natgillin/translations-raw huggingface dataset:
OVERALL SUMMARY OF THE SCIENTIFIC EVALUATION OF PROKANAZOL AND ASSOCIATED NAMES (SEE ANNEX I) 
SPLOŠNI POVZETEK ZNANSTVENEGA VREDNOTENJA ZDRAVILA PROKANAZOL IN Z NJIM POVEZANIH IMEN (GLEJTE DODATEK I)
The product was authorised in the reference member state under Article 10.1 of Directive 2001/83/EC and the application was submitted in the concerned member states under the Mutual recognition procedure. 
Zdravilo je bilo odobreno v referenčni državi članici v skladu s členom 10.1 Direktive 2001/83/ES, v zadevnih državah članicah pa je bila predložena vloga po postopku medsebojnega priznavanja.
However, excluding subject 24 because of low itraconazole plasma concentrations is not acceptable. 
Vendar izključitev preiskovanca št. 24 zaradi nizkih koncentracij itrakonazola v plazmi ni sprejemljiva.
As a consequence, all or almost all the volunteers had one or several points with values below the limit of quantification (BLQ). 
Posledično so imeli vsi ali skoraj vsi prostovoljci eno ali več točk z vrednostmi pod mejo kvantifikacije.
Moreover, in certain volunteers (based on the submitted data) the terminal phase was derived from Cmax. 
Poleg tega je bila pri določenih prostovoljcih (na podlagi predloženih podatkov) terminalna faza izpeljana iz Cmax.
Therefore, bioequivalence can be considered to be proven for the 35 subjects who were included in the analysis. 
Zato lahko šteje, da je biološka enakovrednost dokazana za 35 preiskovancev, ki so bili vključeni v analizo.
Likewise it will be important to take into account the last quantified concentration in comparison with the value of the lower limit of quantification (LLOQ). 
Podobno je treba upoštevati zadnjo kvantificirano koncentracijo v primerjavi z vrednostjo spodnje meje kvantifikacije (LLOQ).
The problem is thus not only the five subjects of the original dossier but also the absence of pharmacokinetic calculations. 
Torej težava ni le zaradi petih preiskovancev v originalni dokumentaciji, ampak tudi zaradi odsotnosti farmakokinetičnih izračunov.
In the Applicant study, mean results of this pharmacokinetic parameter were 19.3 and 19.0 hours for the reference and the test compounds, respectively. 
V študiji predlagatelja sta bila rezultata tega farmakokinetičnega parametra 19,3 ure za referenčno spojino in 19,0 ure za preskusno spojino.
It is therefore unknown how the terminal phase and the residual area were calculated. 
Zato ni znan postopek izračuna terminalne faze in rezidualne površine.
Therefore, selecting the last sample point as being at +96 hours corresponds to more than 3 half-lives (based on the theoretical a priori information) and more than 5 half-lives (based on the experimental value obtained in the study). 
Zato izbrana zadnja točka vzorčenja +96 ur ustreza več kot trikratniku razpolovne dobe (na podlagi teoretične apriorne informacije) ter več kot petkratniku razpolovne dobe (na podlagi eksperimentalne vrednosti, pridobljene v študiji).
Please provide the raw data of all volunteers used for calculations. 
Prosimo, predložite neobdelane podatke vseh prostovoljcev, ki ste jih uporabili za izračune.
Using this approach, the regression with the best adjustment is retained from the experimental data in order to provide a reliable estimation of the elimination constant and thereby of the pharmacokinetic parameters derived from it. 
S tem pristopom se ohrani regresija z najboljšo korekcijo iz eksperimentalnih podatkov, da bi dobili zanesljivo oceno konstante eliminacije in s tem iz nje izpeljanih farmakokinetičnih parametrov.
Please produce calculations of the following after removal of volunteers with values below the LOQ: a. AUCinf; b. AUCt; c. Cmax 
Prosimo vas za izračune naslednjih vrednosti po izključitvi prostovoljcev z vrednostmi pod LOQ: a. AUCinf; b. AUCt; c. Cmax
The confidence intervals and the value of relative bioavailability for the 3 parameters (Cmax, AUCt and AUCinf) were provided. 
Predloženi so bili intervali zaupanja in vrednost relativne biološke razpoložljivosti za 3 parametre (Cmax, AUCt in AUCinf).
- the exclusion of an outlier subject is not accepted, as the data must be interpreted in its totality, 
- izključitev preiskovanca, ki je bil osamelec, ni sprejeta, saj je treba podatke interpretirati v njihovi celovitosti;
Itraconazole is an antimycoticum active against infections caused by dermatophytes, yeasts, Aspergillus spp, Histoplasma spp., Paracoccidioides brasiliensis, Sporothrix schenckii, Fonsecaea spp., Cladosporium spp., Blastomyces dermatitidis, and various other yeasts and fungi. 
Itrakonazol je protiglivno sredstvo, aktivno proti okužbam, ki jih povzročajo dermatofiti, kvasovke, glive Aspergillus spp, Histoplasma spp., Paracoccidioides brasiliensis, Sporothrix schenckii, Fonsecaea spp., Cladosporium spp., Blastomyces dermatitidis ter razne druge kvasovke in glive.
As a result, WinNonlin cannot calculate the portion of area until infinite and the AUCinf therefore appears to be missing. 
Posledično WinNonlin ne more izračunati deleža površine do neskončnosti in zdi se, da vrednost AUCinf manjka.
The CHMP recalculated the 90% confidence intervals and obtained comparable results to those provided by the Applicant. 
CHMP je znova izračunal 90-odstotne intervale zaupanja in dobil rezultate, ki so primerljivi s predlagateljevimi.
The CHMP therefore adopted a List of Outstanding Issues: 
CHMP je zato sprejel seznam nerešenih zadržkov:
The Applicant also provided all the different pharmacokinetic parameters, among others the area under the curve until the last quantified concentration (AUCt). 
Predlagatelj je predložil tudi vse različne farmakokinetične parametre, med drugim površino pod krivuljo do zadnje kvantificirane koncentracije (AUCt).
Therefore, pharmacokinetic and bioequivalence results were analysed with all the data available obtained from 35 of the 36 volunteers included in the study, after removing volunteer 24 who presented a clearly atypical absorption pattern that prevented evaluating the area under the curve. 
Zato so bili rezultati farmakokinetike in biološke enakovrednosti analizirani z vsemi razpoložljivimi podatki, pridobljenimi pri 35 od 36 v študijo vključenih prostovoljcih, po izključitvi prostovoljca št. 24, ki je imel očitno atipičen vzorec absorpcije, kar je onemogočalo vrednotenje površine pod krivuljo.
The Applicant also provided the raw data for all volunteers as requested by the CHMP. 
Predlagatelj je predložil tudi neobdelane podatke za vse prostovoljce, kakor je želel CHMP.
- the benefit risk of the generic product Prokanazol is considered to be negative, 
- razmerje med koristmi in tveganji za generično zdravilo Prokanazol šteje za negativno.
When including the data for subject 24, bioequivalence cannot be proven, as the 90% confidence intervals for AUC and Cmax then fall outside the normal acceptance criteria of 80 - 125%. 
Ob vključitvi podatkov za preiskovanca št. 24 biološke enakovrednosti ni mogoče dokazati, saj 90-odstotni intervali zaupanja za AUC in Cmax ležijo izven običajnih kriterijev sprejemljivosti 80 -125 %.
Peak plasma levels are reached within 3 to 4 hours following an oral dose. 
Največje koncentracije v plazmi so dosežene 3 do 4 ure po peroralnem odmerku.
Some variability coefficients and data on the variability of the main pharmacokinetic parameters of the parent drug were provided but its origin could not be determined. 
Predloženi so bili nekateri koeficienti variabilnosti in podatki o variabilnosti glavnih farmakokinetičnih parametrov starševskega zdravila, vendar njihovega porekla ni mogoče ugotoviti.
If the actual LOQ of the method is much lower than that assumed, this may result in a greater error factor, in particular for the determination of terminal phase of extrapolated line and residual area. 
Če je dejanska vrednost LOQ metode precej nižja od te, predpostavljene vrednosti, je lahko faktor napake večji, zlasti pri določanju terminalne faze ekstrapolirane premice in rezidualne površine.
Regarding the arbitrary acceptance of the lower limit of quantification (LLOQ), the Applicant considered that the LLOQ is complying with the requirements recommended by the FDA in relation to “response compared to blank response” and “precision and accuracy”. 
Predlagatelj je v zvezi z arbitrarno sprejemljivostjo spodnje meje kvantifikacije (LLOQ) upošteval, da je LLOQ v skladu z zahtevami, ki jih priporoča FDA v zvezi z „odzivom v primerjavi s slepim poskusom“ ter „natančnostjo in točnostjo“.
As it was stated in the protocol of the trial, the elimination half-life of the drug is about 26 hours. 
V protokolu preskušanja je bila navedena razpolovna doba eliminacije zdravila približno 26 ur.
No volunteers had to be removed by misinterpretation or an incorrect use of values below the LOQ and furthermore, the Applicant provided the calculated 90% confidence intervals for all 36 subjects and by exclusion of subject 24. 
Prostovoljcev ni bilo treba izključevati zaradi napačne interpretacije ali nepravilne uporabe vrednosti pod LOQ, poleg tega pa je predlagatelj predložil izračunane 90-odstotne intervale zaupanja za vseh 36 preiskovancev in po izključitvi preiskovanca št. 24.
ANNEX I LIST OF THE NAMES, PHARMACEUTICAL FORM(S), STRENGTH(S) OF THE MEDICINAL PRODUCT(S), ROUTE(S) OF ADMINISTRATION, APPLICANT(S) / MARKETING AUTHORISATION HOLDER(S) IN THE MEMBER STATES 
DODATEK I SEZNAM IMEN, FARMACEVTSKIH OBLIK, JAKOSTI ZDRAVILA, POTI UPORABE ZDRAVILA, PREDLAGATELJEV, IMETNIKOV DOVOLJENJA ZA PROMET Z ZDRAVILOM V DRŽAVAH ČLANICAH
Inter-patient variability in serum concentrations following oral administration of itraconazole has been described in the literature, and is most notable with the capsule formulation (up to 15-fold differences). 
Variabilnost serumskih koncentracij med bolniki po peroralnem dajanju itrakonazola je opisana v literaturi in je najbolj izrazita pri kapsulah (do 15-kratne razlike).
The oral bioavailability of itraconazole is maximal when the capsules are taken immediately after a full meal. 
Peroralna biološka razpoložljivost itrakonazola je največja, če bolnik kapsule vzame takoj po celotnem obroku.
Values for the pharmacokinetic parameters were presented, but without any documentation of their calculation, preventing verification. 
Predložene so bile vrednosti farmakokinetičnih parametrov, vendar brez dokumentacije o njihovem izračunu, kar onemogoča preverjanje.
The calculation of AUCinf and z could be affected by the fact that the elimination phase was not achieved in some volunteers, mainly due to the arbitrary acceptance of the limit of quantification (LOQ). 
Na izračun AUCinf in λz lahko vpliva dejstvo, da faza eliminacije pri nekaterih prostovoljcih ni bila dosežena, zlasti zaradi arbitrarne sprejemljivosti meje kvantifikacije (LOQ).
The Applicant provided both values (precision and accuracy) for both products (hidroxi-itraconazol and itraconazol) from the 6 chromatograms obtained. 
Predlagatelj je za obe zdravili (hidroksiitrakonazol in itrakonazol) predložil obe vrednosti (natančnost in točnost) na podlagi pridobljenih šestih kromatogramov.
In nearly all cases (65/70), the obtained values were not higher than 3 times the LLOQ and in no cases was the last quantified sample higher than 4 times the LLOQ. 
V skoraj vseh primerih (65/70) pridobljene vrednosti niso presegale trikratnika LLOQ, v nobenem primeru pa rezultat zadnjega kvantificiranega vzorca ni bil višji od štirikratnika LLOQ.
Acceptable explanations to exclude pharmacokinetic data or to exclude a subject would be protocol violations, which are not observed in this study. 
Sprejemljive razlage izključitve farmakokinetičnih podatkov ali preiskovanca bi bile kršitve protokola, ki niso ugotovljene v tej študiji.
- of the CHMP considered that bioequivalence could not be shown, 
- CHMP je menil, da biološke enakovrednosti ni mogoče dokazati;
The confidence interval range for total and residual areas does not explain nor improve the credibility of the calculations, especially as no estimator points were provided. 
Razpon intervala zaupanja za skupne in rezidualne površine ne pojasnjuje in ne poveča verodostojnosti izračunov, zlasti ker niso bile predložene točke, uporabljene za ocene.
The sampling schedule should cover the plasma concentration time curve long enough to provide a reliable estimate of the extent of exposure which is achieved if AUCt is at least 80% of the AUC . 
Urnik vzorčenja mora pokrivati krivuljo plazemske koncentracije v odvisnosti od časa v tolikšni meri, da zagotovi zanesljivo oceno obsega izpostavitve, ki se doseže, če je AUCt najmanj 80 % vrednosti AUC∞.
The CHMP considers that the lack of assessment of the estimators of kinetic parameters analysis hampers the proper assessment of the data. 
CHMP meni, da odsotnost vrednotenja točk, uporabljenih za ocene v analizi kinetičnih parametrov, onemogoča pravilno vrednotenje podatkov.
Furthermore, the elimination half-life of itraconazole is about 26 hours and blood samples were obtained over at least 3-times the elimination half-life. 
Poleg tega je razpolovna doba eliminacije itrakonazola približno 26 ur, vzorci krvi pa so bili pridobljeni v razponu, ki je obsegal najmanj trikratnik razpolovne dobe eliminacije.
A more detailed analysis of the quantifiable determinations indicated that in the case of the reference formulation, 4 of 9 concentrations did not reach values above 4xLOQ and none reached these levels for the test formulation. 
Podrobnejša analiza koncentracij, ki jih je bilo možno kvantificirati, je pokazala, da v primeru referenčne formulacije štiri koncentracije od devetih niso dosegle vrednosti nad 4xLOQ, v primeru preskusne formulacije pa nobena koncentracija ni dosegla teh ravni.
Based on the totality of the data from all 36 subjects, bioequivalence has not been proven and as such the benefit risk ratio for this generic product is considered negative. 
Na podlagi celovitih podatkov za vseh 36 preiskovancev biološka enakovrednost ni bila dokazana, zato razmerje med koristmi in tveganji za to generično zdravilo šteje za negativno.
The Marketing Authorisation Holder should submit the result of a properly conducted bioequivalence study, in compliance with the Questions & Answers document of the CHMP EWP subgroup on pharmacokinetics on the Bioavailability and Bioequivalence Guideline. 
Imetnik dovoljenja za promet z zdravilom mora predložiti rezultat pravilno izvedene študije biološke enakovrednosti, ki je skladen z dokumentom Vprašanja in odgovori podskupine EWP za farmakokinetiko pri CHMP o priporočilih glede biološke razpoložljivosti in biološke enakovrednosti.
In accordance with the Questions & Answers document of the CHMP EWP subgroup on pharmacokinetics on the bioavailability and bioequivalence guideline, exclusion of data is not justified and cannot be accepted on the basis of statistical analysis or for pharmacokinetic reasons alone, because it is impossible to distinguish between formulation effects and pharmacokinetic effects. 
Skladno z dokumentom Vprašanja in odgovori podskupine EWP za farmakokinetiko pri CHMP o priporočilih glede biološke razpoložljivosti in biološke enakovrednosti izključevanje podatkov ni upravičeno in ni sprejemljivo na podlagi statistične analize ali zaradi vzrokov, ki izvirajo iz farmakokinetike, ker ni mogoče razlikovati med učinki formulacije in učinki farmakokinetike.
The Applicant submitted Cmax, AUCt and AUCinf values for all the volunteers and stated that the design of the study included sampling times in the absorption and late elimination phases in order to use results not exceeding the limit of quantification. 
Predlagatelj je predložil vrednosti Cmax, AUCt in AUCinf za vse prostovoljce ter navedel, da je zasnova študije vključevala čase vzorčenja v fazah absorbcije in pozne eliminacije, da bi uporabili rezultate, ki ne presegajo meje kvantifikacije.
However, the CHMP noted that the Applicant did not properly determine the LOQ limits and did not provide detailed information on the choice of points for the calculation of the terminal phase, nor on the points chosen for the individual profile and segments. 
Vendar je CHMP ugotovil, da predlagatelj ni pravilno določil vrednosti LOQ ter ni predložil podrobnih podatkov niti o izbiri točk za izračun terminalne faze niti o točkah, ki jih je izbral za posamezni profil in segmente.
With regards to the terminal phase being derived from Cmax in certain volunteers, this could be a matter of concern if the pharmacokinetic analysis applied had been compartmental, as it would suggest that a fast disposition phase did not exist in those cases compared with the remaining ones. 
Izpeljava terminalne faze iz Cmax pri določenih prostovoljcih bi lahko predstavljala težavo, če bi se uporabila kompartmentalizirana farmakokinetična analiza, saj bi pokazala, da pri teh preiskovancih ni bilo hitre dispozicijske faze v primerjavi z ostalimi preiskovanci.
One of the metabolites is hydroxy-itraconazole, which has in vitro antifungal activity comparable to itraconazole. 
Eden izmed presnovkov je hidroksiitrakonazol, katerega protiglivna aktivnost in vitro je primerljiva z itrakonazolom.
Regarding the statement that elimination phase was not achieved in some volunteers, the Applicant considered that the assessment of whether a volunteer has achieved elimination phase needs to take into account the experimental sample points and the concentrations values obtained. 
Predlagatelj glede izjave, da faza eliminacije ni bila dosežena pri nekaterih prostovoljcih, meni, da je treba pri vrednotenju začetka faze eliminacije pri prostovoljcu upoštevati eksperimentalne točke vzorčenja in pridobljene vrednosti koncentracij.
Volunteer number 24 showed a decreased absorption with 52% of the sampling points BLQ, and only one sampling point with quantifiable values from his maximum concentration. 
Prostovoljec št. 24 je kazal zmanjšano absorpcijo, saj je bilo 52 % vzorčnih točk pod mejo kvantifikacije in le ena vzorčna točka je imela vrednosti največje koncentracije, ki jih je bilo možno kvantificirati.
The Applicant included data on Clast, providing the last quantified concentration for each volunteer and formulation and the individual semi-logarithm pharmacokinetic figures. 
Predlagatelj je priložil podatke o vrednosti Clast, ki je zadnja kvantificirana koncentracija za vsakega prostovoljca in formulacijo, ter posamezne pollogaritemske farmakokinetične številke.
No valid arguments were provided to justify the lack of credible pharmacokinetic calculations, as the LOQ value used in analytical method was not determined by a validation process, but arbitrarily accepted as 5 ng/ml (the lowest calibrator). 
Veljavni argumenti za utemeljitev odsotnosti verodostojnih farmakokinetičnih izračunov niso bili predloženi, saj v analitični metodi uporabljena vrednost LOQ ni bila določena s postopkom validacije, ampak arbitrarno sprejeta kot 5 ng/ml (najnižji kalibracijski standard).
Czech Republic PRO.MED.CS Praha a.s. Tel ská 1 
Češka republika PRO.MED.CS Praha a.s.
The Applicant stated that because the method to calculate the area under the curve is not described in the European guide (EMA), the method described in the FDA guide (page 9, paragraph III.A.8c) was used, applying the software WinNonlin which uses the module NCA (“Non compartmental Analysis”). 
Predlagatelj je navedel, da metoda za izračun površine pod krivuljo ni opisana v Evropskih priporočilih (EMA), zato so uporabili metodo, opisano v priporočilu FDA (stran 9, odstavek III.A.8c), in programsko opremo WinNonlin z modulom NCA („nekompartmentalizirana analiza“).
The CHMP considered that the applied methods for calculating the AUCt and AUCinf and the ‘last exponential elimination constant' are standard and general accepted methods and noted that the requested data were provided, with at least 3 data points being used for estimation of the elimination phase. 
CHMP je menil, da so uporabljene metode za izračun AUCt in AUCinf ter „zadnje konstante eksponentne eliminacije“ standardne in splošno priznane metode, ter potrdil, da so bili predloženi želeni podatki, iz katerih so bile za oceno faze eliminacije uporabljene vsaj 3 podatkovne točke.
Strength Pharmaceutical 
Farmacevtska oblika
The correctness of the estimator point calculations could not be assessed and there is no summary of the specification calculations for the analysis of variance and intra- and inter-variability, individual ratios and differences for pharmacokinetic parameters. 
Pravilnosti točk, uporabljenih za ocene, ni bilo mogoče vrednotiti, saj ni povzetka izračunov specifikacij za analizo variance ter intra- in intervariabilnosti, posameznih razmerij ter razlik za farmakokinetične parametre.
The CHMP expressed doubts on the quality of LOQ, noting the lack of summary specifications and concluded that similar problems of residual areas are likely to affect further subjects beyond the five already identified. 
CHMP je izrazil dvome o kakovosti LOQ, opozoril na pomanjkanje povzetih specifikacij ter zaključil, da podobne težave rezidualnih površin verjetno vplivajo na druge preiskovance, ne le na odkritih pet preiskovancev.
The algorithm used to calculate the “last exponential elimination constant” in the NCA module is based on least squares regression and adjustment by the determination coefficient (square R) as a function of the number of points employed in the calculations. 
Algoritem za izračun „zadnje konstante eksponentne eliminacije“ v modulu NCA temelji na regresiji z najmanjšimi kvadrati ter korekciji z določitvijo koeficienta (kvadriran R) kot funkcijo števila točk, uporabljenih v izračunih.
Itraconazole shows a rather long tmax (about 6 h) as a result of the long elimination half-life, however estimation of AUC was at least 4 times the tmax, indicating that in these subjects the drug has been absorbed from the gastrointestinal-tract, and that the drug in the body is not dependent on differences between the 2 formulations. 
Itrakonazol ima zaradi dolge razpolovne dobe eliminacije precej dolg tmax (približno 6 ur), vendar je bila ocena AUC najmanj štirikratnik tmax, kar kaže, da se je pri teh preiskovancih zdravilo absorbiralo iz prebavil ter da zdravilo v telesu ni odvisno od razlik med formulacijama.
The applicant is asked to justify the results of the presented bioequivalence study, mainly the calculation of the AUCinf and z (last exponential elimination constant) as well as to provide all AUCt data. 
Predlagatelja so prosili za utemeljitev rezultatov predstavljene študije biološke enakovrednosti, zlasti izračuna AUCinf in λz (zadnja konstanta eksponentne eliminacije), ter za predložitev vseh podatkov AUCt.
The CHMP considered that the bioequivalence between the test and reference product has not been sufficiently proven, and that as such the product is not considered approvable for the sought indications. 
CHMP je menil, da biološka enakovrednost med preskusnim in referenčnim zdravilom ni bila zadostno dokazana in da zdravila kot takega ni mogoče odobriti za predlagane indikacije.
Disagreement remained between the concerned member states regarding the bioequivalence of Prokanazol to the originator, as no agreement could be reached with regards to the limits of quantification (LOQ) of itraconazole, the validation of calculation method of Cx/ z ratio (Cx being the last evaluable concentration and z being the last exponential elimination constant) or the justification of values of AUC residual above 20% of AUC total. 
Zadevne države članice se niso strinjale glede biološke enakovrednosti zdravila Prokanazol in originatorja, saj niso dosegle soglasja o meji kvantifikacije (LOQ) itrakonazola, validaciji metode izračuna razmerja Cx/λz (pri čemer je Cx zadnja koncentracija, ki jo je mogoče ovrednotiti, λz pa zadnja konstanta eksponentne eliminacije) ali utemeljitvi vrednosti ostanka površine pod krivuljo plazemske koncentracije v odvisnosti od časa (AUC) nad 20 % skupne AUC.
In conclusion, the Applicant did not provide sufficient information on the sample size, the power test or the coefficients of inter- and intra-variability. 
CHMP je zaključil, da predlagatelj ni predložil zadostnih podatkov o velikosti vzorca, moči testa ali koeficientih inter- in intravariabilnosti.