Seretide Diskus forte 50 mikrogram/500 mikrogram/dos Inhalationspulver, avdelad dos

Sverige - svenska - Läkemedelsverket (Medical Products Agency)

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Bipacksedel Bipacksedel (PIL)

27-08-2020

Produktens egenskaper Produktens egenskaper (SPC)

27-08-2020

Aktiva substanser:
flutikasonpropionat; salmeterolxinafoat
Tillgänglig från:
Cross Pharma AB
ATC-kod:
R03AK06
INN (International namn):
fluticasone propionate; salmeterol
Dos:
50 mikrogram/500 mikrogram/dos
Läkemedelsform:
Inhalationspulver, avdelad dos
Sammansättning:
laktosmonohydrat Hjälpämne; salmeterolxinafoat 72,5 mikrog Aktiv substans; flutikasonpropionat 500 mikrog Aktiv substans
Klass:
Apotek
Receptbelagda typ:
Receptbelagt
Terapiområde:
Salmeterol och flutikason
Bemyndigande status:
Avregistrerad
Godkännandenummer:
24789
Tillstånd datum:
2008-01-09

Dokument på andra språk

Bipacksedel Bipacksedel - engelska

27-08-2020

Produktens egenskaper Produktens egenskaper - engelska

27-08-2020

Offentlig bedömningsrapport Offentlig bedömningsrapport - engelska

03-11-2016

Läs hela dokumentet

Bipacksedel: Information till användaren

Seretide Diskus mite 50 mikrogram/100 mikrogram/dos

Seretide Diskus 50 mikrogram/250 mikrogram/dos

Seretide Diskus forte 50 mikrogram/500 mikrogram/dos

inhalationspulver, avdelad dos

salmeterol/flutikasonpropionat

Läs noga igenom denna bipacksedel innan du börjar ta detta läkemedel. Den innehåller

information som är viktig för dig.

Spara denna information, du kan behöva läsa den igen.

Om du har ytterligare frågor vänd dig till läkare eller apotekspersonal.

Detta läkemedel har ordinerats enbart åt dig. Ge det inte till andra. Det kan skada dem, även om

de uppvisar sjukdomstecken som liknar dina.

Om du får biverkningar, tala med läkare eller apotekspersonal. Detta gäller även eventuella

biverkningar som inte nämns i denna information. Se avsnitt 4.

I denna bipacksedel finns information om följande

Vad Seretide är och vad det används för

Vad du behöver veta innan du använder Seretide

Hur du använder Seretide

Eventuella biverkningar

Hur Seretide ska förvaras

Förpackningens innehåll och övriga upplysningar

1.

Vad Seretide är och vad det används för

Seretide innehåller två läkemedel, salmeterol och flutikasonpropionat.

Salmeterol är en långverkande luftrörsvidgare. Luftrörsvidgare verkar på luftvägarna i lungorna så

att de hålls vidgade och gör det lättare att andas. Effekten varar under minst 12 timmar.

Flutikasonpropionat är en kortikosteroid (kortison) som minskar svullnad och irritation i lungorna.

Läkaren har ordinerat detta läkemedel för att förebygga andningsproblem vid:

Astma

Kroniskt obstruktiv lungsjukdom (KOL). Seretide Diskus forte (50 mikrogram/500 mikrogram per

dos) minskar antal försämringsperioder av KOL.

Seretide måste tas regelbundet varje dag enligt läkarens anvisningar för att det ska verka på bästa sätt

och ge kontroll över din astma eller KOL.

Seretide förebygger andningsbesvär och väsande andning. Dock ska Seretide inte användas för

att lindra ett plötsligt anfall av andningsbesvär eller väsande andning. Om detta händer så ska

du ta en snabbverkande ”vid behovs” inhalator, som t.ex. salbutamol. Du bör alltid ha din

snabbverkande ”vid behovs” inhalator med dig.

Salmeterol och flutikasonpropionat som finns i Seretide kan också vara godkänd för att behandla andra

sjukdomar som inte nämns i denna produktinformation. Fråga läkare, apotekspersonal eller annan

hälsovårdspersonal om du har ytterligare frågor och följ alltid deras instruktion.

2.

Vad du behöver veta innan du använder Seretide

Använd inte Seretide om:

Du är allergisk (överkänslig) mot salmeterol, flutikasonpropionat eller det övriga innehållsämnet

laktosmonohydrat.

Varningar och försiktighet

Tala med din läkare innan du använder Seretide om du har:

Hjärt-kärlsjukdom inklusive snabb och oregelbunden hjärtklappning

Ökad sköldkörtelfunktion (hypertyreos)

Högt blodtryck

Diabetes (eftersom Seretide kan öka blodsockret)

Minskad kaliumhalt i blodet

eller har haft tuberkulos (tbc) eller andra infektioner i lungorna.

Kontakta läkare om du upplever dimsyn eller andra synrubbningar.

Andra läkemedel och Seretide

Tala om för läkare eller apotekspersonal om du tar eller nyligen har tagit andra läkemedel, eller kan

tänkas ta andra läkemedel, även läkemedel för astma och receptfria läkemedel. Detta beror på att

effekten av behandlingen kan påverkas om Seretide och vissa andra läkemedel tas samtidigt.

Tala om för läkaren om du tar något av följande läkemedel innan du börjar med Seretide:

-blockerare (t.ex. atenolol, propranolol och sotalol).

-blockerare används oftast för att behandla

högt blodtryck eller andra hjärtåkommor

Läkemedel som används för att behandla infektioner (t.ex. ketokonazol, itrakonazol och

erytromycin) inklusive läkemedel för hiv-behandling (t.ex. ritonavir, läkemedel som innehåller

kobicistat). Några av dessa läkemedel kan öka mängden av flutikasonpropionat eller salmeterol i

kroppen. Detta kan öka risken för biverkningar med Seretide, inklusive oregelbunden hjärtrytm,

eller förvärra biverkningarna. Din läkare kan vilja övervaka dig noga om du tar dessa läkemedel.

Kortison (tabletter eller i injektion). Om du nyligen blivit behandlad med dessa läkemedel kan det

öka risken för påverkan av binjurarnas funktion

Diuretika, även känd som vätskedrivande tabletter används för behandling av högt blodtryck

Andra luftrörsvidgande läkemedel (t.ex. salbutamol)

Xantiner. Dessa används ofta för att behandla astma.

Graviditet och amning

Om du är gravid eller ammar, tror att du kan vara gravid eller planerar att skaffa barn rådfråga läkare

eller apotekspersonal innan du använder detta läkemedel.

Körförmåga och användning av maskiner

Det är osannolikt att effekt eller eventuella biverkningar av Seretide skulle påverka din förmåga att

köra bil och använda maskiner. Du är själv ansvarig för att bedöma om du är i kondition att framföra

motorfordon eller utföra arbeten som kräver skärpt uppmärksamhet. En av faktorerna som kan påverka

din förmåga i dessa avseenden är användning av läkemedel på grund av deras effekter och/eller

biverkningar. Beskrivning av dessa effekter och biverkningar finns i andra avsnitt. Läs därför all

information i denna bipacksedel för vägledning. Diskutera med din läkare eller apotekspersonal om du

är osäker.

Seretide innehåller laktos

Seretide Diskus innehåller laktosmonohydrat upp till 12,5 mg/dos. Denna mängd orsakar normalt inga

problem för laktosintoleranta personer. Hjälpämnet laktos innehåller små mängder mjölkprotein som

kan orsaka allergiska reaktioner.

3.

Hur du använder Seretide

Använd alltid detta läkemedel enligt läkarens eller apotekspersonalens anvisningar. Rådfråga läkare

eller apotekspersonal om du är osäker.

Använd Seretide varje dag tills din läkare råder dig att sluta. Använd inte mer än rekommenderad

dos. Rådfråga läkare eller apotekspersonal om du är osäker.

Sluta inte att ta Seretide eller minska dosen av Seretide utan att tala med din läkare först.

Seretide ska inhaleras genom munnen ner i lungorna.

Du kanske inte kan känna smak av eller pulvret på tungan, även om du har använt inhalatorn på

rätt sätt.

För astma:

Vuxna och ungdomar från 12 år

Seretide Diskus mite

1 inhalation 2 gånger dagligen

Seretide Diskus

1 inhalation 2 gånger dagligen

Seretide Diskus forte

1 inhalation 2 gånger dagligen

Barn från 4 år och upp till 12 år

Seretide Diskus mite

1 inhalation 2 gånger dagligen

Seretide rekommenderas inte till barn under 4 år.

För vuxna med kroniskt obstruktiv lungsjukdom (KOL)

Seretide Diskus forte

1 inhalation 2 gånger dagligen

Om besvären är välkontrollerade när du tar Seretide 2 gånger om dagen, kan läkaren minska

doseringen till 1 inhalation 1 gång om dagen:

1 gång till kvällen - om du har besvär

på natten.

1 gång på morgonen - om du har besvär

under dagen.

Det är väldigt viktigt att följa läkarens anvisningar om hur många inhalationer som du ska ta och hur

ofta.

Om du använder Seretide för astma kommer din läkare vilja följa upp dina besvär regelbundet.

Kontakta omedelbart läkare om din astma eller andningen försämras.

Om du känner att

andningen blir mer väsande/pipande, att känslan av trångt i bröstet ökar eller att du behöver ta mer av

din snabbverkande luftrörsvidgande medicin, fortsätt att ta Seretide men öka inte antalet doser. Dina

andningsbesvär kan förvärras och du kan bli allvarligt sjuk. Kontakta din läkare eftersom du kan

behöva ytterligare astmabehandling.

Bruksanvisning

Läkare, sjuksköterska eller apotekspersonal bör visa dig hur du ska använda Seretide Diskus. Då och

då bör de också kontrollera hur du använder den. Det är viktigt att Seretide Diskus används rätt och

som den ordinerats för att du ska få avsedd effekt på din astma eller KOL.

Diskus-inhalatorn innehåller blister med Seretide-pulver.

En dosräknare på ovansidan av Diskus visar hur många doser som finns kvar.

Dosräknaren räknar ner till 0. Numren 5 till 0 är markerade med rött för att

varna att endast några få doser är kvar. När dosräknaren visar 0 är inhalatorn tom.

Så här använder du inhalatorn

1. För att öppna Diskus, håll den som på bilden. För tumgreppet i pilens

riktning så långt det går - ett klick hörs. Ett litet hål i munstycket har nu

öppnats.

2. Håll Diskus med munstycket mot dig. Du kan hålla den antingen i höger

eller vänster hand. För frammatningsspaken från dig, så långt det går –

ett klick hörs. Pulverdosen är nu klar att inhaleras från munstycket.

Varje gång spaken dras fram öppnas en pulverdos som är klar att inhaleras.

Lek inte med frammatningsspaken eftersom detta öppnar pulverdoserna och

medicin slösas bort.

3. Håll Diskus bort från munnen.

Andas ut lugnt och så djupt som känns bekvämt.

Andas aldrig ut genom Diskus.

4. För därefter Diskus till munnen och slut läpparna om munstycket.

Andas in stadigt och djupt genom Diskus; inte genom näsan.

Ta bort Diskus från munnen.

Håll andan i ca 10 sekunder eller så länge som det känns bekvämt.

Andas ut sakta.

5. Risken för svampinfektion och heshet minskar om man sköljer

munnen med vatten och spottar ut och/eller borstar tänderna efter varje

inhalationstillfälle.

6. Stäng inhalatorn genom att föra tumgreppet mot dig så långt det går.

Ett klick hörs när Diskus stängs. Frammatningsspaken har nu

automatiskt återgått till sitt ursprungsläge.

Diskus är nu klar att användas på nytt.

Som med alla inhalatorer bör vårdgivare säkerställa att barn som

föreskrivits Seretide Diskus använder korrekt inhalationsteknik, såsom

beskrivits ovan.

Rengöring

Torka av Diskus-munstycket med en torr pappersservett.

Om du har använt för stor mängd av Seretide

Det är viktigt att du följer doseringsanvisningen. Om du av misstag fått i dig en större mängd än de

rekommenderade doserna, tala med läkare eller apotekspersonal. Du kan känna att hjärtat slår snabbare

än vanligt och att du blir darrig. Du kan också få yrsel, huvud-, led- och muskelvärk.

Om du tagit större mängder läkemedel under en längre tid eller om t.ex. ett barn fått i sig läkemedlet av

misstag, kontakta läkare, sjukhus eller Giftinformationscentralen (tel 112) för bedömning av risken

samt rådgivning. Större mängder av Seretide kan minska kortisonbildningen i binjurarna.

Om du har glömt att använda Seretide

Ta inte dubbel dos för att kompensera för glömd dos. Ta nästa dos på den vanliga tiden.

Om du slutar att använda Seretide

Det är viktigt att du tar Seretide dagligen enligt anvisningar

tills läkare råder dig att sluta. Sluta inte

plötsligt att ta Seretide eller minska din dos

då detta kan förvärra dina symtom.

Dessutom, om du plötsligt slutar att ta Seretide eller minskar dosen av Seretide kan det mycket sällan

leda till att du får problem med binjurarna (binjurebarksvikt) och i vissa fall orsaka biverkningar.

Biverkningarna kan innefatta något av följande:

Magsmärtor

Trötthet och aptitlöshet, sjukdomskänsla

Illamående och diarré

Huvudvärk och dåsighet

Låga sockervärden i blodet

Lågt blodtryck och kramper (anfall).

När din kropp är under stress t.ex. p.g.a. feber, trauma (t.ex. en bilolycka), infektion eller operation,

kan binjurebarksvikt bli värre och du kan ha någon av de biverkningar som beskrivs ovan.

Om du får några biverkningar tala med din läkare eller apotekspersonal. För att förebygga att dessa

biverkningar uppkommer kan din behandling behöva kompletteras med kortison i tablettform (t.ex.

prednisolon).

Om du har ytterligare frågor om detta läkemedel, kontakta läkare, sjuksköterska eller apotekspersonal

.

4.

Eventuella biverkningar

Liksom alla läkemedel kan detta läkemedel orsaka biverkningar men alla användare behöver inte få

dem. För att minska risken för biverkningar kommer din läkare att ordinera den lägsta dos som behövs

för att du ska kunna vara besvärsfri från din astma eller KOL.

Allergiska reaktioner: om du plötsligt märker att du får svårt att andas omedelbart efter att du

tagit Seretide.

Andningen blir väsande

och du får hosta eller andnöd. Du kan också märka klåda,

utslag (nässelutslag) och svullnad (vanligtvis i ansikte, läppar, tunga eller svalg), eller så kan du

plötsligt känna att ditt hjärta slår mycket snabbt eller att du känner dig svag och yr (som kan leda till

kollaps eller medvetslöshet).

Kontakta omedelbart läkare och sluta ta Seretide om du märker

något av detta eller att det händer plötsligt

efter att du tagit Seretide.

Allergiska reaktioner är

mindre vanliga (förekommer hos färre än 1 av 100 personer).

Lunginflammation hos KOL-patienter (vanlig biverkning)

Tala om för läkaren

om du har något av följande symtom medan du tar Seretide eftersom de kan vara

symtom på lunginflammation:

feber eller frossa

ökad slemproduktion, förändrad färg på slemmet

ökad hosta eller ökade andningssvårigheter

Övriga biverkningar:

Mycket vanliga (förekommer hos fler än 1 av 10 personer):

Huvudvärk – som ofta är övergående och brukar försvinna efter några dagars användning

Fler förkylningsperioder (övre luftvägsinfektioner) har rapporterats hos patienter med KOL.

Vanliga

(förekommer hos fler än 1 av 100 personer):

Svampinfektion (så kallad ’torsk’, ömma, gulaktiga, krämiga fläckar) i mun och svalg. Irritation på

tunga och i halsen samt heshet. Risken för svampinfektion minskar om man sköljer munnen med

vatten och spottar ut omedelbart och/eller borstar dina tänder efter varje inhalationstillfälle med

ditt läkemedel. För att behandla ’torsk’ (Candida) kan din läkare eventuellt ordinera läkemedel mot

svampinfektioner

Värkande, svullna leder och muskelvärk

Muskelkramp.

Följande biverkningar har också rapporterats hos patienter med KOL (kroniskt obstruktiv

lungsjukdom):

Blåmärken och benbrott

Bihåleinflammation (en känsla av tryck eller täthet i näsan, kinder eller bakom ögonen, ibland med

dunkande värk)

Minskad kaliumhalt i blodet (som kan ge oregelbundna hjärtslag, muskelsvaghet, kramp).

Mindre vanliga

(förekommer hos färre än 1 av 100 personer):

Förhöjda blodglukosnivåer (hyperglykemi). Om du har diabetes, kan du behöva göra tätare

blodsockerkontroller och eventuellt ändra din vanliga diabetesbehandling

Grå starr (grumlig lins i ögat)

Mycket snabba hjärtslag (takykardi)

Känsla av skakighet (tremor) och snabba eller oregelbundna hjärtslag (palpitationer). Detta är ofta

harmlöst och försvinner efter en viss tids användning

Bröstsmärta

Känsla av oro (främst hos barn)

Sömnsvårigheter

Allergiska hudutslag.

Sällsynta (förekommer hos färre än 1 av 1000 personer):

Andningssvårigheter/ väsande ljud som förvärras strax efter att du tagit Seretide.

Om detta

inträffar:

Sluta att ta

Seretide

. Använd inhalatorn med den snabbverkande luftrörsvidgande

medicinen och

kontakta läkare omedelbart.

Seretide

kan också påverka den normala produktionen av steroidhormoner i kroppen, särskilt om

man har tagit höga doser under en längre tid. Effekter av detta kan ge:

- Fördröjd längdtillväxt hos barn och ungdomar

- Minskad bentäthet

- Grön starr (glaukom)

- Viktökning

- Månansikte (Cushings syndrom).

Din läkare kommer att följa upp din behandling regelbundet för att se till att du står på den lägsta dos

som håller din astma under kontroll för att minska risken för dessa biverkningar.

Beteendestörningar, t.ex. att man blir ovanligt aktiv och irritabel (ses främst hos barn)

Oregelbundna hjärtslag eller extraslag av hjärtat (arytmi). Tala om för din läkare men sluta inte att

ta Seretide förrän läkaren råder dig att sluta.

Svampinfektion i esofagus (matstrupen), som kan orsaka svårigheter att svälja.

Har rapporterats (förekommer hos ett okänt antal användare):

Depression eller aggression. Det är mer troligt att dessa biverkningar förekommer hos barn.

Dimsyn.

Rapportering av biverkningar

Om du får biverkningar, tala med läkare, apotekspersonal eller sjuksköterska. Detta gäller även

biverkningar som inte nämns i denna information. Du kan också rapportera biverkningar direkt till (se

detaljer nedan). Genom att rapportera biverkningar kan du bidra till att öka informationen om

läkemedels säkerhet.

Läkemedelsverket

Box 26

751 03 Uppsala

www.lakemedelsverket.se

5.

Hur Seretide ska förvaras

Förvara detta läkemedel utom syn- och räckhåll för barn

Används före utgångsdatum som anges på etiketten och kartongen efter EXP/Utg.dat.

Utgångsdatumet är den sista dagen i angiven månad.

Förvaras vid högst 30

Läkemedel ska inte kastas i avloppet eller bland hushållsavfall. Fråga apotekspersonalen hur man

kastar läkemedel som inte längre används. Dessa åtgärder är till för att skydda miljön.

6.

Förpackningens innehåll och övriga upplysningar

Innehållsdeklaration

Varje uppmätt dos innehåller 50 mikrogram salmeterol (som salmeterolxinafoat) och 100, 250

eller 500 mikrogram flutikasonpropionat

Övrigt innehållsämne är laktosmonohydrat (som innehåller mjölkprotein)

Läkemedlets utseende och förpackningsstorlekar

Seretide Diskus innehåller en folieremsa. Folien skyddar inhalationspulvret från yttre påverkan.

Varje dos är en avdelad dos

Seretide Diskus är förpackad i kartonger med:

1 Diskus med 28 doser eller

1, 2, 3 eller 10 Diskus med 60 doser

Eventuellt kommer inte alla förpackningsstorlekar att marknadsföras.

Innehavare av godkännande för försäljning och tillverkare:

Innehavare av godkännande för försäljning:

GlaxoSmithKline AB

Box 516

169 29 Solna

Tel 08-638 93 00

E-post: info.produkt@gsk.com

Detta läkemedel är godkänt inom Europeiska ekonomiska samarbetsområdet under namnen:

Österrike

Seretide Diskus

Belgien

Seretide Diskus

Kroatien

Seretide Diskus

Cypern

Seretide Diskus

Tjeckien

Seretide Diskus

Danmark

Seretide

Estland

Seretide Diskus

Finland

Seretide Diskus

Frankrike

Seretide Diskus

Tyskland

atmadisc Diskus

Grekland

Seretide Diskus

Ungern

Seretide Diskus

Island

Seretide

Irland

Seretide Diskus

Italien

Seretide Diskus

Luxemburg

Seretide Diskus

Malta

Seretide Diskus

Nederländerna

Seretide Diskus

Portugal

Seretaide Diskus

Rumänien

Seretide Diskus

Slovakien

Seretide Diskus

Spanien

Seretide Accuhaler

Sverige

Seretide Diskus

Storbritannien

Seretide Accuhaler

Denna bipacksedel ändrades senast: 2020-08-25

Läs hela dokumentet

SUMMARY OF PRODUCT CHARACTERISTICS

NAME OF THE MEDICINAL PRODUCT

Seretide Diskus mite 50 microgram/100 microgram/ dose inhalation powder, pre-dispensed.

Seretide Diskus 50 microgram/250 microgram/ dose inhalation powder, pre-dispensed.

Seretide Diskus forte 50 microgram/500 microgram/ dose inhalation powder, pre-dispensed.

[To be completed nationally]

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

Each single inhalation provides a delivered dose (the dose leaving the mouthpiece) of 47 micrograms

of salmeterol (as salmeterol xinafoate) and 92, 231 or 460 micrograms of fluticasone propionate. This

corresponds to a pre-dispensed dose of 50 micrograms of salmeterol (as salmeterol xinafoate) and

100, 250 or 500 micrograms fluticasone propionate.

Excipients with known effect:

Each delivered dose contains up to 12.5 mg of lactose (as monohydrate).

For the full list of excipients, see section 6.1.

3.

PHARMACEUTICAL FORM

Inhalation powder, pre-dispensed.

Moulded plastic device containing a foil strip with 28 or 60 regularly placed blisters.

4.

CLINICAL PARTICULARS

4.1

Therapeutic indications

Asthma

Seretide is indicated in the regular treatment of asthma where use of a combination product

(long-

acting

agonist

and inhaled corticosteroid) is

appropriate:

patients not adequately controlled with inhaled corticosteroids and ‘as needed’ inhaled

short-acting

agonist

patients already adequately controlled on both inhaled corticosteroid and long-acting

agonist.

Note: Seretide 50 microgram /100 microgram strength is not appropriate in adults and children with

severe asthma.

Chronic Obstructive Pulmonary Disease (COPD)

Seretide is indicated for the symptomatic treatment of patients with COPD, with a FEV

<60%

predicted normal (pre-bronchodilator) and a history of repeated exacerbations, who have significant

symptoms despite regular bronchodilator therapy.

4.2

Posology and method of administration

Posology

Route of administration: Inhalation use.

Patients should be made aware that Seretide Diskus must be used daily for optimum benefit, even

when asymptomatic.

Patients should be regularly reassessed by a doctor, so that the strength of Seretide they are receiving

remains optimal

and is only changed on medical advice.

Patients should be given the strength of Seretide containing the appropriate fluticasone propionate

dosage for the severity of their disease. If an individual patient should require dosages outside the

recommended regimen, appropriate doses of

agonist and/or corticosteroid should be prescribed.

Recommended Doses:

Asthma

Adults and adolescents 12 years and older:

One inhalation of 50 micrograms salmeterol and 100 micrograms fluticasone propionate twice

daily.

One inhalation of 50

micrograms salmeterol and 250 micrograms fluticasone propionate twice

daily.

One inhalation of 50 micrograms salmeterol and500 micrograms fluticasone propionate twice

daily.

The dose should be titrated to the lowest dose at which effective control of symptoms is

maintained. Where the control of symptoms is maintained with the lowest strength of the

combination given twice daily then the next step could include a test of inhaled corticosteroid

alone.

As an alternative, patients requiring a long-acting

agonist could be titrated to Seretide given once

daily if, in the opinion of the prescriber, it would be adequate to maintain disease control. In the event

of once daily dosing when the patient has a history of nocturnal symptoms the dose should be given at

night and when the patient has a history of mainly daytime symptoms the dose should be given in the

morning.

A short-term trial of Seretide may be considered as initial maintenance therapy in adults or

adolescents with moderate persistent asthma (defined as patients with daily symptoms, daily rescue

use and moderate to severe airflow limitation) for whom rapid control of asthma is essential. In these

cases, the recommended initial dose is one inhalation of 50 micrograms salmeterol and 100

micrograms fluticasone propionate twice daily. Once control of asthma is attained treatment should be

reviewed and consideration given as to whether patients should be stepped down to an inhaled

corticosteroid alone. Regular review of patients as treatment is stepped down is important.

A clear benefit has not been shown as compared to inhaled fluticasone propionate alone used as initial

maintenance therapy when one or two of the criteria of severity are missing. In general inhaled

corticosteroids remain the first line treatment for most patients. Seretide is not intended for the initial

management of mild asthma. Seretide 50 microgram/100 micrograms strength is not appropriate in

adults and children with severe asthma; it is recommended to establish the appropriate dosage of

inhaled corticosteroid before any fixed-combination can be used in patients with severe asthma.

Paediatric population

Children 4 years and older:

One inhalation of 50 micrograms salmeterol and 100 micrograms fluticasone propionate twice

daily.

The maximum licensed dose of fluticasone propionate delivered by Seretide Diskus in children is

100 microgram twice daily.

There are no data available for use of Seretide in children aged under 4 years.

COPD

Adults:

One inhalation of 50 micrograms salmeterol and 500 micrograms fluticasone propionate twice

daily.

Special patient groups:

There is no need to adjust the dose in elderly patients or in those with renal impairment. There are no

data available for use of Seretide in patients with hepatic impairment.

Using the Diskus:

The device is opened and primed by sliding the lever. The mouthpiece is then placed in the mouth and

the lips closed round it. The dose can then be inhaled and the device closed.

4.3

Contraindications

Hypersensitivity

to the active substances or to any of the excipients listed in section 6.1.

4.4

Special warnings and precautions for use

Deterioration of disease

Seretide Diskus should not be used to treat

acute asthma

symptoms for which

a fast and short-acting

bronchodilator is required. Patients should be advised to have their inhaler to be used for relief in an

acute asthma attack available at all times.

Patients should not be initiated on Seretide during an exacerbation, or if they have significantly

worsening or acutely deteriorating asthma.

Serious asthma-related adverse events and exacerbations may occur during treatment with Seretide.

Patients should be asked to continue treatment but to seek medical advice if asthma symptoms remain

uncontrolled or worsen after initiation on Seretide.

Increased requirements for use of reliever medication (short-acting bronchodilators), or decreased

response to reliever medication indicate deterioration of control and patients should be reviewed by a

physician.

Sudden and progressive deterioration in control of asthma is potentially life-threatening and the

patient should undergo urgent medical assessment.

Consideration should be given to increasing

corticosteroid therapy.

Once asthma symptoms are controlled, consideration may be given to gradually reducing the dose of

Seretide. Regular review of patients as treatment is stepped down is important. The lowest effective

dose of Seretide should be used (see section 4.2).

For patients with COPD experiencing exacerbations, treatment with systemic corticosteroids is

typically indicated, therefore patients should be instructed to seek medical attention if symptoms

deteriorate with Seretide

Treatment with Seretide should not be stopped abruptly in patients with asthma due to risk of

exacerbation. Therapy should be down-titrated under physician supervision. For patients with COPD

cessation of therapy may also be associated with symptomatic decompensation and should be

supervised by a physician.

As with all inhaled medication containing

corticosteroids, Seretide should be administered with

caution in patients with active or quiescent pulmonary tuberculosis and fungal, viral or other

infections of the airway. Appropriate treatment should be promptly instituted, if indicated.

Cardiovascular effects

Rarely, Seretide may cause cardiac arrhythmias e.g. supraventricular tachycardia, extrasystoles and

atrial fibrillation, and a mild transient reduction in serum potassium at high therapeutic doses.

Seretide should be used with caution in patients with severe cardiovascular disorders or heart rhythm

abnormalities and in patients with diabetes mellitus,

thyrotoxicosis,

uncorrected hypokalaemia or

patients predisposed to low levels of serum potassium.

Hyperglycaemia

There have been very rare reports of increases in blood glucose levels (see section 4.8) and this

should be considered when prescribing to patients with a history of diabetes mellitus.

Paradoxical bronchospasm

As with other inhalation therapy paradoxical bronchospasm may occur with an immediate increase in

wheezing and shortness of breath after dosing. Paradoxical bronchospasm responds to a rapid-acting

bronchodilator and should be treated straightaway. Seretide Diskus should be discontinued

immediately, the patient assessed and alternative therapy instituted if necessary.

The pharmacological side effects of

agonist treatment, such as tremor, palpitations and headache,

have been reported, but tend to be transient and reduce with regular therapy.

Excipients

Seretide contains lactose monohydrate up to 12.5 milligram /dose. This amount does not normally

cause problems in lactose intolerant people. The excipient lactose contains small amounts of milk

proteins, which may cause allergic reactions.

Systemic corticosteroid effects

Systemic effects may occur with any inhaled corticosteroid, particularly at high doses prescribed for

long periods. These effects are much less likely to occur than with oral corticosteroids. Possible

systemic effects include

Cushing’s syndrome, Cushingoid features, adrenal suppression, decrease in

bone mineral density, cataract and glaucoma and more rarely, a range of psychological or behavioural

effects including psychomotor hyperactivity, sleep disorders, anxiety, depression or aggression

(particularly in children) (see Paediatric population sub-heading below for information on the

systemic effects of inhaled corticosteroids in children and adolescents).

It is important, therefore,

that the patient is reviewed regularly and the dose of inhaled corticosteroid is reduced to the

lowest dose at which effective control of asthma is maintained.

Prolonged treatment of patients with high doses of inhaled corticosteroids may result in adrenal

suppression and acute adrenal crisis. Very rare cases of adrenal suppression and acute adrenal crisis

have also been described with doses of fluticasone propionate between 500 and less than 1000

micrograms. Situations, which could potentially trigger acute adrenal crisis include trauma, surgery,

infection or any rapid reduction in dosage. Presenting symptoms are typically vague and may include

anorexia, abdominal pain, weight loss, tiredness, headache, nausea, vomiting, hypotension, decreased

level of consciousness, hypoglycaemia, and seizures. Additional systemic corticosteroid cover should

be considered during periods of stress or elective surgery.

The benefits of inhaled fluticasone propionate therapy should minimise the need for oral steroids, but

patients transferring from oral steroids may remain at risk of impaired adrenal reserve for a

considerable time. Therefore these patients should be treated with special care and adrenocortical

function regularly monitored. Patients who have required high dose emergency corticosteroid therapy

in the past may also be at risk. This possibility of residual impairment should always be borne in mind

in emergency and elective situations likely to produce stress, and appropriate corticosteroid treatment

must be considered.

The extent of the adrenal impairment may require specialist advice before

elective procedures.

Ritonavir can greatly increase the concentration of fluticasone propionate in plasma. Therefore,

concomitant use should be avoided, unless the potential benefit to the patient outweighs the risk of

systemic corticosteroid side effects. There is also an increased risk of systemic side effects when

combining fluticasone propionate with other potent CYP3A inhibitors (see section 4.5).

Pneumonia in patients with COPD

An increase in the incidence of pneumonia, including pneumonia requiring hospitalisation, has been

observed in patients with COPD receiving inhaled corticosteroids. There is some evidence of an

increased risk of pneumonia with increasing steroid dose but this has not been demonstrated

conclusively across all studies.

There is no conclusive clinical evidence for intra-class differences in the magnitude of the pneumonia

risk among inhaled corticosteroid products.

Physicians should remain vigilant for the possible development of pneumonia in patients with COPD

as the clinical features of such infections overlap with the symptoms of COPD exacerbations.

Risk factors for pneumonia in patients with COPD include current smoking, older age, low body mass

index (BMI) and severe COPD.

Interactions with potent CYP3A4 inhibitors

Concomitant use of systemic ketoconazole significantly increases systemic exposure to salmeterol.

This may lead to an increase in the incidence of systemic effects (e.g. prolongation in the QTc interval

and palpitations). Concomitant treatment with ketoconazole or other potent CYP3A4 inhibitors should

therefore be avoided unless the benefits outweigh the potentially increased risk of systemic side

effects of salmeterol treatment (see section 4.5).

Visual disturbance

Visual disturbance may be reported with systemic and topical corticosteroid use. If a patient presents

with symptoms such as blurred vision or other visual disturbances, the patient should be considered

for referral to an ophthalmologist for evaluation of possible causes, which may include cataract,

glaucoma or rare diseases such as central serous chorioretinopathy (CSCR) which have been reported

after use of systemic and topical corticosteroids.

Paediatric Population

Children and adolescents <16 years taking high doses of fluticasone propionate (typically

1000

micrograms/day) may be at particular risk. Systemic effects may occur, particularly at high doses

prescribed for long periods. Possible systemic effects include Cushing’s syndrome, Cushingoid

features

,

adrenal suppression, acute adrenal crisis and growth retardation in children and adolescents

and more rarely, a range of psychological or behavioural effects including psychomotor hyperactivity,

sleep disorders, anxiety, depression or aggression. Consideration should be given to referring the

child or adolescent to a paediatric respiratory specialist.

It is recommended that the height of children receiving prolonged treatment with inhaled

corticosteroid is regularly monitored.

The dose of inhaled corticosteroid should be reduced to the

lowest dose at which effective control of asthma is maintained.

4.5

Interaction with other medicinal products and other forms of interaction

adrenergic blockers may weaken or antagonise the effect of salmeterol. Both non-selective and

selective

blockers should be avoided unless there are compelling reasons for their use. Potentially

serious hypokalaemia may result from

agonist therapy. Particular caution is advised in acute

severe asthma as this effect may be potentiated by concomitant treatment with xanthine derivatives,

steroids and diuretics.

Concomitant use of other

adrenergic containing drugs can have a potentially additive effect.

Fluticasone Propionate

Under normal circumstances, low plasma concentrations of fluticasone propionate are achieved after

inhaled dosing, due to extensive first pass metabolism and high systemic clearance mediated by

cytochrome CYP3A4 in the gut and liver. Hence, clinically significant drug interactions mediated by

fluticasone propionate are unlikely.

In an interaction study in healthy subjects with intranasal fluticasone propionate, ritonavir (a highly

potent cytochrome CYP3A4 inhibitor) 100 mg b.i.d. increased the fluticasone propionate plasma

concentrations several hundred fold, resulting in markedly reduced serum cortisol concentrations.

Information about this interaction is lacking for inhaled fluticasone propionate, but a marked increase

in fluticasone propionate plasma levels is expected. Cases of Cushing’s syndrome and adrenal

suppression have been reported. The combination should be avoided unless the benefit outweighs the

increased risk of systemic glucocorticoid side effects.

In a small study in healthy volunteers, the slightly less potent CYP3A inhibitor ketoconazole

increased the exposure of fluticasone propionate after a single inhalation by 150%. This resulted in a

greater reduction of plasma cortisol as compared with fluticasone propionate alone. Co-treatment with

other potent CYP3A inhibitors, such as itraconazole and cobicistat-containing products, and moderate

CYP3A inhibitors, such as erythromycin, is also expected to increase the systemic fluticasone

propionate exposure and the risk of systemic side effects. Combinations should be avoided unless the

benefit outweighs the potential increased risk of systemic corticosteroid side-effects, in which case

patients should be monitored for systemic corticosteroid side-effects.

Salmeterol

Potent CYP3A4 inhibitors

Co-administration of ketoconazole (400 mg orally once daily) and salmeterol (50 micrograms inhaled

twice daily) in 15 healthy subjects for 7 days resulted in a significant increase in plasma salmeterol

exposure (1.4-fold Cmax and 15-fold AUC). This may lead to an increase in the incidence of other

systemic effects of salmeterol treatment (e.g. prolongation of QTc interval and palpitations) compared

with salmeterol or ketoconazole treatment alone (see section 4.4).

Clinically significant effects were not seen on blood pressure, heart rate, blood glucose and blood

potassium levels. Co-administration with ketoconazole did not increase the elimination half-life of

salmeterol or increase salmeterol accumulation with repeat dosing.

The concomitant administration of ketoconazole should be avoided, unless the benefits outweigh the

potentially increased risk of systemic side effects of salmeterol treatment. There is likely to be a

similar risk of interaction with other potent CYP3A4 inhibitors (e.g. itraconazole, telithromycin,

ritonavir).

Moderate CYP 3A4 inhibitors

Co-administration of erythromycin (500 mg orally three times a day) and salmeterol (50 micrograms

inhaled twice daily) in 15 healthy subjects for 6 days resulted in a small but non-statistically

significant increase in salmeterol exposure (1.4-fold C

and 1.2-fold AUC). Co-administration with

erythromycin was not associated with any serious adverse effects.

4.6

Fertility, pregnancy and lactation

Fertility

There are no data in humans. However, animal studies showed no effects of salmeterol or fluticasone

propionate on fertility.

Pregnancy

A large amount of data on pregnant women (more than 1000 pregnancy outcomes) indicates no

malformative or feto/neonatal toxicity related to Seretide. Animal studies have shown reproductive

toxicity after administration of

adrenoreceptor agonists and glucocorticosteroids (see section 5.3).

Administration of Seretide to pregnant women should only be considered if the expected benefit to

the mother is greater than any possible risk to the fetus.

The lowest effective dose of fluticasone propionate needed to maintain adequate asthma control

should be used in the treatment of pregnant women.

Breastfeeding

It is unknown whether salmeterol and fluticasone propionate/metabolites are excreted in human milk.

Studies have shown that salmeterol and fluticasone propionate, and their metabolites, are excreted

into the milk of lactating rats.

A risk to breastfed newborns/infants cannot be excluded. A decision must be made whether to

discontinue breastfeeding or to discontinue Seretide therapy taking into account the benefit of

breastfeeding for the child and the benefit of therapy for the woman.

4.7

Effects on ability to drive and use machines

Seretide Diskus has no or negligible influence on the ability to drive and use machines.

4.8

Undesirable effects

As Seretide contains salmeterol and fluticasone propionate, the type and severity of adverse reactions

associated with each of the compounds may be expected. There is no incidence of additional adverse

events following concurrent administration of the two compounds.

Adverse events which have been associated with

salmeterol/fluticasone propionate

are given below,

listed by system organ class and frequency. Frequencies are defined as: very common (≥1/10),

common (

1/100 to

1/10), uncommon (

1/1000 to

1/100), rare (

1/10,000 to <1/1000) and not

known (cannot be estimated from the available data). Frequencies were derived from clinical trial

data. The incidence in placebo was not taken into account.

System Organ Class

Adverse Event

Frequency

Infections &

Infestations

Candidiasis of the mouth and throat

Pneumonia (in COPD patients)

Bronchitis

Oesophageal candidiasis

Common

Common

1,3,5

Common

Rare

Immune System

Disorders

Hypersensitivity reactions with the following

manifestations:

Cutaneous hypersensitivity reactions

Angioedema (mainly facial and oropharyngeal

oedema)

Respiratory symptoms (dyspnoea)

Respiratory symptoms (bronchospasm)

Anaphylactic reactions including anaphylactic shock

Uncommon

Rare

Uncommon

Rare

Rare

Endocrine Disorders

Cushing’s syndrome, Cushingoid features,

Adrenal

suppression, Growth retardation in children and

adolescents, Decreased bone mineral density

Rare

Metabolism &

Nutrition Disorders

Hypokalaemia

Hyperglycaemia

Common

Uncommon

Psychiatric Disorders

Anxiety

Sleep disorders

Behavioural changes, including psychomotor

hyperactivity and irritability (predominantly in

children)

Depression, aggression (predominantly in children)

Uncommon

Uncommon

Rare

Not known

System Organ Class

Adverse Event

Frequency

Nervous System

Disorders

Headache

Tremor

Very Common

Uncommon

Eye Disorders

Cataract

Glaucoma

Vision, blurred

Uncommon

Rare

Not known

Cardiac Disorders

Palpitations

Tachycardia

Cardiac arrhythmias (including supraventricular

tachycardia and extrasystoles).

Atrial fibrillation

Angina pectoris

Uncommon

Uncommon

Rare

Uncommon

Uncommon

Respiratory, Thoracic

& Mediastinal

Disorders

Nasopharyngitis

Throat irritation

Hoarseness/dysphonia

Sinusitis

Paradoxical bronchospasm

Very Common

Common

Common

Common

Rare

Skin and

subcutaneous tissue

disorders

Contusions

Common

Musculoskeletal &

Connective Tissue

Disorders

Muscle cramps

Traumatic fractures

Arthralgia

Myalgia

Common

Common

Common

Common

Reported commonly in placebo

Reported very commonly in placebo

Reported over 3 years in a COPD study

See section 4.4

See section 5.1.

Description of selected adverse reactions

The pharmacological side effects of

agonist treatment, such as tremor, palpitations and headache,

have been reported, but tend to be transient and reduce with regular therapy.

As with other inhalation therapy paradoxical bronchospasm may occur with an immediate increase in

wheezing and shortness of breath after dosing. Paradoxical bronchospasm responds to a rapid-acting

bronchodilator and should be treated straightaway. Seretide Diskus should be discontinued

immediately, the patient assessed and alternative therapy instituted if necessary.

Due to the fluticasone propionate component, hoarseness and candidiasis (thrush) of the mouth and

throat and, rarely, of the oesophagus can occur in some patients.

Both hoarseness and incidence of

mouth and throat candidiasis may be relieved by rinsing the mouth with water and/or brushing the

teeth after using the product. Symptomatic mouth and throat candidiasis can be treated with topical

anti-fungal therapy whilst still continuing with the Seretide Diskus.

Paediatric population

Possible systemic effects include Cushing’s syndrome, Cushingoid features

,

adrenal suppression and

growth retardation in children and adolescents (see section 4.4). Children may also experience

anxiety, sleep disorders and behavioural changes, including hyperactivity and irritability.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It

allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare

professionals are asked to report any suspected adverse reactions via the national reporting system

listed in Appendix V

4.9

Overdose

There are no data available from clinical trials on overdose with Seretide, however data on overdose

with both drugs are given below:

The signs and symptoms of salmeterol overdose are dizziness, increases in systolic blood pressure,

tremor, headache and tachycardia. If Seretide therapy has to be withdrawn due to overdose of the

agonist component of the drug, provision of appropriate replacement steroid therapy should be

considered. Additionally, hypokalaemia can occur and therefore serum potassium levels should be

monitored. Potassium replacement should be considered.

Acute:

Acute inhalation of fluticasone propionate doses in excess of those recommended may lead to

temporary suppression of adrenal function. This does not need emergency action as adrenal function

is recovered in a few days, as verified by plasma cortisol measurements.

Chronic overdose of inhaled fluticasone propionate:

Adrenal reserve should be monitored and

treatment with a systemic corticosteroid may be necessary. When stabilised, treatment should be

continued with an inhaled corticosteroid at the recommended dose. Refer to section 4.4: risk of

adrenal suppression.

In cases of both acute and chronic fluticasone propionate overdose Seretide therapy should be

continued at a suitable dosage for symptom control.

5.

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties

Pharmacotherapeutic Group:

Adrenergics in combination with corticosteroids or other drugs, excl.

anticholinergics.

ATC Code:

R03AK06

Mechanism of action and pharmacodynamic effects:

Seretide contains salmeterol and fluticasone propionate which have differing modes of action.

The respective mechanisms of action of both drugs are discussed below.

Salmeterol:

Salmeterol is a selective long-acting (12 hour)

adrenoceptor agonist with a long side chain which

binds to the exo-site of the receptor.

Salmeterol produces a longer duration of bronchodilation, lasting for at least 12 hours, than

recommended doses of conventional short-acting

agonists.

Fluticasone propionate:

Fluticasone propionate given by inhalation at recommended doses has a glucocorticoid anti-

inflammatory action within the lungs, resulting in reduced symptoms and exacerbations of asthma,

with less adverse effects than when corticosteroids are administered systemically.

Clinical efficacy and safety

Seretide Asthma clinical trials

A twelve month study (Gaining Optimal Asthma ControL, GOAL), in 3416 adult and adolescent

patients with persistent

asthma, compared the safety and efficacy of Seretide versus inhaled

corticosteroid (Fluticasone Propionate) alone to determine whether the goals of asthma management

were achievable. Treatment was stepped up every 12 weeks until **

total control

was achieved or the

highest dose of study drug was reached. GOAL showed more patients treated with Seretide achieved

asthma control than patients treated with ICS alone and this control was attained at a lower

corticosteroid dose.

*Well controlled

asthma was achieved more rapidly with Seretide than with ICS alone. The time on

treatment for 50% of subjects to achieve a first individual

well controlled

week was 16 days for

Seretide compared to 37 days for the ICS group. In the subset of steroid naive asthmatics the time to

an individual

well controlled

week was 16 days in the Seretide treatment compared to 23 days

following treatment with ICS.

The overall study results showed:

Percentage of Patients Attaining *Well Controlled (WC) and **Totally Controlled

(TC) Asthma over 12 months

Salmeterol/FP

FP

Pre-Study Treatment

WC

TC

WC

TC

No ICS

(SABA alone)

Low dose ICS

≤500 micrograms BDP

or equivalent/day)

Medium dose ICS

(>500 to 1000

micrograms BDP or equivalent/day)

Pooled results across the 3 treatment

levels

*Well controlled asthma; less than or equal to 2 days with symptom score greater than 1 (symptom

score 1 defined as ‘symptoms for one short period during the day’), SABA use on less than or equal to

2 days and less than or equal to 4 occasions/week, greater than or equal to 80% predicted morning

peak expiratory flow, no night-time awakenings, no exacerbations and no side effects enforcing a

change in therapy

**Total control of asthma; no symptoms, no SABA use, greater than or equal to 80% predicted

morning peak expiratory flow, no night-time awakenings, no exacerbations and no side effects

enforcing a change in therapy

The results of this study suggest

that Seretide 50/100 micrograms bd may be considered as initial

maintenance therapy in patients with moderate persistent asthma for whom rapid control of asthma is

deemed essential (see section 4.2).

A double blind, randomised, parallel group study in 318 patients with persistent asthma aged ≥18

years evaluated the safety and tolerability of administering two inhalations twice daily (double dose)

of Seretide for two weeks. The study showed that doubling the inhalations of each strength of Seretide

for up to 14 days resulted in a small increase in

agonist-related adverse events (tremor; 1 patient

[1%] vs 0, palpitations; 6 [3%] vs 1 [<1%], muscle cramps; 6[3%] vs 1 [<1%]) and a similar

incidence of inhaled corticosteroid related adverse events (e.g. oral candidiasis; 6 [6%] vs 16 [8%],

hoarseness; 2 [2%] vs 4 [2%]) compared to one inhalation twice daily. The small increase in

agonist-related adverse events should be taken into account if doubling the dose of Seretide is

considered by the physician in adult patients requiring additional short-term (up to 14 days) inhaled

corticosteroid therapy.

Seretide COPD clinical trials

TORCH was a 3-year study to assess the effect of treatment with Seretide Diskus 50/500 micrograms

bd, salmeterol Diskus 50 micrograms bd, fluticasone propionate (FP) Diskus 500 micrograms bd or

placebo on all-cause mortality in patients with COPD. COPD patients with a baseline

(pre-bronchodilator) FEV

<60% of predicted normal were randomised to double-blind medication.

During the study, patients were permitted usual COPD therapy with the exception of other inhaled

corticosteroids, long-acting bronchodilators and long-term systemic corticosteroids. Survival status at

3 years was determined for all patients regardless of withdrawal from study medication. The primary

endpoint was reduction in all cause mortality at 3 years for Seretide vs Placebo.

Placebo

N = 1524

Salmeterol 50

N = 1521

FP 500

N = 1534

Seretide

50/500

N = 1533

All cause mortality at 3 years

Number of deaths

(15.2%)

(13.5%)

(16.0%)

(12.6%)

Hazard Ratio vs

Placebo (CIs)

p value

0.879

(0.73, 1.06)

0.180

1.060

(0.89, 1.27)

0.525

0.825

(0.68, 1.00 )

0.052

Hazard Ratio

Seretide 50/500 vs

components (CIs)

p value

0.932

(0.77, 1.13)

0.481

0.774

(0.64, 0.93)

0.007

1. Non significant P value after adjustment for 2 interim analyses on the primary efficacy

comparison from a log-rank analysis stratified by smoking status

There was a trend towards improved survival in subjects treated with Seretide compared with placebo

over 3 years however this did not achieve the statistical significance level p≤0.05.

The percentage of patients who died within 3 years due to COPD-related causes was 6.0% for

placebo, 6.1% for salmeterol, 6.9% for FP and 4.7% for Seretide.

The mean number of moderate to severe exacerbations per year was significantly reduced with

Seretide as compared with treatment with salmeterol, FP and placebo (mean rate in the Seretide group

0.85 compared with 0.97 in the salmeterol group, 0.93 in the FP group and 1.13 in the placebo). This

translates to a reduction in the rate of moderate to severe exacerbations of 25% (95% CI: 19% to

31%; p<0.001) compared with placebo, 12% compared with salmeterol (95% CI: 5% to 19%,

p=0.002) and 9% compared with FP (95% CI: 1% to 16%, p=0.024). Salmeterol and FP significantly

reduced exacerbation rates compared with placebo by 15% (95% CI: 7% to 22%; p<0.001) and 18%

(95% CI: 11% to 24%; p<0.001) respectively.

Health Related Quality of Life, as measured by the St George’s Respiratory Questionnaire (SGRQ)

was improved by all active treatments in comparison with placebo. The average improvement over

three years for Seretide compared with placebo was -3.1 units (95% CI: -4.1 to -2.1; p<0.001),

compared with salmeterol was -2.2 units (p<0.001) and compared with FP was -1.2 units (p=0.017). A

4-unit decrease is considered clinically relevant.

The estimated 3-year probability of having pneumonia reported as an adverse event was 12.3% for

placebo, 13.3% for salmeterol, 18.3% for FP and 19.6% for Seretide (Hazard ratio for Seretide vs

placebo: 1.64, 95% CI: 1.33 to 2.01, p<0.001). There was no increase in pneumonia related deaths;

deaths while on treatment that were adjudicated as primarily due to pneumonia were 7 for placebo, 9

for salmeterol, 13 for FP and 8 for Seretide. There was no significant difference in probability of bone

fracture (5.1% placebo, 5.1% salmeterol, 5.4% FP and 6.3% Seretide; Hazard ratio for Seretide vs

placebo: 1.22, 95% CI: 0.87 to 1.72, p=0.248.

Placebo-controlled clinical trials, over 6 and 12 months, have shown that regular use of Seretide

50/500 micrograms improves lung function and reduces breathlessness and the use of relief

medication.

Studies SCO40043 and SCO100250 were randomised, double-blind, parallel-group, replicate studies

comparing the effect of Seretide 50/250 micrograms bd (a dose not licensed for COPD treatment in

the European Union) with salmeterol 50 micrograms bd on the annual rate of moderate/severe

exacerbations in subjects with COPD with FEV

less than 50% predicted and a history of

exacerbations. Moderate/ severe exacerbations were defined as worsening symptoms that required

treatment with oral corticosteroids and/or antibiotics or in-patient hospitalisation.

The trials had a 4 week run-in period during which all subjects received open-label salmeterol/ FP

50/250 to standardize COPD pharmacotherapy and stabilise disease prior to randomisation to blinded

study medication for 52 weeks. Subjects were randomised 1:1 to salmeterol/ FP 50/250 (total ITT

n=776) or salmeterol (total ITT n=778). Prior to run-in, subjects discontinued use of previous COPD

medications except short-acting bronchodilators. The use of concurrent inhaled long-acting

bronchodilators (

agonist and anticholinergic), ipratropium/salbutamol combination products, oral

agonists, and theophylline preparations were not allowed during the treatment period. Oral

corticosteroids and antibiotics were allowed for the acute treatment of COPD exacerbations with

specific guidelines for use. Subjects used salbutamol on an as-needed basis throughout the studies.

The results of both studies showed that treatment with Seretide 50/250 resulted in a significantly

lower annual rate of moderate/severe COPD exacerbations compared with salmeterol (SCO40043:

1.06 and 1.53 per subject per year, respectively, rate ratio of 0.70, 95% CI: 0.58 to 0.83, p<0.001;

SCO100250: 1.10 and 1.59 per subject per year, respectively, rate ratio of 0.70, 95% CI: 0.58 to 0.83,

p<0.001). Findings for the secondary efficacy measures (time to first moderate/severe exacerbation,

the annual rate of exacerbations requiring oral corticosteroids, and pre-dose morning (AM) FEV

significantly favoured Seretide 50/250 micrograms bd over salmeterol. Adverse event profiles were

similar with the exception of a higher incidence of pneumonias and known local side effects

(candidiasis and dysphonia) in the Seretide 50/250 micrograms bd group compared with salmeterol.

Pneumonia-related events were reported for 55 (7%) subjects in the Seretide 50/250 micrograms bd

group and 25 (3%) in the salmeterol group. The increased incidence of reported pneumonia with

Seretide 50/250 micrograms bd appears to be of similar magnitude to the incidence reported following

treatment with Seretide 50/500 micrograms bd in TORCH.

Asthma

The Salmeterol Multi-center Asthma Research Trial (SMART)

The Salmeterol Multi-center Asthma Research Trial (SMART) was a 28-week US study that

evaluated the safety of salmeterol compared to placebo added to usual therapy in adult and adolescent

subjects. Although there were no significant differences in the primary endpoint of the combined

number of respiratory-related deaths and respiratory-related life-threatening experiences, the study

showed a significant increase in asthma-related deaths in patients receiving salmeterol (13 deaths out

of 13,176 patients treated with salmeterol versus 3 deaths out of 13,179 patients on placebo). The

study was not designed to assess the impact of concurrent inhaled corticosteroid use, and only 47% of

subjects reported ICS use at baseline.

Safety and efficacy of salmeterol-FP versus FP alone in asthma

Two multi-centre 26-week studies were conducted to compare the safety and efficacy of salmeterol-

FP versus FP alone, one in adult and adolescent subjects (AUSTRI trial), and the other in paediatric

subjects 4-11 years of age (VESTRI trial). For both studies, enrolled subjects had moderate to severe

persistent asthma with history of asthma-related hospitalisation or asthma exacerbation in the

previous year. The primary objective of each study was to determine whether the addition of LABA to

ICS therapy (salmeterol-FP) was non-inferior to ICS (FP) alone in terms of the risk of serious asthma

related events (asthma-related hospitalisation, endotracheal intubation, and death). A secondary

efficacy objective of these studies was to evaluate whether ICS/LABA (salmeterol-FP) was superior

to ICS therapy alone (FP) in terms of severe asthma exacerbation (defined as deterioration of asthma

requiring the use of systemic corticosteroids for at least 3 days or an in-patient hospitalisation or

emergency department visit due to asthma that required systemic corticosteroids).

A total of 11,679 and 6,208 subjects were randomized and received treatment in the AUSTRI and

VESTRI trials, respectively. For the primary safety endpoint, non-inferiority was achieved for both

trials (see Table below).

Serious Asthma-Related Events in the 26-Week AUSTRI and VESTRI Trials

AUSTRI

VESTRI

Salmeterol-FP

(n = 5,834)

FP Alone

(n = 5,845)

Salmeterol-FP

(n = 3,107)

FP Alone

(n = 3,101)

Composite endpoint

(Asthma-related

hospitalisation,

endotracheal intubation, or

death)

34 (0.6%)

33 (0.6%)

27 (0.9%)

21 (0.7%)

Salmeterol-FP/FP Hazard

ratio (95% CI)

1.029

(0.638-1.662)

1.285

(0.726-2.272)

Death

Asthma-related

hospitalisation

Endotracheal intubation

If the resulting upper 95% CI estimate for the relative risk was less than 2.0, then non-inferiority

was concluded.

If the resulting upper 95% CI estimate for the relative risk was less than 2.675, then non-inferiority

was concluded.

For the secondary efficacy endpoint, reduction in time to first asthma exacerbation for salmeterol-FP

relative to FP was seen in both studies, however only AUSTRI met statistical significance:

AUSTRI

VESTRI

Salmeterol-FP

(n = 5,834)

FP Alone

(n = 5,845)

Salmeterol-FP

(n = 3,107)

FP Alone

(n = 3,101)

Number of subjects with an

asthma exacerbation

480 (8%)

597 (10%)

265 (9%)

309 (10%)

Salmeterol-FP/FP Hazard

ratio (95% CI)

0.787

(0.698, 0.888)

0.859

(0.729, 1.012)

Paediatric population:

In trial SAM101667, in 158 children aged 6 to 16 years with symptomatic asthma, the combination of

salmeterol/fluticasone propionate is equally efficacious to doubling the dose of fluticasone propionate

regarding symptom control and lung function. This study was not designed to investigate the effect on

exacerbations.

In a 12 week trial of children aged 4 to 11 years [n=257] treated with either salmeterol/fluticasone

propionate 50/100 or salmeterol 50 micrograms + fluticasone propionate 100 micrograms both twice

daily, both treatment arms experienced a 14% increase in peak expiratory flow rate as well as

improvements in symptom score and rescue salbutamol use. There were no differences between the 2

treatment arms. There were no differences in safety parameters between the 2 treatment arms.

In a 12 week trial of children 4 to 11 years of age [n=203] randomized in a parallel-group study with

persistent asthma and who were symptomatic on inhaled corticosteroid, safety was the primary

objective. Children received either salmeterol/fluticasone propionate (50/100 micrograms) or

fluticasone propionate (100 micrograms) alone twice daily. Two children on salmeterol/fluticasone

propionate and 5 children on fluticasone propionate withdrew because of worsening asthma. After 12

weeks no children in either treatment arm had abnormally low 24 hour urinary cortisol excretion.

There were no other differences in safety profile between the treatment arms.

Fluticasone propionate containing medications in asthma during pregnancy

An observational retrospective epidemiological cohort study utilising electronic health records from

the United Kingdom was conducted to evaluate the risk of MCMs following first trimester exposure

to inhaled FP alone and salmeterol-FP relative to non-FP containing ICS. No placebo comparator was

included in this study.

Within the asthma cohort of 5362 first trimester ICS-exposed pregnancies, 131 diagnosed MCMs

were identified; 1612 (30%) were exposed to FP or salmeterol-FP of which 42 diagnosed MCMs were

identified. The adjusted odds ratio for MCMs diagnosed by 1 year was 1.1 (95%CI: 0.5 – 2.3) for FP

exposed vs non-FP ICS exposed women with moderate asthma and 1.2 (95%CI: 0.7 – 2.0) for women

with considerable to severe asthma. No difference in the risk of MCMs was identified following first

trimester exposure to FP alone versus salmeterol-FP. Absolute risks of MCM across the asthma

severity strata ranged from 2.0 to 2.9 per 100 FP-exposed pregnancies which is comparable to results

from a study of 15,840 pregnancies unexposed to asthma therapies in the General Practice Research

Database (2.8 MCM events per 100 pregnancies).

5.2

Pharmacokinetic properties

For pharmacokinetic purposes each component can be considered separately.

Salmeterol:

Salmeterol acts locally in the lung therefore plasma levels are not an indication of therapeutic effects.

In addition there are only limited data available on the pharmacokinetics of salmeterol because of the

technical difficulty of assaying the drug in plasma due to the low plasma concentrations at therapeutic

doses (approximately 200 picogram/mL or less) achieved after inhaled dosing.

Fluticasone propionate:

The absolute bioavailability of a single dose of inhaled fluticasone propionate in healthy subjects

varies between approximately 5 to 11% of the nominal dose depending on the inhalation device used.

In patients with asthma or COPD a lesser degree of systemic exposure to inhaled fluticasone

propionate has been observed.

Systemic absorption occurs mainly through the lungs and is initially rapid then prolonged. The

remainder of the inhaled dose may be swallowed but contributes minimally to systemic exposure due

to the low aqueous solubility and presystemic metabolism, resulting in oral availability of less than

1%. There is a linear increase in systemic exposure with increasing inhaled dose.

The disposition of fluticasone propionate is characterised by high plasma clearance (1150 mL/min), a

large volume of distribution at steady-state (approximately 300 L) and a terminal half-life of

approximately 8 hours.

Plasma protein binding is 91%

.

Fluticasone propionate is cleared very rapidly from the systemic circulation. The main pathway is

metabolism to an inactive carboxylic acid metabolite, by the cytochrome P450 enzyme CYP3A4.

Other unidentified metabolites are also found in the faeces.

The renal clearance of fluticasone propionate is negligible. Less than 5% of the dose is excreted in

urine, mainly as metabolites. The main part of the dose is excreted in faeces as metabolites and

unchanged drug.

Paediatric population

In a population pharmacokinetic analysis utilizing data from 9 controlled clinical trials with different

devices (Diskus, metered dose inhaler) that included 350 patients with asthma aged 4 to 77 years (174

patients 4 to 11 years of age) higher fluticasone propionate systemic exposure following treatment

with Seretide Diskus 50/100 compared to fluticasone propionate Diskus 100 were seen.

Geometric Mean Ratio [90% CI] for the Salmeterol/fluticasone propionate vs. fluticasone propionate

Diskus Comparison in Children and Adolescent/Adult Populations

Treatment (test vs. ref)

Population

AUC

C

max

Salmeterol/

fluticasone

propionate Diskus 50/100

fluticasone propionate Diskus

100

Children

(4–11yr)

1.20 [1.06 – 1.37]

1.25 [1.11 – 1.41]

Salmeterol/fluticasone

propionate Diskus 50/100

fluticasone propionate Diskus

100

Adolescent/Adult

( ≥12yr)

1.52 [1.08 – 2.13]

1.52 [1.08 – 2.16]

The effect of 21 days of treatment with Seretide Inhaler 25/50 micrograms (2 inhalations twice daily

with or without a spacer) or Seretide Diskus 50/100 micrograms (1 inhalation twice daily) was

evaluated in 31 children aged 4 to 11 years with mild asthma. Systemic exposure to salmeterol was

similar for Seretide Inhaler, Seretide Inhaler with spacer, and Seretide Diskus (126 pg hr/mL [95% CI:

70, 225], 103 pg hr/mL [95% CI: 54, 200], and 110 pg hr/mL [95% CI: 55, 219], respectively).

Systemic exposure to fluticasone propionate was similar for Seretide Inhaler with spacer (107 pg

hr/mL [95% CI: 45.7, 252.2]) and Seretide Diskus (138 pg hr/mL [95% CI: 69.3, 273.2]), but lower

for Seretide Inhaler (24 pg hr/mL [95% CI: 9.6, 60.2]).”

5.3

Preclinical safety data

The only safety concerns for human use derived from animal studies of salmeterol and fluticasone

propionate given separately were effects associated with exaggerated pharmacological actions.

In animal reproduction studies, glucocorticosteroids have been shown to induce malformations (cleft

palate, skeletal malformations). However, these animal experimental results do not seem to be

relevant for man given recommended doses. Animal studies with salmeterol have shown embryofetal

toxicity only at high exposure levels. Following co-administration, increased incidences of transposed

umbilical artery and incomplete ossification of occipital bone were found in rats at doses associated

with known glucocorticoid-induced abnormalities. Neither salmeterol xinafoate or fluticasone

propionate have shown any potential for genetic toxicity.

6.

PHARMACEUTICAL PARTICULARS

6.1

List of excipients

Excipient: Lactose monohydrate (which contains milk proteins).

6.2

Incompatibilities

Not applicable.

6.3

Shelf life

2 years.

6.4

Special precautions for storage

Do not store above 30

6.5

Nature and contents of container

The inhalation powder is contained in blisters held on a formed PVC coated base, with a peelable foil

laminate lid. The strip is contained in a moulded purple plastic device.

The plastic devices are available in cardboard containers, which hold

1 x 28 dose Diskus

1 x 60 dose Diskus

2 x 60 dose Diskus

3 x 60 dose Diskus

10 x 60 dose Diskus

Not all pack sizes may be marketed.

6.6

Special precautions for disposal and other handling

The Diskus releases a powder which is inhaled into the lungs. A dose indicator on the Diskus

indicates the number of doses left. For detailed instructions for use see the Patient Information

Leaflet.

7.

MARKETING AUTHORISATION HOLDER

[To be completed nationally]

8.

MARKETING AUTHORISATION NUMBER(S)

[To be completed nationally]

9.

DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation:

[To be completed nationally]

Date of latest renewal:

[To be completed nationally]

10.

DATE OF REVISION OF THE TEXT

23 July 2020

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