natgillin/translations-raw huggingface dataset:
With regards to the consideration of the risk of NSF, whilst PRAC relied on the previous assessment and classification of the risk of NSF across the GdCAs products, PRAC considered that the NSF risk contributes to the safety profile of GdCAs and is taken into account to conclude on the whole safety profile of these products and the subsequent impact on their benefit-risk balance. 
V zvezi s pomislekom glede tveganja NSF je odbor PRAC na podlagi predhodne ocene in razvrstitve tveganja NSF pri izdelkih GdCA menil, da tveganje NSF prispeva k varnostnemu profilu sredstev GdCA ter se upošteva pri zaključku o celotnem varnostnem profilu teh izdelkov in naknadnem vplivu na njihovo razmerje med koristmi in tveganji.
The CHMP, in addition, considers that the benefit-risk balance of intravenous medicinal products containing gadodiamide, gadopentetic acid, and gadoversetamide is no longer favourable. 
Poleg tega meni, da razmerje med koristmi in tveganji zdravil za intravensko uporabo, ki vsebujejo gadodiamid, gadopentetsko kislino in gadoversetamid ni več ugodno.
Based on the data available, no specific patient group that would not experience Gd retention in the brain could be identified, as both children and adults are expected to show accumulation of Gd in the brain. 
Na podlagi razpoložljivih podatkov ne bi bilo mogoče opredeliti specifične skupine bolnikov, pri kateri se gadolinij ne bi zadržal v možganih, saj se pričakuje, da se bo pokazalo, da se gadolinij odlaga v možganih otrok in odraslih.
In view of a potential difference in the frequency of hypersensitivity reactions, PRAC pointed out that these are known infrequent reactions for all GdCAs. 
Odbor PRAC je v zvezi z morebitno različno pogostnostjo preobčutljivostnih reakcij poudaril, da je znano, da te pri vseh sredstvih GdCA niso pogoste.
PRAC also maintained its conclusions that benefits of the intra-articular presentation of the linear GdCA Magnevist outweigh their risks (subject to changes to the product information) as they are administered at very low doses and present a low risk of tissue accumulation. 
Odbor PRAC je tudi vztrajal pri zaključkih, da intraartikularna uporaba linearnega sredstva GdCA Magnevist prevlada nad njegovimi tveganji (vendar je treba spremeniti informacije o izdelku), saj se uporablja v zelo majhnih odmerkih in pomeni majhno tveganje kopičenja v tkivu.
Macrocyclic GdCAs have a very low potential for retention of gadolinium in tissues, are very stable and have a low risk of dechelation. 
Pri makrocikličnih sredstvih GdCA je možnost zadrževanja gadolinija v tkivih zelo majhna, zelo so stabilna in pomenijo majhno tveganje dekelacije.
The implemented risk minimisation measures appear to be effective based on annual reviews of spontaneous case reports. 
Na podlagi letnih pregledov spontanih poročil o primerih se zdi, da so bili izvedeni ukrepi za zmanjšanje tveganja učinkoviti.
However, they described the TEM finding of electrondense lumps in the tissues of ProHance-treated animals which at first were assumed to be Gd deposits, obviously because they looked like them. 
Opisali pa so zatrdline s povečano gostoto elektronov, ki so jih s transmisijsko elektronsko mikroskopijo (TEM) ugotovili v tkivih živalih, obravnavanih s sredstvom ProHance, za katere se je najprej domnevalo, da so depoziti gadolinija, očitno zato, ker so jim bili podobni.
Since the finalisation of the referral, several studies in animals and in humans have been published showing accumulation of gadolinium following administration of GdCAs in tissues such as liver, kidney, muscle, skin and bone. 
Po zaključku napotitve je bilo objavljenih več študij na živalih in ljudeh, ki so po uporabi sredstev GdCA pokazale kopičenje gadolinija v tkivih, npr. v jetrih, ledvicah, mišicah, koži in kosteh.
Final benefit-risk balance 
Končno razmerje med koristmi in tveganji
This is a clinically relevant benefit as they allow enhancement of dynamic phase liver imaging for highly vascularised hepatic lesions and also detection of lesions that are visible only in the delayed phase. 
To je klinično pomembna korist, saj omogočata izboljšanje kontrasta v dinamični fazi slikanja jeter pri zelo vaskulariziranih jetrnih lezijah in tudi za odkrivanje lezij, ki jih je mogoče videti samo v zapozneli fazi.
• PRAC considered options for risk minimisation measures. 
• odbor PRAC je proučil mogoče ukrepe za zmanjšanje tveganja.
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. 
Prvič, odbor PRAC je poudaril, da je kopičenje v možganih intrinzična lastnost linearnih sredstev GdCA za intravensko uporabo, zato se zaradi informacij o kopičenju v možganih v povzetku glavnih značilnosti zdravila ne bodo zmanjšala morebitna tveganja, povezana s tem kopičenjem.
• variation to the terms of the marketing authorisation for the intraarticular linear agent gadopentetic acid (Magnevist), and the intravenous linear agents gadoxetic acid (Primovist) and gadobenic acid (Multihance) with changes to SmPC sections 4.1, 4.2, 4.4 and 5.2, including removal of indications, 
• spremembo pogojev dovoljenja za promet z linearnim sredstvom gadopentetska kislina za intraartikularno uporabo (Magnevist) ter linearnimi sredstvi gadoksetno kislino (Primovist) in gadobensko kislino (Multihance) za intravensko uporabo s spremembami oddelkov 4.1, 4.2, 4.4 in 5.2 v povzetkih glavnih značilnosti zdravila, vključno z izbrisom indikacij,
With regards to the claim of a lower risk of cardiovascular adverse events for Multihance, PRAC considered that nonclinical data as well as available clinical data do not indicate a difference in cardiovascular risk (inducing QT prolongation) within the delayed phase liver imaging agents. 
Odbor PRAC je v zvezi s trditvijo, da pomeni sredstvo Multihance manjše tveganje neželenih kardiovaskularnih dogodkov, menil, da neklinični podatki in razpoložljivi klinični podatki ne kažejo različnega kardiovaskularnega tveganja (vključno s podaljšanjem QT) pri sredstvih za slikanje jeter v zapozneli fazi.
For lifting the suspension, the PRAC recommended that MAHs should provide evidence: 
Za preklic začasnega umika dovoljenja je odbor PRAC priporočil, naj imetniki dovoljenja za promet z zdravilom zagotovijo dokaze:
The benefit-risk balance of medicinal products containing intravenous gadobenic acid (in all other indications than liver imaging), gadodiamide, gadopentetic acid (IV presentation), and gadoversetamide is no longer favourable and these marketing authorisations should be suspended. 
Razmerje med koristmi in tveganji pri zdravilih, ki vsebujejo gadobensko kislino za intravensko uporabo (pri vseh drugih indikacijah, razen slikanja jeter), gadodiamid, gadopentetsko kislino (predstavitev IV ) in gadoversetamid ni več ugodno ter bi bilo treba ta dovoljenja za promet začasno umakniti.
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). 
študija je dokazala, da so po enem letu ravni gadolinija v možganih po uporabi gadoterske kisline, ki je makrociklično sredstvo, več kot 30-krat nižje kot pri gadodiamidu (linearno sredstvo).
Therefore, it can be concluded that renal impairment is not a requirement for Gd deposition, but it may however increase the amount of Gd deposited in the brain. 
Zato je mogoče zaključiti, da ledvična okvara ni zahteva za odlaganje gadolinija, vendar lahko ljub temu poveča količino odloženega gadolinija v možganih.
There are practical difficulties in clinical daily life for implementing an effective restriction of the number of doses administered during the lifetime of a patient. 
V vsakdanjem kliničnem življenju obstajajo praktične težave za izvajanje učinkovite omejitve števila odmerkov, ki jih bolnik prejme v svojem življenju.
PRAC also considered the two linear GdCAs, gadoxetic acid (Primovist) and gadobenic acid (Multihance). 
Odbor PRAC je tudi proučil dve linearni sredstvi GdCA, in sicer gadoksetno kislino (Primovist) in gadobensko kislino (Multihance).
In relation to the statement about the macrocyclic early washout “macrocyclic agents show only a transient increase in Gd in the brain and undergo early washout”, the CHMP considered it sufficient to reflect the observation that measurements of gadolinium in the brain over longer periods showed differences between linear and macrocyclic agents in terms of accumulation over time. 
Odbor CHMP je v zvezi z navedbo, da se makrociklična sredstva kmalu izperejo, „makrociklična sredstva kažejo samo začasno povečanje gadolinija v možganih in se kmalu izperejo“, menil, da to zadostuje za upoštevanje ugotovitve, da so meritve gadolinija v možganih v daljši obdobjih pokazale razlike med linearnimi in makrocikličnimi sredstvi glede kopičenja skozi čas.
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. 
razlog, povezan s kožnimi plaki, „obstajajo dokazi za NSF in dokazi, da so z izpostavitvijo linearnim sredstvom GdCA povezani tudi drugi škodljivi izidi, zlasti kožni plaki, povezani z gadolinijem“, temelji na omejenem številu primerov, zato je odbor CHMP menil, da to ni pomemben razlog za začasni umik dovoljenja za promet z nekaterimi linearnimi sredstvi GdCA (IV);
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. 
Pri podganah z ledvično okvaro je bila večkratna uporaba gadodiamida povezana s povečanjem hipersignala T1 v globokih možganskih jedrih glede na preverjanja pri normalnem delovanju ledvic.
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. 
V študijah na podganah je bilo ugotovljeno, da je bil gadolinij, ki je ostal v možganih podgan po večkratni uporabi linearnih sredstev GdCA, prisoten v vsaj treh različnih oblikah - topne majhne molekule, domnevno nespremenjeno sredstvo GdCA v obliki topnih makromolekul, v največjem obsegu pa v netopni obliki.
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. 
Te podatke pa bi bilo treba proučiti v okviru nekliničnih študij, ki so po izpostavljenosti linearnim sredstvom GdCA pokazale višje ravni gadolinija v možganskem tkivu kot pri izpostavljenosti makrocikličnim sredstvom GdCA.
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. 
Z magnetno resonanco srca, ki vključuje perfuzijsko slikanje in slikanje v zapozneli fazi z izboljšanim kontrastom, se pri različnih kardiovaskularnih boleznih zagotovijo ustrezne informacije o živem tkivu, potrebne za preiskave in zdravljenje teh bolezni.
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. 
Za dve linearni sredstvi GdCA, in sicer za gadoksetno kislino in gadobensko kislino, se je izkazalo, da jih hepatociti absorbirajo in da sta edini sredstvi za jetra, ki omogočata slikanje v dinamični in zapozneli fazi.
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. 
Zato je menil, da omejitev uporabe linearnih sredstev GdCA za nekatere indikacije ali nekatere skupine bolnikov ne bi bila utemeljena in bi bili bolniki še naprej izpostavljeni tveganju kopičenja gadolinija v možganih ter da ukrepi za zmanjšanje tveganja, kot so opozorila v povzetku glavnih značilnosti zdravila ali druge kontraindikacije, ne bi omejile izpostavljenosti sredstvom GdCA, saj varna raven kopičenja gadolinija v možganih ni bila ugotovljena.
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. 
Podatki iz nekliničnih študij možganskega tkiva, pridobljeni z elektronsko mikroskopijo, so zagotovili tudi dokaze o filamentoznih depozitih gadolinija s povečano gostoto elektronov v predelih, kjer je bila po uporabi odmerkov gadodiamida ugotovljena hiperintenzivnost T1.
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. 
Zato se meni, da gadoksetna kislina zagotavlja dodatno korist pri obravnavanju bolnika, pri čemer je izpostavljenost gadoliniju zaradi uporabljenega majhnega odmerka zmanjšana, prehod v hepatocite zelo velik in čas do zapoznele faze slikanja kratek.
Gadobenic acid also has shown to have clinical utility in the liver and undergoes hepatic uptake but to a lesser extent, requires a high dose (0.05 mmol/kg body weight), and a long time to the onset of delayed phase imaging (40 mins). 
Tudi za gadobensko kislino se je izkazalo, da je klinično koristna v jetrih in prav tako prehaja v hepatocite, vendar v manjši meri, pri njej se zahteva večji odmerek (0,05 mmol/kg telesne mase), čas do začetka zapoznele faze slikanja pa je dolg (40 minut).
PRAC recommended restriction of use, in the lowest dose that provides sufficient enhancement for diagnostic purposes and through appropriate warning in the product information in order to minimise the potential for accumulation of gadolinium in the brain and other organs and tissues. 
Priporočil je omejitev uporabe na najmanjši odmerek, ki zagotavlja zadostno izboljšanje kontrasta za diagnostične namene, in z ustreznim opozorilom v informacijah o izdelku za zmanjšanje možnosti kopičenja gadolinija v možganih ter drugih organih in tkivih.
The macrocyclic agent gadobutrol did not show hyperintensity after this time period. 
Pri gadobutrolu, ki je makrociklično sredstvo, se po enakem času hiperintezivnost ni pokazala.
The PRAC confirmed it had considered the totality of the data submitted by the MAHs in the context of the initial referral procedure. 
Odbor PRAC je potrdil, da je v okviru postopka prve napotitve v celoti proučil vse podatke, ki sta jih predložila imetnika dovoljenja za promet z zdravilom.
Non-clinical evidence also shows potential for release of gadolinium from the chelating ligand in the brain with linear GdCAs, but not with macrocyclic GdCAs (Frenzel et al. 2017). 
Neklinični dokazi tudi kažejo možnost sproščanja gadolinija iz kelatnega liganda v možganih pri linearnih sredstvih GdCA, pri makrocikličnih sredstvih GdCA pa ne (Frenzel idr., 2017).
• Based on non-clinical data, both linear and macrocyclic agents have the ability to distribute to the brain. 
• na podlagi nekliničnih podatkov je bilo ugotovljeno, da imajo zmožnost razširitve v možgane linearna in makrociklična sredstva.
Furthermore, the standard deviation of Gd content in the brain was extraordinary high for Gadovist. 
Poleg tega je bil pri Gadovistu odmik od običajne vsebnosti gadolinija v možganih izjemno velik.
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. 
Odbor PRAC je v zvezi s trditvijo, da obstajajo razlike med preobčutljivostnimi reakcijami pri sredstvu Omniscan in drugih sredstvih Gdca, ki temelji na metaanalizah razpoložljivih epidemioloških podatkov, menil, da so te razlike premalo zaznavne, da bi vplivale na razmerje med koristmi in tveganji, ter da bi bilo treba za potrditev statistične razlike v pogostnosti preobčutljivostnih reakcij izvesti izjemno obsežno klinično preskušanje.
In view of (a) the evidence suggesting that linear GdCAs release Gd from their chelating ligand molecules due to the low kinetic and thermodynamic stability; (b) the known toxicity of unchelated gadolinium; (c) the data supporting the ability of linear GdCAs to distribute and accumulate in the brain; (d) the fact that linear agents are retained and persist for up to one year or longer in the brain; and (e) the deposition in other tissues with related harm; PRAC considered that there are reasonable and serious concerns raised as to the potential of neurological harm associated with the accumulation of gadolinium in the brain. 
Odbor PRAC je glede na (a) dokaze, ki nakazujejo, da linearna sredstva GdCA zaradi nizke kinetične in termodinamične stabilnosti sproščajo gadolinij iz svojih molekul kelatnega liganda; (b) znano toksičnost nekelatiranega gadolinija; (c) podatke, ki dokazujejo zmožnost linearnih sredstev GdCA za razširjanje in kopičenje v možganih; (d) dejstvo, da se linearna sredstva zadržijo v možganih do enega leta ali dlje; ter (e) odlaganje v drugih tkivih s povezanimi škodljivimi učinki, menil, da obstajajo upravičeni in resni pomisleki zaradi morebitnih škodljivih nevroloških učinkov, povezanih s kopičenja gadolinija v možganih.
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. 
Izkazalo se je, da je to izboljšanje kontrasta pomembno za vizualizacijo anatomije, fiziologije in funkcionalnosti številnih različnih predelov telesa in notranjih organov v okviru diagnostičnih preiskav pri ugotavljanju najrazličnejših bolezni, vključno z rakom ter vnetnimi in degenerativnimi boleznimi.
Intravenous linear Gadolinium-containing contrast agents (GdCAs) 
Linearna kontrastna sredstva, ki vsebujejo gadolinij (GdCA) za intravensko uporabo
For the suspension of intravenous medicinal products containing gadodiamide, gadopentetic acid, and gadoversetamide to be lifted, the marketing authorisation holder(s) shall submit evidence: 
Za preklic začasnega umika dovoljenja za promet z zdravili za intravensko uporabo, ki vsebujejo gadodiamid, gadopentetsko kislino in gadoversetamid, imetnik(i) dovoljenja za promet z zdravilom predloži(jo) dokaze:
Skin prick testing could facilitate the identification of an alternative GdCA. 
Določitev nadomestnega sredstva GdCA lahko olajša preskus z vbodom v kožo.
For these products, the PRAC considered that the risk can be managed though restriction of use, in the lowest dose that provides sufficient enhancement for diagnostic purposes and through appropriate warning in the product information in order to minimise the potential for accumulation of gadolinium in the brain and other organs and tissues. 
Odbor PRAC je za ta sredstva menil, da je tveganje mogoče obvladovati z omejitvijo uporabe na najmanjši odmerek, ki zagotavlja zadostno izboljšanje kontrasta za diagnostične namene, ter z ustreznim opozorilom v informacijah o izdelku za zmanjšanje možnosti kopičenja gadolinija v možganih ter drugih organih in tkivih.
In view of the claim regarding the cardiac indication of Omniscan, the PRAC highlighted that the primary goal of cardiac perfusion imaging is the detection of myocardial ischemia in patients with suspected coronary artery disease or cardiomyopathy. 
Odbor PRAC je v zvezi z navedbo, da se Omniscan uporablja pri boleznih srca, poudaril, da je glavni cilj perfuzijskega slikanja srca ugotoviti miokardne ishemije pri bolnikih s sumom na koronarno srčno bolezen ali kardiomiopatijo.
• 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. 
• spremembo pogojev dovoljenja za promet z makrocikličnimi sredstvi gadoteridol (Prohance), gadobutrol (Gadovist), gadotersko kislino (Dotarem in Artirem)) s spremembami oddelkov 4.1 in 4.2 v povzetkih glavnih značilnosti zdravila.
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. 
V zvezi s trditvijo, da ima sredstvo Multihance večjo relaksivnost in je zato kontrast slike boljši, diagnostična zmogljivost pa večja kot pri drugih sredstvih GdCA, je bilo opozorjeno, da večja relaksivnost, zaradi katere je signal močnejši, slika pa svetlejša, samodejno ne pomeni drugačne diagnostične zmogljivosti.
The absolute rate of hypersensitivity reactions with GdCAs is low and reported as approximately 0.01% to 0.001% across the studies investigating rates of hypersensitivity reactions. 
V študijah, ki proučujejo stopnje preobčutljivostnih reakcij, je navedeno, da znaša približno 0,01 % do 0,001 %.
The highest amount of gadolinium recovered from the rat brain tissue was found to be with gadodiamide, followed by gadobenate and gadopentetate. 
Ugotovljeno je bilo, da je bilo največ gadolinija pridobljenega iz možganskega tkiva podgan, ki so prejele gadodiamid, sledita mu gadobenat in gadopentetat.
Furthermore the CHMP took the opportunity to clarify that toxicities of non-chelated gadolinium discussed in the non-clinical section of the scientific grounds above have been observed with GdCAs in skin and other tissues (leading to NSF and skin plaques), which are considered to be related to Gadolinium released from the chelate. 
odbor CHMP je to priložnost izkoristil tudi za pojasnilo, da so bili pri sredstvih GdCA ugotovljeni toksični učinki nekelatiranega gadolinija, obravnavani zgoraj v nekliničnem razdelku znanstvenih razlogov, na koži in v drugih tkivih (kjer povzročijo NSF in kožne plake); zanje se domneva, da so povezani z gadolinijem, ki se sprosti iz kelata.
However, in view of the extent of the hepatic uptake, the high dose (0.05 mmol/kg body weight) required and the long time to the onset of delayed phase imaging (40 mins), the PRAC considered that the benefit of gadobenic acid containing products in all the authorised indication including the liver imaging does not outweigh the potential and identified risks associated to the use of this product. 
Odbor PRAC je glede na obseg prehajanja v hepatocite in potrebni velik odmerek (0,05 mmol/kg telesne mase) ter glede na dejstvo, da do začetka zapoznele faze slikanja poteče veliko časa (40 minut), menil, da korist izdelkov, ki vsebujejo gadobensko kislino, pri vseh odobrenih indikacijah, vključno s slikanjem jeter, ne prevlada nad morebitnimi in opredeljenimi tveganji, povezanimi z uporabo tega izdelka.