.
`CENTER FOR DRUG EVALUATION AND RESEARCH
`" ·~-
`
`Application Number 21- fJlr
`
`-
`
`FINAI1 PRINTED LABELING
`
`Exhibit 1030
`IPR2017-00807
`ARGENTUM
`
`000001
`
`

`

`AUG.24.2000
`
`s:07A'1
`
`Gl...AXO WELLCOME
`
`N0.866
`
`P.2
`
`Af i I c22//{J 0
`
`ADVAIR™ -DISKUS® 100/50
`(fluticasone propionate 100 mcg and salmeterof• 50mcg1.nhalation powder)
`
`PRODUCT INFORMATION
`
`ADVAIR™ DISKUS® 250/50
`(fluticasone propionate 250 mcg and -salmeteror 50 m~ Inhalation powder)
`
`ADVAIR™ DISKus• 500/50
`(flutfcasone propionate 500 mcg and salmeteror• SO mcg· inhalation powder)
`
`•) ..
`
`•As salmeterol xlnafoate salt 72.5 mcg, equlvalent to almeterol base 50 mcg
`
`FOR ORAL INHALATION ONLY
`DESCRIPTION: AOV}JR OISKUS 100150, AOVAIR OISKUS 250/SO, and ADVAIR DISKUS so0lo
`i
`are combinations of flutJcasone propionate and salmeterol xinafoate.
`One active component of AOVAIR OISKUS ls fluticasone propionate, 1 corticosteroid having ~
`chemical name ~(fluoromethyl)6«,9~lfluoro-11p,17-dihydroxy-16"-methyl-3-oxoandrosta-1,4-
`diene-17P-carbothloate, 17-propfonate and the following chemical structun::
`
`F
`
`Fluticasone propionate ls a white to off-white powder with a moleoularwelght of 500.6, and the
`empirical formula ls Czsti31FAS. It Js practlcally Insoluble In water, freely soluble In dimethyl
`sulfoxide and dlme1!JYtfonnamide, and slightly soluble In methanol and 95% ethanol.
`The other active component of AOVAIR OISKUS ls salmeterol xinafoate, a highly selective
`betaradranerglc bronchodilator. salmeterol xinafoate is the race.mic form of the 1-hydroxy-2-
`naphthoie aCtd salt of saJmeteral: The chemical name of salmetarol }(fnafoate I~ 4-hydroxy-« 1·[[16-
`(4-phenyl.butoxy)hexy!JamJnoJmethyl)-1.~benzenedimethanol, 1-hydroxy-2:.naphthalenecarboxylate,
`and ft has the foUowing ohemfcal structure: •
`
`1
`2
`3
`4
`s
`6
`7
`8
`9
`10
`11
`12
`13
`14
`15
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`19
`20.
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`21
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`30
`31
`
`I
`f
`
`000002
`
`

`

`AUG.24.2000
`
`s:07PM
`
`N0.866
`
`P.3
`
`ADVAJR. OISKus• 100/50
`(fluticasone pro pf on ate 100 mcg and salmetero,. 50 mcg Inhalation powder)
`ADVAIR. otsKus• 250150
`. (fluticasone propionate 250 mc:g and safmeteror SO mcg Inhalation powder
`ADVAIR. DIS Kus• 100/50
`.
`;..
`-
`(ftutCcasone propionate SOD mcg and ulmeterol* 50 mcg Inhalation powder)
`0.
`lt
`OH
`H~~~0~-
`1....:
`
`H
`
`32
`33
`34
`35
`36
`37
`38
`39
`40
`41
`42
`43
`44
`45·
`'46
`47
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`49
`so
`51
`52
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`SS
`56
`51·
`58
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`61
`62
`63
`64
`
`H
`
`•··
`
`COi.H
`
`.....:
`
`., ..
`Salmeterof xlnafoate is a while to off-whHe powder with a molecular weight of. 803.8, and the
`emplrtcal tonnula Is ~No .. ·C,1H.O,. It Is hely soluble In methanol; slfghUy soluble in ethanol,
`chlorofonn, and isopropanol; and sparingly soluble In water.
`•
`ADVAIR DJSKUS 100/50, ADVAJR DISKUS 250/SO, and ADVAIR DISKUS 500/50 are specially
`designed plastic devices containing 1 double-foD blister strip Qf a powder fonnulaUon of nuticasone
`propionate and salmeterol xinafoate Intend~ for oral lnhalatlon only. Each bUster on the doubt~yoll
`strip within the device contains 100. 250, or 500 mcg of mlcrofine flutJcasone propionate and · ~
`~
`72.5 meg of mtcrofine sarmeterol xlnafoate salt. equivalent to 50 mcg of safmeterof base. In
`i
`12.5 mg of fonnufatlon containing lactose. Each blister contains 1 complete dose of both
`medications. After a bHster containing medication ls o~ed by activating the device, the
`medication is dispersed Into the alrstream created by the patient lnhaltng through the mouthpiece.
`Under standardized In vittO test conditions, ADVAIR OISKUS delivers 93, 233, and 465 mog of
`fJuticasone propionate and 45 mcg Of satmete"°' base per blister from ADVAfR DISKU.s 100/50,
`250/50. and 500/50, respectively, when tested at a flow rate of 60 Umin for 2 seconds. In adult
`patients (n a 9) with obstructive lung disease and severely compromised Jung f\lnctJon (mean
`forced exi>fratory volume Jn 1 second [FEVd 20% to 30% of predicted), mean peak lnspiratory flow
`(PJF) through a DISKus• device was 80.0 Umin (range, 46.1to116.3 llmln).
`Inhalation profd~ for adolescent {n • 13, aged 12 to 17 yeam) and adult (n a 17, aged 18 to
`so years) patients wtth asthma Inhaling maximaltY through the DISKUS device show mean PIF of
`122.2 l!m'n (range, 8t .8 to 152.1 Umin).
`The actual amount of drug delivered to the lung will depend on patient factors, such as
`inspiratory flow-proltle.
`
`CUNICAL-PtlARMACOLOGY:
`Mechanism of Action: ADVAIR D/SKUS: ADVAIR OISKUS is designed to produce a greater
`Improvement Jn pulmonary function and symptom control Ulan either flutJcassme propionate or
`satmeterol used alone at their recommended dosages. SJnce ADVAIR DISKUS contains both
`flutioasone propionate and &almeterot, the mechanisms of adion described below for the Individual
`components apply to ADV/I.JR OISKUS. These drugs represent 2 classes of medications (a
`synthetic corticosteroid and a long.acting beta-adrenerglc receptor agorllst) that have different
`effects on cliilical, physlologJcal, and Inflammatory Indices of asthma.
`
`2
`
`000003
`
`

`

`AUG.24.2000
`
`s:08PM
`
`GLAXO WELLC-Of'E
`
`N0.866
`
`P.4
`
`ADVAIR. DISKus• 100150
`{flutfcasone propionate 100 mcg and salmeteror SO mcg Inhalation powder)
`.
`ADVAIR. ors Kus• 250/SO
`(ftUticasone propJonate 250 mcg and salmeteror- 50 mcg Inhalation poWder
`ADVAJR. DISKus• SOO/SO
`...
`-
`(flutfeasone propionate soo mcg and salmeteror so mcg Inhalation powder)
`
`65
`66
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`15
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`71
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`19
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`82.
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`19
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`JOO
`101
`
`Flutlc:ilsone Proplon.te: FlutJcasone propionate is a synthetic, trfOuorinated corticosteroid with
`potent anti-inflammatory actJvity, In vitro assays using human lung cytosol J,reparatJons have
`established ft~lcasone propionate as a human glucocortloold receptor agonlst with en aMnlty
`18 times gl88terthan dexamethasone, .,most tWfce that of bedomethdrbne-17-monopropionate
`(BMP), the adNe meblbDOte of beclomathasone dlproplonate, and over 3 times that of bUCfesonfde.
`Data from the McKenzie vasoconstrtctor assay In man are consistent with these results.
`The precise mechanisms of tlutlcasone propionate aatlon la asthma are unknown. Inflammation
`Is recognized as 1n Important component In the pmthogenesil of asthma. Co~rolds'have been
`shown to fnhJbft rnultlple cell types. (e.g •• mast cens, eosinophns, basophns, lymphocytes,
`macrophages, and neutrophlls) and mediator production or sectetJon (e.g., histamine, elcosanoids,
`leukotrienes, and cytokines) Involved In the asthmatic resp0nse. These anti-Inflammatory actions of
`'l
`corticosteroids contribute to thalr.efficacy In asthma.
`Salmetero/ X1nafoate: Salmeteroi' Is a long-acUng beta-edrenerglc agonlst. In vitro studies artif
`In vivo phannsoologlc studies demonstrate that salmeterol ls selective for betar&drenooeptors ~ a
`compared wHh lsoproterenol, which has approximately equal agonlst actMty on beta1• and
`beta2.adrenoceptors. In vitro st:.1dies show salmetarol to be at least 50 times more selective for
`beta2·adrenoceptors than afbuterol. AJthough beta,.adrenoc:eptors are the predominant adtenerglc
`receptors In bronchial smooth muscle and beta1..acfrenoceptors are the predomlaant recep!ors In the
`t\eart, there are also betaradrenoceptors in the human heart comprising 10% to 50% Of the total
`beta-adrenoceptors. The precJse function of these receptors bas not been established, but they raise
`the possi~llity that evan highly selective betaz-agonlsts may have c;ardiao effects.
`The pharmacofoglc effects of betaradrenocejJlor aganJst drugs, Including salmeterol, are at least
`In part attributable to stlmul1Uon of fnttacellular adenyl cyclase, the enzyme that catalyzes the
`conversion of adenaslne triphosphate (ATP) to cyclic-3',6'-adenosine monophosphate (cyclic AMP).
`Increased cyclic AMP levels aause relaxation af bronchJaf Smooth muscle and lnhlbftJon of release
`of mediators of Immediate hypersensJtlvlty from cells, especlally from mast oeUs.
`In vitro tests show that saJmeteroJ Is 1 potent and long-lasting Inhibitor of the release of mast cell
`mediators. such.:-as histamine, leukotr1enes, and prostagtandln ~. from human lung. satmeterol
`Inhibits histamine-lnduoed plasm£ protein extravasation and inhibits platelet-activating
`factor-lncli.11."ect-eastnophR ~lation In the lungs of guinea pigs When administered by the Inhaled
`route. In humans, single doses of salmeterof administered via fnhafaUon aerosol attenuate
`
`[
`
`allergen-induced bronchial hyper-responsiveness. .
`
`Phannacokinetics: ADVAJR DISKUS: Following admlnlstratlon of AOVAJR DISICUS to healthy
`subjects, peak plasma .concentrations of fluticasone propionate were achJeved In 1 to 2 hours and
`those of salmeterof were achieved In about 5 minutes.
`In a single-dose crossover study, a higher than recommended dose df AOVAIR OISKUS was
`administered to 14 healthy subjects. Two Inhalations of the following treatments were administered:
`
`3
`
`000004
`
`

`

`AUG.24.2000
`
`s:08PM
`
`GLAXO WELLCOME
`
`N0.866
`
`P.5
`
`ADV AJR,. DISKus• 100150
`(flutlc:asone propionate 100 mcg and salmeterol* 60 mcg inhalation powder)
`.
`ADVAJR- DISKus• 250/50
`.
`. (fluticasone propJonate 250 mcg and salmetero1• &O mcg Inhalation powder
`AOVAJR. DISKus• 100150
`.
`;..
`-
`(flutleasone propionate 600 mcg and salmetero~ 50 mcg Inhalation powder)
`
`.
`
`No slgnlnoant changes Jn excretion of flutJaasone propionate or salmeterol were observed. r+
`
`ADVAIR DlSKUS 600/60, flutJcasone propionate powder 600 mc:g and sa!meterol powder 50 mcg
`given concurrently, and fJutJcasone propionate powder 500 mcg alone. Mean peak plasma
`concentrations of tlutJcasone propionate averaged 107, 94, and 120 pg/ml. respectively; those for
`saln:ieterol averaged 200and150 pgJmL. respectlvely, lndloatlng no siplficant changes In systemic
`exposures of ftutJcasone propJonate and salmetara1.
`In a repeat.dose study, the highest recommended dose of ADV1'~.DISKUS was administered to
`45 aslhmatic patients. One Inhalation twloe dally of the following treatments was administered:
`ADVAJR DISKUS 500/50, ftutlcasone propionate powder 500 mcg and selmeteroi powder so mcg
`given concummtly, orflutlcasone propionate powder 500 mcg alone. Mean peak steady-state
`plasma concentratfons of ftutlcasone propionate averaged 57, 73, and 70 pOJmL, respedlvely,
`lndicaUng no significant changes Jn systemic exposure of flutlcasone propionate. No plasma
`concentrations of salmaterol were measured In this repeat-dose study.
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`102
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`terminal half-life of fluticasorie propionate averaged 5.33 to 7.65 hours when AOVAIR OISKUS ·'fas
`115
`administered, which Is sJmllar to that reported when fluticasone propionate was given concurrentty
`116
`117 with salmeterol or when ftuticasone propionate was given alone (average. 5.30 to 6.91 hours). No
`us
`temunal half-lffe of salmeterol was reported upon admlnlstraUon of ADVAIR DISKUS or salmeterol
`t 19 · given concurrently with flutlcasone propionate.
`Special Populations: Fonnal pharmacokJnetio studies using ADVAIR OISKUS were not
`120
`conducted to examine gender differences or In special populations, such as elder1y patients or
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`patients with hepatic or renal lmpalnnenl
`·
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`Dmg-Drug Interactions: In the repeat- and single-dose studies. there was no evidecee of
`123
`significant drug interaction in systemlc exposure between flutfcasone propionate and salmeterol
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`125 when given as AOVAIR DISKUS.
`·
`126
`Flut/casone Propionate: AbsotpUon: Flutlcasone propionate acts locally In the lung;
`therefore, ptasma 1,vels do not predid therapeutic effect. Studies using oral dosing of labeled and
`127
`unlabeied drug have_ demonstrated that the oral systemlc b1oavanabll!ty of fluticasone proµlonate Is
`128
`negllglble (<19'), pttmarlly due to ln.compiete absorpfion and presystemlc metabolism In the gut and
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`liver •. In co~ the majority of the flutJcasone propionate dellvered to the lung Js systemically
`130
`absorbetf."The.systemlc bloavailabnity of fluti~ne propionate from the DISKUS device In healthy
`131
`volunteers averages 18%.
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`Peak steady-state ftutJcasone· propionate plasma concentrations Jn adult patients (n = 11) ranged
`from undetec.table to 266 pg/mL after a soo.:mcg twice.dally dose of fluticas0ne propionate
`134
`Inhalation powder using the DISKUS device. The mean fluticasooe propionate plasma
`13S
`concentration was 11 o pg/mL
`136
`
`4
`
`000005
`
`

`

`AUG.24.2000
`
`s:09PM
`
`GLAXO li.ELLCOl'E
`
`N0.866
`
`P.6
`
`ADVAIR• DISKUS-100/50
`(fluticasone propionate 100 mcg and salmeterol- 60 mcg Inhalation powder)·
`.
`ADVAIR. DISKus• 260/50
`(flutlcasone propionate 260 mcg and salmeteroit 60 mcg Jnhalation powder
`ADVAIR. DISKus• 600/50
`-
`-
`.
`t
`(flutlcisone propJonate SOD mcg and salmeterol• 60 mcg Inhalation powder)
`
`Distribution: FoUowlng Intravenous administration, the Initial dlspoS!Uon phase for
`137
`tlutlcasone propionate was rapid and consistent with Its blgh lipid solubility and tissue binding. The
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`volume of dlstltbutlon averaged 4.2 Ul<Q.
`139
`The J)elQ9ntage offlutlcasone propionate bound to bwnan plasma pretelns averages 81%.
`140
`Flullcasone propionate Is weakly and naverslbly bound to erythrocytea and Is not sfgnlflcantJy bound
`141
`to human transcortin.
`.. • .
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`Metabollsm: The total dearance of flutJcasone propionate Is high (average, 1093 mUmln),
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`1~ wHh renal clearanee accounting for less than 0.02'<1 of the total. The only clrculating metibollte
`detected In man Is fhe 17~rt>oxylfc acid deflvatJve of flutlcasone propionate, which Is formed
`c- 145
`through the cytochrome P450 3A4 pathway. This metabolite taad less lftinlty (approximately
`146
`112000) than the parent dn1g for the gluaoaortlcold receptor of human lung cytosol In vitro and
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`negligible phannacologlcal activity In animal studies. Other metabolites detected In vitro using
`cu_ltured human hepatoma cells have not been detected ln man.
`"' (
`149
`Elim/nation: Following Intravenous dosing, flutlcasone propionate showed polyexponentlal~
`150
`kinetics and had a tennlnal eJJmlnation half-IJfe of approximately 7.8 hours. Less than 5% of a
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`1
`radiolabeled oral dose was excreted In the urine as metabolites, with the remainder excreted In the
`152
`feces as parent drug and metabolites.
`153
`HeplltJc Impairment: Since tlutlcasone propionate Is predomlnantly cleared by hepatic
`154
`n1etabotism. lmpalnnent of Jlver function may lead to •ccumulatlon of Oulicasone propionate in
`155
`1S6
`plasma. Therefore, patients wfth hepatic disease should be dosely monitored.
`Gender. FUU phannacoklnetlc; profiles were obtained from 9 female and 18 male patients
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`158
`given flutlcasone propionate Inhalation powder 600 mcg twice dally USing the DISKUS. No overall
`differences in fluticasone prcplonate pharmacoklnetlcs wera observed.
`159
`Special Populations: Fonnal phannacoklneuc studies using fJutlcasone propionate were not
`160
`carried out in other speclai populat!ons.
`161
`D!U!!·Orug lntenctlons: In a mult1pl&odose drug interaction study, co ad ml nfstratlon of
`162
`fluticasone propionate (&00 mcg twice dally) and erythromycln (333 mg 3 times daily) did not affect
`163
`ftutlcasone propiortate ph&1Tnacoklnetlcs. In another drug Interaction study, casdmlnfslration of
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`165
`fluticasone propionate (1000 mog) and ketoc;onazole (200 mg once dally) resulted In Increased
`fluticasorje:-pr-0P1onate concentra~o~ and redu~ plasma cortisol area under the plasma
`166
`concentration versus time curve (AUC), but had no effect on urinary excretion of cortisol. Since
`167
`flutlcasone propfonate ls a substrate of cytochrome P450 3A4, caution should be exercised When
`16!
`cytDdvome P450 3A4 inhibitors (e.g., riton.Vtr, ketoconazole) are coadminfstered with flutlcasone
`169
`propionate as this could result In lncnased plasma concentrations of ftutlcasone propionate.
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`171
`Satmeterol Xinafoate: Salmeterol xinafoate, an Ionic saJt, dissociates In solUUon so that the
`salmeterol and 1-hydroxy-_2-naphthOio acid (xfnafoate) moieties are absorbed, distl1buted, ·
`172
`
`(
`
`5
`
`000006
`
`

`

`R.JG.24.2000
`
`s:09PM
`
`Q..AXO i.ELLCOME
`
`N0.866
`
`P.7
`
`ADVAIR. DISKUS11 100/50
`(flutfcasone propionate 100 mcg and salmetero16 SO mtg Inhalation powder)
`ADVAIR• DISKUS11 250/50
`(flutfcasone propionate 260 mcg and salmetero1• so mcg JnhaJation powder
`·
`· "'
`. .
`.
`ADVAIR• DISKUS" 600/SO
`(ftutlc6sone propionate 100 mcg and salmeteror 50 mcg Inhalation powder)
`
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`l&S
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`19S
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`· ·
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`metabolJzed~ and eftmfnated Independently. Salmeterol acts locally In the l~ng: therefore, plasma
`levels do not predict th~peutlc effect.
`Absorption: Because of the small therapeutic dose, systemic levels of salmeterol are low or
`undetectable after inhalation of recommended doses (50 mcg of salmetwol inhalation powder twice
`dally). Fonowlng chronic ad.ministration of an Inhaled dose of 50 mcg of salmetarol lnhalatl~n
`powder twice daily, salmeterol was detected In plasma within 5 to 411 ~utes In 7 asthmatic
`patients; plasma concentrations were very loW, with mean peak concentrations Of 187 pg/mL at
`.
`.
`20 minutes and no aocumutatJon with repeated doses.
`Dlsttfbutlon: Binding of salmeterol to human plasma proteins averages ge;c. fn vitro over the
`concentration range of 8 to T122 ng of ~eterol base per mlDJlltar, much. higher concentrations
`than tho.se achieved following therapeutic doses of salmeterol.
`Metabolism: Salmeterol base Is extensively metabotlzed by hydroxylation, with subsequent
`ellmlnation predominantly In the feces. No significant amount of unchanged salmeterol base was-l
`t
`detected In either urine or feces.
`j
`Effmlnation: In 2 healthy subjects who received 1 mg of radlolabeled salmeterol (as
`salmeterol xlnafoate) orally, approximately 25% and 60% of the radiofabefed salmeterol was
`eliminated In urine and feces, respectively, over a period of 7 days~ The termlnaJ elimination half-life
`wes about 6.5 hours (1 volunteer only).
`The ~nafoate moiety has no apparent pharmacologic activity. The xlnafoate moiety Is highly
`protein t>ound (>99%) and has a long eUmlnatlon half.life of 11 days.
`Spec/al Popufatlons: Formal pbannacoklnetic studies of saJmetarol base have not been
`conducted In special populations. Since nlmeterol ls predomfnanUy deared by hepatic metabolism,
`lmpainnent of Jlver function may lead to accumulation of satmeterol ln plasma. Therefore, patients
`Ylrth hepatic disease should be closely monitored.
`Pharmacodynamlcs: ADVAIR DISKUS: Since systemic phannacodynamlc effects of salmeterol
`are not normany seen at the therapeutic dose, higher doses were used to produce 01easun1hle
`effects. Four studies~ aoaducted In healthy subjects: (1) a sJngle-dose crossover study using
`2 inhalations of AD\IAIR OISKUS 500/50, flutlcasone propionate powder 500 mcg and salmeterol
`powder 50 mcg given concurrently, or flutlcasone propionate powder 500 mcg given alone, (2) a
`c:;umulatlvidose study using 50 t~ 400 mcg of sa_lmeterol powder given alone or as ADVAIR
`DISKUS 500/50, (3) a repeat-dose study for 11 days using 2 Inhalations twice daily of ADVAIR
`OISt<US 250/SO, flutlcasane propionate powder 250 mcg, or salmeterol poWder 50 mcg, and (4) a
`single-dose sludy using 5 lnhalaUons of AOVAIR DISKUS 100/50, fluticasone propionate powder
`100 mcg alone, or placebo. In these studies no slgnfficant differences were observed In the
`pharmacodynamic effects of salmeterol (pulse rate, blood pressure, QTc Interval, potassium. and
`glucose) whether the salmeterol was given as ADVAIR OISKUS. concuR'Bntly with tlutlcasone
`propionate from separate Inhale~. or as salmeterol alone. The systemic pharmacodynamic effects
`
`6
`
`(
`
`000007
`
`

`

`AUG.24.2000
`
`5:10PM
`
`N0.866
`
`P.8
`
`ADVAIR. DISKus• 100/SO
`(flutlcasant propionate 100 mcg and salmeterol* SO mcg Inhalation powder)
`·
`ADVAIR'" DISKUSe 250/SO
`(flutfcasone propionate 250 mcg and salmeteror sa mcg Inhalation powder
`-
`t
`ADVAIR• DISKUSe 500/50
`.
`(ftuticasone propionate 500 m~g and salmetetol* SO mcg Inhalation powder)
`
`~
`
`~
`
`of salmeterol were not altered by the presence of fluti~ne propionate lo-ADVAIR DISKUS. The
`potential effect of salmeterol or. the effects of ftuticasone propionate on the
`hypothalamlD-pltUftary-ldrenaJ (HPA) axis wu also evaluated In these studies. No ~gniflcant
`differences 11c::rass treatments were observed In 2'-hour urinary cortls~excret.ion and, where
`measured, 24-hour plasma cortlsol AUC. The systemic pharmacodynamlc effects of flutfcasone
`.
`propionate were not altered by the presence of salmeterol In ADVAIR DISKUS In beaHhy subjects.
`In dlnlcal studies With ADVAI~ OISKUS In patients with asthma, no significant dlffe~nces were
`observed In the systemic phannacodynaintc effects of salmeterol (pulse rate, bt~od pras9ure, arc
`Interval. potassium, and glucose) whet~erthe salmeterol was glv~n alone or as ADVArR DISKUS.
`In 72 adolescent and adult patients with asthma.given either ADVAIR DISKUS 100/SO'or ADVAIR
`DISKUS 250/SO, continuous 24-hour electrocardlographlc monltortna was performed after the first
`dose and after 12 weeks of therapy, and no dlnlcally significant dYSrhYthmfas were noted.
`~r
`In • 28-week study In patients with asthma. ADVAIR DISKUS 600/50 twice dairy was oompani
`with th.e concurrent use of salmeterol powder 50 mcg plus fluticasone propionate powder 500 mci
`from separate inhalers or ftuUcasone propionate powder 500 mog alone. No significant dlfferen~
`across treatments were observed In plasma cortisol AUC after 12 weeks of dosing or In 24'-hour
`urinary cortisol excretion after 12 and 28 weeks.
`In a 12-w-eek study In patients With as1hma, AOVAIR DISKUS 250/50 twice dally was compared
`with fluUcasone propionate powder 250 mc:g alone, salmeterol powder SO mcg alone, and placebo.
`For most patients. the ablllty to Jncrease cortJsol production In response to stress, as assessed by
`3D-mlnut~ c:osyntropin stimulation, remained Intact with AOVAJ~ DlSKUS. One patient (3%) who
`receJved ADVAIR DISKUS 250/50 had an abnonnar 1'9Sponse (peak serum cortisol <18 mcg/dL)
`after-dosing, compared with 2 patients (6%) who received placebo, 2 patients (6%) who received
`flutlcasone propionate 250 mcg, aDd no patients who received salmeterol.
`Flutlcasone Ptoplonate: In cftnlcal trials With ftutk;asone propionate lnhalaUon powder using
`doses up to and including 250 mcg twice dally, occasional abnormal short cosyntropln tests (peak
`serum cortisol <18 mcg/dL) were noted both In patients receiving fluticasone propionate and In
`patients receiving placebo. Tbe incldence of abnormal tests at 500 mcg twice dally was greater than
`placebo. In a 2-yesr ~earned out In 64 paUents w'lth mild, persistent asthma (mean FEV1 91 %
`of predicted} iandomlzed to flutiC?SSOne proplon.te 500 mcg twice dally or placebo, no patient
`receiving fluticasone propionate had an abnormal response to 6-hour cosyntropin infusion (peak
`-
`serum cortisol. <18 mcg/dL). With a peak cortisol threshold of <35 mcg/dL, one patient receiving
`ftuticasone propionate (4%) had an abnormal response at 1 year; repeat testing at 18 months and
`2 yeBIS was normal. Another patient receiving fluticasone propionate (5%) had an abnonnal
`response at 2 years. No patient ora placebo had an abnormal response at 1 or 2 years.
`Salmetero/ Xlnafoate: Inhaled salmeterol, like other beta-adrenerglc agonlst drugs, can in some
`patients produce dose-related cardiovascular effects and effects on blood glucose and/or serum
`
`...-....
`
`210
`211
`2.12
`213
`214
`215
`216
`217
`218
`219
`220
`221
`222
`223
`224
`225
`226
`'121.
`
`228
`229
`230
`231
`232
`233
`234
`235
`236
`237
`238
`239
`240
`241
`242
`243
`244
`245
`246
`
`.
`
`7
`
`000008
`
`

`

`At.X;.24.2000
`
`5:10PM
`
`GLAXO i.ELL.Cot'E
`
`------ ------------.
`
`.
`
`N0.866
`
`P.9
`
`ADVAIR• DJSKUSe 100/50
`(fluti~sone propionate 100 meg and salmeterol• 50 mcg Inhalation powder)
`ADVAIR .. DISKUSe 250/SO .
`.
`(flutlcasone propionate 250 mcg and satmeterot- 50 mcg Inhalation powder
`ADVA1R· orsKus• 500150
`.
`·
`(flutlcisone propionate 500 mca and salmeteror so mcg Inhalation powder)
`potasslum-(See PRECAUTIONS). The cardtowscular effects (heart rate, blood pressure) associated
`'JA1
`with salmeterol occur with 11mnar frequency, and are of simllar type ·and sivertty, as those noted
`248
`following albuterol administration.
`249
`•..
`The effects of rising doses of salmeterol and standard Inhaled doses of albuterol were studied In
`250
`.
`volunteers Cld In patients with asthma. Salmeterol doses up to 84 mcg administered as Inhalation
`251
`ae"*>I resulted In heart. rate Increases of 3 to 1 e beatslmln. about the same as albuterol dosed at
`252
`180 mcg by lnhalatJon aerosol (4 to 1 o beatslmln). Adolescent and ·~uil patients receiving 60-mcg
`253
`doses of salmeterol lnhalatioa powder (n = 60) underwent continuous electroaardfographtc
`254
`monftoring. dur1ng two 12-hour per1ods after the first dose and after 1 month of therapy, and no
`255
`dlnically significant dysrhythmias were noted.
`256
`studies In laboratory animals (mtnlptgs. rodents. and dogs) have d•manstrated the occurrence of
`257
`cardiac arrhythmias and sudden death (with hlstologlc evidence ef myocardial necrosis) when
`258
`beW-agonlsts and methybcanthlnes are administered concunently. The cltnical significance of tJ\f8
`259
`t
`findings is unknown.
`260
`261
`t
`CLINICAL TRIALS: In dlnlcal trials comparing ADVAIR DISKUS wfth the Individual components.
`262
`Improvements In most efficacy endpoints were gl"9aterwtth ADVAIR OISKUS than with the use of
`263
`264 . either fluticasone propionate or salmeterol alone. In addltlon, cllnlcal trials showed similar results
`26S
`between ADVAIR OISKUS and the concurrent use of flutlcasone propionate plus salmeterol at
`corresponding doses from separate Inhalers.
`266
`Studies Comparing ADVAJR DlSKUS to Fluticasone Propionate Alone or Salmeterol Alone:
`'2117
`Three double-blind, parallel-group dlnfcal trials were conducted with ADVAIR OISKUS In 1208
`268
`269
`adolescent and adult patients ~12 years. baseline FEV1 63% to 72% of predicted normal) with
`asthma that was not optimally controlled on their current therapy. All treatments were inhalation
`2.70
`powders, given as 1 tnhalaUon from Che DISKUS device twice daRy, and other maJntenance
`271
`therapies were discontinued.
`272
`Stuf1Y 1: CDnlcal Trial With ADVAIR DISKUS 100/60: This placebo-controlled, 12-week. US
`273
`-
`study oompared AQVAIR OISKUS 100/50 with Its Individual components. flutlcason.e propion·ate
`274
`1 oo mog and salmtrterol 50 mcg. The study was stratified according to baseline asthma
`rTS
`276
`mainten~therapy: patients were using either Inhaled cortloosterolds (n • 250) (dally doses of
`beclomethasone dlproplonate 252 to 420 mog, tiunisolide 1000 mcg, fluticasone proplooate
`2n
`inhalation aerosol 176 mcg, or triamcinolone acetonide 600 to 1000 mc:g) or $almeterol (n = 106}.
`271
`Baseline FEV1 measul"9ments were stmnar toross treatments: ADVAIR DISKUS 100/50, 2.17 L:
`219
`flutlcasone propionate 100 mcg, 2.11 L: salmeterol, 2.13 L; and placebo, 2.16 L
`2.80
`Predefined withdrawal criteria for lack of efficacy, an indicator of worsening asthma, were utmzed
`2.81
`for this placebo-controlled study. WCJl'Senlng asthma was defined as a ~inlcaUy Important decrease
`282
`283
`In FEV1 or peak expiratory flow (PEF). Increase In use of VENTOLIN9 (albuterol, USP) Inhalation
`
`.
`
`~
`
`8
`
`000009
`
`

`

`AUG.24.2000
`
`s:10PM
`
`N0.866
`
`P.10
`
`ADVAIR• DISKUs• 100/50
`(flutlcasone propionate 100 mcg and salmeterol* SO mcl inhalatlon powder)
`ADVAIR. DISKus• 250/50
`(ftutlcasone propionate 250 mcg and calmeterol9 60 mcg. Inhalation powder
`·
`..
`· -
`ADVAIR .. DISKus• S00/50
`(flutlcasone propionate &00 mcg and salmeteror 10 mcg Inhalation powde.,
`
`Aerosol, Increase In night awakenings due to asthma, emergency lnterven.!lon or hospitalization due
`284
`to asthma, or requirement for asthma medication not allowed by the protocol. As shown In Table 1.
`285 _
`&tatistlcaOy stgnificanUy fewer patients receiving ADVAIR OISKUS 100/50 were withdrawn due to
`216
`217 wotSenlng asthma compared with flulJcasone propionate, nlmetero~ 8Qd. placebo.
`288
`289
`290
`
`.
`Table 1: Percent Of Patients Withdrawn DU8 to Worsening ~a In Patients
`Pnvlousl Treated With -Either Inhaled Corticosteroids or Salmeterol Stud 1
`AOVAIR DISKUS
`Fluticasone Prc>plonate
`SalmeterQI
`100/50
`100 mcg
`50 mcg
`n•
`n=
`35%
`11%
`
`Placebo
`n a:
`
`291
`The FEVt results are displayed In Agura 1. Because this trtal used predetermined criteria foi'
`292
`\vorsenlng aSttuna, which caused mo_re patients In the placebo group to be withdrawn, FEVt resu'-5
`293
`!
`at Endpoint (lastavallable FEV1 resulQ are also provided. Patients receMng ADVAIR DISKUS
`294
`100/50 had slgnHicantly greater Improvements In FEV1 (0.51 L. 26"-) compared with fluticasone
`295
`propionate 100 mcg (D.28 L.15%), salmeterol (0.11L,5%), and placebo (0.01L,1%). These
`296
`fmprovamcnts In FEV1 with ADVAIR OISKUS were achieved regardless of baseline asthma
`291 ·
`298 maintenance therapy (lnhated corticosteroids or salmeterol).
`299
`
`APPEARS THIS WAY
`ON ORIGINAL
`
`-.-- -. -
`
`!
`
`i:
`
`9
`
`000010
`
`

`

`RUG.24.2000
`
`s:UPM
`
`N:>.866
`
`P.11
`
`ADVAIR• DISKus• 100/SO
`(flutlcasone propionate 100 mcg and salmetero,. SO mcg Inhalation powder)
`ADVAIR. DISKus• 250/SO
`.
`(flutfeasone propionate 260 mcg and .salmetero .. so mcg Inhalation powder
`;..
`_
`ADVAIR• DISKUs• S00/50
`.
`(flutlciasone propionate &OD mcg and salmeterol• &O mcg Inhalation powder)
`
`300
`301
`302
`
`303
`304
`sos
`306
`307
`
`- ~ Figure 1: Mean Percent Change From Baseline In FEv 1 I~ Patients
`Previously Treated With Either Inhaled Corticosteroids or saiineterol (Study 1)
`
`. ..
`
`•
`
`25
`
`~ 15
`.Ii I
`
`10
`
`"
`
`•
`
`__ ,
`
`t.
`t
`t
`t
`
`A ADVAIR DISICUS 10Ql!O twtct 11.n..
`__ ,
`• FluUclSant ptODlamte 100 lllCI llltoe dlllY
`• Q&mltnl IO mco lWI daily .
`•
`• Plaatlo
`----------------~-----------------
`
`•
`
`-5
`
`'llttk 0
`.Jl
`r7
`85
`
`'
`ADVAIA DISl<US 11QSD
`FU!cason•
`praplonate 100 mcg
`
`Sunelet'DI '° mcg
`
`PIKebo
`
`88
`77
`
`1
`
`2
`
`a
`
`4
`
`i
`
`ii
`.!.
`79
`71
`
`St
`34
`
`7
`
`I
`
`9
`
`10
`
`11
`
`12 Etidpolnt
`.!.
`J!.
`73
`86
`85
`65
`
`51
`27
`
`86
`74
`
`The effect of AOVAJR DISKUS 100/SO on morning and evening p"ak expiratory flow (PEFJ
`endpoints Is stiown In Table 2.
`
`·-;:!.-· ~ ·-
`
`(
`
`APPEARS THIS WAY
`ON ORIGINAL
`
`10
`
`000011
`
`

`

`AU:;.24.2000
`
`5:11PM
`
`GlAXO i.nl.COME
`
`N0.866
`
`P.12
`
`ADVAIR• DISKUSe 100/SO
`(flutlcasone propionate· 1 oo mcg and salmeteroJ• 50 mcg Inhalation powder)
`ADVAIR. DISKus• 260/SO
`(flutieasone propionate 2SO mcg and salmeterol* SO mcg Inhalation powder
`ADVAJR. DISKus• 500/60
`;
`.
`.
`(ftutlcasone propionate soo mcg and salmeteroF &O mcg tnhalatlon powder)
`Table z: Peak Expiratory Flow Results for Patlel!U
`Previously Treated With Either Inhaled Corticosteroids or Salmeterol (Study 1 l
`ADVAJR
`Flutlcasone
`DISKUS
`Propionate
`· 100mcg
`100/50
`ln = 8Sl
`
`Sallneterol
`50mog
`" •(D II 86)
`
`Placebo .
`
`(n II 77)
`
`'". 87)
`
`Efficacv Variable*
`AM PEF (Umin)
`BasaDne
`Chanae from baseUne
`PM PEF·(l.lmln)
`Baseline
`Chanoe from basellne
`-Chang m baseR ne:: change from
`e fro
`
`393
`53
`
`374
`17
`
`Se9
`·2
`
`390
`418
`396
`35
`.7
`18
`. e
`basehn at EndPolnt (last avalla le data).
`b
`
`'
`
`382
`-24
`
`398
`·13
`
`-
`
`-~
`
`The subjedive Impact of asthma on patients' perception of health was evaluated through ~of
`an Instrument called the Asthma Quality of Ufe QuestloMaJre (AQLQ) (based on a 7·point scale
`where 1 =maximum lmpalnnent and 7 =none). Patients receiving ADVAlR OISKUS 100/50 had
`clinically meaningful Improvements In overall asthmH;peclflc quaflty of life ~ defined ~· a
`difference between groups of ~.5 points In change from baseline AQLQ scores (difference in
`AQLQ scote of 1.25 compared to placebo).
`.
`Study 2: Clinical Trial With AOVAJR DISKUS 250/60: This placebo-controlled, 12-week, US
`study compared ADVAIR DISKUS 250/50 wHh Its Individual components, ftutlcasone propionate
`250 mcg and salmeterol 50 mr.g In 349 patients using Inhaled corticosteroids (dally doses oI
`beclomethasone dlproplonate 462 to 872 mcg, flunlsoUde 1250 to 2000 mcg, fluticasone propionate
`Inhalation aerosol 440 mcg, ot tt1amc1nolone acetonJde 1100 to 1600 mcg). Baseline FEV1
`measurements were slmUar aaoss treatments: ADVAIR DISKUS 250/50, 2.23 L; fluticasone
`propionate 25~ mcg; 2.