natgillin/translations-raw huggingface dataset:
Under hensyntagen til den omfattende eksponering og fraværet af kliniske eller ikkekliniske negative resultater af gadolinium-akkumulering i hjernen fandt CHMP, at sådanne skadelige virkninger og potentiel interaktion med sygdomsprocesser er "mulige" snarere end "plausible", da sidstnævnte ville indebære et stærkere potentiale for skade; i denne sammenhæng blev "endnu" også fjernet. 
Taking into account the extensive exposure and the absence of clinical or non-clinical adverse outcomes of gadolinium accumulation in the brain, CHMP considered that such harmful effects and potential interaction with disease processes are “possible” rather than “plausible”, as the latter would imply a stronger potential for harm; in this sense, “yet” was also removed.
Derfor kan den potentielle risiko for hjerneakkumulering og retention i kroppens væv ikke minimeres gennem anbefalinger om kontraindiceret brug hos bestemte grupper (fx børn, gravide kvinder, personer med nedsat nyrefunktion, andre grupper) eller ved at undgå brug til bestemte scanninger eller kliniske omgivelser herunder gentagen anvendelse eller ved at begrænse geneksponering for visse midler eller lægemiddelklasser. 
Hence, the potential risk of brain accumulation and retention in the body tissues cannot be minimised by recommendations to contraindicate use in particular groups (e.g. children, pregnant women, those with renal impairment, other groups) or by avoiding use for particular scans or clinical settings, including repeated use or by restricting re-exposure to certain agents or product classes.
Ifølge den nuværende viden om gadoliniumaflejring i hjernen er lineære forbindelser blevet påvist i hjernen i højere grad end de makrocykliske forbindelser, og de synes at være lagret dér i en form, der ikke tillader tidlig udvaskning. 
According to the current knowledge about gadolinium deposition in the brain, linear compounds have been detected in the brain at a higher magnitude than the macrocyclic compounds and they appear to be stored there in a form that does not allow an early washout.
Dette forhold styrker yderligere fortolkningen af MRI-undersøgelserne som bevis på, at akkumulering af gadolinium i hjernen er kausalt relateret til eksponering for GdCA'er. 
This relationship further strengthens the interpretation of the MRI studies as evidence that accumulation of gadolinium in the brain is causally related to exposure to GdCAs.
perfusion og billeddannelse med forsinket forbedring giver relevant information i form af levedygtigt væv i forskellige hjerte-kar-lidelser, der er nødvendigt for at oparbejde og styre disse sygdomme. 
Cardiac MR including perfusion and delayed enhancement imaging provides relevant information in terms of viable tissue in various cardiovascular disorders needed for work up and management of these diseases.
En højere in vivo- end in vitro-stabilitet ville kræve forekomsten af stabiliserende midler in vivo, men intet afgørende bevis, der bekræfter stigninger i stabiliteten af Gdkomplekset i kroppen, er blevet tilvejebragt af indehaveren af markedsføringstilladelsen. 
A higher in vivo than in vitro stability would require the occurrence of stabilising agents in vivo, but no conclusive evidence confirming increases of the stability of the Gd complex in the body has been provided by the MAH.
PRAC vurderede de detaljerede begrundelser, som indehaverne af markedsføringstilladelsen havde fremlagt inden for rammerne af denne revurderingsprocedure, foruden de videnskabelige data, der lå til grund for disse begrundelser. 
PRAC considered the detailed grounds as submitted by the MAHs within this re-examination procedure and the scientific data underlying these grounds.
For billeddannelse af leveren giver visse GdCA'er mulighed for forsinket fasebilleddannelse. 
For liver imaging, some GdCAs allow the possibility of a delayed phase imaging.
Det anses for usandsynligt, at sådanne undersøgelser vil være mulige i betragtning af heterogeniteten af patientpopulationen, der gennemgår MR. 
Such studies are considered unlikely to be feasible in view of the heterogeneity of the patient population that undergoes MRI.
For det første bemærkede PRAC, at akkumulering i hjernen er en iboende egenskab hos intravenøse lineære GdCA'er, hvorfor information om hjerneakkumulering i produktresuméet ikke vil føre til en reduktion af potentielle risici forbundet med denne akkumulering. 
Firstly, PRAC noted that accumulation in the brain is an intrinsic property of intravenous linear GdCAs and therefore, information on brain accumulation in the SmPC will not lead to a reduction of potential risks associated with this accumulation.
Frigivelse af gadolinium hos patienter med alvorlig nedsat nyrefunktion kan resultere i nefrogen systemisk fibrose (NSF), et alvorligt og livstruende syndrom, der involverer fibrose i hud, led og indre organer. 
Release of gadolinium in patients with severe renal impairment can result in nephrogenic systemic fibrosis (NSF), a serious and life-threatening syndrome involving fibrosis of the skin, joints and internal organs.
Betingelsen bør derfor ikke indeholde passagen "inkl. 
Therefore the condition should not mention “including the brains in human.”
• Det p.t. ikke er muligt at identificere en specifik patientgruppe med mindre risiko for akkumulering i hjernen. 
• No specific patient group with less risk of accumulation in the brain can currently be identified.
Disse data bør dog overvejes i forbindelse med de ikkekliniske undersøgelser, der viser højere niveauer af gadolinium i hjernevæv efter eksponering for lineære GdCA'er sammenlignet med eksponering for makrocykliske GdCA'er. 
However, these data should be considered in the context of the non-clinical studies showing higher levels of gadolinium in brain tissue after exposure to linear GdCAs, compared with exposure to macrocyclic GdCAs.
Der er blevet rapporteret om gadolinium-associerede plaques med sklerotiske kroppe på histologi med nogle gadoliniumholdige kontrastmidler hos patienter, der ikke ellers havde symptomer eller tegn på nefrogen systemisk fibrose. 
Gadolinium-associated plaques with sclerotic bodies on histology have been reported with some gadolinium-containing contrast agents in patients who do not otherwise have symptoms or signs of nephrogenic systemic fibrosis.
Data i post mortem-vævsprøver har vist, at den højeste koncentration af gadolinium i hjernen blev observeret hos patienter, som havde flere eksponeringer for gadodiamid, hvilket antyder, at antallet af modtagne doser har haft en indvirkning på aflejringen af gadolinium. 
Data in post mortem tissue samples have shown that the highest concentration of gadolinium in the brain was observed in patients that had several exposures to gadodiamide, suggesting that number of doses received had an impact on the deposition of gadolinium.
PRAC overvejede også at begrænse antallet af doser til patienter og konkluderede, at der er praktiske vanskeligheder ved at begrænse antallet af doser, da det ikke er muligt at fastslå, hvilket kontrastmiddel der tidligere er blevet indgivet i patienter, og det ville ikke være muligt at sikre en effektiv begrænsning af antallet af doser indgivet i løbet af en patients levetid. 
PRAC also considered limiting the number of doses for patients and concluded that there are practical difficulties for limiting the number of doses as it is not possible to ascertain which contrast agent was previously administered to patients, and it would not be possible to ensure effective restriction of number of doses administered during the lifetime of a patient.
Gadoliniumholdige lægemidler er blevet stratificeret efter risikokategori for NSF, og advarsler mod og begrænsninger af brugen af de højere NSF-risikoprodukter hos patienter med nedsat nyrefunktion er medtaget i produktinformationen, herunder kontraindikation af de høje NSF-risikoprodukter hos patienter med alvorlig nedsat nyrefunktion eller akut nyreskade (AKI) og skift til brug af lavrisikoprodukter. 
Gadolinium containing products have been stratified by risk category for NSF, and warnings and restrictions on the use of the higher NSF risk products in patients with impaired renal function are included in the product information, including contraindication of the high NSF risk products in patients with severe renal impairment or acute kidney injury (AKI) and a switch to the use of low risk products.
På baggrund af ovenstående vurderede PRAC, at fordelene ved makrocykliske midler opvejer deres risici. 
In view of the above, the PRAC considered that the benefits of macrocyclic agents outweigh their risks.
hudplaques “Foruden NSF er der også evidens for, at andre skadelige resultater er forbundet med eksponering for lineære GdCA'er, især gadolinium-associerede hudplaques” er baseret på et begrænset antal tilfælde, og derfor anså CHMP ikke, at det er relevant som begrundelse for suspenderingen af nogle af de IV lineære GdCA'er. 
The ground concerning the skin plaques “in addition to NSF, there is also evidence that other harmful outcomes are associated with exposure to linear GdCAs, in particular gadolinium-associated skin plaques” is based on a limited number of cases, and therefore CHMP did not consider it relevant as ground for the suspension of some of the IV linear GdCAs.
I betragtning af de påståede forskelle i hypersensitivitetsreaktioner med Omniscan kontra andre GdCA'er baseret på meta-analyser af tilgængelige epidemiologiske data anser PRAC, at disse forskelle er for subtile til at påvirke benefit/risk-forholdet, og at det ville kræves ekstremt store kliniske forsøg at bekræfte en statistisk forskel i hyppigheden af hypersensitivitetsreaktioner. 
In view of the claimed differences of hypersensitivity reactions with Omniscan versus other GdCAs based on meta-analyses of available epidemiological data, PRAC considered these differences are too subtle to influence the benefit-risk balance, and that extremely large clinical trials would be necessary to confirm a statistical difference in frequency of hypersensitivity reactions.
Desuden er to GdCA-lægemidler - gadopentetinsyre og gadoterinsyre - godkendt som formler for intraartikulær indgivelse til magnetisk resonans artrografi, og de er i stand til at forbedre specifikke læsioner. 
In addition, two GdCA products, gadopentetic acid and gadoteric acid, are authorised as formulations for intra-articular administration for magnetic resonance arthrography and they are able to enhance specific lesions.
Derfor anses det, at gadoxetsyre giver en yderligere fordel i patientadministrationen med en eksponering for gadolinium, som minimeres af den lave indgivne dosis, meget betragtelige hepatiske optagelse og den korte tid til den forsinkede fasescanning. 
Therefore, it is considered that gadoxetic acid brings an additional benefit to patient management with an exposure to gadolinium that is minimised by the low dose administered, the very significant hepatic uptake and the short time to the delayed phase scanning.
Desuden var CHMP enig i, at indehaverne af markedsføringstilladelse skulle fremsende en meddelelse til sundhedspersonale i form af en fælles DHCP, hvilket indehaverne af markedsføringstilladelse accepterede. 
Furthermore, CHMP agreed that a communication to healthcare professionals through a joint DHPC should be sent by the MAHs, to which the MAHs agreed.
Med hensyn til den hævdede højere relaksivitet i MultiHance, hvilket giver højere billedforbedring og diagnostisk ydelse end andre GdCA'er, blev det bemærket, at højere relaksivitet, som giver et stærkere signal og et lysere billede, ikke automatisk fører til forskelle i diagnostisk ydeevne. 
With regards to the claimed higher relaxivity of Multihance resulting in a better image enhancement and diagnostic performance than other GdCAs, it was noted that higher relaxivity which results in a stronger signal and a brighter image does not automatically translate into differences in diagnostic performance.
• Data om stabilitet, såvel som in vitro- og ikkekliniske undersøgelser, viser, at lineære gadoliniumholdige kontrastmidler (GdCA'er) frigiver gadolinium fra ligandmolekyler i højere grad end makrocykliske midler. 
• Data on stability, as well as in vitro and non-clinical studies, show that linear gadolinium-containing contrast agents (GdCAs) release gadolinium from the ligand molecules to a greater extent than macrocyclic agents.
PRAC bekræftede, at man havde taget hensyn til de samlede data, som indehaverne af markedsføringstilladelse indsendte i forbindelse med den oprindelige indbringelsesprocedure. 
The PRAC confirmed it had considered the totality of the data submitted by the MAHs in the context of the initial referral procedure.
PRAC anså imidlertid, at den kliniske anvendelighed, som opvejer risiciene i forbindelse med akkumulering af gadolinium, begrænser sig til den forsinkede fasebilleddannelse af leveren, og derfor anbefaler PRAC, at indikationen af gadobensyre begrænses til kun denne brug. 
However, PRAC considered the clinical utility outweighing the risks related to accumulation of gadolinium is limited to the delayed phase liver imaging and thus PRAC recommended that the indication of gadobenic acid is restricted to this use only.
PRAC overvejede også to lineære GdCA'er, gadoxinsyre (Primovist®) og gadobensyre (MultiHance). 
PRAC also considered the two linear GdCAs, gadoxetic acid (Primovist) and gadobenic acid (Multihance).
Samlet set udtrykte eksperterne divergerende synspunkter vedr. 
Overall, the experts expressed divergent views concerning the risk minimisation measures.
Der er blevet foretaget nyere MRI-undersøgelser, som har dokumenteret stigninger i signalintensiteten i hjernen i forbindelse med makrocykliske GdCA'er, hvilket indikerer, at disse midler også kan aflejre gadolinium i hjernen. 
There have been more recent MRI studies that have documented signal intensity increases in the brain in association with macrocyclic GdCAs, suggesting that these agents may also deposit gadolinium in the brain.
Begrundelser for CHMP's udtalelse 
Grounds for CHMP opinion
Med hensyn til ikkekliniske undersøgelser har uchelateret gadolinium i form af gadoliniumchlorid vist sig at være toksisk med virkninger som f.eks. cellulær nekrose, fibrose og læsioner relateret til mineralaflejring (Spencer et al. 1997; Rees et al. 1997), og en in vitro-undersøgelse i rotteneuroner rapporterede om gadolinium-induceret cytotoksicitet via oxidativ skade (Xia et al. 2011). 
With regards to non-clinical studies, unchelated gadolinium in the form of gadolinium chloride has been shown to be toxic with effects including cellular necrosis, fibrosis, and lesions related to mineral deposition (Spencer et al. 1997; Rees et al. 1997), and an in vitro study in rat neurons reported gadolinium-induced cytotoxicity via oxidative injury (Xia et al. 2011).
Faktisk har PRAC gennemgået resultaterne af to intra-individuelle crossover-sammenligninger af 0,1 mmol/kg kropsvægt med MultiHance kontra 0,1 mmol/kg kropsvægt af to aktive komparatorer (dimeglumingadopentetat og Gadodiamid) i patienter med kendt eller mistænkt hjerne- eller rygsøjlesygdom, der gennemgår MRI af centralnervesystemet (CNS) (MH-109, MH-130) og konkluderede, at undersøgelserne brugte en blindet sammenligning af MRI-billeder opnået med to GdCA'er, side om side, og har givet resultater, der favoriserer MultiHance på grundlag af et lysere udseende af billederne, men ikke afspejler nogen forskel i den diagnostiske information eller indflydelsen på diagnostisk tænkning, patientadministration eller klinisk resultat. 
Indeed, PRAC considered the results of two intra-individual, crossover comparisons of 0.1 mmol/kg body weight with Multihance vs 0.1 mmol/kg body weight of two active comparators (gadopentetate dimeglumine and gadodiamide), in patients with known or suspected brain or spine disease undergoing MRI of the central nervous system (CNS) (MH-109, MH-130) and concluded that the studies were using a blinded comparison of MRI images obtained with two GdCAs side by side and have produced results favouring Multihance on the basis of brighter appearance of the images, but not reflecting any difference in the diagnostic information available or the impact on diagnostic thinking, patient management or clinical outcome.
Gentagen indgivelse af gadodiamid hos rotter med nyresvigt var forbundet med en stigning i T1-hypersignalet i de dybe cerebellære kerner i forhold til kontroller med normal nyrefunktion. 
Repetitive administration of gadodiamide in rats with renal failure was associated with an increase in the T1 hypersignal in the deep cerebellar nuclei relative to controls with normal renal function.
Der var også et mellemliggende standpunkt i ekspertgruppen, der tilkendegav, at de lineære midler ikke bør suspenderes, men at makrocykliske midler bør anvendes som det mest foretrukne kontrastmiddel (undtagen for leveren), medmindre indehaverne af markedsføringstilladelsen fremkom med relevante forsøgsdata, der tydeligt indikerede overlegne patientadministrations-resultater med brugen af deres lineære middel sammenlignet med makrocykliske. 
There was also an intermediate position within the expert group that expressed a view that the linear agents should not be suspended but that macrocyclic agents should be used as the first line contrast agent (excepting for the liver), unless the MAHs produced relevant trial data clearly indicating superior patient management outcomes with use of their linear agent compared to macrocyclics.
Intravenøse lineære Gadolinium-holdige kontrastmidler (GdCA'er) 
Intravenous linear Gadolinium-containing contrast agents (GdCAs)
Virkninger af nedsat nyrefunktion 
Impact of renal impairment
Derfor vurderede PRAC, at begrænsning af brugen af lineære GdCA'er for visse indikationer eller for visse patientgrupper ikke kunne retfærdiggøres og stadig ville efterlade patienter med risiko for gadolinium-hjerneakkumulering, og at risikominimeringsforanstaltninger såsom advarsler i produktresuméet eller andre kontraindikationer ville ikke begrænse eksponeringen for lineære GdCA'er, da der ikke er etableret et sikkert niveau for gadolinium-hjerneakkumulering. 
Therefore, PRAC considered that restriction of the use of linear GdCAs to certain indications or to certain groups of patients would not be justified and would still leave patients exposed to the risk of gadolinium brain accumulation and that risk minimisation measures such as warnings in the SmPC or other contraindications would not limit the exposure to linear GdCAs as no safe level of gadolinium brain accumulation has been established.
Ikkechelateret gadolinium har vist sig at være toksisk i ikkekliniske forsøg, med effekter herunder cellulær nekrose, fibrose og læsioner relateret til mineralaflejring. 
Non-chelated gadolinium has been shown to be toxic in non-clinical studies, with effects including cellular necrosis, fibrosis, and lesions related to mineral deposition.
Data fra ikkekliniske elektronmikroskopi-undersøgelser (EM) af hjernevæv har også tilvejebragt evidens for filamentøse elektrontætte Gd-aflejringer i de regioner, hvor der var blevet observeret T1hyperintensitet efter dosering med gadodiamid. 
Data from non-clinical electron microscopy (EM) studies of brain tissue have also provided evidence of filamentous electron-dense Gd deposits in the regions where T1 hyper intensity has been observed following dosing with gadodiamide.
Der er flere publikationer om rottemodeller, som har påvist en T1-vægtet signalforbedring i de dybe cerebellare kerner (DCN)svarende til den tandede kerne (DN) hos mennesker - efter indgivelse af de lineære midler. 
There are several publications in rat models that have demonstrated a T1-weighted signal enhancement in the deep cerebellar nuclei (DCN) - the equivalent to the dentate nucleus (DN) in humans- after administration of the linear agents.
Desuden har man observeret toksiciteter med GdCA'er i andre organer såsom nyre (der fører til NSF) og hud (der fører til huden plaques), hvilket anses for at være relateret til gadolinium, som er frigivet fra chelatet. 
In addition, toxicities have been observed with GdCAs in other organs, such as kidney (leading to NSF) and skin (leading to skin plaques), which are considered to be related to Gadolinium released from the chelate.
Denne kontrastforbedring har vist sig at være vigtig for visualiseringen af anatomien, fysiologien og funktionaliteten af mange forskellige områder af kroppen og indre organer som del af en diagnostisk oparbejdning, der undersøger en bred vifte af sygdomme herunder cancer, inflammatoriske sygdomme og degenerative tilstande. 
physiology and functionality of many different areas of the body and internal organs as part of a diagnostic workup investigating a wide range of diseases including cancer, inflammatory diseases and degenerative conditions.
Makrocykliske midler viser kun en forbigående stigning i Gd i hjernen og gennemgår tidlig udvaskning. 
Macrocyclic agents show only a transient increase in Gd in the brain and undergo early washout.
To lineære GdCA'er - gadoxetsyre og gadobensyre - har vist sig at have en optagelse via hepatocytter og er de eneste leverspecifikke midler, der kan tilvejebringe både den dynamiske og den forsinkede fasebilleddannelse. 
Two linear GdCAs, gadoxetic acid and gadobenic acid, have been shown to have an uptake by hepatocytes and are the only liver-specific agents that can provide both the dynamic and the delayed phase imaging.
En anden undersøgelse viste, at Gd-niveauerne i hjernen et år efter indgivelse af gadoterinsyre, et makrocyklisk middel, er over 30 gange lavere sammenlignet med gadodiamid (lineær). 
Another study showed that at one year, Gd levels in the brain following administration of gadoteric acid, a macrocyclic agent, are over 30 fold lower compared to gadodiamide (linear).
1 ICP-MS: Induktivt koblet plasma-massespektrometri dette er endnu ikke blevet påvist. 
1 ICP-MS: Inductively coupled plasma mass spectrometry
For at minimere risikoen for Gd-akkumulering i hjernen og den potentielle tilknyttede skade i forhold til lineære GdCA'er, vurderede PRAC muligheder for risikominimeringstiltag såsom advarsler i produktresuméet, kontraindikationer og andre yderligere risikominimeringsforanstaltninger. 
In order to minimise the risk of Gd accumulation in the brain and the potential associated harm in relation to linear GdCAs, PRAC considered options for risk minimisation measures such as warnings in the SmPC, contraindications and other additional risk minimisation measures.
I rotteforsøg blev der fundet rest-Gd i rottehjernen efter gentagen indgivelse af lineære GdCA'er i mindst 3 markante former - opløselige små molekyler, formentlig intakt GdCA, opløselige makromolekyler og, i størst omgang, en uopløselig form. 
In rat studies, residual Gd found in the rat brain after repeated administration of linear GdCAs was present in at least 3 distinctive forms - soluble small molecules, presumably intact GdCA, soluble macromolecules and to the largest extent an insoluble form.
På baggrund af ovenstående, og påstanden om den manglende kliniske evidens for neurotoksicitet som følge af aflejret gadolinium, mente PRAC, at da de kliniske konsekvenser af gadolinium-retention i hjernen er ukendte p.t., eller fortsat uklare, kan manglende eller begrænsede oplysninger fra caserapporter ikke tages som bevis for, at en sådan toksicitet ikke forekommer. 
In view of the above, and the claim on the lack of clinical evidence of neurotoxicity due to deposited gadolinium, PRAC considered that while the clinical consequences of gadolinium retention in the brain are currently unknown or remain unclear, absent or limited information from case reports cannot be taken as evidence that such toxicity does not occur.
• ændring af betingelserne i markedsføringstilladelsen for makrocykliske midler (gadoteridol (ProHance), gadobutrol (Gadovist), gadoterinsyre (Dotarem og Artirem)) med ændring af produktresuméets afsnit 4.1 og 4.2. 
• variation to the terms of the marketing authorisation for the macrocyclic agents (gadoteridol (Prohance), gadobutrol (Gadovist), gadoteric acid (Dotarem and Artirem)) with changes to SmPC sections 4.1 and 4.2.
Endeligt benefit/risk-forhold 
Final benefit-risk balance