natgillin/translations-raw huggingface dataset:
I komparative studier er den første dosis af 2 mg < COVERSYL og øvrige navne > hos patienter med mild til moderat hjerteinsufficiens ikke sat i forbindelse med nogen væsentlig nedsættelse af blodtrykket sammenlignet med placebo.
(See 4.4 Special warnings and special precautions for use, Haemodialysis Patients.) Pacemaker therapy is indicated for therapy-resistant bradycardia.
EMEA/ CPMP/ 32703/ 03 5. 2 Farmakokinetiske egenskaber
EMEA/ CPMP/ 32703/ 03
10/ 12
18/ 20
Efter oral indgift absorberes perindopril hurtigt, og den maksimale koncentration nås inden for 1 time.
5.2 Pharmacokinetic properties After oral administration, the absorption of perindopril is rapid and the peak concentration complete within 1 hour.
Biotilgængeligheden er 65 til 70%.
Bioavailability is 65 to 70%.
20% af den totale mængde absorberet perindopril omdannes til perindoprilat, den aktive metabolit.
About 20% of the total quantity of perindopril absorbed is converted into perindoprilat, the active metabolite.
Eftersom indtagelse af føde nedsætter omdannelsen af perindoprilat og dermed biotilgængeligheden, skal < COVERSYL og øvrige navne > indgives oralt i en enkelt daglig dosis om morgenen før et måltid.
As ingestion of food decreases conversion to perindoprilat, hence bioavailability ,< COVERSYL and associated names > should be administered orally in a single daily dose in the morning before a meal.
0, 2 l/ kg for ubundet perindoprilat.
The volume of distribution is approximately 0.2 l/ kg for unbound perindoprilat.
Proteinbindingen er lille (perindoprilats binding til det angiotensinkonverterende enzym er mindre end 30%), men er koncentrationsafhængig.
Protein binding is slight (binding of perindoprilat to angiotensin converting enzyme is less than 30%), but is concentration-dependent.
3 til 5 timer.
Perindoprilat is eliminated in the urine and the half-life of the unbound fraction is approximately 3 to 5 hours.
Dissociering af perindoprilat bundet til det angiotensinkonverterende enzym bevirker en ” effektiv ” halveringstid for eliminering på 25 timer, der resulterer i steady- state inden for 4 dage.
Dissociation of perindoprilat bound to angiotensin converting enzyme leads to an “ effective” elimination half-life of 25 hours, resulting in steady-state within 4 days.
Eliminering af perindoprilat er nedsat hos ældre patienter samt hos patienter med hjerte - eller nyreinsufficiens.
Elimination of perindoprilat is decreased in the elderly, and also in patients with heart or renal failure.
Dialyseclearance for perindoprilat er lig med 70 ml/ min.
Dialysis clearance of perindoprilat is equal to 70 ml/ min.
Perindoprils kinetik er modificeret hos patienter med cirrhosis: leverclearance for grundmolekylet halveres.
Perindopril kinetics are modified in patients with cirrhosis: hepatic clearance of the parent molecule is reduced by half.
Dog reduceres mængden af dannet perindoprilat ikke, og derfor er dosisjustering ikke påkrævet (se også afsnit 4. 2 ” Dosering og indgivelsesmåde ” og 4. 4 “ Særlige advarsler og forsigtighedsregler vedrørende brugen ”).
However, the quantity of perindoprilat formed is not reduced and therefore no dosage adjustment is required (see also sections 4.2 “ Posology and method of administration” and 4.4 “ Special warnings and special precautions for use”).
5. 3 Prækliniske sikkerhedsdata
EMEA/ CPMP/ 32703/ 03 5.3 Preclinical safety data
Der er ikke observeret nogen mutagenicitet i in vitro - eller in vivo - studier.
No mutagenicity has been observed in in vitro or in vivo studies.
Der er observeret nyrelæsioner og en øget peri - og postnatal mortalitet.
However, angiotensin converting enzyme inhibitors, as a class, have been shown to induce adverse effects on late foetal development, resulting in foetal death and congenital effects in rodents and rabbits: renal lesions and an increase in peri- and postnatal mortality have been observed.
6. 1 Fortegnelse over hjælpestoffer < [udfyldes for det respektive land] >
6.1 List of excipients< [To be implemented nationally] >
6. 2 Uforligeligheder < [udfyldes for det respektive land] >
6.2 Incompatibilities< [To be implemented nationally] >
6. 3 Opbevaringstid < [udfyldes for det respektive land] >
6.3 Shelf life< [To be implemented nationally] >
EMEA/ CPMP/ 32703/ 03 6. 4 Særlige opbevaringsforhold < [udfyldes for det respektive land] >
6.4 Special precautions for storage< [To be implemented nationally] >
6. 5 Emballage (art og indhold) < [udfyldes for det respektive land] >
6.5 Nature and contents of container< [To be implemented nationally] >
6. 6 Eventuelle instruktioner vedrørende anvendelse og håndtering < [udfyldes for det respektive land] >
6.6 Instructions for use and handling< [To be implemented nationally] >
< [Se bilag 1 - udfyldes for det respektive land] >
< [See Annex 1 - to be implemented nationally] >
< [udfyldes for det respektive land] >
< [To be implemented nationally] >
DATO FOR ÆNDRING AF TEKSTEN
DATE OF (PARTIAL) REVISION OF THE TEXT
12/ 12
20/ 20
7. november 2005 CHMP/ 408150/ 2005
7 November 2005 CHMP/ 408150/ 2005
Coversyl og tilknyttede navne indeholder perindopril, en velkendt potent ACE- I- hæmmer (angiotensin (angiotensin converting enzyme), som på nuværende tidspunkt er indiceret til behandling af hypertension og symptomatisk hjerteinsufficiens.
Coversyl and associated names contain perindopril, a well-known, potent angiotensin converting enzyme inhibitor (ACE-I), currently indicated for the treatment of hypertension and symptomatic heart failure.
Denne procedure for indbragte sager henviser til en anmodning om voldgift vedrørende en type II - ændring af en ny indikation med henblik på ” reduktion af risikoen for hjerte- kar- tilfælde hos patienter med stabil koronararteriesygdom ”.
This Referral procedure relates to a request for Arbritation concerning a type II variation for a new indication in the “ reduction of risk of cardiovascular events in patients with stable coronary artery disease”.
1084/ 2003, med ændringer, en sag for CHMP med henblik på voldgift.
At the end of the MRP procedure there was a discrepancy between different MS regarding the wording of the indication that adequately reflects the clinical data submitted by the company, and an official referral for arbitration according to Article 6(12) of Commission Regulation EC No 1084/ 2003, as amended, was notified by the Netherlands to the CHMP on 17.03.2005.
Gonzalo Calvo Rojas blev udpeget som rapportør og dr.
The arbitration procedure was discussed and initiated by the CHMP at its plenary meeting in April 2005, and a Rapporteur (Dr Gonzalo Calvo Rojas) and Co-Rapporteur (Dr.
Gottfried Kreutz som medrapportør.
Gottfried Kreutz) were appointed.
De udpegede spørgsmål vedrørte inddragelsen af en bestemt gruppe af revaskulariserede patienter i den foreslåede indikation, begrundelsen for den gavnlige effekt af perindopril ud over selve reduktionen af myokardieinfarkt og en overordnet begrundelse for den indikation, der gøres gældende, på grundlag af resultaterne af relevant offentliggjort dokumentation om andre ACE- I- hæmmere og de patienter og mål for behandlingen, som skal tages i betragtning, Firmaet besvarede de rejste spørgsmål den 20. maj 2005.
The company responded to these points on 20 May 2005.
I lyset af de samlede data, der var blevet fremlagt, og vurderingsrapporterne fra rapportøren/ medrapportøren vedtog CPMP den 27. juli 2205 en udtalelse, som anbefalede godkendelse af ændringen af markedsføringstilladelsen med henblik på tilføjelsen af følgende nye indikation:
Based on the evaluation of the currently available data and the (Co-)Rapporteurs’ assessment reports, the CHMP adopted an opinion on 27 July 2005 recommending the variation of the Marketing Authorisations for the addition of the following new indication:
Reduktion af risikoen for hjerte- kar- tilfælde hos patienter med tidligere myokardieinfarkt og/ eller revaskulation.
Reduction of risk of cardiac events in patients with a history of myocardial infarction and/ or revascularisation.
De faglige konklusioner findes i bilag II og det ændrede produktresumé i bilag III.
The scientific conclusions are provided in Annex II and the amended Summary of Product Characteristics in Annex III.
7 Westferry Circus, Canary Wharf, London E14 4HB, UK Tel.
The final opinion was converted into a Decision by the European Commission on 7 November 2005.
Medlemsstaternes kompetente myndigheder vil fortsat føre regelmæssigt tilsyn med produktet.
The information given in this document and Annexes reflect only the CHMP Opinion dated 27 July 2005.
FORTEGNELSE OVER LÆGEMIDLERNES NAVNE, LÆGEMIDDELFORMER, STYRKER, INDGIVELSESVEJ, INDEHAVERE AF MARKEDSFØRINGSTILLADELSE I MEDLEMSSTATERNE
LIST OF THE NAMES, PHARMACEUTICAL FORM, STRENGTHS OF THE MEDICINAL PRODUCTS, ROUTE OF ADMINISTRATION, MARKETING AUTHORISATION HOLDERS IN THE MEMBER STATES
1 EMEA 2005
1  EMEA 2005 Marketing Authorisation
Indehaver af
Holder
Lægemiddel- form
Pharmaceutical form
markedføringstilladelse Østrig
Austria
2 EMEA 2005
2  EMEA 2005 Marketing Authorisation
markedføringstilladelse Irland
Ireland
Det Forenede Kongerige
United Kingdom United Kingdom
2 mg
2 mg 4 mg
Tabletter
Tablets Tablets
Oral anvendelse EMEA 2005
3  EMEA 2005 ANNEX II
FAGLIGE KONKLUSIONER OG BEGRUNDELSER FOR ÆNDRINGEN AF PRODUKTRESUMÉET FREMLAGT AF EMEA FAGLIGE KONKLUSIONER
SCIENTIFIC CONCLUSIONS AND GROUNDS FOR AMENDMENT OF THE SUMMARY OF PRODUCT CHARACTERISTICS PRESENTED BY THE EMEA SCIENTIFIC CONCLUSIONS
Coversyl og tilknyttede navne indeholder perindopril, en velkendt hæmmer af Angiotensin Converting Enzyme (ACE- hæmmer), der markedsføres i hele EU, bl. a. siden 1988 i Frankrig under navnet Coversyl 2 og 4 mg, foruden i flere end 10 andre lande verden over, herunder USA og Japan.
Coversyl and associated names contain perindopril, a well-known, potent angiotensin converting enzyme inhibitor (ACE-I), marketed in France as Coversyl 2 and 4 mg since 1988, the entire European Union, and world-wide in more than 10 countries including USA and Japan.
Baggrundsoplysninger om type II- ændringen via den gensidige anerkendelsesprocedure I den første dokumentation for ansøgningen om type II- ændringen, der blev indgivet under den gensidige anerkendelsesprocedure (FR/ H/ 246/ 01- 02/ 001), påberåbte ansøgeren sig følgende indikation:
Background information on the type II variation through the MRP In the initial type II variation dossier submitted by MRP (FR/ H/ 246/ 01-02/ 001), the applicant claimed the following indication: “ Stable coronary artery disease:
Reduktion af risiko for kardiovaskulære hændelser hos patienter med stabil koronararteriesygdom. "
Reduction of risk of cardiovascular events in patients with stable coronary artery disease”.
Denne ordlyd byggede på den signifikante relative risikoreduktion (RRR) på 20% (95% SI [9, 4; 28, 6] p=0, 0003) som i EUROPA- undersøgelsen blev iagttaget for det primære kombinerede endepunkt kardiovaskulær dødelighed, ikke- dødeligt myokardieinfarkt (MI) og hjertestop med vellykket genoplivning.
This wording was based on a significant relative risk reduction (RRR) of 20% (95% CI [9.4; 28.6] p=0.0003) in the primary combined endpoint of cardiovascular mortality, non-fatal myocardial infarction (MI) or cardiac arrest with successful resuscitation observed in the EUROPA study.
Der sås en gavnlig virkning af perindopril for hver enkelt delkomponent i det primære kombinerede endepunkt, dog var risikoreduktionen kun signifikant for "ikke- dødelig MI."
A beneficial effect of perindopril was observed for all individual subcomponents of the primary combined endpoint, although only the risk reduction in “ non-fatal MI” reached statistical significance.
I den endelige vurderingsrapport (dateret den 14. 2. 2005) blev den af referencemedlemsstaten foreslåede indikation begrænset til "Reduktion af risiko for recidiv af MI hos patienter med tidligere MI" i betragtning af, at risikoreduktion kun var påvist for komponenten "ikke dødelig MI" i det primære endepunkt, og at virkningen af perindopril kun var klart godtgjort hos patienter med tidligere MI.
In the Final Assessment report (dated on 14.02.2005), the indication proposed by the RMS was restricted to “ Reduction of risk of recurrent MI in patients with a history of MI” considering that the risk reduction was only demonstrated on the “ non fatal MI” component of the primary endpoint and that the effect of perindopril was only clearly established in patients with previous MI.
"Stabil koronararteriesygdom:
The applicant subsequently sent on 23.02.2005 a Position Paper to all MS stating that the indication proposed by the RMS was not acceptable, and that a broader indication reflecting the study population should be approved, namely: “ Stable coronary artery disease:
Reduktion af risiko for kardiale hændelser hos patienter med tidligere myokardieinfarkt og/ eller revaskularisering. "
Reduction of risk of cardiac events in patients with a history of myocardial infarction and/ or revascularisation”.
Ved afslutningen af den gensidige anerkendelsesprocedure havde de berørte medlemsstater anvendt forskellig ordlyd af den indikation, der skulle afspejle oplysningerne fra EUROPA- undersøgelsen.
At the end of the MRP procedure there was a discrepancy between CMS regarding the wording of the indication that adequately reflects the EUROPA data.
Nederlandene indbragte officielt en sag med henblik på voldgift for CHMP den 17. 3. 2005.
An official referral for arbitration was notified by the Netherlands to the CHMP on 17.03.2005.
1. - Ud fra resultaterne af EUROPA- undersøgelsen og relevante publicerede artikler om andre ACE - hæmmere bør ansøgeren begrunde den foreslåede indikation med hensyn til, hvilke patienter der skal indgå, og behandlingens formål.
1. - The Applicant should justify the proposed indication based on the results of the EUROPA trial and relevant published literature on other ACE-Is in terms of patients to be included and goals of therapy.
2. - Det andet punkt vedrører, hvorvidt den gavnlige virkning ud over den blotte reduktion i myokardieinfarkt kan tænkes at strække sig til en reduktion af kardiale hændelser.
2. - The second issue addresses the question whether the beneficial effect may extend beyond a mere reduction of MI to a reduction of cardiac events.
Det bemærkedes, at der var konsistens mellem de forskellige komponenter i det primære endepunkt, selv om der kun var signifikans for beskyttelse mod MI.
Consistency was noted between the various components of the primary endpoint although significance was only reached for prevention of MI.
Der bemærkedes en signifikant virkning på forekomsten af hjerteinsufficiens.
A significant effect was noted on the occurrence of heart failure.
5 EMEA 2005 Vurdering af klinisk virkning Den omhandlede indikation bygger på resultaterne af EUROPA- undersøgelsen, hvis formål var at vurdere Perindoprils evne til at mindske risikoen for det kombinerede endepunkt, der bestod af kardiovaskulære dødsfald, ikke- dødeligt akut MI og hjertestop med vellykket genoplivning, hos patienter med stabil koronar hjertesygdom uden tegn på hjerteinsufficiens.
5  EMEA 2005 Evaluation of Clinical Efficacy The indication under review is based on the results of the EUROPA study, a trial designed to evaluate the ability of Perindopril to reduce the risk of the combined endpoint of cardiovascular death, non-fatal acute MI and cardiac arrest with successful resuscitation in patients with stable coronary heart disease, without evidence of heart failure.
Denne gavnlige virkning var statistisk signifikant for ikke- dødeligt MI, den ene komponent i det kombinerede endepunkt.
This benefit was statistically significant for non-fatal MI, one of the components of the combined endpoint.
For de andre to komponenter sås en ikke- signifikant gunstig tendens.
A non-statistically significant favourable trend was observed in the other two components.
Ansøgeren blev derfor anmodet om at gennemgå dette punkt med henblik på at begrunde medtagelsen af denne særlige gruppe af patienter i den foreslåede indikation.
As it was expected that the subgroup of patients with a history of revascularisation but with no history of MI was heterogeneous in terms of severity of lesions, revascularisation technique and concomitant treatments, the Applicant was asked to address this issue in order to justify the inclusion of this specific group of patients in the proposed indication.
Firmaet har fremlagt oplysninger, der viser, at denne patientgruppe ikke er så uensartet, men i vidt omfang svarer til hele populationen i EUROPA- undersøgelsen, i hvert fald hvad angår revaskulariseringsteknik og ledsagende behandling.
The Company has provided data showing that this population is not so heterogeneous but quite similar to the whole population included in EUROPE study, at least in terms of revascularisation techniques and concomitant treatments.
Den højere procentdel af patienter med en forsnævring på mindst 70% af en eller flere større arterier (82, 4% mod 60, 5%) måtte forventes at afspejle svære koronarforandringer hos gruppen af patienter med tidligere revaskularisering og uden tidligere MI.
60.5%) would reflect serious coronary lesions in the group of patients with a history of revascularisation and with no history of MI.
Ansøgeren blev desuden anmodet om at begrunde indikationen ud fra resultater fra relevant litteratur vedrørende andre ACE- hæmmere, dels hvad angår de patienter, der skal indgå, dels behandlingens formål.
The Applicant was also requested to justify the indication based on the results of relevant published literature on other ACE-Is in terms of patients to be included and goals of therapy.
Resultaterne af HOPE - og PEACE- undersøgelserne synes at underbygge den gavnlige virkning af perindopril, der er iagttaget i EUROPA- undersøgelsen for patienter med middelhøj til høj risiko for kardiale hændelser.
The results of the HOPE and PEACE trials seem to support the beneficial effect of perindopril observed in the EUROPA study for patients with medium to high risk of cardiac events.
Ansøgeren blev desuden anmodet om at begrunde Perindoprils gavnlige virkning ud over den blotte reduktion af MI.
The Applicant was also requested to justify the beneficial effect of Perindopril beyond a mere reduction of MI.
Der blev ikke påvist statistisk signifikant gavnlig virkning for to af de tre komponenter i det sammensatte endepunkt på grund af det mindre antal forekomster, dog var der en positiv tendens i perindoprils favør.
Although a statistically significant benefit was not shown for two of the three components of the composite endpoint due to the smaller number of occurrences, a positive tendency in favour of perindopril was observed.
CHMP finder ikke, at den manglende signifikante forskel for to af de tre komponenter af det sammensatte endepunkt i EUROPA- undersøgelsen giver grund til at begrænse indikationen til en enkelt komponent, eftersom der ses en positiv og fuldstændig konsistent tendens for disse to komponenter.
The CHMP believes that the lack of a statistically significant difference for two of the three components of the composite endpoint in the EUROPA study is not a reason to restrict the indication to a single component, given that a positive and fully consistent trend for these two components is observed.
Da der er vist yderligere konsistens for de sekundære variabler, er det rimeligt at udvide indikationen fra "reduktion af MI" til "reduktion af kardiale hændelser", et begreb, der indbefatter patienter med tidligere MI og/ eller tidligere revaskularisering.
As further consistency is shown for the secondary variables, it is reasonable to extend the indication from “ reduction of MI” to “ reduction of cardiac events”, a term that includes patients with a history of MI and/ or a history of revascularisation.
Denne ordlyd vil være på linje med CHMP' s generelle politik for produkter, hvis virkning evalueres ved hjælp af sammensatte endepunkter.
This wording would be in line with the general CHMP policy regarding products using composite endpoints for evaluation of efficacy.
På baggrund af ovenstående konkluderer CHMP, at den ansøgte indikation for Coversyl "Stabil koronararteriesygdom:
In the light of the above the CHMP concludes that the proposed indication for Coversyl “ Stable coronary artery disease:
Reduktion af risiko for kardiale hændelser hos patienter med tidligere myokardieinfarkt og/ eller revaskularisering "er tilstrækkeligt underbygget af de forelagte oplysninger.
Reduction of risk of cardiac events in patients with a history of myocardial infarction and/ or revascularisation” is adequately supported by the information provided.
Samlet konklusion vedrørende benefit/ risk- forhold
Overall conclusion on benefit/ risk
På sit møde den 25. - 28. juli 2005 behandlede CHMP de af indehaverne af markedsføringstilladelsen fremlagte oplysninger, og konkluderede, at det var godtgjort, at Coversyl og tilknyttede navne var effektivt til reduktion af risiko for kardiale hændelser hos patienter med stabil koronararteriesygdom og tidligere myokardieinfarkt og/ eller revaskularisering.
At its meeting of 25-28 July 2005, the CHMP considered the data on efficacy presented by the MAHs and concluded that it had been shown that Coversyl and associated names was effective in the reduction of risk of cardiac events in patients with stable coronary artery disease with a history of myocardial infarction and/ or revascularisation.
6 EMEA 2005 CHMP anbefalede godkendelse af type II- ændringen med den udvidede indikation.
The CHMP recommended the granting of the type II variation to extend the indication.
7 EMEA 2005 BEGRUNDELSE FOR ÆNDRINGEN AF PRODUKTRESUMÉET
6  EMEA 2005 GROUNDS FOR AMENDMENT OF THE SUMMARY OF PRODUCT CHARACTERISTICS
"Stabil koronararteriesygdom:
Whereas, • the CHMP considered the referral made under article 6.12 of Commission Regulation (EC) No 1084/ 2003, for Coversyl and associated names (see Annex I), • The MAH has implemented the text proposed by the CHMP in the SPC: • It is proposed to add the following indication in section 4.1: “ Stable coronary artery disease:
Reduktion af risiko for kardiale hændelser hos patienter med tidligere myokardieinfarkt og/ eller revaskularisering. "
Reduction of risk of cardiac events in patients with a history of myocardial infarction and/ or revascularisation .”
• Doseringsanvisningen i afsnit 4. 2 er ajourført således:
• The posology in Section 4.2 has been updated as follows:
Til ældre patienter anvendes en dosering på 2 mg én gang dagligt i én uge, stigende til 4 mg én gang dagligt den følgende uge, før doseringen øges til 8 mg én gang dagligt, afhængigt af nyrefunktionen (se tabel 1 "Dosisjustering ved nyrefunktionsnedsættelse").
Elderly patients should receive 2 mg once daily for one week, then 4 mg once daily the next week, before increasing the dose up to 8 mg once daily depending on renal function (see Table 1 “ Dosage adjustment in renal impairment”).
• Der er indsat en advarsel i afsnit 4. 4:
• A warning has been introduced in Section 4.4:
Hvis der inden for den første måned af perindopril- behandlingen optræder en episode med ustabil angina pectoris (uanset om den er alvorlig), bør benefit/ risk- forholdet nøje vurderes, før behandlingen fortsættes.
If an episode of unstable angina pectoris (major or not) occurs during the first month of perindopril treatment, a careful appraisal of the benefit/ risk should be performed before treatment continuation.
• Følgende beskrivelse af de iagttagne bivirkninger er tilføjet i afsnit 4. 8:
• The following description of the observed side-effects has been added in Section 4.8:
Kliniske undersøgelser:
Clinical trials:
I den randomiserede periode af EUROPA- undersøgelsen er kun oplysninger om alvorlige bivirkninger blevet indsamlet.
During the randomised period of the EUROPA study, only serious adverse events were collected.
Alvorlige bivirkninger optrådte hos få patienter:
Few patients experienced serious adverse events:
16 (0, 3%) af de 6 122 perindopril- patienter og 12 (0, 2%) af de 6 107 placebo- patienter.
16 (0.3%) of the 6122 perindopril patients and 12 (0.2%) of the 6107 placebo patients.