natgillin/translations-raw huggingface dataset:
Iloprost kan hæmme trombocytternes funktion, og det kan forøge risikoen for blødning, hvis det anvendes sammen med antikoagulanter (som f. eks. heparin, antikoagulanter af coumarin- typen) eller andre hæmmere af trombocytaggregation (som f. eks. acetylsalicylsyre, non- steroide anti - inflammatoriske lægemidler, ticlopidin, clopidogrel og glykoprotein IIb/ IIIa antagonister: abciximab, eptifibatide og tirofiban).
5 Iloprost can inhibit platelet function and its use with anticoagulants (such as heparin, coumarin-type anticoagulants) or other inhibitors of platelet aggregation (such as acetylsalicylic acid, non-steroidal anti-inflammatory medicinal products, ticlopidine, clopidogrel and glycoprotein IIb/ IIIa antagonists: abciximab, eptifibatide and tirofiban) may increase the risk of bleeding.
Omhyggelig monitorering i overensstemmelse med almindelig lægepraksis af patienter, der tager antikoagulanter, anbefales.
A careful monitoring of the patients taking anticoagulants according to common medical practice is recommended.
Samtidig brug af andre trombocythæmmere bør undgås hos patienter, der tager antikoagulanter.
The concomitant use of other platelet inhibitors should be avoided in patients taking anticoagulants.
Intravenøs infusion af iloprost har hverken virkning på farmakokinetikken af multiple orale doser af digoxin eller på farmakokinetikken af samtidigt administreret vævs- plasminogenaktivator (t- PA) hos patienter.
Intravenous infusion of iloprost has no effect either on the pharmacokinetics of multiple oral doses of digoxin or on the pharmacokinetics of co-administered tissue plasminogen activator (t-PA) in patients.
Selv om der ikke er udført kliniske studier, viste in vitro- studier, der undersøger iloprosts potentielle hæmmende virkning på cytochrome- P450- enzymernes aktivitet, at iloprost ikke kan forventes at have nogen relevant hæmmende effekt på lægemiddelmetabolismen via disse enzymer.
Although, clinical studies have not been conducted, in vitro studies investigating the inhibitory potential of iloprost on the activity of cytochrome P450 enzymes revealed that no relevant inhibition of drug metabolism via these enzymes by iloprost have to be expected.
Der findes ikke tilstrækkelige data fra brugen af Ventavis til gravide kvinder.
There are no adequate data from the use of Ventavis in pregnant women.
4. 3).
Ventavis is contra- indicated during pregnancy (see section 4.3).
Kvinder i den fødedygtige alder bør anvende effektive præventive metoder under behandlingen.
Women of child-bearing potential should use effective contraceptive measures during treatment.
Det vides ikke, om Ventavis udskilles i modermælken.
It is not known whether Ventavis enters the breast milk.
4. 3).
The medicinal product must not be administered to breast feeding mothers (see section 4.3).
Der skal udvises forsigtighed ved behandlingens start, indtil eventuelle virkninger på den enkelte patient er blevet fastslået.
Care should be exercised during initiation of therapy until any effects on the individual have been determined.
Hos patienter, der oplever symptomer på hypertension som f. eks. svimmelhed, kan evnen til at føre motorkøretøj eller betjene maskiner være påvirket.
In patients experiencing hypotensive symptoms such as dizziness, the abilityto drive or operate machines may be affected.
Foruden lokale virkninger, der forekommer som resultat af indtagelse af iloprost ved inhalation, er bivirkninger fra iloprost som f. eks. øget hoste, relateret til de farmakologiske egenskaber af prostacycliner.
In addition to local effects resulting from administration of iloprost by inhalation such as increased cough, adverse reactions with iloprost are related to the pharmacological properties of prostacyclins.
De mest almindelige bivirkninger, der er set ved kliniske forsøg, omfatter vasodilatation, hypotension, hovedpine og øget hoste.
The most common adverse reactions seen in clinical trials include vasodilatation, hypotension, headache and increased cough.
Hyppigheden af bivirkningerne angives som følger: meget almindelig ≥ 1/ 10; almindelig ≥ 1/ 100 til < 1/ 10; ikke almindelig ≥ 1/ 1, 000 og < 1/ 100; sjælden ≥ 1/ 10, 000 til < 1/ 1, 000; meget sjælden < 1/ 10, 000.
Frequencies of adverse reactions are reported as follows: very common ≥ 1/ 10; common ≥ 1/ 100 to < 1/ 10; uncommon ≥ 1/ 1,000 and < 1/ 100; rare ≥ 1/ 10,000 to < 1/ 1,000; very rare < 1/ 10,000.
MedDRA systemorganklasser.
The table below reports adverse reactions by MedDRA system organ classes (MedDRA SOCs).
Bivirkningerne er baseret på data fra kliniske forsøg.
The incidences are based on clinical trial data.
Bivirkningerne vises inden for hver hyppighedsområde efter faldende alvorlighed
6 Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
6 Systemorganklasse
System organ class
Vasodilatation, Hypotension
Vasodilatation, Hypotension
Synkope, Svimmelhed i forbindelse med hypotension
Syncope, Dizziness related to hypotension
Øget hoste
Cough increased
Kæbesmerter/ trismus
Pain in jaw/ trismus
Besvimelse (synkope) er et hyppigt symptom på selve sygdommen, men kan også optræde under behandlingen med Ventavis.
Syncope is a common symptom of the disease itself, but can also occur under therapy.
Se også pkt.
The increased occurrence of syncopes can be related to the deterioration of the disease or insufficient effectiveness of the product (see section 4.4).
Blødning (mest hæmatom) var som forventet almindelig i denne patientpopulation, hvor en stor del af patienterne samtidig tog antikoagulationsmedicin.
Bleeding events (mostly haematoma) were common as expected in this patient population with a high proportion of patients taking anticoagulant co-medication.
Der var ingen forskel i blødningshændelsernes hyppighed hos de patienter, der blev behandlet med iloprost i forhold til de patienter, der blev behandlet med placebo.
The frequency of bleeding events did not differ between iloprost and placebo-treated patients.
Erfaringer efter markedsføringen
Post marketing experience
Der er indberetninger om opkastning, kvalme, diaré og dyspnø i forbindelse med inhalation af Ventavis.
Vomiting, nausea, diarrhoea and dyspnoea have been reported in association with Ventavis inhalation.
4. 4 Særlige advarsler og forsigtighedsregler vedrørende brugen).
Bronchospasm and wheezing have also been reported in patients treated with Ventavis inhalation (see section 4.4 Special warnings and precautions for use).
Bivirkninger hos raske forsøgspersoner
Adverse events in healthy volunteers
I et randomiseret, placebo- kontrolleret forsøg med 160 raske forsøgspersoner blev der givet inhalerede doser af iloprost- opløsning, enten med en fast dosis på 2, 5 mkg iloprost 6 gange dagligt (en daglig samlet eksponeringsdosis på 15 mkg) eller en startdosis på 5, 0 mkg og stigende til 20 mkg, eller den højest tolererede dosis, med et samlet antal på 6 inhalationsdoser (samlet daglig eksponeringsdosis på 70 mkg).
In a randomized placebo-controlled study in 160 healthy volunteers, inhaled doses of iloprost solution were given either with a fixed dose of 2.5 micrograms iloprost 6 times daily (total daily dose of 15 micrograms), or beginning with 5.0 microgram and increasing up to 20 micrograms, or the highest tolerated dose for a total of 6 dose inhalations (total daily dose of 70 micrograms).
I gruppen der modtog en fast dosis på 2, 5 mkg pr. inhalation optrådte symptomerne brystsmerte eller brystubehag (32, 5%), faryngo- larynx smerte eller halsirritation (22, 5%) og kvalme (7, 5%) (alle med en intensitet som var mild og ikke- alvorlig) hyppigere sammenlignet med bivirkningerne, som optrådte i de placebo- kontrollerede fase II og III forsøg med patienter med doser på 2, 5 mkg eller 5 mkg pr. inhalation.
In the fixed dose group of 2.5 micrograms per inhalation chest pain, or chest discomfort (32.5%), pharyngolaryngeal pain, or throat irritation (22.5%) and nausea (7.5%) – (all non-serious and mild in intensity) – occurred more frequently in comparison with the adverse events obtained from the placebo controlled phase II and III studies in patients with doses of 2.5 micrograms or 5 micrograms per inhalation.
Fem forsøgspersoner var ude af stand til at øge dosis til 20 mkg pr. inhalation på grund af mild til moderat forbigående brystsmerte eller brystubehag, generelt ledsaget af hovedpine, svimmelhed og kvalme.
Five volunteers were unable to increase the dose up to 20 micrograms per inhalation because of mild to moderate transient chest pain or chest discomfort, usually accompanied by headache, dizziness and nausea.
Symptomer
• Symptoms
Der er ikke blevet rapporteret om tilfælde med overdosering.
No case of overdose has been reported.
Hypotensive og vasovagale reaktioner kan forventes så vel som hovedpine, rødmen, kvalme, opkastning og diaré.
Hypotensive/ vasovagal reaction might be anticipated as well as headache, flushing, nausea, vomiting, and diarrhoea.
Behandling
• Therapy
Trombocytaggregationshæmmere eksklusive Heparin ATC kode:
Platelet aggregation inhibitors excluding heparin, ATC code:
Det Europæiske Lægemiddelagentur (EMEA) vurderer hvert år ny information vedrørende produktet, og produktresuméet vil om nødvendigt blive opdateret
The European Medicines Agency (EMEA) will review any new information which may become available every year and this SPC will be updated as necessary.
Iloprost, det aktive stof i Ventavis, er en syntetisk prostacyclin- analog.
Iloprost, the active substance of Ventavis, is a synthetic prostacyclin analogue.
• Hæmning af trombocytaggregation, trombocytadhæsion og release- reaktion
• Inhibition of platelet aggregation, platelet adhesion and release reaction
• Dilatation af arterioler og venuler
• Dilatation of arterioles and venules
• Forøgelse af kapillær densitet og reduktion af forøget vaskulær permeabilitet forårsaget af mediatorer som f. eks. serotonin eller histamin i mikrokredsløbet
• Increase of capillary density and reduction of increased vascular permeability caused by mediators such as serotonin or histamine in the microcirculation
Den pulmonale vasodilatatoriske virkning af hver enkelte inhalation finder sit niveau inden for én til to timer.
The pulmonary vasodilatory effect of each single inhalation levels off within one to two hours.
• Effekt hos voksne patienter med pulmonal hypertension
• Efficacy in adult patients with pulmonary hypertension
Et randomiseret, dobbelt- blindt, multi- center, placebo- kontrolleret fase III forsøg (studie RRA02997) er foretaget med 203 voksne patienter (inhaleret iloprost:
8 A randomised, double-blind, multi-centre, placebo-controlled phase III trial (study RRA02997) has been conducted in 203 adult patients (inhaled iloprost:
N=101; placebo n=102) med stabil pulmonal
N=101; placebo n=102) with stable pulmonary hypertension.
Patienternes nuværende behandling, som kunne omfatte en kombination af antikoagulanter, vasodilatorer (f. eks. calciumblokkere), diuretika, ilt og digitalis, men ikke PGI2 (prostacyklin eller analoger) blev suppleret med inhaleret iloprost (eller placebo).
Inhaled iloprost (or placebo) was added to patients' current therapy, which could include a combination of anticoagulants, vasodilators (e. g. calcium channel blockers), diuretics, oxygen, and digitalis, but not PGI2 (prostacyclin or its analogues).
108 af de inkluderede patienter havde diagnosen primær pulmonal hypertension, 95 havde sekundær pulmonal hypertension, hvoraf 56 var forbundet med kronisk tromboembolisk sygdom, 34 med bindevævssygdom (herunder CREST og sclerodermia) og 4 betragtedes som relateret til appetitdæmpende middel.
108 of the patients included were diagnosed with primary pulmonary hypertension, 95 were diagnosed with secondary pulmonary hypertension of which 56 were associated with chronic thromboembolic disease, 34 with connective tissue disease (including CREST and scleroderma) and 4 were considered appetite suppressant drug related.
Den 6 minutters baseline- gangtest viste en moderat motionsindskrænkning: i iloprost- gruppen var middelværien 332 meter (median:
The baseline 6-minute walk test values reflected a moderate exercise limitation: in the iloprost group the mean was 332 meters (median value:
340 meter), og i placebo- gruppen var middelværdien 315 meter (median 321 meter).
321 meters).
I iloprost- gruppen var den gennemsnitlige dosis, der blev inhaleret dagligt, 30 mikrogram (område 12, 5 til 45 mikrogram/ dag).
In the iloprost group, the median daily inhaled dose was 30 micrograms (range 12.5 to 45 micrograms/ day).
Det primære effekt - endpoint, der var defineret for dette studie, var et samlet responskriterium bestående af en bedring af motionskapaciteten (6 minutters gangtest) efter 12 uger med mindst 10% i forhold til baseline, og en bedring med mindst én NYHA- klasse efter 12 uger i forhold til baseline, samt hverken forværring af den pulmonale hypertension eller død inden for de 12 uger.
The primary efficacy endpoint defined for this study, was a combined response criterion consisting of improvement in exercise capacity (6 minute walk test) at 12 weeks by at least 10% versus baseline, and improvement by at least one NYHA class at 12 weeks versus baseline, and no deterioration of pulmonary hypertension or death at any time before 12 weeks.
Målopfyldelsen på iloprost var 16, 8% (17/ 101) og for placebo- gruppen 4, 9% (5/ 102) (p=0, 007).
The rate of responders to iloprost was 16.8% (17/ 101) and the rate of responders in the placebo group was 4.9% (5/ 102) (p=0.007).
Der er ingen databeregninger for død eller manglende værdier).
In the iloprost group, the mean change from baseline after 12 weeks of treatment in the 6 minute walking distance was an increase of 22 meters (-3.3 meters in the placebo group, no data imputation for death or missing values).
I iloprost- gruppen bedredes NYHA- klassen hos 26% af patienterne (placebo:
In the iloprost group the NYHA class was improved in 26% of patients (placebo:
15%) (p=0, 032), var uændret hos 67, 7% af patienterne (placebo:
15%) (p = 0.032), unchanged in 67.7% of patients (placebo:
76%) og forværredes hos 6, 3% af patienterne (placebo:
76%) and deteriorated in 6.3% of patients (placebo:
Der blev observeret en middeløgning i den 6 minutters gangtest på 44, 7 meter fra en baselinemiddelværdi på 329 meter ift. en ændring på – 7, 4 meter fra baselinemiddelværdien på 324 meter i placebo- gruppen (ingen databeregninger for død eller manglende værdier) i undergruppen på 49 patienter med primær pulmonal hypertension, som fik behandling med inhaleret iloprost i 12 uger (46 patienter i placebo - gruppen).
A mean increase in the 6-minute walk test of 44.7 meters from a baseline mean value of 329 meters vs. a change of -7.4 meters from a baseline mean value of 324 meters in the placebo group (no data imputation for death or missing values) was observed in the subgroup of 49 patients with primary pulmonary hypertension receiving treatment of inhaled iloprost for 12 weeks (46 patients in the placebo group).
• Absorption
• Absorption
Når iloprost indgives via inhalation hos patienter med pulmonal hypertension (iloprost- dosis ved mundstykket:
When iloprost is administered via inhalation in patients with pulmonary hypertension (iloprost dose at the mouthpiece:
5 mikrogram), blev der observeret serum- spidsniveauer på 100 til 200 pikogram/ ml ved afslutningen af inhalationsbehandlingen.
5 micrograms), peak serum levels of 100 to 200 picograms/ ml were observed at the end of inhalation session.
Disse niveauer falder med halveringstider på mellem cirka 5 og 25 minutter.
These levels decline with half-lives between approximately 5 and 25 minutes.
Inden for 30 minutter til 1 time efter afslutning på inhalationen kan iloprost ikke påvises i det centrale rum (kvantificeringsgrænse 25 pikogram/ ml).
Within 30 minutes to 1 hour after the end of inhalation, iloprost is not detectable in the central compartment (limit of quantification 25 picograms/ ml).
• Distribution
• Distribution
Efter intravenøs infusion var det tilsyneladende steady- state distributionsvolumen 0, 6 til 0, 8 l/ kg hos sunde forsøgspersoner.
Following intravenous infusion, the apparent steady-state volume of distribution was 0.6 to 0.8 l/ kg in healthy subjects.
Den totale plasmaproteinbinding af iloprost er uafhængig af koncentrationen i området 30 til 3000 pikogram/ ml og er cirka 60%, af hvilke 75% skyldes albuminbinding.
Total plasma protein binding of iloprost is concentration-independent in the range of 30 to 3000 picograms/ ml and amounts to approximately 60%, of which 75% is due to albumin binding.
• Metabolisme
9 • Metabolism
9 Iloprost metaboliseres ekstensivt hovedsagelig via ß- oxydering af carboxyl- sidekæden.
Iloprost is extensively metabolised principally via ß-oxidation of the carboxyl side chain.
Hovedmetabolitten er tetranor- iloprost, som findes i urinen i fri og i konjugeret form i 4 diastereoisomerer.
The main metabolite is tetranor-iloprost, which is found in the urine in free and conjugated form in 4 diastereoisomers.
Som vist i dyreforsøg er tetranor- iloprost farmakologisk inaktiv.
Tetranor-iloprost is pharmacologically inactive as shown in animal experiments.
Resultater af in vitro studier afslørede, at CYP 450- afhængig metabolisme kun spiller en mindre rolle i biotransformationen af iloprost.
Results of in vitro studies reveal that CYP 450-dependent metabolism plays only a minor role in the biotransformation of iloprost.
Desuden antyder in vitro- studier, at metaboliseringen af iloprost i lungerne er nogenlunde ens efter intravenøs indgivelse og inhalation.
Further in vitro studies suggest that metabolism of iloprost in the lungs is similar after intravenous administration or inhalation.
• Elimination
• Elimination
Hos forsøgspersoner med normal nyre - og leverfunktion karakteriseres dispositionen af iloprost efter intravenøs infusion i de fleste tilfælde af en tofaset profil med gennemsnitlige halveringstider på 3 til 5 minutter og 15 til 30 minutter.
In subjects with normal renal and hepatic function, the disposition of iloprost following intravenous infusion is characterised in most cases by a two-phase profile with mean half-lives of 3 to 5 minutes and 15 to 30 minutes.
Der blev udført et masse- balance- studie med 3H- iloprost hos sunde forsøgspersoner.
A mass-balance study was done using 3H-iloprost in healthy subjects.
Efter intravenøs infusion var recovery af total radioaktivitet 81%, og recovery i urin og fæces henholdsvis 68% og 12%.
Following intravenous infusion, the recovery of total radioactivity is 81%, and the respective recoveries in urine and faeces are 68% and 12%.
• Farmakokinetik efter brug af forskellige nebulisatorer
• Pharmacokinetics after use with different nebulisers
I et randomiseret overkrydsningsstudie med 20 raske mænd blev farmakokinetikken efter inhalation af Ventavis (5 mikrogram iloprost) med I- Neb AAD sammenlignet med ProDose (5 mikrogram disk).
In a randomized, crossover study with 20 healthy adult men, pharmacokinetics was investigated following inhalation of Ventavis (5 mcg iloprost) by the I-Neb AAD in comparison to the ProDose (5 mcg disk).
Der blev fundet højere maksimale serumkoncentrationer (Cmax) og højere systemisk eksponering (AUC( 0- tlast)) samt kortere tid til at nå maksimale serumkoncentrationer (tmax) efter inhalation af Ventavis med I- Neb AAD sammenlignet med ProDose nebulisator.
Higher maximum serum level (Cmax) and systemic exposure (AUC(0-tlast)) as well as a shorter time to reach maximum serum concentration (tmax) were found following Ventavis inhalation via the I-Neb AAD in comparison to the ProDose nebulizer.
4. 2).
The pharmacokinetic results reflect the slightly different in vitro characteristics of these nebulizers (see Section 4.2).
Farmakokinetiske parametre for iloprost efter inhalation af 5 mikrogram iloprost med I- Neb AAD og ProDose
ProDose
Tmax
t max
(timer)
(h),
(pg· time/ ml)
(pg·h/ mL)
geometrisk gennemsnit (CV%)
geometric mean (CV%)
median (spændvidde)
median (range)
AUC( 0- tsidst) =
AUC(0-tlast) = serum level
Arealet under koncentrations- tids- kurven fra tidspunktet 0 til sidst målte serumkoncentration
Area under the concentration time curve from 0h data point up to last measurable
CV = variationskofficient
CV = coefficient of variation
• Karakteristika hos patienter
10 • Characteristics in patients
Renal dysfunktion:
Renal dysfunction:
I et studie med intravenøs infusion af iloprost har patienter med nyreinsufficiens i slutstadiet, der gennemgik regelmæssig dialysebehandling, vist sig at have en signifikant lavere clearance (middel CL = 5 ± 2 ml/ minut/ kg) end observeret hos patienter med nyresvigt, som ikke gennemgik regelmæssig dialysebehandling (middel CL = 18 ± 2 ml/ minut/ kg).
In a study with intravenous infusion of iloprost, patients with end-stage renal failure undergoing intermittent dialysis treatment are shown to have a significantly lower clearance (mean CL = 5 ± 2 ml/ minute/ kg) than that observed in patients with renal failure not undergoing intermittent dialysis treatment (mean CL = 18 ± 2 ml/ minute/ kg).
Hepatisk dysfunktion:
Hepatic dysfunction:
Iloprosts middel- clearance vurderes til at være 10 ml/ minut/ kg.
The mean clearance of iloprost is estimated to be 10 ml/ minute/ kg.
10 Alder og køn:
Age and gender:
Alder og køn er ikke af klinisk relevans i forbindelse med iloprosts farmakokinetik.
Age and gender are not of clinical relevance to the pharmacokinetics of iloprost.
• Systemisk toksicitet
• Systemic toxicity
I studier omhandlende akut toksicitet forårsagede intravenøse og orale enkeltdoser af iloprost alvorlige symptomer på intoksikation eller død (IV) ved doser i en størrelsesorden på cirka to gange den intravenøse terapeutiske dosis.
In acute toxicity studies, single intravenous and oral doses of iloprost caused severe symptoms of intoxication or death (IV) at doses about two orders of magnitude above the intravenous therapeutic dose.
Som forventet for prostacycliner fremkaldte iloprost hæmodynamiske virkninger (vasodilatation, rødmen af huden, hypotension, hæmning af trombocytfunktionen, respirationsbesvær) samt generelle tegn på intoksikation som f. eks. apati, gangforstyrrelser samt posturale ændringer.
As expected for a prostacyclin, iloprost produced haemodynamic effects (vasodilatation, reddening of skin, hypotension, inhibition of platelet function, respiratory distress) and general signs of intoxication such as apathy, gait disturbances, and postural changes.
Kontinuerlig IV/ SC- infusion af iloprost i op til 26 uger hos gnavere og ikke- gnavere forårsagede ikke organtoksicitet ved dosisniveauer, som overskred den humane, terapeutiske, systemiske dosis mellem 14 og 47 gange (baseret på plasmaniveauer) Kun forventede farmakologiske virkninger som hypotension, rødmen af huden, dyspnø og forøget tarmmotilitet blev observeret.
Only expected pharmacological effects like hypotension, reddening of skin, dyspnoea, increased intestinal motility were observed.
Baseret på Cmax- værdier hos rotter var den systemiske udsættelse i disse parenterale studier cirka 3, 5 gange højere end den maksimalt opnåelige udsættelse efter inhalation.
Based on Cmax values in rats the systemic exposure in these parenteral studies was approximately 3.5 times higher than the maximum achievable exposure after inhalation.
Denne højest opnåelige dosis på 48, 7 mikrogram/ kg/ dag var også et nul- effekt- niveau (NOAEL) (no observed adverse effect level), som evalueret i inhalationstoksicitetsstudier hos rotter i op til 26 uger.
This highest achievable dose of 48.7 micrograms/ kg/ day was also the “ no observed adverse effect level” (NOAEL) as evaluated in inhalation toxicity studies in rats up to 26 weeks.
Efter inhalation overskred det systemiske niveau, baseret på AUC- værdier hos rotter, det tilsvarende terapeutiske niveau hos mennesker med cirka 13 gange.
Following inhalation the systemic exposure based on AUC values in rats exceeded the corresponding therapeutic exposure in human patients by approximately 13 times.
• Genotoksisk potentiale, tumorgenicitet
• Genotoxic potential, tumorigenicity