natgillin/translations-raw huggingface dataset:
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.
The CHMP noted that no values were used below the estimated LOQ of 5 ng/ml and that the last value above the LOQ was used for the estimation of AUCinf.
CHMP je ugotovil, da predlagatelj ni uporabil nobene vrednosti pod ocenjenim LOQ 5 ng/ml in da je za oceno AUCinf uporabil zadnjo vrednost nad LOQ.
The analytical centre gives only numerical results when the concentration is not BLQ, so is not possible to perform any calculations with these results.
Ko koncentracija ni bila pod mejo kvantifikacije, je analitični center podajal le številske rezultate, zato s temi rezultati ni možno opraviti izračunov.
Due to these outstanding concerns and the lack of documentation, the CHMP was unable to consider Prokanazol as being bioequivalent to the reference product and considered that more data was needed before an opinion could be provided.
CHMP zaradi nerešenih zadržkov in pomanjkljive dokumentacije ni mogel šteti zdravila Prokanazol za biološko enakovrednega referenčnemu zdravilu, ter je menil, da je za mnenje potrebnih več podatkov.
the CHMP has recommended the refusal of the granting of the Marketing Authorisations in the Concerned Member States and the suspension of the Marketing Authorisation in the Reference Member State, where the product is currently authorised, for Prokanazol and associated names (see Annex I).
CHMP je za zdravilo Prokanazol in z njim povezana imena (glejte Dodatek I) priporočil zavrnitev odobritve dovoljenj za promet z zdravilom v zadevnih državah članicah ter umik dovoljenja za promet z zdravilom v referenčni državi članici, kjer je zdravilo trenutno odobreno.
The pharmacokinetic analysis applied, following the recommendations from the regulatory agencies, was non-compartmental amodelistic.
Uporabljena pa je bila nekompartmentalizirana amodelistična farmakokinetična analiza skladno s priporočili regulativnih agencij.
EU/EEA
Država članica EU/EGP
Form
Jakost
This overview was last updated in 10-2019.
Povzetek je bil nazadnje posodobljen 10-2019.
Treatment should last for at least 3 weeks and continue until the patient no longer has symptoms.
Zdravljenje mora trajati vsaj tri tedne in se nadaljevati, dokler simptomi pri bolniku ne izzvenijo.
What measures are being taken to ensure the safe and effective use of Defitelio?
Kateri ukrepi se izvajajo za zagotovitev varne in učinkovite uporabe zdravila Defitelio?
Every year, the Agency will review any new information that becomes available and this overview will be updated as necessary.
Agencija bo vsako leto ponovno pregledala vse nove podatke, ki bodo na voljo.
Defitelio is used in adults and in children from one month of age.
Zdravilo Defitelio se lahko uporablja pri odraslih in otrocih, starejših od enega meseca.
Further information on Defitelio can be found on the Agency's website: ema.europa.eu/Find medicine/Human medicines/European public assessment reports.
Nadaljnje informacije o zdravilu Defitelio so na voljo na spletni strani agencije: ema.europa.eu/Find medicine/Human medicines/European public assessment reports.
The European Medicines Agency decided that Defitelio's benefits are greater than its risks and it can be authorised for use in the EU.
Evropska agencija za zdravila je zaključila, da so koristi zdravila Defitelio večje od z njim povezanih tveganj in da se lahko odobri za uporabo v EU.
Further information on the orphan designation can be found here: ema.europa.eu/Find medicine/Human medicines/Rare disease designation.
Nadaljnje informacije glede določitve zdravila sirote lahko najdete tukaj: ema.europa.eu/Find medicine/Human medicines/Rare disease designation.
Severe VOD has a high mortality rate of 75% or higher.
Stopnja umrljivosti zaradi hude venookluzivne bolezni je visoka in znaša 75 % ali več.
Defitelio received a marketing authorisation valid throughout the European Union on 18 October 2013.
Za zdravilo Defitelio je bilo 18. oktobra 2013 izdano dovoljenje za promet, veljavno po vsej Evropski uniji.
As for all medicines, data on the use of Defitelio are continuously monitored.
Tako kot za vsako zdravilo se tudi podatki o uporabi zdravila Defitelio stalno spremljajo.
Recommendations and precautions to be followed by healthcare professionals and patients for the safe and effective use of Defitelio have been included in the summary of product characteristics and the package leaflet.
Priporočila in previdnostni ukrepi, ki jih morajo za varno in učinkovito uporabo zdravila Defitelio upoštevati zdravstveni delavci in bolniki, so vključeni v povzetek glavnih značilnosti zdravila in navodilo za uporabo.
Defitelio lowered the mortality rate to 62% at 100 days after transplantation, and 24% of patients had no symptoms of severe VOD after 100 days.
Zdravilo Defitelio je po 100 dneh po presaditvi zmanjšalo stopnjo umrljivosti na 62 %, 24 % bolnikov pa po 100 dneh ni imelo nobenih simptomov hude venookluzivne bolezni.
Benefits of Defitelio were also seen in data from a United States patient registry (information about patients collected in a standard way), where patients with severe VOD after blood stem cell transplantation who received Defitelio plus standard care had better outcomes than those given standard care alone, including a higher 100-day survival rate (39% versus 31%) and a higher proportion of patients whose VOD resolved (51% versus 29%).
Koristi zdravila Defitelio so bile opažene tudi pri podatkih iz registra bolnikov v ZDA (informacije o bolnikih, zbrane na standarden način), na podlagi katerih so imeli bolniki s hudo venookluzivno boleznijo, ki so po presaditvi krvotvornih matičnih celic prejemali zdravilo Defitelio v kombinaciji s standardnim zdravljenjem, boljše izide kot tisti, ki so prejemali samo standardno zdravljenje, vključno z višjo stopnjo preživetja po 100 dneh (39 % v primerjavi z 31 %) in višjim odstotkom bolnikov, pri katerih so simptomi venookluzivne bolezni izginili (51 % v primerjavi z 29 %).