natgillin/translations-raw huggingface dataset:
Cyclosporin blev ikke stoppet hos patienter, som oplevede Banff Grade 3 akutte afstødelsesepisoder, som var dialyseafhængige, som havde serumkreatinin > 400 µmol/ l, eller som havde utilstrækkelig nyrefunktion til at støtte ophør med cyclosporin.
Ciclosporin was not withdrawn in patients experiencing Banff Grade 3 acute rejection episodes, who were dialysis-dependent, who had a serum creatinine > 400  mol/ l, or who had inadequate renal function to support ciclosporin withdrawal.
Patienter med stor immunologisk risiko for afstødning blev ikke undersøgt i tilstrækkeligt antal i cyclosporin elimination- Rapamune vedligeholdelsesstudiet, og dette behandlingsregimen anbefales ikke til dem.
Patients at high immunological risk of graft loss were not studied in sufficient number in the ciclosporin elimination- Rapamune maintenance trials and are not recommended for this treatment regimen.
11 I måned 12, 24 og 36 var graft - og patientoverlevelsen den samme for begge grupper.
At 12, 24 and 36 months, graft and patient survival were similar for both groups.
I måned 48 var der en statistisk signifikant forskel på graftoverlevelsen til fordel for den gruppe, som fik Rapamune efter cyclosporin- elimination, sammenlignet med den behandlingsgruppe, som fik Rapamune med cyclosporin (med og uden de patienter, som var tabt for opfølgning).
At 48 months, there was a statistically significant difference in graft survival in favour of the Rapamune following ciclosporin elimination group compared to the Rapamune with ciclosporin therapy group (including and excluding loss to follow-up).
Der var en signifikant højere frekvens af første afvisninger, der er påvist via biopsi, i gruppen med cyclosporin- elimination sammenlignet med cyclosporin- vedligeholdelsesgruppen i perioden efter randomisering og op til 12 måneder (henholdsvis 9, 8% over for 4, 2%).
4.2%, respectively).
Derefter var forskellen mellem de to grupper ikke signifikant.
Thereafter, the difference between the two groups was not significant.
Den gennemsnitlige beregnede glomerulære filtrationshastighed (GFR) i måned 12, 24, 36, 48 og 60 var signifikant større for de patienter, som fik Rapamune efter cyclosporin- elimination end hos den behandlingsgruppe, som fik Rapamune med cyclosporin.
The mean calculated glomerular filtration rate (GFR) at 12, 24, 36, 48 and 60 months was significantly higher for patients receiving Rapamune following ciclosporin elimination than for those in the Rapamune with ciclosporin therapy group.
Det blev besluttet at seponere behandlingen med Rapamune hos forsøgspersonerne i den gruppe, som også fik cyclosporin, på baggrund af analysen af data fra måned 36 og frem, som viste en større og større forskel mellem graftoverlevelse og nyrefunktion samt et signifikant lavere blodtryk hos gruppen med cyclosporin- elimination.
Based upon the analysis of data from 36 months and beyond, which showed a growing difference in graft survival and renal function, as well as significantly lower blood pressure in the ciclosporin elimination group, it was decided to discontinue subjects from the Rapamune with ciclosporin group.
Efter 60 måneder var forekomsten af cancer, som ikke var hudcancer, signifikant højere i den patientgruppe, som fortsatte med at tage cyclosporin, end i den patientgruppe, hvor cyclosporin blev seponeret (henholdsvis 8, 4% over for 3, 8%).
By 60 months, the incidence of non-skin malignancies was significantly higher in the cohort who continued ciclosporin as compared with the cohort who had ciclosporin withdrawn
I forbindelse med hudkarcinom var den gennemsnitlige tid til første forekomst signifikant forlænget.
For skin carcinoma, the median time to first occurrence was significantly delayed.
Sikkerheden ved og effekten af skift fra calcineurinhæmmere til Rapamune til vedligeholdelsesbehandling af nyretransplanterede patienter (6- 120 måneder efter transplantation) blev vurderet i et randomiseret, kontrolleret multicenterforsøg, som blev stratificeret efter beregning af den glomerulære filtrationshastighed ved baseline (20- 40 ml/ min. i forhold til > 40 ml/ min.).
The safety and efficacy of conversion from calcineurin inhibitors to Rapamune in maintenance renal transplant patients (6-120 months after transplantation) was assessed in a randomised, multicentre, controlled trial, stratified by calculated GFR at baseline (20-40 mL/ min vs > 40 mL/ min).
Samtidige immunosuppresiva omfattede mycophenolat mofetil, azathioprin og kortikosteroider.
Concomitant immunosuppressive agents included mycophenolate mofetil, azathioprine, and corticosteroids.
4. 8.).
Enrollment in the patient stratum with baseline calculated GFR < 40 mL/ min was discontinued due to an imbalance in safety events (see section 4.8).
I det patientstratum, som havde en beregnet baseline- GFR på > 40 ml/ min., var der ikke tale om en generel forbedring af nyrefunktionen.
In the patient stratum with baseline calculated GFR > 40 mL/ min, renal function was not improved overall.
Frekvenserne for akut rejektion, grafttab og død var de samme i år 1 og 2.
The rates of acute rejection, graft loss, and death were similar at 1 and 2 years.
Bivirkninger opstået under behandling opstod oftere i de første 6 måneder efter skift til Rapamune.
Treatment emergent adverse events occurred more frequently during the first 6 months after Rapamune conversion.
4. 4).
In the stratum with baseline calculated GFR > 40 mL/ min, the mean and median urinary protein to creatinine ratios were significantly higher in the Rapamune conversion group as compared to those of the calcineurin inhibitors continuation group at 24 months (see section 4.4).
4. 8).
New onset nephrosis (nephrotic syndrome) was also reported (see section 4.8).
Efter 2 år var frekvensen af nonmelanomhudcancer signifikant lavere i den gruppe, som var skiftet til Rapamune, end i den gruppe, hvor behandlingen med calcineurinhæmmere blev seponeret (1, 8% og 6, 9%).
At 2 years, the rate of non-melanoma skin malignancies was significantly lower in the Rapamune conversion group as compared to the calcineurin inhibitors continuation group (1.8% and 6.9%).
I en patientundergruppe med de patienter, som havde en baseline- GFR på > 40 ml/ min. og normal udskillelse af urinprotein, var den beregnede GFR højere ved år 1 og 2 hos de patienter, som var skiftet til Rapamune, end for den tilsvarende patientundergruppe, hvor behandlingen med calcineurinhæmmere blev seponeret.
In a subset of the study patients with a baseline GFR > 40 mL/ min and normal urinary protein excretion, calculated GFR was higher at 1 and 2 years in patients converted to Rapamune than for the corresponding subset of calcineurin inhibitor continuation patients.
Frekvenserne for akut rejektion, grafttab og død var de samme, men udskillelsen af urinprotein var forøget i behandlingsarmen for Rapamune i denne patientundergruppe.
The rates of acute rejection, graft loss, and death were similar, but urinary protein excretion was increased in the Rapamune treatment arm of this subset.
I to kliniske multicenterforsøg havde de novo nyretransplanterede patienter, som blev behandlet med Rapamune, mycophenolat mofetil, kortikosteroider og en IL- 2- receptorantagonist, en signifikant højere akut rejektionsfrekvens og en numerisk højere dødsfrekvens end de patienter, som blev behandlet med en calcineurinhæmmer, mycophenolat mofetil, kortikosteroider og en IL- 2 - receptorantagonist (se pkt.
In two multi-centre clinical studies, de novo renal transplant patients treated with Rapamune, mycophenolate mofetil (MMF), corticosteroids, and an IL-2 receptor antagonist had significantly higher acute rejection rates and numerically higher death rates compared to patients treated with a calcineurin inhibitor, MMF, corticosteroids, and an IL-2 receptor antagonist (see section 4.4).
Nyrefunktionen var ikke bedre i behandlingsarmene med de novo Rapamune uden en calcineurinhæmmer.
Renal function was not better in the treatment arms with de novo Rapamune without a calcineurin inhibitor.
Der blev anvendt en kortere doseringsplan for daclizumab i ét af forsøgene.
An abbreviated dosing schedule of daclizumab was used in one of the studies.
12 anamnesen og/ eller med tilstedeværelsen af kronisk allograftnefropati bekræftet ved nyrebiopsi.
Rapamune was assessed in a 36-month controlled clinical trial enrolling renal transplant patients  18 years of age considered at high-immunologic risk, defined as having a history of one or more acute allograft rejection episodes and/ or the presence of chronic allograft nephropathy on a renal biopsy.
Forsøgspersonerne fik Rapamune (med målkoncentrationer af sirolimus på 5 til 15 ng/ ml) i kombination med en calcineurinhæmmer og kortikosteroider, eller de fik calcineurinhæmmerbaseret immunosuppression uden Rapamune.
Subjects were to receive Rapamune (sirolimus target concentrations of 5 to 15 ng/ mL) in combination with a calcineurin inhibitor and corticosteroids or to receive calcineurin-inhibitor-based immunosuppression without Rapamune.
Det kunne ikke påvises, at behandlingen med Rapamune var bedre end den behandling, som kontrolgruppen fik, når de blev vurderet ud fra den første forekomst af biopsibekræftet akut afstødning, grafttab eller dødsfald.
The Rapamune group failed to demonstrate superiority to the control group in terms of the first occurrence of biopsy confirmed acute rejection, graft loss, or death.
Brugen af Rapamune i kombination med calcineurinhæmmere og kortikosteroider blev forbundet med en øget risiko for svækkelse af nyrefunktionen, abnorme niveauer af serumlipider (herunder, men ikke begrænset til, forhøjede niveauer af serumtriglycerider og serumkolesterol) samt urinvejsinfektioner (se afsnit 4. 8).
The use of Rapamune in combination with calcineurin inhibitors and corticosteroids was associated with an increased risk of deterioration of renal function, serum lipid abnormalities (including but not limited to increased serum triglycerides and total cholesterol), and urinary tract infections (see section 4.8).
Der blev set en uacceptabel høj frekvens af PTLD i et pædiatrisk klinisk transplantationsforsøg, når den fulde dosis Rapamune blev administreret til børn og unge som supplement til den fulde dosis calcineurinhæmmere med basiliximab og kortikosteroider (se afsnit 4. 8).
An unacceptably high frequency of PTLD was seen in a paediatric clinical transplant study when full dose Rapamune was administered to children and adolescents in addition to full dose calcineurin inhibitors with basiliximab and corticosteroids (see section 4.8).
Efter indgivelse af oral opløsning absorberes sirolimus hurtigt med en peak koncentration efter 1 time hos sunde individer, der har fået en enkelt dosis, og 2 timer hos patienter med stabile nyretransplantater, der har fået flere doser.
Following administration of the oral solution, sirolimus is rapidly absorbed, with a time to peak concentration of 1 hour in healthy subjects receiving single doses and 2 hours in patients with stable renal allografts receiving multiple doses.
Den systemiske tilgængelighed af sirolimus i kombination med samtidig administration af cyclosporin (Sandimmun) er ca.
The systemic availability of sirolimus in combination with simultaneously administered ciclosporin (Sandimune) is approximately 14%.
14%.
Upon repeated
3 gange.
13 administration, the average blood concentration of sirolimus is increased approximately 3-fold.
Eliminationshalveringstiden hos stabile nyretransplanterede patienter efter indgift af mange orale doser var 62±16h.
The terminal half-life in stable renal transplant patients after multiple oral doses was 62 16h.
Den effektive halveringstid er dog kortere og mean steady- state koncentrationer blev nået efter 5 til 7 dage.
The effective half-life, however, is shorter and mean steady-state concentrations were achieved after 5 to 7 days.
Blod til plasma ratio (B/ P) på 36 angiver, at sirolimus i meget høj grad opdeles i formede blodelementer.
The blood to plasma ratio (B/ P) of 36 indicates that sirolimus is extensively partitioned into formed blood elements.
Cmax, ss 12, 2±6, 2 ng/ ml, tmax, ss 3, 01±2, 40 h, AUC J, ss 158±70 ng. • h/ ml, CL/ F/ W 182±72 ml/ h/ kg (parametre beregnet efter LC- MS/ MS prøveresultater).
Pharmacokinetic parameters for sirolimus obtained from 19 renal transplant patients receiving microemulsion ciclosporin (4 hours prior to Rapamune) and corticosteroids, following daily doses of 2 mg Rapamune solution in a phase III clinical trial, were; Cmax, ss 12.2 6.2 ng/ ml, tmax, ss 3.01  2.40h, AUC, ss 158  70 ng h/ ml, CL/ F/ W 182 72 ml/ h/ kg (parameters calculated from LC-MS/ MS assay results).
Der var ingen signifikant forskel på nogen af disse parametre i en periode på op til 6 måneder efter transplantationen.
There was no significant difference in any of these parameters over time up to 6 months after transplantation.
4. 2).
Mean sirolimus whole blood trough levels from the same phase III trial were 7.2 ng/ ml (4.0 to 11 ng/ ml, expressed as chromatographic assay values; n=226) for the 2 mg per day dose and 14 ng/ ml (8.0 to 22 ng/ ml, expressed as chromatographic assay values; n=219) for the 5 mg per day dose (see section 4.2).
Sirolimus er et substrat for både cytochrome P450 IIIA4 (CYP3A4) og P- glycoprotein.
Sirolimus is a substrate for both cytochrome P450 IIIA4 (CYP3A4) and P-glycoprotein.
Sirolimus metaboliseres i vid udstrækning af O- demethylation og/ eller hydroxylation.
Sirolimus is extensively metabolised by O-demethylation and/ or hydroxylation.
Syv hovedmetabolitter, inkl. hydroxy, demethyl og hydroxydemethyl kan identificeres i helblod.
Seven major metabolites, including hydroxyl, demethyl, and hydroxydemethyl, are identifiable in whole blood.
Sirolimus er hovedkomponenten i humant helblod og bidrager til mere end 90% af den immunhæmmende aktivitet.
Sirolimus is the major component in human whole blood and contributes to greater than 90% of the immunosuppressive activity.
Efter en enkelt dosis [14C] sirolimus til sunde frivillige personer blev størstedelen (91%) af radioaktiviteten genfundet i fæces, og kun en mindre del (2, 2%) blev udskilt i urinen.
After a single dose of [14C] sirolimus in healthy volunteers, the majority (91.1%) of radioactivity was recovered from the faeces, and only a minor amount (2.2%) was excreted in urine.
Kliniske undersøgelser med Rapamune omfattede ikke et tilstrækkeligt antal patienter > 65 år til at kunne afgøre, om de vil respondere anderledes end yngre patienter.
Clinical studies of Rapamune did not include a sufficient number of patients > 65 years of age to determine whether they will respond differently than younger patients.
Data over laveste sirolimus blodkoncentrationer hos 35 nyretransplanterede patienter > 65 år var de samme som hos en voksenpopulation (n = 822) i alderen 18 til 65 år.
Sirolimus trough concentration data in 35 renal transplant patients > 65 years of age were similar to those in the adult population (n=822) from 18 to 65 years of age.
Hos sunde frivillige personer ændrede et måltid med højt fedtindhold karakteristikaene for biotilgængeligheden af oral flydende sirolimus.
In healthy volunteers, a high fat meal altered the bioavailability characteristics of oral liquid sirolimus.
Der var et fald på 34% i peak koncentrationen af sirolimus i blodet (Cmax), en stigning på 3, 5 gange i tid til peak koncentration (tmax) og en stigning på 35% i den samlede optagelse (AUC).
There was a 34% decrease in the peak blood sirolimus concentration (Cmax), a 3.5-fold increase in the time to peak concentration (tmax), and a 35% increase in total exposure (AUC).
Det anbefales, at Rapamune tages konsekvent enten med eller uden mad.
It is recommended that Rapamune be taken consistently either with or without food.
Anvendelse af appelsinjuice og vand til fortynding af Rapamune var ens med hensyn til Cmax og AUC.
The use of orange juice and water to dilute Rapamune were equivalent with respect to Cmax, and AUC.
Grapejuice påvirker den CYP3A4- formidlede metabolisme og skal derfor undgås.
Grapefruit juice affects CYP3A4 mediated metabolism and must therefore be avoided.
13 Hos pædiatriske patienter i dialyse (fald på 30% til 50% i det glomerulære filtreringsforhold) inden for aldersgruppen 5 til 11 år og 12 til 18 år var den gennemsnitlige vægtnormaliserede CL/ F større hos yngre pædiatriske patienter (580 ml/ h/ kg) end hos ældre pædiatriske patienter (450 ml/ h/ kg) sammenlignet med voksne (287 ml/ h/ kg).
In paediatric patients on dialysis (30% to 50% reduction in glomerular filtration rate) within age ranges of 5 to 11 years and 12 to 18 years, the mean weight-normalised CL/ F was larger for younger paediatric patients (580 ml/ h/ kg) than for older paediatric patients (450 ml/ h/ kg) as compared with adults (287 ml/ h/ kg).
Der var stor individuel variation inden for aldersgrupperne.
There was a large variability for individuals within the age groups.
Koncentrationerne af sirolimus blev målt i koncentrationskontrollerede forsøg hos pædiatriske nyretransplanterede patienter, der også fik cyclosporin og kortikosteroider.
Sirolimus concentrations were measured in concentration-controlled trials of paediatric renal-transplant patients who were also receiving ciclosporin and corticosteroids.
Målet for trough - koncentrationerne var 10- 20 ng/ ml.
The target for trough concentrations was 10-20 ng/ mL.
Ved steady state fik 8 børn i alderen 6- 11 år middel ± SD- doser på 1, 75 ± 0, 71 mg/ dag (0, 064 ± 0, 018 mg/ kg, 1, 65 ± 0, 43 mg/ m2), mens 14 unge i alderen 12- 18 år fik middel ± SD- doser på 2, 79 ± 1, 25 mg/ dag (0, 053 ± 0, 0150 mg/ kg, 1, 86 ± 0, 61 mg/ m2).
At steady state, 8 children aged 6-11 years received mean  SD doses of 1.75  0.71 mg/ day (0.064  0.018 mg/ kg, 1.65  0.43 mg/ m2) while 14 adolescents aged 12-18 years received mean  SD doses of 2.79  1.25 mg/ day (0.053  0.0150 mg/ kg, 1.86  0.61 mg/ m2).
De yngre børn havde en højere vægtnormaliseret Cl/ F (214 ml/ t. / kg) i forhold til de unge (136 ml/ t. / kg).
The younger children had a higher weight-normalized Cl/ F (214 mL/ h/ kg) compared with the adolescents (136 mL/ h/ kg).
Disse data tyder på, at yngre børn muligvis kræver højere kropsvægtsjusterede doser end unge og voksne for at opnå målkoncentrationer af tilsvarende størrelse.
These data indicate that younger children might require higher bodyweight-adjusted doses than adolescents and adults to achieve similar target concentrations.
61% og 43%, og CL/ F faldt med 33% sammenlignet med normale sunde individer.
In mild and moderate hepatically impaired patients (Child-Pugh classification A or B), mean values for sirolimus AUC and t1/ 2 were increased 61% and 43%, respectively, and CL/ F was decreased 33% compared to normal healthy subjects.
Hos patienter med svært nedsat hepatisk funktion (Child - Pugh klassifikation C) var middelværdierne for sirolimus AUC og t½ øget med henholdsvis 210% og 170%, og CL/ F var nedsat med 67% sammenlignet med normale sunde individer.
In severe hepatically impaired patients (Child-Pugh classification C), mean values for sirolimus AUC and t1/ 2 were increased 210% and 170% respectively, and CL/ F was
Den længere halveringstid hos patienter med nedsat hepatisk funktion forsinker opnåelse af steady- state.
The longer half-lives observed in hepatically impaired patients delay reaching steady state.
De farmakokinetiske egenskaber for sirolimus var de samme hos forskellige grupper med en nyrefunktion, der strækker sig fra normal til manglende (dialysepatienter).
The pharmacokinetics of sirolimus were similar in various populations with renal function ranging from normal to absent (dialysis patients).
Disse bivirkninger er ikke set i de kliniske forsøg, men de anses for at være relevante for den kliniske anvendelse: pancreas- øcelle- vacuolation, tubulær testikeldegeneration, gastrointestinale sårdannelser, knoglefrakturer og – callus, hepatisk hæmatopoiesis og pulmonær phospholipidose.
Adverse reactions not observed in clinical studies, but seen in animals at exposure levels similar to clinical exposure levels and with possible relevance to clinical use were as follows: pancreatic islet cell vacuolation, testicular tubular degeneration, gastrointestinal ulceration, bone fractures and calluses, hepatic haematopoiesis, and pulmonary phospholipidosis.
Sirolimus var ikke mutagent i in vitro bakteriel omvendt mutationsbestemmelse, kromosomafvigelsesbestemmelse i en kinesisk hamsters ovariecelle, fremadrettet mutationsbestemmelse i muselymfecelle eller in vivo mikronuklear bestemmelse i mus.
Sirolimus was not mutagenic in the in vitro bacterial reverse mutation assays, the Chinese Hamster Ovary cell chromosomal aberration assay, the mouse lymphoma cell forward mutation assay, or the in vivo mouse micronucleus assay.
Carcinogenicitetsundersøgelser udført på mus og rotter viste øget incidens af lymfomer (han - og hunmus), hepatocellulært adenom og carcinom (hanmus) og granulocytisk leukæmi (hunmus).
Carcinogenicity studies conducted in mouse and rat showed increased incidences of lymphomas (male and female mouse), hepatocellular adenoma and carcinoma (male mouse) and granulocytic leukaemia (female mouse).
Det er kendt, at maligne sygdomme (lymfom) sekundært til kronisk anvendelse af immunhæmmende midler, kan forekomme og er rapporteret hos patienter i sjældne tilfælde.
It is known that malignancies (lymphoma) secondary to the chronic use of immunosuppressive agents can occur and have been reported in patients in rare instances.
Hos mus øgedes kroniske ulcerøse hudskader.
In mouse, chronic ulcerative skin lesions were increased.
Hos rotter var testikulær, interstitiel celleadenom sandsynligvis tegn på en artsafhængig respons over for luteiniseringshormon- niveauer og betragtes normalt som værende begrænset klinisk relevant.
In rat, testicular interstitial cell adenomas were likely indicative of a species dependent response to lutenising hormone levels and are usually considered of limited clinical relevance.
I undersøgelser af reproduktionstoksicitet blev der observeret nedsat fertilitet hos hanrotter.
In reproduction toxicity studies decreased fertility in male rats was observed.
Delvist reversible reduktioner i sædtællinger blev rapporteret i et 13 uger langt rottestudie.
Partly reversible reductions in sperm counts were reported in a 13-week rat study.
Fald i testikelvægt og/ eller histologiske skader (f. eks. tubulær atrofi og tubulære gigantceller) blev observeret hos rotter og i et studie med aber.
Reductions in testicular weights and/ or histological lesions (e. g. tubular atrophy and tubular giant cells) were observed in rats and in a monkey study.
Hos rotter forårsagede sirolimus foster/ føtal toksicitet, som manifesterede sig ved død og nedsat føtal vægt (med tilhørende forsinkelse af knogledannelsen).
In rats, sirolimus caused embryo/ foetotoxicity that was manifested as mortality and reduced foetal weights (with associated delays in skeletal ossification).
4. 6.
(see section 4.6).
14 Phosal 50 PG (fosfatidylcholin, propylenglycol, mono -, diglycerider, ethanol (1, 5- 2, 5%), soja fedtsyrer og ascorbyl palmitat).
Polysorbate 80 Phosal 50 PG (phosphatidylcholine, propylene glycol, mono-, di-glycerides, ethanol (1.5% to 2.5%), soya fatty acids and ascorbyl palmitate).
6. 6.
Rapamune must not be diluted in grapefruit juice or any other liquid other than water or orange juice (see section 6.6).
Rapamune oral opløsning indeholder polysorbat- 80, som er kendt for at øge hastigheden af di - (2 - ethylhexyl) phthalat ekstraktionen fra polyvinylklorid (PVC).
Rapamune oral solution contains polysorbate-80, which is known to increase the rate of di-(2-ethylhexyl)phthalate (DEHP) extraction from polyvinyl chloride (PVC).
6. 6).
It is important to follow the instructions to administer Rapamune oral solution at once when a plastic container is used for the dilution and/ or administration (see section 6.6).
6. 3 Opbevaringstid
15 6.3 Shelf life
24 timer i doseringssprøjten (ved stuetemperatur, må dog ikke overstige 25°C).
24 hours in the dosing syringe (at room temperature, but not to exceed 25 C).
6. 6) skal opløsningen anvendes umiddelbart.
After dilution, (see section 6.6) the preparation should be used immediately.
Opbevares i køleskab (2°C – 8°C).
Store in a refrigerator at 2 C - 8  C.