natgillin/translations-raw huggingface dataset:
Der skal foretages en vurdering af blødningstider, der i løbet af behandlingen overskrider et i protokollen foruddefineret område, og foreslås passende risikominimeringsforanstaltninger, når den endelige rapport foreligger. 
Excesses in bleeding time during cilostazol treatment outside a prespecified range as to be defined in the protocol will be assessed and appropriate risk minimisation measures will be proposed when the final study report is available.
En undersøgelse af lægemiddelanvendelsen i en spansk region viste, at de patienter, der fik cilostazol, var ældre og fik mere samtidig medicin end patienterne i de kliniske undersøgelser. 
A drug utilisation study conducted in one region of Spain found that patients receiving cilostazol were older and used more concomitant medications than those in the clinical trials.
Cilostazol metaboliseres hovedsagelig af CYP3A4 og CYP2C19 og har to aktive hovedmetabolitter, OPC13015 (dehydrocilostazol, 3-7 gange mere potent end cilostazol) og OPC-13213 (trans-hydroxycilostazol, 2-5 gange mindre potent end cilostazol). 
Cilostazol is mainly metabolised by CYP3A4, and CYP2C19 and has two main active metabolites, OPC13015 (dehydrocilostazol, 3-7 times more potent than cilostazol), and OPC-13213 (trans-hydroxycilostazol, 2 - 5 times less potent than cilostazol).
De farmakologiske virkninger af cilostazol giver dog formodning om, at det hos visse patienter kan forårsage mere alvorlige kardiale arytmier. 
However, the pharmacological effects of cilostazol suggest that it may cause more serious cardiac arrhythmias in some patients.
CHMP fandt det vanskeligt at vurdere årsagssammenhængen i disse indberetninger, navnlig på grund af omfanget af konfunderende faktorer i form af patienternes baggrundsbetingelser. 
The CHMP considered that causality was difficult to assess in these reports, especially given the level of confounding due to the background conditions in these patients.
CHMP godkendte en direkte meddelelse til fagfolk i sundhedssektoren (DHPC) med henblik på en hurtig formidling af resultatet af denne gennemgang. 
Direct Healthcare Professional Communication (DHPC), to rapidly communicate the outcome of the present review.
Ekspertgruppen noterede sig de spontane indberetninger om blødning ved anvendelse sammen med et eller to trombocytfunktionshæmmende lægemidler, men fandt det betryggende, at der ikke var evidens herfor i de publicerede placebokontrollerede undersøgelser. 
The expert group noted the spontaneous reports of haemorrhage when used with one or two antiplatelet drugs, but were reassured by the absence of evidence from the published placebo-controlled studies.
Eksperterne vedgik dog, at der er en vis risiko forbundet med tredobbelt behandling, og at tredobbelt behandling bør undgås (cilostazol og to trombocytfunktionshæmmende lægemidler). 
However, they recognised that there is a risk of bleeding with triple therapy and that triple therapy should be avoided (cilostazol and two antiplatelet drugs).
Dette hæmmer trombocytaktivering og -aggregation og standser afgivelsen af protrombotiske inflammatoriske og vasoaktive stoffer. 
This leads to inhibition of platelet activation and aggregation and prevents the release of prothrombotic inflammatory and vasoactive substances.
Eksperterne blev først bedt om at drøfte den gældende standardtilgang til den kliniske behandling af perifer arteriel okklusiv sygdom, karakteristikaene af de patienter, der behandles med cilostazol, og den kliniske relevans af fordelene ved cilostazol. 
The experts were first asked to discuss the current standard approach to the clinical management of peripheral arterial occlusive disease (PAOD), the characteristics of the patients treated with cilostazol and the clinical relevance of the benefits of cilostazol.
Virkningen af cilostazol er blevet vurderet i 14 kliniske undersøgelser, hvori der deltog mere end 4 000 patienter med claudicatio intermittens. 
The efficacy of cilostazol has been evaluated in 14 clinical trials which enrolled more than 4000 intermittent claudication (IC) patients.
Gruppen fandt det acceptabelt at udelukke patienter med høj kardiovaskulær risiko i klinisk praksis, hvilket desuden ville begrænse risikoen for interaktion med trombocytfunktionshæmmende midler (da størstedelen af patienterne i disse grupper ville få to forskellige trombocytfunktionshæmmende midler). 
The group considered that it was feasible to exclude high cardiovascular risk patients in practice, and that this would also limit the risk of drug interaction with antiplatelet agents (as most patients in these groups would receive dual antiplatelet therapy).
Skønt de kliniske undersøgelser ikke underbyggede de sikkerhedsmæssige betænkeligheder, der blev rejst af de spontane bivirkningsindberetninger, konkluderede CHMP, at man ikke kan udelukke risiko for blødning og visse kardiovaskulære hændelser, herunder takyarytmier, hos udsatte patienter. 
Although clinical trial data did not substantiate safety concerns raised from spontaneous ADR reporting, the CHMP concluded that the risk of bleeding and some cardiovascular events including tachyarrhythmias cannot be excluded in at-risk patients.
CHMP anbefalede desuden dosisreduktion til 50 mg to gange dagligt af cilostazol ved samtidig anvendelse af sådanne lægemidler. 
The CHMP also recommended a dose reduction to 50mg bid of cilostazol during concomitant use with such medicines.
Desuden blev der udført en dobbeltblindet, placebokontrolleret fase IV-undersøgelse af virkning (PACE-undersøgelse), ligeledes med pentoxifyllin som aktivt sammenligningsstof. 
In addition, a phase IV double-blind placebo-controlled efficacy study (PACE study), was performed also with pentoxifylline as active comparator.
Det primære endepunkt i de ni undersøgelser af virkning (betegnet som mellemlange undersøgelser) var maksimal gangdistance (absolut claudicatio-distance, ACD), målt ved motionstest i trædemølle. 
The primary endpoint in the nine efficacy trials (called mid-term trials) was maximum walking distance (absolute claudication distance - ACD), measured by exercise treadmill testing.
På grundlag af alle de foreliggende data om sikkerheden og virkningen af cilostazol samt konklusionerne fra ekspertgruppen vedtog CHMP en række forholdsregler, herunder begrænsning af indikationen til “andetvalgsbehandling af patienter, hos hvem livsstilsændringer (herunder rygestop og (overvågede) motionsprogrammer) og andre passende interventioner ikke medfører tilfredsstillende bedring i symptomerne på claudicatio intermittens”, og indsættelse af tre nye kontraindikationer: dels svær takyarytmi i anamnesen, dels samtidig behandling med to eller flere trombocytfunktionshæmmende midler/antikoagulantia, og dels ustabil angina pectoris, myokardieinfarkt inden for de seneste 6 måneder eller koronar intervention inden for de seneste 6 måneder. 
Considering all available data on the safety and efficacy of cilostazol as well as the conclusions of the ad-hoc expert group meeting, the CHMP has agreed on a number of measures including the restriction of the indication to “second-line use, in patients in whom lifestyle modifications (including stopping smoking and [supervised] exercise programs) and other appropriate interventions have failed to sufficiently improve their intermittent claudication symptoms”, and the introduction of three new contraindications, in patients with history of severe tachyarrhythmia, patients treated concomitantly with two or more additional anti-platelet/anticoagulant agents and patients with unstable angina pectoris, myocardial infarction within the last 6 months, or a coronary intervention in the last 6 months.
Udvalget finder, at metaboliseringen af cilostazol medfører potentiale for interaktioner, der øger risiciene ved cilostazol, 
The Committee is of the opinion, considering the metabolism of cilostazol, that there is a potential for interactions that could increase the risks associated with cilostazol.
Årsagssammenhængen og størrelsen af denne risiko er dog vanskelig at kvantificere, da der ikke var noget klart signal i de kliniske undersøgelser, og da der var konfunderende faktorer i form af patienternes samtidige baggrundsmedicinering. 
However, causality and magnitude of this risk is difficult to quantify given the lack of a clear signal in clinical trials and given the level of confounding due to the background concomitant medication used by these patients.
konkluderede desuden, at blødningsrisikoen var højere hos patienter i samtidig behandling med to eller flere andre trombocytfunktionshæmmende midler eller antikoagulantia. 
The CHMP also concluded that the risk of bleeding was higher in patients treated concomitantly with two or more additional antiplatelet or anticoagulants agents.
• på baggrund af ovenstående sikkerhedsmæssige betænkeligheder vedtog udvalget en række risikominimeringsforanstaltninger, herunder ændringer af produktinformationen med skærpelse af ordlyden for at mindske risikoen for hæmoragiske hændelser, kardiale hændelser og potentielle lægemiddelinteraktioner (kontraindikation hos udsatte patienter, anbefaling af dosisjustering, 
• In view of the above safety concerns, the Committee agreed on a number of risk minimisation measures, including changes to the product information to strengthen the wording of the PI to reduce the risk of haemorrhagic events, cardiac events and potential drug-drug interactions (contra-indication in at-risk patients, recommendation of adjustment of the dose, strengthening of the warning to ensure suitability of the treatment with cilostazol).
Lægemiddelovervågningen bør skærpes ved indsendelse af PSUR hver 6. måned, herunder sikkerhedsindberetninger med fokus på kardiovaskulære bivirkninger, hæmoragiske bivirkninger og ikke godkendt anvendelse. 
The pharmacovigilance measures should be increased by submitting 6-monthly PSURs including safety reports focused on cardiovascular adverse events, haemorrhagic adverse events and off-label use.
Poolede metaanalyser af patientrapporterede udfald i short-form health survey (SF-36) og Walking Impairment Questionnaire (WIQ) viste betydeligt bedre virkning af cilostazol end placebo på fysisk funktion og fysisk komponentscore i SF-36 samt betydeligt bedre score for WIQ-hastighed og -distance. 
Pooled meta-analyses of patient reported outcomes from the short-form health survey (SF-36) and the Walking Impairment Questionnaire (WIQ) demonstrated significant effects of cilostazol over placebo on physical functioning and the physical component score of the SF-36, as well as significant improvements in WIQ speed and distance scores.
Det blev dog bemærket, at cilostazols hæmmende virkning på fosfodiesterase (PDE-3) giver anledning til sikkerhedsmæssig betænkelighed ved potentialet for kardiale arytmier som følge af forhøjet hvilende hjertefrekvens (cilostazol er påvist at øge hjertefrekvensen med ~5,1 og ~7.4 slag/min ved den godkendte dosering). 
However, it was noted that the activity of cilostazol as a phosphodiesterase enzyme (PDE-3) inhibitor raises a potential safety concern over cardiac arrhythmias that may result from the increase in resting heart rate (cilostazol has been demonstrated to increase heart rate by ~5.1 and ~7.4 beats per minute at the authorised doses).
På baggrund af den beskedne fordel ved cilostazol og de eksisterende sikkerhedsmæssige betænkeligheder er det udvalgets opfattelse, at anvendelsen af cilostazol bør begrænses til de patienter, der har størst gavn heraf, dvs. dem, hos hvem livsstilsændringer (rygestop og motionsprogrammer) og andre relevante interventioner ikke har haft tilfredsstillende virkning. 
In view of the modest benefits of cilostazol and of the existing safety concerns, the Committee is of the view that the use of cilostazol should be restricted to those who would benefit the most from treatment, i.e. patients for whom life-style modifications (stopping smoking and exercise programs)
CHMP fandt derfor, at cilostazol bør være kontraindiceret hos patienter med ustabil angina pectoris, myokardieinfarkt inden for de seneste 6 måneder eller koronar intervention inden for de seneste 6 måneder, og at der skal indsættes supplerende advarsler herom i produktinformationen. 
The CHMP therefore considered that cilostazol should be contraindicated in patients with unstable angina pectoris, myocardial infarction within the last 6 months, or a coronary intervention in the last 6 months, and that additional warning should be included in the PI.
For at minimere risikoen for metabolisk lægemiddelinteraktion er der indsat advarsler i produktresuméet, og der anbefales nu dosisreduktion til 50 mg to gange dagligt for patienter, som får medicin, der hæmmer CYP3A4 eller 2C19. 
In order to minimise the risk of drug metabolism interaction, warnings have been introduced in the SmPC and it is now recommended to reduce the dose to 50mg bid in patients taking medicines that inhibit CYP3A4 or 2C19.
De spanske myndigheders hovedbetænkeligheder samlede sig om indberettede kardiovaskulære reaktioner (herunder fatale tilfælde af myokardieinfarkt, angina pectoris og arytmier) og hæmoragiske reaktioner samt lægemiddelinteraktioner. 
The Spanish authority's main concerns centred on reports received of cardiovascular reactions (including fatal cases of MI, angina pectoris and arrhythmias) and haemorrhagic reactions as well as drug interactions.
Otte af dem var dobbeltblindede, kontrollerede fase IIIundersøgelser, hvoraf de to sammenlignede virkningen af cilostazol med et aktivt sammenligningsstof (pentoxifyllin) og med placebo i 24 uger. 
These included eight double-blind controlled phase III trials, two of which compared the efficacy of cilostazol with an active comparator (pentoxifylline) and placebo over 24 weeks.
• udvalget finder, at fordelene ved cilostazol er beskedne, men at der er påvist statistisk signifikant forøgelse af gangdistancen i forhold til placebo ved claudicatio intermittens, 
• The Committee considers that the benefit of cilostazol is modest but that a statistically significant increase in walking distance compared with placebo has been shown in patients with intermittent claudication;
Gennemgangen omfattede de foreliggende sikkerhedsdata for cilostazol fra undersøgelserne af virkning (mellemlange undersøgelser), den langsigtede sikkerhedsundersøgelse CASTLE og undersøgelserne vedrørende apopleksiforebyggelse samt case-rapporterne fra spontane indberetninger og ikkeinterventionelle undersøgelser. 
Safety data for cilostazol available from the efficacy trials (mid-term trials), the long-term safety trial CASTLE and stroke prevention studies, as well as case reports from spontaneous sources and noninterventional studies were considered in this review.
Den terapeutiske indikation, der er godkendt i Europa for produkter indeholdende cilostazol, er forbedring af maksimal og af smertefri gangdistance hos patienter med claudicatio intermittens uden hvilesmerter og uden tegn på perifer vævsnekrose (perifer arteriel sygdom Fontaine stadie II). 
The therapeutic indication that has been approved for cilostazol products in Europe is the improvement of the maximal and pain-free walking distances in patients with intermittent claudication (IC), who do not have rest pain and who do not have evidence of peripheral tissue necrosis (peripheral arterial disease (PAD) Fontaine stage II).
Også de vasodilaterende virkninger af cilostazol kan være medieret af en stigning i koncentrationen af cAMP. 
The vasodilatory effects of cilostazol may also be mediated through an increase in cAMP.
Det hæmmer desuden proliferationen af glatmuskulaturceller, nedsætter triglyceridkoncentrationen og øger koncentrationen af HDL-kolesterol. 
It also inhibits the vascular smooth muscle cell proliferation as well as decreases triglycerides and increases HDL-cholesterol.
På grund af den forhøjede eksponering for cilostazol ved samtidig brug af CYP3A4- og CYP2C19-hæmmere (såsom erythromycin, ketoconazol og omeprazol) fandt CHMP, at der er stort potentiale for interaktion med andre lægemidler, som kan øge risiciene ved cilostazol, hvorfor ordlyden af produktresuméets punkt 4.5 bør skærpes. 
Given the increase in exposure to cilostazol resulting from concomitant use of CYP3A4 and CYP2C19 inhibitors (such as erythromycin, ketoconazole and omeprazole), the CHMP considered that there is a high potential for interactions with other medicinal products that could increase the risks associated with cilostazol and therefore considered that the SmPC wording in section 4.5 should be strengthened.
Betænkelighederne ved interaktioner med andre lægemidler (navnlig CYP3A4- og CYP2C19-hæmmere) og muligheden for øget bivirkningsrisiko er imødekommet gennem anbefalingen om dosisreduktion til 50 mg to gange dagligt for patienter, der samtidig får lægemidler, som hæmmer disse enzymer. 
The concerns relating to interactions with other medications (in particular CYP3A4 and CYP2C19 inhibitors) and the possibility of an increased risk for adverse effects have been addressed by the recommendation of a dose reduction to 50mg bid in patients taking concomitant medicines that inhibit these enzymes.
Cilostazols virkning på absolut gangdistance i trædemølle, angivet som absolut forøgelse i forhold til baseline, var mellem +23 m og +109 m, sammenholdt med mellem -2 m og +65 m for placebo. 
Cilostazol's effect on absolute walking distances on the treadmill, expressed as an absolute increase over baseline walking distance ranged from +23m to +109m, compared with -2m to +65m for placebo.
Den beregnede WMD viser en gennemsnitlig forbedring i gangdistance fra baseline på 87,4 m for cilostazol, 100 mg to gange dagligt, og 43,7 m for placebo (p<0,0001), hvor den gennemsnitlige gangdistance ved baseline var ca. 133 m (66 % forbedring med cilostazol). 
The WMD estimates a mean improvement from baseline for walking distance of 87.4m for cilostazol 100mg bid and 43.7m for placebo (p<0.0001) with a mean baseline walking distance of about 133m (66% improvement with cilostazol).
Eksperterne var af den opfattelse, at cilostazol er til fordel for patienter, der har begrænsende claudicatio intermittens og ikke kan klare et motionsprogram, da de lettere vil kunne komme over “den første forhindring”, så de får mulighed for yderligere at forbedre deres gangdistance ved træning. 
The experts were of the view that cilostazol has a beneficial effect in patients with limiting intermittent claudication who cannot manage an exercise program in getting such patients over “the first hurdle” that would then allow them to continue progression of their walking distance through exercise.
Desuden påtog indehaveren af markedsføringstilladelsen sig at udføre en mekanismeundersøgelse, der skal give bedre indblik i cilostazols virkninger på trombocytaggregationen med acetylsalicylsyre eller clopidogrel og indvirkningen heraf på blødningstiden. 
In addition, the MAH agreed to perform a mechanistic study to provide further insight into the effects on platelet aggregation of cilostazol with aspirin or clopidogrel and their consequences on bleeding time.
De sekundære endepunkter for virkning var smertefri gangdistance (initial claudicatio-distance, ICD), målt ved motionstest i trædemølle, og livskvalitetsvurdering. 
Secondary efficacy endpoints included painfree walking distance (initial claudication distance - ICD) measured by treadmill exercise; and Quality of Life assessments.
• udvalget konkluderede følgelig, at benefit/risk-forholdet for lægemidler indeholdende cilostazol under normale anvendelsesbetingelser kun er positivt til andetvalgsbehandling af patienter, hos hvem livsstilsændringer og andre hensigtsmæssige interventioner ikke har medført tilstrækkelig bedring i symptomerne på claudicatio intermittens, og under forudsætning af gennemførelse af de vedtagne risikominimeringsforanstaltninger, herunder ændringer i produktinformationen, 
• The Committee, as a consequence, concluded that the benefit-risk balance of cilostazol-containing medicinal products is positive under normal conditions of use only for second-line use, in patients in whom lifestyle modifications and other appropriate interventions have failed to sufficiently improve their intermittent claudication symptoms, and subject to the agreed risk minimisation measures, including changes to the product information.
De hyppigste bivirkninger var hovedpine, diarré, abnorm afføring, svimmelhed, palpitationer og takykardi, hvilke i forvejen er anført i produktinformationen. 
The most common adverse events included headache, diarrhoea, abnormal stools, dizziness, palpitations and tachycardia, already listed in the Product Information.
Cilostazol er et dihydroquinolinonderivat, der hæmmer nedbrydningen af cAMP ved at hæmme cyklisk adenosinmonofosfat- (cAMP-) fosfodiesterase og derved øger koncentrationen af cAMP i trombocytter og blodkar. 
Cilostazol is a dihydroquinolinone derivative that inhibits cyclic adenosine monophosphate (cAMP) phosphodiesterase, suppressing cAMP degradation and thereby increasing cAMP levels in platelets and blood vessels.
Metaanalysen af vægtet middelforskel (WMD) for alle ni undersøgelser viste ligeledes konsistent virkning af cilostazol i alle undersøgelserne. 
The meta-analysis of weighted mean difference (WMD) across the nine trials also demonstrated consistent efficacy of cilostazol across the trials.
I CASTLE-undersøgelsen bemærkedes en lille overhyppighed af hjertesvigt (cilostazol: 2,9 %, mod placebo: 2,4 %) og af hypotension (cilostazol: 0,7 %, mod placebo: 0,1 %). 
It was noted that there was a small excess of cases of heart failure (cilostazol: 2.9%, vs. placebo: 2.4%) and hypotension (cilostazol: 0.7%, vs. placebo: 0.1%) in the CASTLE study.
I CASTLE-undersøgelsen var der færre blødningsepisoder i cilostazolarmen end i placeboarmen, og samtidig brug af acetylsalicylsyre øgede ikke blødningsfrekvensen i den undergruppe, der fik cilostazol. 
In the CASTLE trial, a lower bleeding event rate was observed in the cilostazol arm than in the placebo arm and the use of concomitant aspirin did not increase the frequency of bleeding in the sub-group treated with cilostazol.
I den første undersøgelse indhentes baseline-data til karakterisering af nye brugere af cilostazol og mønsteret for anvendelsesvarighed og seponering. 
The first DUS' will obtain baseline data with the objective to describe the characteristics of new users of cilostazol and the duration of the use of cilostazol and discontinuation patterns.
Overordnet var det gruppens opfattelse, at dette lægemiddel kan have berettigelse hos en lille patientgruppe, som har lav risiko for kardiovaskulær komorbiditet, som lider af begrænsende claudicatio intermittens, og som ikke kan klare den indledende rehabilitering med motion eller er uegnede til revaskularisering. 
Overall, the group was of the view that for a small group of patients with low risk of cardiovascular co-morbidities, limiting intermittent claudication who cannot manage initial exercise rehabilitation, or who are unsuitable for revascularisation, this drug may have a role.
CHMP fandt derfor, at cilostazol har en statistisk signifikant, omend moderat virkning på gangdistancen hos patienter med claudicatio intermittens, og at nogle patienter kan have klinisk relevant gavn heraf. 
The CHMP was therefore of the opinion that cilostazol has a statistically significant, albeit modest effect on walking distances in patients with IC and that some patients may benefit to a clinically relevant degree.
Cilostazol medfører en beskeden, men statistisk signifikant forøgelse i gangdistance i forhold til placebo hos patienter med claudicatio intermittens, og dette er også påvist ved livskvalitetsvurderinger. 
Cilostazol is associated with a modest but statistically significant increase in walking distance compared with placebo in patients with IC, and this has also been demonstrated using quality of life measurements.
Hazard ratio for dødelighed (cilostazol mod placebo) var 0,94 med 95 % SI 
The hazard ratio for mortality (cilostazol vs. placebo) was 0.94, 95% CI [0.63-1.39].