FrancophonIA/ELRC3.0 huggingface dataset:
English: For this reason, it was considered reliable to assume that further investigations would not substantially add to this favourable safety profile and should hence be avoided for reasons of animal welfare as has been common practice in other European procedures in the past.
Slovenian: Zaradi tega se je za zanesljivo štela domneva, da nadaljnje raziskave ne bi bistveno prispevale k temu ugodnemu varnostnemu profilu in se jim je treba posledično izogniti v dobrobit živali, kar je bila običajna praksa v drugih evropskih postopkih v preteklosti.
English: It was therefore argued that this could not be used as supportive of a similar safety profile as required by the guideline.
Slovenian: Zato so ugovarjale, da tega ni mogoče uporabiti v podporo podobnemu varnostnemu profilu, kar zahtevajo smernice.
English: Consequently, the requirements set in these regulations have been taken rather as recommendations by European Member States and applicants in the past than absolute requirements.
Slovenian: Posledično so v preteklosti države članice Evropske unije in predlagatelji zahteve v teh pravilih šteli za priporočila in ne kot absolutne zahteve.
English: Hence, efficacy and systemic tolerability of the active substance remains unaffected.
Slovenian: Zato učinkovitost in sistemska toleranca zdravilne učinkovine ostajata nespremenjeni.
English: As there is currently no explicit EU guidance available on the evaluation of local tolerability of transdermal systems, and considering previous experience with marketing authorisations of several other transdermal patches in the EU, the CHMP noted that skin tolerability had always been assessed as part of the pharmacokinetic studies.
Slovenian: Ker trenutno ni jasnih smernic EU za vrednotenje lokalne tolerance transdermalnih sistemov in ob upoštevanju preteklih izkušenj z dovoljenji za promet z več drugimi transdermalnimi obliži v EU, je CHMP izpostavil, da se je kožna toleranca vedno vrednotila kot del farmakokinetičnih študij.
English: Fentanyl is 75-100 times more potent than parenteral morphine.
Slovenian: Fentanil je 75-100-krat močnejši od parenteralnega morfina.
English: The guideline on non-clinical investigations of local tolerance was developed before the introduction of transdermal systems.
Slovenian: Smernice o nekliničnih raziskavah lokalne tolerance so bile zasnovane pred uvedbo transdermalnih sistemov.
English: In order to assess the applicability of this objection, the CHMP took into account that the subsequent points:
Slovenian: Za vrednotenje smiselnosti tega ugovora, je CHMP upošteval naslednje točke:
English: Taking all these aspects into consideration, the CHMP accepted the argument that the available nonclinical data sufficiently demonstrate the comparable local tolerability of Fentrix and Dorogesic.
Slovenian: Ob upoštevanju vseh omenjenih vidikov je CHMP sprejel argument, da razpoložljivi neklinični podatki zadostno dokazujejo primerljivo lokalno toleranco zdravil Fentrix in Dorogesic.
English: It was therefore argued that specific dermal irritation studies are required according to the guidelines mentioned above.
Slovenian: Zato so ugovarjale, da so potrebne posebne študije draženja kože v skladu z zgoraj omenjenimi smernicami.
English: Initially, the Applicant submitted the data comparing the adverse events without any statistical analysis and a statistical comparison was requested.
Slovenian: Najprej je predlagatelj predložil podatke o primerjavi neželenih učinkov brez statističnih analiz, zato je bila naročena statistična primerjava.
English: Skin reactions with a score 1 were not included in the analysis because these are very mild and could be found in any transdermal product in the market.
Slovenian: Kožnih reakcij z rezultatom 1 niso vključili v analizo, ker so zelo blage in jih lahko ugotovimo pri vseh transdermalnih zdravilih v prometu.
English: Single dose: OR estimate: 5.67, 95 % CI [1.12; 28.78] p = 0.0371 Multiple dose: OR estimate: 1.41, 95 % CI [0.97; 2.05] p = 0.0716
Slovenian: Študija z enim odmerkom: ocena razmerja verjetnosti: 5,67; 95-odstotni IZ [1,12; 28,78] p = 0,0371 Študija z več odmerki: ocena razmerja verjetnosti: 1,41; 95-odstotni IZ [0,97; 2,05] p = 0,0716
English: The objecting MS were of the view that the study results needed to be reanalysed because initially the irritation data had not been appropriately assessed.
Slovenian: Mnenje nasprotujočih držav članic je bilo, da je treba rezultate študije znova analizirati, ker na začetku podatki o draženju niso bili primerno ovrednoteni.
English: More importantly, the Applicant reproduced the statistically significant product effect for the single dose study (p= 0.0371), whereas for the multiple dose study the differences were not statistically significant (p=0.0716).
Slovenian: Pomembneje je, da je predlagatelj reproduciral statistično pomemben učinek zdravila v študiji z enim odmerkom (p = 0,0371), vendar razlike v študiji z več odmerki niso bile statistično pomembne (p = 0,0716).
English: The valid Summary of Product Characteristics, labelling and package leaflet are the final versions achieved during the Coordination group procedure.
Slovenian: Veljavni povzetek glavnih značilnosti zdravila, označevanje in navodilo za uporabo so zadnje različice, do katerih so prišli med postopkom koordinacijske skupine.
English: From experience, these values were considered to be well in line with the results of other fentanyl generic patches.
Slovenian: Z vidika izkušenj so te vrednosti šteli za dobro skladne z rezultati drugih generičnih obližev s fentanilom.
English: This reservoir was introduced between the layer exposed to the skin (donor layer) and the backing film.
Slovenian: To zalogo so vstavili med plast, ki je izpostavljena koži (darovalni sloj), in podložni film.
English: - Non-clinical issues
Slovenian: - Neklinični zadržki
English: Therefore, the objecting MS were of the view that the difference was not only statistically significant but that the difference was also considered to be clinically relevant.
Slovenian: Zato so nasprotujoče države članice menile, da razlika ni pomembna le statistično, ampak tudi klinično.
English: As absence of any sensitising potential is also well-known for the active substance and all other excipients of the patch and could be clinically confirmed (see below), no new information can be reasonably expected from additional studies in animals.
Slovenian: Ker je odsotnost potenciala za povečanje preobčutljivosti kože tudi dobro znana pri zdravilni učinkovini in vseh pomožnih snoveh obliža in jo je mogoče klinično potrditi (glejte v nadaljevanju), novih podatkov iz dodatnih študij na živalih ne moremo upravičeno pričakovati.
English: The transdermal fentanyl patch technology has been used clinically to provide analgesia since 1991.
Slovenian: Tehnologija transdermalnega fentanilnega obliža se klinično uporablja za analgezijo od leta 1991.
English: Due to the mechanical stressing during the detachment of the adhesive layer from the upper skin area, irritation is unavoidable; therefore slight skin irritation is always induced by the repetitive use of transdermal patches.
Slovenian: Zaradi mehanskega stresa med odstranjevanjem lepilnega sloja z gornjega področja kože je draženje neizogibno; zato ponavljajoča se raba transdermalnih obližev vedno povzroči majhno draženje kože.
English: However, the objecting Concerned Member State (CMS) considered that the authorisation of this medicinal product Fentrix, transdermal patch, may present a potential serious risk to public health on the grounds of non-clinical and clinical safety.
Slovenian: Vendar je zadevna država članica ugovarjala, saj je menila, da odobritev zdravila Fentrix transdermalni obliž lahko predstavlja možno resno tveganje za javno zdravje zaradi neklinične in klinične varnosti.
English: If it can be agreed that irritation scores at or below 1 are without clinical relevance and that more than 90 % of the reported incidences are well within this accepted range, it would consequently be erroneous to base the decision about a potential serious risk solely on a small portion (less than 4 % (SD) respectively 9 % (MD)) of the entity.
Slovenian: Če se lahko doseže soglasje, da rezultati draženja 1 ali manj nimajo kliničnega pomena in da je več kot 90 % opisanih pojavov znotraj tega sprejemljivega območja, bi bilo posledično napačno osnovati odločitev o možnem resnem tveganju samo na majhnem deležu (manj kot 4 % (en odmerek) in 9 % (več odmerkov)) vseh podatkov.
English: The CHMP assessed the dossier and the available data, including the issues raised by the objecting CMS.
Slovenian: CHMP je ovrednotil dokumentacijo in razpoložljive podatke, vključno z zadržki, ki jih je navedla nasprotujoča zadevna država članica.
English: The dermal tolerability of the current bilayer patch formulation was non-clinically analysed in comparison to the reference product “Dorogesic 25” in rabbits as part of the pharmacokinetic studies A/PK 02-P012 and A/PK 02-P013.
Slovenian: Kožna toleranca trenutne dvoslojne formulacije obliža je bila analizirana neklinično v primerjavi z referenčnim zdravilom „Dorogesic 25“ na kuncih v okviru farmakokinetičnih študij A/PK 02-P012 in A/PK 02-P013.
English: This proves that even the visually inspected, slightly increased incidence of skin irritations obviously has no further influence on the permeability of the drug substance, if compared to the reference medicinal product.
Slovenian: To dokazuje, da tudi s prostim očesom pregledana nekoliko zvišana pojavnost draženja kože očitno nima nadaljnjega učinka na prepustnost zdravilne učinkovine v primerjavi z referenčnim zdravilom.
English: It is an accepted clinical reality that for transdermal therapy a skin irritation score of 1 is common and without further clinical relevance.
Slovenian: Sprejeto klinično realno stanje je, da je pri transdermalnem zdravljenju rezultat draženja kože 1 pogost in brez dodatnega kliničnega pomena.
English: ANNEX I LIST OF THE NAMES, PHARMACEUTICAL FORM, STRENGTHS OF THE MEDICINAL PRODUCTS, ROUTE OF ADMINISTRATION, APPLICANT IN THE MEMBER STATES
Slovenian: DODATEK I SEZNAM IMEN, FARMACEVTSKIH OBLIK, JAKOSTI ZDRAVILA, POTI UPORABE ZDRAVILA, PREDLAGATELJEV IN IMETNIKOV DOVOLJENJA ZA PROMET Z ZDRAVILOM V DRŽAVAH ČLANICAH
English: The reference medicinal product is Dorogesic 25 - 100 µg/h, (MAH Janssen-Cilag, Neuss, Germany).
Slovenian: Referenčno zdravilo je Dorogesic 25 - 100 µg/h, (imetnik dovoljenja za promet z zdravilom: JanssenCilag, Neuss, Nemčija).
English: The OR estimates are close to the ones reported by the objecting CMS, although not exactly identical.
Slovenian: Oceni razmerja verjetnosti sta blizu tistim, o katerih so poročale nasprotujoče države članice, čeprav niso povsem enake.
English: This test does not take into account the temporal evolution of events - only if the subject suffered adverse events with the test, or with reference, or with both, or with none.
Slovenian: Ta preskus ne upošteva časovne evolucije dogodkov-samo, ali se je pri preiskovancu pojavil neželeni učinek zaradi preskusnega ali referenčnega zdravila, zaradi obeh ali zaradi nobenega od zdravil.
English: However it was the view of the objecting Member States (MS) that the excipients in this application are qualitatively different to those of the reference product and that the Applicant had used the monolayer instead of the bilayer version of the patch in some non-clinical investigations.
Slovenian: Vendar je bilo mnenje nasprotujočih držav članic, da so pomožne snovi v tej aplikaciji kvalitativno drugačne od tistih v referenčnem zdravilu ter da je predlagatelj v nekaterih nekliničnih raziskavah uporabil enoslojno in ne dvoslojne različice obliža.
English: The objecting MS argued that although this study was neither designed nor powered to assess the tolerability profile, its results suggest a worse safety profile for the test product.
Slovenian: Nasprotujoča država članica je ugovarjala, da študija ni bila zasnovana za vrednotenje profila tolerance in je prešibka, vendar njeni rezultati kažejo na slabši varnostni profil preskušanega zdravila.
English: The current bilayer patch differs from the earlier monolayer formulation only by the additional insertion of a reservoir layer.
Slovenian: Trenutni dvoslojni obliž se razlikuje od prvotne enoslojne formulacije le v dodatni vstavitvi založnega sloja.
English: On the contrary, the visual inspection of the data was suggestive of a worse skin irritation potential.
Slovenian: Nasprotno, pregled podatkov s prostim očesom je kazal na slabši potencial draženja kože.
English: Once the patch is applied to the skin the drug diffuses in the subcutaneous tissues and forms a reservoir.
Slovenian: Ko je obliž nanesen na kožo, zdravilo difundira v podkožna tkiva in napravi zalogo.
English: Therefore, the objecting CMS performed a new statistical analysis based on a logistic regression mixed model where the likelihood of having an AE depended both on the number of observations and treatments (fixed effects) and subject (as a random effect).
Slovenian: Zato so nasprotujoče države članice opravile novo statistično analizo na podlagi logističnega regresijskega mešanega modela, kjer je verjetnost neželenega učinka odvisna od števila opažanj, od zdravljenja (fiksni vplivi) in od preiskovanca (kot naključni vplivi).
English: Fentanyl is a synthetic opioid analgesic, belonging to the piperidine derivatives, and is chemically related to pethidine.
Slovenian: Fentanil je sintetični opioidni analgetik, ki spada med derivate piperidina in je kemijsko soroden petidinu.
English: In principle, the non-clinical data on local tolerance of the bilayer patch should have been complemented by an analysis of its sensitisation potential.
Slovenian: Načeloma bi morali neklinične podatke o lokalni toleranci dvoslojnega obliža dopolniti z analizo potenciala za povečanje preobčutljivosti.
English: The Applicant acknowledged that only non-clinical single dose studies have been performed.
Slovenian: Predlagatelj je potrdil, da je opravil le neklinične študije z enim odmerkom.
English: Nevertheless, the crucial donor layer has the identical composition in both monolayer and bilayer patches.
Slovenian: Vendar pa ima ključna darovalna plast identično sestavo v enoslojnih in dvoslojnih obližih.
English: Based on the bioequivalence studies, Fentrix patches have confirmed comparability to the reference medicinal product, Dorogesic SMAT.
Slovenian: Na podlagi študij biološke enakovrednosti so obliži Fentrix potrjeno primerljivi z referenčnim zdravilom, Dorogesic SMAT.
English: The Applicant acknowledged that only non-clinical single dose studies have been performed in spite of the fact that section 4.2 “Dermal tolerance testing” of the Note for Guidance on Non-clinical Tolerance Testing of Medicinal Products (CPMP/SWP/2145/00), indicates that dermal tolerance is tested by a single and repeat dose administration and an evaluation of the sensitising potential.
Slovenian: Predlagatelj je potrdil, da je opravil le neklinične študije z enim odmerkom, čeprav je v razdelku 4.2 „Preskušanje kožne tolerance“ v Navodilih za neklinično preskušanje tolerance za zdravila (CPMP/SWP/2145/00) navedeno, da se kožna toleranca preskuša z enim odmerkom in ponavljajočimi se odmerki ter vrednotenjem potenciala za povečanje preobčutljivosti.
English: In the statistical analysis performed by the objecting CMS, only a small percentage of incidences of skin irritations, calculated as 3.28 % (SD)/8.46%(MD) for the Fentrix patch and 0.64 % (SD)/5.93%(MD) for the reference patch, have been included to evaluate the comparability of the safety profile.
Slovenian: V statistični analizi, ki so jo opravile nasprotujoče države članice, je bil le majhen odstotek pojavov draženja kože, izračunan kot 3,28 % (en odmerek)/8,46 % (več odmerkov) za zdravilo Fentrix obliž in 0,64 % (en odmerek)/5,93 %(več odmerkov) za referenčni obliž, vključen v vrednotenje primerljivosti varnostnega profila.
English: Fentanyl has a high lipid solubility which makes it suitable for transdermal administration.
Slovenian: Fentanil je zelo topen v maščobah, zaradi česar je primeren za transdermalno uporabo.
English: However, the predominant constituents of the patch - mainly two of the adhesives, were not found to be sensitive to the skin of guinea pigs when tested alone according to guidelines CPMP/SWP/2145/00 and OECD 406 (Buehler method).
Slovenian: Vendar za prevladujoče sestavine obliža-v glavnem dve lepili-ni bila ugotovljena občutljivost kože buder ob preskušanju v skladu s smernicami CPMP/SWP/2145/00 in OECD 406 (Buehlerjeva metoda).
English: Each of the clinical pharmacokinetic studies (single dose (SD) as well as multiple dose (MD)), confirmed that for the Fentrix patch, the percentage of skin irritation scores of 0 (no irritation) and score 1 (minimal erythema, barely perceptible, scoring according to the FDA Guidance for industry, Skin Irritation and Sensitization Testing of Generic Transdermal Products) reached more than 90 %.
Slovenian: V obeh kliničnih farmakokinetičnih študijah (z enim odmerkom in več odmerki) so potrdili, da je za zdravilo Fentrix obliž odstotek rezultatov preskusov draženja kože 0 (brez draženja) in 1 (minimalna pordelost, komaj zaznavna, točkovanje v skladu s smernicami FDA za industrijo, Preskušanje draženja kože in preobčutljivosti za generična transdermalna zdravila) višji od 90 %.
English: Single dose study: the mean score for test was 0.39 and 0.25 for the reference.
Slovenian: Študija z enim odmerkom: povprečni rezultat za preskusno zdravilo je bil 0,39, rezultat za referenčno zdravilo pa 0,25.
English: The rate controlling step of drug absorption is commonly the permeation through the skin.
Slovenian: Hitrost absorpcije zdravila v kožo običajno omejuje prodiranje skozi kožo.
English: - Clinical issues
Slovenian: - Klinični zadržki
English: Today fentanyl is extensively used as an anaesthetic and analgesic.
Slovenian: Danes je uporaba fentanila kot anestetika in analgetika zelo razširjena.
English: Choosing the binary endpoint ("skin reaction > 1") included treatment (test vs. reference) and observation (in h from first administration) as fixed explanatory variables and a random subject effect.
Slovenian: Z izbiro binarnega končnega izida („kožna reakcija > 1“) so vključili zdravljenje (preskusno zdravilo proti referenčnemu zdravilu) in opazovanje (v urah po prvi uporabi) kot fiksni eksplanatorni spremenljivki in kot naključen vpliv preiskovanca.
English: Local irritation potential
Slovenian: Možnost lokalnega draženja
English: Therefore, the elimination half-life is longer compared to other administration routes, with about 17 h for fentanyl after transdermal administration, compared to parenteral and transmucosal administered drug of 7 h. The release of the drug from the patch is controlled without membrane.
Slovenian: Zato je razpolovna doba eliminacije daljša kot pri drugih poteh uporabe zdravila, tj. 17 ur za fentanil po transdermalni uporabi v primerjavi s 7 urami po parenteralni ali transmukozni uporabi.
English: Transdermal patches are applied to intact skin in order to deliver at a constant rate the active substance to the systemic circulation.
Slovenian: Transdermalni obliži se nanesejo na nepoškodovano kožo za vnos zdravilne učinkovine v sistemski obtok s stalno hitrostjo.
English: For this reason, it was argued that the non-clinical studies testing the monolayer version should also be accounted for when the local tolerability is assessed.
Slovenian: Zaradi tega je bil izraženo nasprotovanje, da je treba pri vrednotenju lokalne tolerance upoštevati tudi neklinične študije, v katerih so preskušali enoslojno različico.
English: Fentanyl has been marketed as iv anaesthetic since the 1960s.
Slovenian: anestetik od 1960-ih.
English: - the Fentrix transdermal patch was shown to be well tolerated and comparable to the reference medicinal product Dorogesic the CHMP has recommended the granting of the Marketing Authorisation for which the Summary of Product Characteristics, labelling and package leaflet remain as per the final versions achieved during the Coordination group procedure as mentioned in Annex III for Fentrix and associated names (see Annex I).
Slovenian: CHMP je priporočil odobritev dovoljenja za promet z zdravilom, katerega povzetek glavnih značilnosti zdravila, označevanje in navodila za uporabo ostanejo enaki zadnjim različicam, pripravljenim v postopku koordinacijske skupine in navedenim v Dodatku III za zdravilo Fentrix in z njim povezana imena (glejte Dodatek I).
English: These findings have been corroborated by a comparable tolerability profile determined in clinical studies (see below).
Slovenian: Ta odkritja so podkrepili s kliničnimi študijami (glejte v nadaljevanju), kjer so ugotovili primerljiv profil tolerance.
English: SAS User Group International (SUGI) Conference Proceedings 27, Paper 261-27 (2002)), the Applicant recalculated the logistic mixed model using the SAS Procedure NLMIXED (SAS Version 9.1.3).
Slovenian: Zbornik konference SAS User Group International (SUGI) 27, referat 261-27 (2002)).
English: The justification for this was that the evaluation of the local tolerance after repeat dose administration had been carried out during the multiple dose bioequivalence study in humans.
Slovenian: Utemeljitev za to je bila, da je bilo vrednotenje lokalne tolerance po dajanju ponavljajočih se odmerkov opravljeno med študijo biološke enakovrednosti večkratnih odmerkov pri ljudeh.
English: Multiple dose study: the number of observations with skin irritation above score 1 was 77 for the test and 56 for the reference, in the same number (26) of subjects with skin irritation.
Slovenian: Študija z več odmerki: ob enakem številu (26) preiskovancev z draženjem kože je bilo število opažanj z rezultatom draženja kože nad 1 za preskusno zdravilo 77, za referenčno zdravilo pa 56.
English: Both clinical pharmacokinetic studies, single dose (SD) as well as multiple dose (MD), confirmed that the Fentrix patch is in general well tolerated when applied to the human skin.
Slovenian: Klinične farmakokinetične študije enega odmerka in več odmerkov so potrdile, da je človeška koža obliž Fentrix na splošno dobro prenašala.
English: - it was considered to be reasonable and ethical to assess skin tolerability of opioid containing transdermal patches as part of comparative bioavailability studies
Slovenian: - Izraženo je bilo mnenje, da je razumno in etično vrednotiti kožno toleranco za transdermalne obliže z opioidom v okviru primerjalnih študij biološke enakovrednosti;
English: The McNemar test was then used investigating whether significant differences between the test and the reference in the number of patients who suffered adverse events were observed or not.
Slovenian: Za ugotovitev statistično pomembnih razlik med preskusnim in referenčnim zdravilom v številu bolnikov z neželenimi učinki so uporabili McNemarjev preskus.
English: The Applicant's justification was that the evaluation of the local tolerance after repeat dose administration has been carried out during the multiple dose bioequivalence study in humans.
Slovenian: Utemeljitev predlagatelja je bila, da je bilo vrednotenje lokalne tolerance po dajanju ponavljajočih se odmerkov opravljeno med študijo biološke enakovrednosti večkratnih odmerkov pri ljudeh.
English: Slovenia
Slovenian: Slovenije
English: To clarify the clinical relevance of these concerns and to assess the significance of the statistical analysis performed by the CMS, the following points were considered by the CHMP:
Slovenian: CHMP je za razjasnitev kliničnega pomena teh zadržkov in vrednotenje pomembnosti statistične analize, ki so jo opravile nasprotujoče države članice, obravnaval naslednje točke:
English: The analgesic and sedative action of fentanyl is proposed to be mediated mainly through µ-opioid-receptors.
Slovenian: Analgetični in sedativni učinek fentanila naj bi bil posredovan predvsem preko opioidnih receptorjev µ. Fentanil je v prometu kot i.v.