natgillin/translations-raw huggingface dataset:
Blandt andre risikominimeringsaktiviteter, der blev foreslået af markedsføringstilladelsesindehaveren, var, at ordinationsretten begrænses til læger med erfaring i behandling af sjældne mykotiske hudsygdomme og sjældne undergrupper af almindelige mykoser. 
Amongst other risk minimisation activities proposed by the MAH were the restriction of prescribing by physicians experienced in treating rare fungal skin disease and rare sub-sets of common fungal disease, Limitation of the use: short treatment periods and treatment of susceptible infecting pathogens only (Candida) and enhanced communication on the risks.
Der blev indhentet yderligere ekspertrådgivning fra en ad hoc-ekspertgruppe. 
Additional expert advice was sought from an ad-hoc expert group.
Der er desuden kommet nye resultater fra CRYSTAL. 
New results from CRYSTAL have also become available.
Der skal imidlertid gennemføres supplerende foranstaltninger til at minimere de potentielle risici for sådanne patienter. 
However additional measures must be implemented to minimise potential risks in these patients.
Benefit/risk-forhold 
Benefit risk balance
I henhold til EU-lovgivningen kræver sådanne handlinger, at der foretages en EUgennemgangsprocedure. 
In accordance with the EU legislation, this type of action required that an EU review procedure be carried out.
Mens den fornyede gennemgang foregik, besluttede medlemsstaterne at suspendere eller begrænse markedsføringen eller anvendelsen af disse lægemidler på deres områder. 
While the re-examination was ongoing some Member States decided to suspend or limit the marketing or use of these medicines in their territories.
Opløsninger af HES har været omfattet af to gennemgange. 
HES solutions have been the object of two reviews.
Protokollerne for og resultaterne af disse undersøgelser skal forelægges de nationale kompetente myndigheder i henhold til aftalte tidsfrister. 
Protocols and results of these studies will be submitted to national competent authorities according to agreed timelines.
Dette er betinget af begrænsninger, advarsler og andre ændringer i produktinformationen, 
This is subject to restrictions, warnings and other changes to the product information.
Detaljer vedrørende denne anbefaling fremgår af nedenstående. 
Details of this recommendation are presented hereafter.
Skønt 90-dages dødeligheden var lavere hos de patienter, der fik kolloider, kræver dette yderligere undersøgelser. 
Although 90-day mortality was lower among patients receiving colloids, this requires further investigations.
Der anbefales overvågning af nyrefunktionen i mindst 90 dage. 
Monitoring of renal function in patients is recommended for at least 90 days.
CMDh afgjorde følgelig, at der ikke behøvedes en synopsis inden den anbefalede videnskabelige rådgivning. 
Consequently the CMDh decided that synopsis were not required in advance of the recommended scientific advice.
Desuden skal udføres en undersøgelse af lægemiddelanvendelse i Europa til vurdering af effektiviteten af de anbefalede risikominimeringsforanstaltninger. 
An European drug utilisation study will also be conducted to evaluate the effectiveness of the recommended risk minimisation measures.
Produktoplysningerne skal ajourføres med disse begrænsninger og advarsler. 
The product information will be updated to reflect these restrictions and warnings.
Virksomhederne var blevet opfordret til at forelægge hovedelementerne i risikostyringsplanen, men CMDh fandt, at dette burde være en betingelse. 
Companies had been encouraged to submit core elements of the risk management plan, but the CMDh considered that this should be a condition.
Indehaverne af markedsføringstilladelserne opfordres desuden til at forelægge risikohåndteringsplaner for de nationale kompetente myndigheder. 
The MAHs are also encouraged to submit risk management plans to national competent authorities.
PRAC fremsatte i juni 2013 en anbefaling om de foreliggende data med henblik på denne gennemgang og konkluderede, at opløsninger indeholdende HES bør suspenderes til alle patientpopulationer. 
The PRAC issued a recommendation on available data for this review in June 2013, concluding that HES solutions should be suspended in all patient populations.
I betragtning af ovenstående og af, at protokollerne for undersøgelsen af lægemiddelanvendelse og for de to randomiserede kliniske undersøgelser er betingelser for markedsføringstilladelsen, bemærkede CMDh, at disse elementer skulle afspejles i en risikostyringsplan. 
In view of the above and considering that the study protocols of the drug utilisation study and of the two randomised clinical trials are conditions to the marketing authorisation, the CMDh noted that these elements should be reflected in a risk management plan.
Samlet resumé af PRAC's videnskabelige vurdering af lægemidler indeholdende opløsninger af hydroxyethylstivelse til infusion 
Overall summary of the scientific evaluation of solutions for infusion containing hydroxyethyl starch medicinal products by PRAC
Opløsninger af hydroxyethylstivelse (HES) til infusion er produkter med stivelse udvundet af kartofler eller majs med forskellige molekylvægte og substitutionsforhold. 
Hydroxyethyl starch (HES) solutions for infusion include products with starch derived from potato or corn with different molecular weights and substitution ratios.
Opløsninger indeholdende HES til infusion var hovedsagelig indiceret til behandling og forebyggelse af hypovolæmi og hypovolæmisk shock. 
HES containing solutions for infusion were indicated mainly for the treatment and prophylaxis of hypovolaemia and hypovolemic shock.
• PRAC konkluderede endvidere, at der behøves yderligere risikominimeringsforanstaltninger såsom information til patienter og sundhedspersoner. 
• The PRAC also concluded that there was need for further risk minimisation measures such as information to patients and healthcare professionals.
Hos hypovolæmiske patienter med normal lungefunktion kan anvendelse af kolloider til opretholdelse af det kolloidosmotiske tryk begrænse udviklingen af såvel perifert ødem som lungeødem (Vincent, JL, 2000). 
In hypovolaemic patients with normal pulmonary function, the use of colloids to maintain colloid-osmotic pressure may limit the development of peripheral as well as pulmonary oedema (Vincent JL 2000).
Efter at have gennemgået PRAC's anbefaling tilsluttede CMDh (koordinationsgruppen vedrørende gensidig anerkendelse og decentraliserede procedurer (human)) sig de overordnede videnskabelige konklusioner og begrundelsen for anbefalingen. 
Having reviewed the PRAC recommendation, the CMDh agreed with the overall scientific conclusions and grounds for recommendation.
Efter anmodninger om fornyet gennemgang fra indehaverne af markedsføringstilladelse fastholdt PRAC i oktober 2013 sit tidligere standpunkt i henhold til artikel 31. 
Following requests for re-examination by marketing authorisation holders (MAHs), the PRAC confirmed its previous position under the Article 31 in October 2013.
Nogle publikationer tyder desuden på, at kolloider kan medvirke til at undgå positiv væskebalance og/eller overinfusion af væsker (Wills, 2005, Naing, CM og Win, DK, 2010). 
Some publications also suggest that colloids might help to prevent positive fluid balance and/or overinfusion of fluids (Wills 2005, Naing CM and Win DK 2010).
Hamaji et al., 2013, viste ligeledes, at der krævedes væsentligt færre transfusioner af erytrocytter i HES-gruppen. 
Hamaji et al 2013 also showed that significantly fewer red blood cell transfusions were required in the HES group.
• PRAC tog konklusionerne af en gennemgang i henhold til artikel 31 i direktiv 2001/83/EF til efterretning. 
• The PRAC noted the conclusions of a review under article 31 of Directive 2001/83/EC.
Nogle af forfatterne hævder, at en positiv nettovæskebalance er forbundet med nedsat organperfusion og øget dødelighed (f.eks. Sadaka, F., et al., 2013, Payen, D., et al., 2008). 
Some of authors argue that a positive net fluid balance is associated with a decrease in organ perfusion and an increased mortality (e.g. Sadaka F et al. 2013, Payen D et al. 2008).
Den første blev oprindeligt iværksat i rammerne af artikel 31 i direktiv 2001/83/EF. 
The first review was initially started under the framework of Article 31 of Directive 2001/83/EC.
Der er også set nogen gavnlig virkning hos elektive operationspatienter i form af kortsigtede hæmodynamiske surrogatudfald sammen med en beskeden volumenbesparende virkning (Hartog et al. 2011). 
Some benefit for elective surgical patients has also been shown in short-term surrogate hemodynamic outcomes along with a modest volume sparing effect (Hartog et al. 2011).
CMDh ændrede fristen for indsendelse af protokollen til undersøgelsen af lægemiddelanvendelse til også at være 6 måneder fra Europa-Kommissionens beslutning, således at indsendelsesdatoerne er ensrettet for alle betingelserne. 
The CMDh amended the due date for the submission of the protocol of the drug utilisation study which is now also due within 6 months of the European Commission Decision in order to harmonise submission dates of all conditions.
Der blev vedtaget hovedelementer i en direkte henvendelse til sundhedspersoner, ligesom en tidsplan for udsendelsen samt udførelse af undersøgelser. 
Core elements of a direct healthcare professional communication were agreed, together with the timelines for distribution, and that studies should be conducted.
Desuden var der i BaSES-undersøgelsen væsentligt kortere indlæggelsestid ved behandling med 6 % HES 130/0,4 end med 0,9 % natriumchlorid. 
In addition, in the BaSES study, the hospitalisation time was significantly reduced in patients treated with 6% HES 130/0.4 compared to 0.9% NaCl.
Indehaverne af markedsføringstilladelse blev stærkt tilrådet at søge videnskabelig rådgivning herom hos Det Europæiske Lægemiddelagentur i tide før indsendelse af undersøgelsernes protokoller til de nationale kompetente myndigheder inden for seks måneder efter Europa-Kommissionens beslutning. 
To this end the MAHs were strongly advised to seek scientific advice with the European Medicines Agency, in time for the submission of the study protocols to the national competent authorities (NCAs) within 6 months of the European Commission Decision.
Særlig forsigtighed bør udvises ved behandling af patienter med nedsat leverfunktion eller koagulationsforstyrrelser. 
Particular caution should be exercised when treating patients with impaired hepatic function or in patients with blood coagulation disorders.
Detaljeret begrundelse for afvigelserne fra PRAC's anbefaling 
Detailed explanation for the differences from the PRAC recommendation
Eksperterne pegede på, at fordelene ved hydroxyethylstivelse muligvis navnlig ses ved perioperativ blødning. 
The experts suggested that benefit of HES may be seen in particular in perioperative bleeding.
Skønt de mekanismer, der medfører øget nyreskade og dødelighed, ikke er velbeskrevet, er det muligt, at det iagttagne omfang af inflammatoriske processer hos sepsispatienter og kritisk syge patienter er større og er forbundet med betydelig kapillærutæthed sammenlignet med andre patientpopulationer såsom patienter i det perioperative forløb ved elektive operationer eller patienter med ukomplicerede traumer, hvor den systemiske inflammatoriske proces og omfanget af kapillærutætheden kan være mindre. 
Although the mechanisms by which increased renal injury and mortality occur is not well established, it is possible that the degree of inflammatory processes seen in sepsis and critically ill patients is greater and associated with significant capillary leakage compared with other patient populations such as the perioperative setting after elective surgery or un-complicated trauma where the systematic inflammatory process and the extent of capillary leak may be lower.
PRAC noterede sig begrænsningerne i disse undersøgelser, herunder deres begrænsede størrelse og kortvarige opfølgningsperiode, men bemærkede, at der var beskrevet nogen volumenbesparende virkning i MadiJebara et al. 2008, der tydede på, at HES 130/0,4 6 % synes at have fordele frem for det dobbelte volumen Ringers laktat til forebyggelse af hypotension fremkaldt af spinalanæstesi. 
Whilst recognising the limitations of these studies which included limited size and short duration of follow-up, the PRAC noted that some volume sparing effect was reported in Madi-Jebara et al. 2008, that suggested that HES 130/0.4 6% seems to have benefits over twice the volume of Ringer's lactate in preventing spinal anaesthesia induced hypotension.
Der er desuden tilføjet særlige advarsler vedrørende operationspatienter og traumepatienter, 
In addition, special warnings in surgery and trauma patients have been included.
Det er på grundlag af alle foreliggende data, herunder den nye evidens, at PRAC fremsatte sin konklusion om proceduren i oktober 2013, der er fastlagt ved artikel 107i af direktiv 2001/83/EF. 
It is on the basis of the totality of the data available, including the new evidence, that the PRAC issued conclusion on the procedure provided for in Article 107i of Directive 2001/83/EC in October 2013.
PRAC anerkendte derfor resultaterne af disse undersøgelser, der ikke viser dødelighedsrisiko forbundet med anvendelse af hydroxyethylstivelse, men fandt, at denne undersøgelse i betragtning af sine begrænsninger ikke kunne tilsidesætte resultaterne af 6S- og VISEP-undersøgelserne, der havde vist øget dødelighedsrisiko hos kritisk syge patienter. 
The PRAC therefore acknowledged the results of this studies which shows no risk of mortality associated with the use of HES but considered that given the limitations of this study its findings could not negate the findings from 6S and VISEP studies that had shown an increased risk of mortality in critically ill patients.
Trods de konstaterede begrænsninger af undersøgelserne viste sammenligningen af kolloider med krystalloider i CRYSTAL-undersøgelsen, at kolloider til hypovolæmiske patienter ikke medførte signifikant forskellig 28-dages dødelighed fra krystalloider. 
Despite the studies' limitations which were noted, the results from the CRYSTAL study comparing colloids to crystalloids showed that in patients with hypovolaemia, the use of colloids vs crystalloids did not result in a significant difference in 28-day mortality.
Det blev dog konstateret, at der er iagttaget kortvarige hæmodynamiske forbedringer hos andre patientpopulationer, herunder operationspatienter og traumepatienter. 
However, it was noted that short-term haemodynamic improvements have been observed in other patient populations, including surgical and trauma patients.
Produkter indeholdende HES er kontraindiceret hos patienter med nedsat nyrefunktion eller renal substitutionsterapi, men kontraindikationerne bør udvides til andre patientpopulationer, herunder sepsispatienter, kritisk syge patienter og brandsårspatienter. 
HES products are contraindicated in patients with renal impairment or renal replacement therapy but the contraindications should also be extended to include other patient populations including patients with sepsis, critically ill patients and burns patients.
Desuden skal der udføres to randomiserede kliniske fase IV-undersøgelser med passende kontrol og klinisk meningsfulde endepunkter for at tilvejebringe mere evidens om virkningen og sikkerheden, herunder 90-dages mortalitet og nyresvigt, samt hos populationerne perioperative patienter og traumepatienter. 
In addition, two phase IV randomised clinical trials with an appropriate control and clinically meaningful endpoints will need to be conducted to provide more evidence on the efficacy and safety, including the risk of 90-day mortality and renal failure, in perioperative and trauma populations.
Konklusionerne vedrørende artikel 107i afspejler således den mest fuldstændige og ajourførte vurdering af de foreliggende data vedrørende lægemidler indeholdende HES. 
Therefore the conclusions on the Article 107i reflect the most complete and up-to-date evaluation of the available data relating to HES containing medicinal products.
Der blev derfor indledt endnu en gennemgang af opløsninger af HES i henhold til artikel 107i i direktiv 2001/83/EC; denne gennemgang foregik særskilt, men sideløbende med den fornyede overvejelse i henhold til artikel 31, der ligeledes skulle være afsluttet i oktober 2013. 
Consequently, a second review of HES solutions under Article 107i of Directive 2001/83/EC was initiated, and it ran separately but in parallel with the re-examination of the Article 31, also finalising in October 2013.
Af de foreliggende data, navnlig resultaterne af VISEP-, 6S- og CHEST-undersøgelserne, konkluderede PRAC, at HES er forbundet med øget risiko for dødelighed og nyresvigt hos sepsispatienter, kritisk syge patienter og brandsårspatienter, og at fordelene ved HES ikke overstiger risiciene hos disse patientpopulationer. 
On the basis of the available data, in particular results from VISEP, 6S and CHEST studies, the PRAC concluded that HES is associated with an increased risk of mortality and renal failure in patients with sepsis, in critically ill and burn patients and that the benefits of HES do not outweigh the risks in these patient populations.
CMDh gennemgik PRAC's anbefaling af 10. oktober 2013 i henhold til artikel 107k, stk. 1 og 2, i direktiv 2000/83/EF og de mundtlige fremlæggelser fra indehaverne af markedsføringstilladelse den 21. oktober 2013 og indtog på dette grundlag sit standpunkt om ændring af betingelserne for markedsføringstilladelserne for lægemidler indeholdende opløsninger af hydroxyethylstivelse til infusion, for hvilke de relevante afsnit af produktresuméet og indlægssedlen er gengivet i bilag III, og betingelserne fremgår af bilag IV. 
The CMDh having considered the PRAC recommendation dated 10 October 2013 pursuant to Article 107k(1) and (2) of Directive 2001/83/EC and the oral explanations by the Marketing Authorisation Holders on 21 October 2013, reached a position on the variation to the terms of the marketing authorisations of Hydroxyethyl starch solutions for infusion containing medicinal products for which the relevant sections of the summary of product characteristics and package leaflet are set out in Annex III and subject to the conditions set out in Annex IV.
Senest seks måneder efter Europa-Kommissionens beslutning skulle indehaverne af markedsføringstilladelse forelægge hovedelementerne i en risikostyringsplan i EU-format (protokol for undersøgelse af lægemiddelanvendelse, protokoller for randomiserede kliniske undersøgelser), og dette blev indført i bilag IV. 
The MAHs should submit within 6 months of the European Commission Decision, the core elements (including protocol of DUS, protocols of the RCTs) of a risk management plan in EU format and this was included in Annex IV.
PRAC fandt derfor, at den terapeutiske indikation for produkter indeholdende hydroxyethylstivelse bør begrænses til behandling af hypovolæmi ved akut blodtab, hvor krystalloider alene ikke skønnes at have sufficient virkning. 
Therefore, the PRAC agreed that the therapeutic indication of hydroxyethyl starch containing products should be restricted to treatment of hypovolaemia due to acute blood loss when crystalloids alone are not considered sufficient.
Afsnittet om dosering bør fastlægge den maksimale dagsdosis og anbefale, at der anvendes den lavest mulige effektive dosis. 
HES solutions should be restricted to the initial phase of volume resuscitation with a maximum time interval of 24 h. The posology section should identify the maximum daily dose and should recommend that the lowest possible effective dose should be employed.
PRAC fandt desuden, at der burde udføres undersøgelser til tilvejebringelse af mere evidens om virkningen og sikkerheden af hydroxyethylstivelse hos perioperative patienter og traumepatienter, 
The PRAC also considered that studies should be conducted to provide more evidence on the efficacy and safety of hydroxyethyl starch in the perioperative setting and trauma.
• Udvalget for Risikovurdering inden for Lægemiddelvurdering (PRAC) fulgte proceduren i overensstemmelse med artikel 107i, i direktiv 2001/83/EF for lægemidler indeholdende hydroxyethylstivelse til infusion, 
• The Pharmacovigilance Risk Assessment Committee (PRAC) considered the procedure under Article 107i of Directive 2001/83/EC, for hydroxyethyl starch containing products for solutions for infusion.
Denne nye evidens forelå endnu ikke ved fremsættelsen af PRAC's anbefaling om proceduren i henhold til artikel 31 i direktiv 2001/83/EF i juni 2013 og kunne derfor ikke blive omfattet af den fornyede overvejelse heraf i oktober 2013. 
This new evidence was not available when the PRAC recommendation on the procedure under Article 31 of Directive 2001/83/EC was issued in June 2013 and could therefore not be considered in the re-examination of the latter in October 2013.
• PRAC fandt, at anvendelse af hydroxyethylstivelse er forbundet med øget risiko for dødelighed og nyresubstitutionsterapi eller nedsat nyrefunktion hos sepsispatienter, kritisk syge patienter og brandsårspatienter, 
• The PRAC considered that the use of hydroxyethyl starch is associated with an increased risk of mortality and renal replacement therapy or renal impairment in patients with sepsis, critically ill and burn patients.
CMDh fandt desuden, at den direkte henvendelse til sundhedspersoner i henhold til den aftalte kommunikationsplan senest en uge efter vedtagelsen af CMDh's stillingtagen skulle forelægges de nationale kompetente myndigheder, hvor HES-produkterne markedsføres. 
The CMDh also considered that the direct healthcare professional communication (DHPC) should be submitted to the NCAs where HES products are marketed, within one week of the CMDh adopted position as per agreed communication plan.
• PRAC konkluderede, at produkter indeholdende hydroxyethylstivelse bør være kontraindiceret hos sepsispatienter, kritisk syge patienter og brandsårspatienter. 
• The PRAC concluded that hydroxyethyl starch containing products should be contraindicated in patients with sepsis, in critically ill and burn patients.
Det må dog bemærkes, at der i proceduren i henhold til artikel 107i i direktiv 2001/83/EF blev vurderet ny evidens. 
However, it must be noted that new evidence was considered in the procedure under Article 107i of Directive 2001/83/EC.
På baggrund af den samlede foreliggende evidens i proceduren i henhold til artikel 107i i direktiv 2001/83/Ef fandt PRAC, at anvendelsen af hydroxyethylstivelse bør begrænses til behandling af hypovolæmi ved akut blodtab, hvor krystalloider alene ikke skønnes at give sufficient virkning, og at der indføres de vedtagne begrænsninger, kontraindikationer, advarsler, andre ændringer af produktinformationen og supplerende risikominimeringsforanstaltninger. 
In view of the totality of the evidence available in the procedure under Article 107i of Directive 2001/83/EC, the PRAC considered that Hydroxyethyl starch should be restricted to the treatment of hypovolaemia due to acute blood loss when crystalloids alone are not considered sufficient subject to agreed restrictions, contraindications, warnings, other changes to the product information and additional risk minimisation measures.
Konklusionerne vedrørende artikel 107i i direktiv 2001/83/EF afspejler således den mest fuldstændige og ajourførte vurdering af de foreliggende data om lægemidler indeholdende HES. 
Therefore the conclusions on the Article 107i of Directive 2001/83/EC reflect the most complete and up-to-date evaluation of the available data relating to the HES containing medicinal products.
PRAC tog derfor de foreliggende data fra undersøgelser hos operationspatienter og traumepatienter til efterretning og fandt, at uanset disse undersøgelsers begrænsede størrelse og opfølgningsvarighed gav de faktisk anledning til nogen formodning om, at risikoen for dødelighed og nyreskader hos operationspatienter og traumepatienter er lavere end hos kritisk syge patienter og sepsispatienter. 
Therefore, the PRAC noted the available data from studies in surgical and trauma patients and considered that although these studies were limited in size and duration of follow-up they did provide some reassurance that the risks of mortality and renal injury in surgical and trauma patients may be lower than those in the critically ill and sepsis patients.