natgillin/translations-raw huggingface dataset:
• 1 case due to exposure during the foetal period (i.e. a case of foetotoxic effects that resulted in foetal or neonatal type of achieving growth impact, or histological or functional maturation of organs in place (the period during which the greatest risk begins in the second quarter of pregnancy),
• 1 slučaj zbog izlaganja tijekom fetalnog razdoblja (odnosno slučaj fetotoksičnog djelovanja koje rezultira fetalnim ili neonatalnim tipom postizanja učinka rasta ili histološkim odnosno funkcionalnim sazrijevanjem organa u mjestu (razdoblje tijekom kojeg počinje najveći rizik u drugom kvartalu trudnoće),
• 20 cases due to exposure during the embryonic period, of which: o two cases of teratogenic effects (malformations) associated with exposure in early pregnancy (the first quarter is the period during which the risk is the greatest), o four cases resulting in discontinuation of the pregnancy (3 spontaneous abortions and one voluntary abortion not due to medical reason), o five cases with a favourable evolution (no effect on the new born), o nine cases with an unknown evolution of the pregnancy due to lack of documentation.
• 20 slučajeva zbog izlaganja tijekom stadija embrija, od kojih su: o dva slučaja teratogenskog djelovanja (malformacija) povezanog s izlaganjem u ranoj trudnoći (prvi kvartal je razdoblje tijekom kojeg je rizik najveći), o četiri slučaja rezultirala su prekidom trudnoće (3 spontana pobačaja i jedan dobrovoljan pobačaj koji nije bio proveden zbog medicinskih razloga), o pet slučajeva s povoljnom evolucijom (bez učinka za novorođenče), o devet slučajeva s nepoznatom evolucijom trudnoće zbog nedostatka dokumentacije.
To address the risks of teratogenicity and embryo-toxicity/spontaneous abortions the CHMP agreed on contraindicating TCC during the entire pregnancy period, during lactation, and in women of childbearing potential not using contraception.
Kako bi se uklonio rizik od teratogenosti i embrionalne toksičnosti/spontanih pobačaja, CHMP je suglasan s kontraindiciranjem TCC-a tijekom cijelog razdoblja trudnoće, tijekom laktacije i u žena s reproduktivnim potencijalom koje ne koriste kontracepciju.
However, more concern was raised in relation to the potential risk of foetal anomalies due to elevated sperm aneuploidy rather than to the male infertility per se.
No, veću zabrinutost je izazvao potencijalni rizik od fetalnih anomalija zbog povećane aneuploidije kromosoma spermija nego neplodnost u muškaraca kao takva.
Genotoxicity data on aglycone metabolite SL59.0955 (M2)
Podaci o genotoksičnosti metabolita aglikona SL59.0955 (M2)
Continuous monitoring of any safety signal correlated with aneuploidy (i.e. teratogenicity, embryo-foetal toxicity / spontaneous abortion, impaired male fertility and cancer) and pregnancy reporting to collect structured data on accidental exposure to the drug should be performed.
Potrebno je provoditi kontinuirano praćenje svih sigurnosnih signala povezanih s aneuploidijom (odnosno teratogenost, embrio-fetalna toksičnost / spontani pobačaj, poremećena plodnost u muškaraca i rak) i prijave trudnoća kako bi se prikupili strukturirani podaci o slučajnom izlaganju lijeku.
But no NOAEL for aneugenic effects was identified in rat females (LOEL = 25 mg/kg) and no clear dose related effect was observed because only slight difference in exposure (AUC0-24 and Cmax) with 3demethylthiocolchicine (SL59.0955) were observed between the different doses in males and females.
No NOAEL za aneugeno djelovanje nije identificiran u ženki štakora (LOEL = 25 mg/kg) te nije uočeno učinak jasno povezan s dozom jer je uočena samo neznatna razlika u izlaganju (AUC0-24 i Cmax) s 3-demetiltiokolhikinom (SL59.0955) između različitih doza u mužjaka i ženki.
The in vitro MN test in human lymphocytes showed that M2 induced micronuclei in cultured human peripheral blood lymphocytes in all treatment conditions.
Testom in vitro MN u ljudskih limfocita utvrđeno je da M2 izaziva mikronukleuse u kultiviranim ljudskim perifernim krvnim limfocitima u svim uvjetima liječenja.
Subsequent mechanistic analysis via the use of fluorescence in situ hybridization (FISH) with pan centromeric DNA probes demonstrated that micronuclei were predominantly generated via an aneugenic (numerical chromosome abnormality) mechanism under all treatment conditions; aneuploidy was clearly confirmed by centromere staining.
Naknadna mehanistička analiza putem primjene fluorescentne svjetlosti in situ hibridizacija (FISH) s pancentromernim probama DNK-a pokazala je da su mikronukleusi uglavnom prevladavali u aneugenom (numerička abnormalnost kromosoma) mehanizmu u svim stanjima liječenja; aneuploidija jasno je potvrđena bojanjem centromere.
However, having considered the risks, thiocolchicoside containing medicinal products for systemic use should only be administered to patients over 16 years of age in acute conditions, with treatment duration limited to 7 (oral) and 5 (IM) consecutive days.
No, uzimajući u obzir rizike, lijekovi koji sadrže tiokolhikozid za sistemsku primjenu smiju se davati samo bolesnicima starijima od 16 godina u slučaju akutnih stanja, pri čemu je trajanje liječenja ograničeno na 7 (peroralno) i 5 (intramuskularno) uzastopnih dana.
In the two in vitro and in vivo preclinical studies conducted, the findings (increase in the incidence of micronucleated cells) were observed at concentrations/exposures close to the exposures measured in human at therapeutic doses.
U dva provedena in vitro i in vivo predklinička ispitivanja, nalazi (povećanje u incidenciji mikronukleatidnih stanica) uočeni su u koncentracijama/izlaganjima u blizini izlaganja izmjerenih u ljudi pri terapijskim dozama.
• The Committee considered all available data from pre-clinical, clinical studies, pharmacoepidemiological studies, published literature, post-marketing experience on the safety of thiocolchicoside containing medicinal products for systemic use with regards to its genotoxicity.
• Povjerenstvo je razmotrilo sve dostupne podatke iz predkliničkih ispitivanja, kliničkih ispitivanja, farmakoepidemioloških ispitivanja, objavljene literature, iskustva nakon stavljanja lijeka u promet o sigurnosti lijekova koji sadrže tiokolhikozid za sistemsku primjenu s obzirom na njegovu genotoksičnost.
Aneuploidy (variation in the number of chromosomes and loss of heterozygosity) is recognised as a potential risk factor for cancer when impacting somatic cells, and teratogenicity, embryotoxicity/spontaneous abortions and impaired male fertility when impacting germ cells1.
Aneuploidija (varijacija u broju kromosoma i gubitak heterozigotnosti) prepoznata je kao potencijalan čimbenik rizika od raka u slučaju kada utječe na somatske stanice, i teratogenosti, toksičnost embrija/spontanih pobačaja te poremećaja plodnosti u muškaraca kada utječe na zametne stanice1.
In conclusion, the results of the above pre-clinical studies showed that M2 (SL59.0955) induced micronuclei in vitro and in vivo, generated via a predominantly aneugenic mechanism under all treatment conditions.
Zaključno, rezultati prethodno navedenih kliničkih ispitivanja pokazuju da su mikronukleusi inducirani M2 (SL59.0955) in vitro i in vivo generirani putem uglavnom aneugenog mehanizma u svim uvjetima liječenja.
After discontinuation of the above-mentioned phase I clinical trial with TCC, the genotoxic potential of the aglycone metabolite SL59.0955 (M2) was further investigated.
Nakon prekida prethodno spomenute faze I kliničkog ispitivanja sa TCC-om dalje je istražen genotoksični potencijal metabolita aglikona SL59.0955 (M2).
The study protocol should be provided within the RMP.
Protokol ispitivanja mora se dostaviti u sklopu RMPa.
• an in vitro micronucleus (MN) test in primary culture of human lymphocytes with the aglycone metabolite (SL59.0955), with centromere staining (Whitwell J., 2012);
• test in vitro mikronukleusa (MN) u primarnoj kulturi ljudskih limfocita s metabolitom aglikona (SL59.0955), s bojenjem centromere (Whitwell J., 2012.);
The CHMP reviewed all available data from pre-clinical and clinical studies, literature and post-marketing experience on aneuploidy for TCC containing medicinal products for systemic use.
CHMP je pregledao sve dostupne podatke iz predkliničkih i kliničkih ispitivanja, literature i iskustva nakon stavljanja lijeka u promet o aneuploidiji za lijekove koji sadrže TCC-a za sistemsku uporabu.
The CHMP was therefore of the view that risk minimisation measures (RMMs) should be undertaken in order to address the risks of teratogenicity, embryo-toxicity/spontaneous abortions, impaired male fertility and cancer.
Stoga je CHMP mišljenja da se mjere smanjivanja rizika trebaju poduzeti kako bi se uklonili rizici od teratogenosti, embrionalne toksičnosti/spontanih pobačaja, poremećene plodnosti u muškaraca i raka.
In that respect, the CHMP was of the view that the indication in “Parkinson's disease and druginduced Parkinsonism with special consideration to neurodyslectic syndrome” should be removed as this is a chronic condition which requires longer treatment duration.
U tom pogledu, mišljenje je CHMP-a da se indikacija u „Parkinsonove bolesti i lijekom izazvanom Parkinsonizmu s posebnom pažnjom na neurodislektični sindrom” treba ukloniti s obzirom da je ovo kronično stanje koje zahtjeva dulje trajanje liječenja.
In that respect, the CHMP was of the view that the indication in “Parkinson's disease and drug-induced Parkinsonism with special consideration to neurodyslectic syndrome” should be removed as this is an indication for chronic use.
U tom smislu, mišljenje je CHMP-a da se indikacija u „Parkinsonovoj bolesti i Parkinsonizmu izazvanom lijekovima s posebnim razmatranjem neurodisleksičnog sindroma” treba ukloniti s obzirom da je to indikacija za kroničnu primjenu.
• Firstly, since the TCC metabolite M2 has been shown to be aneugenic at exposure levels close to human therapeutic exposure, the CHMP considered that the dose should be restricted (to 8 mg bid PO and 4 mg bid by IM) and long-term use avoided.
• Prvo, s obzirom da je utvrđeno kako je M2 metabolit TCC-a aneugen pri izlaganju razinama koje su blizu ljudskom terapijskom izlaganju, CHMP smatra da se doza mora ograničiti (do 8 mg peroralno dva puta dnevno i 4 mg intramuskularno dva puta dnevno), te da se dugotrajna primjena mora izbjeći.
Widely used by prescribers in the concerned Member States (see Annex I), the benefits of TCC containing medicinal products are recognised in clinical practice.
Propisivači u državama članicama u kojima je lijek odobren (vidjeti Dodatak I) uvelike primjenjuju ovaj lijek, a koristi lijekova koji sadrže TCC prepoznate su u kliničkoj praksi.
New studies were performed in 2011 and 2012 regarding the genotoxicity of the parent compound (TCC), its main circulating metabolite SL18.0740 and the aglycone metabolite SL59.0955.
Provedena su nova ispitivanja u 2011. i 2012. godini u vezi s genotoksičnošću početnog spoja (TCC-a), njegovog glavnog metabolita u opticaju SL18.0740 i metabolita aglikona SL59.0955.
These PSURs should include a report compiling continuous monitoring of any safety signal correlated with aneuploidy and pregnancy on accidental exposure to the drug.
Ovi PSUR-ovi trebaju uključivati izvješće o slučajnom izlaganju lijeku, koji sadrži kontinuirano praćenje prijava o bilo kakvim sigurnosnim signalima povezanim s aneuploidijom i trudnoćom.
After discontinuation by a Company of a phase I clinical trial with TCC because of new non-clinical findings, the Italian medicines agency (AIFA) requested one of the Marketing Authorisation Holders (MAH) of TCC to further investigate the genotoxic potential of TCC and in particular of its metabolites; the MAH was requested to perform in vivo and in vitro preclinical studies to address the potential genotoxicity of the metabolites of TCC.
Nakon što je tvrtka prekinula fazu I kliničkog ispitivanja sa TCC-om zbog novih predkliničkih nalaza, Talijanska agencija za lijekove (AIFA) zatražila je od jednog od nositelja odobrenja za stavljanje u promet TCC-a da pobliže istraži genotoksični potencijal TCC-a, a posebice njegovih metabolita.
The corresponding product information sections were updated accordingly.
M2. Prema tome obnovljeni su odgovarajući dijelovi informacija o lijeku.
Various genetic toxicology studies were conducted on TCC and on its major identified metabolite 3-O-glucuronidated aglycone (SL18.0740), which is the active metabolite.
Različita ispitivanja genetske toksikologije provedena su za TCC-u i njegov glavni identificirani metabolit 3-O-glukuronidat aglikon (SL18.0740), koji je aktivan metabolit.
Amendments to the warnings and pregnancy and lactation sections of the product information were also endorsed.
Potvrđene su dopune dijelova Upozorenja i Trudnoća i laktacija informacija o lijeku.
• an in vivo MN test in rat bone marrow following administration of aglycone metabolite (SL59.0955) by oral route in rats with centromere staining and with a full assessment of exposure to SL59.0955 and to 3-O-glucuronidated aglycone metabolite (SL18.0740) to better assess the threshold of exposure (Wase K., October 2012).
• test in vivo MN u koštanoj srži štakora nakon peroralne primjene metabolita aglikona (SL59.0955) u štakora s bojenjem centromere i s potpunom ocjenom izlaganja metabolitu SL59.0955 i metabolitu 3-O-glukuronidiranog aglikona (SL18.0740) sa ciljem bolje ocjene praga izlaganja (Wase K., listopad 2012.).
In addition, three-yearly PSURs should be submitted by all MAHs of these products.
Nadalje, nositelji odobrenja za ove lijekove moraju dostaviti PSUR-ove svake tri godine.
To address it, the proposed RMM (indication limited to acute conditions, treatment duration limited to seven consecutive days, avoidance of long-term use) were considered appropriate by the CHMP.
Kako bi se ovaj rizik uklonio, CHMP smatra primjerenim predloženi RMM (indikaciju ograničenu na akutna stanja, trajanje liječenja ograničeno na sedam uzastopnih dana, izbjegavanje dugotrajne primjene).
Overall summary of the scientific evaluation of thiocolchicoside containing medicinal products for systemic use (see Annex I)
Cjelokupan sažetak znanstvene ocjene lijekova koji sadrže tiokolhikozid za sistemsku primjenu (vidjeti Dodatak I)
Genotoxicity data on TCC and its main circulating metabolite SL18.0740 (M1)
Podaci o genotoksičnosti TCC-a i njegovih metabolita u opticaju SL18.0740 (M1)
Having noted the above, the CHMP concluded that the benefit-risk balance of TCC containing medicinal products indicated as adjuvant treatment of painful muscle contractures in acute spinal pathology in adults and adolescents from 16 years onwards remains favourable subject to the restrictions, warnings, other changes to the product information, additional pharmacovigilance activities and RMMs agreed.
Uzimajući u obzir prethodno navedeno, CHMP je zaključio da omjer koristi i rizika za lijekove koji sadrže TCC-a indicirane za adjuvantno liječenje bolnih mišićnih kontraktura u akutnoj patologiji kralježnice u odraslih i adolescenata u dobi od 16 godina i starijih ostaje povoljan, no predmetom je ograničenja, upozorenja, ostalih promjena u informacijama o lijeku, dodatnim radnjama na području farmakovigilancije i usuglašenih RMM-ova.
The CHMP was therefore of the view that the available data allow to confirm a clear aneugenic effect of the thiocolchicoside metabolite M2 at concentrations which are 4 fold the human exposure in plasma after oral 8 mg TCC treatment bid (recommended dose) and starting from 25 mg/kg dose.The submitted data did not allow establishing a NOEL for aneuploidy, thus not excluding the potential for a human risk.
Stoga je CHMP mišljenja da dostupni podaci omogućuju potvrdu jasnog aneugenog djelovanja metabolita tiokolhikozida M2 u koncentraciji koje su četverostruke u odnosu na ljudsko izlaganje u plazmi nakon peroralne terapije TCC-om od 8 mg (preporučena doza) dva puta dnevno i počevši od doze od 25 mg/kg.
The Committee, as consequence, concluded that the benefit-risk balance of thiocolchicoside containing medicinal products for systemic use as adjuvant treatment of painful muscle contractures in acute spinal pathology in adults and adolescents from 16 years onwardsremains favourable, subject to the restrictions, warnings, other changes to the product information, additional pharmacovigilance activities and risk minimisation measures agreed.
Slijedom navedenog, Povjerenstvo je zaključilo da je omjer koristi i rizika lijekova koji sadrže tiokolhikozid za sistemsku primjenu kao adjuvantnu terapiju za bolne mišićne kontrakture u akutnoj spinalnoj patologiji u odraslih osoba i adolescenata u dobi od 16 godina i starijih ostaje povoljan, no predmetom je ograničenja, upozorenja, drugih promjena u informacijama o lijeku, dodatnim farmakovigilancijskim postupcima i usuglašenih mjera smanjivanja rizika.
This was associated with M1 plasma AUC of 4073 ng.h/mL, which is more than 20 times higher than M1 exposure observed in human after a 8 mg bid oral dose of TCC (175 ng.h/mL at 30 min).
je više od 20 puta veća vrijednost od M1 izlaganja uočenog u ljudi nakon 8 mg peroralne doze TCC-a (175 ng.h/mL u 30. minuti) uzete dva puta dnevno.
An amendment to the product information was agreed to address this concern.
Usuglašena je dopuna informacija o lijeku kako bi se uklonilo ovo sigurnosno pitanje.
Clinical trials and post marketing spontaneous reports were submitted by the MAHs.
Nositelji odobrenja dostavili su klinička ispitivanja i spontane prijave nakon stavljanja lijeka u promet.
Based on common use in acute settings, other recommendations for the posology were included as the limitation of the treatment duration to 7 days in case of oral administration and to 5 days in case of IM administration; a reference to the maximum dose allowed was also recommended .Finally a 12 hours interval between 2 consecutive administrations was requested in view of the elimination half-life of the M2 metabolite.
Na temelju uobičajene primjene u akutnom okruženju, ostale preporuke za doziranje uključene su kao ograničenje liječenja u trajanju od 7 dana u slučaju peroralne primjene i do 5 dana u slučaju intramuskularne primjene.
• Carcinogenicity and impaired fertility are categorised as important potential risks.Concerning the risk of male infertility: elevated sperm chromosome aneuploidy is known to be associated with male infertility.
Vezano uz rizik neplodnosti u muškaraca: poznato je da se povećana aneuploidija kromosoma spermija povezuje s neplodnošću u muškaraca.
No cases of cancer, congenital abnormalities, spontaneous abortion and impaired male fertility were retrieved from a review of clinical trials and literature.
Pregledom kliničkih ispitivanja i literature nisu utvrđeni slučajevi raka, kongenitalnih abnormalnosti, spontanih pobačaja i poremećene plodnosti u muškaraca.
The use of the product should therefore be limited to acute conditions in patients over 16 years old; an updated SmPC with restriction for use and duration therapy was endorsed accordingly.
Primjena lijeka se stoga treba ograničiti na akutna stanja u bolesnika starijih od 16 godina.
Pre-clinical studies
Predklinička ispitivanja
If a longer duration of use is required, other pharmaceutical forms are available.
Ako je potrebna duža primjena, dostupni su drugi farmaceutski oblici.
[The currently approved indications should be deleted and replaced by the following:]
[Trenutno odobrene indikacije potrebno je izbrisati i zamijeniti sljedećim:]
Very common: Transaminases increased.
Vrlo često: povišene transaminaze.
For single dose application in adults with postoperative pain.
Za jednokratnu primjenu u odraslih bolesnika s postoperativnom boli.
[All pharmaceutical forms]
[Svi farmaceutski oblici]
If you get any side effects, talk to your <doctor> <or> <,> <pharmacist> <or nurse>.
Ako primijetite bilo koju nuspojavu, potrebno je obavijestiti <liječnika> <ili> <,> <ljekarnika> <ili medicinsku sestru>.
Not known: Hepatitis, liver failure.
Nije poznato: hepatitis, zatajenje jetre.
Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V*.
Od zdravstvenih djelatnika se traži da prijave svaku sumnju na nuspojavu lijeka putem nacionalnog sustava prijave nuspojava navedenog u Dodatku V.*.
Very common: Liver enzymes increased Frequency not known: Hepatitis, liver failure
Vrlo često: povišene vrijednosti jetrenih enzima Učestalost nije poznata: hepatitis, zatajenje jetre
< Product Name > must only be used if treatment with other analgesics (e.g. non-steroidal antiinflammatory drugs, weak opioids) is contraindicated.
< Naziv lijeka > smije se koristiti samo ako je liječenje drugim analgeticima (npr. nesteroidnim protuupalnim lijekovima, slabim opioidima) kontraindicirano.
[All pharmaceutical forms] Liver disorders:
[Svi farmaceutski oblici] Poremećaji jetre:
Section 4.5 Interaction with other medicinal products and other forms of interaction [The wording below should be inserted in this section]
Dio 4.5 Interakcije s drugim lijekovima i drugi oblici interakcija [U ovaj je dio potrebno uvrstiti sljedeći tekst]
What you need to know before you use < product name > [The wording below should be inserted in the relevant sections]
Što morate znati prije nego što počnete uzimati < naziv lijeka > [U odgovarajuće je dijelove potrebno uvrstiti sljedeći tekst]
<Product name > must only be used if treatment with other analgesics is contraindicated.
<Naziv lijeka> smije se koristiti samo ako je liječenje drugim analgeticima kontraindicirano.
If you observe any symptoms that may indicate hepatic damage during treatment with <Product Name> (e.g. loss of appetite, nausea, vomiting, abdominal discomfort, fatigue, dark urine, jaundice, pruritus) you have to discontinue intake/use of <Product Name> and to seek medical advice immediately if any such symptoms occur.
Ako tijekom liječenja < naziv lijeka > primijetite bilo koje simptome koji mogu upućivati na oštećenje jetre (npr. gubitak apetita, mučnina, povraćanje, bol u trbuhu, umor, tamna mokraća, žutica, svrbež), morate prestati uzimati/primjenjivati < naziv lijeka > i u slučaju pojave bilo kojih od tih simptoma odmah zatražite savjet liječnika.
[Oral pharmaceutical forms and suppositories] Do not <take><use><Product name> if you: suffer from pre-existing liver disease suffer from alcoholism concomitantly use other medicinal products known to cause drug induced liver injury.
[Oralni farmaceutski oblici i supozitoriji] Nemojte <uzimati> <primjenjivati ><naziv lijeka> ako: imate postojeću bolest jetre ste alkoholičar istovremeno uzimate druge lijekove za koje je poznato da izazivaju oštećenje jetre.
Patients should be advised to remain vigilant for any symptoms compatible with hepatic damage during treatment with <Product Name> (e.g. loss of appetite, nausea, vomiting, abdominal pain, fatigue, dark urine, jaundice, pruritus) and to discontinue intake of <Product Name> and to seek medical advice immediately if any such symptoms occur.
Bolesnike je potrebno upozoriti da tijekom liječenja <naziv lijeka> prate simptome koji upućuju na oštećenje jetre (npr. gubitak apetita, mučnina, povraćanje, bol u abdomenu, umor, tamna mokraća, žutica, pruritus) i u slučaju pojave bilo kojih od tih simptoma prestanu uzimati <naziv lijeka> i odmah zatraže savjet liječnika.
If liver function tests show pathological results your doctor will ask you to discontinue intake/use of <Product Name> immediately.
U slučaju poremećenih vrijednosti laboratorijskih testova funkcije jetre, liječnik će Vam reći da odmah prestanete uzimati /primjenjivati <naziv lijeka >.
Concomitant use of flupirtine with other drugs known to cause drug induced liver injury must be avoided (see Section 4.5).
Mora se izbjegavati istovremena primjena flupirtina i drugih lijekova za koje je poznato da induciraju oštećenje jetre (vidjeti dio 4.5).
Concomitant use of flupirtine with other drugs known to cause drug induced liver injury must be avoided (see Section 4.3).
Mora se izbjegavati istovremena primjena flupirtina i drugih lijekova za koje je poznato da induciraju oštećenje jetre (vidjeti dio 4.3).