natgillin/translations-raw huggingface dataset:
Ved gennemgangen blev der taget hensyn til 15 tilfælde af alvorlige bivirkninger, der er indberettet i Norge.
The review took into account 15 cases of serious adverse reactions reported in Norway.
Betingelsen for ophævelse af suspenderingen af markedsføringstilladelserne fremgår af bilag IV.
The condition for lifting the suspension of these marketing authorisations is set out in Annex IV.
De foreliggende data viser imidlertid ikke, at povidon er effektivt til at afbøde denne risiko.
However, available data do not demonstrate the effectiveness of povidone in mitigating this risk.
Det blev overvejet at indsætte yderligere advarsler i produktinformationen, men direkte information til patienterne er vanskelig, og ifølge eksperterne vil sådanne foranstaltninger næppe yderligere kunne minimere risikoen for injektion.
Additional warnings in the label were further considered, but a direct information to the patients is challenging and according to the experts, such measures are unlikely to further minimise the risk of injection.
For 12 af de 15 patienter var der evidens for, at de havde fået ordineret metadon eller anvendte dette (urinprøve eller patientens udsagn).
For 12 of the 15 patients, evidence that they had been prescribed or used methadone (urine sample or patient's statement) was available.
Dette medfører povidon-aflejringssygdom, som kan føre til alvorlige skader.
This leads to ‘povidone storage disease' that may cause serious harm.
For at suspenderingen kan ophæves, sikrer medlemsstaternes kompetente nationale myndigheder, at indehaveren af markedsføringstilladelsen opfylder følgende vilkår:
For the suspension to be lifted, the National competent authorities of Member States shall verify that the following conditions are fulfilled by the MAH:
Produktinformationen for denne orale opløsning af metadon indeholder i forvejen klare anvisninger om, at den ikke må ikke injiceres.
The product information of this methadone oral solution already contains clear advice that it should not be injected.
Fordelingen og eliminationen af povidon efter intravenøs administration er velundersøgt, og undersøgelser med radioaktivt mærket povidon af forskellig molekylvægt har vist, at clearance af polymerer efter intravenøs administration afhænger af molekylvægten.
The distribution and elimination of povidone when administered intravenously has been well investigated and studies using radioactive labelled povidone of different molecular weight have demonstrated that clearance of polymers after intravenous administration is dependent on molecular weight.
Hvis denne orale opløsning injiceres gentagne gange, vil povidon blive permanent tilbageholdt og ophobet i organer og væv med påfølgende potentielle alvorlige skadevirkninger.
Should this oral solution be repeatedly injected, povidone would be permanently retained and accumulate within organs and tissues, leading to potential serious harm.
Metadonbehandling bør anvendes i sammenhæng med et bredere rehabiliteringsprogram, opioidsubstitutionsterapi.
Treatment with methadone should be given in the context of a wider rehabilitation program, opioid substitution therapy (OST).
Samlet resumé af den videnskabelige vurdering af orale metadonlægemidler indeholdende povidon
Overall summary of the scientific evaluation of methadone products for oral use containing povidone
Gennemgangen af orale metadonlægemidler indeholdende povidon begyndte den 10. april 2014 i henhold til artikel 107i i direktiv 2001/83/EF.
The review of oral methadone medicines containing povidone started on 10 April 2014 under Article 107i of Directive 2001/83/EC.
Overvåget administration af hver dosis blev ligeledes drøftet, man ville være vanskeligt at indføre konsekvent i daglig praksis med opioidsubstitutionsterapi og ville føre til alvorlig manglede compliance.
Supervised administration of every dose was also discussed but this would be difficult to consistently incorporate into daily OST practice and would lead to serious non-compliance.
Størstedelen af patienterne deltog på daværende tidspunkt eller tidligere i programmer for opioidsubstitutionsterapi.
Most of the patients were currently or previously included in OST programs.
Den oprindelige hensigt med anvendelsen af povidon K90 i orale metadonopløsninger var at øge viskositeten og mindske risikoen for misbrug ved injektion.
The inclusion of povidone K90 in oral methadone solutions was initially intended to enhance viscosity and reduce the risk of misuse by injection.
For at ophæve suspenderingen skal lægemidlet omformuleres på passende måde under hensyn til sit misbrugspotentiale.
To lift the suspension, this product should be appropriately reformulated taking into account its misuse potential.
For de øvrige otte tilfælde manglede der nyrebiopsier, men der blev fundet aflejringer af povidon i andre væv.
For the other eight cases, renal biopsies were lacking, but povidone deposits were detected in biopsies from other tissues.
I alle tilfældene underbygger farvning af biologiske prøver konklusionen om, at der var ophobning af povidon i de berørte organer.
In all cases, staining of biological samples supports the conclusion that povidone accumulated in the affected organs.
Den overordnede effektivitet af vedligeholdelsesbehandling med metadon er anerkendt i litteraturen og har været genstand for flere oversigtsartikler.
The overall effectiveness of methadone maintenance treatment is established in the literature and has been reviewed in several articles.
PRAC bemærkede, at der for alle disse 15 tilfælde var anført »forsætligt stofmisbrug«, »aflejringer af lægemiddel« og »lægemidlet administreret ad ukorrekt vej«, og at det regionale lægemiddelovervågningscenter i Norge anså dem for at have sandsynlig eller mulig sammenhæng med injektion af povidon.
The PRAC noted that all these 15 cases reported “intentional drug misuse”, “product deposit” and “drug administered via inappropriate route” and were assessed by the regional pharmacovigilance centre in Norway as possibly or probably related to the injection of povidone.
De foreliggende data fra den videnskabelige litteratur tyder på, at der ikke er fastslået en tydelig sammenhæng mellem aflejringer af povidon og nedsat nyrefunktion.
Available data from the scientific literature suggests that an association between deposits of povidone and renal impairment has not been well established.
Hos en af de fem patienter viste knoglemarvsbiopsi, at knoglemarven var ca. 90 % infiltreret med histiocytter, hvilket er karakteristisk for aflejring af povidon, og kun ca. 5 % af knoglemarven var til rådighed for erythropoiese.
For one of the five patients the bone marrow biopsy showed about 90% histiocytic infiltration characteristic for povidone deposit and only about 5% of bone marrow available for erythropoiesis.
I de fleste tilfælde kan ordination eller anvendelse af metadon bekræftes, og for nogles vedkommende blev det vedgået, at der var injiceret oralt metadon,
In most cases, prescription or use of methadone can be confirmed, while some of them also have admitted injecting oral methadone.
Der blev forelagt seks nyrebiopsier, der alle viste aflejringer af povidon i det tubulære interstitielle område.
Six kidney biopsies were presented and all demonstrated deposits of povidone in the tubular-interstitial area.
Gennemgangen fulgte NOMA's beslutning om at suspendere den eneste nationalt markedsførte metadonholdige orale opløsning, der indeholder povidon, efter indberetninger om alvorlige bivirkninger hos tidligere og nuværende stofmisbrugere i Norge.
It followed the decision of NOMA to suspend the only methadonecontaining oral solution that contains povidone present on the national market, on the basis of reports of serious adverse events in former or current drug abusers in Norway.
Efter parenteral administration er det almindelig anerkendt, at lavmolekylært povidon (molekylvægt <25 000) let udskilles gennem nyrerne: Glomerulus kan inden for få dage udskille alt povidon med molekylvægt 40 000 eller derunder; hos raske voksne personer er den normale glomerulus relativt upermeabel for povidon ved molekylvægt >70 000 (hvorimod der ved nefrotisk sygdom er øget permeabilitet for større molekyler); det retikuloendoteliale system tilbageholder molekyler med molekylvægt >110,000 (Ravin et al., 1952 og Hulme og Hardwicke, 1968).
Following parenteral administration, it is generally accepted that low molecular weight povidone (Mw <25 000) is readily excreted by the kidney: the glomerulus can excrete within a few days all povidone of Mw 40 000 or below; the normal glomerulus of healthy human subjects is relatively impermeable to povidone Mw >70 000 (while in humans with nephrotic disease, the permeability for larger molecules was increased); the reticuloendothelial system (RES) retains molecules with a Mw >110,000 (Ravin et al. 1952; Hulme and Hardwicke 1968).
Der blev iagttaget patologiske frakturer hos to af de fem patienter, hos hvem der ligeledes var aflejring af povidon i knoglevævet.
Pathological fractures were observed in two of the five patients, with deposits of povidone also in the bone tissue.
PRAC gennemgik alle foreliggende sikkerhedsdata, navnlig vedrørende risiciene forbundet med misbrug bestående i injektion af orale metadonlægemidler indeholdende povidon.
The PRAC reviewed all available safety data, in particular with regards to the risks associated with the misuse by injection of methadone products for oral use containing povidone.
I ni tilfælde var der misbrug af stoffer ved injektion i anamnesen, og i otte af disse ni tilfælde blev det vedgået, at der var sket injektion af metadon til oral anvendelse.
In nine cases a history of drug abuse with substances that have been injected was specified and in eight of these nine cases a history of injecting methadone intended for oral use was reported.
Metadon anvendes til behandling af moderate til svære smerter og desuden som vedligeholdelses- eller substitutionsbehandling ved opioidafhængighed.
Methadone is used in the treatment of moderate to severe pain and is also used as maintenance/substitution medication in the management of opioid dependence.
• PRAC mente, at de foreliggende prækliniske og kliniske data giver evidens for, at højmolekylært povidon (>110,000) ved injektion må forventes at blive permanent tilbageholdt i kroppen, navnlig i knoglemarv og knoglevæv.
• The PRAC was of the opinion that available pre-clinical and clinical data provide evidence that high molecular weight povidone (>110,000) when injected is likely to be permanently retained in the body, in particular in the bone marrow and bone tissue.
Der er dokumentation for, at povidon med lavere molekylvægt (<25,000) udskilles let, men at povidon med højere molekylvægt (>110 000) slet ikke eller (>70 000) kun delvis udskilles,
There is evidence that lower molecular weight povidone (<25,000) is readily excreted but that higher Mw povidone (>110,000) is not, or (>70,000) only partially excreted;
Det blev desuden bemærket, at misbrug med injektion af metadonlægemidler er en iboende risiko hos målpopulationen, da injektion af metadon til oral anvendelse forekommer hos mellem 5 % og 79,5 % af stiknarkomaner (Winstock et al., 2010; Guichard et al., 2003; Waldvogel et al., 2005; Judson G. et al., 2010, og Vlahov D et al., 2007), og underrapportering anses for sandsynlig.
It was also noted that misuse by injection of methadone product is an inherent risk in the target population with evidence showing an occurrence of injection of methadone for oral use among injecting drug users varying from 5.0% to 79.5% (Winstock et al. 2010, Guichard et al. 2003, Waldvogel et al 2005, Judson G et al. 2010, and Vlahov D et al. 2007) and an underreporting considered to be likely.
• PRAC gennemgik alle foreliggende data fra den videnskabelige litteratur, prækliniske og kliniske undersøgelser og erfaringer efter markedsføring vedrørende sikkerheden af orale metadonholdige lægemidler indeholdende povidon, dels fra indehaverne af markedsføringstilladelsernes skriftlige besvarelser og mundtlige fremlæggelser, dels resultatet af ad hoc-ekspertgruppens møde og dels materiale fra interessenter, navnlig vedrørende den velkendte misbrugsrisiko med injektion af lægemidlerne hos målpopulationen,
• The PRAC reviewed all available data from published literature, pre-clinical and clinical studies and post-marketing experience on the safety of methadone medicinal products for oral use containing povidone, responses submitted by the marketing authorisation holders (MAHs) in writing and during the oral explanations, the outcome of the ad-hoc expert advisory group meeting as well as stakeholders' submissions in particular with regards to the risks associated with the misuse of the products by injection which is a well-known risk in the target population;
Højmolekylært povidon (>110 000) udskilles ikke gennem nyrerne og vil ved gentagne injektioner blive tilbageholdt i kroppen og kan medføre alvorlig skade,
High Mw povidone (>110,000) will not be excreted by the kidney and therefore will be retained in the body if repeatedly injected and may lead to serious harm;
For fem patienter blev der beskrevet knogledestruktion og/eller knoglemarvspåvirkning (herunder anæmi), og biopsierne viste ophobning af povidon i knoglemarven.
For five patients, bone destruction and/or bone marrow affection (including anaemia) were reported and findings from biopsies showed accumulation of povidone in the bone marrow.
• PRAC gennemgik case-rapporter om tidligere eller nuværende stiknarkomaner, herunder fatale tilfælde, og noterede sig de alvorlige bivirkninger (herunder knoglemarvspåvirkning og patologiske frakturer), hvis art var overensstemmende med ophobning af povidon, og bemærkede desuden, at der i biopsier var set aflejring af povidon i organer og væv.
• The PRAC considered case reports, including fatal cases, in former or current injecting drug users, and noted the serious adverse reactions, the nature of which (including bone marrow adverse effects and pathological fractures) was consistent with the accumulation of povidone and also noted that povidone deposition in organs and tissues had been seen on biopsies.
Årsagssammenhængen mellem aflejringer af povidon og knoglemarvssvigt og fraktur er imidlertid rimeligt veldokumenteret, og den patofysiologiske mekanisme synes at hænge sammen med spatial konkurrence mellem aflejringerne og knoglemarven (Kepes et al., 1993; Kuo et al., 1997; Dunn et al., 1998, og Huang et al., 2012).
However, the causality of povidone deposits and bone marrow failure and skeletal fracture has been reasonably demonstrated, and the mechanism of pathophysiology appears to be related to the spatial competition of deposits and bone marrow (Kepes et al 1993; Kuo et al 1997; Dunn et al 1998; Huang et al 2012).
PRAC konkluderede, at benefit/risk-forholdet for disse lægemidler var positivt, forudsat at produktinformationen ændres med henblik på at harmonisere og styrke advarslen om, at tabletterne kun er til oral administration og ikke må injiceres.
The PRAC concluded that the benefit-risk of these products was favourable provided that amendments are introduced in the product information, to harmonise and reinforce the message that tablets are for oral administration only and must not be injected.
• PRAC bemærkede, at risikoen for misbrug ved injektion af metadonlægemidler til oral anvendelse er velkendt hos målpopulationen og desuden er beskrevet i litteraturen,
• The PRAC noted that the risk of misuse by injection of methadone products for oral use is wellknown in the target population, evidence of which is available from the literature;
Virkningen af metadon til opioidsubstitutionsterapi blev anset for anerkendt i denne indbringelsesprocedure.
The efficacy of methadone in OST was acknowledged in this referral procedure.
Metadontabletter indeholdende lavmolekylært povidon (K25 eller K30)
Methadone tablets containing low Mw povidone (K25 or K30)
Det anvendes hovedsagelig i orale opløsninger som viskositetsforøgende middel (K90) samt i tabletter som bindemiddel (f.eks. K25 og K30).
It is mainly used in oral solutions (K90) as a viscosity-increasing agent, or as a binding agent (e.g. K25, K30) in tablets.
Andre af gennemgangen omfattede metadonlægemidler, der indeholder povidon, er tabletter med povidon med lavere molekylvægt (f.eks. K25 og K30, også i lavere mængde), som vides at udskilles gennem nyrerne og derfor ikke forventes tilbageholdt i kroppen.
Other methadone products containing povidone concerned by the review are tablets and have lower Mw povidone (e.g. K25, K30, also in lower amount), which is known to be excreted from the kidney and therefore is expected not to be retained in the body.
Oral metadonopløsning med højmolekylært povidon (K90)
Methadone oral solution containing high molecular weight povidone (K90)
Povidon er et hjælpestof, der findes i forskellige molekylstørrelser fra K12 (lavmolekylært, gennemsnitlig molekylvægt ~ 2000) til K90 (højmolekylært, gennemsnitlig molekylvægt 1 100 000).
Povidone is an excipient available in a variety of different molecular sizes from K12 (low molecular weight (Mw), average Mw ~ 2000) to K90 (high Mw, average Mw 1,100,000).
• PRAC fandt, at potentialet for skade måtte forventes at være forbundet med misbrug af orale opløsninger af metadon indeholdende højmolekylært povidon K90,
• The PRAC considered that the potential for harm was likely to be associated with the misuse of methadone oral solutions containing high molecular weight povidone K90;
• PRAC bemærkede, at højmolekylært povidon kun fandtes i en enkelt oral metadonopløsning med styrken 2 mg/ml, som indeholder povidon K90 med en gennemsnitlig molekylvægt på 1 100 000.
• The PRAC noted that high molecular weight povidone was present only in one methadone oral solution dosed at 2 mg/ml, which contains povidone K90 with an average molecular weight of 1,100,000.
Vedligeholdelsesbehandling med metadon i fleksibel dosering ved opioidafhængighed er mere effektiv end ingen narkotikabehandling.
Flexible-dose methadone maintenance therapy is more clinically effective than no drug therapy in dependent opioid users.
Disse lægemidler har derfor ikke samme skadespotentiale som orale opløsninger indeholdende højmolekylært povidon.
These products are therefore not associated with the potential for harm of oral solutions containing high Mw.
CMD(h) vedtog ligeledes ændrede betingelser for markedsføringstilladelserne for metadontabletter indeholdende lavmolekylært povidon (K25 ellers K30), for hvilke ændringerne af produktresuméet og indlægssedlen fremgår af bilag III.
The CMDh also reached an agreement on the variation to the terms of the Marketing Authorisations for methadone tablets containing low molecular weight povidone (K25 or K30) for which the amendments to be introduced to the Summary of Product Characteristics and package leaflet are set out in Annex III.
Skønt det ikke med sikkerhed kan fastslås, hvilket metadonlægemiddel, der var tale om, antages de iagttagne alvorlige bivirkninger (f.eks. anæmi og knoglemarvslidelser) at skyldes aflejring af povidon hos stofmisbrugere, som har misbrugt orale opløsninger af metadon indeholdende povidon K90.
Although the brand of methadone cannot be confirmed with certainty it is suspected, based on the availability of the product and pattern of usage in Western Norway that the observed serious adverse reactions (e.g. anaemia and bone marrow disorder) were caused by povidone deposition in drug abusers who have misused methadone oral solutions containing povidone K90.
• PRAC fulgte proceduren i overensstemmelse med artikel 107i i direktiv 2001/83/EF for metadonholdige lægemidler indeholdende povidon,
• The PRAC considered the procedure under Article 107i of Directive 2001/83/EC, for methadone medicinal products for oral use containing povidone.
Styrelsen anmodede PRAC om at gennemgå benefit/risk-forholdet for alle i EU godkendte orale metadonlægemidler, der indeholder polyvinylpyrrolidon (bedre kendt under navnet povidon eller PVP), og fremsætte en anbefaling til koordinationsgruppen vedrørende gensidig anerkendelse og decentral procedure - lægemidler til mennesker (CMD(h)) om eventuelle nødvendige foranstaltninger til at sikre sikker og effektiv anvendelse, og om hvorvidt markedsføringstilladelsen for disse lægemidler bør opretholdes, ændres, suspenderes eller inddrages.
On 2nd April 2014, the Norwegian Medicines Agency, NOMA, triggered a referral under Article 107i of Directive 2001/83/EC concerning methadone-containing medicines for oral use containing povidone asking the PRAC to review the benefit-risk balance of all oral methadone medicines containing polyvinylpyrrolidone (more commonly known as povidone or PVP) authorised in the EU and to make a recommendation to the Human Co-ordination Group for Mutual Recognition and Decentralised Procedures (CMDh) on any measures necessary to ensure the safe and effective use, and on whether the marketing authorisation for these products should be maintained, varied, suspended or withdrawn.
Højmolekylært povidon ophobes derfor efter intravenøs injektion, og i litteraturen er beskrevet aflejring af povidon (navnlig i knoglemarv og knoglevæv) efter intravenøs administration af væsentlige mængder, hvilket medfører povidon-aflejringssygdom (»storage disease«) (Kepes et al., 1993; Kuo et al., 1997; Dunn et al., 1998, og Huang et al., 2012).
High molecular weight povidone therefore accumulates if injected intravenously and povidone deposition in organs and tissues (in particular bone marrow and bone tissue) have been reported in the literature after substantial intravenous administration leading to ‘povidone storage disease' (Kepes et al. 1993; Kuo et al. 1997; Dunn et al. 1998; Huang et al. 2012).
PRAC fandt derfor, at yderligere risikominimeringsforanstaltninger ikke kunne afhjælpe den kendte risiko for misbrug hos den påtænkte målpopulation og de tilknyttede alvorlige skader ved injektion af højmolekylært povidon (K90).
Therefore, the PRAC considered that additional risk minimisation measures could not mitigate the known risk of misuse by the intended target population and the associated potential serious harm caused by the injection of high molecular weight povidone (K90).
• PRAC fandt derfor, at de foreslåede yderligere risikominimeringsforanstaltninger til ajourføring af produktinformationen ikke kunne afhjælpe den kendte risiko for misbrug hos den påtænkte målpopulation og de tilknyttede potentielle alvorlige skader forårsaget af injektion af højmolekylært povidon (K90),
• The PRAC considered that the proposed risk minimisation measures to update the product information could not mitigate the known risk of misuse by the intended target population and the associated potential serious harm caused by the injection of high molecular weight povidone (K90);
Ved gennemgangen af metadonlægemidler indeholdende povidon konstaterede PRAC, at højmolekylært povidon kun fandtes i én oral metadonopløsning med styrken 2 mg/ml (indeholdende 11,7 mg/ml højmolekylært povidon, K90).
In the context of the review of methadone products containing povidone, the PRAC noted that high molecular weight povidone was present only in one methadone oral solution dosed at 2 mg/ml (containing high molecular weight povidone, K90).
Efter gennemgang af PRAC's anbefaling af 23. juli 2014 nåede CMD(h) til enighed om, at markedsføringstilladelserne for oral metadonopløsning indeholdende højmolekylært povidon (K90) suspenderes i medfør af artikel 107k, stk. 1 og 2, i direktiv 2001/83/EF.
The CMDh, having considered the PRAC recommendation dated 23 July 2014 pursuant to Article 107k(1) and (2) of Directive 2001/83/EC, reached an agreement on the suspension of the marketing authorisations for methadone oral solution containing high molecular weight povidone (K90).