FrancophonIA/ELRC3.0 huggingface dataset:
English: Warnings and precautions Talk to your doctor before taking RILUTEK: if you have any liver problems: yellowing of your skin or the white of your eyes (jaundice), itching all over, feeling sick, being sick if your kidneys are not working very well if you have any fever: it may be due to a low number of white blood cells which can cause an increased risk of infection If any of the above applies to you, or if you are not sure, tell your doctor who will decide what to do.
Danish: Kontakt lægen, før du tager Rilutek: - hvis du har nogen form for leverproblemer: gulfarvning af huden eller det hvide i dine øjne
English: Liver impairment
Danish: Prikken i munden
English: Benefit/risk assessment
Danish: Benefit/risk-vurdering
English: RE-EXAMINATION OF THE CHMP OPINION ADOPTED ON 23 APRIL 2009
Danish: REVURDERING AF CHMP'S UDTALELSE AF 23. APRIL 2009
English: SCIENTIFIC CONCLUSIONS
Danish: VIDENSKABELIGE KONKLUSIONER
English: ANNEX II SCIENTIFIC CONCLUSIONS AND GROUNDS FOR REFUSAL
Danish: BILAG II VIDENSKABELIGE KONKLUSIONER OG BEGRUNDELSER FOR AFSLAG
English: -The safety profile of ciclosporin is also critical.
Danish: - Sikkerhedsprofilen for ciclosporin er også kritisk.
English: ANNEX III CONDITION FOR THE LIFTING OF THE MARKETING AUTHORISATIONS SUSPENSION
Danish: BILAG III BETINGELSER FOR OPHÆVELSE AF SUSPENDERINGEN AF MARKEDSFØRINGSTILLADELSERNE
English: Variable
Danish: Variabel
English: In clinical routine practice therapeutic drug monitoring is done in order to control for and monitor safety.
Danish: Som en del af den kliniske rutinemæssige praksis udføres monitorering af terapeutiske lægemidler med henblik på at kontrollere og overvåge sikkerheden.
English: Summary of Grounds for Re-Examination
Danish: Sammendrag af begrundelserne for revurdering
English: ANNEX I LIST OF THE NAMES, PHARMACEUTICAL FORM, STRENGTHS OF THE MEDICINAL PRODUCTS, ROUTE OF ADMINISTRATION, APPLICANT / MARKETING AUTHORISATION HOLDER IN THE MEMBER STATES
Danish: BILAG I FORTEGNELSE OVER LÆGEMIDLERNES NAVNE, LÆGEMIDDELFORM, STYRKE, INDGIVELSESVEJ, ANSØGER/INDEHAVER AF MARKEDSFØRINGSTILLADELSE I MEDLEMSSTATERNE
English: The Reference medicinal product authorised in Germany is: Sandimmun Optoral 25 mg Kapseln.
Danish: Referencelægemidlet, som er godkendt i Tyskland, er: Sandimmun Optoral 25 mg Kapseln.
English: In the MRP procedure (NL/H/1402/001-003/MR) potential serious risk for public health concern was raised on the following grounds: bioequivalence has not been sufficiently demonstrated.
Danish: Under den gensidige anerkendelsesprocedure (NL/H/1402/001-003/MR) blev der givet udtryk for betænkeligheder grundet potentiel alvorlig risiko for folkesundheden af følgende grunde: Der er ikke påvist tilstrækkelig bioækvivalens.
English: 2) The second question raised by CHMP was whether the same acceptance range (either normal or narrowed) should be applied both for AUC and Cmax.
Danish: 2) CHMP's andet punkt var, om det samme godkendelsesinterval (enten normalt eller snævert) burde anvendes for både AUC og Cmax.
English: Ciclosporin is indicated in transplantation (e.g. prevention or treatment of rejection of solid organ transplantation, bone marrow transplantation, graft-versus-host-disease) and auto-immune diseases (e.g nephrotic syndrome, rheumatoid arthritis, psoriasis, atopic dermatitis).
Danish: Ciclosporin er indiceret til transplantation (f.eks. forebyggelse eller behandling af afstødning ved transplantation af solide organer, knoglemarvstransplantation, graft versus host-sygdom) og autoimmune sygdomme (f.eks. nefrotisk syndrom, rheumatoid arthritis, psoriasis, atopisk dermatitis).
English: Differences in Cmax were considered less important, because a peak level is maintained for only a short period of time, whereas AUC represents the total exposure to the drug, but it was felt that the conventional range should be used.
Danish: Forskelle i Cmax blev betragtet som mindre væsentlige, da det maksimale niveau kun opretholdes i en kort periode, mens AUC udgør den samlede eksponering for lægemidlet, men det blev besluttet, at det normale interval skulle anvendes.
English: In particular the upper confidence limit for the comparison of Cmax was outside even the standard acceptance range.
Danish: Navnlig en øvre grænse for konfidensintervallet til sammenligning af Cmax var uden for selv det normale godkendelsesinterval.
English: 4) The fourth issue raised by CHMP was about the food effect on ciclosporin.
Danish: 4) CHMP's fjerde punkt drejede sig om kostens indvirkningen på ciclosporin.
English: In addition, in the Transplant Patient Guide (University of Southern California-Cardiothoracic Surgery and Pancreas Transplant Program), it is recommended to take ciclosporin before meals, for better absorption by the stomach.
Danish: Desuden anbefales det i vejledningen til transplanterede patienter (University of Southern CaliforniaCardiothoracic Surgery and Pancreas Transplant Program), at ciclosporin tages inden et måltid for at opnå bedre absorption i maven.
English: The authors considered both cyclosporine and tacrolimus to be critical-dose drugs.
Danish: Forfatterne fandt, at både cyclosporin og tacrolimus var "critical-dose drugs".
English: The issue here is clearly not a problem of interchangeability between Sandimmune and its optimized formulation of Neoral, but a lack of proof of bioequivalence, since this is a generic procedure.
Danish: Dette spørgsmål drejer sig tydeligvis ikke om substituerbarhed mellem Sandimmun og dets optimerede formulering af Neoral, men om manglende dokumentation for bioækvivalens, da dette er en generisk procedure.
English: The RMS, the Netherlands, will assess data from a new bioequivalence study and, if the following condition is fulfilled and satisfactory data provided, the suspension of the Marketing Authorisations can be lifted:
Danish: Referencemedlemsstaten, Nederlandene, vil vurdere data fra en ny bioækvivalensundersøgelse, og hvis de følgende betingelser opfyldes, kan suspenderingen af markedsføringstilladelserne ophæves.
English: This narrow range should apply to both AUC and Cmax as outside range values for any of both parameters can lead to efficacy and/or safety unwanted consequences.
Danish: Det snævre interval bør anvendes for både AUC og Cmax, da værdier uden for intervallet kan medføre uønskede konsekvenser i forhold til virkning og/eller sikkerhed for begge disse parametre.
English: Slightly smaller particles size of Ciclosporin IDL should be seen as an advantage for the absorption regarding food intake.
Danish: Den lidt mindre partikelstørrelse for Ciclosporin IDL skal ses som en fordel, hvad angår absorption i forbindelse med fødeindtagelse.
English: Bioequivalence and safe switch
Danish: Bioækvivalens og sikkert skifte
English: The MAH quoted a publication from The National Kidney Foundation of 1999 raising inequivalence concerns for transplant organ immunosuppressants and introduced the term “critical-dose drug”.
Danish: Indehaveren af markedsføringstilladelsen citerede en publikation fra The National Kidney Foundation fra 1999, der gav udtryk for bekymring om manglende ækvivalens for immunosuppressiv behandling efter organtransplantation og indførte termen "critical-dose drug".
English: Fasting Point estimate (%) for test / reference (90% CI)
Danish: Pointoverslag (%) for test/reference (90 % CI)
English: A generic product should be possible to use interchangeably with an originator product without taking any extra measurements.
Danish: Et generisk lægemiddel skal kunne anvendes substituerbart med et originalpræparat uden ekstra forholdsregler.
English: The CHMP did not agree upon the lack of safety concerns in fasting conditions and did not endorse the use of asymmetric CIs.
Danish: CHMP var ikke enigt i, at der ikke var anledning til betænkeligheder vedrørende sikkerheden i fastende tilstand, og godkendte ikke anvendelsen af asymmetriske konfidensintervaller.
English: 3) The third point raised by CHMP was whether the same set of requirements should be applied for assessing bioequivalence under high-fat fed conditions.
Danish: 3) CHMP's tredje punkt var, hvorvidt de samme krav skulle gælde ved vurdering af bioækvivalens efter et fedtrigt måltid.
English: Ciclosporin is considered a ‘critical dose drug' with narrow therapeutic index.
Danish: - Ciclosporin betegnes som et "critical-dose drug" med et snævert terapeutisk indeks.
English: Marketing Authorisation Holder
Danish: Indehaver af markedsføringstilladelsen Ansøger
English: This may result in major swings in blood concentrations, since it has been shown that the intake of food has a very negative effect on absorption (up to about 30% reduction of Cmax and 15% reduction in AUC) of the reference product.
Danish: Dette kan medføre store udsving i koncentrationen i blodet, da det er påvist, at kostindtaget har en særdeles negativ indvirkning på optagelsen (op til 30 % reduktion af Cmax og 15 % reduktion af AUC) af referencelægemidlet.
English: For generic applications no other data than bioequivalence is assessed and therefore approval should be based with confidence that such risk is reduced at maximum by narrowing the CI.
Danish: Ved generiske ansøgninger vurderes udelukkende bioækvivalensdata, og derfor bør en godkendelse kun gives, hvor der er sikkerhed for, at en sådan risiko er reduceret mest muligt gennem indsnævring af konfidensintervallet.
English: The MAH stated that this issue needs to be addressed by the Regulatory Authorities and should be taken into consideration when evaluating IDL test product formulation, because this could play a definite role for safety issues, knowing that efficacy was preserved in any case as shown by the AUCs results.
Danish: Indehaveren af markedsføringstilladelsen anførte, at dette spørgsmål skal behandles af tilsynsmyndighederne og skal tages i betragtning ved evalueringen af IDL-testlægemiddelformuleringen, fordi dette kan spille en afgørende rolle for sikkerhedsproblemer, eftersom effekten under alle omstændigheder blev bevaret, som det fremgår af resultaterne for AUC.
English: - the 90% CI relates to the population effects, whereas in clinical practice the substantial intraindividual variability is critical for the variable ciclosporin blood levels and this is the reason why it is monitored by frequent plasma through concentration even with the brand leader and these determinations which are routinely performed will allow to correct immediately deviation of the 10% or 20%.
Danish: - Konfidensintervallet på 90 % vedrører virkningen på populationen, mens det i klinisk praksis er den intraindividuelle variation, der er af afgørende betydning for det varierende indhold af ciclosporin i blodet, og dette er årsagen til, at mindstekoncentrationen i plasma hyppigt monitoreres, selv ved det førende mærke, og disse resultater, der udføres rutinemæssigt, gør det muligt at korrigere afvigelser på 10 eller 20 % med det samme.
English: The data showed that the variability with each formulation between fed versus fasted is much lower for the test then for the reference drug, although the area under the curve is not much different.
Danish: Dataene viste, at variabiliteten for de enkelte formuleringer mellem ikkefastende og fastende tilstand er meget lavere for testlægemidlet end for referencelægemidlet, selv om arealet under kurven ikke adskiller sig væsentligt.
English: Key results from the dossier supporting the MAA are reproduced below.
Danish: De centrale resultater fra det dossier, der dokumenterer markedsføringstilladelserne, er gengivet nedenfor.
English: The MAH stated that in the particular case of ciclosporin, and because of inter-subject variability, the monitoring of blood concentrations is the most important criterion to prevent from any public health issue.
Danish: Indehaveren af markedsføringstilladelsen anførte, at netop i forbindelse med ciclosporin og som følge af variabiliteten hos den enkelte forsøgsperson er monitorering af blodkoncentrationer det vigtigste kriterium for forebyggelse af eventuelle folkesundhedsproblemer.
English: As result, the size of the emulsion droplets of the test and the reference are comparable and the slight difference of the particles size could explain the lower impact of food on the intestinal absorption.
Danish: Dette bevirker, at størrelsen af emulsionsdråber for test- og referencelægemidlet er sammenlignelige, og at den lille forskel i partikelstørrelsen kan forklare den lavere indvirkning af fødeindtagelse på absorptionen i tarmsystemet.
English: The MAH answered that there doesn't seem to be a convincing reason why the range (80-125%) should be different for Cmax and AUC.
Danish: Indehaveren af markedsføringstilladelsen svarede, at der ikke foreligger nogen overbevisende begrundelse for, at intervallet (80-125 %) skulle være forskelligt for Cmax og AUC.
English: Thus the CHMP retains its opinion and assessment report dated 23 April 2009 that the bioequivalence to the originator has not been shown and the benefit/risk ratio of Ciclosporin IDL is considered to be negative.
Danish: CHMP fastholder derfor sin udtalelse og vurderingsrapport fra den 23. april 2009, som konkluderer, at bioækvivalens med originalpræparatet ikke er blevet påvist, og at benefit-/risk-forholdet for Ciclosporin IDL må anses for negativt.
English: Bioequivalence in fast conditions
Danish: Bioækvivalens i fastende tilstand
English: The CHMP considered that the size of the particles is not a relevant argument for accepting wider bioequivalence range for ciclosporin.
Danish: CHMP fandt, at partikelstørrelsen ikke er et relevant argument for godkendelsen af et bredere bioækvivalensinterval for ciclosporin.
English: CHMP concluded that the bioequivalence data observed were inadequate to establish efficacy and safety.
Danish: CHMP konkluderede, at de observerede bioækvivalensdata var utilstrækkelige til at bestemme virkning og sikkerhed.
English: The SPC for Sandimmun Optoral allows administration regardless of food, indicating that the known food effect for ciclosporin (approximately 26% reduction of Cmax and 15% reduction of AUC) is considered not clinically relevant.
Danish: Produktresuméet for Sandimmun Optoral tillader indgivelse uden hensyn til kost, hvilket viser, at den kendte indvirkning af kosten i forbindelse med ciclosporin (ca. 26 % reduktion af Cmax og 15 % reduktion af AUC) ikke anses som klinisk relevant.
English: However, in the absence of other data, it is not possible to confirm that under fed conditions the test product is bioequivalent and therefore will have the same efficacy and safety profile of the innovator.
Danish: Grundet manglen på andre data er det dog ikke muligt at bekræfte, om testlægemidlet er bioækvivalent i ikkefastende tilstand og derfor vil have den samme virknings- og sikkerhedsprofil som originalpræparatet.
English: The MAH decided to appeal, and triggered a re-examination of the CHMP opinion on the following grounds:
Danish: Indehaveren af markedsføringstilladelsen besluttede at indgive en klage, og en revurdering af CHMP's udtalelse blev foretaget med følgende begrundelse:
English: The Efficacy Working Party PK expert group, consulted by the CHMP, understood that in clinical practice, ciclosporin is often recommended to be taken in a standardised way in relation to food.
Danish: Den farmakokinetiske ekspertgruppe under Arbejdsgruppen vedrørende virkninger, som CHMP rådførte sig med, vidste, at det ofte anbefales i klinisk praksis, at ciclosporin tages på standardiseret vis i forhold til kosten.
English: The other study in fed conditions showed that Ciclosporin IDL was less affected by food than Novartis Neoral reference product.
Danish: Den anden undersøgelse i ikkefastende tilstand viste, at Ciclosporin IDL i mindre grad blev påvirket af føde end referencelægemidlet Novartis Neoral.
English: Taking this into account, the question was whether a reduced effect of food on generic ciclosporin pharmacokinetics could be considered acceptable for a ‘generic application', even in case that this results in a failure to comply with the predefined acceptance criteria (e.g. 80-125%) for concluding bioequivalence under fed conditions (in this case with a 90% CI for Cmax of 1.09-1.37).
Danish: Set i lyset af dette var spørgsmålet, hvorvidt en reduceret indvirkning af kosten på generisk ciclosporins farmakokinetik kunne anses for at være acceptabel for et "generisk lægemiddel", også selv om det gør, at man ikke kan overholde de prædefinerede godkendelseskriterier (f.eks. 80-125 %) ved vurderingen af bioækvivalens i ikkefastende tilstand (i dette tilfælde et konfidensinterval på 90 % for et Cmax på 1,09-1,37).
English: As ciclosporin is administered in high doses and for long periods of time in the clinical setting of transplantation, the CHMP refer to this indication for the justification of ciclosporin as being a NTI
Danish: Da ciclosporin gives i høje doser og i lange perioder i kliniske miljøer i forbindelse med transplantationer, henviser CHMP til denne indikation i begrundelsen for at betegne ciclosporin som et lægemiddel med et snævert terapeutisk indeks.
English: The CHMP concluded that bioequivalence has not been demonstrated in fasting conditions.
Danish: CHMP konkluderede, at bioækvivalens ikke er blevet påvist i fastende tilstand.
English: The CHMP adopted a final negative opinion recommending the refusal of the Marketing Authorisation in the Concerned Member States and the suspension of the Marketing Authorisation where the product is currently authorised.
Danish: CHMP vedtog en negativ udtalelse, der anbefalede afslag på ansøgningen i de berørte medlemsstater og suspendering af markedsføringstilladelsen i de medlemsstater, hvor lægemidlet er godkendt på nuværende tidspunkt.
English: The MAH claimed that these results showed efficacy equivalence without safety issues in fast conditions.
Danish: Indehaveren af markedsføringstilladelsen anførte, at disse resultater påviste ækvivalens for virkning uden sikkerhedsproblemer i fastende tilstand.
English: The MAH noted that the SPCs of Sandimune and Neoral state that these two products are not bioequivalent, but a switch between these products is allowed with an appropriate therapeutic drug monitoring (TDM), indicating that this is well established common practice blood concentration guided dosing of ciclosporin.
Danish: Indehaveren af markedsføringstilladelsen bemærkede, at det i produktresuméerne for Sandimmun og Neoral anføres, at disse to lægemidler ikke er bioækvivalente, men at et skifte mellem disse lægemidler tillades med passende terapeutisk monitorering af lægemidler, hvilket viser, at dette er en veletableret almindelig praksis for dosering af ciclosporin baseret på blodkoncentration.
English: The CHMP, after the oral explanation, found that the data and the justification presented were not adequate to confirm the bioequivalence between the test and the originator.
Danish: Efter den mundtlige redegørelse besluttede CHMP, at de data og den begrundelse, der var blevet fremlagt, ikke var tilstrækkelige til at bekræfte bioækvivalens mellem testlægemidlet og originallægemidlet.
English: Further, the MAH did not submit any data showing that Cmax values outside the bioequivalence criteria do not change the efficacy/safety performance of the product in comparison to the reference product.
Danish: Indehaveren af markedsføringstilladelsen indsendte endvidere ingen data, der påviste, at værdier for Cmax uden for bioækvivalenskriterierne ikke ændrer lægemidlets virknings- og sikkerhedsprofil sammenlignet med referencelægemidlet.
English: The CHMP considered also the data the MAH submitted for PK simulations of ciclosporin concentrations for both reference and test product repeated dosing in fed and fasted states.
Danish: CHMP overvejede også de data, som indehaveren af markedsføringstilladelsen havde indgivet vedrørende PK-simuleringer af ciclosporinkoncentrationer for gentagne doser af både reference- og testlægemidlet i ikkefastende og fastende tilstand.
English: Although this may be the explanation of the diminished food effect of the product, do not add any additional information with regard to Ciclosporin IDL possibly being approved as a generic bioequivalent to a reference product.
Danish: Selv om dette kan forklare den lavere effekt af føde i forbindelse med lægemidlet, tilføres der ikke yderligere oplysninger, der kan begrunde en godkendelse af Ciclosporin IDL som et generisk lægemiddel, der er bioækvivalent med referencelægemidlet.
English: It is essential the therapeutic monitoring of renal, liver functions and blood pressure as adverse events are reported as very common and in a transplant population can be clinically devastating.
Danish: Det er af afgørende betydning, at terapeutisk monitorering af nyre- og leverfunktion samt blodtryk bliver rapporteret som almindelige bivirkninger, da de kan have katastrofale følger i klinisk sammenhæng for transplanterede patienter.
English: The CHMP addressed a list of questions to the Marketing Authorisation Holder and to the Efficacy Working Party PK expert group for consultation on the following points:
Danish: CHMP udfærdigede en liste med spørgsmål til indehaveren af markedsføringstilladelsen og den farmakokinetiske ekspertgruppe under Arbejdsgruppen vedrørende virkninger med henblik på en høring.
English: The number of adverse events may be associated with the huge variation in blood concentrations of the reference drug that will follow if it is taken regardless of food intake and the lack of instructions given regarding food intake.
Danish: Antallet af bivirkninger kan hænge sammen med den store variation i blodkoncentrationen for referencelægemidlet, som vil forekomme, hvis det tages uden hensyntagen til kostindtag og manglende rådgivning om kostindtag.
English: Pharmaceutical properties of Sandimmune Optoral and Ciclosporin IDL micro emulsions
Danish: Farmaceutiske egenskaber for Sandimmun Optoral- og Ciclosporin IDL-mikroemulsioner
English: 1) The first issue raised by the CHMP was whether a normal (80-125%) or narrowed (90-111%) acceptance range should be applied for assessing bioequivalence under fasting conditions, considering ciclosporin is to be regarded a 'highly variable drug' with a Narrow Therapeutic Range.
Danish: 1) Det første punkt, der blev taget op af CHMP, var, hvorvidt der burde anvendes et normalt (80125 %) eller et snævert (90-111 %) godkendelsesinterval i forbindelse med vurdering af bioækvivalens i fastende tilstand, eftersom ciclosporin anses som et foranderligt lægemiddel med et snævert terapeutisk område.
English: The evidence for bioequivalence, which meets narrow (90-111%) acceptance criteria for AUC under fasting conditions, meets standard (80-125%) acceptance criteria for Cmax in the fasted state, and fails to meet even standard acceptance criteria the fed state, is regarded as inadequate to support a conclusion of bioequivalence.
Danish: Dokumentationen for bioækvivalens, som opfylder snævre (90-111 %) godkendelseskriterier for AUC i fastende tilstand, som opfylder de normale godkendelseskriterier (80-125 %) for Cmax i fastende tilstand, og som end ikke opfylder de normale godkendelseskriterier i ikkefastende tilstand, vurderes at være utilstrækkelig til at understøtte en konklusion vedrørende bioækvivalens,
English: In view of the MAH, from the data generated by the bioequivalence studies, the ciclosporin test product is in the range 90%-111% for the AUC and less than 111% of the reference for the Cmax in the fasted conditions study which reflects the pharmacokinetic parameters without any interaction.
Danish: I henhold til indehaveren af markedsføringstilladelsen ligger ciclosporintestlægemidlet ifølge data genereret under bioækvivalensundersøgelserne i intervallet 90-111 % for AUC og mindre end 111 % af referencen for Cmax i undersøgelsen i fastende tilstand, hvilket afspejler de farmakokinetiske parametre uden interaktion.
English: The CHMP has recommended the refusal of the granting of the Marketing Authorisations in the Concerned Member States and the suspension of the Marketing Authorisations for Ciclosporin IDL where the product is currently authorised.
Danish: anbefaler CHMP, at der gives afslag på markedsføringstilladelse i de berørte medlemsstater, og at markedsføringstilladelserne for Ciclosporin IDL suspenderes i de medlemsstater, hvor lægemidlet er godkendt på nuværende tidspunkt.