Valsartan/Hydrochlorothiazide 2care4 320 mg/12,5 mg Filmdragerad tablett

Sverige - svenska - Läkemedelsverket (Medical Products Agency)

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Bipacksedel Bipacksedel (PIL)

29-04-2021

Produktens egenskaper Produktens egenskaper (SPC)

16-01-2019

Aktiva substanser:
hydroklortiazid; valsartan
Tillgänglig från:
2care4 ApS,
ATC-kod:
C09DA03
INN (International namn):
hydrochlorothiazide; valsartan
Dos:
320 mg/12,5 mg
Läkemedelsform:
Filmdragerad tablett
Sammansättning:
hydroklortiazid 12,5 mg Aktiv substans; valsartan 320 mg Aktiv substans
Receptbelagda typ:
Receptbelagt
Bemyndigande status:
Avregistrerad
Godkännandenummer:
54640
Tillstånd datum:
2016-11-16

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16-01-2019

Produktens egenskaper Produktens egenskaper - engelska

16-01-2019

Offentlig bedömningsrapport Offentlig bedömningsrapport - engelska

21-02-2013

Läs hela dokumentet

Bipacksedel: Information till användaren

Valsartan/Hydrochlorothiazide Sandoz 160 mg/25 mg filmdragerade tabletter

Valsartan/Hydrochlorothiazide Sandoz 320 mg/12,5 mg filmdragerade tabletter

Valsartan/Hydrochlorothiazide Sandoz 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 Valsartan/Hydrochlorothiazide Sandoz är och vad det används för

Vad du behöver veta innan du tar Valsartan/Hydrochlorothiazide Sandoz

Hur du tar Valsartan/Hydrochlorothiazide Sandoz

Eventuella biverkningar

Hur Valsartan/Hydrochlorothiazide Sandoz ska förvaras

Förpackningens innehåll och övriga upplysningar

1.

Vad Valsartan/Hydrochlorothiazide Sandoz är och vad det används för

Valsartan/Hydrochlorothiazide Sandoz 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.

Valsartan/Hydrochlorothiazide Sandoz 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.

Valsartan och hydroklortiazid som finns i Valsartan/Hydrochlorothiazide Sandoz kan också vara godkända för

att behandla andra sjukdomar som inte nämns i denna produktinformation. Fråga läkare, apoteks- eller annan

hälso- och sjukvårdspersonal om du har ytterligare frågor och följ alltid deras instruktion.

2.

Vad du behöver veta innan du tar Valsartan/Hydrochlorothiazide Sandoz

Ta inte Valsartan/Hydrochlorothiazide Sandoz

om du är allergisk mot valsartan, hydroklortiazid, sulfonamidderivat (substanser som är kemiskt

besläktade med hydroklortiazid) eller något annat innehållsämne i detta läkemedel (anges i avsnitt 6).

om du är

mer än 3 månader gravid

(det är också bättre att undvika Valsartan/Hydrochlorothiazide

Sandoz, under tidig graviditet - se avsnittet ”Graviditet och amning”).

om du har

svår

leversjukdom, förstörelse av de små gallvägarna i levern (biliär cirros) vilket leder till att

galla ansamlas i levern (kolestas).

om du har

svår

njursjukdom.

om du inte kan producera urin (anuri).

om du behandlas med 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 behandlas med ett blodtryckssänkande läkemedel som

innehåller aliskiren.

Om något av ovanstående gäller dig ska du inte ta detta läkemedel. Tala med din läkare.

Varningar och försiktighet

Tala med läkare innan du tar Valsartan/Hydrochlorothiazide Sandoz

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 läkemedel (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 Valsartan/Hydrochlorothiazide Sandoz 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 Valsartan/Hydrochlorothiazide Sandoz, sluta ta

Valsartan/Hydrochlorothiazide Sandoz 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 kolesterol- eller 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 din syn försämras eller du får ont i ögonen. Detta kan vara symtom på vätskeansamling i ögat

(mellan åderhinnan och senhinnan) eller en ökning av trycket i ögat och kan ske inom några timmar till

veckor efter att du tagit Valsartan/Hydrochlorothiazide Sandoz. Det kan leda till kvarstående

synnedsättning om det inte behandlas. Om du tidigare fått en allergisk reaktion mot penicillin eller

sulfonamid kan risken för denna biverkning vara högre.

eftersom det kan öka hudens känslighet för sol.

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 Valsartan/Hydrochlorothiazide Sandoz

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

en ACE-hämmare (till exempel enalapril, lisinopril, ramipril), särskilt om du har diabetesrelaterade

njurproblem.

aliskiren

Tala med din läkare om något av detta gäller dig.

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

jämna mellanrum.

Se även informationen under rubriken ”Ta inte Valsartan/Hydrochlorothiazide Sandoz”.

Du måste berätta för din läkare om du tror att du är (eller kan bli) gravid. Valsartan/Hydrochlorothiazide Sandoz

rekommenderas inte i början av graviditeten och får inte användas om du är mer än 3 månader gravid eftersom

läkemedlet kan orsaka fosterskador om det används i detta skede (se avsnittet ”Graviditet och amning”).

Barn och ungdomar

Valsartan/Hydrochlorothiazide Sandoz rekommenderas inte till barn och ungdomar (under 18 år).

Andra läkemedel och Valsartan/Hydrochlorothiazide Sandoz

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

Behandlingseffekten kan påverkas om Valsartan/Hydrochlorothiazide Sandoz tas tillsammans med vissa andra

läkemedel. Din läkare kan behöva ändra din dos och/eller 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 är kaliumtillskott eller

saltersättningsmedel som innehåller kalium, kaliumsparande läkemedel och heparin

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

laxermedel, karbenoxolon, amfotericin och 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 förstärka effekten av Valsartan/Hydrochlorothiazide Sandoz.

läkemedel som kan orsaka ”torsades de pointes” (oregelbundna hjärtslag) såsom antiarytmika

(läkemedel mot hjärtproblem) och vissa antipsykotika (mot psykiska sjukdomar)

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

antiepileptika (mot kramper)

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

D-vitamin och kalciumtillägg

diabetesläkemedel (sådana som intas via munnen t.ex. metformin, eller insulinpreparat)

andra blodtryckssänkande läkemedel, inklusive metyldopa, ACE-hämmare (t.ex. enalapril, lisinopril

etc.) eller aliskiren (se även informationen under rubrikerna ”Ta inte Valsartan/Hydrochlorothiazide

Sandoz” och ”Varningar och försiktighet”)

läkemedel som höjer blodtrycket, t.ex. noradrenalin eller adrenalin

digoxin eller andra digitalisglykosider (läkemedel för behandling av hjärtproblem)

läkemedel som kan höja blodsockret, t.ex. diazoxid eller betablockerare

cytostatika (läkemedel mot cancer), t.ex. metotrexat eller cyklofosfamid

smärtstillande medel, t.ex. icke-steroida antiinflammatoriska medel (NSAID), vilket omfattar bl.a.

selektiva cyklooxygenas 2-hämmare (Cox 2-hämmare) och acetylsalicylsyra i högre dos än 3 gram per

muskelavslappande medel, t.ex. tubokurarin

antikolinerga läkemedel (används för behandling av flera olika sjukdomar t.ex. krampartade smärtor i

magtarmkanalen, kramp i urinblåsan, astma, åksjuka, muskelkramper och Parkinsons sjukdom, samt för

att underlätta anestesi)

amantadin (används vid Parkinsons sjukdom och även för att behandla eller förhindra vissa

virusorsakade sjukdomar)

kolestyramin och kolestipol (läkemedel som främst används vid höga lipidvärden (fettämnen) i blodet)

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

alkohol, sömntabletter och anestetika (läkemedel med sömngivande eller bedövande effekt som t.ex.

används vid operationer)

jodkontrastmedel (används vid bildundersökning).

Valsartan/Hydrochlorothiazide Sandoz med mat, dryck och alkohol

Du kan ta Valsartan/Hydrochlorothiazide Sandoz med eller utan mat.

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

apotekspersonal innan du använder detta läkemedel.

Du måste berätta för din läkare om du tror att du är (eller kan bli) gravid.

Din läkare råder dig vanligen att sluta ta Valsartan/Hydrochlorothiazide Sandoz innan du blir gravid eller så fort

du vet att du är gravid och kommer att råda dig att ta ett annat läkemedel istället för

Valsartan/Hydrochlorothiazide Sandoz. Valsartan/Hydrochlorothiazide Sandoz rekommenderas inte i början av

graviditeten och får inte tas när du är mer än 3 månader gravid, eftersom det kan orsaka fosterskador om det

används efter tredje graviditetsmånaden.

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

Valsartan/Hydrochlorothiazide Sandoz rekommenderas inte för mödrar som ammar och din läkare kan välja en

annan behandling för dig

om du vill amma, 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 Valsartan/Hydrochlorothiazide Sandoz påverkar dig. Liksom många andra läkemedel för behandling

av högt blodtryck kan Valsartan/Hydrochlorothiazide Sandoz 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 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.

3.

Hur du tar Valsartan/Hydrochlorothiazide Sandoz

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 Valsartan/Hydrochlorothiazide Sandoz-tabletter som du ska ta. Beroende

på behandlingsresultatet kan läkaren höja eller sänka dosen.

Rekommenderad dos av Valsartan/Hydrochlorothiazide Sandoz 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 Valsartan/Hydrochlorothiazide Sandoz med eller utan mat.

Svälj Valsartan/Hydrochlorothiazide Sandoz med ett glas vatten.

Om du har tagit för stor mängd av Valsartan/Hydrochlorothiazide Sandoz

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

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

apotek, sjukhus eller Giftinformationscentralen (tel. 112) för bedömning av risken samt rådgivning.

Om du har glömt att ta Valsartan/Hydrochlorothiazide Sandoz

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 Valsartan/Hydrochlorothiazide Sandoz

Om du slutar din behandling med Valsartan/Hydrochlorothiazide Sandoz 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.

Om du får något av dessa symtom ska du sluta ta Valsartan/Hydrochlorothiazide Sandoz och kontakta

läkare omedelbart (se även avsnitt 2 ”Varningar och försiktighet”).

Andra biverkningar är:

Mindre vanliga, förekommer hos 1 till 10 av 1 000 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, förekommer hos färre än 1 av 10 000 användare

yrsel

diarré

smärta i lederna.

Ingen känd frekvens enligt tillgängliga data

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, förekommer hos 1 till 10 av 1 000 användare

känsla av att snurra

smärta i buken.

Ingen känd frekvens enligt tillgängliga data

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

låga nivåer av natrium i blodet (som kan utlösa trötthet, förvirring, muskelryckningar och/eller kramper i

svåra fall).

Hydroklortiazid

Mycket vanliga, förekommer hos fler än 1 av 10 användare

låg kaliumhalt i blodet

förhöjd lipidhalt i blodet.

Vanliga, förekommer hos 1 till 10 av 100 användare

låg natriumhalt i blodet

låg magnesiumhalt i blodet

hög urinsyrehalt i blodet

kliande utslag och andra typer av utslag

minskad aptit

lätt illamående och kräkningar

yrsel, svimning då man reser sig upp

oförmåga att få eller bibehålla erektion.

Sällsynta, förekommer hos 1 till 10 av 10 000 användare

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

hög kalciumhalt i blodet

högt blodsocker

socker i urinen

försämrad ämnesomsättningsstatus vid diabetes

förstoppning, diarré, obehag i mage och tarm, leverstörningar (som kan visa sig som 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, förekommer hos färre än 1 av 10 000 användare

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

utslag, klåda, nässelutslag, problem med att andas eller svälja, yrsel (överkänslighetsreaktioner)

allvarlig hudsjukdom som orsakar utslag, rodnad hud, blåsor på läppar, ögon eller mun, fjällande hud,

feber (toxisk epidermal nekrolys)

utslag i ansiktet, smärta i lederna, muskelsjukdom, feber (lupus erythematosus)

svår smärta i övre delen av magen (pankreatit, dvs. inflammation i bukspottkörteln)

andningssvårigheter med feber, hosta, väsande/pipande andning, andfåddhet (respiratorisk distress med

pneumonit och lungödem)

feber, halsont eller täta infektioner (agranulocytos)

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

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

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

Ingen känd frekvens, kan inte beräknas från tillgängliga data

svaghet, blåmärken och täta infektioner (aplastisk anemi)

drastiskt minskade urinmängder (kan vara tecken på njursjukdom eller njursvikt)

försämrad syn eller ont i ögonen på grund av högt tryck (möjligt tecken på vätskeansamling i ögat

(mellan åderhinnan och senhinnan) eller akut trångvinkelglaukom)

utslag, rodnad hud, blåsor på läppar, ögon eller mun, fjällande hud, feber (kan vara tecken på erythema

multiforme)

muskelkramper

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. www.lakemedelsverket.se.

5.

Hur Valsartan/Hydrochlorothiazide Sandoz ska förvaras

Förvara detta läkemedel utom syn- och räckhåll för barn.

Används före utgångsdatum som anges på blister och kartongen. Utgångsdatumet är den sista dagen i

angiven månad.

Förvaras vid högst 30 °C. Förvaras i originalförpackningen. Fuktkänsligt.

Använd inte tabletter från en Valsartan/Hydrochlorothiazide Sandoz förpackning som är skadad eller visar

tecken på att ha öppnats tidigare.

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

De aktiva substanserna är valsartan och hydroklortiazid.

Varje tablett innehåller 160 mg valsartan och 25 mg hydroklortiazid.

Varje tablett innehåller 320 mg valsartan och 12,5 mg hydroklortiazid.

Varje tablett innehåller 320 mg valsartan och 25 mg hydroklortiazid.

Övriga innehållsämnen är:

Valsartan/Hydrochlorothiazide Sandoz 160 mg/25 mg filmdragerade tabletter

Tablettkärna:

Mikrokristallin cellulosa, krospovidon, magnesiumstearat, kolloidal vattenfri kiseldioxid.

Dragering:

Hypromellos, makrogol 4000, talk, titandioxid (E171), röd järnoxid (E172), gul järnoxid (E172), svart

järnoxid (E172).

Valsartan/Hydrochlorothiazide Sandoz 320 mg/12,5 mg filmdragerade tabletter

Tablettkärna:

Mikrokristallin cellulosa, krospovidon, magnesiumstearat, kolloidal vattenfri kiseldioxid.

Dragering:

Hypromellos, makrogol 4000, talk, titandioxid (E171), röd järnoxid (E172), svart järnoxid (E172).

Valsartan/Hydrochlorothiazide Sandoz 320 mg/25 mg filmdragerade tabletter

Tablettkärna:

Mikrokristallin cellulosa, krospovidon, magnesiumstearat, kolloidal vattenfri kiseldioxid.

Dragering:

Hypromellos, makrogol 4000, talk, titandioxid (E171), gul järnoxid (E172).

Läkemedlets utseende och förpackningsstorlekar

Valsartan/Hydrochlorothiazide Sandoz 160 mg/25 mg filmdragerade tabletter

Filmdragerad tablett, brunorange, oval, något konvexa sidor, märkt med ”HXH” på ena sidan och ”NVR” på

andra sidan.

Valsartan/Hydrochlorothiazide Sandoz 320 mg/12,5 mg filmdragerade tabletter

Filmdragerad tablett, rosa, oval, avfasade kanter, märkt med ”NVR” på ena sidan och ”HIL” på andra sidan.

Valsartan/Hydrochlorothiazide Sandoz 320 mg/25 mg filmdragerade tabletter

Gul, oval, filmdragerad tablett med avfasade kanter, märkt med “NVR” på ena sidan och “CTI” på andra sidan.

Förpackningsstorlekar: 7, 10, 14, 15, 20, 28, 30, 50, 50x1, 56, 60, 84, 90, 98, 100 eller 280 filmdragerade

tabletter.

Eventuellt kommer inte alla förpackningsstorlekar att marknadsföras.

Innehavare av godkännande för försäljning och tillverkare

Innehavare av godkännande för försäljning

Sandoz A/S, Edvard Thomsens Vej 14, 2300 Köpenhamn S, Danmark

Tillverkare

Salutas Pharma GmbH, Otto-von-Guericke-Allee 1, DE-39179 Barleben, Tyskland

eller

Lek Pharmaceuticals d.d, Verovskova 57, SI-1526 Ljubljana, Slovenien

eller

Lek S.A., ul. Domaniewska 50 C, PL-02-672 Warszawa, Polen

eller

Lek Pharmaceuticals d.d, Trimlini 2 D 9220 Lendava, Slovenien

eller

LEK S.A., Ul. Podlipie 16 C, 95 010 Strykow, Polen

eller

Novartis Farma S.p.A., Via Provinciale Schito 131, I-800058 Torre Annunziata / NA, Italien

eller

S.C. Sandoz S.R.L., Str. Livezeni nr. 7A, 540472 Targo-Mures, Rumänien.

Denna bipacksedel ändrades senast

2021-04-28

Läs hela dokumentet

SUMMARY OF PRODUCT CHARACTERISTICS

1.

NAME OF THE MEDICINAL PRODUCT

Valsartan/Hydrochlorothiazide Sandoz 80 mg /12.5 mg film-coated tablets

Valsartan/Hydrochlorothiazide Sandoz 160 mg /12.5 mg film-coated tablets

Valsartan/Hydrochlorothiazide Sandoz 160 mg /25 mg film-coated tablets

Valsartan/Hydrochlorothiazide Sandoz 320 mg /12.5 mg film-coated tablets

Valsartan/Hydrochlorothiazide Sandoz 320 mg /25 mg film-coated tablets

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 80 mg of valsartan and 12.5 mg of hydrochlorothiazide

Each tablet contains 160 mg of valsartan and 12.5 mg of hydrochlorothiazide

Each tablet contains 160 mg of valsartan and 25 mg of hydrochlorothiazide

Each tablet contains 320 mg of valsartan and 12.5 mg of hydrochlorothiazide.

Each 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 tablet.

Valsartan/Hydrochlorothiazide Sandoz 80 mg/12.5 mg film-coated tablets

Film-coated tablet, light orange, ovaloid, slightly convex faces, imprinted (debossed) with

“HGH” on one side and “CG" on the reverse side

Valsartan/Hydrochlorothiazide Sandoz 160 mg/12.5 mg film-coated tablets

Film-coated tablet, dark red, ovaloid, slightly convex faces, imprinted (debossed) with “HHH” on

one side and “CG" on the reverse side Valsartan/Hydrochlorothiazide Sandoz 160 mg/25 mg

film-coated tablets

Valsartan/Hydrochlorothiazide Sandoz 160 mg/25 mg film-coated tablets

Film-coated tablet, brown orange, ovaloid, slightly convex faces, imprinted (debossed) with

“HXH” on one side and “NVR" on the reverse side

Valsartan/Hydrochlorothiazide Sandoz 320 mg/12.5 mg film-coated tablets

Film-coated tablet , pink, ovaloid shaped, beveled edge, imprinted (debossed) with “NVR” on

one side and “HIL” on the reverse side

Valsartan/Hydrochlorothiazide Sandoz 320 mg/25 mg film-coated tablets

Yellow, ovaloid shaped, beveled edge, film coated tablet, imprinted (debossed) with “NVR” on

one side and “CTI” on the reverse side

4.

CLINICAL PARTICULARS

4.1

Therapeutic indications

Treatment of essential hypertension in adults.

Valsartan/Hydrochlorothiazide Sandoz 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 Valsartan/Hydrochlorothiazide Sandoz 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 Valsartan/Hydrochlorothiazide Sandoz 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 Valsartan/Hydrochlorothiazide

Sandoz 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.

If no relevant additional effect is seen with Valsartan/Hydrochlorothiazide Sandoz 320 mg/25 mg

after 8 weeks, treatment with an additional or alternative antihypertensive medicinal product

should be considered. (see sections 4.3, 4.4, 4.5 and 5.1)

Special populations

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,

Valsartan/Hydrochlorothiazide Sandoz is contraindicated in patients with severe renal impairment

(GFR < 30 mL/min) and anuria (see sections 4.3, 4.4 and 5.2).

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,

Valsartan/Hydrochlorothiazide Sandoz is contraindicated in patients with severe hepatic

impairment or with biliary cirrhosis and cholestasis (see sections 4.3, 4.4 and 5.2).

Older patients

No dose adjustment is required in older patients.

Paediatric population

Valsartan/hydrochlorothiazide is not recommended for use in children below the age of 18 years

due to a lack of data on safety and efficacy.

Method of administration

Valsartan/Hydrochlorothiazide Sandoz can be taken with or without food and should be

administered with water.

4.3

Contraindications

Hypersensitivity to the active substances, 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 (GFR < 30 ml/min/1.73m

), anuria.

Refractory hypokalaemia, hyponatraemia, hypercalcaemia, and symptomatic

hyperuricaemia.

The concomitant use of Valsartan/Hydrochlorothiazide Sandoz with aliskiren-containing

products is contraindicated in patients with diabetes mellitus or renal impairment (GFR

< 60 ml/min/1.73 m

) (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

valsartan/hydrochlorothiazide. Sodium and/or volume depletion should be corrected before

starting treatment with Valsartan/Hydrochlorothiazide Sandoz.

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

valsartan/hydrochlorothiazide 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 Valsartan/Hydrochlorothiazide Sandoz as well may be associated with

impairment of the renal function. Valsartan/hydrochlorothiazide should not be used in these

patients.

Renal artery stenosis

Valsartan/hydrochlorothiazide 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

valsartan/hydrochlorothiazide 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 GFR

≥ 30 ml/min/1.73 m

(see section 4.2). Periodic monitoring of serum potassium, creatinine and

uric acid levels is recommended when Valsartan/Hydrochlorothiazide Sandoz is used in patients

with renal impairment.

Kidney transplantation

There is currently no experience on the safe use of valsartan/hydrochlorothiazide in patients who

have recently undergone kidney transplantation.

Hepatic impairment

In patients with mild to moderate hepatic impairment without cholestasis,

valsartan/hydrochlorothiazide 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. Valsartan/Hydrochlorothiazide Sandoz should be immediately discontinued in

patients who develop angioedema, and valsartan/hydrochlorothiazide 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.

Acute angle-closure glaucoma

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

in 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 week 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 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

(HCTZ) exposure has been observed in two epidemiological studies based on the Danish National

Cancer Registry. Photosensitizing actions of HCTZ could act as a possible mechanism for

NMSC.

Patients taking HCTZ 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 HCTZ 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

valsartan/hydrochlorothiazide. If the combination proves necessary, a careful monitoring of

serum lithium levels is recommended.

Concomitant use requiring caution

Other antihypertensive agents

Valsartan/hydrochlorothiazide 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

valsartan/hydrochlorothiazide 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 (e.g. rifampin,

ciclosporin) or efflux transporter (e.g. 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

Valsartan/Hydrochlorothiazide Sandoz (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 antihypertensive 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 breast-feeding.

Hydrochlorothiazide is excreted in human milk. Therefore, the use of

Valsartan/Hydrochlorothiazide Sandoz 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.

Fertility

There is no information on the effects of valsartan or hydrochlorothiazide on fertility.

4.7

Effects on ability to drive and use machines

No studies on the effect of valsartan/hydrochlorothiazide, 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 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 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 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 (cannot be estimated

from the available data). Within each frequency grouping, adverse 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 Valsartan/Hydrochlorothiazide Sandoz 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 Valsartan/Hydrochlorothiazide Sandoz. The following adverse

reactions have been reported in patients treated with monotherapy of thiazide diuretics, including

hydrochlorothiazide:

Blood and lymphatic system disorders

Rare

Thrombocytopenia sometimes with purpura

Very rare

Agranulocytosis, leucopenia, haemolytic

anaemia, bone marrow failure

Not known

Aplastic anaemia

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

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

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

Not known

Non-melanoma skin cancer (Basal cell

carcinoma and Squamous cell carcinoma)*

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

dose-dependent association between HCTZ 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; to be completed nationally].

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

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%).

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%).

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%).

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 HCTZ 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 HCTZ use (≥50,000 mg cumulative) was

associated with an adjusted 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

HCTZ: 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 patients

A somewhat higher systemic exposure to valsartan was observed in some older 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 older subjects compared to young healthy volunteers.

Renal impairment

At the recommended dose of Valsartan/Hydrochlorothiazide Sandoz 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 Valsartan/Hydrochlorothiazide Sandoz. 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:

Microcrystalline cellulose

Crospovidone

Magnesium stearate

Colloidal anhydrous silica

Coating

Valsartan/Hydrochlorothiazide Sandoz 80 mg/ 12.5 mg

Hypromellose

Macrogol 8000

Talc

Titanium dioxide (E171)

Red iron oxide (E172)

Yellow iron oxide (E172)

Valsartan/Hydrochlorothiazide Sandoz 160 mg /12.5mg:

Hypromellose

Macrogol 8000

Talc

Titanium dioxide (E171)

Red iron oxide (E172)

Valsartan/Hydrochlorothiazide Sandoz 160 mg/ 25 mg:

Hypromellose

Macrogol 4000

Talc

Titanium dioxide (E 171)

Iron oxide, red (E 172)

Iron oxide, yellow (E 172)

Iron oxide, black (E 172)

Valsartan/Hydrochlorothiazide Sandoz 320 mg/ 12.5 mg:

Hypromellose

Macrogol 4000

Talc

Titanium dioxide (E 171)

Iron oxide, red (E 172)

Iron oxide, black (E 172)

Valsartan/Hydrochlorothiazide Sandoz 320 mg/ 25 mg:

Hypromellose

Macrogol 4000

Talc

Titanium dioxide (E 171)

Iron oxide, yellow (E 172)

6.2

Incompatibilities

Not applicable.

6.3

Shelf life

Valsartan/Hydrochlorothiazide Sandoz

80 mg/12.5 mg, -160 mg/12.5 mg, -160 mg/25 mg, -320

mg/12.5 mg, -320 mg/25 mg film-coated tablets:

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

Valsartan/Hydrochlorothiazide Sandoz

80 mg/12.5 mg, -160 mg/12.5 mg, -160 mg/25 mg film-

coated tablets:

PVC/PVDC/AL blister packs

PVC/PE/PVDC/AL blister packs

PA/AL/PVC/AL blister packs

Pack sizes: one pack containing 7, 10, 14, 15, 20, 28, 30, 50, 50x1, 56, 60, 84, 90, 98, 100 or 280

film-coated tablets.

Valsartan/Hydrochlorothiazide Sandoz

320 mg/12.5 mg, -320 mg/25 mg film-coated tablets:

PVC/PVDC/AL blister packs

PA/AL/PVC/AL blister packs

Pack sizes: one pack containing 7, 10, 14, 15, 20, 28, 30, 50, 50x1, 56, 60, 84, 90, 98, 100 or 280

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]

8.

MARKETING AUTHORISATION NUMBER(S)

[To be completed nationally]

9.

DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

[To be completed nationally]

10.

DATE OF REVISION OF THE TEXT

2019-01-16

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