natgillin/translations-raw huggingface dataset:
Udvalget for Humanmedicinske Lægemidler (CHMP) konkluderede, at fordelene ved Refludan er større end risiciene ved behandling af heparin- induceret trombocytopeni og tromboembolisk sygdom.
As the disease is very severe, and there is no other effective treatment approved, the Committee for Medicinal Products for Human Use (CHMP) decided that Refludan’ s benefits are greater than its risks for the treatment of patients with heparin-induced thrombocytopenia and thromboembolic disease.
Udvalget anbefalede udstedelse af markedsføringstilladelse for Refludan.
They recommended that Refludan be given marketing authorisation.
Europa- Kommissionen udstedte en markedsføringstilladelse med gyldighed i hele Den Europæiske Union for Refludan den 13. marts 1997.
The European Commission granted a marketing authorisation valid throughout the European Union, for Refludan on 13 March 1997.
Indehaveren af markedsføringstilladelsen er Pharmion Ltd.
The marketing authorisation holder is Pharmion Ltd.
Den fuldstændige EPAR for Refludan kan ses her.
The full EPAR for Refludan is available here.
Dette sammendrag blev sidst ajourført i 03- 2007
This summary was last updated in 03-2007.
Koncentrat til injektionsvæske, opløsning
Powder for solution for injection or infusion
(Lepirudin er et DNA- recombinantprodukt fremstillet i gærceller)
(Lepirudin is a recombinant DNA product derived from yeast cells)
Pulver til injektionsvæske og infusionsvæske, opløsning.
Powder for solution for injection or infusion.
Antikoagulation hos voksne patienter med type II heparin- induceret thrombocytopeni (HIT) og thromboembolisk sygdom, hvor parenteral antitrombotisk behandling er indiceret.
Anticoagulation in adult patients with heparin-induced thrombocytopenia (HIT) type II and thromboembolic disease mandating parenteral antithrombotic therapy.
- efterfulgt af 0, 15 mg / kg legemsvægt / time som kontinuerlig intravenøs infusion i 2 - 10 dage
– 0.4 mg / kg body weight intravenously as a bolus dose – followed by 0.15 mg / kg body weight / hour as a continuous intravenous infusion for 2 - 10 days or longer if clinically needed.
eller længere afhængigt af det kliniske behov.
Normally, the dosage depends on the patient's body weight.
- Dosis (infusionshastighed) bør sædvanligvis justeres i henhold til aktiveret partiel
Monitoring: – In general, the dosage (infusion rate) should be adjusted to the activated partial thromboplastin time, aPTT. – The first aPTT determination should be done 4 hours after start of Refludan therapy.
tromboplastin- tid, APTT.
2 – The aPTT should be monitored at least once daily.
- Den første APTT- bestemmelse skal laves 4 timer efter Refludanbehandlingens start.
More frequent determinations may be necessary, for example, in patients with renal impairment or with an increased risk of bleeding. – Target range (therapeutic window) for the aPTT:
Mere hyppige bestemmelser kan blive
- Using "Actin FS" or "Neothromtin" on automated coagulometers the target range for the
nødvendige, fx hos patienter med nedsat nyrefunktion eller med forøgede risiko for blødning.
aPTT is 1.5 fold to 3 fold prolongation of the normal control value.
- Målintervallet (det terapeutiske vindue) for APTT:
- With other reagents, the upper limit of the therapeutic aPTT window should be reduced to
Dosisjustering:
2.5 fold prolongation of the normal control value.
- Enhver APTT- værdi uden for målintervallet bør straks bekræftes, før der drages
- To obtain specific and exact aPTT limits, the laboratory equipment / test reagent used may
konklusioner med hensyn til justering af dosis, medmindre det er klinisk nødvendigt at handle øjeblikkeligt.
be calibrated by spiking standardised human plasma with 0.15 μ g/ ml lepirudin (lower limit) and 1.5 μ g/ ml lepirudin (upper limit).
- Såfremt det bekræftes, at APTT ligger over målintervallet, bør infusionen afbrydes i 2 timer.
Dose modifications: – Any aPTT value out of the target range is to be confirmed at once before drawing conclusions with respect to dose modifications, unless there is a clinical need to react immediately. – If the confirmed aPTT value is above the target range, the infusion should be stopped for two hours.
Når infusionen genoptages, bør infusionshastigheden nedsættes med 50% (yderligere intravenøst bolus bør ikke administreres).
At restart, the infusion speed should be decreased by 50% (no additional intravenous bolus should be administered).
APTT bør bestemmes igen 4 timer senere.
The aPTT should be determined again 4 hours later. – If the confirmed aPTT value is below the target range, the infusion speed should be increased by 20%.
- Generelt bør en infusionshastighed på 0, 21 mg/ kg/ t ikke overstiges uden at undersøge om der er
The aPTT should be determined again 4 hours later. – In general, an infusion rate of 0.21 mg/ kg/ hour should not be exceeded without checking for coagulation abnormalities which might be preventing an appropriate aPTT response.
koagulationsanormaliteter, som muligvis forhindrer en passende APPT respons.
Recommendations for use in patients scheduled for a switch to oral anticoagulation
Hvis det er planlagt, at en patient skal behandles med et coumarinderivat (vitamin K antagonister) som peroral antikoagulation efter Refludanbehandlingen, gælder følgende:
If a patient is scheduled to receive coumarin derivatives (vitamin K antagonists) for oral anticoagulation after Refludan therapy, the following should apply:
Behandling med coumarin - derivater bør kun påbegyndes, når trombocyttallet er normaliseret.
Coumarin derivatives should be initiated only when platelet counts are normalising.
For at undgå protrombotisk effekt i begyndelsen af coumarinbehandlingen, bør parenteral antikoagulationsbehandling forsættes i 4- 5 dage (se indlægsseddel for oralt antikoagulerende middel).
To avoid prothrombotic effects when initiating coumarin, continue parenteral anticoagulation for 4 to 5 days (see oral anticoagulant package insert for information).
5. 2), skal patientens nyrefunktion tages i betragtning før administrationen.
As lepirudin is almost exclusively excreted and metabolised renally (see also section 5.2), the patient’ s renal function should be considered prior to administration.
Derfor bør bolusdosen og infusionshastigheden reduceres ved kendt eller ved mistanke om nyreinsufficiens (kreatininclearance under 60 ml/ min. eller S- kreatinin over 15 mg/ l [133 µmol/ l]).
Therefore, the bolus dose and infusion rate must be reduced in case of known or suspected renal insufficiency (creatinine clearance below 60 ml/ min or creatinine value above 15 mg/ l [133 μ mol/ l]).
I kliniske forsøg er Refludan ikke blevet anvendt terapeutisk til type II HIT- patienter med væsentlig nedsat nyrefunktion.
In clinical trials, Refludan was not therapeutically administered to HIT type II patients with significant renal impairment.
De følgende dosisrekommendationer er baseret på enkelt- dosisundersøgelser på et mindre antal patienter med nedsat nyrefunktion.
The following dosage recommendations are based on single-dose studies in a small number of patients with renal impairment.
I alle andre tilfælde baseres dosisjusteringen på S- kreatinin.
In all other cases the dose adjustment is based on the creatinine value.
I alle tilfælde bør bolusdosis reduceres til 0, 2 mg / kg legemsvægt.
In any case, the bolus dose must be reduced to 0.2 mg / kg body weight.
Ekstra APTT- måling er obligatorisk.
Additional aPTT monitoring is mandatory.
Reduktion af infusionshastighed hos patienter med nedsat nyrefunktion
Reduction of infusion rate in patients with renal impairment
[ml/ mm]
Creatinine clearance [ml/ min]
[mg (μmol/ l)]
Creatinine value [mg/ l (μ mol/ l)]
[% af oprindelig dosis]
Adjusted infusion rate [% of original dose]
45 - 60 30 - 44 15 - 29
45 – 60 30 – 44 15 – 29
- 20 (141 - 177) - 30 (178 – 265) - 60 (266 - 530)
16 – 20 (141 - 177) 21 – 30 (178 - 265) 31 - 60 (266 - 530)
under 15 *
below 15*
over 6. 0 (530) *
above 60 (530)*
undgå eller AFBRYD infusionen! *
avoid or STOP infusion! *
* Hos hæmodialysepatienter eller ved akut nyresvigt (kreatininclearance under 15 ml/ min eller S - kreatinin over 6 mg [530 μmol/ l)] bør infusion af Refludan undgås eller afbrydes.
* In haemodialysis patients or in case of acute renal failure (creatinine clearance below 15 ml/ min or creatinine value above 60 mg/ l [530 μ mol/ l]), infusion of Refludan is to be avoided or stopped.
Kun såfremt APPT ligger under den øvre terapeutiske grænse (se Monitorering: målinterval), kan yderligere i. v. bolusdoser på 0, 1 mg/ kg legemsvægt hver andet døgn overvejes.
Only if aPTT values have fallen below the lower therapeutic limit (see Monitoring: target range), further intravenous bolus doses of 0.1 mg / kg body weight may be considered every other day.
Injektions - / infusionssubstansen rekonstitueres som beskrevet i afsnit 6. 6.
Reconstitute the lyophilisate as described in section 6.6.
Til intravenøs bolusdosis skal anvendes en injektionsvæske med styrken 5 mg/ ml.
For intravenous bolus injection, a solution with a concentration of 5 mg/ ml is needed.
Eksempler på standardinjektionsvolumen i forhold til legemsvægten
Examples for standard injection volume according to body weight
100
[kg] 50 60 70 80 90 100
8, 0
Dosage 0.4 mg / kg body weight 4.0 4.8 5.6 6.4 7.2 8.0
4, 0
Dosage 0.2 mg / kg body weight 2.0 2.4 2.8 3.2 3.6 4.0
≥110
≥ 110
Til kontinuerlig intravenøs infusion skal anvendes en infusionsvæske med styrken 2 mg/ ml.
For continuous intravenous infusion, a solution with a concentration of 2 mg/ ml is needed.
Eksempler på standardinfusionshastighed i forhold til legemsvægten
Examples for standard infusion speed according to body weight
Injektionsvolumen [ml/ time]
Infusion speed [ml/ h]
≥110
weight / h Dosage 0.1 mg / kg body weight / h 2.5 3.0 3.5 4.0 4.5 5.0 5.5
- Kendt hypersensitivitet over for hirudiner eller andre indholdsstoffer i Refludan
– Known hypersensitivity to lepirudin, to hirudins or to any of the excipients – Pregnancy and lactation (see section 4.6)
Lægen skal nøje afveje risikoen ved Refludan- administration mod de forventede fordele samtidig med at lægen tager højde for mulige metoder for at kontrollere blødning.
The physician should carefully weigh the risk of Refludan administration versus its anticipated benefit, taking into account possible measures to control bleeding.
Vurderingen omfatter især følgende situationer med forøgede risiko for blødning:
This particularly includes the following situations with increased bleeding risk: – Recent puncture of large vessels or organ biopsy – Anomaly of vessels or organs – Recent cerebrovascular accident, stroke, or intracerebral surgery – Severe uncontrolled hypertension – Bacterial endocarditis – Advanced renal impairment – Haemorrhagic diathesis – Recent major surgery – Recent bleeding (e. g. intracranial, gastrointestinal, intraocular, pulmonary) – Overt signs of bleeding – Recent active peptic ulcer – Age > 65 years.
- Svær ukontrolleret hypertension
4.4 Special warnings and precautions for use
Åbenlyse tegn på blødning
– Anaphylaxis:
Refludan kan fremkalde allergiske reaktioner inklusive anafylaksi og chok (se pkt.
Refludan may cause allergic reactions including anaphylaxis and shock (see section 4.8).
Behandling med Refludan bør kun startes op i et miljø, hvor medicinsk hjælp er hurtig tilgængelig, og hvor der er adgang til behandling for anafylaktiske reaktioner.
Treatment initiation with Refludan should be undertaken only in a setting where medical assistance is readily available and where there is access to treatment for anaphylactic reactions. – Patients should be informed that they have received Refludan. – In case of renal impairment relative overdose may occur even under a standard dosage regimen.
det nødvendigt at den behandlende læge nøje vurderer og overvejer risikoen ved administration kontra dens forventede fordel.
Therefore, the treating physician should carefully weigh the risk of administration versus its anticipated benefit.
2).
The rate of infusion must be reduced in case of known or suspected renal insufficiency (see sections 4.2, and 5.2). – There is no experience with lepirudin in patients with significant liver impairment.
Lever cirrhosis kan
Liver cirrhosis may also affect the renal excretion of lepirudin.
40% af patienterne med type II HIT og
Serious liver injury (e. g. liver cirrhosis) may enhance the anticoagulant effect of lepirudin due to coagulation defects secondary to reduced generation of vitamin K-dependent coagulation factors. – Formation of anti-hirudin antibodies was observed in about 40% of HIT type II patients and have been reported especially with a treatment period exceeding five days.
Dette kan resultere i en øget antikoagulerende virkning af lepirudin muligvis på grund af forsinket nyre udskillelse af aktive lepirudi- antihirudin komplekser.
This may result in an enhanced anticoagulant effect of lepirudin, possibly due to delayed renal elimination of active lepirudin-antihirudin complexes.
Der fandtes ikke tegn på neutralisation af lepirudin eller på en allergisk reaktion associeret med det positive antistoffund.
No evidence of a neutralisation of lepirudin or of an allergic reaction associated with the positive antibody test results was found. – Experience of combined therapy with thrombolytic agents in patients with HIT type II is very limited.
- Erfaring med kombinationsbehandling med trombolytika til patienter med type II HIT er meget
Since the risk of serious bleeding is considerable in this situation, the dosage of Refludan should be substantially reduced.
Da risikoen for alvorlig blødning i disse tilfælde er betragtelig, skal Refludandosis reduceres væsentligt.
The optimal dose regimen of Refludan in these circumstances is not known. – Paediatric Use:
Refludans optimale dosering under disse omstændigheder kendes ikke.
Safety and effectiveness in paediatric patients have not been established. – Elderly:
Sikkerheden og effektiviteten til behandling af pædiatriske patienter er ikke
Patients of advanced age have an increased risk of bleeding complications with anticoagulation.
Patienter af en høj alder har en forøgede risiko for blødningskomplikationer med anti -
With respect to lepirudin dosage the potential of renal impairment in elderly
koagulation.
5 patients is to be taken into account.
4. 2).
Dosing adjustments are based on renal function, weight, and aPTT (see section 4.2).
- i betydelig grad potensere Refludans virkning på APTT forlængelsen.
Concomitant treatment with thrombolytics (e. g. rt-PA or streptokinase) may – increase the risk of bleeding complications – considerably enhance the effect of Refludan on aPTT prolongation.
Samtidig behandling med − anti- blodplade stoffer udover acetylsalicylsyre, så som ticlopidin eller clopidogrel, − GpIIb/ IIIa receptor antagonister, så som eptifibatid, irofiban eller abciximab, − andre trombin inhibitorer, så som lav molekulær vægt hepariner − er ikke blevet vurderet.
Concomitant use with – antiplatelet agents other than acetylsalicylic acid, such as ticlopidine or clopidogrel, – GpIIb/ IIIa receptor antagonists such as eptifibatide, tirofiban, or abciximab, – other thrombin inhibitors such as low molecular weight heparins has not been assessed.
I en standardiseret embryo- føtal toxicitetstest observeredes nedsat overlevelse hos unger og mater.
In a standard embryo-foetal toxicity trial, decreased pup and maternal survival was observed.
Hovedparten af de bivirkninger, som patienterne fik under behandlingen med Refludan var generelt relateret til blødning (> 1/ 10).
The majority of undesirable effects experienced by patients treated with Refuldan were generally related to bleeding (> 1/ 10).
Livstruende blødningshændelser (inklusive intrakraniel blødning) blev rapporteret som ikke almindelige (≥1/ 1, 000 til < 1/ 100) hos patienter med akut koronar syndrom, der var inkluderet i kliniske studier.
Life-threatening bleeding events (including intracranial bleeding) were uncommonly reported (≥ 1/ 1,000 to < 1/ 100) in patients with acute coronary syndrome included in clinical studies.
I en intensiv post - marketingundersøgelse i HIT type II blev der rapporteret om fatal blødning hos 1% og intrakraniel blødning hos 0, 2% af patienterne
In intensified post-marketing surveillance in HIT type II, fatal bleeding was reported in 1% and intracranial bleeding in 0.2% of patients
6 Tabellen nedenfor viser de bivirkninger, der er rapporteret for Refludan:
Adverse events reported on Refuldan are shown in the table below:
Meget almindelig (> 1/ 10); Almindelig (> 1/ 100, < 1/ 10); Ikke almindelig (> 1/ 1, 000 < 1/ 100); Sjælden (> 1/ 10, 000 < 1/ 1, 000); Meget sjælden (< 1/ 10, 000)
6 Very common (> 1/ 10); Common (> 1/ 100 ,< 1/10); Uncommon (> 1/1 ,000 < 1/100); Rare (> 1/10,000 < 1/ 1,000); Very Rare (< 1/10,000)
Systemorganklasser Immunsystemet
System Organ Class Immune System Disorders
Sjælden Anafylaktiske/ oide reaktioner
Rare Anaphylactic/ oid reactions
Anæmi eller fald i hæmoglobinværdi uden tydelig blødningskilde Hæmatom Blødning fra injektionssteder Epistaksis Hæmaturia Gastrointestinal blødning Vaginalblødning Rectalblødning Pulmonal blødning Postoperativ hæmothorax Hæmopericardium Intrakraniel blødning
Anemia or drop in the haemoglobin value without obvious source of bleeding Haematoma Bleeding from puncture sites Epistaxis Haematuria Gastrointestinal bleeding Vaginal bleeding Rectal bleeding Pulmonary haemorrhage Postoperative haemothorax Haemopericardium Intracranial bleeding
Allergiske hudreaktioner (inklusive udslæt) Kløe Nældefeber Angioødem (inklusiv: ansigtsødem, tungeødem, larynksødem)
Allergic Skin Reactions (including rash) Pruritus Urticaria Angio-oedema (including: face oedema, tongue oedema, larynx oedema)
Feber Kuldegysninger Reaktioner ved injektionsstedet inklusive smerte.
Fever Chills Injection site reactions including pain.
Ved livstruende blødning og mistanke om for højt plasma- lepirudin bør følgende retningslinjer følges:
If life-threatening bleeding occurs and excessive plasma levels of lepirudin are suspected, the following recommendations should be followed: – Immediately STOP Refludan administration – Determine aPTT and other coagulation parameters as appropriate – Determine haemoglobin and prepare for blood transfusion – Follow the current guidelines for shock-therapy.
7 Enkeltpatient- rapporter og in- vitro data tyder på, at enten hæmofiltration eller hæmodialyse (her anvendes high flux dialysemembraner med et “ cut- off point ” på 50. 000 Dalton) kan være nyttig i denne situation.
Additionally, individual case reports and in-vitro data suggest that either haemofiltration or haemodialysis (using high flux dialysis membranes with a cut-off point of 50,000 Dalton) may be useful in this situation.
Undersøgelser på grise viser, at applikation af von Willebrand Factor (WF, 66 IE/ kg legemsvægt.) tydeligt reducerer blødningstiden.
7 Results from studies in pigs showed that the application of von Willebrand Factor (vWF, 66 I. U. / kg body weight) markedly reduced the bleeding time.
Antithrombosemiddel - direkte thrombininhibitor (ATC- kode:
Antithrombotic agent - direct thrombin inhibitor, ATC Code:
B01AE02)
B01AE02
Lepirudin ([Leu1, Thr2] - 63- desulfohirudin] er et rekombinant hirudin fremstillet i gærceller.
Lepirudin ([Leu1, Thr2]-63-desulfohirudin) is a recombinant hirudin derived from yeast cells.
Polypeptidet består af 65 aminosyrer og har en molekylevægt på 6979, 5 Dalton.
The polypeptide composed of 65 amino acids has a molecular weight of 6979.5 Dalton.
Naturligt hirudin dannes af iglen Hirudo medicinalis i spormængder som en gruppe af meget homologe iso - polypeptider.
Natural hirudin is produced in trace amounts as a family of highly homologous iso-polypeptides by the leech Hirudo medicinalis.
Lepirudin er en meget specifik direkte thrombin- inhibitor.
Lepirudin is a highly specific direct inhibitor of thrombin.
1 antithrombin- enhed (ATU) er den mængde hirudin, som neutraliserer 1 enhed af WHO- thrombin - standard 89/ 588.
One anti-thrombin unit (ATU) is the amount of hirudin that neutralises one unit of WHO preparation 89/ 588 of thrombin.
16. 000 ATU/ mg.
The specific activity of lepirudin is approximately 16,000 ATU/ mg.
Ét lepirudin- molekyle bindes til ét thrombin- molekyle og blokerer herved thrombins thrombogene aktivitet.
One molecule of hirudin binds to one molecule of thrombin and thereby blocks the thrombogenic activity of thrombin.
Som følge heraf påvirkes alle thrombin- afhængige koagulationsassay, fx stiger APTT dosisafhængigt.
As a result all thrombin dependent coagulation assays are affected, e. g. the aPTT values increase in a dose-dependent fashion.
Den kliniske information om type II HIT er i dette produktresumé baseret på data fra 2 prospektive kliniske afprøvninger, som i alt omfatter 198 type II HIT- patienter, der er behandlet med Refludan.
The clinical information on HIT type II in this SPC is based upon the data of two prospective trials comprising a total of 198 HIT type II patients treated with Refludan.
9%, medens amputationer og thromboemboliske komplikationer blev registreret i henholdsvis 6% og 10% af patienterne.
In the indication HIT type II with thromboembolic disease (125 patients) the overall mortality during the study period was approximately 9% while amputations and new thromboembolic complications were recorded in 6% and 10%, respectively.
Lepirudins farmakokinetiske egenskaber efter intravenøs administration beskrives tilfredsstillende som en to- kompartment model.
The pharmacokinetic properties of lepirudin following intravenous administration are well described by a two-compartment model.
10 minutter.
Distribution is essentially confined to extra-cellular fluids and is characterised by an initial half-life of approximately 10 minutes.
1, 3 timer hos unge og raske frivillige forsøgs- personer.
Elimination follows a first order process and is characterised by a terminal half-life of about 1.3 hours in young healthy volunteers.
45% af den indgivne dosis kan påvises i urinen.
Both, excretion and metabolism take place in the kidney, and about 45% of the dose administered is detectable in the urine.
35% af dosis udskilles uændret.
About 35% of the dose is excreted as unchanged compound.
Hos kvindelige patienter er den systemiske clearance ca.
The systemic clearance of lepirudin decreases in proportion to the existing glomerular filtration rate.
25% lavere end hos mandlige patienter.
In female patients the systemic clearance is about 25% lower as compared to male patients.
25% lavere end hos unge voksne.
In elderly patients the systemic clearance of lepirudin is about 25% lower as compared to younger patients.
Alder alene bevirker en 7% reduktion i clearance i aldersgruppen 30- 70 år.
Age alone causes a 7% reduction in clearance from the age of 30 to 70 years.
2 døgn.
In patients with terminal renal insufficiency prolonged elimination half-lives of about 2 days were observed.
Generel toksikologi Enkeltdoser og gentagne doser anvendt i toxicitetsstudier på mus, rotter og aber påviste de uønskede virkninger, som kunne forventes ud fra en overdreven kraftig farmakodynamisk effekt af lepirudin.
General toxicity Single and repeat-dose toxicity studies in mice, rats and monkeys showed the adverse responses that could be expected from an exaggerated pharmacodynamic impact of lepirudin.
Endvidere sås let til moderat sinushistiocytose i de regionale lymfeknuder og fald i hæmosiderindepoterne i milten hos rotter.
8 nodes and decreased haemosiderin deposits in the spleen were observed.
- Natriumhydroxid, justering til pH 7
– Mannitol – Sodium hydroxide for adjustment to pH 7
Må ikke opbevare over 25º C.
Do not store above 25°C.
Farveløst glasbeholder (glas type I) lukket med bromobutyl gummiprop, plast flip- off låg og aluminiumshætte.
Colourless glass vial (glass type I) sealed with bromobutyl rubber infusion stopper, plastic flip-off cap and aluminium cap.
- Pakning 1 hætteglas
Presentations: – Pack with 1 vial – Pack with 10 vials
- Pakning med 10 hætteglas.
Not all pack sizes may be marketed.