natgillin/translations-raw huggingface dataset:
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.
U pogledu tvrdnji o većoj relaksiviteta lijeka Multihance koja omogućuje poboljšavanje slike i dijagnostičke izvedbe u usporedbi s drugim GdCA sredstvima, utvrđeno je da veći relaksivitet koji rezultira jačim signalom i svjetlijom slikom ne dovodi nužno do razlika u dijagnostičkoj izvedbi.
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 temelju dostupnih podataka, nije moguće utvrditi određenu skupinu bolesnika koja neće doživjeti taloženje gadolinija u mozgu, budući da se taloženje gadolinija u mozgu očekuje i u djece i odraslih.
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.
U okviru stručne skupine izraženo je i mišljenje da linearna sredstva ne bi trebalo obustaviti, ali bi se makrociklička sredstva trebala koristiti kao prvi odabir kontrastnog sredstva (osim za jetru), osim u slučaju da nositelji odobrenja za stavljanje u promet provedu relevantna ispitivanja koja jasno dokazuju da linearna sredstva omogućuju znatno bolje ishode pri upravljanju bolesnikom u usporedbi s makrocikličkim sredstvima.
The CHMP, in addition, considers that the benefit-risk balance of intravenous medicinal products containing gadodiamide, gadopentetic acid, and gadoversetamide is no longer favourable.
CHMP nadalje smatra da omjer koristi i rizika za intravenske lijekove koji sadržavaju gadodiamid, gadopentetičnu kiselinu i gadoversetamid više nije povoljan.
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.
Kako bi se smanjio rizik od taloženja gadolinija u mozgu i moguće štete povezane s linearnim GdCAovima, PRAC je razmotrio opcije mjera za smanjenje rizika, kao što su upozorenja u sažetku opisa svojstava lijeka, kontraindikacije te druge dodatne mjere za smanjenje rizika.
Elimination of GdCAs is therefore reduced in patient with renal dysfunction.
Izlučivanje GdCA-ova stoga je smanjeno u bolesnika s bubrežnom disfunkcijom.
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.
Neklinička ispitivanja pokazala su da je nekelirani gadolinij toksičan te ima učinke kao što su stanična nekroza, fibroza i lezije povezane s taloženjem minerala.
Particularly zinc, copper and iron (Frenzel et al., 2008) are described as competing metals which can liberate Gd; glycosaminoglycans like heparin may bind Gd and thereby remove it from its pharmacological chelator.
Kao metali koji mogu osloboditi gadolinij posebno se navode cink, bakar i željezo (Frenzel i dr., 2008.); glikosaminoglikani poput heparina mogu vezati gadolinij i tako ga ukloniti iz farmakološkog kelatora.
Regarding the validity of an ex-vivo distribution study by Frenzel et al (2017), PRAC acknowledged the study does not contribute to the understanding in which form exactly Gd-based contrast agents are stored in the body, however PRAC considered that the study confirms, in line with other studies, that linear chelators lead to a higher amount of stored Gd and that there is a difference between linear and macrocyclic chelators in respect to binding to insoluble macromolecules.
U pogledu valjanosti ex-vivo distribucijskog ispitivanja koje su proveli Frenzel i dr. (2017.), PRAC je utvrdio da ispitivanje ne objašnjava u kojem se točno obliku kontrastna sredstva koja se temelje na gadoliniju pohranjuju u tijelu, međutim PRAC smatra da ispitivanje potvrđuje, u skladu s drugim ispitivanjima, da linearni kelatori dovode do veće količine pohranjenog gadolinija te da postoji razlika između linearnih i makrocikličkih kelatora u pogledu vezanja na netopive makromolekule.
Non-clinical evidence also shows potential for release of gadolinium from the chelating ligand in the brain with linear GdCAs; the potential of release from the chelating ligand is not seen with macrocyclic GdCAs.
Neklinički dokazi također pokazuju potencijal otpuštanja gadolinija iz kelirajućeg liganda u mozgu nakon primjene linearnih GdCA-ova; potencijal otpuštanja iz kelirajućeg liganda nije primijećen kod makrocikličkih GdCA-ova.
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).
Gadobenska kiselina također je pokazala kliničku korist za jetru, njezin unos u jetru manjeg je razmjera, potrebna je veća doza (0,05 mmol/kg tjelesne mase) i dugo snimanje do nastupanja odgođene faze (40 minuta).
• In relation to the Magnevist (gadopentetic acid) for intra-articular injection, in view of the low dose, the limited potential for repeated exposure for patients and the absence of evidence of brain accumulation, CHMP considered that the benefits of this product outweigh its risks.
• U pogledu Magnevista (gadopentetična kiselina) za intraartikularnu injekciju, uzimajući u obzir nisku dozu, ograničenu mogućnost za ponovno izlaganje bolesnika i manjak dokaza o taloženju u mozgu, CHMP smatra da koristi tog lijeka nadmašuju s njime povezane rizike.
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 klinički važna korist jer omogućuju poboljšanje snimanja jetre u dinamičnoj fazi za lezije jetre s visokom vaskularizacijom te za otkrivanje lezija koje su vidljive samo u odgođenoj fazi.
Spontaneous release of Gd from its chelator, competition of Gd with other metals (e.g. in metal rich areas of the brain), and competition of the chelator with other chelators (e.g. macromolecules) can occur in the body.
U tijelu se može dogoditi spontano otpuštanje gadolinija iz kelatora, nadmetanje gadolinija s drugim metalima (npr. u područjima mozga koja su bogata metalima) i nadmetanje kelatora s drugim kelatorima (npr. makromolekule).
PRAC also considered the two linear GdCAs, gadoxetic acid and gadobenic acid in the liver imaging indication.
PRAC je također razmotrio dva linearna GdCA-a, gadoksetičnu kiselinu i gadobensku kiselinu u indikaciji snimanja jetre.
Duration of gadolinium retention in the brain
Vrijeme zadržavanja gadolinija u mozgu
Intra-articular GdCA products
Intraartikularni GdCA lijekovi
Therefore, taking into account the serious concerns about the potential neurological harm, deposition in other tissues and its potential risks, and the already identified risks associated with the use of linear GdCAs (including the significant risk of NSF and the gadolinium-associated plaques), the PRAC considered that the benefit in enhancement of MR images does not outweigh the known and potential risks of these products.
Uzimajući u obzir ozbiljne zabrinutosti u pogledu moguće štete za neurološki sustav, taloženja u drugim tkivima i moguće rizike od taloženja, kao i već utvrđene rizike povezane s uporabom linearnih GdCA-ova (uključujući značajan rizik od NSF-a i plakova povezanih s gadolinijem), PRAC smatra da korist poboljšavanja snimki magnetske rezonancije ne nadmašuje poznate i moguće rizike tih proizvoda.
• The rather high and particularly highly variable Gd tissue level in saline control animals.
• Poprilično visoka i iznimno promjenjiva razina gadolinija u tkivu životinja koje su primale fiziološku otopinu.
These products have an uptake by hepatocytes and can provide in addition to the dynamic phase imaging a delayed phase imaging for highly vascularised hepatic lesions and to detect lesions that are visible only in the delayed phase.
Ti proizvodi unose se u hepatocite te uz dinamičnu fazu snimanja omogućuju i odgođenu fazu snimanja za lezije na jetri s visokom vaskularizacijom, kao i otkrivanje lezija koje su vidljive samo u odgođenoj fazi.
In view of the affected brain areas (including DN and GP), potential neurological effects would include effects on fine motor skills or cognitive impairment, particularly in patients with ongoing neurological disease, which may mask these events.
U pogledu zahvaćenih područja mozga (uključujući DN i GP), u moguće neurološke učinke treba uvrstiti učinke na fine motoričke vještine ili kognitivno oštećenje, posebno u bolesnika s trajnom neurološkom bolesti koja može prikriti te događaje.
Gadolinium-associated plaques
Plakovi povezani s gadolinijem
Based on the knowledge of the function of the affected brain areas (including DN and GP), these effects would include effects on fine motor skills or cognitive impairment, particularly in those with ongoing neurological disease which may mask these events.
Na temelju znanja o funkciji zahvaćenih područja mozga (uključujući DN i GP), u štetne učinke treba uvrstiti učinke na fine motoričke vještine ili kognitivno oštećenje, posebno u bolesnika s trajnom neurološkom bolesti koja može prikriti te događaje.
Gadoxetic acid has a substantial liver uptake, is administered at a low dose (0.025 mmol/kg of body weight) and has a short time to delayed phase scanning (20 mins).
Gadoksetična kiselina ima značajan unos u jetri, primjenjuje se mala doza (0,025 mmol/kg tjelesne mase), a snimanje u odgođenoj fazi kratko traje (20 min).
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.
PRAC smatra da se rizikom povezanim s tim lijekovima može upravljati putem ograničenja uporabe, primjenom najmanje doze koja pruža dovoljno poboljšanje u dijagnostičke svrhe i odgovarajućih upozorenja u informacijama o lijeku kako bi se smanjila mogućnost taloženja gadolinija u mozgu, drugim organima i tkivima.
Furthermore, as no specific patient group with less risk of accumulation in the brain or a safe threshold level for retention in the brain could be identified, the restriction of the use of linear GdCAs to certain indications or certain groups of patients was considered not appropriate.
Štoviše, budući da nije bilo moguće utvrditi skupinu bolesnika s manjim rizikom od taloženja u mozgu ili sigurnu razinu za zadržavanje u mozgu, ograničenje uporabe linearnih GdCA-ova na određene indikacije ili određene skupine bolesnika smatra se neprimjerenim.
• Based on non-clinical and clinical data, both linear and macrocyclic agents have the ability to distribute to the brain.
• Neklinički i klinički podaci pokazuju da se i linearna i makrociklička sredstva mogu distribuirati u mozgu.
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.
Upozorenja i ograničenja za primjenu lijekova koji imaju veći rizik od NSF-a u bolesnika s oštećenom bubrežnom funkcijom navedena su u informacijama o lijeku, uključujući kontraindikaciju lijekova s visokim rizikom od NSF-a u bolesnika s teškim oštećenjem bubrega ili akutnom ozljedom bubrega (AKI) te njihovu zamjenu lijekovima s niskim rizikom.
Data appears to suggest that macrocyclic agents are also deposited in the brain but show only a transient increase in Gd and undergo early washout.
Čini se da podaci pokazuju da se makrociklička sredstva također talože u mozgu, ali razina gadolinija samo se malo povećava i rano se povlači.
Therefore, in view of the evidence regarding accumulation of Gd in brain and the plausible harmful effects, and accumulation of Gd in other tissues and the identified related risk, and considering that less restrictive risk minimisation measures are not feasible or not sufficient to bring the risk of accumulation of gadolinium in the brain and other tissues to an acceptable level, PRAC considered the suspension of the marketing authorisation of intravenous linear GdCAs is the most appropriate measure to mitigate the risks related to these products.
Stoga, uzimajući u obzir dokaze o taloženju gadolinija u mozgu i mogućim štetnim učincima, taloženju gadolinija u drugim tkivima i povezanom riziku, kao i to da manje stroge mjere za smanjenje rizika nisu provedive ni dovoljne za smanjivanje taloženja gadolinija u mozgu i drugim tkivima na prihvatljivu razinu, PRAC smatra da je obustava odobrenja za stavljanje u promet za intravenske linearne GdCAove najprikladnija mjera za ublažavanje rizika povezanih s tim lijekovima.
• Furthermore, dense deposits in various tissues were detected after GdCA administration by Transmission electron microscopy (TEM), which were regarded as Gd deposits.
• Štoviše, gusti talog u raznim tkivima primijećen je nakon primjene GdCA-a putem prijenosne elektronske mikroskopije (TEM).
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.
PRAC je prvenstveno istaknuo da je taloženje u mozgu intrinzično svojstvo intravenskih linearnih GdCA sredstava te da navođenje informacija o taloženju u mozgu u sažecima opisa svojstava lijeka neće dovesti do smanjenja mogućih rizika povezanih s tim taloženjem.
Only a transient increase in T1signal intensity and gadolinium concentration (measured by ICP-MS1, thus not distinguishing the molecular form of Gd) was observed with macrocyclic agents.
Kod makrocikličkih sredstava primijećeno je samo prolazno povećanje intenziteta T1 signala i koncentracija gadolinija (mjereno po ICP-MS-u1 bez utvrđivanja razlike molekularnog oblika gadolinija).
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.
Uzimajući u obzir razmatranje rizika od NSF-a, PRAC se oslonio na prethodnu ocjenu i razvrstavanje rizika od NSF u odnosu na razne lijekove koji sadrže GdCA sredstva te smatra da rizik od NSF-a doprinosi sigurnosnom profilu GdCA-ova te se taj rizik uzima u obzir pri donošenju zaključka o ukupnom sigurnosnom profilu tih lijekova te o utjecaju tog rizika na ukupni omjer koristi/rizika.
For the suspension of intravenous medicinal products containing gadodiamide, gadopentetic acid, and gadoversetamide to be lifted, the marketing authorisation holder(s) shall submit evidence:
Kako bi se ukinula obustava odobrenja za intravenske lijekove koji sadržavaju gadodiamid, gadopentetičnu kiselinu i gadoversetamid, nositelji odobrenja trebaju podnijeti sljedeće dokaze:
Therefore the CHMP recommends the variation to the terms of the marketing authorisations for medicinal products containing intravenous gadobutrol, gadoteric acid, gadoteridol, gadoxetic acid, intravenous gadobenic acid in the indication of liver imaging, intra-articular gadoteric acid and intraarticular gadopentetic acid.
Stoga CHMP preporučuje izmjenu uvjeta za odobrenje za stavljanje lijeka u promet za lijekove koji sadržavaju intravenski gadobutrol, gadoteričnu kiselinu, gadoteridol, gadoksetičnu kiselinu, intravensku gadobensku kiselinu za indikaciju snimanja jetre, intraartikularnu gadoteričnu kiselinu i intraartikularnu gadopentetičnu kiselinu.
Accumulation in the brain
Taloženje u mozgu
• High Gd levels with high inter-individual variability were detected in saline-treated controls.
• Visoke razine gadolinija s visokom pojedinačnom promjenjivosti primijećene su u pretragama sa fiziološkom otopinom.
The CHMP also concluded that there are practical difficulties for an effective restriction of the number of doses administered during the lifetime of a patient.
CHMP je također zaključio da postoje praktične poteškoće za djelotvorno ograničavanje broja doza koji bolesnik primi tijekom cijelog života.
Although no adverse neurological effects have yet been demonstrated to be caused by gadolinium accumulation in the brain, long-term safety data are limited.
Iako još nije pokazano da taloženje gadolinija u mozgu ima štetne neurološke učinke, podaci o dugoročnoj sigurnosti ograničeni su.
Taking into account the evidence of accumulation of GdCAs in the brain, the fact that linear compounds have been detected in the brain to a much higher amount than the macrocyclic compounds and that they persist in the brain for a longer period, and considering the toxicity of Gd shown in non-clinical studies, the serious concerns about potential neurological harm, deposition in other tissues and its potential risks, and the identified risks associated with the use of linear GdCAs (including the risk of NSF and the gadolinium-associated plaques) and in view of the whole safety profile of these agents, PRAC maintained its conclusion that that the benefit in enhancement of MR images of intravenous linear agents does not outweigh the known and potential risks of these products.
Uzimajući u obzir dokaze o taloženju GdCA-ova u mozgu, činjenicu da su otkriveni linearni spojevi u mozgu u mnogo većoj mjeri nego nakon primjene makrocikličkih spojeva, da se u mozgu zadržavaju duže vremensko razdoblje, kao i toksičnost gadolinija pokazanu u nekliničkim ispitivanjima, ozbiljne zabrinutosti u pogledu moguće štete za neurološki sustav, taloženje u drugim tkivima i moguće rizike od taloženja, kao i već utvrđene rizike povezane s uporabom linearnih GdCA-ova (uključujući značajan rizik od NSF-a i plakova povezanih s gadolinijem), kao i ukupni sigurnosni profil tih sredstava, PRAC donosi isti zaključak da korist intravenskih linearnih sredstava u pogledu poboljšavanja snimki magnetske rezonancije ne nadmašuje poznate i moguće rizike tih lijekova.
• 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.
• Postoje dokazi i o tome da je izlaganje linearnim GdCA-ovima povezano ne samo s NSF-om nego i s drugim štetnim ishodima, a posebno kožnim plakovima koje uzrokuje gadolinij.
Deposition of gadolinium in the brain
Taloženje gadolinija u mozgu
• Based on non-clinical data, both linear and macrocyclic agents have the ability to distribute to the brain.
• Neklinički podaci pokazuju da se i linearna i makrociklička sredstva mogu distribuirati u mozgu.
The PRAC also concluded that there are practical difficulties for an effective restriction of the number of doses administered during the lifetime of a patient.
PRAC je također zaključio da postoje praktične poteškoće za djelotvorno ograničavanje broja doza koje bolesnik primi tijekom cijelog života.
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 koji se odnosi na kožne plakove „postoje dokazi i o tome da je izlaganje linearnim GdCA-ovima povezano ne samo s NSF-om nego i s drugim štetnim ishodima, a posebno kožnim plakovima koje uzrokuje gadolinij“ temelji se na ograničenom broju slučajeva.
• The PRAC considered that the risk related to linear intravenous GdCAs gadobenic acid (in all indications besides liver imaging), gadodiamide, gadopentetic acid, and gadoversetamide, taking into account the whole safety profile, including the additional potential risk of harm from brain and other tissues accumulation outweighs the benefits.
• PRAC smatra da rizik povezan s linearnim intravenskim GdCA-ovima, gadobenskom kiselinom (za sve indikacije, osim za snimanje jetre), gadodiamidom, gadopentetičnom kiselinom i gadoversetamidom, uzimajući u obzir cijeli sigurnosni profil, uključujući mogući rizik od oštećenja uzrokovanih taloženjem u mozgu i drugim tkivima, nadmašuje koristi.
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.
Stoga se može zaključiti da oštećenje bubrega nije preduvjet za taloženje gadolinija, ali može povećati količinu gadolinija koji se taloži na mozgu.
The CHMP concluded that the risk of NSF is different for the different gadolinium-containing contrast agents, which lead to the categorisation of GdCAs into three risk groups for NSF (high risk, medium risk and low risk).
Stoga se GdCA-ovi kategoriziraju u tri rizične skupine u odnosu na NSF (visokorizičnu, srednjerizičnu i niskorizičnu).
• The CHMP considered that the risk related to linear intravenous GdCAs gadobenic acid (in all indications besides liver imaging), gadodiamide, gadopentetic acid, and gadoversetamide, taking into account the whole safety profile, including the additional potential risk of harm from brain and other tissues accumulation outweighs the benefits.
• CHMP smatra da rizik povezan s linearnim intravenskim GdCA-ovima, gadobenskom kiselinom (za sve indikacije, osim za snimanje jetre), gadodiamidom, gadopentetičnom kiselinom i gadoversetamidom, uzimajući u obzir cijeli sigurnosni profil, uključujući mogući rizik od oštećenja uzrokovanih taloženjem u mozgu i drugim tkivima, nadmašuje koristi.
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.
PRAC je razmotrio rezultate dviju pojedinačnih, recipročnih usporedbi, odnosno 0,1 mmol/kg tjelesne mase za Multihance u usporedbi s 0,1 mmol/kg tjelesne mase dvaju aktivnih sredstava za usporedbu (gadopentetat dimeglumin i gadodiamid) u bolesnika s poznatom ili mogućom bolesti mozga ili kralježnice koji se podvrgavaju magnetnoj rezonanciji središnjeg živčanog sustava (CNS) (MH-109, MH-130).
Gadobenic acid undergoes hepatic uptake.
Gadobenska kiselina unosi se u jetru.
• 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,
(Primovist) te gadobensku kiselinu (Multihance), uz izmjene odjeljaka u sažetku opisa svojstava lijeka 4.1., 4.2., 4.4. i 5.2., uključujući izbacivanje indikacija,