiiergic Rhinitis .
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`1.4.3 SeasonaiAiierg|c Rhinitis .
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`1.4.4 Studies in Children.
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`1.4.5 Topical vs Oral Antihistamines .
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`1.4.6 Safety .
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`2. Corticosteroids .
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`2.1 Generaiconsideratlons .
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`2.2 i_nt_r_a_nasai Corticosteroids .
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`_;;;,2.3,_C9_Lnp_aLative,,Etf§_gj_gf_intrana§giCorticosteroids
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`2.3.1 PerennialAilergic Rhinitis .
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`2.3.2 SeasonaiAiiergic Rhinitis .
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`2.3.3 Safety'.[....__._... .
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`3. Comparing Antihistamines and intranasai Corticosteroids .
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`3.1 Perennia|Aiiergic Rhinitis .
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`3.2 SeasonaiA|iergic Rhinitis .
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`3.3 Combination of Antihistamines and intranasai Corticosteroids
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`3.4 Safety .
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`3.5 Cost Effectiveness
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`4. Conclusion ... .
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`Abstract ,
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`1
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`Whether firstvline pharmacological treatment of allergic rhinitis should be
`antihistamines or imranasal corticosteroids has been discussed for severalyears.
`First-generation antihistamines are rarely used in.the treatment of allergic
`rhinitis, mainly because of sedative and anticholinergic adverse effects. On the
`basis of clinical, evidence of efficacy, no second-generation antihistamine seems
`preferable to another. Similarly, comparisons of topical and oral antihistamines
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`Case 1:14-cv-01453-LPS Document 43-16 Filed 10/22/15 Page 3 of 119 PageID #: 1183
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`1564
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`‘:f"_"‘-“"
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`Nielsen ‘et al.
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`....-._.i
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`have been unable todemonstrate superior efficacy for one method of adi/ninistra-
`tion over the other.
`Current data documents no striking differences in eficacy andsafety param-
`etersieetween-intranasal cor-tieestereids.—
`, '
`When the efficacy. of antihistaminesand inuanasal corticosteroids are com- -
`pared in patients with allergic rhinitis, present data‘ favours intranasal cor;ticoste-
`roids. Interestingly, data do not show antihistamines as superior for the uéittmefit
`of conjunctivitis. Safety data from comparative studies in patients with allergic
`rhinitis do not indicate differences between antihistamines and intranasal coni-
`costeroids. Combining antihistamines and intranasal corticosteroids in the treat-
`ment of allergic rhinitis does not provide any additional effect to intranasal
`corticosteroids alone. On the basis ofcurrent data, intranasal corticosteroids seem-
`to offer superior relief in allergic rhinitis than antihistamines.
`"
`'
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`‘
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`
`miergic rhinitisis a commofmdrtfieliafiétr """"""‘1:"A?ifih1sTéi"rfiifiesj""'"" I "
`by animmunoglobulin (Ig)E-mediated allergic in.-
`flammation of the’ nasal iiiucosa and characterised
`
`.1.1 General Considerations
`
`by nasal obstruction’, rhinorrhoea,'sneezing and na-
`sal itch, and often accompanied by conjunctivitis.
`It is present in 10 to 20% of the population in in-
`dustrialised countries.m Moreover, this prevalence
`seems to be increasing.[2»3] Although allergic rhini-
`tis is not a life-threatening disease, it can severely
`impact on quality of 1ife[4'6] and be associated with
`comorbidity from other diseases, for example,
`'*asthma'and'conjunctivitis:[7'3'
`'
`'
`Treatment of allergic rhinitis consists of aller-
`gen avoidance, allergen-specific immunotherapy and
`pharmacological intervention, of which the former-
`two lie beyond the scope of the present review. Two
`mainstream options have evolved for pharmaco- ‘
`logical treatment, antihistamines and topical corti-
`costeroids. The choice between these options has
`been extensively discussed since the introduction
`of intranasal corticosteroid treatment.[33
`This review considers first-1i_ne pharmacologi-
`cal treatment of allergic rhinitis and will deal only
`with antihistamines ‘and intranasal corticosteroids
`(INCS), as we consider cromones, anticholiner-
`gics, leukotriene modifiers, decongestants and sys-
`ternic corticosteroids as secondary treatment op-
`tions in allergic rhinitis.
`‘
`Only data obtained in patients with allergic rhi-
`nitis have been considered for the comparative ev-
`idence presented in this review.
`
`Histamine is the major pathophysiological_ me-
`, diator of allergic rhinitis. Its role is almost exclu-
`- sively mediated through the histamine H1-receptor,
`whereas the role of other histamine receptors in’
`allergic rhinitis remains to be clarified. Thus,‘ in the
`context of -allergic rhinitis, antihistamines are H1-
`receptor antagonists.”-1°] In addition to H1-recep-
`tor blockade, an -anti-i-nfl ammatory--ef-fect of anti-
`histamines has been proposed, as"_some of the newer
`compounds have been shown to influence cytolcine
`production, mediator release and inflammatory cell
`flux.[“'19] However, other studies have been unable
`to confirm these findings.[2°‘231 Whether antihista-
`mines offer a clinically beneficial anti-inflarnmatory
`effect in addition to inhibition of histamine remains
`a question to be answered.
`
`1.2 Oral Antihistamines
`
`Numerous H1-receptor antagonists have been
`developed. For oral use, these can be divided into
`older first-generation [e.g. chlorphenarnine (ch101'- ’
`pheniramine), diphenhydrarnine,‘ promethazine
`and -triprolidine] and newer second-generation an-
`tihistamines (acrivastine, astemizole, cetirizine,
`ebastine, fexofenadine, loratadine, mizolastine and
`terfenadine). This review deals with the newer aI1- -'
`tihistainines as the use of the older drugs in allergic
`
`® At‘-lls International Limited. Al rights reserved.
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`Drugs2OD1;6l (113
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`I.-——-—-
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`Com-costeroids in Allergic
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`izole remains unknown as there is a lack of data on
`the other second-generation antihistaminesfor this
`measure’.
`-
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`Whereas CNS-related adverse effects were a
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`major characteristic of «the first-generation antihis-
`tamines, the piperaizine/piperiidine-derived struc-
`tures of the newer‘ generation agents reduce CNS
`_ penetration, although sedative effects have been
`described for some of the compounds, for example,
`. acrivast:ine[‘‘41 and cetiriz.ine.[451 The binding affin-
`ity to muscarinic receptors is also decreased with
`the ‘second-generation agents. With the exception
`' of the cardiac adverse effects, this provides a more
`acceptable therapeutic index for the second-gener-
`ation antihistamines.
`
`'_ l .3 _Topica‘|’_An,t|histcmines
`
`Two newer I_-I1-receptor antagonists are avail-
`able for topical use, azelastine and levocabastine.
`When applied intranasally, they have both proven
`effective ._in the treatment of allergic rhinitis,
`mainly relieving nasal itching and sneezing.[_4°»47]
`They have a faster onset ofaction than oral antihis-
`tamines and act within 15 to 30_ minutes. They only
`need to be applied "twice daily.
`'
`No sedative effects have been seen with either
`drug,[45'481 whereasthe occurrence of a short last-
`iriapsfvctsion ’<.>f...ta.st;=.,;1.1_'=1S. .*299¥£.d°$9FiP°_‘? ft"
`aze1astine.[f‘91
`
`rhinitis is limited by their adverse effects, mainly
`Sedation and anticholinergic activity.
`'
`All of the newer _antihistamines are effective in
`the treatment of allergic rhinitis by decreasing na-
`Sal itching, sneezing and rhinorrhoea, but they are
`less effective for nasal congestion.[2"‘3” They are
`also effective for conjunctivitis and recent‘ results
`seem to indicate some influence on lower airway
`symptomS_{32.331
`'
`‘
`1
`Moreover, the pharmacolcinetic profile of second-
`generation antihistamines are advantageous when
`compared with the first-generation agents.[343 They
`have an onset of action of 1 to 2‘hours which lasts
`for 12 to 24 hours, except for acrivastine, which
`has to be administered at 8-hourly interval's.iW"1th'
`the exception of cetirizine and fexofenadine,
`which are excreted alrnost.'unchanged,.the remain-
`ing drugs in this group are metabolised via the he-
`patic cytochrome P450 (CYP) system by CYP3A.
`As a number of other compounds, that is, anti-
`znycotic azoles, macrolide antibiotics and grape-
`fruit juice, are also substrates for this enzyme, this
`obviously provides a risk for interactio_ns.[35] This
`is probably a contributive factor tovthe occurrence
`of severe cardiac arrhythmias, for example, ‘tor-
`sade de pointes’, and fatalities, which have been
`described following treatment with terfenadine
`.~__.a.nd asternizstzlelfii?-8L".I1ti_ese--effects seem to been-_
`abled through a quinidine—like action, causing a
`prolongation of the QT interval.[39-4°] _At present,
`1.4 Comparative Effect of Antihlstdmines
`no clinical evidence has demonstrated cardiac ad-
`verse effects with other second-generation antihis-
`1.4. I Single Dose studies
`tamines when they are used at therapeutically ap-
`. Many studies have been performed to compare
`propriate levels. However, it is recommended to
`the efiects of oral second-generation antihista-
`avoid antihistamines which are CYP450~metabo-
`mines in the treatment of allergic rhinitis. Single
`lised or which possess quinidine-like actions in
`dose studies in patients with allergic rhinitis have
`demonstrated that cetiriz‘-ine and terfenadine have
`risk groups, that is, patients with impaired hepatic
`' a‘fas'te‘r o'n's'et 'of‘action thanloratadine a'nd'astem-‘
`function or ca“rdiac’a1rhythrni‘a;[4~1]
`—
`AsteIrtizoie'car1"aiso-act-asan-appetite-stimulant--—-—jz0}e-;I50.5t]—,a;H——4- -dmgs wen, V equ.agy_e1-:f¢e.fiVe,__;....
`and result in increased bodyweight. [43243] The cause
`_ against nasal symptoms and histamine-induced in-
`creases in nasal airway resistance. This contrasts
`for this action remains obscure, although a central
`nervous system (CNS)-mediated mechanism, for ex-
`somewhat
`the resultsof 2 studies in which
`cetiiizine was superior to loratadine after adminis-
`ample, serotonin (5-hydroxytryptamine)-antago-
`tration of a single dose in both symptom re1ief[521 '
`nism, is a theoretical possibility. However,'whether
`and response to histamine cha;llenge.[53] One study
`this adverse effect is seen exclusively with astem-
`_
`‘-I
`-.—._-..-:" -
`-2-:
`
`@ Adls lntemqfionai Limited. All rights reserved.
`
`Drugs 2001; 61 (11)
`
`M ED_DYM_00005346
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`Case 1:14-cv-01453-LPS Document 43-16 Filed 10/22/15 Page 5 of 119 PageID #: 1185
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`was able to demonstrate a significantly faster onset
`of action for fexofenadine compared with terfenad-
`ine in relief of rhinorrhoea and sneezing i.mrnedi-
`:f‘atel l_aHergen challeng—e.l5‘*3 This may be ""
`explained on the basis of fexofenadine being the '
`active metabolite of terfenadine.
`’
`
`shows cetirizine to have a faster onset of action
`than terfenadine,l7-°’] while another t;lai'ms ebastine
`to achieve maximum effect,fas'ter than cetiriz-
`" me.f73}’Theimm ch
`as nasal peak~flow[793; and inflammatory-mediators
`in nasal lavage fluid[741 has ‘not shown differences
`between agents.
`
`1.4.2 Perennial Allergic Rhinitis
`V
`7.4.4 5TUdIe$ in Children
`Relatively few studies investigating continuous
`Data on the efficacy in children with-allergic
`administration of antihistamines are inpatients
`rhinitis are sparse.'One single-b1i_n'd study in chil-» V
`with perennial allergic rhinitis (PAR). Six studies
`dren with SAR for 2 weeks shgwejd‘equal effect of
`ranging from 1 to 8'.WeekS, included comparisons of
`ast‘err1iz'iole‘55-551 cetir-iz.ine,‘56_'53] ebastine,‘571 lorata-
`loratadjne and astemizole.‘75] In another 4‘-week.
`dine,[55-595°] rnizolastine‘-"91 and tetfenadine.‘58-5°]
`study in children with PAR, cetirizine was superior
`No differences 7eetween'agents—.were—seen—except_.._..._tO lorafaafhél.écT:6Td1.Et.(Tp§fefifa:t,a,S§€§Sment_[46}?_
`that astemizole was more effective than loratadine
`for rhinorrhoea in 1 shortterm study,‘55] and cetiri2-
`"ine was better than ebastine according to the inves-
`tigators opinion in another study.[577 Interestingly,
`in 1 of the studies, nonresponders were crossed to
`theopposite drug at the end of a 2 week treatment
`period, resulting in an effect in 11 of the 16 pa-
`tients.l5°]
`'
`'
`
`,
`‘ 1.4.5 Topical vs Oral'Anlihislumlnes
`In comparisons between oral and topical anti-
`histamines, most topical regimens have included
`intranasal as well as ocular medications or reports
`have only addressed nasal symptoms. In 1 study,
`intranasal azelastine was more effective thancetir-
`izine at relieving nasal congestion',[771 whereas other
`studies have demonstrated azelastine to be equally
`effective as cetirizine,[78] ebastine,l791 Ioratadine‘3°l
`terfenadineJ§U..I1'n2 studies, .i_ntr_anasal..lcYQ-
`cabastine has ‘been marginally more effective than
`nterfenadine in relieving single symptoms,
`ie.
`sneezingm] and nasal itching,‘33] whereas a third
`study did not show any difference.‘3“1 In 1 study,‘83]
`levocabastine given as eye drops were also judged
`superior to terfenadine for relieving ocular symp-
`toms. A comparison of levocabastine a.nd_ loratad—
`ine showed identical efficacy.l85]
`
`,
`1.4.3 Seasonal'Allorglc Rhirillls _
`The lack of difference in effectiveness between
`Vsecond-generation-drugs-is also -found in patients
`with seasonal allergic rhinitis (SAR); One placebo-
`controlled study in 202 patients with SAR seems
`to designate cetirizine as superior to loratadine,‘514]
`as seen in the single—dose study,[511 when all symp-
`toms following allergen challenge were consid-
`ered. However, this effectiveness in symptom re-
`lief after a quite short treatment period of 2 days
`could not be confirmed in another placebo-control-
`led, cross-over study'of identical treatments given ,
`for 1 week.‘°2]
`.
`Several seasonal studies involving ac1ivastine,l°31
`asternizolem-54] cetiIizine,‘5“"59] ebastine,‘571 fexo—
`fenadine,l531 loratadine,l“2-7°]. rnizolas'tine‘59] and
`terfenadine‘55»55~7°] have been unable to demonstr-
`ate any difference in efficacy for symptom relief.
`Some studies demonstrate small differences, that
`is, ‘subjective rating’ of cetirizine over astemiz-
`oleml or investigator preference of ebastine over
`cetirizineml without any support for this in other
`endpoints, for. example,.symptom relief. One study
`
`'
`
`0 Ad|s_|n’rerno‘iion<:i| Limi1ed. All rights reserved.
`/
`
`_
`1.4.6 Safely
`When considering adverse effects, only 2 of the
`previously mentioned studies indicate-differences.
`A large, placebo-'control'led',“2-Week study‘ in 821
`patients with SAR showed a significantly higher
`degree .of sedation after cetirizine than fexofenad-
`ine.‘53]
`'
`In another smaller 8-week study in 27 patients
`with SAR, terfenadine revealed more. adverse ef-
`fects, that is, headache and dizziness, than a com-
`bination of intranasal and ocular levocabastine-ml
`
`, Drugs2w'l;6l (11)
`
`.4
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`M ED_DYM_00005347
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`Cor
`
`ficosteroicls in Allergic Rhinitis
`
`'
`
`1567
`
`2. Corticosteroids
`
`‘
`
`.;- —-
`
`intranasal application, all characterised by a high 4
`receptor afiinity and an extensive first—pass meta-
`bolism in the liver. Effectiveness in relieving the
`2.1 General Considerations
`symptoms of allergic, rhinitis, including nasal con-
`Allergic rhinitis is an inflammatory disease of
`gestion, havebeen demonstrated for beclometh-
`the nasal mucosa and corticosteroids are, at pres-
`asone,[1°41 budesonide,[1°51fluriiso1ide,[1°°1 fluticasone
`ent, the most potent anti-inflammatory medica-
`propionate,[1°71 mometasonenbsl and triamcin'o-
`tions commercially available for the treatment of ,
`lone.[,1°91 In addition, some reports’ have indicated
`allergic rhinitis.[35] Corticosteroids exert their ef-
`that INCS may have a, beneficial effect towards
`fect by combining with a glucocorticoid receptor
`bronchial hyperresponsiveness and asthma symp-
`localised in target cell cytoplasm. The resulting ac-
`tom3_[110-115]
`tivated glucocorticoid receptor complex is able to
`It has been generally considered that INCS
`interact withicellular D_NA, thereby enabling reg-
`have a slow onset of action. However, they usu-
`ulation of cellular functions.[37-33}
`' ally act within 12 to 24 hours.[115'1131 Recent re-
`Corticosteroids act upon many of the cell ‘types
`sults have even indicated that budesonide acts after
`and inflammatory mediators participati.ng'in' ‘aller-
`3 h'our’s.[1191,However, maximum treatment effi-
`gic inflamrnation. Antigen-presenting Langerhans’
`cacy occurs after days or a'few-weeks:[‘12°1-Once:
`cells are reduced ‘ih'n‘u1'rIber“‘by'‘INCS;'[399991 More-
`daily application has proven sufficient to treat
`over, such treatment seems to impair their process-
`most patients with allergic rhinitis,[m'125] al-
`ing of antigen.[91] Similarly, the migration of baso-
`though those with severe symptoms may benefit
`phils ‘and mast cells to the nasal epithelium is
`from twice daily 'administration.[1125]
`,
`inhibited by INCS.[91‘9"1 Evidence suggesting an
`' The different potencies of INCS are important
`impact on the release of mast cell mediators, that '
`when considering comparative data. It is well es-
`is,'histamine, has also been presented.‘[951_ Cortico-
`tablished that fluticasone propionate'is twice as po-
`steroid therapy interferes with several pivotal as-
`tent as beclomethasone.[1°71 There is controversy
`pects of eosinophil function. Cell survival is‘ de-
`regarding relative potencies between other INCS.
`creased and the ability to release preformed
`However, it appears that the newer drugs_,_ that is,
`cytotoxic proteins, that is,_ eosinophil cationic pro-
`ifluticasenerpropionate and~nL1ornetasone,—ar<=r3;aore-
`teiu and_eosino.phil .p.ero.Xidase, is_inhihited.[9.5-'97]
`potent than the others.[1i71 U
`Moreover, formation of ‘a number of cytolcines and-
`Currently. available INCS are generally _well tol-
`V chemokines vital to eosinophil lifespan are inhib-
`ited, for example,
`interleukin (IL)-5 (forma-
`erated. Sneezing.caused by nasal hyperactivity can _
`occur at the start of therapy but this usually disap-
`tion),[°31 IL-4 (adhesion)[991 and RANTES [Regu-
`lated on Activation,- Normal T cell Expressed and
`pears with time.[1?71
`'
`Secreted] (chemo_taxis)._“°°] Results demonstrating
`Occasionally, mild and transient dryness, crusting
`an inhibitory effect of intranasal corticosteroid on
`and b1ood—stained secretions occur,‘and these are often
`activated T cells in nasal epithelium_have been pre-
`responsive to a reduction of INCS dose.[12°-1234291
`sented.[.1°1] In 2 studies, the ,al:lergen-induced in-
`Septal perforation‘ has been described as ‘a rare
`co‘r‘riplic'a'tion.H3’°'~T311 Atrophymof the mucoséf’cor-
`‘
`crease of specific IgE'inpatie_nts'with‘PAR during '
`
`
`_...season—was—abelish,e.dJ——-—3—1—."°2l°La—a:ll,-tlais-i1=ielieates——r——(jln—t—(1——eSPong 0 ,e1.mé1—a&«o-f, ,,I61. Pm onge use --—-
`profound effects of corticosteroids on the inflam-
`of INCS has not been‘ observed.[132-1331
`matory process seen in allergic rhinitis.
`' Because a proportion of intranasally applied
`corticosteroids end up in the gastrointestinal tract
`and is systemically absorbed, the risk of systemic
`' adverse effects has been a concemfor this class of
`drugs. However, these compounds, especially the
`
`2.2 lntranosol Corticosteroids
`
`Since the introduction of beclomethasone,[31
`several corticosteroids have been developed for
`
`
`© Adls lnternofionol Limlfed. All rights resewed.
`
`Dmas 2001: 61 (1 1)
`
`M ED_DYM_00005348
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`
`
`
`1568
`
`',
`
`newer fluticasone propionate and mometasone,
`have low systemic bioava_ilability, mainly because
`of their massive first-pass metabolism in the
`I1'ver.m77 Wfien used é)'i’cIus1veIy 1nfian§s"aTIy'at
`therapeutic dosages, the drugs‘ in this class do not
`seem to exhibitany influence on the hypothala-
`mus-pituitary-adrenal (HPA)-axis.[134'137-I How-
`ever, alack of HZPA-axis suppression does not guar-
`antee against other systemic adverse effects. Data
`demonstrating an inhibitory effect on the short
`term growth rate of children have been presented
`_for beclomethasone and-, b_udesonide,[133-_1391 al-
`though the result for budesonide.was only achieved
`by giving an adult dose of 200_LLg twice daily. More-
`'ovef,_T1i'sEf1‘ld'fi6t be rEcE1'fi dy
`in which the impact on child growth, as measured
`. by lower legknemometry, of budesonide 400p.g
`daily was comparable to placebo.[14°] Other sys-
`temic adverse effects, which have been linked to
`inhaled therapy, for example, cataract, glaucoma
`and dermal thinning, do not seem to occur in pa- <
`tients receiving treatment exclusively by the intra-
`nasal route.“413
`
`2.3 Comparative Effect of
`- —: elntranosal Corticosteroids -
`
`-
`
`_
`
`2.3. I Perennial Allergic Rhinitis
`As corticosteroids need continuous application
`to achieve maximum effect, single dose studies are,
`obviously, not very useful for comparing efficacy.
`Considering the many comparisons performed, not"
`many have used _a randomised, double-blind and
`eventually placebo-controlled design. Unless oth-
`erwise stated_, the comparative studies discussed in
`this section (2.3) have used the drugs in standard
`recommended doses for allergic rhinitis.
`Four placebo-controlled studies in patients with
`PAR have beenpublished. Two studies[14?-1431’com-
`pared 1 dose of beclomethasone with 2 dose levels
`of fluticasone propionate in -183 patients for 12
`weeks and in 466 patients for 26 weeks, respec-
`tively. The 2 remaining studies, each lasting 12
`weeks, both considered mometasone. One was a
`comparison with beclomethasone at twice the
`standard daily dose in 387 patients[1231 and the.
`
`0 Ads International Limited. All rights reserved.
`/
`
`Nielsen-ét al.
`
`i
`
`other regarded an equi—nominal dose offluticasone
`propionate in 459 patients.[144],N6ne of these
`studies revealed any difference in the relief of
`‘synu$rr7rns"of'a1re*r§lc—1-rrirrrtisror i mr
`assessment of treatment-efficacy. Moreover, nasal-
`cytology _sp'ec'im'en's' were 'uiiablé"to dernonsuate
`differences betweentreatments in 23? the stud-
`ie‘s.[142,143]
`'
`'
`’
`
`‘ One randomised, double-blind, 1-year study in
`251 patients reported’ a significantlyvbetfer effect
`with fluticasone propionate compared with an‘
`equi-nominal dose of beclomethasone on nasal
`congestion and secretion as well as relief of ocular
`symptoms.[1451 These findings can paJ1.1y be ex-
`"§17ii?1EEil53'.'t11‘e757g°'17é.T,p5t'>“t€rEy bf flufi ¥ "
`onate. Of note, the difference was not reconfirmed
`by the 2 studies discussed in the previous para-
`graph. “,42~1431 A smaller randomised, double-blind,
`cross—over study comparing beclomethasone and
`flunisolide in 23 patients with perennial rhinitis, 15
`of whom were allergic, did not show differences in
`efficacy for symptom relief or on more objective
`parameters of nasal blockage, that is, nasal peak
`flow and posterior rhinomanometry.[1451'
`In contrast, 2 studies comparing beclometh-
`asone. and budesonide;witl1single—.b1indE147] or non-
`blind[14’31 design seem.to favour the latter. Two
`_ single-blind studies have compared fluticasone
`propionate and budesonide. One study[1491 demon-
`strated budesonide to be_superior, especially for re-
`lief of nasal congestion. The other study,[1231 which
`compared budesonide 200 and 400p.g daily given
`by turbuhaler to fluticasone propionate 200p.g
`daily, did not reconfirm this. One single-b1ind[‘5°]
`and l non-blind study[1511 have shown beclometh-
`asone and flunisolide to be equally effective.
`
`_
`2.3.2 seasonal Allergic Rhinitis
`Comparisonsof e'ffi'c'acyi betw?'_eeri‘IN‘CS in pa-
`tients. with SAR do not differ. significantly from
`those in patients with PAR. Two ‘randomised, dou-
`ble-blind, placebo-controlled comparisons Of
`beclomethasone and mometasone, which both in-
`cluded >300 patients, over a period of 4 and 8
`weeks, respectively,[153-15.33 did not demonstrate
`differences between the 2 agents. Similarly, no dif-
`
`. Dmgs200l;ol (H)
`
`.114
`
`M ED_DYM_00005349
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`1:
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`Corticosteroids in Allergic
`
`_
`
`1569
`
`a single-blind, cross-over, placebo-controlled de-
`" sign with treatment periods_of five days in 20 pa-
`tients with allergic rhinitis. No differences between -
`treatments were seen for any of th_e‘paran1eters.
`
`'
`
`3. Comparing Antihlstarnines and
`_ Intrcrnascrl Corticosteroids
`
`3.1 Perennial Allergic Rhinitis
`
`_
`
`'
`
`.
`
`1
`
`fercnce in treatment effect was seen in another
`study of similar design, which compared beclo-
`_methasone and fluticasone propionate in 313 pa-
`tients for2 weeks.[‘541 Only 1 randomised, double-
`blind study has shown ‘a difference between 2 ‘A
`INCS, that is, beclomethasone and budesonide.[1551
`However, this 7-week study, which included 56 pa-
`tients, had variable dose administration, ranging
`from 0 to 800l.l.g daily, and the difference was seen "-
`as less consumption of doses in the budesonide
`group.
`‘
`No differences in treatment effect were seen in
`1 non-blind“55] and 2 single-bli’nd[157’153] compar-
`isons of beclomethasone and flunisolide, :even
`though 1 study used a rather low dose of beclo-
`methasone.[1531 Similarly, in single-blind compar- _
`isons, flunisolide.,.W.as cquiyalent .to_b1;des_oj;lide_F1.5?]
`and triarncinolone was equivalentto fluticasone
`propionate.[1°°1. Budesonide was superior to beclo-
`methasone in relief of Sneezing in 1 single-‘blind
`compatisonlml and for relief of sneezing, nasal _,
`secretion and itching in another.”52] In a single- _
`blind study, 2 dose levels of budesonide were com-
`pared with 1 dose level -of fluticasone propi o-
`naIe.[1531 This showed a marginally better effect of
`the higher dose of budesonide on’ sneezing but oth-
`erwise no differences between the 2 drugs.
`
`A number of studies have compared antihista-
`mines and INCS in patients with allergic rhinitis
`(table I and II).
`Few studies have been performed in patients
`’with'PAR. 'IWo 4-week studies compared terfenad-
`ine to beclomethasone[1541 and astemizole with
`,.budesonide,”_§51 respectively. Both demonstrated
`that the INGS was~superi-or for the relief of nasal .
`symptoms. One small (n = 8) l2-week study of
`astemizole and" beclomethasone was unable ‘to
`show differences between the 2 d:rugs.[156]
`Topical antihistamines and INCS have also
`been compared, with no demonstrable differences
`shown between azelastine and beclomethasone for
`relief of. symptoms, physicians assessment of effi-
`cacy or'nasal blockage, as measured by,rhino—
`'manometry.[1571 However, when azelastine was
`compared with budesonide, the INCS was signifi-
`_‘.;.__._-c_an_t_l)L_.superior for_all nasal sy1'_n_p_t_oms:[1,§¥1 A
`“+2.‘3.‘3“saler;r '
`single—blind comparison of levocabasfine and beclo-
`The occurrence of adverse effects was similar
`methasone, which was a follow-up on_ a double-
`in all of the comparisons of INCS discussed in this
`blind comparison of 'levocabastine and placebo,
`section (2.3), apart from 2 studies showing less na-
`demonstrated that beclomethasone provided better '
`sal irritation with budesonide than flunisolide and '
`relief of nasal obst1'ucti_on.[1°91
`beclomethasone, respectively.[155-1591Only 3 stud-
`ies have compared the systemic impact of INCS in
`patients with allergic rhinitis. Two of these have,“
`been mentioned already, one comparing budeson-
`ide and fluticas_o_n_e'pro_pionatej’i'r1 adults[1281 and the
`other budesonide and mometasone in"children.[14°]
`_
`erences 1ni11T1e
`" ' Ifie f11'StWaSl1Il'ab, _e'to
`sc ose
`cortisol levels-,'v'vhile the second didnot reveal any
`differences‘ in short term leg growth rate.‘ The third
`study considered the influence of budesonide,
`mometasone and triamcinolone on plasma and .
`urine cortisol levels as well as serum osteocalcin
`. ‘.7
`levels and blood eosinophil,-cou_nts.[1371 It applied
`.“.’-,-“:"' '
`55;
`
`3.2 Seasonal Allergic Rhinitis
`Several comparisons of antihistamines and
`JNCS have been conducted in patients with SAR,
`almost_ all beingrandomised and double“-blind"'
`“stufl'ie‘s‘Ctab‘Ie‘I’a:trd’II);" --
`-
`_
`The results of_14 comparative studies of oral anti-
`histamines, in a total of >2500 patients, have been
`presented (terfenadine vs beclomethasone”7°-1711
`and fluticasone propionate;[2°=172=1731 loratadine vs
`beclomethasone,[1741 n,-lamcinolone“75r1751 and fluti-
`casone propionate;[177r1731 astemizole vs beclometh-
`
`Drugs200l:6l (11)
`
`O Adis International Limited. All rights reserved.
`
`MED_DYM_00005350
`
`

`
` ,,,,
`
`Case 1:14-cv-01453-LPS Document 43-16 Filed 10/22/15 Page 9 of 119 PageID #: 1189
`Case 1:14—cv—O1453—LPS Document 43-16 Filed 10/22/15 Page 9 of 119 PagelD #: 1189
`
`1570.
`
`.
`
`
`.
`
`Nielsén et al.
`
`Table Lcomperative studies of oral antihistamines and intranasal corticosteroids in patients with allergic rhinitis.
`Reference
`Study design
`No. of ms Active treatments (daily dose)
`Duration
`'
`'_
`(weeks)
`
`,
`
`.
`
`Qomparative efficacy“
`. /’
`-
`
`..Pere"nia,_alm,gic7hihitis.
`Robinson et al.l‘5“1
`._
`_
`__ _
`Bunna9 et a|."°53
`
`_
`
`_
`
`Sibbald et a1.i‘°°l
`
`Seasonal allergic rhinitis
`Bronsky et a|.l3°]
`.
`Beswick et al.“7°1
`'
`Lancer et a|.“7‘3
`‘ "'—._'_:'j'_“' """-
`Darnell et al.[‘721
`
`van Bavel et aI."7°1
`
`. ..
`
`_,
`
`H
`
`r,db.co
`__
`r.db
`
`nb.co
`
`r.db
`‘
`r.db
`
`r.db
`" F
`r,db,p
`
`_
`
`__
`
`4
`
`,
`
`_.
`
`..
`_._a__—_.. ._.__.--_... ..
`..
`.
`.
`18 .
`.
`. Terfenadine
`_
`._
`120mg/beclomethasone 40014.9
`67
`Astemlzole 10mg/budesoni
`400149‘
`-
`.
`Astemizole
`10-30m’g/beclomethasone 400149
`
`..
`
`. .2x4.
`
`4
`
`2x1 2
`
`.. .. Beclornethasone > V
`terfenadine
`Budesooide >
`astemizole
`NS
`
`'
`
`8
`
`"
`'
`.
`Terfenadlne 120mg/flutlcasone
`proplonate 20014.9
`'
`Terfenadine
`120mg/beclomethasone 400149
`Terfenadlne
`-
`
`348
`
`49
`
`18
`
`214 '
`
`'
`
`232
`
`’ '60
`
`_
`
`4
`
`_
`
`4
`I
`8 '
`
`6
`
`2
`
`3 .
`
`,
`
`’
`
`'
`
`Fluficajsone propionate
`$. terfenadine
`" Beclomethasone >
`_
`terfenadine“
`-NS
`-Wu" -‘fl.-..--—“—— -_ —_—_—.’¢T—.j‘_-
`Fluticasone propionate
`> terfenadine
`1
`Fluticasone propionate
`> terfenadlne
`Beclo