natgillin/translations-raw huggingface dataset:
Videnskabelige konklusioner og begrundelse for ændring af betingelserne for markedsføringstilladelserne eller, i givet fald, suspendering af markedsføringstilladelserne, alt efter de godkendte indikationer for hvert produkt
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
Desuden blev der i litteraturen indberettet alvorlige tilfælde af symptomer på perifer vasokonstriktion.
In addition, severe cases of peripheral vasoconstrictive symptoms were reported in the literature.
• udvalget fandt, at der ikke kan udelukkes potentiel årsagssammenhæng mellem dihydroergotoxin og fibrotiske reaktioner eller ergotisme.
• The Committee considered that a potential causal association between fibrotic reactions or ergotism and dihydroergotoxine cannot be excluded.
CHMP fremhævede, at “kronisk kognitiv funktionsnedsættelse med undtagelse af Alzheimers sygdom og anden demens” ikke anses for at være en almindeligt anerkendt definition af en patologisk tilstand med henblik på fordel af behandling.
The CHMP highlighted that “chronic cognitive impairment excluding Alzheimer's disease and other dementia” is not considered a generally accepted definition of a pathological condition aimed to benefit from treatment.
Demens og demensrelaterede indikationer er ligesom akut migrænebehandling ikke omfattet af denne indbringelse.
Dementia and dementia related indications, as well as the acute treatment of migraine, are outside the scope of this referral procedure.
• ændring af betingelserne for markedsføringstilladelsen for de i bilag I anførte lægemidler indeholdende dihydroergotoxin, således at nedenstående indikationer slettes fra produktinformationen (den konkrete ordlyd af indikationerne kan variere fra produkt til produkt og fra land til land) ligesom enhver relevant omtale af disse indikationer, når andre terapeutiske indikationer er godkendt som en del af markedsføringstilladelsen:
• The variation to the terms of the marketing authorisation for dihydroergotoxine containing medicinal products referred to in Annex I, to delete the below indications from the Product Information (specific wording of the indication may vary from product to product and from country to country) as well as any relevant reference to these indications, when there are other therapeutic indications approved as part of their marketing authorisation:
• Akutte retinopatier af vaskulær årsag
• Acute retinopathies of vascular origin
På ovenstående baggrund fandt udvalget, at der er risiko for sjældne, men svære fibrotiske reaktioner og ergotisme ved behandling med dihydroergotoxin.
In view of the above, the Committee considered that there is a risk for rare but severe fibrotic reactions and ergotism associated with dihydroergotoxine treatment.
Disse bestod i ændring af udleveringsstatus, begrænsning af behandlingsvarigheden ved visse sygdomme, kontraindikation af produktet ved præeksisterende fibrose og sammen med andre lægemidler, udsendelse af en direkte henvendelse til sundhedspersoner, hvor risikoen påpeges, en tjekliste for ordinerende læger og en farmakologisk en vitro-undersøgelse med henblik på affiniteten af receptorer i 5-HT-subklassen for produktet.
These included changing the prescription status, limiting treatment duration in certain conditions, contraindicating the product in patients with pre-existing fibrosis or in association with other drugs, the issuing of a DHPC highlighting the risk, a checklist for prescribers, and a pharmacological in vitro study for 5-HT subclass receptors affinity to the product.
De fleste ergotderivater er kendt for at kunne fremkalde fibrose, navnlig af hjerteklapperne.
Ergot derivatives are recognised as being capable of inducing fibrosis, in particular heart valve fibrosis.
Agonistisk påvirkning af 5-HT2B-receptorer fremkalder en proliferativ og mitogen respons af de celler, der udtrykker denne receptor, hvilket medfører fibrogenese.
Agonism to 5-HT2B receptors induces a proliferative response and mitogenicity of the cells expressing this receptor leading to fibrogenesis.
Andre fibrosefremkaldende mekanismer kan således ikke udelukkes, hvilket peger på en årsagssammenhæng mellem fibrose og agonistisk påvirkning af 5-HT2A- og 5-HT1B-receptorer og sandsynligvis også en virkning på serotonintransporteren.
Therefore, other mechanisms inducing fibrosis cannot be excluded, which suggests a causal link between fibrosis and agonism of 5-HT2A and 5-HT1B receptors and also plausible effect on serotonin transporter.
• udvalget gennemgik alle data, der var forelagt af indehaverne af markedsføringstilladelse, og resultatet fra de videnskabelige rådgivende grupper,
• The Committee considered the overall submitted data and grounds provided by the MAHs and the outcome of the scientific advisory groups.
Det må derudover understreges, at der er tale om alvorlige bivirkninger med muligt fatalt udfald, og at der er forhøjet risiko for udvikling af en fibrotisk sygdom ved langvarig behandling i henhold til de godkendte indikationer.
Moreover the severity of such adverse effects, their possible fatal outcome and the raised risk for patient to develop a fibrotic disorder with long term use according to the authorised indications should be underlined.
Dihydroergotoxin modulerer koncentrationerne af de synaptiske neurotransmittere og øger blodtilførslen til hjernen; denne sidstnævnte mekanisme mentes tidligere at være den primære virkningsmekanisme for dihydroergotoxins kliniske virkninger.
Dihydroergotoxine modulates synaptic neurotransmitter levels and increases blood flow to the brain; at one time, it was believed that the latter mechanism was the primary mode of action by which dihydroergotoxine exerts clinical effects.
CHMP har vurderet samtlige foreliggende data om sikkerheden og virkningen af dihydroergotoxin.
The CHMP has considered the totality of the available data on the safety and efficacy of dihydroergotoxine.
På grundlag af disse data og den farmakologiske plausibilitet anses dihydroergotoxin for at have sammenhæng med fibrotiske reaktioner.
Based on these data and based on the pharmacological plausibility, dihydroergotoxine is considered to be associated with fibrotic reactions.
CHMP var derfor ikke i stand til at drage videnskabelige konklusioner om fordelen af dihydroergotoxin ved perifer vaskulær sygdom ud fra disse undersøgelser, og der kunne efterfølgende ikke drages konklusioner om supplerende behandling af Raynauds syndrom.
Consequently, it was not possible for the CHMP to draw scientific conclusions regarding the benefit of dihydroergotoxine in peripheral vascular disease based on these study results and subsequently no conclusions could be drawn for the ancillary treatment of Raynaud's syndrome.
Dataene fra de indberettede tilfælde af fibrose (n=9) er begrænsede i forhold til at drage faste konklusioner, men det kan ikke udelukkes, at dihydroergotoxin er i stand til at inducere fibrotiske reaktioner lokaliseret i det retroperitoneale, pulmonale og kardiale område, navnlig fordi der i visse af de vurderede tilfælde ikke var nogen anden ætiologi, og på grund af ergotderivaters virkningsmekanisme.
The data from the reported cases of fibrosis (n=9) are limited in order to draw firm conclusions, however, the capacity of dihydroergotoxine to induce fibrotic reactions, localised in the retroperitoneal, pulmonary and cardiac area cannot be excluded notably based on the absence of any other aetiology for some of the assessed cases and the mechanism of action of ergot derivatives.
• udvalget finder, at der kun er meget begrænset evidens for en væsentlig klinisk virkning af oralt dihydroergotoxin til de aktuelt vurderede indikationer og til den indikation, der foreslås af markedsføringstilladelsesindehaveren ved den fornyede overvejelse, og at de potentielle fordele for patienterne ved disse indikationer derfor ikke opvejer den ovenfor omtalte risiko,
• The Committee is of the opinion that the evidence for clinically significant efficacy of dihydroergotoxine in the currently assessed indications as well as in the indication proposed by the MAH in the re-examination is very limited, and therefore the potential benefit for patients in these indications is outweighed by the above identified risk.
På ovenstående baggrund fandt CHMP, at de forelagte undersøgelser ikke godtgjorde, at dihydroergotoxin har klinisk relevant virkning på patienter med nedsat kognitiv funktion.
In view of the above, the CHMP was of the opinion that the studies submitted could not demonstrate that dihydroergotoxine has a clinically relevant effect on patients with cognitive impairment.
Fibrotiske reaktioner er blevet sat i forbindelse med kronisk brug af ergotderivater, og skønt indberetningshyppigheden for dihydroergotoxin er lav, er risikoen for alvorlig til at kunne lades ude af betragtning, navnlig i lyset af den potentielle langtidsanvendelse hos en bred patientpopulation.
Fibrotic reactions have been associated to chronic use of ergot derivatives and although the reporting rate for dihydroergotoxine is low, the risk is sufficiently serious not to be dismissed particularly when considering its potential use in long-term treatment in a broad patient population.
På grundlag af de kliniske erfaringer fandt gruppen, at der ikke er nogen nærmere bestemt population, der kan have fordel af behandling med dette aktive stof til forebyggelse af migræne.
Based on the clinical experience the group considered that no special population exists that could benefit from the treatment with this active substance in the prophylaxis of migraine headache.
Dihydroergotoxinmesilat er et ergotalkaloid, der også kaldes codergocrinmesilat og ergoloidmesilat og består af lige dele mesilater af dihydroergocornin, dihydroergocristin og dihydroergocryptin.
Dihydroergotoxine mesilate is an ergot alkaloid, known also as codergocrine mesilate and ergoloid mesilate, which is composed of equal parts of mesilates of dihydroergocornine, dihydroergocristine, and dihydroergocryptine.
De foreslåede risikominimeringsforanstaltninger blev af udvalget ikke fundet effektive til at reducere risikoen for de to betragtede reaktioner (fibrose og ergotisme) ved anvendelse til den brede indikation, der foreslås af indehaveren af markedsføringstilladelsen.
The risk minimisation measures proposed were not considered by the Committee to effectively reduce the risk for the two highlighted reactions (fibrosis and ergotism) in the broad indication proposed by the MAH.
Desuden består dihydroergotoxin af dihydroergocryptin og dihydroergocristin, som også anses for at have sammenhæng med fibrotiske reaktioner.
In addition, dihydroergotoxine is composed of dihydroergocryptine and dihydroergocristine which are also considered to be associated with the induction of fibrotic reactions.
Skønt propranolol og flunarizin er anerkendt til forebyggelse af migræne, kan der på grund af den manglende placebogruppe ikke drages konklusioner om virkningen af dihydroergotoxin til forebyggelse af migræne.
In spite of the fact that propranolol and flunarizine are recognized in migraine prophylaxis, the absence of a placebo group does not allow to conclude on the efficacy of dihydroergotoxine in the prophylaxis of migraine.
Om indikationen “supplerende behandling af Raynauds syndrom” bemærkede CHMP, at den af markedsføringstilladelsesindehaveren påberåbte indikation er perifer vaskulær sygdom, og at supplerende behandling af Raynauds syndrom i nogle medlemsstater er godkendt for dihydroergotoxin som del af en mere generel indikation (f.eks. “perifer vaskulær sygdom”).
For the indication “ancillary treatment of Raynaud's syndrome” the CHMP noted that the indication claimed by the MAH is peripheral vascular disease and that in some Members States the ancillary treatment of Raynaud's syndrome is approved for dihydroergotoxine as part of this more general indication (i.e. “peripheral vascular disease”).
Overordnet gentog CHMP, at det ikke anser markedsføringstilladelsesindehaverens foreslåede risikominimeringsforanstaltninger for at være i stand til effektivt at nedsætte risikoen for fibrotiske reaktioner og ergotisme.
Overall, the CHMP reiterated that the risk minimisation measures proposed by the MAH are not considered by the Committee to effectively reduce the risk of fibrotic reactions and ergotism.
Mere konkret anførte CHMP, at bortset fra “ergotisme” er også andre foretrukne betegnelser forbundet med symptomer på ergotisme (således paræstesi, formikation, snurren, intestinal/cerebrovaskulær/perifer iskæmi eller iskæmi af tungen, angina pectoris, koronaropati, brystsmerter, kvalme, opkastning, diarré, abdominalsmerter, kuldefornemmelse, trombose, apopleksi, gangræn, nekrose, vasokonstriktion/vasospasme, cyanose, myalgi, muskelkramper, ekstremitetssmerter, vertigo, hypæstesi, følelsesløshed, hovedpine, konfusion og hallucinationer).
More specifically, the CHMP stated that apart from “ergotism” other preferred terms are also related to symptoms of ergotism (i.e paraesthesia, formication, tingling, intestinal/cerebrovascular/peripheral/tongue ischaemia, angina pectoris, coronaropathy, thoracic pain, nausea, vomiting, diarrhoea, abdominal pain, cold sensation, thrombosis, stroke, gangrene, necrosis, vasoconstriction/vasospasm, cyanosis, myalgia, muscular cramps, pain in extremities, vertigo, hypoaesthesia, numbness, headache, confusion, hallucinations).
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 mm.) samt ergotisme med deres lægemidler indeholdende ergotderivater.
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.
Da der ikke er forelagt data til støtte for indikationen “symptomatisk behandling af venolymfatisk insufficiens”, kunne CHMP ikke drage konklusioner om virkningen.
No data were submitted in support of the indication “symptomatic treatment of veno-lymphatic insufficiency” and consequently no conclusion on efficacy could be drawn by the CHMP.
CHMP gennemgik alle foreliggende data til støtte for dihydroergotoxins fordele og sikkerhed og behandlede ovennævnte begrænsede indikation, der blev foreslået af indehaveren af markedsføringstilladelsen.
The CHMP reviewed all available data in support of the benefit and safety on dihydroergotoxine and considered the above restricted indication proposed by the MAH.
Overordnet var den videnskabelige rådgivende gruppe ikke enige i den indikation og de målpopulationer, der foreslås af indehaveren af markedsføringstilladelsen.
Overall, the SAG disagreed with the indication and the target population definitions proposed by the MAH.
Desuden blev der på anmodning af CHMP i december 2012 indkaldt en videnskabelig rådgivende gruppe, hvor eksperterne ud fra deres kliniske erfaring drøftede, om dette stof har nogen virkning ved symptomatisk behandling af kronisk patologisk kognitiv og neurosensorisk funktionsnedsættelse hos ældre (undtagen Alzheimers sygdom og andre former for demens).
In addition, a scientific advisory group (SAG) was convened in December 2012 at the request of the CHMP during which the experts discussed, based on their clinical experience, whether this substance plays a role in the symptomatic treatment of chronic pathological cognitive and neurosensorial impairment in elderly (excluding Alzheimer's disease and other dementia).
Til indikationen “forebyggelse af migræne” er der to publikationer, der beskriver en dobbeltblindet, kontrolleret undersøgelse af virkningen af dihydroergocryptin sammenlignet med propranolol og flunarizin (ingen placebogruppe) (dihydroergotoxin består for en tredjedels vedkommende af dihydroergocryptin).
For the indication “prophylaxis of migraine headache”, two publications describe a double-blind, active, not placebo-controlled study on the effect of dihydroergocryptine (dihydroergotoxine is composed of a third of dihydroergocryptine) as compared to propranolol and flunarizine.
CHMP tog i betragtning, at skønt risikoen for fibrotiske reaktioner og ergotisme i forbindelse med dihydroergotoxin er lille, er den fastslået, og at det er bivirkninger med muligt fatalt udfald.
The CHMP considered that, although the risk of fibrotic reactions and ergotism associated with dihydroergotoxine is rare, it is established and these are severe adverse events with a possible fatal outcome.
I de forelagte undersøgelser blev oralt dihydroergotoxin imidlertid vurderet ved meget heterogene venesygdomme: Perifer og cerebrovaskulær insufficiens, kronisk varikøst eksem, venøs insufficiens, ulcus cruris, cerebrale vaskulære læsioner, tromboflebitis af superficielle vener, post-tromboflebitis syndromer.
However, the presented studies assessed oral dihydroergotoxine in very heterogeneous vein diseases: peripheral and cerebrovascular insufficiency, chronic varicose eczema, ulcus cruris, varicose veins, venous insufficiency, cerebral vascular lesions, thrombophlebitis of the superficial veins, post-thrombophlebitis syndromes.
CHMP fandt, at disse undersøgelser ikke gav holdbar evidens for virkningen af dihydroergotoxin til den påtænkte målpopulation.
The CHMP considered that these studies did not provide robust evidence supporting the efficacy of dihydroergotoxine in the proposed target population.
CHMP gennemgik markedsføringstilladelsesindehavernes forslag til risikominimeringsforanstaltninger.
The CHMP considered the MAHs proposals for risk minimisation measures.
Udvalget konkluderede, at benefit/risk-forholdet for produkter indeholdende dihydroergotoxin ikke er gunstigt i henhold til artikel 116 i direktiv 2000/83/EF til symptomatisk behandling af kronisk patologisk kognitiv og neurosensorisk funktionsnedsættelse hos ældre (bortset fra Alzheimers sygdom og anden form for demens), supplerende behandling af Raynauds syndrom, supplerende behandling af nedsat synsstyrke og synsfeltforstyrrelser af formodet vaskulær årsag, forebyggelse af migræne eller symptomatisk behandling af venolymfatisk insufficiens.
The Committee concluded that the benefit-risk balance of dihydroergotoxine containing products is not favourable pursuant to Article 116 of Directive 2001/83/EC for symptomatic treatment of chronic pathological cognitive and neurosensorial impairment in elderly (excluding Alzheimer's disease and other dementia), for ancillary treatment of Raynaud's syndrome, for ancillary treatment of visual acuity decrease and visual field disturbances presumably of vascular origin, for prophylaxis of migraine headache and for symptomatic treatment of veno-lymphatic insufficiency.
Den videnskabelige rådgivende gruppe fandt endvidere, den af markedsføringstilladelsesindehaveren fremlagte evidens var af ringe kvalitet.
The SAG further considered that the evidence presented by the MAH was of poor quality.
CHMP tog de af markedsføringstilladelsesindehaveren foreslåede risikominimeringsforanstaltninger til efterretning.
The CHMP took note of the risk minimisation measures proposed by the MAH.
Vedrørende virkningen ved indikationen “symptomatisk behandling af kronisk patologisk kognitiv og neurosensorisk funktionsnedsættelse hos ældre (undtagen Alzheimers sygdom og andre former for demens)” fremlagde indehaveren af markedsføringstilladelsen data fordelt på de undergrupper af sygdomme, der griber ind i den kognitive funktion: Cerebrovaskulær funktionsnedsættelse med arteriosklerose, cerebrovaskulær insufficiens og apopleksi samt andre årsager med aldersbetinget/senil funktionsnedsættelse, primær eller uspecifik funktionsnedsættelse samt organisk hjernesyndrom.
On the efficacy side for the indication “symptomatic treatment of chronic pathological cognitive and neurosensorial impairment in elderly (excluding Alzheimer's disease and other dementia)”, data were presented by the MAH by sub-areas of the cognitive function diseases: cerebrovascular impairment with arteriosclerosis, cerebrovascular insufficiency and stroke; and other causes with elderly/senile impairment, primary or not otherwise specified impairment, and organic brain syndrome.
Begrundelse for suspendering af markedsføringstilladelserne/ændring af betingelserne for markedsføringstilladelserne Ud fra følgende betragtninger:
Grounds for the suspension/variation to the terms of the marketing authorisations
• Supplerende behandling af claudicatio intermittens ved symptomatisk perifer arteriel okklusiv sygdom (PAOD stadium II)
• Ancillary treatment of intermittent claudication in symptomatic peripheral arterial occlusive disease
CHMP bemærkede, at forekomsten af bivirkninger med dihydroergotoxin indberettet af indehaveren af markedsføringstilladelsen (dvs. retroperitoneal fibrose, lungefibrose, hjerteklapsygdom, ergotisme) er lav.
The CHMP noted that the incidence of adverse events (i.e. retroperitoneal fibrosis, pulmonary fibrosis, cardiac valvulopathy, ergotism) reported by the MAH with dihydroergotoxine is low.
CHMP var derfor af den opfattelse, at de forelagte data ikke giver mulighed for at drage nogen konklusion om virkningen af dihydroergotoxin til “adjuverende symptomatisk behandling af kronisk patologisk kognitiv og neurosensorisk funktionsnedsættelse hos ældre (bortset fra Alzheimers sygdom og andre former for demens” eller til nogen anden indikation.
The CHMP was therefore of the opinion that no conclusion on the efficacy of dihydroergotoxine as “Adjuvant symptomatic treatment of chronic pathological cognitive and neurosensorial impairment in elderly (excluding Alzheimer's disease and other dementia)” or in another indication could be drawn.
− ikke er positivt til supplerende behandling af Raynauds syndrom,
− Is not favourable for ancillary treatment of Raynaud's syndrome.
− ikke er positivt til symptomatisk behandling af venolymfatisk insufficiens,
− Is not favourable for symptomatic treatment of veno-lymphatic insufficiency.
De iagttagne forskelle i indberetningshyppigheden af fibrotiske reaktioner kan overordnet tænkes forklaret dels af de forskellige ergotderivaters varierende affinitet for serotoninerge receptorer, dels de anvendte terapeutiske doser.
Overall, the varying affinity for serotoninergic receptors with the different ergot derivatives and the therapeutic doses used may explain the differences observed for notification rates for the fibrotic reactions.
• Symptomatisk behandling af venolymfatisk insufficiens
• Symptomatic treatment of veno-lymphatic insufficiency
− Symptomatisk behandling af kronisk patologisk nedsat kognitiv og neurosensorisk funktion hos ældre (bortset fra Alzheimers sygdom og anden form for demens)
− Symptomatic treatment of chronic pathological cognitive and neurosensorial impairment in elderly (excluding Alzheimer's disease and other dementia).
Under gennemgangen foreslog indehaveren af markedsføringstilladelsen at begrænse indikationen til “symptomatisk behandling af kronisk kognitiv funktionsnedsættelse hos ældre (bortset fra Alzheimers sygdom og anden form for demens)”.
During the review, the MAH has suggested to restrict the indication to ‘symptomatic treatment of chronic cognitive impairment in elderly (excluding Alzheimer's disease and other dementia)'.
− ikke er positivt til supplerende behandling af synsnedsættelse og synsfeltforstyrrelser af formodet vaskulær årsag,
− Is not favourable for ancillary treatment of visual acuity decrease and visual field disturbances presumably of vascular origin.