FrancophonIA/ELRC3.0 huggingface dataset:
English: On 18 January 2012, France triggered a referral under Article 31 of Directive 2001/83/EC for the following ergot derivatives containing medicinal products: dihydroergocryptine/caffeine, dihydroergocristine, dihydroergotamine, dihydroergotoxine and nicergoline.
Danish: Den 18. januar 2012 indbragte Frankrig en sag i henhold til artikel 31 i direktiv 2001/83/EF vedrørende følgende lægemidler indeholdende ergotderivater: dihydroergocryptin/caffein, dihydroergocristin, dihydroergotamin, dihydroergotoxin og nicergolin.
English: In addition, it was the IV formulation of the product that was used and not the oral formulation that is in the scope of this referral procedure.
Danish: Desuden var det den intravenøse formulering af produktet, der blev anvendt, ikke den orale formulering, som denne indbringelsesprocedure vedrører.
English: • Fibrosis is mentioned in several current European Summaries of Product Characteristics (SmPCs) and expected reactions are often under-reported
Danish: • fibrose nævnes i flere gældende europæiske produktresuméer, og forventede reaktioner bliver ofte underindberettet
English: The Committee therefore pointed out that the proposed measures are insufficient to avoid that some patients develop fibrosis and ergotism during treatment.
Danish: Udvalget fastslog derfor, at de foreslåede foranstaltninger er utilstrækkelige til at undgå, at nogle patienter udvikler fibrose og ergotisme under behandlingen.
English: The CHMP was therefore requested to give its opinion on whether the marketing authorisations for ergot derivatives containing medicinal products should be maintained, varied, suspended or withdrawn in relation to the below mentioned indications:
Danish: CHMP blev derfor anmodet om at udtale sig om, hvorvidt markedsføringstilladelserne for lægemidler indeholdende ergotderivater burde opretholdes, ændres, suspenderes eller inddrages i forbindelse med nedenstående indikationer:
English: The studies presented are old and of poor methodological quality: uncontrolled, open designed, with a low number of patients (n=12 in Wenzel, 1989, the most recent study).
Danish: De forelagte undersøgelser er gamle og af ringe metodologisk kvalitet: ukontrolleret, åbent design med et lille antal patienter (n=12 i Wenzel, 1989, den nyeste undersøgelse).
English: The design of this study was considered acceptable by the CHMP (i.e. controlled, randomised, double-blind) but the size of the study was considered small (n=58).
Danish: Undersøgelsens design blev anset for acceptabelt af CHMP (dvs. kontrolleret, randomiseret, dobbeltblindet), men undersøgelsens størrelse blev anset for at være lille (n=58).
English: Dihydroergotamine mesilate (dihydroergotamine - DHE) is a semi-synthetic derivative of ergotamine.
Danish: Dihydroergotaminmesylat (dihydroergotamin - DHE) er et halvsyntetisk derivat af ergotamin.
English: Some of them assessed the injection route or doses higher than recommended (up to 42mg daily, instead of 10mg daily).
Danish: Nogle af undersøgelserne vedrørte injektionspræparater eller doser højere end de anbefalede (op til 42 mg dagligt i stedet for 10 mg dagligt).
English: Systolic blood pressure of the placebo and the dihydroergotamine group differed already at baseline.
Danish: Det systoliske blodtryk i placebogruppen og i dihydroergotamin-gruppen var allerede forskelligt ved baseline.
English: A post-hoc analysis was performed in the sub-group of patients (n=288) with functional handicap and quality of life (QOL) decrease (defined by Migraine Specific Quality of Life, MSQ<80).
Danish: Der blev udført en post hoc-analyse i undergruppen af patienter (n=288) med funktionelt handicap og nedsat livskvalitet (defineret som Migraine Specific Quality of Life, MSQ<80).
English: • Fibrosis is also an insidious reaction that occurs after a long period of treatment and thus with often a delayed diagnosis.
Danish: • fibrose desuden er en snigende reaktion, der opstår efter lang tids behandling og derfor ofte diagnosticeres med forsinkelse.
English: It has long been used in the treatment of migraine on the grounds of its vasoconstrictor activity, which is milder than that of ergotamine.
Danish: Det har længe været anvendt til behandling af migræne på grund af sin vasokonstriktoriske virkning, som er mildere end den af ergotamin.
English: In the reported cases, dihydroergotamine is mostly indicated for migraine or headache (30 patients) and used with the recommended daily dosage.
Danish: I de indberettede tilfælde var dihydroergotamin hovedsagelig indiceret til migræne eller hovedpine (30 patienter) og blev anvendt i den anbefalede daglige dosering.
English: These included restricting the therapeutic indications, recommending close monitoring of patients and the issuing of a DHPC.
Danish: Disse bestod i begrænsning af de terapeutiske indikationer og anbefaling af tæt overvågning af patienter samt udsendelse af en direkte meddelelse til sundhedspersoner (DHPC).
English: In order to lift the suspension, MAHs must identify a specific patient population for which the benefits of the product outweigh the risk.
Danish: For at ophæve suspenderingen skal indehaverne af markedsføringstilladelse udpege en konkret patientpopulation, for hvilken fordelene ved produktet opvejer risikoen.
English: The seriousness of such adverse effects and their possible fatal outcome is underlined.
Danish: Alvorligheden af sådanne bivirkninger og deres potentielle fatale udfald understreges.
English: In addition, patients were included if they displayed a reduction of systolic blood pressure of more than 10 mmHg, which does not comply with the established definition of orthostatic hypotension (at least 20 mm Hg below baseline).
Danish: Desuden blev patienterne inkluderet, hvis de udviste et fald i systolisk blodtryk på mere end 10 mmHg, hvilket ikke er i overensstemmelse med den anerkendte definition af ortostatisk hypotension (mindst 20 mm Hg under baseline).
English: Ergotism is a serious reaction, which leads in rare cases reported to important sequelae following amputation or colon resection for example.
Danish: Ergotisme er en alvorlig reaktion, der i sjældne tilfælde er beskrevet at medføre alvorlige sequelae efter f.eks. amputation eller colonresektion.
English: The authorised oral doses seem to have weak or null efficacy due to the low bioavailability of the drug.
Danish: Den godkendte orale dosering synes at have svag eller ingen virkning på grund af stoffets lave biotilgængelighed.
English: Almost all cases were serious (93% of the cases where seriousness was reported) and treatment with dihydroergotamine was discontinued in 91% of the cases (for which information is available) and in 57% of these cases, the outcome has been reported as improved or recovered.
Danish: Næsten alle tilfældene var alvorlige (93 % af de tilfælde, hvor alvorligheden blev angivet), og behandlingen med dihydroergotamin blev seponeret i 91 % af de tilfælde, hvor oplysning herom foreligger; i 57 % af disse tilfælde blev udfaldet angivet som bedring eller restitution.
English: For the indication “symptomatic treatment of veno-lymphatic insufficiency” very few studies have been conducted.
Danish: For indikationen “symptomatisk behandling af venolymfatisk insufficiens” er der kun udført meget få undersøgelser.
English: • The Committee considered that a potential causal association between fibrotic reactions or ergotism and oral dihydroergotamine cannot be excluded.
Danish: • udvalget fandt, at der ikke kan udelukkes en potentiel årsagssammenhæng mellem dihydroergotamin og fibrotiske reaktioner eller ergotisme.
English: The double-blind, randomised, placebo-controlled studies were old and generally not carried out with the current up-to-date methodology.
Danish: De dobbeltblindede, randomiserede, placebokontrollerede undersøgelser var gamle og sædvanligvis ikke udført med metoder, der lever op til en nutidig standard.
English: Patient population was heterogeneous, or patients with hypotension induced by treatment with psychotropic drugs.
Danish: Patientpopulationen var uensartet eller bestod af patienter med hypotension fremkaldt af psykoaktive lægemidler.
English: The number of patients included was small and the duration of treatment was too short and the clinical efficacy parameters used are not in line with the European Guidelines on clinical investigation of medicinal products for the treatment of migraine.
Danish: Det inkluderede antal patienter var lavt, og behandlingsvarigheden for kort, og de anvendte parametre for klinisk virkning er ikke i overensstemmelse med de europæiske retningslinjer for klinisk undersøgelse af lægemidler til behandling af migræne.
English: Therefore, the group was of the opinion that based on the available evidence there is no need for this substance as there is no clear subset of patients that would benefit from it.
Danish: Det var derfor gruppens opfattelse, at den foreliggende evidens viser, at der ikke er behov for dette stof, da der ikke findes nogen klar undergruppe af patienter, som vil have fordel af det.
English: As expected, fibrosis occurred mostly in female patients (68%) after long time of treatment with dihydroergotamine (9.1 years on average) and the most frequent type of fibrosis reaction reported was retroperitoneal (36%), followed by cardiac (30%) and pleural (18%).
Danish: Som forventet optrådte fibrose hovedsagelig hos kvindelige patienter (68 %) efter langtidsbehandling med dihydroergotamin (gennemsnitligt 9,1 år), og den hyppigste indberettede type fibrosereaktion var retroperitoneal (36 %), efterfulgt af kardial (30 %) og pleural (18 %).
English: • The Committee is of the opinion that the evidence for clinically significant efficacy of oral dihydroergotamine in the currently assessed indications is very limited, and therefore the potential benefit for patients in these indications is outweighed by the above identified risk.
Danish: • udvalget finder, at dokumentationen for en væsentlig klinisk virkning af oral anvendelse af dihydroergotamin til de nuværende godkendte indikationer er meget begrænset, og at de potentielle fordele for patienterne ved disse indikationer derfor ikke opvejer den ovenfor omtalte risiko
English: • The Committee considered the procedure under Article 31 of Directive 2001/83/EC for ergot derivatives containing medicinal products in the concerned indications.
Danish: • udvalget fulgte proceduren i overensstemmelse med artikel 31 i direktiv 2001/83/EF for de pågældende indikationer for lægemidler indeholdende ergotderivater
English: In some published literature, they are considered as aetiology of retroperitoneal fibrosis (P. Meier et al, La fibrose rétropéritonéale, une maladie inflammatoire méconnue.
Danish: I visse publicerede artikler anses de for at være årsag til retroperitoneal fibrose (P. Meier et al, La fibrose rétropéritonéale, une maladie inflammatoire méconnue.
English: Twelve patients suffering from peripheral venous insufficiency were treated first with intravenous dihydroergotamine followed by oral dihydroergotamine administration for one week.
Danish: 12 patienter med perifer venøs insufficiens blev først behandlet med intravenøst dihydroergotamin, efterfulgt af oralt dihydroergotamin i en uge.
English: In these studies, dihydroergotamine seems to have some efficacy only by injection route or at doses higher than the authorised dose.
Danish: I disse undersøgelser synes det aktive stof at have nogen virkning, men kun ved injektion eller ved doser højere end den godkendte dosering.
English: Moreover, safety data provided by some MAHs are incomplete (gap between reviewing period and marketing period of the product) and it cannot be excluded that cases reported with their products are lacking.
Danish: Desuden er de sikkerhedsdata, der er forelagt af visse markedsføringstilladelsesindehavere, ufuldstændige (der er tidsmæssig forskydning mellem den betragtede periode og markedsføringsperioden for produktet), og det kan ikke udelukkes, at der er udeladt indberettede tilfælde med de pågældende produkter.
English: Symptoms of ergotism are listed in the sections 4.8, 4.9 of all the SmPCs and ergotism is identified in section 4.4 as a consequence of a prolonged use of dihydroergotamine or high dosage.
Danish: Symptomerne på ergotisme er anført i punkt 4.8 og 4.9 i alle produktresuméer, og ergotisme nævnes i punkt 4.4 som en følge af anvendelse af dihydroergotamin i lang tid eller i høje doser.
English: The CHMP considered the MAHs' proposals for risk minimisation measures.
Danish: CHMP gennemgik markedsføringstilladelsesindehavernes forslag til risikominimeringsforanstaltninger.
English: However, the CHMP noted that for most of these patients an improvement or recovering had been observed after corticosteroid treatment or surgery (valve replacement), and in most cases the improvement is stated based on clinical symptoms (no scan).
Danish: CHMP bemærkede imidlertid, at for de fleste af disse patienter var den iagttagne bedring eller restitution forudgået af kortikosteroidbehandling eller operativ behandling (hjerteklapudskiftning), og at angivelsen af bedring i de fleste tilfælde er baseret på kliniske symptomer (ingen scanning).
English: Grounds for the suspension/variation to the terms of the marketing authorisations
Danish: Begrundelse for suspendering af markedsføringstilladelserne/ændring af betingelserne for markedsføringstilladelserne
English: A total of 363 subjects were treated with dihydroergotamine or placebo during 4 months after 1 month of placebo “run-in”.
Danish: I alt 363 patienter blev behandlet med dihydroergotamin eller placebo i fire måneder efter en 1-måneds indkøringsperiode på placebo.
English: Some of them were conducted with the intravenous administration which is not in the scope of this referral procedure for dihydroergotamine.
Danish: Til nogle af dem blev der anvendt intravenøs administration, som ikke er omfattet af denne indbringelsesprocedure for dihydroergotamin.
English: A review of all other available data (i.e. literature data, pre-clinical data, and other clinical data including epidemiological studies) that were relevant to evaluate the risk of fibrosis was provided where possible.
Danish: I det omfang det var muligt, blev der desuden forelagt en gennemgang af alle andre foreliggende data (dvs. litteraturdata, prækliniske data og andre kliniske data, herunder epidemiologiske undersøgelser), som var relevante for vurdering af risikoen for fibrose.
English: One case was confounded by medical history and in 25 cases co-suspected drugs were reported: benfluorex (4 cases), dexflenfuramine (4 cases), pergolide (1 case), beta blockers (9 cases), fenofibrate (2 cases) and ergot derivative drug (8 cases).
Danish: Ét tilfælde var konfunderet af anamnesen, og i 25 tilfælde angaves der at have været anvendt samtidigt mistænkte lægemidler: benfluorex (4 tilfælde), dexflenfuramin (4 tilfælde), pergolid (1 tilfælde), betablokkere (9 tilfælde), fenofibrat (2 tilfælde) og ergotderivater (8 tilfælde).
English: Therefore, the group was of the opinion that there is not a clearly defined population, which unsatisfactorily responds to standard migraine prophylaxis treatment, where there is a therapeutic need for this substance as alternative/last line treatment.
Danish: Gruppen var derfor af den opfattelse, at der ikke findes nogen klart afgrænset population, som responderer utilfredsstillende på sædvanlig forebyggende migrænebehandling og har behov for behandling med dette stof som en alternativ/sidste behandlingsmulighed.
English: The CHMP has considered the totality of the available data on the safety and efficacy of dihydroergotamine.
Danish: CHMP har vurderet samtlige tilgængelige data om sikkerheden og virkningen af dihydroergotamin.
English: The MAHs also submitted their own overviews and critical summaries of all spontaneous reports of fibrotic reactions (cardiac with or without pulmonary arterial hypertension, pulmonary, pleural, peritoneal, retroperitoneal, etc) and ergotism with their ergot derivatives-containing medicinal products.
Danish: Indehaverne af markedsføringstilladelserne fremlagde desuden deres egne oversigter og kritiske sammenfatninger af alle spontane indberetninger af fibrotiske reaktioner (kardiale med eller uden pulmonal arteriel hypertension, pulmonale, pleurale, peritoneale, retroperitoneale osv.) samt ergotisme med lægemidler indeholdende ergotderivater.
English: For the indication “orthostatic hypotension” the submitted studies were considered by the CHMP of poor methodological quality: they were mainly uncontrolled trials with only 1 double-blind study but with low number of patients.
Danish: For indikationen “ortostatisk hypotension” anså CHMP de forelagte undersøgelse for at være af ringe metodemæssig kvalitet: Det var hovedsagelig ukontrollerede undersøgelser, og der var kun én dobbeltblindet undersøgelse, men med et lille antal patienter.
English: The open label study (Wenzel-E et al, 1989) that became available after the granting of the initial marketing authorisation discusses the use of dihydroergotamine in venous insufficiency.
Danish: Den åbne undersøgelser (Wenzel-E et al, 1989), der blev tilgængelig efter udstedelsen af den oprindelige markedsføringstilladelse, omhandler anvendelse af dihydroergotamin ved venøs insufficiens.
English: • The Committee considered the overall submitted data provided by the MAHs and the outcome of the scientific advisory group.
Danish: • udvalget gennemgik alle data, der var forelagt af indehaverne af markedsføringstilladelse, og resultatet af mødet i den videnskabelige rådgivende gruppe
English: Scientific conclusions and grounds for variation to the terms of the marketing authorisations or suspension of the marketing authorisations, as applicable, taking into consideration the approved indications for each product
Danish: Videnskabelige konklusioner og begrundelse for ændring af betingelserne for markedsføringstilladelserne eller, i givet fald, suspendering af markedsføringstilladelserne, under hensyntagen til de godkendte indikationer for de enkelte produkter
English: In conclusion, the studies provided by the MAHs were not carried out with up-to-date methodology.
Danish: Som konklusion var de af markedsføringstilladelsesindehaverne forelagte undersøgelser ikke udført med tidssvarende metoder.
English: Following a national pharmacovigilance review held in 2011 new spontaneous notifications reported with some of those products identified serious cases of fibrosis and ergotism and France considered that this safety concern is not outweighed by the limited evidence of efficacy.
Danish: Ved en national gennemgang af lægemiddelovervågning i 2011 fandtes nye spontane indberetninger af alvorlige tilfælde af fibrose og ergotisme med nogle af disse produkter, og Frankrig fandt ikke, at denne sikkerhedsmæssige betænkelighed opvejes af den begrænsede dokumentation for virkning.
English: • Orthostatic hypotension
Danish: • ortostatisk hypotension
English: Overall, 8 cases of fibrotic adverse reactions from a French survey conducted in 2011 and 50 cases among the 75 cases reported by the MAHs have been considered as potentially related to dihydroergotamine including 24 with no confounding factor.
Danish: Totalt var der 8 tilfælde af fibrotiske bivirkninger i en fransk oversigt udarbejdet i 2011, og af de 75 tilfælde, der blev indberettet af markedsføringstilladelsesindehaverne, blev 50 anset for potentielt at have sammenhæng med dihydroergotamin, herunder 24 uden konfunderende faktor.
English: • The suspension of the marketing authorisation for dihydroergotamine containing medicinal products referred to in Annex I in the event that no other indications are approved as part of their marketing authorisation.
Danish: • suspendering af markedsføringstilladelsen for de i bilag I omhandlede lægemidler indeholdende dihydroergotamin, når ingen andre indikationer er godkendt som en del af markedsføringstilladelsen.
English: However the CHMP noted that beta blockers are not widely recognised as a cause of fibrosis.
Danish: CHMP bemærkede dog, at betablokkere ikke er almindeligt anerkendt som årsag til fibrose.
English: The Committee concluded that the benefit-risk balance of dihydroergotamine containing products for oral use is not favourable pursuant to Article 116 of Directive 2001/83/EC for prophylaxis of migraine, for orthostatic hypotension and for symptomatic treatment of veno-lymphatic insufficiency.
Danish: Udvalget konkluderede, at benefit/risk-forholdet for produkter indeholdende dihydroergotamin til oral anvendelse ikke er positivt i henhold til artikel 116 i direktiv 2001/83/EF til forebyggelse af migræne, til ortostatisk hypotension eller til symptomatisk behandling af venolymfatisk insufficiens.
English: The marketing authorisation holders (MAHs) submitted all available efficacy data from clinical trials and observational studies, including data that became available since the granting of the initial marketing authorisation.
Danish: Indehaverne af markedsføringstilladelserne fremlagde alle foreliggende data om virkning fra kliniske undersøgelser og observationsundersøgelser, herunder data, der er blevet tilgængelige siden udstedelsen af den oprindelige markedsføringstilladelse.
English: However, more than half of the cases of ergotism reported have been described out of a context of overdose or without the use of a contraindicated drug.
Danish: I over halvdelen af de indberettede tilfælde af ergotisme var der imidlertid ingen overdosering eller anvendelse af et kontraindiceret lægemiddel.
English: Based on the clinical experience the group considered that dihydroergotamine has only been used rarely for the treatment of orthostatic hypotension with no clear benefit to the patients.
Danish: På grundlag af de kliniske erfaringer fandt gruppen, at dihydroergotamin kun sjældent er blevet anvendt til behandling af ortostatisk hypotension, og uden klar fordel for patienterne.
English: Agonism to 5-HT2B receptors induces a proliferative response and mitogenicity of the cells expressing this receptor leading to fibrogenesis.
Danish: Agonistisk påvirkning af 5-HT2B-receptorer fremkalder en proliferativ respons og mitogenicitet af de celler, der udtrykker denne receptor, hvilket medfører fibrogenese.
English: Moreover, the 8 new spontaneous notifications reported during the French survey conducted in 2011 show that the risk minimisation measures that are currently in place are not sufficient to prevent the risk of fibrotic reactions.
Danish: I den franske oversigt fra 2011 blev der desuden fundet 8 nye spontane indberetninger, der viser, at de nuværende risikominimeringsforanstaltninger ikke er tilstrækkelige til at forhindre udvikling af fibrotiske reaktioner.
English: This reaction occurred in young patients (mean age among cases reported: 41 years-old), with a short time to onset after dihydroergotamine initiation (less than 2 months, mean: 2 days).
Danish: Denne reaktion forekom hos unge patienter (gennemsnitsalderen blandt de indberettede tilfælde var 41 år), og tiden til indsætten efter initiering af behandlingen med dihydroergotamin var kort (under to år, gennemsnit: 2 dage).
English: • Ancillary treatment of Raynaud's syndrome
Danish: • supplerende behandling af Raynauds syndrom
English: Ergot derivatives are recognised as being capable of inducing fibrosis, in particular heart valve fibrosis.
Danish: Ergotderivater er kendt for at kunne inducere fibrose, navnlig af hjerteklapperne.
English: These co-suspected drugs are known to induce fibrosis.
Danish: Disse samtidigt mistænkte lægemidler vides at fremkalde fibrose.
English: • Acute retinopathies of vascular origin
Danish: • akutte retinopatier af vaskulær årsag
English: To conclude, ergotism is an adverse reaction of ergot derivative drugs well-known to occur in a context of overdose or interaction.
Danish: Som konklusion er ergotisme en velkendt bivirkning af ergotderivater i forbindelse med overdosering eller interaktion.
English: After 4 months of treatment, the attack frequency decreased by 2.0 ± 1.6 (-60.0%) with dihydroergotamine versus 1.7 ± 1.5 (-48.8%) with placebo (p = 0.014 for the relative variations).
Danish: Efter 4-måneders behandling aftog anfaldshyppigheden med 2,0 ± 1,6 (-60,0 %) med dihydroergotamin, mod 1,7 ± 1,5 (-48,8 %) med placebo (p=0,014 for de relative ændringer).