FrancophonIA/ELRC3.0 huggingface dataset:
English: At the request of the CHMP, an Anti-Infective Scientific Advisory group (SAG) meeting was held on 3 September 2012.
Danish: På anmodning af CHMP blev der den 3. september 2012 holdt et møde i den videnskabelige rådgivende gruppe (SAG) vedrørende antiinfektiøse midler.
English: Ketoconazole was first registered as tablets and oral suspension in December 1980.
Danish: Ketoconazol blev første gang registreret som tabletter og oral suspension i december 1980.
English: Moreover, these cases were derived from old publications (from 1980 to 1986) while changes could be expected in the management of patients over more than 25 years.
Danish: Disse tilfælde var udledt af gamle publikationer (fra 1981 til 1986), skønt behandlingspraksis må forventes at have ændret sig i løbet af de mere end 25 år.
English: Grounds for suspension of the marketing authorisations
Danish: Begrundelse for suspenderingen af markedsføringstilladelserne
English: Several potential mechanisms for this toxicity have been identified but uncertainties still remain.
Danish: Der er fundet flere mulige mekanismer bag den toksiske virkning, men der består fortsat usikkerheder.
English: Particular attention was dedicated to the issue of hepatotoxicity.
Danish: Opmærksomheden var især rettet mod hepatotoksicitet.
English: The marketing authorisation holder extensively discussed the mechanism of hepatotoxicity, widely supported with literature data from 1986 to 2007.
Danish: Indehaveren af markedsføringstilladelsen gennemgik udførligt mekanismen i hepatotoksicitet, bredt støttet med litteraturdata fra 1986 til 2007.
English: Overall summary of the scientific evaluation of ketoconazole-containing products for oral use (see Annex I)
Danish: Samlet resumé af den videnskabelige vurdering af lægemidler, der indeholder ketoconazol til oral anvendelse (se bilag I)
English: Topical forms have not been considered in the present review.
Danish: De topikale former er ikke omfattet af denne gennemgang.
English: Ketoconazole does not penetrate well in the Central Nervous System.
Danish: Ketoconazol penetrerer ikke let centralnervesystemet.
English: In Europe, oral formulations of ketoconazole are currently approved in 20 Member States as well as in Iceland and Norway.
Danish: I Europa er orale formuleringer af ketoconazol godkendt i 20 medlemsstater foruden Island og Norge.
English: The level of risk appears to be higher than that observed with other antifungal agents.
Danish: Risikoen synes at være højere end den, der ses med andre antimykotika.
English: Results from non-clinical toxicity studies indicated the liver and endocrine system as primary target organs.
Danish: Resultaterne af ikke-kliniske toksicitetsundersøgelser viste, at leveren og det endokrine system er primære målorganer.
English: This was followed by the registration of topical pharmaceutical forms such as cream /ointment/shampoo.
Danish: Derefter fulgte registreringen af topikale lægemiddelformer såsom creme/salve/shampoo.
English: • The Committee considered the procedure under Article 31 of Directive 2001/83/EC for ketoconazole-containing products for oral use;
Danish: • udvalget fulgte proceduren i overensstemmelse med artikel 31 i direktiv 2001/83/EF for lægemidler indeholdende ketoconazol til oral anvendelse,
English: This issue has not been mitigated because ketoconazole has not been used as an active comparator for newer drugs since 2001.
Danish: Denne mangel er ikke afhjulpet, da ketoconazol ikke har været anvendt som aktivt sammenligningsstof til nyere lægemidler siden 2001.
English: Characteristics of acute injuries mainly included cytolysis and may lead to serious outcomes including liver transplantation.
Danish: De akutte skader blev hovedsagelig karakteriseret som cytolyse og kan have alvorligt udfald, herunder levertransplantation.
English: Divergent positions are presented in Appendix III.
Danish: Mindretalsudtalelser fremgår af bilag III.
English: Of the 1,505 cases of interest; 880 (58%) were medically validated serious of which 18 life-threatening cases did not present any confounding factors and therefore are supportive of a causal role of ketoconazole.
Danish: At de 1 505 tilfælde af interesse var de 880 (58 %) lægeligt valideret som alvorlige; heraf var der 18 livstruende tilfælde, som var uden konfunderende faktorer og således underbygger en kausal rolle af ketoconazol.
English: The experts were asked to discuss any restricted indication where the benefit/risk could be regarded as positive in the current armamentarium, and particularly the restricted indication proposed by the MAH.
Danish: Eksperterne blev bedt om at drøfte alle begrænsede indikationer, hvor benefit/risk-forholdet kan anses for positivt i det nuværende armamentarium, herunder den begrænsede indikation, der var foreslået af indehaveren af markedsføringstilladelsen.
English: Marketing authorisations have been withdrawn by the MAH in several Member States for commercial reasons and only the 200mg tablet formulation is still available in the EEA.
Danish: I flere medlemsstater har markedsføringstilladelsesindehaveren trukket markedsføringsgodkendelsen tilbage af kommercielle grunde, og kun 200 mg tabletformuleringen er endnu på markedet i EØS.
English: In children, dosing recommendations are also broadly consistent with 100 mg daily for children weighing 15-30 kg and the same dose as for adults in children weighing more than 30 kg.
Danish: Hos børn er doseringsanbefalingerne også stort set ens og foreskriver 100 mg dagligt til børn mellem 15 og 30 kg, og samme dosis som til voksne hos børn over 30 kg.
English: Of note, while ketoconazole was available since 1982, fluconazole and itraconazole became later available in the 1990's.
Danish: Det bemærkes, at ketoconazol har været tilgængeligt siden 1982, hvorimod fluconazol og itraconazol først blev tilgængelige i 1990'erne.
English: The CHMP, having considered the data submitted by the MAH, was of the opinion that the proposed risk minimisation activities were not appropriate to reduce the risks to an acceptable level taking into account the restrictions and warnings already in place.
Danish: Efter gennemgang af de af markedsføringstilladelsesindehaveren forelagte data fandt CHMP ikke de foreslåede risikominimeringsforanstaltninger tilstrækkelige til at nedsætte risiciene til et acceptabelt niveau i betragtning af de allerede gældende begrænsninger og advarsler.
English: However, the experts unanimously agreed that these cases were anecdotal and that there was no scientific evidence available to support this claim.
Danish: Eksperterne udtalte imidlertid samstemmende, at der var tale om anekdotiske tilfælde, og at der ikke forelå videnskabelig evidens til støtte herfor.
English: The CHMP was requested to give its opinion on whether the marketing authorisations for medicinal products containing ketoconazole for oral use, and associated names should be maintained, varied, suspended or withdrawn.
Danish: CHMP blev anmodet om at fremsætte en udtalelse om, hvorvidt markedsføringstilladelserne for lægemidler indeholdende ketoconazol til oral anvendelse og relaterede navne burde opretholdes, ændres, suspenderes eller inddrages.
English: In the literature, incidence of acute injuries is variable and ranged from 1/2000 patients exposed to 12%.
Danish: I litteraturen varierer forekomsten af akutte skader fra 1/2 000 eksponerede patienter til 12 %.
English: In view of the above, the French Agency considered in June 2011 that the benefit-risk balance of oral ketoconazole was negative, suspended the existing marketing authorisations in France and informed the healthcare professionals and the public of its conclusions.
Danish: På ovenstående baggrund afgjorde den franske lægemiddelmyndighed i juni 2011, at benefit/riskforholdet for oralt ketoconazol var negativt, og suspenderede de eksisterende markedsføringstilladelser i Frankrig og informerede sundhedspersoner og offentligheden om deres konklusioner.
English: In general, the clinical studies submitted to support the efficacy of oral ketoconazole were limited and not conducted in line with the current guidelines.
Danish: Generelt var de kliniske undersøgelser, der blev forelagt som dokumentation af virkningen af oralt ketoconazol, begrænsede og ikke udført i overensstemmelse med de nuværende retningslinjer.
English: Since no additional study was provided, the hypothesis that high cumulative dose of ketoconazole is a possible risk factor for the development of serious hepatotoxicity could not be supported at this stage.
Danish: Da der ikke blev fremlagt yderligere undersøgelser, kunne hypotesen om, at høje kumulative doser af ketoconazol er en mulig risikofaktor for udvikling af alvorlig hepatotoksicitet, ikke støttes på dette stadium.
English: Dosing recommendations in adults are largely consistent across Member States, at 200 mg per day which can be increased to 400 mg in cases where there is no adequate response.
Danish: Den anbefalede dosering for voksne, der stort set er ens i alle EU's medlemsstater, er 200 mg dagligt, som kan øges til 400 mg ved utilstrækkelig respons.
English: Finally, the SAG recognised that ketoconazole could potentially be used as a last treatment option in some very rare cases.
Danish: Endelig vedgik den videnskabelige rådgivende gruppe, at ketoconazol potentielt kunne anvendes som sidste behandlingsmulighed i visse meget sjældne tilfælde.
English: Efficacy studies of ketoconazole on Malassezia folliculitis, Pityriasis versicolor, Tinea Capitis and Tinea Barbae, Tinea Corporis, Tinea Cruris, Tinea Pedis, and Tinea Manuum were scarce.
Danish: Undersøgelserne af virkningen af ketoconazol ved Malassezia-follikulitis, pityriasis versicolor, tinea capitis og tinea barbae, tinea corporis, tinea cruris, tinea pedis og tinea manuum var sparsomme.
English: Treatment duration ranges from 5 consecutive days (vaginal candidosis) to up to 6 months for systemic fungal infections such as paracoccidioidomycosis and histoplasmosis.
Danish: Behandlingsvarigheden er fra fem på hinanden følgende dage (vaginal candidiasis) op til seks måneder ved systemiske mykoser såsom paracoccidioidomykose og histoplasmose.
English: Seven fatal/life-threatening cases were reported with event dates after 2006 i.e., after the CCDS update that contained substantial hepatotoxicity-related revisions.
Danish: Der blev indberettet syv fatale/livstruende tilfælde med hændelsesdato efter 2006, dvs. efter at det centrale datablad var blevet opdateret med bl.a. væsentlige hepatotoksicitetsrelaterede ændringer.
English: The therapeutic indications included in the current version of the Company Core Data Sheet (CCDS) of the originator product are as follows:
Danish: Følgende terapeutiske indikationer er indeholdt i den gældende version af det centrale datablad for det oprindelige produkt:
English: In addition, a literature review retrieved more than 100 publications related to hepatotoxicity of ketoconazole.
Danish: Desuden fandtes ved en litteratursøgning over 100 publikationer om hepatotoksicitet af ketoconazol.
English: Infections of the skin, hair, and mucosa, induced by dermatophytes and/or yeasts that cannot be treated topically because of the site or the extent of the lesion or deepinfection of the skin.
Danish: Infektioner i hud, hår og slimhinder med dermatofytter og/eller gærsvampe, der ikke kan behandles topikalt som følge af infektionsstedets beliggenhed, læsionens omfang eller dybden af infektionen i huden.
English: Taking into account all the above, the CHMP could not identify any situation that could justify exposing a patient to the level of hepatotoxicity of ketoconazole for oral use.
Danish: I betragtning af alt det ovenstående kunne CHMP ikke udpege nogen situation, der berettiger at eksponere en patient for den hepatotoksicitet, der forbundet med oral anvendelse af ketoconazol.
English: Based on those conclusions, the Committee recommended the suspension of the marketing authorisations for all ketoconazole-containing products for oral use.
Danish: På grundlag af disse konklusioner anbefalede udvalget suspendering af markedsføringstilladelserne for alle lægemidler indeholdende ketoconazol til oral anvendelse.
English: The SAG was also of the opinion that the pharmacokinetics / pharmacodynamics profile of ketoconazole presents similar limitations as the other systemic antifungal treatments (i.e. limited absorption, distribution) and the drug-drug interaction profile could be even worse.
Danish: Den videnskabelige rådgivende gruppe fandt også, at den farmakokinetiske/farmakodynamiske profil af ketoconazol har samme begrænsninger som de andre systemiske antimykotika (dvs. begrænset absorption og fordeling), og at lægemiddelinteraktionsprofilen kan tænkes at være endnu dårligere.
English: The potential for hepatotoxicity is a class effect of azole antifungals and has been long reported for ketoconazole in numerous nonclinical and clinical references.
Danish: Det hepatotoksiske potentiale er en klassevirkning af azol-antimykotika og er længe blevet beskrevet for ketoconazol af talrige ikke-kliniske og kliniske kilder.
English: Therefore, fungal meningitis should not be treated with oral ketoconazole.
Danish: Mykotisk meningitis bør derfor ikke behand les oralt med ketoconazol.
English: Given its level of efficacy and its poor distribution in the central nervous system, the use of ketoconazole in systemic mycoses might expose patients to sub-optimal management, as translated in the therapeutic guidelines.
Danish: På baggrund af graden af ketoconazols virkning og dets dårlige fordeling i centralnervesystemet kan anvendelse af ketoconazol ved systemiske mykoser tænkes at udsætte patienterne for suboptimal behandling i henhold til behandlingsretningslinjerne.
English: The experts unanimously agreed that there was no scientific evidence to support the MAH's revised indication proposal.
Danish: Eksperterne var samstemmende af den opfattelse, at der ikke fandtes videnskabelig evidens til støtte for markedsføringstilladelsesindehaverens forslag om en revideret indikation.
English: In order to assess the general safety of ketoconazole, relevant information from pre-clinical studies, clinical trials, post-marketing spontaneous case reports, pharmaco-epidemiological studies and published literature was assessed.
Danish: Vurderingen af den generelle sikkerhed af ketoconazol blev baseret på relevante oplysninger fra prækliniske undersøgelser, kliniske undersøgelser, spontane case-rapporter efter markedsføring, farmakoepidemiologiske undersøgelser og den publicerede litteratur.
English: In addition, based on the literature review, ketoconazole seemed to be the only antifungal agent associated with development of chronic hepatitis and cirrhosis.
Danish: Baseret på en litteraturgennemgang syntes ketoconazol desuden at være det eneste antimykotiske middel, der sættes i forbindelse med udvikling af kronisk hepatitis og cirrhose.
English: In addition, the use of ketoconazole in those cases would likely require a long term or repeated treatment which would be of concern for the SAG given the hepatotoxicity profile of the compound.
Danish: Desuden måtte anvendelse af ketoconazol i sådanne tilfælde forventes at kræve langvarig eller gentagen behandling, hvilket gruppen anså for betænkeligt i betragtning af stoffets hepatotoksiske profil.
English: • The Committee could not identify any further adequate measures to reduce the risks of ketoconazole for oral use as antifungal treatment to an acceptable level.
Danish: • udvalget kunne ikke udpege yderligere passende foranstaltninger, der mindsker risiciene ved oral antimykotisk behandling med ketoconazol til et acceptabelt niveau.
English: Indeed, the SAG considered that the activity of the newer systemic antifungals is expected to be superior to ketoconazole.
Danish: Den videnskabelige rådgivende gruppe fandt således, at aktiviteten af de nyere systemiske antimykotika forventes at være overlegen i forhold til ketoconazol.
English: The SAG was of the opinion that there are no data to support the efficacy of ketoconazole when other treatments (including other azoles) have failed or resistance has been detected.
Danish: Gruppen var af den opfattelse, at der ikke er data, der støtter virkningen af ketoconazol ved behandlingssvigt af andre midler (herunder andre azoler) eller ved konstateret resistens.
English: From 1985 to 2010, around a hundred cases of hepatic disorders with oral ketoconazole were reported to the French Pharmacovigilance Regional Centres network, including hepatitis NOS, toxic hepatitis, cytolytic hepatitis, cholestatic hepatitis, hepatic failure.
Danish: Fra 1985 til 2010 blev der til de franske regionale lægemiddelovervågningscentre indberettet ca. 100 tilfælde af leversygdom med oralt ketoconazol, herunder hepatitis uden nærmere beskrivelse, toksisk hepatitis, cytolytisk hepatitis, kolestatisk hepatitis og leversvigt.
English: In addition, the claimed indications concern superficial fungal infections which are mainly confined to skin involvement (also mucous membranes for CMC), and while the social burden/inconvenience of this type of infections is not denied, the fact that they are mostly benign is also per se to be balanced with the level of hepatotoxicity of the drug.
Danish: De påberåbte indikationer vedrører desuden superficielle mykoser, der hovedsagelig er begrænset til huden (også slimhinderne ved kronisk mukokutan candidiasis), og uanset den sociale byrde/ulempe ved denne type infektioner må det forhold, at de i de fleste tilfælde er godartede, også i sig selv holdes op mod stoffets grad af hepatotoksicitet.
English: Moreover, tests for susceptibility to ketoconazole are not commercially available.
Danish: I øvrigt fås test til følsomhedsbestemmelse over for ketoconazol ikke i handelen.
English: The clinical safety of oral ketoconazole was evaluated in 4735 subjects in 92 company-sponsored clinical trials of ketoconazole tablets (or suspension), administered either to treat a variety of fungal infections in patients or to healthy-volunteer subjects.
Danish: Den kliniske sikkerhed af oralt ketoconazol blev vurderet hos 4 735 personer i 92 kliniske undersøgelser, der var sponsoreret af virksomheden og vedrørte ketoconazol tabletter (eller suspension), dels anvendt terapeutisk ved en række forskellige mykoser, dels givet til frivillige, raske forsøgspersoner.
English: Based on this analysis, the point-estimate risk, in terms of the commonly-used Frequency Categories in the Summary of Product Characteristics (SmPCs), was “Common” (≥ 1/100 to < 1/10) for any Hepatic Function Test result being abnormal, and “Rare” (≥ 1/10,000 to < 1/1,000) for Hepatitis and/or Jaundice.
Danish: Ved analysen var punktestimatet for risikoen i de i produktresuméer sædvanligt anvendte hyppighedskategorier “almindelig” (≥ 1/100 til < 1/10) for enhver unormal leverfunktionstest og “sjælden” (≥ 1/10 000 til < 1/1 000) for hepatitis og/eller ikterus.
English: The incidence of symptomatic hepatic reactions in the setting of treatment with oral ketoconazole was estimated in several epidemiology studies to be between 1/10,000 and 1/15,000 patients.
Danish: I scenarier med oral anvendelse af ketoconazol blev forekomsten af symptomatiske leverreaktioner i flere epidemiologiske undersøgelser anslået til mellem 1/10 000 og 1/15 000 patienter.
English: All but 5 tinea capitis (no case of Malassezia folliculitis) corresponded to Chronic Mucocutaneous Candidiasis (n=16).
Danish: Bortset fra 5 tilfælde af tinea capitis svarede alle tilfældene til kronisk mukokutancandidiasis (n=16) (der var ingen tilfælde af Malassezia-follikulitis).
English: The demonstrate the effectiveness of ketoconazole in these indications, the MAH provided a total of 40 cases, 19 cases based on clinical visits of two clinicians who kept a registry of such patients and 21 cases based on a review of the literature.
Danish: Til påvisning af virkningen af ketoconazol ved disse indikationer fremlagde indehaveren af markedsføringstilladelsen i alt 40 tilfælde, 19 tilfælde baseret på klinikbesøg hos to klinikere, der førte register over sådanne patienter, og 21 tilfælde baseret på en litte raturgennemgang.
English: Overall, although hepatotoxicity is a class effect of azoles, the quantitative and qualitative aspects of the hepatotoxicity of ketoconazole are of particular concern.
Danish: Skønt hepatotoksicitet er en klassevirkning af azoler, giver de kvantitative og kvalitative aspekter af ketoconazols hepatotoksicitet samlet set grund til særlig betænkelighed.
English: In 2011, a review performed by the French National Competent Authority concluded that spontaneous reports and literature data indicate that oral ketoconazole is associated with a high level of liver toxicity.
Danish: Efter en gennemgang i 2011 konkluderede den franske nationale kompetente myndighed, at spontane indberetninger og litteraturdata viser høj hepatotoksicitet ved oral anvendelse af ketoconazol.
English: A cumulative search through 15 July 2011 for adverse events coded to the MedDRA (version 14.0) Preferred Terms (PTs) listed in the Standardised MedDRA Queries (SMQ) Hepatic disorders (broad terms) retrieved 1,512 cases, of which 1,505 cases were part of the sub-SMQ Drug related hepatic disorders (comprehensive search excluding non-drug related events such as congenital, infection, alcohol and pregnancy related events).
Danish: Ved at søge kumulativt frem til 15. juli 2011 efter bivirkninger kodet i henhold til foretrukne MedDRA betegnelser (version 14.0) på listen over de standardiserede MedDRA-søgetermer (SMQ) blev der for “Hepatic disorders” (brede betegnelser) fundet 1 512 tilfælde, hvoraf 1 505 var omfattet af undersøgetermen lægemiddelrelaterede hepatiske lidelser (udtømmende søgning, der undtog ikkelægemiddelrelaterede hændelser såsom medfødte lidelser, infektioner og alkohol- og graviditetsrelaterede hændelser).
English: • The Committee could not identify a fungal infection where the level of hepatotoxicity of the drug could be balanced by an adequately substantiated benefit; the Committee noted that there are currently alternatives available for the treatment of fungal infections;
Danish: • udvalget kunne ikke udpege nogen mykose, hvor lægemidlets grad af hepatotoksicitet kunne opvejes af en fyldestgørende underbygget fordel; udvalget bemærkede, at der på nuværende tidspunkt er andre behandlingsmuligheder for mykoser,
English: • Malassezia folliculitis
Danish: • Malassezia-follikulitis
English: • Histoplasmosis
Danish: • Histoplasmose
English: The Committee could not identify a fungal infection where the level of hepatotoxicity of the drug could be balanced by an adequately substantiated benefit and therefore concluded that the benefits of oral ketoconazole in the treatment of all antifungal indications listed above do not outweigh the risks.
Danish: Udvalget kunne ikke udpege en mykotisk infektion, hvor lægemidlets grad af hepatotoksicitet opvejes af en fyldestgørende dokumenteret fordel, og konkluderede derfor, at fordelene ved oralt ketoconazol til behandling af alle ovennævnte antimykotiske indikationer ikke opvejer risiciene.
English: The experts all concurred that ketoconazole safety profile was worse than the other systemic antifungal treatments, and there's no evidence that it would represent an option when other azoles are not tolerated.
Danish: Alle eksperterne var af den opfattelse, at sikkerhedsprofilen af ketoconazol er ringere end af de øvrige systemiske antimykotika, og at der ikke er evidens for, at ketoconazol repræsenterer et behandlingsalternativ, når andre azoler ikke tolereres.
English: Within the EU, the indications approved for ketoconazole-containing products vary amongst Members States.
Danish: I EU er der godkendt forskellige indikationer for ketoconazol i forskellige medlemsstater.