natgillin/translations-raw huggingface dataset:
- For all MAHs, in addition to routine pharmacovigilance activities, identified and potential risks highlighted for increased monitoring and follow-up should include: 
- Vsi imetniki dovoljenj za promet z zdravilom bi morali poleg rutinskih aktivnosti farmakovigilance za poostreno opazovanje izpostaviti tudi prepoznana in morebitna tveganja, ki vključujejo:
For patients with localised disease receiving CASODEX alone, there was no significant difference in progression free survival. 
Pri bolnikih z lokalizirano boleznijo, ki so dobivali samo zdravilo CASODEX, ni bilo bistvenih razlik pri preživetju brez napredovanja.
In 2004, 2 publications were published detailing a pre-planned 2nd analysis of the Casodex (bicalutamide) Early Prostate Cancer (EPC) study programme. 
V letu 2004 sta bili izdani dve publikaciji, ki podrobno opisujeta predhodno načrtovano drugo analizo raziskovalnega programa za zdravilo Casodex (bikalutamid) pri zgodnjem raku prostate (EPC).
Due to a small number of relevant subjects, no conclusions could be drawn regarding the contribution of tamoxifen or radiotherapy to cardiovascular outcomes, or on whether tamoxifen exposure had a synergistic effect on efficacy. 
Zaradi majhnega števila oseb, udeleženih na testiranju, ni bilo mogoče priti do zaključka o prispevku tamoksifena ali radioterapije k kardiovaskularnim rezultatom ali glede vprašanja, ali ima izpostavljenost tamoksifenu sinergijski vpliv na učinkovitost.
Benefit/ Risk considerations 
Pomisleki ob razmerju med koristmi in tveganji
However, it is not possible to entirely “rule out” thromboembolic events as contributory explanation of increased cardiovascular mortality. 
Kljub temu pa ni mogoče povsem izključiti vpliva tromboemboličnih dogodkov, kot razlage za povečano kardiovaskularno smrtnost.
To address this concern, a new epidemiological study will be performed, as part of an agreed Risk Management Plan. 
Za odgovor na to vprašanje se bo izvedla nova študija, ki bo del dogovorjenega načrta za obvladovanje tveganja.
Disease progression may be associated with problems such as painful bone metastases, cord compression, pathological fractures and urinary obstruction. 
Napredovanje bolezni je lahko povezano s težavami, kakršne so boleče kostne metastaze, stiskanje hrbtenjače, patološki zlomi in oviranje urinarnega pretoka.
The median PSA levels on initiation of active therapy for each subgroup are above the thresholds in current European Association of Urology (EAU) guidance. 
Mediane ravni PSA ob uvajanju aktivnega zdravljenja so pri vsaki izmed podskupin nad pražnimi vrednostmi, opredeljenimi v trenutno veljavnih smernicah Evropskega združenja za urologijo (EAU).
As a consequence, the CHMP has recommended to maintain the Marketing Authorisations for all medicinal products and to grant Marketing Authorisations for all applications referred to in Annex I of the Opinion in accordance with the amendments to the relevant sections of the Summary of Product Characteristics, set out in Annex III of the Opinion. 
Kot posledica tega je CHMP predlagal, da družba zadrži dovoljenja za promet za vsa zdravila in da se ji odobri dovoljenja za vse aplikacije, ki so bile omenjene v Dodatku I mnenja, v skladu z dopolnili predmetnih poglavij Povzetka glavnih značilnosti zdravila, kot so bile zastavljene v Dodatku III mnenja.
OVERALL SUMMARY OF THE SCIENTIFIC EVALUATION OF BICALUTAMIDE 150 mg CONTAINING MEDICINAL PRODUCTS (see Annex I) 
SPLOŠNI POVZETEK ZNANSTVENEGA VREDNOTENJA ZDRAVIL, KI VSEBUJEJO BIKALUTAMID 150 mg (glejte Dodatek I)
Bicalutamide 150 mg is marketed in the EU following national and Mutual Recognition application procedures. 
Bikalutamid 150 mg se trži v EU po odobritvi vloge za dovoljenje za promet v skladu z nacionalnimi postopki in postopki medsebojnega priznavanja.
In these patients there was also a trend toward decreased survival compared with placebo patients (HR=1.16; 95% CI 0.99 to 1.37). 
Pri teh bolnikih je obstajal trend h krajšemu preživetju v primerjavi z bolniki, ki so dobivali placebo (RO = 1,16; 95% IZ: 0,99 - 1,37).
None of the EPC trials mandated that treatment be withheld from patients in the placebo group until clinical progression. 
V nobenem od preizkušanj EPC niso zahtevali, da bi bolnikom v placebo skupini odrekli zdravljenje do kliničnega napredovanja bolezni.
Whilst the pattern of adverse events argues against a role for raised oestrogen levels, it is known that the myocardium has androgen receptors, and it might be affected by long-term androgen deprivation. 
Čeprav vzorec neželenih dogodkov ne podpira vloge povišanih ravni estrogena pri tem, pa je znano, da ima miokard androgene receptorje in da nanj lahko vpliva dolgotrajna odtegnitev androgena.
Based on the concerns raised, the following questions were posed to the Applicants/ MAHs as part of the consolidated CHMP List of Questions, the responses to which were the basis of the CHMP reassessment of the benefit/risk balance: 
Na temelju spornih vprašanj so predlagateljem/imetnikom dovoljenj za promet z zdravilom zastavili naslednja vprašanja, ki so bila del konsolidiranega seznama vprašanj CHMP, odgovori nanje pa so bili osnova za ponovno oceno razmerja med koristmi in tveganji:
With reference to heart failure mortality, the MAHs have submitted a limited amount of new data since this issue was last assessed, namely results from a further clinical study, an updated literature review and an updated review of their safety database. 
Glede smrtnosti zaradi odpovedi srca so imetniki dovoljenj za promet z zdravilom predložili omejeno količino podatkov, ki bi bili novejši od tistih, pridobljenih ob zadnjemu ocenjevanju tega spornega vprašanja in so se v glavnem nanašali na nadaljnjo klinično študijo, posodobljen pregled literature in posodobljen pregled njihove podatkovne baze o varnosti zdravila.
The numbers involved are relatively small, there is no consistent pattern for heart failure deaths over the longer term, and there is some unreliability in selecting this as a cause of death. 
Predstavljena števila so relativno nizka, dolgoročno ni doslednega vzorca umrljivosti zaradi odpovedi srca, prav tako pa je prisotne tudi nekaj nezanesljivosti pri izbiri odpovedi srca za vzrok smrti.
A reduction in risk of objective disease progression was seen across most patient groups but was most evident in those at highest risk of disease progression. 
Tveganje za objektivno napredovanje bolezni se je zmanjšalo v večini skupin bolnikov, a najočitneje pri bolnikih z največjim tveganjem za napredovanje bolezni.
- In view of the available data, the CHMP concluded that a potential association between the use of bicalutamide 150 mg and heart failure cannot be ruled out and therefore considered that the need to further study cardiovascular morbidity and mortality remains. 
- Glede na razpoložljive podatke je CHMP zaključil, da morebitne povezave med uporabo bikalutamida 150 mg in srčno odpovedjo ni mogoče izključiti in je zato mnenja, da potreba po nadaljnjem raziskovanju kardiovaskularne obolevnosti in smrtnosti ostaja.
At 7.4 years median follow up, 27.4% and 30.7% of all CASODEX and placebo-treated patients, respectively, had experienced objective disease progression. 
Po mediano 7,4 leta spremljanja se je objektivno napredovanje bolezni pojavilo pri 27,4% vseh bolnikov, ki so dobivali CASODEX, in pri 30,7% vseh bolnikov, ki so dobivali placebo.
A more specific target population is hard to define from the EPC data, and the general term “high risk” better accommodates wide differences in local practice and inevitable changes in the standard of care, and takes into account the many variables in the individual patient which may contribute to risk of progression. 
Iz podatkov o EPC je težko opredeliti še bolj specifično ciljno populacijo, tako da splošni izraz „visoko tveganje“ bolj odgovarja velikim razlikam v lokalni praksi in neizbežnim spremembam v standardu oskrbe, pri tem pa upošteva mnoge spremenljivke pri posameznem bolniku, ki lahko prispevajo k tveganju za napredovanje bolezni.
These results should of course be balanced against the well-known tolerability issues of Casodex (bicalutamide). 
Seveda bi bilo treba te rezultate pretehtati ob upoštevanju dobro znanih težav s prenašanjem zdravila Casodex (bikalutamid).
Further, the referral concerned only the locally advanced prostate cancer indication based on the Early Prostate Cancer study programme, and the directly related wording in sections 4.1 and 5.1 of the SPC. 
Poleg tega se je nanašal samo na indikacijo v zvezi z lokalno napredovalim rakom prostate, ki temelji na programu preučevanja zgodnjega raka prostate, in na besedilo, neposredno povezano s tem, ki se nahaja v poglavju 4.1 in 5.1 Povzetka glavnih značilnosti zdravila.
The majority of patients with heart failure had confounding factors at study entry, and the causality assessment of investigators for all deaths ascribed to heart failure was “not related”. 
Večina bolnikov z odpovedjo srca je imela pri vstopu v študijo zmedene faktorje, tako da je bila ocena preiskovalcev o vzročnosti pri vseh primerih smrti zaradi domnevne odpovedi srca „ni povezave“.
The requested additional analyses of the EPC trial data confirm an increased risk for deaths coded as heart failures (however, with no overall excess risk in the cardiovascular system), an increased risk of urogenital symptoms (including gynaecomastia and breast pain) mainly during the first year of intake, and further indicate the absence of an adverse effect on thromboembolic events during the follow-up (supported by a pattern of events inconsistent with hormonal effects). 
Zahtevane dodatne analize podatkov preizkušanj EPC potrjujejo povečano tveganje smrti, označenih kot odpovedi srca (vendar brez celotnega prekomernega tveganja v kardiovaskularnem sistemu), povečano tveganje pojava urogenitalnih simptomov (vključno z ginekomastijo in bolečinami v prsih) predvsem med prvim letom jemanja, poleg tega pa še odsotnost neželenega učinka na tromboembolične dogodke med spremljanjem po koncu študije (podpira ga vzorec dogodkov, ki niso skladni z učinki hormonov).
For these reasons, the CHMP considers that the progression-free survival results are important and can be considered on their merits. 
Zaradi omenjenih razlogov CHMP misli, da so rezultati o preživetju brez napredovanja bolezni pomembni in jih je treba preveriti same po sebi.
In addition, the survival advantage observed in patients with locally advanced disease receiving radiotherapy appears to be consistent with that seen in previous studies, and a synergistic effect with radiotherapy is plausible. 
Poleg tega se zdi prednost v preživetju pri bolnikih z lokalno napredovalo boleznijo, ki so prejemali radioterapijo, dosledna s preživetjem, ki so ga opazili v prejšnjih študijah, tako da je sinergijski učinek z radioterapijo verjeten.
EL - Greece Astrazeneca SA 4 Theotocopoulou & Astronauton 151 25 Marousi-Athens 
4 Theotocopoulou & Astronauton 151 25 Marousi-Athens
In view of the concerns related to safety and efficacy for bicalutamide 150 mg the National Competent Authority (NCA) in Belgium considered it to be in the interest of public health to perform a new benefit/risk assessment. 
Zaradi zadržkov glede varnosti in učinkovitosti bikalutamida 150 mg je pristojni nacionalni organ (NCA) v Belgiji zaključil, da bi bila izvedba nove ocene tveganj in koristi v interesu javnega zdravja.
Following their own review of these data carried out in 2004 and due to their resulting concerns over the benefit/risk balance of bicalutamide 150 mg in locally advanced prostate cancer, the Belgian Regulatory Authority suspended their national Marketing Authorisation for Casodex (bicalutamide) 150 mg in August 
Na podlagi lastnega pregleda teh podatkov, opravljenega leta 2004, in zaradi posledičnih zadržkov glede razmerja med koristmi in tveganji bikalutamida 150 mg pri lokalno napredovalem raku prostate, je belgijski regulativni organ avgusta leta 2005 začasno razveljavil dovoljenje za promet z zdravilom Casodex (bikalutamid) 150 mg.
15 Stanhope Gate London, W1K 1LN United Kingdom 
15 Stanhope Gate London, W1K 1LN United Kingdom tableta
EAU guidelines suggest the use of prophylactic breast radiation, tamoxifen or aromatase inhibitors to manage these symptoms, although they are not licensed in this use. 
V smernicah EAU je predlagano, da bi za urejanje teh simptomov uporabljali obsevanje prsi, tamoksifen ali zaviralce aromataze, čeprav slednji niso odobreni za uporabo v te namene.
In conclusion, the heart failure data remain a concern and are inconclusive, but do not significantly alter the benefit/risk balance in locally advanced prostate cancer patients. 
Podatki o odpovedi srca ostajajo s tem sporni in ne omogočajo jasnega zaključka, vendar ne pomenijo znatne spremembe razmerja med koristmi in tveganji pri bolnikih z lokalno napredovalim rakom prostate.
- The Committee considered the referral made under article 31 of Directive 2001/83/EC, as amended, for medicinal products containing bicalutamide 150 mg. 
- Odbor je upošteval napotitev v skladu s členom 31 Direktive 2001/83/ES z vsemi dopolnili za zdravila, ki vsebujejo bikalutamid 150 mg.
Note: This Annex III (Amendments to the Summary of Product Characteristics) is the one that was Annexed to the Commission Decision on this Article 31 referral for bicalutamide 150 mg containing medicinal products. 
Opomba: Ta Dodatek III (Spremembe Povzetka glavnih značilnosti zdravila) je identičen tistemu, ki je bil priložen odločbi Komisije v zvezi z napotitvenim postopkom, sproženim v skladu s členom 31, za zdravila, ki vsebujejo bikalutamid 150 mg.
Watchful waiting 
Oprezno čakanje
Other aspects of the SPC and the other indication for bicalutamide 150 mg, which is approved in some EU member states, were not within the scope of the referral. 
Drugi vidiki Povzetka glavnih značilnosti zdravila in druga indikacija za bikalutamid 150 mg, odobrena v nekaterih državah članicah EU, niso bili predmet te napotitve.
Gynaecomastia may not resolve spontaneously following cessation of therapy, particularly after prolonged treatment. 
Spontan izzven ginekomastije po končanem zdravljenju ni nujen, kar velja še posebej za dolgotrajno zdravljenje.
- The outcome of the 4th analysis of the EPC data should be provided to the RMS and the NCAs where bicalutamide 150 mg is authorised. 
- Izide četrte analize podatkov o EPC bi moral predložiti RMS in nacionalnim pristojnim organom, kjer je bikalutamid 150 mg odobren.
How does the company justify the absence of adjustment for tests of multiplicity in the analysis of the EPC results? 
Kako družba utemeljuje odsotnost prilagajanj za teste multiplikativnosti pri analizi rezultatov za zgodnji rak prostate?
- A new pharmacoepidemiological study(ies) should be undertaken to get a better understanding of cardiovascular risk. 
- Imetnik mora opraviti novo farmakoepidemiološko študijo (ali študije), ki bodo pripomogle k boljšemu razumevanju kardiovaskularnega tveganja.
The scope of the referral included all pending Marketing Authorisation applications as well as all Marketing Authorisations for medicinal products containing 150 mg bicalutamide. 
Napotitveni postopek se je nanašal na vse vloge za izdajo dovoljenja za promet, ki so bile v postopku odobritve, kot tudi na dovoljenja za promet za zdravila, ki vsebujejo 150 mg bikalutamida.
After the Commission Decision, the Member State competent authorities will update Annex III as required. 
Pristojne oblasti držav članic bodo posodobile Dodatek III v skladu z zahtevami, ko bo podana odločba Komisije.
It seems intuitive that for good prognosis patients who have also received treatment of curative intent, the addition of bicalutamide might confer less benefit than in other patients. 
Zdi se samoumevno, da bi lahko imel dodatek bilakutamida pri bolnikih z dobro napovedjo, ki so prejemali tudi zdravljenje kurativnega značaja, manj koristnih učinkov kot pri drugih bolnikih.
- The Committee considered that bicalutamide 150 mg is effective in the treatment of locally advanced prostate cancer; however the CHMP considered that the therapeutic indication should be restricted to treatment of patients at high risk of disease progression. 
- Odbor je upošteval, da je bikalutamid 150 mg učinkovit pri zdravljenju lokalno napredovalega raka prostate, vendar pa je bil CHMP mnenja, da bi morale biti indikacije za zdravljenje omejene na zdravljenje bolnikov z visokim tveganjem za napredovanje bolezni.
Regarding the heart failure deaths, the allocation of cause of death is known to be unreliable, and very few post-mortems were done. 
Kar se tiče primerov smrti zaradi odpovedi srca, je ugotavljanje vzroka za smrt ugotovljeno nezanesljivo, opravili pa so tudi le majhno število obdukcij.
The EPC study was an empirical design, that is to say, it generally compared Casodex (bicalutamide) to the standard of care in each region involved. 
Študija EPC je temeljila na empiričnem načrtu, kar pomeni, da je na splošno primerjala Casodex (bikalutamid) s standardno nego, značilno za vsako regijo, vključeno v študijo.
At the initial authorisation of the early prostate cancer indication, the data for overall survival were too immature to allow an analysis, however it makes sense to subsequently analyse this endpoint in the same subgroups, and there are favourable trends in overall survival for patients with locally advanced disease receiving Casodex (bicalutamide) alone, and for patients also receiving radiotherapy. 
V času začetne odobritve za indikacijo zgodnjega raka prostate so bili podatki za celotno preživetje še preveč nerazviti, da bi omogočali analizo, vendar pa je naknadna analiza te končne točke v istih podskupinah smiselna, saj obstajajo koristni trendi pri celotnem preživetju bolnikov z lokalno napredovalo boleznijo, ki prejemajo zdravilo Casodex (bikalutamid) bodisi samostojno ali v kombinaciji z radioterapijo.
When the EPC programme was initiated more than 8 years ago, the aim was to document the benefit of early bicalutamide therapy versus placebo as monotherapy or adjuvant therapy to surgery or radiotherapy. 
Ob začetku programa EPC pred več kot osmimi leti je bil cilj dokumentirati primerjavo koristnih učinkov zgodnjega zdravljenja z bikalutamidom glede na placebo, uporabljenega kot monoterapija ali adjuvantno zdravljenje h kirurgiji ali radioterapiji.
How does the company justify that the placebo arm did not receive an adequate treatment according to the present standard of care and why this is not taken into account in the analysis of the EPC results? 
Kako družba utemeljuje dejstvo, da placebo skupina glede na veljavne standarde nege ni prejela ustreznega zdravljenja in zakaj to ni bilo upoštevano pri analizi rezultatov za zgodnji rak prostate?
Benefit is generally a function of risk progression and in patients with locally advanced disease; benefit is reduced after surgery or in cases where radiotherapy is likely to be curative. 
Koristni učinki so navadno funkcija napredovanja tveganja in so opazni pri bolnikih z lokalno napredovalo boleznijo; koristni učinki se zmanjšajo po kirurškemu posegu ali tam, kjer bo radioterapija po vsej verjetnosti imela zdravilen učinek.
AMENDMENTS TO THE SUMMARY OF PRODUCT CHARACTERISTICS 
SPREMEMBE POVZETKA GLAVNIH ZNAČILNOSTI ZDRAVILA
In particular, there is a statistically significant and clinically meaningful improvement in progression-free survival in the patients with locally advanced prostate cancer who received Casodex (bicalutamide) as compared to placebo (58% versus 69% progressors in patients who were not receiving adjuvant surgery or radiotherapy). 
Opaziti je statistično značilno in klinično pomembno izboljšanje preživetja brez napredovanja bolezni pri bolnikih z lokalno napredovalim rakom prostate, ki so prejemali zdravilo Casodex (bikalutamid), glede na tiste, ki so prejemali placebo (58 % napram 69 % bolnikov z napredovanjem bolezni in ki niso prejemali adjuvantne kirurgije ali radioterapije).
As regards the multiplicity issue raised, it is considered appropriate to look at subgroups from a statistical viewpoint, as they have helped to narrow the indication to patients with a more favourable benefit/risk balance for bicalutamide 150 mg. 
Kar se tiče vprašanja multiplikativnosti, se zdi primerno pregledati podskupine iz statističnega stališča, saj so pri bikalutamidu 150 mg pomagale zožiti indikacijo na bolnike z bolj ugodnim razmerjem med koristmi in tveganji.
CASODEX (Bicalutamide) 150 mg was studied as a treatment for patients with localised (T1-T2, N0 or NX, M0) or locally advanced (T3-T4, any N, M0; T1-T2, N+, M0) non-metastatic prostate cancer in a combined analysis of 3 placebo controlled double-blind studies in 8113 patients, where CASODEX was given as immediate hormonal therapy or as adjuvant to radical prostatectomy or radiotherapy, (primarily external beam radiation). 
CASODEX (bikalutamid) 150 mg je bil preučevan kot terapija za bolnike z lokaliziranim (T1-T2, N0 ali NX, M0) ali lokalno napredovalim (T3-T4, katerikoli N, M0; T1-T2, N+, M0) nemetastatskim rakom prostate v kombinirani analizi treh s placebom kontroliranih, dvojno slepih študij pri 8113 bolnikih.
How does the company justify the indication of bicalutamide 150 mg for locally advanced prostate cancer knowing the absence of statistically significant overall survival and the important side effects? 
Kako družba utemeljuje indikacijo bikalutamida 150 mg za lokalno napredovali rak prostate, če ve, da so statistično značilno celotno preživetje in pomembni neželeni učinki odsotni?
AMENDMENTS TO BE INCLUDED IN THE RELEVANT SECTION OF THE SUMMARY OF PRODUCT CHARACTERISTICS FOR BICALUTAMIDE 150MG CONTAINING MEDICINAL PRODUCTS 
SPREMEMBE, KI BODO VKLJUČENE V USTREZEN ODSTAVEK POVZETKOV GLAVNIH ZNAČILNOSTI ZDRAVIL, KI VSEBUJEJO BIKALUTAMID 150 MG
With reference to the adequacy of treatment in the placebo group in the EPC studies, given that at the time of initiation of these studies there was no widely agreed standard of care in locally advanced prostate cancer (something which remains the case), the empirical design of the studies, which compared Casodex (bicalutamide) 150mg or placebo when given as an adjunct to “standard care” is considered reasonable. 
Z ozirom na primernost zdravljenja v placebo skupini v študijah EPC in glede na dejstvo, da v času uvajanja teh študij ni bilo široko sprejetega standarda nege lokalno napredovalega raka prostate (to še vedno velja), velja empirična zasnova študij, v katerih so primerjali dajanje zdravila Casodex (bikalutamid) 150 mg ali placeba kot dodatek „standardni negi“, za sprejemljivo.
Its authorised indications include the treatment of patients with locally advanced prostate cancer, as an immediate therapy either alone or as adjuvant to treatment by radical prostatectomy or radiotherapy. 
Odobrene indikacije vključujejo takojšnje zdravljenje bolnikov z lokalno napredovalim rakom prostate, bodisi samostojno bodisi kot adjuvans k zdravljenju z radikalno prostatektomijo ali radioterapijo.
The 4 issues raised in the referral concern the analyses of the Early Prostate Cancer Programme (EPC): - the lack of an overall survival benefit versus adverse events in ‘locally advanced prostate cancer'; - statistical concerns regarding multiplicity; - the standard of care for the placebo group in the relevant studies; - the number of deaths due to cardiac failure. 
Štiri sporna vprašanja v napotitvenem postopku so bila: - pomanjkanje koristnega učinka za celotno preživetje napram neželenim učinkom pri „lokalno napredovalemu raku prostate“; - statistični zadržki glede multiplikativnosti; - standard oskrbe za skupino, ki je prejemala placebo, v zadevnih študijah; - število smrti zaradi odpovedi srca.