natgillin/translations-raw huggingface dataset:
Kritisk vurdering CHMP har vurderet en række områder, hvor der fandtes uoverensstemmelser i produktinformationen for Diovan, og en revideret produktinformation blev vedtaget.
Critical Evaluation A number of areas of disharmony in the product information for Diovan have been evaluated by the CHMP and a revised PI was adopted.
4. 1 - Terapeutiske indikationer
4.1 - Therapeutic Indications
Den foreslåede harmoniserede tekst for dette afsnit kan accepteres af størstedelen af CHMP' s medlemmer for denne indikation, hvorfor følgende formulering blev vedtaget:
The proposed harmonized text for this section is acceptable by the majority of CHMP members in regard to this indication; therefore the following wording was adopted:
"Behandling af essentiel hypertension"
“ Treatment of essential hypertension”
Med hensyn til indikationen ved nyligt myokardieinfarkt bemærkede CHMP, at denne indikation i nogle medlemsstater var begrænset til patienter, der er intolerante over for ACE- hæmmere.
Regarding the indication in recent myocardial infarction the CHMP noted that this indication was limited to patients intolerants to ACE inhibitors in some Member States.
CHMP mente, at VALIANT- undersøgelsen, der viste, at valsartan givet som monoterapi er mindst lige så effektiv som captopril givet som monoterapi til nedbringelse af dødeligheden efter akut myokardieinfarkt.
The CHMP considered the VALIANT study which demonstrated that valsartan given as monotherapy is at least as effective as captopril given as monotherapy in the reduction of total mortality after an acute myocardial infarction.
På grund af valsartans non- inferioritet i kliniske resultater sammenlignet med den aktuelle standardbehandling, en ACE- hæmmer, vedtog CHMP følgende harmoniserede formulering for denne indikation:
Considering the non inferiority in clinical outcome of valsartan compared to current standard treatment, an ACEI, the CHMP adopted the following harmonised wording for this indication:
"Behandling af klinisk stabile patienter med symptomatisk hjerteinsufficiens eller asymptomatisk systolisk dysfunktion i venstre ventrikel efter en nylig (12 timer – 10 dage) myokardieinfarkt"
“ Treatment of clinically stable patients with symptomatic heart failure or asymptomatic left ventricular systolic dysfunction after a recent (12 hours – 10 days) myocardial infarction”
Valsartan nedbragte risikoen i tilknytning til den første patologiske hændelse, dødeligheden, det samlede antal indlæggelser med hjertesvigt.
The therapeutic indication for heart failure is supported primarily by a large long-term morbidity trial Valsartan Heart Failure Trial (Val-HeFT) Valsartan reduced the risk related to first morbid event, mortality, the total number of Heart Failure (HF) hospitalizations.
"Behandling af symptomatisk hjertesvigt, når ACE- hæmmere (Angiotensin Converting Enzyme) ikke kan anvendes, eller som supplerende behandling til ACE- hæmmere, når betablokkere ikke kan anvendes"
“ Treatment of symptomatic heart failure when Angiotensin Converting Enzyme (ACE) inhibitors could not be used, or as add-on therapy to ACE inhibitors when beta blockers could not be used”
4. 2 - Dosering
4.2 - Posology
Det første område, hvor der findes uoverensstemmelser, er anvendelsen af den tredobbelte kombination (Valsartan + ACE- hæmmer + betablokker) ved kronisk hjertesvigt.
The first area of disagreement is about the use of triple combination (Valsartan + ACEI+ BB) in chronic HF.
Doseringsplanen for den terapeutiske anvendelse af valsartan ved hjertesvigt var baseret på Val- HeFT - undersøgelsen.
The dosing schedule for the therapeutic use of valsartan in heart failure was based on the Val-HeFT study.
Derudover viste VALIANT- undersøgelsen, at dødeligheden ikke steg hos patienter, der modtog den tredobbelte kombination.
In addition the VALIANT study demonstrated that mortality was not increased in patients receiving the triple combination.
Derfor er den potentielle anvendelse af den tredobbelte
Therefore in the situation of potential use of the triple combination
22 kombination i produktresuméet blevet tilpasset, så det fremgår, at forsigtighed (frem for "frarådes") er hensigtsmæssig.
24 the text within the SPC has been adjusted to indicate that caution (rather than “ not recommended”) is appropriate
Efter CHMP' s opfattelse bør formuleringen "frarådes" anvendes, indtil der foreligger et mere fast understøttende risk/ benefit- forhold for den tredobbelte kombination.
In CHMP’ s opinion the wording “ not recommended” should be used until there is more solid supportive benefit/ risk-profile evidence to triple combination.
"Den anbefalede startdosis for Diovan er 40 mg to gange daglig.
Therefore the MAH should address the lack of (additional) clinical benefit and increased adverse events In conclusion; the CHMP adopts the revised text: “ The recommended starting dose of Diovan is 40 mg twice daily.
Forøgelse af dosis til 80 mg og 160 mg to gange daglig bør ske med intervaller på mindst 2 uger til den højeste dosis, patienten kan tåle.
Uptitration to 80 mg and 160 mg twice daily should be done at intervals of at least two weeks to the highest dose, as tolerated by the patient.
Den maksimale daglige dosis, der er indgivet i kliniske undersøgelser, er 320 mg fordelt på flere doser.
The maximum daily dose administered in clinical trials is 320 mg in divided doses.
Valsartan kan gives samtidig med anden behandling for hjertesvigt.
Valsartan may be administered with other heart failure therapies.
Den tredobbelte kombination med en ACE- hæmmer, en betablokker og valsartan frarådes dog (jf. afsnit 4. 4 og 5. 1).
However, the triple combination of an ACE inhibitor, a beta blocker and valsartan is not recommended (see sections 4.4 and 5.1).
Vurderingen af patienter med hjertesvigt bør altid omfatte en vurdering af nyrefunktionen. "
Evaluation of patients with heart failure should always include assessment of renal function .”
Indehaveren af markedsføringstilladelsen accepterede CHMP' s og ordførernes bemærkninger og foreslog, da der ikke fandtes nye data om tredobbelt behandling med valsartan, at indsætte formuleringen "den tredobbelte kombination med en ACE- hæmmer, en betablokker og valsartan frarådes" ved konisk hjertesvigt, som krævet i de relevante afsnit af produktresuméet (afsnit 4. 2 og 4. 4).
Acknowledging the comments from the CHMP and the Rapporteurs and in the absence of any new data regarding triple therapy with valsartan, the MAH proposed to substitute the wording “ the triple combination of an ACE inhibitor, a beta blocker and valsartan is not recommended” in chronic heart failure as requested in the relevant sections of the SPC (sections 4.2 and 4.4).
Indehaveren af markedsføringstilladelsen har accepteret CHMP' s forslag til en formulering.
The CHMP proposed wording has been accepted by the MAH.
I produktresuméets afsnit 4. 2 vedrørende den anbefalede dosering til patienter med nyre - og leverinsufficiens, er der også forskelle mellem medlemsstaterne.
In section 4.2 there are also differences in SPC across Member States in relation to the dosage recommendation in patients with renal and hepatic impairment.
Med hensyn til nyreinsufficiens understøttes brugen af valsartan 80 mg som startdosis uden dosisjustering hos patienter med nedsat nyrefunktion (kreatininclearance > 10 ml/ min) af både data om sikkerhed og effekt fra undersøgelse 27 og af farmakokinetiske data fra undersøgelse 12.
Regarding renal impairment, the use of valsartan 80 mg as the starting dose, with no dosage adjustment, in patients with reduced renal function (creatinine clearance rate > 10 ml/ min) is supported by both efficacy and safety data from Study 27 and by pharmacokinetic data from Study 12.
I undersøgelse 27 blev valsartans kinetik hos patienter med hypertension og nedsat nyrefunktion (kreatininclearance:
In Study 27 the kinetic of valsartan was also investigated in hypertensive patients with impairment of renal function (creatine clearance rate:
16- 116 ml/ min) ligeledes undersøgt.
16-116 mL/ min).
"Der kræves ingen dosisjustering for patienter med en kreatininclearance ≥ 10 ml/ min."
The CHMP considered that the elimination of valsartan at steady-state is similar in patients with renal impairment when compared with healthy volunteers and adopted the following wording: “ No dosage adjustment is required for patients with a creatinine clearance > 10 ml/ min .”
Valsartan undergår ikke nogen omfattende biotransformation, og 70% af den tilgængelige dosis udskilles.
Valsartan does not undergo extensive biotransformation and 70% of the available dose is excreted.
På baggrund af en farmakokinetisk undersøgelse bør dosis af valsartan ikke overstige 80 mg hos disse patienter, og det bør anvendes med forsigtighed.
Based on a pharmacokinetic study, the dose of valsartan should not exceed 80 mg in these patients and should be used with caution.
"Hos patienter med mildt til moderat nedsat leverfunktion uden cholestasis bør valsartan - dosis ikke overstige 80 mg (jf. afsnit 4. 4)."
The wording proposed by the MAH in the SPC was acceptable to the CHMP and the following wording was adopted: “ In patients with mild to moderate hepatic impairment without cholestasis the dose of valsartan should not exceed 80 mg (see section 4.4) .”
4. 3 - Kontraindikationer Der var uenighed om, hvorvidt anvendelsen af Diovan skulle være kontraindiceret hos patienter med nyresvigt.
4.3 - Contraindications There was disagreement on whether the use of Diovan should be contraindicated in patients with renal failure.
Efter vurdering af alle tilgængelige data fandt CHMP, at brugen af valsartan 80 mg som startdosis uden dosisjustering hos patienter med nedsat nyrefunktion (kreatininclearance > 10 ml/ min)
Having assessed the data available, the CHMP considered that the use of valsartan 80 mg as the starting dose, with no dosage adjustment, in patients with reduced renal function (creatinine
23 understøttes af data om både sikkerhed og effekt fra forskellige undersøgelser.
25 clearance rate > 10 ml/ min) is supported by both efficacy and safety data from various studies.
Sikkerheden og tolerabiliteten for valsartan hos patienter med alvorlig nyreinsufficiens (kreatininclearance < 10 ml/ min) blev ikke vurderet i nogen klinisk undersøgelse.
The safety and tolerability of valsartan in patients with severe renal failure (creatinine clearance of < 10 ml/ min) was not evaluated in any clinical study.
CHMP fandt det acceptabelt at fjerne denne kontraindikation, da den primære eliminationsvej for valsartan er biliær, og nyreclearance tegner sig for mindre end 30% af plasmaclearance.
The CHMP considered it acceptable to remove this contraindication, as the primary route of elimination of valsartan is via biliary route and renal clearance accounts for less than 30% of plasma clearance.
Da Diovan elimineres biliært fandt CHMP også, at der skulle fastsættes en kontraindikation for patienter med alvorlige leversygdomme, og at det "ikke bør gives til patienter med alvorlig leverinsufficiens, cirrhose eller biliær obstruktion".
The CHMP also considered that in view of the fact that Diovan is eliminated via the biliary route, it should be contraindicated in patients with severe liver diseases and “ should not be administered in patients with severe hepatic impairment, cirrhosis or biliary obstruction.
"Da der ikke foreligger nogen oplysninger om brugen af valsartan under amning, frarådes Diovan (Valsartan), og alternativ behandling med bedre sikkerhedsprofiler under amning foretrækkes, navnlig ved amning af nyfødte eller for tidligt fødte spædbørn".
With reference to the contraindication for the use of Diovan during pregnancy or lactation, the CHMP in line with the recommendations of the Pharmacovigilance experts considered that the contraindication shall be removed and the following recommendation included in the specific section relevant to pregnancy and lactation as follows: “ Because no information is available regarding the use of valsartan during breastfeeding, Diovan (Valsartan) is not recommended and alternative treatments with better established safety profiles during breast-feeding are preferable, especially while nursing a newborn or preterm infant”.
4. 5 - Interaktion med andre lægemidler og andre former for interaktion
4.5 - Interaction with other medicinal products and other forms of interaction
"Hvis et lægemiddel, der påvirker kaliumindholdet, anses for at være nødvendigt i kombination med valsartan, anbefales overvågning af plasmakaliumniveau".
The CHMP considered the precautions for the concomitant use of other medicinal products containing or raising the level of potassium and adopted the following wording: “ If a medicinal product that affects potassium levels is considered necessary in combination with valsartan, monitoring of potassium plasma levels is advised”.
CHMP fandt også, at der var behov for særlige forsigtighedsregler for patienter med leverinsufficiens og/ eller cholestasis, da størstedelen af valsartan hovedsageligt elimineres som uforandret lægemiddel i galden via leverclearance.
The CHMP also considered that special precaution would be needed for patients with hepatic impairment and/ or cholestasis, as the majority of valsartan is eliminated, mainly as unchanged drug in the bile, by hepatic clearance.
På grundlag af en farmakokinetisk undersøgelse bør valsartan- dosis ikke overstige 80 mg hos disse patienter, og det bør anvendes med forsigtighed.
Based on a pharmacokinetic study, the dose of valsartan should not exceed 80 mg in these patients and should be used with caution.
CHMP var enig i den foreslåede formulering af forsigtighedsreglerne for dosering af Diovan, da der ikke kræves dosisjustering for patienter med en kreatininclearance > 10 ml/ min, og da valsartan- dosis hos patienter med mild til moderat leverinsufficiens uden cholestasis ikke bør overstige 80 mg (jf. afsnit 4. 4).
The CHMP agreed about the proposed wording for precautions in dosing Diovan, considering that no dosage adjustment is required for patients with a creatinine clearance > 10ml/ min and that in patients with mild to moderate hepatic impairment without cholestasis the dose of valsartan should not exceed 80 mg (see section 4.4).
Afsnit 4. 5, 5. 1 og 5. 2 er blevet ajourført for at garantere lægemidlets sikkerhed.
Sessions 4.5, 5.1, and 5.2 have been updated in order to guarantee the safety of the medicine.
"Diovan er ikke blevet undersøgt hos patienter med alvorlig leverdysfunktion".
The following sentence has been added to Section 5.2: “ Diovan has not been studied in patients with severe hepatic dysfunction”.
Der findes ingen data for patienter med en kreatininclearance < 10 ml/ min og patienter i dialysebehandling, og valsartan bør derfor anvendes med forsigtighed hos disse patienter.
In patients with a creatinine clearance < 10 ml/ min and patients undergoing dialysis no data are available, therefore valsartan should be used with caution in these patients.
4. 8 - Bivirkninger
4.8 - Undesirable effect
Indehaveren af markedsføringstilladelsen udarbejdede en enkelt tabel indeholdende alle relevante bivirkninger ved alle tre indikationer: hypertension, post- myokardieinfarkt og CHF.
The MAH created a single table containing all relevant ADRs from all three indications: hypertension, post- MI, and CHF.
CHMP anmodede dog om, at alle indikationerne blev sammenfattet i en enkelt tabel i overensstemmelse med vejledningen vedrørende produktresuméer:
However, the CHMP, requested to summarize all indications in one table, according to the ` Guideline of SPC `.
Indehaveren af markedsføringstilladelsen foreslog, at der blev indsat indikationsspecifikke fodnoter, men CHMP fandt, at den foreslåede omfattende brug af fodnoter har ringe værdi for den ordinerende læge, og bivirkningerne er blevet flyttet til den kategori, der repræsenterer den højeste frekvens (jf. det vedhæftede produktresumé og indlægsseddel).
The MAH proposed to add indication-specific foot-notes, but the CHMP considered that the proposed extensive use of footnotes has little value for the prescriber and ADRs have been moved to the frequency category representing the highest frequency (see attached SPC and PIL).
24 BEGRUNDELSER FOR ÆNDRING AF PRODUKTRESUME, ETIKETTERING OG INDLÆGSSEDDEL
26 GROUNDS FOR AMENDMENT OF THE SUMMARIES OF PRODUCT CHARACTERISTICS, LABELLING AND PACKAGE LEAFLET
- Formålet med indbringelsen af sagen var at harmonisere produktresuméet, etiketteringen og
- the scope of the referral was the harmonisation of the Summaries of Products Characteristics,
indlægssedlen.
labelling and package leaflet.
- Produktresuméet, etiketteringen og indlægssedlen, som indehaveren af markedsføringstilladelsen har
- the Summaries of Products Characteristic, labelling and package leaflet proposed by the Marketing
foreslået, er blevet vurderet på baggrund af den indsendte dokumentation og udvalgets faglige drøftelse -
Authorisation Holders have been assessed based on the documentation submitted and the scientific discussion within the Committee,
anbefaler CHMP en ændring af de( n) markedsføringstilladelse( r), for hvilke( n) produktresuméet, etiketteringen og indlægssedlen fremgår af bilag III for Diovan og tilknyttede navne (se bilag I).
the CHMP has recommended the amendment of the Marketing Authorisation(s) for which the Summary of Product Characteristics, labelling and package leaflet are set out in Annex III for Diovan and associated names (see Annex I).
27 1.
27 ANNEX III
Diovan og tilhørende navne (se bilag I) 40 mg filmovertrukne tabletter Diovan og tilhørende navne (se bilag I) 40 mg kapsler, hårde Diovan og tilhørende navne (se bilag I) 80 mg filmovertrukne tabletter Diovan og tilhørende navne (se bilag I) 80 mg kapsler, hårde Diovan og tilhørende navne (se bilag I) 160 mg filmovertrukne tabletter Diovan og tilhørende navne (se bilag I) 160 mg kapsler, hårde Diovan og tilhørende navne (se bilag I) 320 mg filmovertrukne tabletter [Se Bilag I – Udfyldes nationalt]
Diovan and associated names (see Annex I) 40 mg film-coated tablets Diovan and associated names (see Annex I) 40 mg capsules, hard Diovan and associated names (see Annex I) 80 mg film-coated tablets Diovan and associated names (see Annex I) 80 mg capsules, hard Diovan and associated names (see Annex I) 160 mg film-coated tablets Diovan and associated names (see Annex I) 160 mg capsules, hard Diovan and associated names (see Annex I) 320 mg film-coated tablets [See Annex I – To be completed nationally]
5. 1).
Recent myocardial infarction Treatment of clinically stable patients with symptomatic heart failure or asymptomatic left ventricular systolic dysfunction after a recent (12 hours-10 days) myocardial infarction (see sections 4.4 and 5.1).
4. 4 og 5. 1).
Heart failure Treatment of symptomatic heart failure when Angiotensin Converting Enzyme (ACE) inhibitors cannot be used, or as add-on therapy to ACE inhibitors when beta blockers cannot be used (see sections 4.4 and 5.1).
28 Hypertension Behandling af essentiel hypertension.
30 Hypertension Treatment of essential hypertension.
Nyligt myokardieinfarkt Til klinisk stabile patienter kan behandling initieres helt ned til 12 timer efter et myokardieinfarkt.
Recent myocardial infarction In clinically stable patients, therapy may be initiated as early as 12 hours after a myocardial infarction.
Valsartan kan anvendes af patienter, som er i anden behandling for post- myokardieinfarkt, f. eks. trombolytika, acetylsalicylsyre, betablokkere, statiner og diuretika.
Valsartan may be used in patients treated with other post-myocardial infarction therapies, e. g. thrombolytics, acetylsalicylic acid, beta blockers, statins, and diuretics.
5. 1).
The combination with ACE inhibitors is not recommended (see sections 4.4 and 5.1).
Evaluering af patienter med post- myokardieinfarkt bør altid inkludere vurdering af nyrefunktionen.
Evaluation of post-myocardial infarction patients should always include assessment of renal function.
Hjertesvigt Den anbefalede startdosis af Diovan er 40 mg 2 gange daglig.
Heart failure The recommended starting dose of Diovan is 40 mg twice daily.
Det bør overvejes at reducere dosis af samtidigt administreret diuretika.
Consideration should be given to reducing the dose of concomitant diuretics.
5. 1).
However, the triple combination of an ACE inhibitor, a beta blocker and valsartan is not recommended (see sections 4.4 and 5.1).
Hypertension Den anbefalede startdosis af Diovan er 80 mg en gang daglig.
Hypertension The recommended starting dose of Diovan is 80 mg once daily.
Hos nogle patienter, hvis blodtryk ikke er tilstrækkeligt kontrolleret, kan dosis øges til 160 mg og til maksimalt 320 mg.
In some patients whose blood pressure is not adequately controlled, the dose can be increased to 160 mg and to a maximum of 320 mg.
Diovan kan også administreres sammen med andre antihypertensive lægemidler.
Diovan may also be administered with other antihypertensive agents.
Ved tilføjelse af et diuretikum som f. eks. hydrochlorthiazid vil blodtrykket falde yderligere hos disse patienter.
The addition of a diuretic such as hydrochlorothiazide will decrease blood pressure even further in these patients.
Optitrering til 80 mg og 160 mg 2 gange daglig skal foretages med intervaller på mindst to uger til højeste dosis, som tolereres af patienten.
Uptitration to 80 mg and 160 mg twice daily should be done at intervals of at least two weeks to the highest dose, as tolerated by the
29 Valsartan kan administreres med andre hjertesvigtsbehandlinger.
Valsartan may be administered with other heart failure therapies.
Hypertension.
Hypertension.
Hos nogle patienter, hvis blodtryk ikke er tilstrækkelig kontrolleret, kan dosis øges til 160 mg og til maksimalt 320 mg.
In some patients whose blood pressure is not adequately controlled, the dose can be increased to 160 mg and to a maximum of 320 mg.
4. 4 og 5. 2).
Renal impairment No dosage adjustment is required for patients with a creatinine clearance > 10 ml/ min (see sections 4.4 and 5.2)
Nedsat leverfunktion Hos patienter med let til moderat leverinsufficiens uden cholestasis bør dosis af valsartan ikke overskride 80 mg.
Hepatic impairment In patients with mild to moderate hepatic impairment without cholestasis, the dose of valsartan should not exceed 80 mg.
4. 3, 4. 4 og 5. 2).
Diovan is contraindicated in patients with severe hepatic impairment and in patients with cholestasis (see sections 4.3, 4.4 and 5.2).
Pædiatriske patienter Diovan bør ikke anvendes til børn under 18 år pga. manglende dokumentation for sikkerhed og virkning.
Paediatric patients Diovan is not recommended for use in children below the age of 18 years due to a lack of data on safety and efficacy.
- Alvorlig leverinsufficiens, biliær cirrose og cholestasis.
-Hypersensitivity to the active substance or to any of the excipients. -Severe hepatic impairment, biliary cirrhosis and cholestasis. -Second and third trimester of pregnancy (see sections 4.4 and 4.6).
- Andet og tredje trimester af graviditet (se pkt.
4.4 Special warnings and precautions for use
Samtidig brug af kaliumtilskud, kaliumbesparende diuretika, salterstatninger indeholdende kalium eller andre produkter, som kan øge kaliumniveauet (heparin o. lign.) kan ikke anbefales.
Hyperkalaemia 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.
Patienter med natrium - og/ eller væskemangel Symptomatisk hypotension kan i sjældne tilfælde opstå efter påbegyndt behandling med Diovan hos patienter med alvorlig natrium - og/ eller væskemangel, såsom de, der får høje doser af diuretika.
Sodium- and/ or volume-depleted patients 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.
Natrium - og/ eller væskemangel bør derfor korrigeres før behandlingsstart med Diovan som for eksempel ved reduktion af diuretikadosis.
Sodium and/ or volume depletion should be corrected before starting treatment with Diovan, for example by reducing the diuretic dose.