natgillin/translations-raw huggingface dataset:
CHMP konstaterede dog, at resultatet ikke var statistisk signifikant, så det kunne ikke konkluderes, at der var en statistisk signifikant reduktion i det kombinerede primære endepunkt i forhold til placebo. 
However, the CHMP noted that the analysis did not demonstrate statistical significance and that the results therefore did not allow to conclude on a statistically significant reduction in the combined primary endpoint compared to placebo.
CHMP noterede sig, at ud af de 24 rapporterede tilfælde (ca. 5 % af alle bivirkninger registreret i databasen hos indehaveren af markedsføringstilladelsen) vedrørte størstedelen (13 ud af 24) accidentel overdosering. 
The CHMP noted that of the 24 reported cases (about 5% of all adverse drug reactions recorded in the MAH database), a majority (13 out of 24) were cases of accidental overdose.
Undersøgelsen viste, at ca. 30 % af alle patienter med nyreinsufficiens fortsat får for stor dosis, skønt det bemærkedes, at denne procentdel var aftaget fra 75 % procent før udsendelsen af den pågældende DHPC. 
The study showed that about 30% of patients with renal failure still receive an excessive dose, although it was noted that this had decreased from 75% prior to the DHPC.
Buflomedil er på nuværende tidspunkt godkendt i Frankrig til behandling af "symptomer på symptomatisk perifer arteriel okklusiv sygdom-2 (PAOD Stage II)". 
Buflomedil is currently approved in France in the treatment of ”symptomatic peripheral arterial occlusive disease (PAOD Stage II) symptoms”.
Ved gennemgang af alle foreliggende individuelle patientsikkerhedsdata for buflomedil fandtes desuden 28 tilfælde med overdosering af ældre patienter (over 65 år). 
In addition, review of all available individual case safety data related to buflomedil identified 28 cases of overdoses in elderly patients (over 65
Der var seks tilfælde af alvorlige kardiovaskulære og seks tilfælde af alvorlige neurologiske bivirkninger. 
There were 6 cases of cardiovascular and 6 cases of neurological serious adverse events.
Diskussion af virkning 
Discussion on efficacy
I 70 % af disse tilfælde var den anvendte dosis af buflomedil uhensigtsmæssig som følge af underliggende nyreinsufficiens. 
In 70% of the cases, the dose of buflomedil received by the patients was inappropriate because of underlying renal failure.
Vedrørende den foreslåede supplerende lægemiddelovervågning var det CHMP's opfattelse, at signaldetektion ikke længere er en prioritet, nu hvor risiciene knyttet til buflomedil er kortlagt og bekræftet. 
Regarding the proposed additional pharmacovigilance activities, the CHMP was of the opinion that signal detection is no longer a priority, given that the risks associated with buflomedil are now identified and confirmed.
CHMP gennemgik endvidere dels en oversigt over alle foreliggende individuelle patientsikkerhedsdata vedrørende buflomedil, der af indehaveren af markedsføringstilladelsen var udarbejdet på grundlag af sikkerhedsdata efter markedsføring fra Abbott Laboratories' globale sikkerhedsdatabase og Amdipharms sikkerhedsdatabase, dels publiceret medicinsk litteratur (globalt) og dels en række andre kilder, herunder toksikologiske centre/giftcentre og tilsynsmyndigheder. 
The CHMP also examined a review of all available individual case safety data related to buflomedil, conducted by the MAH, based on post-marketing safety data from Abbott Laboratories' global safety database and Amdipharm's safety database, published medical literature (worldwide) and from a number of other sources, including Toxicology/Poison Control Centres and Regulatory Authorities.
Alvorlige kardiovaskulære og neurologiske bivirkninger under normale anvendelsesbetingelser 
Serious cardiovascular and neurological adverse events under normal conditions of use
CHMP var vidende om, at ændringsansøgninger til gennemførelse af den europæiske harmoniseret produktresumé stadig er under behandling i visse lande, men konstaterede, at den af Amdipharm i maj 2010 foreslåede risikostyringsplan stort set svarer til dem, der allerede er indført i Frankrig. 
The CHMP acknowledged that variations to implement the European harmonisation of the SmPC are still ongoing in some countries but noted that the RMP proposed by Amdipharm in May 2010 was largely equivalent to the RMPs already implemented in France.
Den godkendte maksimale daglige dosis er 600 mg til patienter med normal nyrefunktion, og 300 mg til patienter med nedsat nyrefunktion. 
The approved maximum daily dose in patients with normal renal function is 600 mg and 300 mg in patients with renal impairment.
Desuden konstaterede CHMP med betænkelighed, at indledende vurdering af nyrefunktionen kun fandt sted hos 20 % af patienterne, og at kreatininclearance kun blev målt hos 17 % af patienterne trods anbefalingen herom i produktresuméet. 
In addition, the CHMP observed with concern that an initial assessment of renal function was only carried out in 20% of patients and that measurements of creatinine clearance were only performed in 17% of patients, despite the SmPC recommendations.
Ved den af indehaveren af markedsføringstilladelsen foretagne gennemgang af ICSR-databasen fandtes 5 tilfælde med kendt dosering til ældre patienter, som krævede dosisjustering. 
The MAH review of the ICSR database identified 5 cases with known dosage occurring in elderly patients for whom dosage adjustment was required.
Alvorlige kardiovaskulære og neurologiske bivirkninger hos ældre patienter og patienter med nedsat nyrefunktion 
Serious cardiovascular and neurological adverse events in elderly patients and patients with renal impairment
Derudover fandtes 32 tilfælde med kardiologiske bivirkninger, hvoraf de hyppigste var takykardi, hypertension, blussen og hypotension. 
In addition, 32 cardiological adverse events were retrieved; the most frequent reactions were tachycardia, hypertension, flushing and hypotension.
Det var CHMP's opfattelse, at disse data viser de risici, der er knyttet til buflomedil i lys af dets smalle terapeutiske margin. 
The CHMP was of the opinion that this data showed the risks associated with buflomedil in view of its narrow therapeutic margin.
CHMP konkluderede, at de gennemførte foranstaltninger kun havde haft meget ringe virkning, og at den forventede virkning af de foreslåede foranstaltninger var utilstrækkelig til at imødegå de fundne risici ved brug af buflomedil på betryggende vis. 
The CHMP concluded that the impact of the implemented measures was very weak and that the expected impact of the proposed measures was insufficient to adequately address the identified risks observed with buflomedil.
Efter disse undersøgelser traf tilsynsmyndighederne i Frankrig en række nationale foranstaltninger til mindskelse af risikoen for bivirkninger relateret til buflomedil. 
Following these enquiries, France took a number of national regulatory actions to minimise the risk of adverse events associated with buflomedil.
• Udvalget tog i betragtning, at der er indberettet en række alvorlige kardiale og neurologiske bivirkninger i forbindelse med brug af buflomedil under normale anvendelsesbetingelser, navnlig hos ældre patienter, 
• The Committee considered that a number of serious cardiac and neurological adverse events have been reported with the use of buflomedil under normal conditions of use, particularly in elderly patients.
Samlet vurdering af benefit/risk-forholdet 
Overall benefit-risk assessment
• udvalget vurderede derfor, at benefit/risk-forholdet for lægemidler indeholdende buflomedil ikke er gunstigt under normale anvendelsesbetingelser, 
• The Committee therefore considered that the risk-benefit balance of buflomedil-containing medicinal products is not positive under normal conditions of use.
CHMP foretog desuden en separat vurdering af sikkerheden af de parenterale buflomedilformuleringer, der anvendes på hospitaler til behandling af svær kronisk iskæmi af underekstremiteterne. 
The CHMP also carried out a separate assessment of the safety of the parenteral formulations of buflomedil, which are used in the hospital setting for the treatment of severe chronic ischaemia of the lower limbs.
CHMP noterede sig desuden forslaget fra indehaveren af markedsføringstilladelsen om at mindske pakningsstørrelsen for at minimere følgerne af forsætlig overdosering. 
The CHMP also noted the MAH proposal to reduce the pack size, to minimise the consequences of an intentional overdose.
• på grundlag af en vurdering af virkningen af de i nogle medlemsstater allerede gennemførte foranstaltninger til risikominimering og af den publicerede litteratur fandt udvalget, at de af indehaveren af markedsføringstilladelsen påtænkte foranstaltninger til risikominimering ikke vil være tilstrækkelige til at mindske risiciene for alvorlige bivirkninger til et klinisk acceptabelt niveau, 
• The Committee considered, based on the assessment of the impact of risk minimisation measures already implemented in some Member States and on the published literature, that the risk minimisation measures proposed by the Marketing Authorisation Holder would not be able to adequately reduce the risks of serious adverse events to a clinically acceptable level.
• udvalget vurderede, at lægemidler indeholdende buflomedil kun udviste begrænset klinisk virkning til symptomatisk behandling af kroniske perifere kredsløbsforstyrrelser, 
• The Committee considered that buflomedil-containing medicinal products showed only limited clinical efficacy in the symptomatic treatment of chronic peripheral vascular disease.
CHMP fandt procentdelen af udsatte patienter uacceptabelt høj trods denne reduktion. 
The CHMP was of the opinion that despite this reduction, the percentage of patients at risk remained unacceptably high.
CHMP noterede sig endvidere resultaterne af Thalès-undersøgelsen af lægemiddelanvendelse, der omfattede 300 000 patienter og havde til formål at vurdere, hvordan ordinationsmønsteret blev påvirket af de risikostyringsforanstaltninger, der var implementeret i Frankrig. 
The CHMP also noted the results of the Thalès observational drug utilisation study, including 300 000 patients and conducted to assess the impact of the RMMs implemented in France on prescription patterns.
CHMP gennemgik de af indehaveren af markedsføringstilladelsen fremlagte data om virkning, herunder den forholdsvis nye store placebokontrollerede LIMB-undersøgelse (Limbs International Medicinal Buflomedil). 
The CHMP noted the efficacy data submitted by the MAH, including the relatively recent large placebocontrolled LIMB (Limbs International Medicinal Buflomedil) study.
Efter en europæisk PSUR-vurdering og en gennemgribende risk/benefit-vurdering foretaget af indehaveren af markedsføringstilladelsen i januar 2010 foreslog indehaveren af markedsføringstilladelsen en række foranstaltninger til imødegåelse af de fundne problemer. 
Following a European PSUR assessment and a full benefit-risk assessment completed by the MAH in January 2010, the MAH proposed a number of measures to address the identified concerns.
Blandt tilfældene var der i alt 12, hvor dosis ikke havde oversteget det maksimale terapeutiske område (dvs. op til 600 mg dagligt) for buflomedil. 
From these cases, a total of 12 cases were identified in which patients were treated within the maximum therapeutic range (i.e. up to 600 mg daily) of buflomedil.
Ifølge den godkendte indikation anvendes den parenterale formulering af buflomedil til initiering af behandlingen af PAOD, hvorefter patienten overgår til oral behandling. 
According to the approved indication, the injection formulation of buflomedil is used to initiate PAOD therapy, to be followed by a switch to oral therapy.
Disse risici forstærkes af det forhold, at buflomedil har et smalt terapeutisk indeks og kræver tilpasning af dosis efter nyrefunktionen. 
These risks are compounded by the fact that buflomedil is a substance with a narrow therapeutic index and that buflomedil treatment requires dose-adaptation to adjust for renal function.
Ved analysen af risk/benefit-forholdet for buflomedil under normale anvendelsesbetingelser forudsatte CHMP, at der blev skiftet til orale formuleringer, og var derfor af den opfattelse, at risk/benefit-forholdet for buflomedil injektionsvæske må vurderes som led i den overordnede diskussion af risk/benefit-forholdet for buflomedil. 
As a result, when addressing the risk-benefit of buflomedil under normal conditions for use, the CHMP assumed a switch to oral formulations and therefore considered that the risk/benefit of buflomedil injectable needs to be considered within the overall discussion of the risk-benefit of buflomedil.
Skønt disse 12 tilfælde var kompliceret af underliggende sygdomme og samtidig anden medicinering, vurderede CHMP, at de bekræftede risikoen for alvorlige bivirkninger relateret til buflomedil under normale anvendelsesbetingelser. 
Although the 12 cases were complicated by underlying clinical conditions and other concomitant medications, the CHMP considered them to confirm the risk of serious adverse events associated with the use of buflomedil under normal conditions of use.
Buflomedil er en 1-, 2-adrenoceptorantagonist, hvis vasoaktive og hæmoreologiske egenskaber øger blodgennemstrømningen i mikrokredsløbet og iltningen af vævet. 
Buflomedil is an α1-, α2-adrenolytic agent with vasoactive and haemorheologic properties, improving the blood flow in the microcirculation as well as tissue oxygenation.
CHMP noterede sig desuden dokumentationen for den begrænsede kliniske virkning af buflomedil, som demonstreres af de seneste kliniske undersøgelser. 
In addition, the CHMP noted the evidence of limited clinical efficacy of buflomedil, as demonstrated in recent clinical trials.
Virkningen er således i det store hele uændret siden udstedelsen af den oprindelige markedsføringstilladelse, og det er CHMP's opfattelse, at den foreliggende dokumentation ikke støtter, at buflomedil har nogen væsentlig klinisk virkning på kardiovaskulære hændelser og gangdistance. 
Consequently, while the efficacy remains largely unchanged since the granting of the initial MA, the CHMP was of the opinion that the available evidence is not supportive of a significant clinical efficacy of buflomedil on cardiovascular events and on walking distance.
Frankrig har tidligere foretaget to undersøgelser af lægemiddelovervågning og toksikologisk overvågning, efter at der var indberettet om alvorlige neurologiske og kardiale bivirkninger relateret til brug af buflomedil. 
France previously conducted two pharmacovigilance and toxicovigilance investigations following reports of nervous system and cardiac serious adverse events (SAEs) associated with the use of buflomedil.
• udvalget udtrykte betænkelighed ved, at der hos patienter med perifer vaskulær sygdom forekommer et hurtigt fald i nyrefunktionen, som kræver regelmæssig og hyppig overvågning, 
• The Committee raised concerns regarding the rapid deterioration of renal function in patients with peripheral vascular disease, requiring regular and frequent monitoring.
LIMB-undersøgelsen viste en tendens til bedring af symptomer (symptomatisk forværring af PAOD, amputationer), men der var en stigning i kardiovaskulære hændelser (myokardieinfarkt, slagtilfælde, kardiovaskulært betingede dødsfald). 
Regarding the LIMB study, the results indicated a trend of a decrease in symptoms (symptomatic deterioration of PAOD, amputations) although there was an increase in cardiovascular events (MI, stroke, CV deaths).
• udvalget konkluderede derfor, at de risici for alvorlige kardiale og neurologiske bivirkninger, der er forbundet med brug af lægemidler indeholdende buflomedil til symptomatisk behandling af kroniske perifere kredsløbsforstyrrelser, under normale anvendelsesbetingelser overstiger de begrænsede fordele, 
• The Committee therefore concluded, in view of the available data, that the risks of serious cardiac and neurological adverse events associated with the use of buflomedil-containing medicinal products in the symptomatic treatment of chronic peripheral vascular disease, under normal conditions of use, outweigh the limited benefits.
CHMP fandt imidlertid, at de af indehaveren af markedsføringstilladelsen foreslåede foranstaltninger til risikominimering næppe vil kunne reducere de alvorlige kardiale og neurologiske bivirkninger, der er forbundet med brug af buflomedil, til et klinisk acceptabelt niveau. 
However, the CHMP considered that the risk minimisation measures proposed by the MAH are unlikely to reduce the serious cardiac and neurological adverse events associated with the use of buflomedil to a clinically acceptable level.
Alt i alt anså the CHMP de forelagte kliniske data til dokumentation af virkningen af buflomedil for at være begrænsede. 
Overall, the CHMP considered the clinical data submitted in support of the efficacy of buflomedil to be limited.
Skønt disse indberettede tilfælde er iatrogene, fandt CHMP, at de giver støttende evidens for de kardiovaskulære og neurologiske risici ved buflomedil, eftersom der blev konstateret bivirkninger ved det dobbelte af dagsdosis, hvad der tyder på, at der er risici ved forholdsvis små overdoser. 
While acknowledging the iatrogenic nature of the reported cases, the CHMP considered that these cases provide supportive evidence of the cardiovascular and neurological risks of buflomedil, as adverse events were noted in patients administered twice the daily dosage, which suggests that the risks are associated with overdoses of relatively small magnitudes.
• udvalget fandt, at buflomedils smalle terapeutiske indeks giver anledning til stor betænkelighed, da patienter med perifere kredsløbsforstyrrelser, der behandles med buflomedil, under alle omstændigheder kan forventes at ville udvikle nedsat nyrefunktion på grund af deres sygdom, 
• The Committee considered that in this context, the narrow therapeutic index of buflomedil is of major concern, as patients with peripheral vascular disease treated with buflomedil are inherently likely to experience decreased renal function, due to the nature of their condition.
Dette giver anledning til særlig betænkelighed, fordi patienter med perifere kredsløbsforstyrrelser under alle omstændigheder kan forventes at udvikle nedsat nyrefunktion på grund af deres sygdom. 
This is of particular concern as patients with peripheral vascular disease are inherently likely to experience decreased renal function due to the nature of their condition.
Som konklusion fandt CHMP - i betragtning af de alvorlige kardiologiske og neurologiske bivirkninger, der er forbundet med brug af lægemidler indeholdende buflomedil under normale anvendelsesbetingelser, dokumentationen for den kliniske virkning, der er utilstrækkelig til at opveje risiciene ved anvendelse af buflomedil samt de fundne betænkeligheder vedrørende effektiviteten af foranstaltningerne til risikominimering - at risk/benefit-forholdet for lægemidler indeholdende buflomedil til oral indgivelse ikke er positivt under normale anvendelsesbetingelser. 
In conclusion, taking into account the serious cardiac and neurological adverse events associated with the use of buflomedil-containing medicinal products under normal conditions of use, the evidence of limited clinical efficacy which is insufficient to compensate for the risks associated with the use of buflomedil and the established concerns regarding the effectiveness of the risk minimisation measures, the CHMP considered that the risk-benefit balance of buflomedil-containing medicinal products is not positive under normal conditions of use.
Disse betingelser anses for at være normale anvendelsesbetingelser for buflomedil. 
Usage of buflomedil according to these conditions is considered to be under normal conditions of use.
CHMP vurderede virkningen af de foranstaltninger til risikominimering, der tidligere var indført i Frankrig og hovedsagelig bestod i en revision af produktresumé og kommunikation. 
The CHMP assessed the impact of the risk minimisation measures previously implemented in France, consisting mainly of revisions to the SmPC and communication and noted the proposed extension of these measures to other member states.
CHMP konstaterede desuden, at lægemiddelovervågningsdata og toksikologiske overvågningsdata viser, at sikkerhedsprofilen af buflomedil ikke er blevet bedre trods implementeringen af risikostyringsplanen i Frankrig i 2006. 
The CHMP also noted the pharmacovigilance and toxicovigilance data which show no improvement of the safety profile of buflomedil despite the implementation of the RMP in France in 2006; instead, a two fold increase of misuse compared to the previous period was observed.
Efter at have gennemgået alle de af indehaveren af markedsføringstilladelsen foreslåede foranstaltninger til risikominimering konkluderede CHMP, at på baggrund af den høje risiko ved buflomedil, navnlig for patienter med nedsat nyrefunktion og ældre patienter, har det ikke været muligt at udpege foranstaltninger, der kan mindske risiciene relateret til buflomedil til et acceptabelt niveau. 
Having assessed the totality of the risk minimisation measures proposed by the MAH, the CHMP concluded that given the high risk with buflomedil, notably in patients with impaired renal function and in elderly patients, no measures could be identified to reduce the risks associated with buflomedil to an acceptable level.
Undersøgelserne viste, at de indberettede alvorlige neurologiske bivirkninger hovedsagelig var krampeanfald, myokloni og status epilepticus, og at de kardiale bivirkninger hovedsagelig var takykardi, hypotension, ventrikulære arytmier og hjertestop. 
In these enquires, the reported nervous system SAEs consisted mainly of convulsions, myoclonia and status epilepticus while the cardiac SAEs consisted mainly of tachycardia, hypotension, ventricular rhythm disorders and cardiac arrest.
Ændringerne begrænsede populationen gennem yderligere indskrænkning af indikationen PAOD og gennem en revideret ordlyd af kontraindikationen svær nyrefunktionsnedsættelse med henblik på at forbedre efterlevelsen af ordinationsreglerne ved nyreinsufficiens. 
The CHMP noted the proposed additional revisions to the SmPC, restricting the population by further narrowing the PAOD indication and revising the wording of the contraindication in severe renal impairment in order to improve compliance to prescribing in the event of renal insufficiency.
CHMP konstaterede, at de franske erfaringer (herunder resultaterne af Thalès-undersøgelsen og publikationen af Bruhat et al.) viser, at der fortsat forekommer eksempler på manglende overholdelse af den anbefalede dosis, manglende dosisjustering hos patienter med nedsat nyrefunktion og manglende overvågning af nyrefunktionen. 
The CHMP noted that according to the French experience (including the results of the Thalès study and the publication by Bruhat et al.), cases of non-compliance with the recommended dose, nonadjustment of dose in patients with renal impairment and lack of monitoring of renal function persist, resulting in cases of serious adverse events, which is unacceptable for a product for which the only benefit is a limited level of efficacy in the lower limb peripheral vascular disease indication.
CHMP gennemgik de af indehaveren af markedsføringstilladelsen trufne foranstaltninger til risikominimering og konkluderede, at det på baggrund af den høje risiko forbundet med buflomedil - navnlig hos patienter med fremskreden vaskulær sygdom og/eller diabetes og metabolisk syndrom, patienter med nedsat nyrefunktion og ældre patienter - ikke har været muligt at udpege foranstaltninger, der kan mindske de med buflomedil forbundne risici til et acceptabelt niveau. 
Having assessed the risk minimisation measures proposed by the MAH, the CHMP concluded that given the high risk with buflomedil, notably in patients with advanced vascular disease and/or diabetes and metabolic syndrome, in patients with impaired renal function and in elderly patients, no adequate or sufficient measures could be identified to reduce the risks associated with buflomedil to an acceptable level.