natgillin/translations-raw huggingface dataset:
De kontraindikationer, der blev fjernet, var: leverencefalopati, biliær obstruktion, urinsyregigt og Addisons sygdom. 
The contraindications removed were: hepatic encephalopathy, biliary obstruction, gout and Addison's disease.
Alvorlig leverinsufficiens, biliær cirrhose og cholestasis. 
Severe hepatic impairment, biliary cirrhosis and cholestasis.
Angiotensin II er et stof i kroppen, der medfører forsnævring af blodkarrene og dermed en stigning i blodtrykket. 
Angiotensin II is a substance in the body that causes vessels to tighten, thus causing blood pressure to increase.
EMEA's Udvalg for Humanmedicinske Lægemidler (CHMP) er af den opfattelse, at der er behov for at harmonisere ordinationsoplysningerne for Diovan Comp i Den Europæiske Union (EU) og Det Europæiske Økonomiske Samarbejdsområde (EØS). 
The Agency's Committee for Medicinal Products for Human Use (CHMP) has concluded that there is a need to harmonise the prescribing information for Diovan Comp in the European Union (EU) and the European Economic Area (EEA).
CHMP godkendte også en harmoniseret formulering af kontraindikationer (situationer, hvor lægemidlet ikke må anvendes): Overfølsomhed over for valsartan, hydrochlorthiazid, andre sulfonamid-afledte lægemidler eller over for et eller flere af hjælpestofferne. 
The CHMP also agreed on a harmonised wording for the contra-indications (situations where the medicine must not be used): Hypersensitivity to valsartan, hydrochlorothiazide, other sulfonamide-derived medicinal products or to any of the excipients.
CHMP nåede navnlig til enighed om, at patienter, som ikke opnår tilstrækkelig blodtrykskontrol med valsartan eller hydrochlorthiazid, kan skifte direkte til Diovan Comp, når blot den nye behandling er i overensstemmelse med de anbefalede doser for de enkelte aktive stoffer. 
In particular, the CHMP agreed that patients not adequately controlled with valsartan or hydrochlorothiazide can be switched directly to Diovan Comp as long as the new treatment is in line with the recommended dosages for the individual active substances.
CHMP drøftede, hvordan Diovan Comp, der er en fastdosiskombination af to aktive stoffer, skulle indføres i behandlingen af patienter, som ikke opnår tilstrækkelig blodtrykskontrol med et af de aktive stoffer alene. 
The CHMP discussed how Diovan Comp, which is a fixed-dose combination of two active substances, should be introduced in to the treatment of patients whose blood pressure is not controlled with either of the active substances used alone.
CHMP harmoniserede afsnittet i produktresuméet om særlige advarsler og medtog advarsler om lysfølsomhed og problemer med biskjoldbruskkirtlernes funktion hos patienter, der tager thiaziddiuretika, herunder hydrochlorthiazid. 
The CHMP harmonised the SPC section on special warnings and included warnings about photosensitivity and problems with the function of the parathyroid glands in patients taking ‘thiazide' diuretics such as hydrochlorothiazide.
CHMP drøftede brugen af Diovan Comp til patienter, der tidligere er blevet behandlet med andre angiotensin II-receptorantagonister, og nåede til enighed om, at patienter, der tidligere er blevet behandlet med valsartan, skulle kunne skifte til Diovan Comp. 
The CHMP discussed the use of Diovan Comp in patients previously treated with other angiotensin II receptor antagonists and agreed that the switch to Diovan Comp should only be for patients previously treated with valsartan.
Diovan Comp fastdosiskombination er indiceret til patienter, hvis blodtryk ikke kan bringes tilfredsstillende under kontrol med valsartan eller hydrochlorthiazid monoterapi". 
patients whose blood pressure is not adequately controlled on valsartan or hydrochlorotiazide monotherapy”
Det blev bestemt af den humanmedicinske koordineringsgruppe for gensidig anerkendelse og decentrale procedurer (CMD(h)), at Diovan Comp skulle harmoniseres. 
Diovan Comp was identified as needing harmonisation by the Co-ordination Group on the Mutual and Decentralised Procedures - Human (CMD(h)).
Udvalget bemærkede, at nogle kontraindikationer i produktresuméet i nogle medlemsstater kunne fjernes, da de nu var omfattet af den harmoniserede formulering. 
Refractory hypokalaemia, hyponatraemia, hypercalcaemia, and symptomatic hyperuricaemia.” The Committee noted that some contra-indications that were included in the SPC in some member states could be removed, as they were now covered by the harmonised wording.
Dette kan muligvis tilskrives modellens forskellige algoritmer/specifikationer eller lignende årsager. 
This can be possibly attributed to different algorithms/specifications of the model or similar reasons.
Denne tilgang er generelt accepteret og understøttet af myndigheder i både andre EU- og ikke-EUlande. 
This approach has generally been accepted and supported by other EU and non-EU authorities as well.
Risiko for lokal irritation 
Local irritation potential
De resultater, som ansøgeren opnåede for behandlingseffekten ved hjælp af denne model, er som følger: 
The results the Applicant obtained for the treatment effect using this model are as follows:
Retsgrundlaget for denne ansøgning er artikel 10, stk. 1, i direktiv 2001/83/EF, med senere ændringer. 
The legal basis for this application refers to: Article 10(1) of Directive 2001/83/EC, as amended.
SAMLET RESUMÉ AF DEN FAGLIGE VURDERING AF FENTRIX OG TILKNYTTEDE NAVNE (SE BILAG I) 
OVERALL SUMMARY OF THE SCIENTIFIC EVALUATION OF FENTRIX AND ASSOCIATED NAMES (SEE ANNEX I)
20097 Hamburg 
Belgium20097 Hamburg
Hudreaktioner med en score på 1 blev ikke medtaget i analysen, da disse er meget milde og kunne ses ved et hvilket som helst transdermalt produkt på markedet. 
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.
Indledningsvis indsendte ansøgeren data, der sammenlignede bivirkningerne uden nogen statistisk analyse, og der blev anmodet om en statistisk sammenligning. 
Initially, the Applicant submitted the data comparing the adverse events without any statistical analysis and a statistical comparison was requested.
Enkeltdosis: OR-estimat: 5,67, 95 % CI [1,12; 28,78] p=0,0371 Flerdosis: OR-estimat: 1,41, 95 % CI [0,97; 2,05] p=0,0716 
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
Det blev derfor fremført, at specifikke undersøgelser af dermal irritation er påkrævet i henhold til de retningslinjer, der henvises til i det ovenstående. 
It was therefore argued that specific dermal irritation studies are required according to the guidelines mentioned above.
Fentanyl er 75-100 gange stærkere end parenteral morfin. 
Fentanyl is 75-100 times more potent than parenteral morphine.
Derfor blev det vurderet som sikkert at antage, at yderligere undersøgelser ikke ville bibringe væsentlige nye oplysninger til denne positive sikkerhedsprofil, og derfor burde de undgås af hensyn til dyrevelfærden, som det har været almindelig praksis ved andre europæiske procedurer gennem tiden. 
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.
- Ikkekliniske aspekter 
- Non-clinical issues
De medlemsstater, der havde gjort indsigelser, var derfor af den overbevisning, at forskellen ikke kun var statistisk signifikant, men at forskellen også var klinisk relevant. 
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.
Det blev derfor fremført, at de ikke kunne anvendes som understøttelse af en lignende sikkerhedsprofil, som det kræves i retningslinjerne. 
It was therefore argued that this could not be used as supportive of a similar safety profile as required by the guideline.
Da der på nuværende tidspunkt ikke findes nogen specifikke europæiske retningslinjer for vurderingen af transdermale systemers lokale tolerabilitet, og set i lyset af den tidligere erfaring med markedsføringstilladelser for flere andre depotplastre i EU, bemærkede CHMP, at hudtolerabilitet altid var blevet vurderet som en del af de farmakokinetiske undersøgelser. 
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.
Ansøgeren erkendte, at der kun er blevet udført ikkekliniske enkeltdosisundersøgelser. 
The Applicant acknowledged that only non-clinical single dose studies have been performed.
Disse resultater er blevet bekræftet af en sammenlignelig tolerabilitetsprofil, som er fastlagt gennem kliniske undersøgelser (se nedenfor). 
These findings have been corroborated by a comparable tolerability profile determined in clinical studies (see below).
Derfor er de krav, der er indeholdt i disse bestemmelser, blevet betragtet som anbefalinger snarere end deciderede krav af de europæiske medlemsstater og ansøgere. 
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.
De medlemsstater, der havde gjort indsigelser, var af den opfattelse, at undersøgelsesresultaterne skulle analyseres på ny, fordi irritationsdataene oprindelig ikke var blevet vurderet tilstrækkelig grundigt. 
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.
Retningslinjerne for ikkekliniske undersøgelser af lokal tolerance blev udviklet, før transdermale systemer blev indført. 
The guideline on non-clinical investigations of local tolerance was developed before the introduction of transdermal systems.
CHMP vurderede dossieret og de tilgængelige data, herunder de spørgsmål, der var rejst af de berørte medlemsstater, der havde gjort indsigelse. 
The CHMP assessed the dossier and the available data, including the issues raised by the objecting CMS.
Fentanyl er blevet markedsført som intravenøs bedøvelse siden 1960'erne. 
Fentanyl has been marketed as iv anaesthetic since the 1960s.
Hvis der kan opnås enighed om, at irritationsscorer på eller under 1 er uden klinisk relevans, og at mere end 90 % af de rapporterede forekomster ligger inden for dette godkendte interval, ville det som en følge heraf være fejlagtigt udelukkende at basere beslutningen om en potentiel alvorlig risiko på en lille andel (mindre end 4 % (enkeltdosis) henholdsvis 9 % (flerdosis)) af enheden. 
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.
BILAG I FORTEGNELSE OVER LÆGEMIDLERNES NAVNE, LÆGEMIDDELFORM, STYRKER, INDGIVELSESVEJ, ANSØGERE, INDEHAVERE AF MARKEDSFØRINGSTILLADELSE I MEDLEMSSTATERNE 
ANNEX I LIST OF THE NAMES, PHARMACEUTICAL FORM, STRENGTHS OF THE MEDICINAL PRODUCTS, ROUTE OF ADMINISTRATION, APPLICANT IN THE MEMBER STATES
Det gyldige produktresumé, etiketteringen og indlægssedlen er de endelige versioner, der er opnået under koordinationsgruppens procedure. 
The valid Summary of Product Characteristics, labelling and package leaflet are the final versions achieved during the Coordination group procedure.
Det aktive stofs effekt og systemiske tolerabilitet forbliver således uændret. 
Hence, efficacy and systemic tolerability of the active substance remains unaffected.
Det er vigtigt at understrege, at ansøgeren genskabte den statistisk signifikante produkteffekt for enkeltdosisundersøgelsen (p=0,0371), mens forskellene for flerdosisundersøgelsen ikke var statistisk signifikante (p=0,0716). 
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).
De medlemsstater, der havde gjort indsigelser, fremførte, at selv om denne undersøgelse hverken var udformet eller havde tilstrækkelig statistisk styrke til at vurdere tolerabilitetsprofilen, tyder dens resultater på en dårligere sikkerhedsprofil for testproduktet. 
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.
På grund af den mekaniske belastning under fjernelse af det klæbende lag fra overhuden er irritation uundgåelig, hvorfor en smule hudirritation altid vil forekomme ved gentagen anvendelse af depotplastre. 
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.
- Kliniske aspekter 
- Clinical issues
Referencelægemidlet er Dorogesic 25-100 µg/h, (MAH Janssen-Cilag, Neuss, Tyskland). 
The reference medicinal product is Dorogesic 25 - 100 µg/h, (MAH Janssen-Cilag, Neuss, Germany).
Dette beviser, at selv den visuelt påviste mindre stigning i forekomsterne af hudirritation tydeligvis ikke har nogen indvirkning på lægemiddelstoffets permeabilitet i sammenligning med referencelægemidlet. 
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.
Med henblik på at bedømme denne indsigelses anvendelighed overvejede CHMP nedenstående punkter: 
In order to assess the applicability of this objection, the CHMP took into account that the subsequent points:
For at klarlægge disse betænkeligheders kliniske relevans og vurdere signifikansen af den statistiske analyse udført af de berørte medlemsstater blev følgende punkter taget i betragtning af CHMP: 
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:
Dette reservoir er lagt ind mellem det lag, der er i kontakt med huden (donorlaget) og filmen på bagsiden. 
This reservoir was introduced between the layer exposed to the skin (donor layer) and the backing film.
Fentanyls smertestillende og beroligende effekt foreslås medieret hovedsagelig gennem µ-opioid-receptorer. 
The analgesic and sedative action of fentanyl is proposed to be mediated mainly through µ-opioid-receptors.
Fentanyl er et syntetisk opioidanalgetikum, der hører under piperidinderivaterne, og som er kemisk forbundet med petidin. 
Fentanyl is a synthetic opioid analgesic, belonging to the piperidine derivatives, and is chemically related to pethidine.
Den berørte medlemsstat, der havde gjort indsigelser, var dog af den opfattelse, at godkendelsen af lægemidlet Fentrix, depotplastre, kan udgøre en potentiel alvorlig risiko for folkesundheden for så vidt angår ikkeklinisk og klinisk sikkerhed. 
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.
Tværtimod antydede den visuelle inspektion af dataene en større risiko for hudirritation. 
On the contrary, the visual inspection of the data was suggestive of a worse skin irritation potential.
Fentanyl har en høj lipid opløselighed, hvilket gør det velegnet til transdermal indgivelse. 
Fentanyl has a high lipid solubility which makes it suitable for transdermal administration.
Når plastret er påsat huden, breder lægemidlet sig i det subkutane væv og danner et reservoir. 
Once the patch is applied to the skin the drug diffuses in the subcutaneous tissues and forms a reservoir.
Under udførelsen af denne model blev der fundet statistiske forskelle mellem behandlingerne i begge undersøgelser (enkeltdosisundersøgelsen og flerdosisundersøgelsen), og pointoverslaget over odds ratioen var 8,35 i enkeltdosisundersøgelsen og 1,45 i flerdosisundersøgelsen. 
Performing this model, statistically significant differences were found between treatments in both studies (the single dose study and the multiple dose study), and the point estimate of the odds ratio was 8.35 in the single dose study and 1.45 in the multiple dose study.
Disse værdier anses på baggrund af de gængse erfaringer for at være i overensstemmelse med resultaterne for andre generiske plastre indeholdende fentanyl. 
From experience, these values were considered to be well in line with the results of other fentanyl generic patches.
McNemartesten blev derefter anvendt til at undersøge, hvorvidt der blev observeret signifikante forskelle mellem testproduktet og referenceproduktet i forhold til antallet af patienter, der led af bivirkninger. 
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.
Det nuværende dobbeltlagsplasters dermale tolerabilitet blev i en ikkeklinisk analyse sammenlignet med referencelægemidlet "Dorogesic 25" hos kaniner som en del af de farmakokinetiske undersøgelser A/PK 02-P012 og A/PK 02-P013. 
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.
Testen tager ikke højde for hændelsernes tidsmæssige udvikling, men kun for, om forsøgspersonen led af bivirkninger i forbindelse med testproduktet, referenceproduktet, begge produkter eller ingen af produkterne. 
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.
OR-estimaterne ligger tæt på dem, der er rapporteret af de berørte medlemsstater, der havde gjort indsigelse, men er dog ikke helt identiske med dem. 
The OR estimates are close to the ones reported by the objecting CMS, although not exactly identical.
Det er en almindeligt anerkendt klinisk realitet, at når det gælder transdermal terapi, er en hudirritationsscore på 1 almindelig og uden videre klinisk relevans. 
It is an accepted clinical reality that for transdermal therapy a skin irritation score of 1 is common and without further clinical relevance.
Da det er fastslået, at der ikke er risiko for hudoverfølsomhed ved det aktive stof og alle andre af plastrets hjælpestoffer, hvilket blev bekræftet under kliniske forhold (se nedenfor), kan der ikke forventes at fremkomme flere oplysninger fra yderligere dyreforsøg. 
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.
Derfor udførte de berørte medlemsstater, der havde gjort indsigelse, en ny statistisk analyse baseret på en blandet logistisk regressionsmodel, hvor sandsynligheden for at få en bivirkning afhang af både antallet af observationer og behandlinger (faste effekter) og forsøgsperson (som en randomiseret effekt). 
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).
CHMP medtog alle disse aspekter i sine overvejelser og godtog argumentet om, at de tilgængelige kliniske data i tilstrækkelig grad påviser den sammenlignelige lokale tolerabilitet hos Fentrix og Dorogesic. 
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.
Baseret på Kuss' tilgang (Kuss, O.: "How to use SAS for logistic regression with correlated data", SAS User Group International (SUGI) Conference Proceedings 27, Paper 261-27 (2002)) genberegnede ansøgeren den blandede logistiske model i henhold til SAS-proceduren NLMIXED (SAS Version 9.1.3). 
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).
I hver af de kliniske farmakokinetiske undersøgelser (enkeltdosis- såvel som flerdosisundersøgelsen) bekræftedes det, at for Fentrixplastret var procentdelen af en hudirritationsscore på 0 (ingen irritation), og scoren 1 (minimalt erytem, næsten ikke synligt, scoren beregnes i henhold til FDA's branchevejledning "Skin Irritation and Sensitization Testing of Generic Transdermal Products") nået op på over 90 %. 
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 %.
Enkeltdosisundersøgelse: Den gennemsnitlige score var 0,39 for testproduktet og 0,25 for referenceproduktet. 
Single dose study: the mean score for test was 0.39 and 0.25 for the reference.
Nordkanalstrasse 28 20097 Hamburg Tyskland anvendelse 
Nordkanalstrasse 28 20097 Hamburg Germany transdermico
I princippet skulle de ikkekliniske data om lokal tolerance af dobbeltlagsplastret have været suppleret af en analyse af risikoen for overfølsomhed. 
In principle, the non-clinical data on local tolerance of the bilayer patch should have been complemented by an analysis of its sensitisation potential.
Ansøgeren erkendte, at der kun er blevet udført ikkekliniske enkeltdosisundersøgelser, til trods for at punkt 4.2 "Dermal tolerance testing" i "Note for Guidance on Non-clinical Tolerance Testing of Medicinal Products" (CPMP/SWP/2145/00) angiver, at dermal tolerance skal testes med enkelte og gentagne doser samt en vurdering af risikoen for overfølsomhed. 
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.
Begge kliniske farmakokinetiske undersøgelser, enkeltdosis- såvel som flerdosisundersøgelser, bekræftede, at Fentrixplastret generelt er veltolereret på menneskelig hud. 
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.
Flerdosisundersøgelse: Antallet af observationer af hudirritation med en score over 1 var 77 for testproduktet og 56 for referenceproduktet, hvor antallet af forsøgspersoner med hudirritation var det samme (26). 
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.
Plastrets fremherskende bestanddele - hovedsageligt to af klæbestofferne - virkede ikke irriterende på marsvins hud, når de blev testet alene i henhold til retningslinjerne CPMP/SWP/2145/00 og OECD 406 (Buehlermetoden). 
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).