Case 1:14-cv-01453-LPS Document 43-9 Filed 10/22/15 Page 1 of 51 PageID #: 589
`F5 Case 1:14-cv-O
`. e|D #5 589
`
`REVIEW ARTICLE
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`D
`2001; 61 (11): 1563-1579
`0D12—[:6gé>S7/01/0011-1563/$27.50/O
`©AdisInternat1‘ona1 Limited. A11 rights reserved.
`
`Intranasal Corticosteroids for A
`Allergic Rhinitis
`Superior Relief?
`
`Lars Peter z'elsen,1r2‘ 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
`
`Contents
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`Abstract‘
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`. .1 .
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`1. Antihistamines
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`' 1.71"GeneraiCon’sid&&§tiEjns .2 .
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`1.2 Oral Antihistamines .
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`1.3 TopicalAntihistamines .
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`.1.4 Comparative Effect of Antihistamines .
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`1.4.1 Single Dose Studies .
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`1.4.2 Perennia1A1lergic Rhinitis .
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`1.4.3 SeasonaiAliergic 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 General Considerations .
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`2.2 intranasai Corticosteroids .
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`.;__2.3 Co_r_np_a.r_ative.Effect o1‘_1ntranasgigorticosteroids
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`2.3.1 Perennial Allergic Rhinitis .
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`2.3.2 Seasona1Al1ergic Rhinitis
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`2.3.3 Safety._....__.... .
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`3. Comparing Antihistamines and intranasal Corticosteroids .
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`3.1 Perer1niaiA1lergic Rhinitis .
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`3.2 SeasonaIAilergic Rhinitis .
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`3.3 Combination of Antihistamines and lntranasai Corticosteroids
`3.4 Safety '
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`3.5 CostE1‘fectiveness
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`4. Conclusion .
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`5.
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`AbSl'fC|Cl'
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`I
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`Whether f1rst~1ine pharmacological treatment of. allergic rhinitis should be
`antihistamines or intranasal corticosteroids has been discussed for several years.
`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
`‘S:
`:.>:.:--»-
`
`MED_DYM_00001383
`
`

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`.,....n.......+i
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`?
`2
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`Case 1:14-cv-01453-LPS Document 43-9 Filed 10/22/15 Page 2 of 51 PageID #: 590
`Case 1:_14—cv—O1453—LPS Document 4349 Filed 10/22/15 Page 2 of 51 Pa_ge|D #: 590
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`Nielsen 'et al.
`_
`1564
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`have been unable to_demonstrate superior efficacy for one method of administra-
`tion over the other.
`I, /
`Current data documents no striking differences in efficacy and/safety param-
`eters-between——int1=an—asal-eortieesteroidsf-
`_r
`O
`O
`1
`
`When the efficacy of antihistamines and intranasal corticosteroids are com- V
`pared in patients with allergic rhinitis, present datafavoursintranasal cor_’gicoste—
`roids. Interestingly, data do not show antihistamines as superior for the treatment
`of conjunctivitis. Safety data from comparative studies in patients with allergic
`rhinitis do not indicate differences between antihistamines and intranasal corti-
`
`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 of current data, intranasal corticosteroids seem
`to ‘offer superior relief in allergic rhinitis than antihistamines.
`'
`‘
`
`i Allergic rhinitis is a commoficfili ed7
`by animmunoglobulin (Ig)E—mediated allergic in.-
`flammation of the nasal ifiucosa and characterised
`
`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 countriesm Moreover, this prevalence
`seems to be increasing.l2=3] Although allergic rhini-
`tis is not a life—threatening disease, it can severely
`impact on quality of life[4'6] and be associated with
`comorbidity from other diseases, for example,
`asthma and conjunctivitis;[7l
`‘
`’
`Treatment of allergic rhinitis consists of aller-
`gen avoidance, allerg.en—specific irnmunotherapy 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.[8]
`
`This review considers first-line 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-
`temic 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.
`
`"Mi ."A‘fifihi§féIr7r?es
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`.
`
`‘l
`
`11 General Considerations
`
`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.[9’1°] In addition to H1-recep-
`tor blockade, an anti-inflammatory-effect of anti-
`histamines has been proposed, as some of the newer
`compounds have beenshown to influence cytokine
`production, mediator release and inflammatory cell
`flux.[“'193 However, other studies have been unable
`to confirm these findings.[2°'23l Whether antihista-
`mines offer a clinically beneficial anti—inflammatory
`effect in addition to inhibition ofhistamine 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. chlorphenamine (chlor-
`pheniramine), diphenhydramine,‘ promethazine
`and ltriprolidine] and newer second—generation an-
`tihistamines (acrivastine, astemizole, cetirizinei
`ebastine, fexofenadine, loratadine, mizolastine and
`terfenadine). This review deals with the newer an-A
`
`tihistamines as the use of the older drugs in allergic
`
`© Adis International Limited. All rights reserved.
`
`Drugs 2001; 61 (ll)
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`MED_DYM_00001384
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`

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`Case 1:14-cv-01453-LPS Document 43-9 Filed 10/22/15 Page 3 of 51 PageID #: 591
`7'5”.ase 1:14-cv-01453-LPS Document 43-9 Filed 10/22/15 Page 3 of 51 Page|D ii.’ 591
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`1565
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`rhinitis is limited by their adverse effects, mainly
`Sedation and anticholinergic activity.
`a
`A11 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‘"311 They are
`also effective for conjunctivitis and recent results
`Seem to indicate some influence on lower airway
`SymptOmS.[32’33]
`W
`W
`Moreover, the pharmacokinetic profile of second-
`aeneration antihistamines are advantageous when
`ggmpared with the first-generation agents.[34] They
`have an onset of action of 1 to Zhours which lasts
`fgr 12 to 24 hours, except for acrivastine, which
`has to be administered at 8-hourly intervals. With‘
`the exception of cetirizine and fexofenadine,
`which are excreted almostiunchanged, 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-
`mycotic azoles, macrolide antibiotics and grape-
`fruit juice, are also substrates for this enzyme, this
`obviously provides a risk for interacti0_ns.[35] This
`is probably a contributive factor tothe occurrence
`of severe cardiac arrhythmias, for example, ‘tor-
`sade de pointes’, and fatalities, which have been
`described following treatment with terfenadine
`;__and astemiz9_1:c_L.[§-6;.3,E:lIh<?..s,_e -effect_s_.s§;<:1r1 tO_.b.6_¢!1:_
`abled through “a quinidine—like action, causing a
`prolongation of the QTpinterv.al.[39’4°] At present,
`no clinical evidence has demonstrated cardiac ad-
`
`izole remains unknown as there is a lack of data on
`the other second-generation antihistamines for this
`measure.
`
`Whereas CNS—related adverse effects were a
`major characteristic of the first—generation antihis-
`tamines, the piperazine/piperidine-derived struc-
`tures of the newer generation agents reduce CNS
`\ penetration, although sedative effects have been
`described for some of the compounds, for example,
`b acrivastine[441 and cetirizine.[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.
`
`1 ,3 TopicoFAntihistqmines
`
`Two newer Hyreceptor 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.[f‘5’47]
`They have a faster onset of action 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=48] whereas the occurrence of a short last-
`ing perversion of vtastjcphas beenpdescribed for
`azelastine. [491
`
`1.4 Compc1ro’rive'Effec’r otAn’rihistc1mi-hes
`
`verse effects with other second-generation antihis-
`tamines when they are used at therapeutically ap-
`propriate levels. However, it is recommended to
`avoid antihistamines which are CYP450 metabo-
`
`1.4.1 Single Dose Studies
`_ Many studies have been performed to compare
`the effects of oral second-generation antihista-
`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 cetirizine and terfenadine have
`risk groups, that is, patients with impaired hepatic
`function or cardiac*'arrhythmi'a;[411
`T a faster onset of“action than loratadine and astem-
`/
`Astern1zole*can“also~act~as~anappetitestimulant~~~~1z01e-t50,5-1—]—AH_4 dmgs Were. equa.1]_,y.effeetj_Ve
`and result in increasedbodyweight. [42,43] The cause
`against nasal symptoms and histamine—induced in-
`for this action remains obscure, although a central
`creases in nasal airway resistance. This contrasts
`somewhat with the results of 2 studies in which
`nervous system (CNS)-mediated mechanism, for ex-
`cetirizine was superior to loratadine after adminis-
`ample, serotonin (5—hydroxytryptan1ine)—antago-
`tration of a single dose in both symptom reliefm] ‘
`nism, is a theoretical possibility. Howevenwhether
`and response to histamine challenge.[531 One study
`this adverse effect is seen exclusively with astem—
`.
`‘39’
`;—_'~.:-'' ~
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`A
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`© Adis International Limited. All rights reserved.
`
`Drugs 2001;61 (1 1)
`
`MED_DYM_00001385
`
`

`
`Case 1:14-cv-01453-LPS Document 43-9 Filed 10/22/15 Page 4 of 51 PageID #: 592
`Case 1:,14—cv—O1453—LPS Document 43-59 Filed 10/22/15 Page 4 of 51 Pa_ge|D #: 592
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`
`Nielsen at :11.
`1566
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`
`was able to dernonstrate a significantly faster onset
`of action for fexofenadine compared with terfenad-
`ine in relief of rhinorrhoea and sneezing immedi-
`atel §1_allergen challerig"e:‘.[5’4‘] This may be_"’
`explained on the basis of fexofenadine being the c
`active metabolite of terfenadine.
`
`shows cetirizine to have a faster "onset of action
`than terfenadine,[731 while another gclairns ebastine
`to achieve maximum effect/faster than cetiriz-
`i ine. W3‘ Theiu’s‘e'ofothe“robjectiverendpoirrts-snch
`as nasal peak _flow[7.°l and inflarrrmatoryirnediators
`in nasal lavage fluidm] has not shown, differences
`between agents;
`
`.?
`
`i
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`5;
`
`A
`
`1.4.2 Perennial Allergic Rhinifis
`Relatively few studies investigating continuous
`administration of antihistamines are in patients
`with perennial allergic rhinitis (PAR). Six studies
`ranging from 1 to 8‘ weeks, included comparisons of
`astemiz'ole[55v563 cetirizine,[5‘?‘-535] ebastine,[57] lorata—
`dine,[55’59~6°] mizo1astine[59] and terfenadine.[58»5°]
`No d-iffereneees» between ’ agents—wereseen_4except-..._-.
`that asternizole was more effective than loratadine
`for rhinorrhoea in 1 shortterrn study, [55] and cetiriz-
`fine was better than ebastine according to the inves-
`tigators opinion in another study.[57] Interestingly,
`in 1 of the studies, nonresponders were crossed to
`the opposite drug at the end of a 2 week treatment
`period, resulting in an effect in 11 of the 16 pa-
`tients.[6°]
`‘
`‘
`
`V
`1.4.3 SeasonoiIAllergic Rhinitis _
`The lack of difference in effectiveness between
`
`I second-generation drugsis also found in patients
`with seasonal allergic rhinitis (SAR9. One placebo-
`controlled study in 202 patients with SAR seems
`to designate cetirizine as superior to 1oratadine,[61_]
`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—con1:rol-
`led, cross—over studyof identical treatments given ,
`for 1 weel<.[5‘°-1
`.
`Several seasonal studies involving acr-ivastine,[633
`asternizole[42=641 cetirizine,[64'69] ebastine,[67] fexo~
`fenadine,[58] loratadine,[42s7°1rnizolastine[593 and
`terfenadine[65=56’70] 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 asterniz-
`olem] or investigator preference of ebastine over
`cetirizinem] without any support for this in other
`endpoints, for eXarnple,.syrnptom relief. One study
`
`to Adisylnrernotioncil Limited. All rights reserved.
`
`/
`
`1.4.4 Studies in Children
`
`Data on the ‘efficacy in children with-allergic
`rhinitis are sparse.iOne sing1e—blind study in chil-
`dren with SAR for 2 weeks showed’ equal effect of
`loratadine and asternizole.[75]’ In [another I4-week
`study in children with PAR, cetirizine was superior
`to loratadine' aceomirgr6parejnta1j'assjessirnentiiéiv '
`I
`
`_
`7.4.5 Topical vs Oramnrihistcimines
`A 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 than cetir-
`izine at relieving nasal congestion,[771 whereas other
`studies have demonstrated azelastine to be equally
`effective as cetirizine,[731 ebastine,[79] loratadineigol
`and . terfenadine.[81] In ,2 studies, . intranasal levo-
`cabastine has been marginally more effective than
`‘terfenadine in relieving single symptoms,
`ie.
`sneezing”?-3 and nasal itching,[83] whereas a third
`study did not show any difference.[841 In 1 study,[83]
`levocabastine given as eye dropswere also judged
`superior to terfenadine for relieving ocular symp-
`toms. A comparison of levocabastine and loratad-
`ine showed identical efficacy.[35]
`
`,
`1.4.6 Safely
`When considering adverse effects, only 2 of the
`previously mentioned studies indicate differences.
`A large, placebo—icontrolled,“ 2—’wee‘k"study'in 821
`patients with SAR showed a significantly highef
`degree of sedation after cetirizine than'fexofenad-
`ir1e.[58]
`
`In another smaller 8-week study in 27 patients
`with SAR, terfenadine revealed more adverse 61°‘
`fects, that is, headache and dizziness, than a com-
`bination of intranasal and ocular levocabastine.[82]
`
`Drugs 2001; 61 (1 ‘I?
`
`MED_DYM_00001386
`
`

`
`
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`
`Corticosteroids in Allergic Rhinitis
`
`
`15.67
`
`2, Corticosteroids
`
`2.1 General Considerations
`
`intranasal application, all characterised by a high »
`receptor amnity and an extensive first-pass meta-
`bolism in the liver. Effectiveness in relieving the
`symptoms of allergic, rhinitis, including nasal con-
`gestion, have been demonstrated for beclometh—
`asone,E1°4] budesonide,[1°51 flunisolide,[1°5] fluticasone
`propionate,[107] mometasoneimgl and triamcino—
`lone.[1°9] In addition, some reports" have indicated
`that 1NCS~may have a beneficial effect towards
`
`bronchial hyperresponsiveness and asthma symp-
`toms.[11°‘115]
`
`It has been generally considered that INCS
`g
`have a slow onset of action. However, they usu-
`C ally act within 12 to 24 hours.[“5'“8] Recent re-
`sults have even indicated that budesonide acts after
`
`Allergic rhinitis is an inflammatory disease of
`the nasal mucosa and corticosteroids are, at pres-
`ent, the most potent anti-inflammatory medica-
`tions commercially available for the treatment of ,
`allergic rhinitis.[86] Corticosteroids exert their ef— ‘
`feet by combining with a glucocorticoid receptor
`localised in target cell cytoplasm. The resulting ac-
`[ivated glucocorticoid receptor complex is able to
`interact withlcellular DNA, thereby enabling reg-
`ulation of cellular functions.[87’88]
`Corticosteroids act upon many of the cell types
`and inflammatory mediators participating in aller-
`3 hours.[”9] -However, maximum treatment effi-
`gic inflammation. Antigen-presenting Langerhans’
`cacy occurs after days or acfewcweeks;[‘12°] Once:
`cells are reduced i’n”’nufi1‘b”er"l5y"INCS.[89v9Q] More-
`daily application has proven sufficient to treat
`over, such treatrnent seems to impair their process-
`most patients with allergic rhinitis,[121‘1253 al-
`ing of antigen.[91] Similarly, the migration of baso-
`though those with severe symptoms may benefit
`phils ‘and m.ast cells to the nasal epithelium is
`from twice daily As,1drriinistrat_ion.N['-125]
`inhibited by lNCS.[91‘941 Evidence suggesting an
`The different potencies of INCS are important
`impact on the release of mast cell mediators, that
`is,'histamine, has also been p_resented.[95]_ Cortico-
`when considering comparative data. It is well es-
`tablished that fluticasone propionatewis twice as po-
`steroid therapy interferes with several pivotal as-
`pects of eosinophil function. Cell survival is de-
`tent as beclomethasone.“°71 There is controversy
`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-
`,..__';_‘l:€.l.Il andeosinophil peroxidase, isinhib.iIed.l9_6:’97l
`-1——fl—ut—ieasoI-iepro-pie-nate and-mo-metasone,-are-more~
`Moreover, formation of a number of cytokines and
`potent than the others.[“7] A
`.
`chemokines vital to eosinophil lifespan are inhib-
`Currently. available INCS are generally well tol-
`ited, for example,
`interleukin (IL)—5 (forma-
`erated. Sneezing caused by nasal hyperactivity can _
`tion),[98] IL-4 (adhesion)[99] and RANTES [Regu-
`occur at the start of therapy but this usually disap-
`lated on Activation,‘ Normal T cell Expressed and
`pears with time.[127]
`_
`Secreted] (chemotaxis).[1°°1 Results demonstrating
`Occasionally, mild and transient dryness, crusting
`an inhibitory effect of intranasal corticosteroid on
`and blood—stained secretions occur, and these are often
`activated T cells in nasal epithelium have been pre-
`responsive to a reduction of ll\ICS.dose.512°=128r1291—
`sented.[.1011 In 2 studies, the,al;lergen-induced in-
`Septal perforation has been described as a rare
`c
`crease of specific IgE*inpatients*with*cPAR during ‘
`cornp1icatio”n.[1”3°v1311 Atrophy” of the mucosgéor-
`season-w—a-s-a-boli—shed4fll‘51—In—all:this—i-ndieates————
`re al atrophy, after prolonged use
`profound effects of corticosteroids on the inflam-
`of INCS has not been observed.-[132=133]
`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 concern for this class of
`drugs. However, these cornpounds, especially the
`
`2.2 lntrcinoisol Corticosteroids
`
`Since the introduction of beclomethasone,[3]
`several corticosteroids have been developed "for
`
`
`© Adis internotionoi Limited. All rights reserved.
`
`Drugs 2001: 61 (1 l)
`
`MED_DYM_00001387
`
`

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`
`
`
`Nielseil-ét lzl.
`
`
`
`1568
`
`.
`
`'
`
`newer fluticasone propionate and mometasone,
`have low systemic bioavailability, mainly because
`of their massive, first—pass metabolism in the
`%IiveE['1‘1’7‘1‘Wli‘e1T used éXC_lEV37l'}7—ifi’fIW1§S“3.'ll7 ‘at
`therapeutic dosages, the drugs in this class do not
`seem to exhibit any influence on the hypothala-
`mus-pituitary—adrenal (HPA)-axis.[134'137], How-
`ever, a lack of HPA—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-T,budesonide,[138:139] al-
`though the result for budesonidewas only achieved
`by giving an adult dose of 200itg twice daily. More-
`*ov‘eE3HfsE6n‘1a‘fi6t be i€cmifim dy
`in which the impact on child growth, as measured
`. by lower legknernometry, of budesonide 400iLg
`daily was comparable to placebo.[14°l Other sys-
`ternic 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}-141]
`
`2.3 Comparative Effect of T
`~ lntronosol 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 been published. Two studies[142_=143] com-
`pared l 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”23] and the
`
`© Adis International Limited. All rights reserved.
`
`/
`
`other regarded an equi—noIninal dose offluticasone
`propionate in 459 patients.[144},N6ne of these
`studies revealed any difference in the relief of
`’sTympfoI'r1's"’of allergic rlTiT1“itis or in the plryeicians“
`assessment of treatrnentrefficacy. Moreover, nasal-
`cytology _spec'imens' were 'ufiable"to' demonstrate
`differences between treatments in 2_iff the stud-
`ieS_[14-2,143]
`-
`n
`
`One randomised, double—blind, 1-year study in
`251 patients reported a significantly better 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 partly be ex-
`ipilaiiiedby 'tHe7Hi*gher_p_otency’of f1iiliC_.a,sorie ‘propi-
`onate. Of note, the difference was not "reconfirmed
`by the 2 studies discussed in the previous para-
`graph.[142v14-°’l 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.[145]
`In contrast, 2 studies comparing beclometh-
`asone and budesonide:with—single-blindtm1 or non-
`blind[1483 design seemto favour the latter. Two
`, single-blind studies have compared fluticasone
`propionate and budesonide. One study[149] demon-
`strated budesonide to be superior, especially for re-
`lief of nasal congestion. The other studying] which
`compared budesonide 200 and 400tLg daily given
`by turbuhaler to fluticasone propionate 200l.Lg
`daily, did not reconfirm this. One single—blind[15°i
`and l non-blind study[151] have shown beclometh-
`asone and flunisolide to be equally effective.
`
`2.3.2 Seasonal Allergic Rhinitis
`Comparisons of efficacy between’ INCS 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,[152=15.3] did not demonstrate
`differences between the 2 agents. Similarly, no dif-
`
`. Drugs 2001/61 (ll)
`
`MED_DYM_00001388
`
`

`
`Case 1:14-cv-01453-LPS Document 43-9 Filed 10/22/15 Page 7 of 51 PageID #: 595
`1'“ Case l:l4—cv—O1453—LPS Document 43-9 Filed 10/22/15 Page 7 of 51 PagelD #1/595
`
`Corticosteroids in Allergic Rhinitis
`M
`
`
`1569
`
`a single-blind, cross-over, placebo—controlled de-
`sign with treatment periodsof five days in 20 pa-
`tients with allergic rhinitis. No differences between -
`treatments were seen for any of thepararneters.
`
`n
`
`3. Comparing Antihistamines and
`lntrancisol Corticosteroids
`
`3.1 Perennial Allergic Rhinitis
`
`ference in treatment effect was seen in another
`study of similar design, which compared beclo-
`methasone and fluticasone propionate in 313 pa-
`tients for 2 weeks.[154] Only 1 randomised, double-
`blind study has shown a difference between 2 n
`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 800ug 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[155l and 2 single—blind[157=1581 compar-
`isons of beclomethasone and flunisolide, even
`though 1 study used a rather low dose of beclo-
`methasone.l1583 Similarly, in single-blind compar-
`isons, flunisolide was equivalent to_budesonideU59_l
`and triamcinolone was equivalent to fluticasone
`propionate.l15°l. Budesonide was superior to beclo-
`methasone in relief of sneezing in 1 single-blind
`oomparisonm” and for relief of sneezing, nasal
`secretion and itching in another.[152] In a single- V
`blind study, 2 dose levels of budesonide were com-
`pared with 1 dose level of fluticasone propio—
`nate.[153] 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 11).
`Few studies have been performed in patients
`'withPAR. Two 4-week studies compared terfenad—
`ine to beclomethasonelml and astemizole with
`.budesonide,[1§5l respectively. Both demonstrated
`that the INCS was superior -for the relief of nasal
`"symptoms. One small (n = 8) 12-week study of
`astemizole andibeclomethasone was unable to
`show differences between the 2 dn1gs.[1561
`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.[157] However, when azelastine was
`' ‘compared with budesonide, the INCS was signifi-
`. _..-.cant_ly_superior fo_r_al_l_nasal syr_nptorns;[1f53l A
`single-blind comparison of levocabastjne andbeclo-
`methasone, which was a follow—up on a double-
`blind comparison of levocabastine and placebo,
`demonstrated that beclomethasone provided better '
`. relief of nasal obstruction.[169]
`
`.
`_
`s
`,
`an
`’
`"
`’
`*2-Ifsaferv
`The occurrence of adverse effects was similar
`
`in all of the comparisons of INCS discussed in this
`section (2.3), apart from 2 studies showing less na-
`sal irritation with budesonide than flunisolide and
`
`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— H
`ide and fluticasonelpropionatei/n_adults[123] and the
`other budesonide and rnometasone in"children.[14°] T 7
`iTlTe”fi"r"st_wEun'a5Ie'to disclose differences in iifihe
`cortisol levelsi,/while the second did not 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
`levels and blood eosinophil counts.[137] It applied
`«V
`
`3.2 Seosonol Allergic Rhinitis
`
`Several comparisons of antihistamines and
`INCS have been conducted in patients with SAR,
`almost all beingrandomised and double-blind ’
`'S‘fi1'i‘i*€s“('t7ibTe_I‘afI1'd‘II)’;"
`"
`‘
`_
`-
`The results of 14 comparative studies of oral anti-
`histamines, in a total of >2500 patients, have been
`presented (terfenadine vs beclometl1asone“70’1713
`and fluticasone propionate;[2°-174173] loratadine vs
`beclomethasonefml t1iamcinolone[175=176] and fluti- ‘
`casone propionate;“77’178l asternizole vs beclometh-
`
`© Adis lnternotionoi Limited. All rights reserved.
`
`Drugs 2001: bl (1 l)
`
`MED_DYM_00001389
`
`

`
`Case 1:14-cv-01453-LPS Document 43-9 Filed 10/22/15 Page 8 of 51 PageID #: 596
`Case 1:,14—cv—O1453—LPS Document 43-59 Filed 10/22/15 Page 8 of 51 Pa_gelD #: 596
`
`Nielsen et Lil.
`
`
`
`
`.
`/
`Table l. Comparative studies of oral antihistamines and intranasal corticosteroids in patients with allergic rhinitis.
`Comparative efficacya
`Reference
`Study design
`No. of pts— Active treatments (daily dose)
`Duration
`‘ - ’ (weeks) / /
`
`
`
`
`
`_
`
`“Perennia|‘allergi'c‘1'hinitis’ ‘ "
`Robinson et al.l‘6‘”
`W _7 _
`p
`,_
`
`A
`
`7
`
`Bunnag et al_[1ss1_
`
`Sibbald et a|.[155]
`
`Seasonal allergic rhinitis
`
`Bronsky et a|.l2°l
`.
`Beswick et al.“7°}
`
`Lancer et al.[‘7”
`"’ ’A’’”‘'’ '’ " ’
`Darnell et al.[‘721
`
`‘
`
`van Bavel et ai.[‘733
`
`'
`
`r,db,co
`_V
`
`r,db
`
`nb,co
`
`r,db
`-
`r,db
`
`r,db
`"'
`r,db,p
`
`r,db,p
`,
`‘
`
`"
`" “ "
`. ..
`.
`.
`18 .
`.
`Terfenadine
`, _
`120mg/beclomethasone 400ug
`
`.
`
`__
`
`. - 2x4.. .
`
`.
`
`.. .. Beclomethasone > .
`terfenadine
`
`67
`
`-
`
`8
`
`348
`
`49
`
`18
`
`.
`
`214
`
`’
`
`232
`
`Astemizole 10mg/budesonide
`400i.ig
`—
`Astemizole
`10-30mg/beclomethasone 400ug
`
`4
`
`2x12
`
`Budesorjlde >
`astemizole
`NS
`
`’
`
`Fluticasone propionate
`'>/teifenadiiie
`Beclomethasone >
`terfenadine”
`-NS
`
`i
`
`W
`
`4
`
`4
`
`8
`
`6
`
`2
`
`Terfenadine 120mg/fluticasone
`propionate 200pg'
`*
`Terfenadine
`120mg/beclomethasone 400pg
`Terfenadine
`'0m97,beCl0m9ThaS0TT9' 4'00’FF9
`Terfenadine 120mg/fluticasone
`propionate 200ug
`K
`Terfenadine 120mg/fluticasone
`propionate 200ug
`
`Loratadine
`10mg/beclomethasone 400i.i.g
`Loratadine 10mg/triamcinolone
`220p.g
`
`Loratadine 10mg/triamcinolone
`220ug
`
`3
`
`4
`
`4
`
`W Z "W"
`Fluticasone propionate
`> terfenadine
`‘
`Fluticasone propionate
`> terfenadine
`
`Beclomethasone >
`Ioratadine‘
`‘
`4
`Triamcinolone >
`Ioratadine
`
`Triamcinolone >
`Ioratadine ’
`-
`‘
`
`Frolund[‘7"]
`,
`Condemi et al.“75]
`
`Schoenwetter and Lim[l7.51
`
`r,db
`
`I r,db
`
`r,db
`
`‘ I60
`'
`348
`
`274
`
`Gehanno and