Diovan Comp 80 mg/12,5 mg Filmdragerad tablett

Sverige - svenska - Läkemedelsverket (Medical Products Agency)

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Bipacksedel Bipacksedel (PIL)

31-08-2020

Produktens egenskaper Produktens egenskaper (SPC)

31-08-2020

Aktiva substanser:
hydroklortiazid; valsartan
Tillgänglig från:
Orifarm AB
ATC-kod:
C09DA03
INN (International namn):
hydrochlorothiazide; valsartan
Dos:
80 mg/12,5 mg
Läkemedelsform:
Filmdragerad tablett
Sammansättning:
hydroklortiazid 12,5 mg Aktiv substans; valsartan 80 mg Aktiv substans
Receptbelagda typ:
Receptbelagt
Terapiområde:
Valsartan och diuretika
Bemyndigande status:
Avregistrerad
Godkännandenummer:
22609
Tillstånd datum:
2006-04-06

Dokument på andra språk

Produktens egenskaper Produktens egenskaper - engelska

31-08-2020

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BIPACKSEDEL: INFORMATION TILL ANVÄNDAREN

Diovan Comp 80 mg/12,5 mg filmdragerade tabletter

Diovan Comp 160 mg/12,5 mg filmdragerade tabletter

Diovan Comp 160 mg/25 mg filmdragerade tabletter

Diovan Comp 320 mg/12,5 mg filmdragerade tabletter

Diovan Comp 320 mg/25 mg filmdragerade tabletter

Valsartan/hydroklortiazid

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 Diovan Comp är och vad det används för

Vad du behöver veta innan du tar Diovan Comp

Hur du tar Diovan Comp

Eventuella biverkningar

Hur Diovan Comp ska förvaras

Förpackningens innehåll och övriga upplysningar

1.

Vad Diovan Comp är och vad det används för

Diovan Comp filmdragerade tabletter innehåller två verksamma substanser, valsartan och

hydroklortiazid. Båda substanserna bidrar till att kontrollera högt blodtryck.

Valsartan

tillhör en läkemedelsgrupp som kallas ”angiotensin II-receptorblockerare” och

används för att sänka förhöjt blodtryck. Angiotensin II är ett ämne som finns i kroppen och som

drar ihop blodkärlen, vilket ökar blodtrycket. Valsartan verkar genom att hämma effekten av

angiotensin II. Detta leder till att kärlen vidgar sig och blodtrycket sjunker.

Hydroklortiazid

tillhör en läkemedelsgrupp som kallas tiaziddiuretika (kallas även

vätskedrivande medel). Hydroklortiazid ökar urinproduktionen, vilket också sänker blodtrycket.

Diovan Comp används för att behandla högt blodtryck som inte kan sänkas tillräckligt med bara en av

substanserna.

Högt blodtryck ökar belastningen på hjärta och kärl. Om det inte behandlas kan det skada blodkärlen i

hjärnan, hjärtat och njurarna, och leda till slaganfall (stroke), hjärtsvikt eller njursvikt. Högt blodtryck

ökar risken för hjärtinfarkt. En sänkning av blodtrycket till normal nivå minskar risken för dessa

sjukdomar.

2.

Vad du behöver veta innan du tar Diovan Comp

Ta inte Diovan Comp

om du är allergisk (överkänslig) mot valsartan, hydroklortiazid, sulfonamidderivat (substanser

som är kemiskt besläktade med hydroklortiazid) eller mot något av övriga innehållsämnen i

detta läkemedel (anges i avsnitt 6).

Gravida kvinnor ska inte använda Diovan Comp under de 6 sista månaderna av graviditeten.

(Även tidigare under graviditeten är det bra att undvika Diovan Comp), se Graviditet och

amning).

om du har

svår

leversjukdom, förstörelse av de små gallgångarna i levern (biliär cirros) som

leder till uppbyggnad av galla i levern (kolestas).

om du har

svår

njursjukdom.

om du inte kan producera urin (anuri).

om du behandlas med en konstgjord njure.

om ditt kalium- eller natriumvärde i blodet är lägre än normalt eller om kalciumvärdet i blodet

är högre än normalt trots behandling.

om du har gikt.

om du har diabetes eller nedsatt njurfunktion och du behandlas med ett blodtryckssänkande

läkemedel som innehåller aliskiren.

Om något av ovanstående gäller dig, tala med din läkare och ta inte Diovan Comp

Varningar och försiktighet

Tala med din läkare

om du tar kaliumsparande läkemedel, kaliumtillägg, saltersättningar som innehåller kalium eller

andra läkemedel som ökar mängden kalium i blodet, till exempel heparin. Din läkare kan

behöva kontrollera mängden kalium i blodet regelbundet.

om du har lågt kaliumvärde i blodet.

om du har diarré eller svåra kräkningar.

om du tar höga doser av vätskedrivande tabletter (diuretika).

om du har en allvarlig hjärtsjukdom.

om du har hjärtsvikt eller har haft en hjärtinfarkt. Följ din läkares instruktion för startdosen

noggrant. Din läkare kan också kontrollera din njurfunktion.

om du har förträngning i njurartärerna.

om du nyligen har genomgått njurtransplantation (fått en ny njure).

om du har hyperaldosteronism. Detta är en sjukdom där dina binjurar bildar för mycket av

hormonet aldosteron. Om detta gäller dig, bör inte Diovan Comp användas.

om du har lever- eller njursjukdom.

om du någonsin har upplevt svullnad av tunga och ansikte som orsakas av en allergisk reaktion

som kallas angioödem när du tar ett annat läkemedel (inklusive ACE-hämmare), tala med din

läkare. Om dessa symtom uppträder när du tar Diovan Comp, sluta ta Diovan Comp omedelbart

och ta det aldrig igen. Se även avsnitt 4, "Eventuella biverkningar".

om du har feber, utslag och ledsmärta, som kan vara tecken på systemisk lupus erythematosus

(SLE, en så kallad autoimmun sjukdom).

om du har diabetes, gikt, höga kolesterolvärden eller höga triglyceridvärden i blodet.

om du fått en allergisk reaktion vid användning av andra blodtryckssänkande medel som tillhör

denna läkemedelsgrupp (angiotensin II-receptorblockerare) eller om du har allergi eller astma.

om du upplever en synnedsättning eller ögonsmärta. Dessa kan vara symtom på

vätskeansamling i ögat (mellan åderhinnan och senhinnan) eller en ökning av trycket i ögat och

kan ske inom timmar till veckor efter att du tagit Diovan Comp. Detta kan leda till permanent

synförlust, om det inte behandlas. Om du tidigare har haft en penicillin- eller sulfonamidallergi

kan du löpa större risk att utveckla detta.

om du tar något av följande läkemedel som används för att behandla högt blodtryck:

en ACE-hämmare (t.ex. enalapril, lisinopril, ramipril), särskilt om du har

diabetesrelaterade njurproblem.

aliskiren

om du har haft hudcancer eller om du får en oförutsedd hudförändring under behandlingen.

Behandling med hydroklortiazid, särskilt långvarig användning med höga doser, kan öka risken

för vissa typer av hud- och läppcancer (icke-melanom hudcancer). Skydda din hud från

exponering för solljus och UV-strålar medan du tar Diovan Comp.

Din läkare kan behöva kontrollera din njurfunktion, blodtryck och mängden elektrolyter (t.ex. kalium)

i ditt blod med jämna mellanrum.

Se även informationen under rubriken ”Ta inte Diovan Comp”.

Diovan Comp kan öka hudens känslighet för sol.

Användning av Diovan Comp till barn och ungdomar (yngre än 18 år) rekommenderas inte.

Kontakta din läkare om du tror att du är gravid eller blir gravid under behandlingen. Diovan Comp

rekommenderas inte under graviditet och ska inte användas under de 6 sista månaderna av graviditeten

eftersom det då kan orsaka fosterskador, se Graviditet och amning.

Andra läkemedel och Diovan Comp

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

ta andra läkemedel.

Behandlingseffekten kan påverkas om Diovan Comp tas tillsammans med vissa andra läkemedel. Det

kan vara nödvändigt att ändra dos, vidta andra försiktighetsåtgärder eller i vissa fall avbryta

behandlingen med ett av läkemedlen. Detta gäller särskilt för följande läkemedel:

litium, ett läkemedel som används för att behandla vissa typer av psykiska sjukdomar

läkemedel eller substanser som kan öka mängden kalium i blodet. Dessa inkluderar

kaliumtillägg eller saltersättningar som innehåller kalium, kaliumsparande läkemedel och

heparin

läkemedel som kan minska mängden kalium i blodet, t.ex. diuretika (vätskedrivande tabletter),

kortikosteroider, laxermedel, karbenoxolon, amfotericin eller penicillin G

vissa antibiotika (rifamycingruppen), ett läkemedel som används för att skydda mot

transplantatavstötning (ciklosporin) eller ett antiretroviralt läkemedel mot HIV-/AIDS-infektion

(ritonavir). Dessa läkemedel kan öka effekten av Diovan Comp

läkemedel som kan framkalla "torsades de pointes" (oregelbunden hjärtrytm), t.ex. antiarytmika

(läkemedel som används för behandling av hjärtproblem) och vissa antipsykotika

läkemedel som kan minska mängden natrium i blodet, t.ex. antidepressiva, antipsykotika,

antiepileptika

läkemedel mot gikt, t.ex. allopurinol, probenecid, sulfinpyrazon

terapeutiska D-vitaminer och kalciumtillägg

diabetesmedel (orala medel, t.ex. metformin eller insuliner)

andra blodtryckssänkande läkemedel inklusive metyldopa, ACE-hämmare (såsom enalapril,

lisinopril, etc.) eller aliskiren (se även information under rubrikerna ”Ta inte Diovan Comp” och

”Varningar och försiktighet”).

läkemedel för att öka blodtrycket, t.ex. noradrenalin eller adrenalin

digoxin eller andra digitalisglykosider (läkemedel som används för behandling av hjärtproblem)

läkemedel som ökar blodsockret, t.ex. diazoxid eller betablockerare

cytotoxiska läkemedel (används för att behandla cancer), t.ex. metotrexat eller cyklofosfamid

smärtlindrande medel såsom icke-steroida anti-inflammatoriska medel (NSAID), inklusive

selektiva cyklooxygenas 2-hämmare (COX 2-hämmare) och acetylsalicylsyra mer än 3 gram

muskelavslappande medel, t.ex. tubokurarin

antikolinerga läkemedel (medel för behandling av en mängd olika störningar, såsom

gastrointestinala kramper, urinblåsespasm, astma, åksjuka, muskelspasmer, Parkinsons sjukdom

och som ett hjälpmedel för anestesi)

amantadin (ett medel som används för behandling av Parkinsons sjukdom och även för att

behandla eller förebygga vissa sjukdomar som orsakas av virus)

kolestyramin och kolestipol (läkemedel som vanligen används vid höga värden på lipider

(fetter) i blodet)

ciklosporin, ett läkemedel som används vid organtransplantation för att förhindra avstötning

alkohol, sömntabletter och bedövningsmedel (läkemedel med sövande eller smärtstillande effekt

som används till exempel vid operation)

jodkontrastmedel (medel som används vid bildundersökningar).

Diovan Comp med mat, dryck och alkohol

Undvik att ta alkohol tills du har talat med din läkare. Alkohol kan sänka blodtrycket ytterligare

och/eller öka risken för att du blir yr eller svimmar.

Graviditet och amning

Om du tror att du är gravid eller blir gravid under behandlingen, kontakta din läkare.

Vanligtvis föreslår din läkare att du ska sluta ta Diovan Comp före graviditet eller så snart du

vet att du är gravid och istället rekommendera ett annat läkemedel till dig. Diovan Comp bör

inte användas i början av graviditeten och ska inte användas under de 6 sista månaderna av

graviditeten eftersom det då kan orsaka fosterskador.

Berätta för din läkare om du ammar eller tänker börja amma.

Diovan Comp rekommenderas inte vid amning och din läkare kan välja en annan behandling till

dig om du vill amma ditt barn, särskilt om ditt barn är nyfött eller föddes för tidigt.

Körförmåga och användning av maskiner

Innan du kör fordon, använder verktyg eller maskiner, eller utför aktiviteter som kräver koncentration,

se till att du vet hur Diovan Comp påverkar dig. Liksom många andra läkemedel för behandling av

högt blodtryck kan Diovan Comp i sällsynta fall orsaka yrsel och påverka koncentrationsförmågan.

Du är själv ansvarig för att bedöma om du är i kondition att framföra motorfordon eller utföra arbete

som kräver skärpt vaksamhet. 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 läkare eller apotekspersonal om du är osäker.

3.

Hur du tar Diovan Comp

Ta alltid detta läkemedel enligt läkarens anvisningar. Det kommer att ge det bästa resultatet och

minskar risken för biverkningar. Rådfråga läkare eller apotekspersonal om du är osäker. Personer med

högt blodtryck känner ofta inte av några symtom på detta. Många känner sig som vanligt. Det är därför

viktigt att du går på dina läkarbesök som planerat även om du känner dig bra.

Din läkare talar om för dig hur många Diovan Comp tabletter som du ska ta. Beroende på

behandlingsresultatet kan läkaren höja eller sänka dosen.

Rekommenderad dos av Diovan Comp är en tablett per dag.

Ändra inte dosen eller avbryt behandlingen utan att rådgöra med läkaren.

Läkemedlet ska tas vid samma tidpunkt varje dag, vanligen på morgonen.

Du kan ta Diovan Comp oberoende av måltid.

Svälj Diovan Comp med ett glas vatten.

Om du har tagit för stor mängd av Diovan Comp

Om du fått i dig för stor mängd läkemedel eller om t ex ett barn fått i sig läkemedlet av misstag

kontakta läkare, sjukhus eller Giftinformationscentralen (tel. 112 i Sverige) för bedömning av risken

samt rådgivning. Om du får svår yrsel och/eller svimmar, lägg dig ned och kontakta omedelbart läkare.

Om du har glömt att ta Diovan Comp

Om du glömmer ta en dos, ta den så snart du kommer ihåg det. Om det snart är tid för nästa dos, hoppa

då över den missade dosen.

Ta inte dubbel dos för att kompensera för glömd tablett.

Om du slutar att ta Diovan Comp

Om du slutar din behandling med Diovan Comp kan ditt höga blodtryck förvärras. Sluta inte att ta din

medicin om inte din läkare säger till dig att sluta.

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

4.

Eventuella biverkningar

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

dem.

Vissa biverkningar kan vara allvarliga och kräver omedelbar medicinsk vård:

Du ska kontakta din läkare omedelbart om du får symtom på angioödem, såsom:

svullet ansikte, tunga eller svalg

svårighet att svälja

nässelutslag och svårighet att andas

Svår hudsjukdom som orsakar hudutslag, rodnad, blåsor på läpparna, ögonen eller munnen,

hudavlossning, feber (toxisk epidermal nekrolys)

Synförsämring eller smärta i dina ögon på grund av högt tryck (möjliga tecken på

vätskeansamling i ögat (mellan åderhinnan och senhinnan) eller akut trångvinkelglaukom)

Feber, halsont, mer frekventa infektioner (agranulocytos)

Dessa biverkningar är mycket sällsynta eller med ingen känd frekvens (frekvens kan inte beräknas från

tillgängliga data).

Om du får något av dessa symtom, sluta ta Diovan Comp och kontakta din läkare omedelbart

(se avsnitt 2 "Varningar och försiktighet").

Biverkningarna är:

Mindre vanliga

(kan förekomma hos upp till 1 av 100 användare):

hosta

lågt blodtryck

yr i huvudet

uttorkning (med symtom som törst, torrhet i munnen och på tungan, sällan behöva tömma

blåsan, mörkfärgad urin, torr hud)

smärta i musklerna

trötthet

stickningar och domningar

dimsyn

brusande och surrande i öronen

Mycket sällsynta

(kan förekomma hos upp till 1 av 10 000 användare):

yrsel

diarré

smärta i lederna

Har rapporterats

(förekommer hos ett okänt antal användare):

svårigheter att andas

betydligt minskad urinmängd

lågt natriumvärde i blodet (som kan utlösa trötthet, förvirring, muskelryckningar och/eller

kramper i svåra fall)

lågt kaliumvärde i blodet (ibland med muskelsvaghet, muskelkramper, onormal hjärtrytm)

lågt värde på vita blodkroppar i blodet (med symtom som feber, hudinfektioner, ont i halsen

eller munsår på grund av infektion, svaghet)

förhöjt bilirubinvärde i blodet (vilket i allvarliga fall kan ge gul hud och gula ögon)

förhöjda värden på ureakväve och kreatinin i blodet (vilket kan tyda på försämrad njurfunktion)

förhöjt urinsyravärde i blodet (vilket i allvarliga fall kan utlösa gikt)

synkope (svimning)

Följande biverkningar har rapporterats för produkter som innehåller valsartan eller

hydroklortiazid:

Valsartan

Mindre vanliga

(kan förekomma hos upp till 1 av 100 användare):

känsla av att snurra

smärta i buken

Har rapporterats

(förekommer hos ett okänt antal användare):

blåsbildning på huden (tecken på hudinflammation, även kallat bullös dermatit)

hudutslag med eller utan klåda tillsammans med något av följande symtom: feber, smärta i

lederna, smärta i musklerna, svullna lymfkörtlar och/eller influensaliknande symtom

utslag, rödlila-röda fläckar, feber, klåda (symtom på inflammation i blodkärlen)

lågt värde på blodplättar (ibland med ovanliga blödningar eller blåmärken)

högt kaliumvärde i blodet (ibland med muskelkramper, onormal hjärtrytm)

allergiska reaktioner (med symtom som utslag, klåda, nässelfeber, svårighet att andas eller

svårighet att svälja, yrsel)

svullnad framförallt i ansikte och svalg, utslag, klåda

förhöjda leverfunktionsvärden

minskat hemoglobinvärde och minskad andel röda blodkroppar i blodet (båda kan i allvarliga

fall ge blodbrist (anemi))

njursvikt

låg nivå av natrium i blodet (som kan utlösa trötthet, förvirring, muskelryckningar och/eller

kramper i svåra fall)

Hydroklortiazid

Mycket vanliga

(kan förekomma hos fler än 1 av 10 användare):

låg nivå av kalium i blodet

förhöjda lipidvärden i blodet

Vanliga

(kan förekomma hos upp till 1 av 10 användare):

låg nivå av natrium i blodet

låg nivå av magnesium i blodet

hög nivå av urinsyra i blodet

kliande utslag och andra typer av utslag

minskad aptit

lätt illamående och kräkningar

yrsel, svimning när du reser dig upp

oförmåga att få eller bibehålla erektion

Sällsynta

(kan förekomma hos upp till 1 av 1 000 användare):

svullnad och blåsor på huden (på grund av ökad känslighet för sol)

hög nivå av kalcium i blodet

hög blodsockernivå

socker i urinen

försämring av metabolt diabetestillstånd

förstoppning, diarré, obehag i mage och tarm, leverstörningar som kan uppstå tillsammans med

gul hud och gula ögon

oregelbundna hjärtslag

huvudvärk

sömnstörningar

nedstämdhet (depression)

lågt värde på blodplättar (ibland med blödning eller blåmärken under huden)

yrsel

stickningar eller domningar

synrubbningar

Mycket sällsynta

(kan förekomma hos upp till 1 av 10 000 användare):

inflammation i blodkärlen med symtom som utslag, rödlila-röda fläckar, feber (vaskulit)

utslag, klåda, nässelfeber, svårighet att andas eller svälja, yrsel (överkänslighetsreaktioner)

utslag i ansiktet, ledvärk, muskelsjukdom, feber (kutan lupus erythematosus)

svår smärta i övre delen av magen (pankreatit)

svårighet att andas med feber, hosta, väsande andning, andfåddhet (andnöd inklusive

pneumonit och lungödem)

blek hud, trötthet, andfåddhet, mörk urin (hemolytisk anemi)

feber, halsont eller sår i munnen på grund av infektioner (leukopeni)

förvirring, trötthet, muskelryckningar och spasmer, snabb andning (hypokloremisk alkalos)

Har rapporterats

(förekommer hos ett okänt antal användare):

svaghet, blåmärken och täta infektioner (aplastisk anemi)

kraftigt minskad urinproduktion (möjliga tecken på njursjukdom eller njursvikt)

hudutslag, rodnad, blåsor på läppar, ögon eller mun, flagning av huden, feber (möjliga tecken på

erythema multiforme)

muskelkramp

feber (pyrexi)

svaghet (asteni)

hud- och läppcancer (icke-melanom hudcancer)

Rapportering av biverkningar

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

nämns i denna information. Du kan också rapportera biverkningar direkt (se detaljer nedan). Genom

att rapportera biverkningar kan du bidra till att öka informationen om läkemedels säkerhet.

Läkemedelsverket

Box 26

751 03 Uppsala

Webbplats: www.lakemedelsverket.se

5.

Hur Diovan Comp ska förvaras

Förvaras utom syn- och räckhåll för barn.

Används före utgångsdatum som anges på kartongen eller på blistret efter ”Utg.dat.” respektive

”EXP”. Utgångsdatumet är den sista dagen i angiven månad.

Förvaras vid högst 30

C. Förvaras i originalförpackningen. Fuktkänsligt.

Använd inte detta läkemedel om du upptäcker att förpackningen är skadad eller visar tecken på

att ha öppnats tidigare.

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

man kastar mediciner som du inte längre använder. Dessa åtgärder är till för att skydda miljön.

6.

Förpackningens innehåll och övriga upplysningar

Innehållsdeklaration

Den aktiva substansen är valsartan och hydroklortiazid. Varje tablett innehåller 80 mg, 160 mg

respektive 320 mg valsartan och 12,5 mg respektive 25 mg hydroklortiazid.

Tablettens kärna innehåller mikrokristallin cellulosa, kolloidal, vattenfri kiseldioxid,

krospovidon, magnesiumstearat.

Tablettens filmhölje innehåller hypromellos, makrogol 8000 (enbart 80 mg/12,5 mg och

160 mg/12,5 mg), makrogol 4000 (enbart 160 mg/25 mg, 320 mg/12,5 mg och 320 mg/25 mg),

talk, röd järnoxid (E 172, ej 320 mg/25 mg), gul järnoxid (E 172, enbart 80 mg/12,5 mg,

160 mg/25 mg och 320 mg/25 mg), svart järnoxid (E 172, enbart 160 mg/25 mg och

320 mg/12,5 mg), titandioxid (E 171).

Läkemedlets utseende och förpackningsstorlekar

Diovan Comp 80 mg/12,5 mg filmdragerade tabletter är ljust orange, ovala tabletter, märkta med

”HGH” på den ena sidan och ”CG” på den andra sidan.

Diovan Comp 160 mg/12,5 mg filmdragerade tabletter är mörkröda, ovala tabletter, märkta med

“HHH” på ena sidan och “CG” på den andra sidan.

Diovan Comp 160 mg/25 mg filmdragerade tabletter är bruna, ovala tabletter, märkta med “HXH” på

ena sidan och “NVR” på den andra sidan.

Diovan Comp 320 mg/12,5 mg filmdragerade tabletter är rosa, ovala tabletter med fasade kanter,

märkta med “NVR” på ena sidan och “HIL” på den andra sidan.

Diovan Comp 320 mg/25 mg filmdragerade tabletter är gula, ovala tabletter med fasade kanter, märkta

med “NVR” på ena sidan och “CTI” på den andra sidan.

Tabletterna tillhandahålls i blisterförpackning med 7 st (enbart Diovan Comp 320 mg/12,5 mg och

320 mg/25 mg), 14 st, 28 st som kalenderförpackning, 30 st (enbart Diovan Comp 80 mg/12,5 mg),

56 st, 98 st som kalenderförpackning eller 280 st tabletter.

Perforerad endosblisterförpackning med 56x1, 98x1 eller 280x1 tabletter finns också tillgänglig.

Eventuellt kommer inte alla förpackningsstorlekar att marknadsföras.

Innehavare av godkännande för försäljning och tillverkare

Novartis Sverige AB,

Box 1218

164 28 Kista

Telefon: 08-732 32 00

Denna bipacksedel godkändes senast

2020-08-31

Läs hela dokumentet

SUMMARY OF PRODUCT CHARACTERISTICS

1.

NAME OF THE MEDICINAL PRODUCT

Diovan Comp 80 mg/12.5 mg film-coated tablets

Diovan Comp 160 mg/12.5 mg film-coated tablets

Diovan Comp 160 mg/25 mg film-coated tablets

Diovan Comp 320 mg/12.5 mg film-coated tablets

Diovan Comp 320 mg/25 mg film-coated tablets

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

Each film-coated tablet contains 80 mg of valsartan and 12.5 mg of hydrochlorothiazide.

Each film-coated tablet contains 160 mg of valsartan and 12.5 mg of hydrochlorothiazide

Each film-coated tablet contains 160 mg of valsartan and 25 mg of hydrochlorothiazide.

Each film-coated tablet contains 320 mg of valsartan and 12.5 mg of hydrochlorothiazide.

Each film-coated tablet contains 320 mg of valsartan and 25 mg of hydrochlorothiazide.

For the full list of excipients, see section 6.1.

3.

PHARMACEUTICAL FORM

Film-coated tablets.

80 mg/12.5 mg: Light orange, ovaloid tablet imprinted with HGH on one side and CG on the other

side.

160 mg/12.5 mg: Dark red, ovaloid tablet imprinted with HHH on one side and CG on the other side.

160 mg/25 mg: Brown, ovaloid tablet imprinted with HXH on one side and NVR on the other side.

320 mg/12.5 mg: Pink, ovaloid shaped, beveled edge tablet, imprinted with NVR on one side and HIL

on the other side.

320 mg/25 mg: Yellow, ovaloid shaped, beveled edge tablet, imprinted with NVR on one side and CTI

on the other side.

4.

CLINICAL PARTICULARS

4.1

Therapeutic indications

Treatment of essential hypertension in adults.

Diovan Comp fixed-dose combination is indicated in patients whose blood pressure is not adequately

controlled on valsartan or hydrochlorothiazide monotherapy.

4.2

Posology and method of administration

Posology

The recommended dose of Diovan Comp is one film-coated tablet once daily. Dose titration with the

individual components is recommended. In each case, up-titration of individual components to the

next dose should be followed in order to reduce the risk of hypotension and other adverse events.

When clinically appropriate direct change from monotherapy to the fixed combination may be

considered in patients whose blood pressure is not adequately controlled on valsartan or

hydrochlorothiazide monotherapy, provided the recommended dose titration sequence for the

individual components is followed.

The clinical response to Diovan Comp should be evaluated after initiating therapy and if blood

pressure remains uncontrolled, the dose may be increased by increasing either one of the components

to a maximum dose of Diovan Comp 320 mg/25 mg.

The antihypertensive effect is substantially present within 2 weeks.

In most patients, maximal effects are observed within 4 weeks. However, in some patients 4-8 weeks

treatment may be required. This should be taken into account during dose titration.

Diovan Comp (320 mg/ 25 mg only)

If no relevant additional effect is seen with Diovan Comp 320 mg/25 mg after 8 weeks, treatment with

an additional or alternative antihypertensive medicinal product should be considered (see section 4.3,

4.4, 4.5 and 5.1).

Method of administration

Diovan Comp can be taken with or without food and should be administered with water.

Special populations

Patients with renal impairment

No dose adjustment is required for patients with mild to moderate renal impairment (Glomerular

Filtration Rate (GFR)

30 ml/min). Due to the hydrochlorothiazide component, Diovan Comp is

contraindicated in patients with severe renal impairment (GFR < 30 mL/min) and anuria (see sections

4.3, 4.4 and 5.2).

Patients with hepatic impairment

In patients with mild to moderate hepatic impairment without cholestasis the dose of valsartan should

not exceed 80 mg (see section 4.4). No adjustment of the hydrochlorothiazide dose is required for

patients with mild to moderate hepatic impairment. Due to the valsartan component, Diovan Comp is

contraindicated in patients with severe hepatic impairment or with biliary cirrhosis and cholestasis (see

sections 4.3, 4.4 and 5.2).

Older people

No dose adjustment is required in elderly patients.

Paediatric patients

Diovan Comp is not recommended for use in children below the age of 18 years due to a lack of data

on safety and efficacy.

4.3

Contraindications

Hypersensitivity to the active substance(s

, other sulfonamide-derived medicinal products or to

any of the excipients listed in section 6.1.

Second and third trimester of pregnancy (section 4.4 and 4.6).

Severe hepatic impairment, biliary cirrhosis and cholestasis.

Severe renal impairment (creatinine clearance < 30 ml/min), anuria.

Refractory hypokalaemia, hyponatraemia, hypercalcaemia, and symptomatic hyperuricaemia.

Concomitant use of Diovan Comp with aliskiren-containing products in patients with diabetes

mellitus or renal impairment (GFR <60 mL/min/1.73m

) (see sections 4.5 and 5.1).

4.4

Special warnings and precautions for use

Serum electrolyte changes

Valsartan

Concomitant use with potassium supplements, potassium-sparing diuretics, salt substitutes containing

potassium, or other agents that may increase potassium levels (heparin, etc.) is not recommended.

Monitoring of potassium should be undertaken as appropriate.

Hydrochlorothiazide

Hypokalaemia has been reported under treatment with thiazide diuretics, including

hydrochlorothiazide. Frequent monitoring of serum potassium is recommended.

Treatment with thiazide diuretics, including hydrochlorothiazide, has been associated with

hyponatraemia and hypochloraemic alkalosis. Thiazides, including hydrochlorothiazide, increase the

urinary excretion of magnesium, which may result in hypomagnesaemia. Calcium excretion is

decreased by thiazide diuretics. This may result in hypercalcaemia.

As for any patient receiving diuretic therapy, periodic determination of serum electrolytes should be

performed at appropriate intervals.

Sodium and/or volume-depleted patients

Patients receiving thiazide diuretics, including hydrochlorothiazide, should be observed for clinical

signs of fluid or electrolyte imbalance.

In severely sodium-depleted and/or volume-depleted patients, such as those receiving high doses of

diuretics, symptomatic hypotension may occur in rare cases after initiation of therapy with Diovan

Comp. Sodium and/or volume depletion should be corrected before starting treatment with Diovan

Comp.

Patients with severe chronic heart failure or other conditions with stimulation of the renin-angiotensin-

aldosterone-system

In patients whose renal function may depend on the activity of the renin-angiotensin-aldosterone

system (e.g. patients with severe congestive heart failure), treatment with angiotensin converting

enzyme inhibitors has been associated with oliguria and/or progressive azotaemia, and in rare cases

with acute renal failure and/or death. Evaluation of patients with heart failure or post-myocardial

infarction should always include assessment of renal function. The use of Diovan Comp in patients

with severe chronic heart failure has not been established.

Hence it cannot be excluded that because of the inhibition of the renin-angiotensin-aldosterone system

the application of Diovan Comp as well may be associated with impairment of the renal function.

Diovan Comp should not be used in these patients.

Renal artery stenosis

Diovan Comp should not be used to treat hypertension in patients with unilateral or bilateral renal

artery stenosis or stenosis of the artery to a solitary kidney, since blood urea and serum creatinine may

increase in such patients.

Primary hyperaldosteronism

Patients with primary hyperaldosteronism should not be treated with Diovan Comp as their renin-

angiotensin system is not activated.

Aortic and mitral valve stenosis, hypertrophic obstructive cardiomyopathy

As with all other vasodilators, special caution is indicated in patients suffering from aortic or mitral

stenosis, or hypertrophic obstructive cardiomyopathy (HOCM).

Renal impairment

No dosage adjustment is required for patients with renal impairment with a creatinine clearance

30 ml/min (see section 4.2). Periodic monitoring of serum potassium, creatinine and uric acid levels

is recommended when Diovan Comp is used in patients with renal impairment.

Kidney transplantation

There is currently no experience on the safe use of Diovan Comp in patients who have recently

undergone kidney transplantation.

Hepatic impairment

In patients with mild to moderate hepatic impairment without cholestasis, Diovan Comp should be

used with caution (see sections 4.2 and 5.2). Thiazides should be used with caution in patients with

impaired hepatic function or progressive liver disease, since minor alterations of fluid and electrolyte

balance may precipitate hepatic coma.

History of angioedema

Angioedema, including swelling of the larynx and glottis, causing airway obstruction and/or swelling

of the face, lips, pharynx, and/or tongue has been reported in patients treated with valsartan; some of

these patients previously experienced angioedema with other drugs including ACE inhibitors. Diovan

Comp should be immediately discontinued in patients who develop angioedema, and Diovan Comp

should not be re-administered (see section 4.8).

Systemic lupus erythematosus

Thiazide diuretics, including hydrochlorothiazide, have been reported to exacerbate or activate

systemic lupus erythematosus.

Other metabolic disturbances

Thiazide diuretics, including hydrochlorothiazide, may alter glucose tolerance and raise serum levels

of cholesterol, triglycerides and uric acid. In diabetic patients dosage adjustments of insulin or oral

hypoglycaemic agents may be required.

Thiazides may reduce urinary calcium excretion and cause an intermittent and slight elevation of

serum calcium in the absence of known disorders of calcium metabolism. Marked hypercalcaemia

may be evidence of underlying hyperparathyroidism. Thiazides should be discontinued before carrying

out tests for parathyroid function.

Photosensitivity

Cases of photosensitivity reactions have been reported with thiazide diuretics (see section 4.8). If

photosensitivity reaction occurs during treatment, it is recommended to stop the treatment. If a re-

administration of the diuretic is deemed necessary, it is recommended to protect exposed areas to the

sun or to artificial UVA.

Pregnancy

Angiotensin II Receptor Antagonists (AIIRAs) should not be initiated during pregnancy. Unless

continued AIIRAs therapy is considered essential, patients planning pregnancy should be changed to

alternative anti-hypertensive treatments which have an established safety profile for use in pregnancy.

When pregnancy is diagnosed, treatment with AIIRAs should be stopped immediately, and, if

appropriate, alternative therapy should be started (see sections 4.3 and 4.6).

General

Caution should be exercised in patients who have shown prior hypersensitivity to other angiotensin II

receptor antagonists. Hypersensitivity reactions to hydrochlorothiazide are more likely in patients with

allergy and asthma.

Choroidal effusion, acute myopia and secondary acute Angle-Closure Glaucoma

Hydrochlorothiazide, a sulfonamide, has been associated with an idiosyncratic reaction resulting in

choroidal effusion with visual field defect, acute transient myopia and acute angle-closure glaucoma.

Symptoms include acute onset of decreased visual acuity or ocular pain and typically occur within

hours to weeks of a drug initiation. Untreated acute-angle closure glaucoma can lead to permanent

vision loss.

The primary treatment is to discontinue hydrochlorothiazide as rapidly as possible. Prompt medical or

surgical treatment may need to be considered if the intraocular pressure remains uncontrolled. Risk

factors for developing acute angle closure glaucoma may include a history of sulfonamide or penicillin

allergy.

Dual Blockade of the Renin-Angiotensin-Aldosterone System (RAAS)

There is evidence that the concomitant use of ACE inhibitors, angiotensin II receptor blockers or

aliskiren increases the risk of hypotension, hyperkalaemia, and decreased renal function (including

acute renal failure). Dual blockade of the RAAS through the combined use of ACE inhibitors,

angiotensin II receptor blockers or aliskiren is therefore not recommended (see sections 4.5 and 5.1). If

dual blockade therapy is considered absolutely necessary, this should only occur under specialist

supervision and subject to frequent close monitoring of renal function, electrolytes and blood pressure.

ACE inhibitors and angiotensin II receptor blockers should not be used concomitantly in patients with

diabetic nephropathy.

Non-melanoma skin cancer

An increased risk of non-melanoma skin cancer (NMSC) [basal cell carcinoma (BCC) and squamous

cell carcinoma (SCC)] with increasing cumulative dose of hydrochlorothiazide exposure has been

observed in two epidemiological studies based on the Danish National Cancer Registry.

Photosensitising actions of hydrochlorothiazide could act as a possible mechanism for NMSC.

Patients taking hydrochlorothiazide should be informed of the risk of NMSC and advised to regularly

check their skin for any new lesions and promptly report any suspicious skin lesions. Possible

preventive measures such as limited exposure to sunlight and UV rays and, in case of exposure,

adequate protection should be advised to the patients in order to minimize the risk of skin cancer.

Suspicious skin lesions should be promptly examined potentially including histological examinations

of biopsies. The use of hydrochlorothiazide may also need to be reconsidered in patients who have

experienced previous NMSC (see also section 4.8).

4.5

Interaction with other medicinal products and other forms of interaction

Interactions related to both valsartan and hydrochlorothiazide

Concomitant use not recommended

Lithium

Reversible increases in serum lithium concentrations and toxicity have been reported during

concomitant administration of lithium with ACE inhibitors, angiotensin II receptor antagonists or

thiazides, including hydrochlorothiazide. Since renal clearance of lithium is reduced by thiazides, the

risk of lithium toxicity may presumably be increased further with Diovan Comp. If the combination

proves necessary, a careful monitoring of serum lithium levels is recommended.

Concomitant use requiring caution

Other antihypertensive agents

Diovan Comp may increase the effects of other agents with antihypertensive properties (e.g.

guanethidine, methyldopa, vasodilators, ACEI, ARBs, beta blockers, calcium channel blockers and

DRIs).

Pressor amines

(e.g. noradrenaline, adrenaline)

Possible decreased response to pressor amines. The clinical significance of this effect is uncertain and

not sufficient to preclude their use.

Non-steroidal anti-inflammatory medicines (NSAIDs), including selective COX-2 inhibitors,

acetylsalicylic acid (>3 g/day), and non-selective NSAIDs

NSAIDS can attenuate the antihypertensive effect of both angiotensin II antagonists and

hydrochlorothiazide when administered simultaneously. Furthermore, concomitant use of Diovan

Comp and NSAIDs may lead to worsening of renal function and an increase in serum potassium.

Therefore, monitoring of renal function at the beginning of the treatment is recommended, as well as

adequate hydration of the patient.

Interactions related to valsartan

Dual blockade of the Renin-Angiotensin-Aldosterone System (RAAS) with ARBs, ACEIs, or aliskiren

Clinical trial data has shown that dual blockade of the renin-angiotensin-aldosterone-system (RAAS)

through the combined use of ACE inhibitors, angiotensin II receptor blockers or aliskiren is associated

with a higher frequency of adverse events such as hypotension, hyperkalaemia and decreased renal

function (including acute renal failure) compared to the use of a single RAAS-acting agent (see

sections 4.3, 4.4 and 5.1).

Concomitant use not recommended

Potassium-sparing diuretics, potassium supplements, salt substitutes containing potassium and other

substances that may increase potassium levels

If a medicinal product that affects potassium levels is considered necessary in combination with

valsartan, monitoring of potassium plasma levels is advised.

Transporters

In vitro data indicates that valsartan is a substrate of the hepatic uptake transporter

OATP1B1/OATP1B3 and the hepatic efflux transporter MRP2. The clinical relevance of this finding

is unknown. Co-administration of inhibitors of the uptake transporter (eg. rifampin, ciclosporin) or

efflux transporter (eg. ritonavir) may increase the systemic exposure to valsartan. Exercise appropriate

care when initiating or ending concomitant treatment with such drugs.

No interaction

In drug interaction studies with valsartan, no interactions of clinical significance have been found with

valsartan or any of the following substances: cimetidine, warfarin, furosemide, digoxin, atenolol,

indomethacin, hydrochlorothiazide, amlodipine, glibenclamide. Digoxin and indomethacin could

interact with the hydrochlorothiazide component of Diovan Comp (see interactions related to

hydrochlorothiazide).

Interactions related to hydrochlorothiazide

Concomitant use requiring caution

Medicinal products affecting serum potassium level

The hypokalaemic effect of hydrochlorothiazide may be increased by concomitant administration of

kaliuretic diuretics, corticosteroids, laxatives, ACTH, amphotericin, carbenoxolone, penicillin G,

salicylic acid and derivatives.

If these medicinal products are to be prescribed with the hydrochlorothiazide-valsartan combination,

monitoring of potassium plasma levels is advised (see section 4.4).

Medicinal products that could induce torsades de pointes

Due to the risk of hypokalaemia, hydrochlorothiazide should be administered with caution when

associated with medicinal products that could induce torsades de pointes, in particular Class Ia and

Class III antiarrhythmics and some antipsychotics.

Medicinal products affecting serum sodium level

The hyponatraemic effect of diuretics may be intensified by concomitant administration of drugs such

as antidepressants, antipsychotics, antiepileptics, etc. Caution is advised in long-term administration of

these drugs.

Digitalis glycosides

Thiazide-induced hypokalaemia or hypomagnesaemia may occur as undesirable effects favouring the

onset of digitalis-induced cardiac arrhythmias (see section 4.4).

Calcium salts and vitamin D

Administration of thiazide diuretics, including hydrochlorothiazide, with vitamin D or with calcium

salts may potentiate the rise in serum calcium. Concomitant use of thiazide type diuretics with calcium

salts may cause hypercalcaemia in patients pre-disposed for hypercalcaemia (e.g.

hyperparathyroidism, malignancy or vitamin-D-mediated conditions) by increasing tubular calcium

reabsorption.

Antidiabetic agents

(oral agents and insulin)

Thiazides may alter glucose tolerance. Dose adjustment of the antidiabetic medicinal product may be

necessary. Metformin should be used with caution because of the risk of lactic acidosis induced by

possible functional renal failure linked to hydrochlorothiazide.

Beta blockers and diazoxide

Concomitant use of thiazide diuretics, including hydrochlorothiazide, with beta blockers may increase

the risk of hyperglycaemia. Thiazide diuretics, including hydrochlorothiazide, may enhance the

hyperglycaemic effect of diazoxide.

Medicinal products used in the treatment of gout

(probenecid, sulfinpyrazone and allopurinol)

Dose adjustment of uricosuric medications may be necessary as hydrochlorothiazide may raise the

level of serum uric acid. Increase of dosage of probenecid or sulfinpyrazone may be necessary. Co-

administration of thiazide diuretics, including hydrochlorothiazide, may increase the incidence of

hypersensitivity reactions to allopurinol.

Anticholinergic agents

and other medicinal products affecting gastric motility

The bioavailability of thiazide-type diuretics may be increased by anticholinergic agents (e.g. atropine,

biperiden), apparently due to a decrease in gastrointestinal motility and the stomach emptying rate.

Conversely, it is anticipated that prokinetic drugs such as cisapride may decrease the bioavailability of

thiazide-type diuretics.

Amantadine

Thiazides, including hydrochlorothiazide, may increase the risk of adverse effects caused by

amantadine.

Ion exchange resins

Absorption of thiazide diuretics, including hydrochlorothiazide, is decreased by cholestyramine or

colestipol. This could result in sub-therapeutic effects of thiazide diuretics. However, staggering the

dosage of hydrochlorothiazide and resin such that hydrochlorothiazide is administered at least 4 h

before or 4-6 h after the administration of resins would potentially minimise the interaction.

Cytotoxic agents

Thiazides, including hydrochlorothiazide, may reduce renal excretion of cytotoxic agents (e.g.

cyclophosamide, methotrexate) and potentiate their myelosuppressive effects.

Non-depolarising skeletal muscle relaxants

(e.g. tubocurarine)

Thiazides, including hydrochlorothiazide, potentiate the action of skeletal muscle relaxants such as

curare derivatives.

Ciclosporin

Concomitant treatment with ciclosporin may increase the risk of hyperuricaemia and gout-type

complications.

Alcohol, barbiturates or narcotics

Concomitant administration of thiazide diuretics with substances that also have a blood pressure

lowering effect (e.g. by reducing sympathetic central nervous system activity or direct vasodilatation

activity) may potentiate orthostatic hypotension.

Methyldopa

There have been isolated reports of haemolytic anaemia in patients receiving concomitant treatment

with methyldopa and hydrochlorothiazide.

Iodine contrast media

In case of diuretic-induced dehydration, there is an increased risk of acute renal failure, especially with

high doses of the iodine product. Patients should be rehydrated before the administration.

4.6

Fertility, pregnancy and lactation

Pregnancy

Valsartan

The use of Angiotensin II Receptor Antagonists (AIIRAs) is not recommended during first trimester of

pregnancy (see section 4.4).The use of AIIRAs is contra-indicated during the second and third

trimester of pregnancy (see sections 4.3 and 4.4).

Epidemiological evidence regarding the risk of teratogenicity following exposure to ACE inhibitors

during the first trimester of pregnancy has not been conclusive; however a small increase in risk

cannot be excluded. Whilst there is no controlled epidemiological data on the risk with Angiotensin II

Receptor Inhibitors (AIIRAs), similar risks may exist for this class of drugs. Unless continued AIIRAs

therapy is considered essential, patients planning pregnancy should be changed to alternative anti-

hypertensive treatments which have an established safety profile for use in pregnancy. When

pregnancy is diagnosed, treatment with AIIRAs should be stopped immediately and, if appropriate,

alternative therapy should be started.

AIIRAs therapy exposure during the second and third trimesters is known to induce human

fetotoxicity (decreased renal function, oligohydramnios, skull ossification retardation) and neonatal

toxicity (renal failure, hypotension, hyperkalaemia) (see also section 5.3).

Should exposure to AIIRAs have occurred from the second trimester of pregnancy, ultrasound check

of renal function and skull is recommended.

Infants whose mothers have taken AIIRAs should be closely observed for hypotension (see also

section 4.3 and 4.4).

Hydrochlorothiazide

There is limited experience with hydrochlorothiazide during pregnancy, especially during the first

trimester. Animal studies are insufficient. Hydrochlorothiazide crosses the placenta. Based on the

pharmacological mechanism of action of hydrochlorothiazide its use during the second and third

trimester may compromise foeto-placental perfusion and may cause foetal and neonatal effects like

icterus, disturbance of electrolyte balance and thrombocytopenia.

Breast-feeding

No information is available regarding the use of valsartan during breastfeeding. Hydrochlorothiazide

is excreted in human milk. Therefore the use of Diovan Comp during breast feeding is not

recommended. Alternative treatments with better established safety profiles during breast-feeding are

preferable, especially while nursing a newborn or preterm infant.

4.7

Effects on ability to drive and use machines

No studies on the effect of Diovan Comp on the ability to drive and use machines have been

performed. When driving vehicles or operating machines it should be taken into account that

occasionally dizziness or weariness may occur.

4.8

Undesirable effects

Adverse drug reactions reported in clinical trials and laboratory findings occurring more frequently

with valsartan plus hydrochlorothiazide versus placebo and individual postmarketing reports are

presented below according to system organ class. Adverse drug reactions known to occur with each

component given individually but which have not been seen in clinical trials may occur during

treatment with valsartan/hydrochlorothiazide.

Adverse Drug Reactions

Adverse drug reactions are ranked by frequency, the most frequent first, using the following

convention: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100);

rare (≥ 1/10,000 to <

1/1,000); very rare (< 1/10,000); not known (frequency cannot be estimated from

the available data).

Within each frequency grouping, adverse drug reactions are ranked in order of decreasing seriousness.

Table 1. Frequency of adverse reactions with valsartan/hydrochlorothiazide

Metabolism and nutrition disorders

Uncommon

Dehydration

Nervous system disorders

Very rare

Dizziness

Uncommon

Paraesthesia

Not known

Syncope

Eye disorders

Uncommon

Vision blurred

Ear and labyrinth disorders

Uncommon

Tinnitus

Vascular disorders

Uncommon

Hypotension

Respiratory, thoracic and mediastinal disorders

Uncommon

Cough

Not known

Non cardiogenic pulmonary oedema

Gastrointestinal disorders

Very rare

Diarrhoea

Musculoskeletal and connective tissue disorders

Uncommon

Myalgia

Very rare

Arthralgia

Renal and urinary disorders

Not known

Impaired renal function

General disorders and administration site conditions

Uncommon

Fatigue

Investigations

Not known

Serum uric acid increased, Serum bilirubin and Serum

creatinine increased, Hypokalaemia, Hyponatraemia,

Elevation of Blood Urea Nitrogen, Neutropenia

Additional information on the individual components

Adverse reactions previously reported with one of the individual components may be potential

undesirable effects with Diovan Comp as well, even if not observed in clinical trials or during

postmarketing period.

Table 2. Frequency of adverse reactions with valsartan

Blood and lymphatic system disorders

Not known

Decrease in haemoglobin, decrease in

haematocrit, thrombocytopenia

Immune system disorders

Not known

Other hypersensitivity/allergic reactions

including serum sickness

Metabolism and nutrition disorders

Not known

Increase of serum potassium, hyponatraemia

Ear and labyrinth disorders

Uncommon

Vertigo

Vascular disorders

Not known

Vasculitis

Gastrointestinal disorders

Uncommon

Abdominal pain

Hepatobiliary disorders

Not known

Elevation of liver function values

Skin and subcutaneous tissue disorders

Not known

Angioedema, dermatitis bullous, rash, pruritus

Renal and urinary disorders

Not known

Renal failure

Table 3: Frequency of adverse reactions with hydrochlorothiazide

Hydrochlorothiazide has been extensively prescribed for many years, frequently in higher doses than

those administered with Diovan Comp. The following adverse reactions have been reported in patients

treated with monotherapy of thiazide diuretics, including hydrochlorothiazide:

Neoplasms benign, malignant and unspecified (incl. cysts and polyps)

Not known

Non-melanoma skin cancer (Basal cell

carcinoma and Squamous cell carcinoma)

Blood and lymphatic system disorders

Rare

Thrombocytopenia sometimes with purpura

Very rare

Agranulocytosis, leucopenia, haemolytic

anaemia, bone marrow failure

Not known

Aplastic anemia

Immune system disorders

Very rare

Hypersensitivity reactions

Metabolism and nutrition disorders

Very common

Hypokalaemia, blood lipids increased (mainly

at higher doses)

Common

Hyponatraemia, hypomagnesaemia,

hyperuricaemia

Rare

Hypercalcaemia, hyperglycaemia, glycosuria

and worsening of diabetic metabolic state

Very rare

Hypochloraemic alkalosis

Psychiatric disorders

Rare

Depression, sleep disturbances

Nervous system disorders

Rare

Headache, dizziness, paraesthesia

Eye disorders

Rare

Visual impairment

Not known

Choroidal effusion, acute angle-closure

glaucoma

Cardiac disorders

Rare

Cardiac arrhythmias

Vascular disorders

Common

Postural hypotension

Respiratory, thoracic and mediastinal disorders

Very rare

Respiratory distress including pneumonitis and

pulmonary oedema

Gastrointestinal disorders

Common

Loss of appetite, mild nausea and vomiting

Rare

Constipation, gastrointestinal discomfort,

diarrhoea

Very rare

Pancreatitis

Hepatobiliary disorders

Rare

Intrahepatic cholestasis or jaundice

Renal and urinary disorders

Not known

Renal dysfunction, acute renal failure

Skin and subcutaneous tissue disorders

Common

Urticaria and other forms of rash

Rare

Photosensitisation

Very rare

Necrotising vasculitis and toxic epidermal

necrolysis, cutaneous lupus erythematosus-like

reactions, reactivation of cutaneous lupus

erythematosus

Not known

Erythema multiforme

General disorders and administration site conditions

Not known

Pyrexia, asthenia

Musculoskeletal and connective tissue disorders

Not known

Muscle spasm

Reproductive system and breast disorders

Common

Impotence

Description of selected adverse reactions

Non-melanoma skin cancer: based on available data from epidemiological studies, cumulative

dose-dependent association between hydrochlorothiazide and NMSC has been observed (see also

sections 4.4 and 5.1).

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

Symptoms

Overdose with valsartan may result in marked hypotension, which could lead to depressed level of

consciousness, circulatory collapse and/or shock. In addition, the following signs and symptoms may

occur due to an overdose of the hydrochlorothiazide component: nausea, somnolence, hypovolaemia,

and electrolyte disturbances associated with cardiac arrhythmias and muscle spasms.

Treatment

The therapeutic measures depend on the time of ingestion and the type and severity of the symptoms,

stabilisation of the circulatory condition being of prime importance.

If hypotension occurs, the patient should be placed in the supine position and salt and volume

supplementation should be given rapidly.

Valsartan cannot be eliminated by means of haemodialysis because of its strong plasma binding

behaviour whereas clearance of hydrochlorothiazide will be achieved by dialysis.

5.

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties

Pharmacotherapeutic group: Angiotensin II antagonists and diuretics, valsartan and diuretics; ATC

code: C09D A03.

Valsartan/hydrochlorothiazide

80 mg/12.5 mg only:

In a double-blind, randomised, active-controlled trial in patients not adequately controlled on

hydrochlorothiazide 12.5 mg, significantly greater mean systolic/diastolic BP reductions were

observed with the combination of valsartan/hydrochlorothiazide 80/12.5 mg (14.9/11.3 mmHg)

compared to hydrochlorothiazide 12.5 mg (5.2/2.9 mmHg) and hydrochlorothiazide 25 mg

(6.8/5.7 mmHg). In addition, a significantly greater percentage of patients responded (diastolic BP

<90 mmHg or reduction ≥10 mmHg) with valsartan/hydrochlorothiazide 80/12.5 mg (60%) compared

to hydrochlorothiazide 12.5 mg (25%) and hydrochlorothiazide 25 mg (27%).

In a double-blind, randomised, active-controlled trial in patients not adequately controlled on valsartan

80 mg, significantly greater mean systolic/diastolic BP reductions were observed with the combination

of valsartan/hydrochlorothiazide 80/12.5 mg (9.8/8.2 mmHg) compared to valsartan 80 mg

(3.9/5.1 mmHg) and valsartan 160 mg (6.5/6.2 mmHg). In addition, a significantly greater percentage

of patients responded (diastolic BP <90 mmHg or reduction ≥10 mmHg) with

valsartan/hydrochlorothiazide 80/12.5 mg (51%) compared to valsartan 80 mg (36%) and valsartan

160 mg (37%).

In a double-blind, randomised, placebo-controlled, factorial design trial comparing various dose

combinations of valsartan/hydrochlorothiazide to their respective components, significantly greater

mean systolic/diastolic BP reductions were observed with the combination of

valsartan/hydrochlorothiazide 80/12.5 mg (16.5/11.8 mmHg) compared to placebo (1.9/4.1 mmHg)

and both hydrochlorothiazide 12.5 mg (7.3/7.2 mmHg) and valsartan 80 mg (8.8/8.6 mmHg). In

addition, a significantly greater percentage of patients responded (diastolic BP <90 mmHg or

reduction ≥10 mmHg) with valsartan/hydrochlorothiazide 80/12.5 mg (64%) compared to placebo

(29%) and hydrochlorothiazide (41%).

160 mg/12.5 mg and 160 mg/25 mg only:

In a double-blind, randomised, active-controlled trial in patients not adequately controlled on

hydrochlorothiazide 12.5 mg, significantly greater mean systolic/diastolic BP reductions were

observed with the combination of valsartan/hydrochlorothiazide 160/12.5 mg (12.4/7.5 mmHg)

compared to hydrochlorothiazide 25 mg (5.6/2.1 mmHg). In addition, a significantly greater

percentage of patients responded (BP <140/90 mmHg or SBP reduction ≥20 mmHg or DBP reduction

≥10 mmHg) with valsartan/hydrochlorothiazide 160/12.5 mg (50%) compared to hydrochlorothiazide

25 mg (25%).

In a double-blind, randomised, active-controlled trial in patients not adequately controlled on valsartan

160 mg, significantly greater mean systolic/diastolic BP reductions were observed with both the

combination of valsartan/hydrochlorothiazide 160/25 mg (14.6/11.9 mmHg) and

valsartan/hydrochlorothiazide 160/12.5 mg (12.4/10.4 mmHg) compared to valsartan 160 mg

(8.7/8.8 mmHg). The difference in BP reductions between the 160/25 mg and 160/12.5 mg doses also

reached statistical significance. In addition, a significantly greater percentage of patients responded

(diastolic BP <90 mmHg or reduction ≥10 mmHg) with valsartan/hydrochlorothiazide 160/25 mg

(68%) and 160/12.5 mg (62%) compared to valsartan 160 mg (49%).

In a double-blind, randomised, placebo-controlled, factorial design trial comparing various dose

combinations of valsartan/hydrochlorothiazide to their respective components, significantly greater

mean systolic/diastolic BP reductions were observed with the combination of

valsartan/hydrochlorothiazide 160/12.5 mg (17.8/13.5 mmHg) and 160/25 mg (22.5/15.3 mmHg)

compared to placebo (1.9/4.1 mmHg) and the respective monotherapies, i.e., hydrochlorothiazide 12.5

mg (7.3/7.2 mmHg), hydrochlorothiazide 25 mg (12.7/9.3 mmHg) and valsartan 160 mg

(12.1/9.4 mmHg). In addition, a significantly greater percentage of patients responded (diastolic BP

<90 mmHg or reduction ≥10 mmHg) with valsartan/hydrochlorothiazide 160/25 mg (81%) and

valsartan/ hydrochlorothiazide 160/12.5 mg (76%) compared to placebo (29%) and the respective

monotherapies, i.e. hydrochlorothiazide 12.5 mg (41%), hydrochlorothiazide 25 mg (54%), and

valsartan 160 mg (59%).

320 mg/12.5 mg and 320 mg/25 mg only:

In a double-blind, randomised, active-controlled trial in patients not adequately controlled on valsartan

320 mg, significantly greater mean systolic/diastolic BP reductions were observed with both the

combination of valsartan/hydrochlorothiazide 320/25 mg (15.4/10.4 mmHg) and

valsartan/hydrochlorothiazide 320/12.5 mg (13.6/9.7 mmHg) compared to valsartan 320 mg

(6.1/5.8 mmHg). The difference in systolic BP reduction between the 320/25 mg and 320/12.5 mg

doses also reached statistical significance. In addition, a significantly greater percentage of patients

responded (diastolic BP <90 mmHg or reduction ≥10 mmHg) with valsartan/hydrochlorothiazide

320/25 mg (75%) and 320/12.5 mg (69%) compared to valsartan 320 mg (53%).

In a double-blind, randomised, placebo-controlled, factorial design trial comparing various dose

combinations of valsartan/hydrochlorothiazide to their respective components, significantly greater

mean systolic/diastolic BP reductions were observed with the combination of

valsartan/hydrochlorothiazide 320/12.5 mg (21.7/15.0 mmHg) and 320/25 mg (24.7/16.6 mmHg)

compared to placebo (7.0/5.9 mmHg) and the respective monotherapies, i.e. hydrochlorothiazide

12.5 mg (11.1/9.0 mmHg), hydrochlorothiazide 25 mg (14.5/10.8 mmHg) and valsartan 320 mg

(13.7/11.3 mmHg). In addition, a significantly greater percentage of patients responded (diastolic BP

<90 mmHg or reduction ≥10 mmHg) with valsartan/hydrochlorothiazide 320/25 mg (85%) and

320/12.5 mg (83%) compared to placebo (45%) and the respective monotherapies, i.e.

hydrochlorothiazide 12.5 mg (60%), hydrochlorothiazide 25 mg (66%), and valsartan 320 mg (69%).

80 mg/12.5 mg, 160 mg/12.5 mg, 160 mg/25 mg, 320 mg/12.5 mg and 320 mg/25 mg:

Dose-dependent decreases in serum potassium occurred in controlled clinical studies with valsartan +

hydrochlorothiazide. Reduction in serum potassium occurred more frequently in patients given 25 mg

hydrochlorothiazide than in those given 12.5 mg hydrochlorothiazide. In controlled clinical trials with

valsartan/hydrochlorothiazide the potassium lowering effect of hydrochlorothiazide was attenuated by

the potassium-sparing effect of valsartan.

Beneficial effects of valsartan in combination with hydrochlorothiazide on cardiovascular mortality

and morbidity are currently unknown.

Epidemiological studies have shown that long-term treatment with hydrochlorothiazide reduces the

risk of cardiovascular mortality and morbidity.

Valsartan

Valsartan is an orally active and specific angiotensin II (Ang II) receptor antagonist. It acts selectively

on the AT

receptor subtype, which is responsible for the known actions of angiotensin II. The

increased plasma levels of Ang II following AT

receptor blockade with valsartan may stimulate the

unblocked AT

receptor, which appears to counterbalance the effect of the AT

receptor. Valsartan

does not exhibit any partial agonist activity at the AT

receptor and has much (about 20,000-fold)

greater affinity for the AT

receptor than for the AT

receptor. Valsartan is not known to bind to or

block other hormone receptors or ion channels known to be important in cardiovascular regulation.

Valsartan does not inhibit ACE, also known as kininase II, which converts Ang I to Ang II and

degrades bradykinin. Since there is no effect on ACE and no potentiation of bradykinin or substance P,

angiotensin II antagonists are unlikely to be associated with coughing. In clinical trials where valsartan

was compared with an ACE inhibitor, the incidence of dry cough was significantly (P <0.05) lower in

patients treated with valsartan than in those treated with an ACE inhibitor (2.6% versus 7.9%

respectively). In a clinical trial of patients with a history of dry cough during ACE inhibitor therapy,

19.5% of trial subjects receiving valsartan and 19.0% of those receiving a thiazide diuretic

experienced cough compared to 68.5% of those treated with an ACE inhibitor (P <0.05).

Administration of valsartan to patients with hypertension results in reduction of blood pressure

without affecting pulse rate. In most patients, after administration of a single oral dose, onset of

antihypertensive activity occurs within 2 hours, and the peak reduction of blood pressure is achieved

within 4–6 hours. The antihypertensive effect persists over 24 hours after dosing. During repeated

dosing, the maximum reduction in blood pressure with any dose is generally attained within 2–

4 weeks and is sustained during long-term therapy. Combined with hydrochlorothiazide, a significant

additional reduction in blood pressure is achieved.

Abrupt withdrawal of valsartan has not been associated with rebound hypertension or other adverse

clinical events.

In hypertensive patients with type 2 diabetes and microalbuminuria, valsartan has been shown to

reduce the urinary excretion of albumin. The MARVAL (Micro Albuminuria Reduction with

Valsartan) study assessed the reduction in urinary albumin excretion (UAE) with valsartan

(80-160 mg/od) versus amlodipine (5-10 mg/od), in 332 type 2 diabetic patients (mean age: 58 years;

265 men) with microalbuminuria (valsartan: 58 µg/min; amlodipine: 55.4 µg/min), normal or high

blood pressure and with preserved renal function (blood creatinine <120 µmol/l). At 24 weeks, UAE

was reduced (p <0.001) by 42% (–24.2 µg/min; 95% CI: –40.4 to –19.1) with valsartan and

approximately 3% (–1.7 µg/min; 95% CI: –5.6 to 14.9) with amlodipine despite similar rates of blood

pressure reduction in both groups. The Diovan Reduction of Proteinuria (DROP) study further

examined the efficacy of valsartan in reducing UAE in 391 hypertensive patients (BP=150/88 mmHg)

with type 2 diabetes, albuminuria (mean=102 µg/min; 20-700 µg/min) and preserved renal function

(mean serum creatinine = 80 µmol/l). Patients were randomised to one of 3 doses of valsartan (160,

320 and 640 mg/od) and treated for 30 weeks. The purpose of the study was to determine the optimal

dose of valsartan for reducing UAE in hypertensive patients with type 2 diabetes. At 30 weeks, the

percentage change in UAE was significantly reduced by 36% from baseline with valsartan 160 mg

(95%CI: 22 to 47%), and by 44% with valsartan 320 mg (95%CI: 31 to 54%). It was concluded that

160-320 mg of valsartan produced clinically relevant reductions in UAE in hypertensive patients with

type 2 diabetes.

Other: dual blockade of the renin-angiotensin-aldosterone system (RAAS)

Two large randomised, controlled trials (ONTARGET (ONgoing Telmisartan Alone and in

combination with Ramipril Global Endpoint Trial) and VA NEPHRON-D (The Veterans Affairs

Nephropathy in Diabetes)) have examined the use of the combination of an ACE-inhibitor with an

angiotensin II receptor blocker.

ONTARGET was a study conducted in patients with a history of cardiovascular or cerebrovascular

disease, or type 2 diabetes mellitus accompanied by evidence of end-organ damage. VA NEPHRON-

D was a study in patients with type 2 diabetes mellitus and diabetic nephropathy.

These studies have shown no significant beneficial effect on renal and/or cardiovascular outcomes and

mortality, while an increased risk of hyperkalaemia, acute kidney injury and/or hypotension as

compared to monotherapy was observed. Given their similar pharmacodynamic properties, these

results are also relevant for other ACE inhibitors and angiotensin II receptor blockers.

ACE inhibitors and angiotensin II receptor blockers should therefore not be used concomitantly in

patients with diabetic nephropathy.

ALTITUDE (Aliskiren Trial in Type 2 Diabetes Using Cardiovascular and Renal Disease Endpoints)

was a study designed to test the benefit of adding aliskiren to a standard therapy of an ACE inhibitor

or an angiotensin II receptor blocker in patients with type 2 diabetes mellitus and chronic kidney

disease, cardiovascular disease, or both. The study was terminated early because of an increased risk

of adverse outcomes. Cardiovascular death and stroke were both numerically more frequent in the

aliskiren group than in the placebo group and adverse events and serious adverse events of interest

(hyperkalaemia, hypotension and renal dysfunction) were more frequently reported in the aliskiren

group than in the placebo group.

Hydrochlorothiazide

The site of action of thiazide diuretics is primarily in the renal distal convoluted tubule. It has been

shown that there is a high-affinity receptor in the renal cortex as the primary binding site for the

thiazide diuretic action and inhibition of NaCl transport in the distal convoluted tubule. The mode of

action of thiazides is through inhibition of the Na

symporter perhaps by competing for the Cl

site,

thereby affecting electrolyte reabsorption mechanisms: directly increasing sodium and chloride

excretion to an approximately equal extent, and indirectly by this diuretic action reducing plasma

volume, with consequent increases in plasma renin activity, aldosterone secretion and urinary

potassium loss, and a decrease in serum potassium. The renin-aldosterone link is mediated by

angiotensin II, so with co-administration of valsartan the reduction in serum potassium is less

pronounced as observed under monotherapy with hydrochlorothiazide.

Non-melanoma skin cancer:

Based on available data from epidemiological studies, cumulative dose-dependent association between

hydrochlorothiazide and NMSC has been observed. One study included a population comprised of

71,533 cases of BCC and of 8,629 cases of SCC matched to 1,430,833 and 172,462 population

controls, respectively. High hydrochlorothiazide use (≥50,000 mg cumulative) was associated with an

adjusted Odds Ratio (OR) of 1.29 (95% CI: 1.23-1.35) for BCC and 3.98 (95% CI: 3.68-4.31) for

SCC. A clear cumulative dose response relationship was observed for both BCC and SCC. Another

study showed a possible association between lip cancer (SCC) and exposure to hydrochlorothiazide:

633 cases of lip-cancer were matched with 63,067 population controls, using a risk-set sampling

strategy. A cumulative dose- response relationship was demonstrated with an adjusted OR 2.1 (95%

CI: 1.7-2.6) increasing to OR 3.9 (3.0-4.9) for high use (~25,000 mg) and OR 7.7 (5.7-10.5) for the

highest cumulative dose (~100,000 mg) (see also section 4.4).

5.2

Pharmacokinetic properties

Valsartan/hydrochlorothiazide

The systemic availability of hydrochlorothiazide is reduced by about 30% when co-administered with

valsartan. The kinetics of valsartan are not markedly affected by the co-administration of

hydrochlorothiazide. This observed interaction has no impact on the combined use of valsartan and

hydrochlorothiazide, since controlled clinical trials have shown a clear anti-hypertensive effect, greater

than that obtained with either active substance given alone, or placebo.

Valsartan

Absorption

Following oral administration of valsartan alone, peak plasma concentrations of valsartan are reached

in 2–4 hours. Mean absolute bioavailability is 23%. Food decreases exposure (as measured by AUC)

to valsartan by about 40% and peak plasma concentration (C

) by about 50%, although from about

8 h post dosing plasma valsartan concentrations are similar for the fed and fasted groups. This

reduction in AUC is not, however, accompanied by a clinically significant reduction in the therapeutic

effect, and valsartan can therefore be given either with or without food.

Distribution

The steady-state volume of distribution of valsartan after intravenous administration is about 17 litres,

indicating that valsartan does not distribute into tissues extensively. Valsartan is highly bound to

serum proteins (94–97%), mainly serum albumin.

Biotransformation

Valsartan is not biotransformed to a high extent as only about 20% of dose is recovered as metabolites.

A hydroxy metabolite has been identified in plasma at low concentrations (less than 10% of the

valsartan AUC). This metabolite is pharmacologically inactive.

Elimination

Valsartan shows multiexponential decay kinetics (t

½α

<1 h and t

½ß

about 9 h). Valsartan is primarily

eliminated in faeces (about 83% of dose) and urine (about 13% of dose), mainly as unchanged drug.

Following intravenous administration, plasma clearance of valsartan is about 2 l/h and its renal

clearance is 0.62 l/h (about 30% of total clearance). The half-life of valsartan is 6 hours.

Hydrochlorothiazide

Absorption

The absorption of hydrochlorothiazide, after an oral dose, is rapid (t

about 2 h). The increase in

mean AUC is linear and dose proportional in the therapeutic range.

The effect of food on hydrochlorothiazide absorption, if any, has little clinical significance. Absolute

bioavailability of hydrochlorothiazide is 70% after oral administration.

Distribution

The apparent volume of distribution is 4–8 l/kg.

Circulating hydrochlorothiazide is bound to serum proteins (40–70%), mainly serum albumin.

Hydrochlorothiazide also accumulates in erythrocytes at approximately 3 times the level in plasma.

Elimination

Hydrochlorotiazide is eliminated predominantly as unchanged drug. Hydrochlorothiazide is eliminated

from plasma with a half-life averaging 6 to 15 hours in the terminal elimination phase. There is no

change in the kinetics of hydrochlorothiazide on repeated dosing, and accumulation is minimal when

dosed once daily. There is more than 95% of the absorbed dose being excreted as unchanged

compound in the urine. The renal clearance is composed of passive filtration and active secretion into

the renal tubule.

Special populations

Older people

A somewhat higher systemic exposure to valsartan was observed in some elderly subjects than in

young subjects; however, this has not been shown to have any clinical significance.

Limited data suggest that the systemic clearance of hydrochlorothiazide is reduced in both healthy and

hypertensive elderly subjects compared to young healthy volunteers.

Renal impairment

At the recommended dose of Diovan Comp no dose adjustment is required for patients with a

Glomerular Filtration Rate (GFR) of 30–70 ml/min.

In patients with severe renal impairment (GFR <30 ml/min) and patients undergoing dialysis no data

are available for Diovan Comp. Valsartan is highly bound to plasma protein and is not to be removed

by dialysis, whereas clearance of hydrochlorothiazide will be achieved by dialysis.

In the presence of renal impairment, mean peak plasma levels and AUC values of hydrochlorothiazide

are increased and the urinary excretion rate is reduced. In patients with mild to moderate renal

impairment, a 3-fold increase in hydrochlorothiazide AUC has been observed. In patients with severe

renal impairment an 8-fold increase in AUC has been observed. Hydrochlorothiazide is

contraindicated in patients with severe renal impairment (see section 4.3).

Hepatic impairment

In a pharmacokinetics trial in patients with mild (n=6) to moderate (n=5) hepatic dysfunction,

exposure to valsartan was increased approximately 2-fold compared with healthy volunteers (see

sections 4.2 and 4.4).

There is no data available on the use of valsartan in patients with severe hepatic dysfunction (see

section 4.3). Hepatic disease does not significantly affect the pharmacokinetics of hydrochlorothiazide.

5.3

Preclinical safety data

The potential toxicity of the valsartan - hydrochlorothiazide combination after oral administration was

investigated in rats and marmosets in studies lasting up to six months. No findings emerged that would

exclude the use of therapeutic doses in man.

The changes produced by the combination in the chronic toxicity studies are most likely to have been

caused by the valsartan component. The toxicological target organ was the kidney, the reaction being

more marked in the marmoset than the rat. The combination led to kidney damage (nephropathy with

tubular basophilia, rises in plasma urea, plasma creatinine and serum potassium, increases in urine

volume and urinary electrolytes from 30 mg/kg/day valsartan + 9 mg/kg/day hydrochlorothiazide in

rats and 10 + 3 mg/kg/d in marmosets), probably by way of altered renal haemodynamics. These doses

in rat, respectively, represent 0.9 and 3.5-times the maximum recommended human dose (MRHD) of

valsartan and hydrochlorothiazide on a mg/m

basis. These doses in marmoset, respectively, represent

0.3 and 1.2-times the maximum recommended human dose (MRHD) of valsartan and

hydrochlorothiazide on a mg/m

basis. (Calculations assume an oral dose of 320 mg/day valsartan in

combination with 25 mg/day hydrochlorothiazide and a 60-kg patient.)

High doses of the valsartan - hydrochlorothiazide combination caused falls in red blood cell indices

(red cell count, haemoglobin, haematocrit, from 100 + 31 mg/kg/d in rats and 30 + 9 mg/kg/d in

marmosets). These doses in rat, respectively, represent 3.0 and 12 times the maximum recommended

human dose (MRHD) of valsartan and hydrochlorothiazide on a mg/m

basis. These doses in

marmoset, respectively, represent 0.9 and 3.5 times the maximum recommended human dose (MRHD)

of valsartan and hydrochlorothiazide on a mg/m

basis. (Calculations assume an oral dose of

320 mg/day valsartan in combination with 25 mg/day hydrochlorothiazide and a 60-kg patient).

In marmosets, damage was observed in the gastric mucosa (from 30 + 9 mg/kg/d). The combination

also led in the kidney to hyperplasia of the afferent aterioles (at 600 + 188 mg/kg/d in rats and from

30 + 9 mg/kg/d in marmosets). These doses in marmoset, respectively, represent 0.9 and 3.5 times the

maximum recommended human dose (MRHD) of valsartan and hydrochlorothiazide on a mg/m

basis.

These doses in rat, respectively, represent 18 and 73 times the maximum recommended human dose

(MRHD) of valsartan and hydrochlorothiazide on a mg/m

basis. (Calculations assume an oral dose of

320 mg/day valsartan in combination with 25 mg/day hydrochlorothiazide and a 60-kg patient).

The above mentioned effects appear to be due to the pharmacological effects of high valsartan doses

(blockade of angiotensin II-induced inhibition of renin release, with stimulation of the renin-producing

cells) and also occur with ACE inhibitors. These findings appear to have no relevance to the use of

therapeutic doses of valsartan in humans.

The valsartan - hydrochlorothiazide combination was not tested for mutagenicity, chromosomal

breakage or carcinogenicity, since there is no evidence of interaction between the two substances.

However, these tests were performed separately with valsartan and hydrochlorothiazide, and produced

no evidence of mutagenicity, chromosomal breakage or carcinogenicity.

In rats, maternally toxic doses of valsartan (600 mg/kg/day) during the last days of gestation and

lactation led to lower survival, lower weight gain and delayed development (pinna detachment and

ear-canal opening) in the offspring (see section 4.6). These doses in rats (600 mg/kg/day) are

approximately 18 times the maximum recommended human dose on a mg/m2 basis (calculations

assume an oral dose of 320 mg/day and a 60-kg patient). Similar findings were seen with

valsartan/hydrochlorothiazide in rats and rabbits. In embryo-fetal development (Segment II) studies

with valsartan/hydrochlorothiazide in rat and rabbit, there was no evidence of teratogenicity; however,

fetotoxicity associated with maternal toxicity was observed.

6.

PHARMACEUTICAL PARTICULARS

6.1

List of excipients

Tablet core:

80 mg/12.5 mg, 160 mg/12.5 mg, 160 mg/25 mg, 320 mg/12.5 mg and 320 mg/25 mg:

Microcrystalline cellulose

Silica, colloidal anhydrous

Crospovidone

Magnesium stearate.

Coating:

80 mg/12.5 mg:

Hypromellose

Macrogol 8000

Talc

Red iron oxide (E 172)

Yellow iron oxide (E 172)

Titanium dioxide (E 171).

160 mg/12.5 mg:

Hypromellose

Macrogol 8000

Talc

Titanium dioxide (E 171)

Red iron oxide (E 172).

160 mg/25 mg:

Hypromellose

Macrogol 4000

Talc

Titanium dioxide (E 171)

Red iron oxide (E 172)

Yellow iron oxide (E 172)

Black iron oxide (E 172).

320 mg/12.5 mg:

Hypromellose

Macrogol 8000

Talc

Titanium dioxide (E171)

Black iron oxide (E172)

Red iron oxide (E172)

320 mg/25 mg:

Hypromellose

Macrogol 4000

Talc

Titanium dioxide (E 171)

Yellow iron oxide (E 172)

6.2

Incompatibilities

Not applicable.

6.3

Shelf life

3 years.

6.4

Special precautions for storage

Do not store above 30° C. Store in the original package in order to protect from moisture.

6.5

Nature and contents of container

80 mg/12.5 mg

PVC/PE/PVDC/Alu or PVC/PVDC/Alu blisters.

14; 28 as calendar pack; 30, 56; 98 as calendar pack; 280 film-coated tablets.

PVC/PE/PVDC/Alu or PVC/PVDC/Alu perforated unit dose blisters.

56x1, 98x1; 280x1 film-coated tablets.

Not all pack sizes may be marketed.

160 mg/12.5 mg

PVC/PE/PVDC/Alu or PVC/PVDC/Alu blisters.

14, 28 as calendar pack, 56, 98 as calendar pack, 280 film-coated tablets

PVC/PE/PVDC/Alu or PVC/PVDC/Alu perforated unit dose blisters

56x1, 98x1, 280x1 film-coated tablets

Not all pack sizes may be marketed.

160 mg/25 mg

PVC/PE/PVDC/Alu or PVC/PVDC/Alu blisters.

14, 28 as calendar pack, 56, 98 as calendar pack, 280 film-coated tablets.

PVC/PE/PVDC/Alu or PVC/PVDC/Alu perforated unit dose blisters

56x1, 98x1, 280x1 film-coated tablets.

Not all pack sizes may be marketed.

320 mg/12.5 mg

PVC/ PVDC/Alu blisters.

7, 14, 28 as calendar pack, 56, 98 as calendar pack, 280 film-coated tablets

PVC/PVDC/Alu perforated unit dose blisters

56x1, 98x1, 280x1 film-coated tablets

Not all pack sizes may be marketed.

320 mg/25 mg

PVC /PVDC/Alu blisters

7, 14, 28 as calendar pack, 56, 98 as calendar pack, 280 film-coated tablets

PVC/PVDC/Alu perforated unit dose blisters

56x1, 98x1, 280x1 film-coated tablets

Not all pack sizes may be marketed.

6.6

Special precautions for disposal

No special requirements.

7.

MARKETING AUTHORISATION HOLDER

<[To be completed nationally]>

{Name and address}

<{tel}>

<{fax}>

<{e-mail}>

8.

MARKETING AUTHORISATION NUMBER(S)

<[To be completed nationally]>

9.

DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

<Date of first authorisation: {DD month YYYY}>

<Date of latest renewal: {DD month YYYY}>

<[To be completed nationally]>

10.

DATE OF REVISION OF THE TEXT

2020-08-28

< [To be completed nationally]>

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