natgillin/translations-raw huggingface dataset:
Hæmatologiske bivirkninger De hyppigst rapporterede bivirkninger, der blev relateret til behandling med azacitidin, var hæmatologiske, herunder trombocytopeni, neutropeni og leukopeni.
Haematologic adverse reactions The most commonly reported adverse reactions associated with azacitidine treatment were haematological including thrombocytopenia, neutropenia and leukopenia, and were usually Grade 3 or 4.
Der var størst risiko for, at disse bivirkninger opstod i løbet af de første 2 behandlingscyklusser.
There is a greater risk of these events occurring during the first 2 cycles, after which they occur with less frequency in patients with restoration of haematological function.
De fleste hæmatologiske bivirkninger blev håndteret ved hjælp af rutinemæssig monitorering af relevante hæmatologiske laboratorietal kombineret med udsættelse af administrationen af azacitidin til den næste cyklus, profylaktiske antibiotika og/ eller understøttende vækstfaktorer (f. eks.
Most haematological adverse reactions were managed by routine monitoring of complete blood counts and delaying azacitidine administration in the next cycle, prophylactic antibiotics and/ or growth factor support (e. g.
G- CSF) mod neutropeni samt transfusioner mod anæmi eller trombocytopeni, efter behov.
G-CSF) for neutropenia and transfusions for anaemia or thromobocytopenia as required.
Infektioner Myelosuppression kan føre til neutropeni og forøget infektionsrisiko.
Infections Myelosupression may lead to neutropenia and an increased risk of infection.
Alvorlige bivirkninger, så som neutropen sepsis (0, 8%) og pneumoni (2, 5%), blev rapporteret hos patienter, der modtog azacitidin.
Serious adverse reactions such as neutropenic sepsis (0.8%) and pneumonia (2.5%) were reported in patients receiving azacitidine.
Infektioner kan håndteres med anvendelse af anti- infektionsmidler samt understøttende behandling med vækstfaktorer (f. eks.
Infections may be managed with the use of anti-infectives plus growth factor support (e. g.
G- CSF) mod neutropeni.
G-CSF) for neutropenia.
Blødning Der kan forekomme blødninger hos patienter, der får azacitidin.
Bleeding Bleeding may occur with patients receiving azacitidine.
Alvorlige bivirkninger, så som gastrointestinal blødning (0, 8%) og intrakraniel blødning (0, 5%), er blevet rapporteret.
Serious adverse reactions such as gastrointestinal haemorrhage (0.8%) and intracranial haemorrhage (0.5%) have been reported.
Patienter bør monitoreres for objektive tegn og for symptomer på blødning - især patienter, som har forudgående eller behandlingsrelateret trombocytopeni.
Patients should be monitored for signs and symptoms of bleeding, particularly those with pre-existing or treatment-related thrombocytopenia.
Overfølsomhed Der er rapporteret alvorlige overfølsomhedsreaktioner (0, 25%) hos patienter, der får azacitidin.
Hypersensitivity Serious hypersensitivity reactions (0.25%) have been reported in patients receiving azacitidine.
I tilfælde af en anafylaktisk- lignende reaktion bør behandlingen med azacitidin øjeblikkeligt seponeres, og en passende symptomatisk behandling indledes.
In case of an anaphylactic-like reaction, treatment with azacitidine should be immediately discontinued and appropriate symptomatic treatment initiated.
7 Bivirkninger i hud og subkutant væv Størstedelen af bivirkningerne i hud og subkutant væv kunne henføres til injektionsstedet.
Skin and subcutaneous tissue adverse reactions The majority of skin and subcutaneous adverse reactions were associated with the injection site.
I det pivotale studie førte ingen af disse bivirkninger til midlertidig seponering, permanent seponering eller dosisreduktion af azacitidin.
None of these adverse reactions led to temporary or permanent discontinuation of azacitidine, or reduction of azacitidine dose in the pivotal study.
Størstedelen af bivirkningerne opstod i løbet af de første 2 behandlingscyklusser og havde tendens til at aftage i de efterfølgende cyklusser.
7 2 cycles and tended to decrease with subsequent cycles.
Subkutane bivirkninger, som f. eks. udslæt/ inflammation/ pruritus på injektionsstedet, udslæt, erytem og hudlæsion, kan kræve samtidig behandling med andre lægemidler, som f. eks. antihistaminer, kortikosteroider og non- steroide antiinflammatoriske lægemidler (NSAID).
Subcutaneous adverse reactions such as injection site rash/ inflammation/ pruritus, rash, erythema and skin lesion may require management with concomitant medicinal products, such as antihistamines, corticosteroids and non-steroidal anti- inflammatory drugs (NSAIDs).
Bivirkninger i mave- tarm- kanalen De hyppigst rapporterede bivirkninger i mave- tarm- kanalen relateret til azacitidinbehandling inkluderede konstipation, diarré, kvalme og opkastning.
Gastrointestinal adverse reactions The most commonly reported gastrointestinal adverse reactions associated with azacitidine treatment included constipation, diarrhoea, nausea and vomiting.
Disse bivirkninger blev behandlet symptomatisk med antiemetika mod kvalme og opkastning, anti- diarré midler mod diarré og laksantia og/ eller blødgørende afføringsmidler mod konstipation.
These adverse reactions were managed symptomatically with anti-emetics for nausea and vomiting; antidiarrhoeals for diarrhoea, and laxatives and/ or stool softeners for constipation.
290 mg/ m2, hvilket er næsten 4 gange den anbefalede startdosis.
A patient experienced diarrhoea, nausea, and vomiting after receiving a single intravenous dose of approximately 290 mg/ m2, almost 4 times the recommended starting dose.
Antineoplastisk middel, pyrimidin- analog; ATC- kode:
Antineoplastic agent, Pyrimidine analogues; ATC code:
Virkningsmekanisme Det vurderes, at Azacitidin udøver sine antineoplastiske virkninger ved flere mekanismer, herunder cytotoksicitet på abnorme hæmatopoietiske celler i knoglemarven og hypometylering af DNA.
Mechanism of action Azacitidine is believed to exert its antineoplastic effects by multiple mechanisms including cytotoxicity on abnormal haematopoietic cells in the bone marrow and hypomethylation of DNA.
Azacitidins cytotoksiske virkninger kan forklares ud fra flere mekanismer, herunder hæmning af DNA -, RNA - og proteinsyntese, inkorporering i RNA og DNA og aktivering af mekanismer, der fører til DNA- skade.
The cytotoxic effects of azacitidine may result from multiple mechanisms, including inhibition of DNA, RNA and protein synthesis, incorporation into RNA and DNA, and activation of DNA damage pathways.
Non- prolifererende celler er relativt ufølsomme over for azacitidin.
Non-proliferating cells are relatively insensitive to azacitidine.
Inkorporering af azacitidin i DNA resulterer i inaktivering af DNA- metyltransferaser, hvilket fører til hypometylering af DNA.
Incorporation of azacitidine into DNA results in the inactivation of DNA methyltransferases, leading to hypomethylation of DNA.
DNA- hypometylering af afvigende metylerede gener, der er involveret i regulering af normal cellecyklus, differentiering og celledød, kan resultere i reekspression af genet og genopretning af cancersupprimerende funktioner til cancerceller.
DNA hypomethylation of aberrantly methylated genes involved in normal cell cycle regulation, differentiation and death pathways may result in gene re-expression and restoration of cancer- suppressing functions to cancer cells.
Det er ikke fastlagt, hvordan vægtningen af azacitidins forskellige effekter på henholdsvis DNA- hypometylering, cytotoksicitet og andre virkninger kan relateres til de kliniske resultater.
The relative importance of DNA hypomethylation versus cytotoxicity or other activities of azacitidine to clinical outcomes has not been established.
Klinisk virkning og sikkerhed Vidazas virkning og sikkerhed blev undersøgt i et international, kontrolleret, open- label, randomiseret, komparativ, parallel- gruppe, fase 3- multicenterstudie (AZA PH GL 2003 CL 001) hos patienter med: intermediær- 2 og højrisiko MDS i henhold til International Prognostic Scoring System (IPSS), refraktær anæmi med overskud af blaster (RAEB), refraktær anæmi med overskud af blaster i transformation (RAEB- T) og modificeret kronisk myelomonocytleukæmi (mCMML) i henhold til French American British - (FAB -) klassifikationen.
Clinical efficacy and safety The efficacy and safety of Vidaza were studied in an international, multicenter, controlled, open-label, randomised, parallel-group, Phase 3 comparative study (AZA PH GL 2003 CL 001) in patients with: intermediate-2 and high-risk MDS according to the International Prognostic Scoring System (IPSS), refractory anaemia with excess blasts (RAEB), refractory anaemia with excess blasts in transformation (RAEB-T) and modified chronic myelomonocytic leukaemia (mCMML) according to the French American British (FAB) classification system.
RAEB- T- patienter (21- 30% blaster) anses nu for at være AML- patienter i henhold til den gældende WHO- klassifikation.
RAEB-T patients (21-30% blasts) are now considered to be AML patients under the current WHO classification system.
Patienter blev udvalgt forud af deres læge til 1 af de 3 CCR’ er inden randomiseringen.
Patients were pre-selected by their physician to 1 of the 3 CCR prior to randomisation.
8 Patienterne fik dette forud valgte regime, hvis de ikke blev randomiseret til Vidaza.
Patients received this pre-selected regimen if not randomised to Vidaza.
Som en del af inklusionskriterierne var det påkrævet, at patienterne skulle have en performancestatus på 0- 2 i henhold til Eastern Cooperative Oncology Group (ECOG).
As part of the inclusion criteria, patients were required to have an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2.
Vidaza blev administreret ved en subkutan dosis på 75 mg/ m2 dagligt i 7 dage, efterfulgt af en hvileperiode på 21 dage (28 dages behandlingscyklus) i en median på 9 cyklusser (range = 1- 39) og et gennemsnit på 10, 2 cyklusser.
Vidaza was administered at a subcutaneous dose of 75 mg/ m2 daily for 7 days, followed by a rest period of 21 days (28-day treatment cycle) for a median of 9 cycles
Medianalderen inden for "Intent to Treat" - populationen (ITT) var 69 år (range fra 38 til 88 år).
Within the Intent to Treat population (ITT), the median age was 69 years (range 38 to 88 years).
Dette er en forskel på 9, 4 måneder med en stratificeret log- rank p- værdi på 0, 0001.
In the ITT analysis of 358 patients (179 azacitidine and 179 CCR), Vidaza treatment was associated with a median survival of 24.46 months versus 15.02 months for those receiving CCR treatment, a difference of 9.4 months, with a stratified log-rank p-value of 0.0001.
Hazard ratio for behandlingseffekten, var 0, 58 (95% CI:
The hazard ratio for the treatment effect was 0.58 (95% CI:
To- års overlevelsesraterne var 50, 8% hos patienter, der fik azacitidin kontra 26, 2% for patienter, der fik CCR (p < 0, 0001).
The two-year survival rates were 50.8% in patients receiving azacitidine versus 26.2% in patients receiving CCR (p < 0.0001).
0, 43- 0, 77] Dødsfald:
0.43-0.77] Deaths:
AZA = 82, CCR = 113 Andel, der overlevede
AZA = 82, CCR = 113 Proportion Surviving
Tid (måneder) fra randomisering antal med risiko
Time (months) from Randomization # at risk
NØGLE:
KEY:
AZA = azacitidin; CCR = konventionelle behandlingsregimer (conventional care regimens); CI = konfidensinterval; HR = hazard ratio
AZA = azacitidine; CCR = conventional care regimens; CI = confidence interval; HR = hazard ratio
Overlevelsesgevinsten ved Vidaza var konsekvent, uanset hvilken CCR- behandlingsoption (BSC alene, lavdosis cytarabin plus BSC eller standard induktionskemoterapi plus BSC), der blev anvendt i kontrolgruppen.
The survival benefits of Vidaza were consistent regardless of the CCR treatment option (BSC alone, low-dose cytarabine plus BSC or standard induction chemotherapy plus BSC) utilised in the control arm.
Behandling med Vidaza var associeret med en median tid til dødsfald eller transformation til AML på 13, 0 måneder kontra 7, 6 måneder for de patienter, der fik CCR- behandling, hvilket er en forbedring på 5, 4 måneder med en stratificeret log- rank p- værdi på 0, 0025.
Vidaza treatment was associated with a median time to death or transformation to AML of 13.0 months versus 7.6 months for those receiving CCR treatment, an improvement of 5.4 months with a stratified log-rank p-value of 0.0025.
Behandling med Vidaza førte til et reduceret behov for transfusioner med røde 9 blodlegemer (RBC) og trombocytter.
Vidaza treatment led to a reduced need for red blood cell (RBC) and platelet transfusions.
Af de patienter i azacitidingruppen, som var afhængige af transfusion af røde blodlegemer ved baseline, blev 45, 0% uafhængige af transfusion med røde blodlegemer under behandlingsperioden, sammenlignet med 11, 4% af patienterne i den kombinerede CCR- gruppe (en statistisk signifikant (p < 0, 0001) forskel på 33, 6% (95% CI:
Of the patients in the azacitidine group who were RBC transfusion dependent at baseline, 45.0% of these patients became RBC transfusion independent during the treatment period, compared with 11.4% of the patients in the combined CCR groups (a statistically significant (p < 0.0001) difference of 33.6% (95% CI:
Responsen blev vurderet af investigatoren eller af den uafhængige evalueringskomité (Independent Review Committee, IRC).
9 Response was assessed by the investigator or by the Independent Review Committee (IRC).
Samlet respons (komplet remission [CR] + partiel remission [PR], som fastlagt af investigatoren, var 29% i azacitidingruppen og 12% i den kombinerede CCR- gruppe (p = 0, 0001).
Overall response (complete remission [CR] + partial remission [PR]) as determined by the investigator was 29% in the azacitidine group and 12% in the combined CCR group (p = 0.0001).
Samlet respons (CR + PR), som fastlagt af den uafhængige evalueringskomité (IRC) i undersøgelsen AZA PH GL 2003 CL 001, var 7% (12/ 179) i azacitidingruppen sammenlignet med 1% (2/ 179) i den kombinerede CCR- gruppe (p = 0, 0113).
Overall response (CR + PR) as determined by the IRC in AZA PH GL 2003 CL 001 was 7% (12/ 179) in the azacitidine group compared with 1% (2/ 179) in the combined CCR group (p = 0.0113).
Forskellene mellem IRC’ er og investigatorens vurderinger af respons var en konsekvens af kriterierne i den internationale arbejdsgruppe (International Working Group, IWG), som kræver forbedring i perifere blodtællinger og opretholdelse af disse forbedringer i mindst 56 dage.
The differences between the IRC and investigator assessments of response were a consequence of the International Working Group (IWG) criteria requiring improvement in peripheral blood counts and maintenance of these improvements for a minimum of 56 days.
En overlevelsesfordel blev ligeledes påvist hos patienter, som ikke havde opnået et komplet/ partielt respons efter behandling med azacitidin.
A survival benefit was also demonstrated in patients that had not achieved a complete/ partial response following azacitidine treatment.
Hæmatologisk forbedring (større eller mindre), som fastlagt af den uafhængige evalueringskomité (IRC), blev opnået hos 49% af de patienter, som fik azacitidin, sammenlignet med 29% af de patienter, som blev behandlet med kombineret CCR (p < 0, 0001).
Haematological improvement (major or minor) as determined by the IRC was achieved in 49% of patients receiving azacitidine compared with 29% of patients treated with combined CCR (p < 0.0001).
Hos patienter med en eller flere cytogenetiske anomalier ved baseline var procentdelen af de patienter, som opnåede større cytogenetisk respons, ens i azacitidingruppen og den kombinerede CCR- gruppe.
In patients with one or more cytogenetic abnormalities at baseline, the percentage of patients with a major cytogenetic response was similar in the azacitidine and combined CCR groups.
Mindre cytogenetisk respons var statistisk signifikant (p = 0, 0015) højere i azacitidingruppen (34%) sammenlignet med den kombinerede CCR- gruppe (10%).
Minor cytogenetic response was statistically significantly (p = 0.0015) higher in the azacitidine group (34%) compared with the combined CCR group (10%).
Azacitidins farmakokinetiske egenskaber blev undersøgt efter enkeltdoser med 75 mg/ m2 subkutan og intravenøs administration.
The pharmacokinetics of azacitidine were studied following single 75 mg/ m2 doses given by subcutaneous and intravenous administration.
Absorption Azacitidin blev hurtigt absorberet efter subkutan administration med peak- plasma - azacitidinkoncentrationer på 750 ± 403 ng/ ml ved 0, 5 t (det første prøvetagningstidspunkt) efter dosering.
Absorption Azacitidine was rapidly absorbed after subcutaneous administration with peak plasma azacitidine concentrations of 750 ± 403 ng/ ml occurring at 0.5 h (the first sampling point) after dosing.
89% baseret på arealet under kurven (AUC).
The absolute bioavailability of azacitidine after subcutaneous relative to intravenous administration was approximately 89% based on area under the curve (AUC).
Distribution Efter intravenøs administration var det gennemsnitlige distributionsvolumen 76 ± 26 l og systemisk clearance var 147 ± 47 l/ t.
Distribution Following intravenous administration, the mean volume of distribution was 76 ± 26 l, and systemic clearance was 147 ± 47 l/ h.
Metabolisme På baggrund af in vitro- data ser azacitidinmetabolismen ikke ud til at være medieret af cytokrom - P450- isoenzymer (CYP’ er), UDP- glucuronosyltransferaser (UGT’ er), sulfotransferaser (SULT’ er) eller glutathiontransferaser (GST’ er).
Metabolism Based on in vitro data, azacitidine metabolism does not appear to be mediated by cytochrome P450 isoenzymes (CYPs), UDP-glucuronosyltransferases (UGTs), sulfotransferases (SULTs), and glutathione transferases (GSTs).
Azacitidins metabolisme sker ved spontan hydrolyse og ved deaminering medieret af cytidindeaminase.
Metabolism of azacitidine is by spontaneous hydrolysis and by deamination mediated by cytidine deaminase.
I S9- fraktioner fra human lever var dannelsen af metabolitter uafhængig af NADPH, hvilket antyder, at metabolisme vil blive katalyseret af cytosole enzymer.
In human liver S9 fractions, formation of metabolites was independent of NADPH implying any metabolism would be catalysed by cytosolic enzymes.
30 gange højere end klinisk tilgængelige koncentrationer).
In vitro studies of azacitidine with cultured human hepatocytes indicate that at concentrations of 1.0 µM to 100 µM (i. e. up to approximately 30-fold higher than clinically achievable concentrations), azacitidine does not induce cytochrome P450 isoenzymes (CYP) 1A2, 2C19, or 3A4 or 3A5.
I en undersøgelse til vurdering af hæmning af P450- isozymer (CYP 1A2, 2C9, 2C19, 2D6, 2E1 og 3A4) inkuberet ved 100 µM azacitidin, kunne der ikke fastlægges IC50- værdier, og derfor er enzymhæmning pga. azacitidin ved klinisk opnåelige plasmakoncentrationer usandsynlig.
In a study to assess inhibition of a series of P450 isoenzymes (CYP 1A2, 2C9, 2C19, 2D6, 2E1 and 3A4) incubated with 100 µM azacitidine, IC50 values could not be determined, therefore, enzyme inhibition by azacitidine at clinically achievable plasma concentrations is unlikely.
Potentialet for at hæmme CYP2B6 eller 2C8 er ikke blevet undersøgt.
The potential to inhibit CYP2B6 or 2C8 has not been studied.
10 Udskillelse Azacitidin udskilles hurtigt fra plasma med en gennemsnitlig elimineringshalveringstid (t½) efter subkutan administration på 41 ± 8 minutter.
Excretion Azacitidine is cleared rapidly from plasma with a mean elimination half-life (t½) after subcutaneous administration of 41 ± 8 minutes.
Urinudskillelse er den primære elimineringsvej for azacitidin og/ eller dets metabolitter.
Urinary excretion is the primary route of elimination of azacitidine and/ or its metabolites.
Efter intravenøs og subkutan administration af 14C- azacitidin, blev 50- 85% af den administrerede radioaktivitet genfundet i urin, mens < 1% blev genfundet i fæces.
Following intravenous and subcutaneous administration of 14C-azacitidine, 50-85% of the administered radioactivity was recovered in urine, while < 1% was recovered in faeces.
4. 2), køn, alder eller race på azacitidins farmakokinetiske egenskaber er ikke blevet formelt undersøgt.
10 Special populations The effects of renal or hepatic impairment (see section 4.2), gender, age, or race on the pharmacokinetics of azacitidine have not been formally studied.
Farmakogenomik Virkningen af kendte cytidindeaminase- polymorfismer på metabolismen af azacitidin er ikke formelt undersøgt.
Pharmacogenomics The effect of known cytidine deaminase polymorphisms on azacitidine metabolism has not been formally investigated.
En tumorgenicitets- undersøgelse hos rotter afslørede en øget incidens af testikeltumorer.
A tumorigenicity study in rats revealed an increased incidence of testicular tumours.
Tidlige embryotoksicitetsundersøgelser hos mus afslørede en frekvens på 44% af intrauterin embryo - død (øget resorption) efter en intraperitoneal enkeltinjektion af azacitidin under organogenesen.
Early embryotoxicity studies in mice revealed a 44% frequency of intrauterine embryonal death (increased resorption) after a single intraperitoneal injection of azacitidine during organogenesis.
Azacitidin forårsagede ingen bivirkninger hos rotter, når det blev givet præ- implantation, men det var klart embryotoksisk, når det blev givet under organogenesen.
In rats, azacitidine caused no adverse effects when given pre-implantation, but it was clearly embryotoxic during when given during organogenesis.
Fosteranomalier, der blev forårsaget under organogenesen, omfattede:
Foetal abnormalities caused during organogenesis included:
Anomalier i centralnervesystemet (exencefali, encephalocele), ekstremitetsanomalier (mikromeli, klumpfod, syndaktyli, oligodaktyli) og andre (mikrognati, gastroschise, ødem og ribbensanomalier).
CNS anomalies (exencephaly/ encephalocele), limb anomalies (micromelia, club foot, syndactyly, oligodactyly) and others (micrognathia, gastroschisis, oedema, and rib abnormalities).
4. 4).
Treatment of male rats resulted in decreased weight of the testes and epididymides, decreased sperm counts, decreased pregnancy rates, an increase in abnormal embryos and increased loss of embryos in mated females (see section 4.4).
Uåbnet hætteglas med pulver:
Unopened powder vial:
11 Det rekonstituerede lægemiddels kemiske og fysiske stabilitet under brug er blevet påvist ved 25 °C i 45 minutter og ved 2 °C- 8 °C i 8 timer.
Chemical and physical in-use stability of the reconstituted medicinal product has been demonstrated at 25°C for 45 minutes and at 2°C to 8°C for 8 hours.
Hvis det ikke anvendes øjeblikkeligt, er opbevaringstider og opbevaringsforhold efter rekonstitution og inden anvendelse brugerens ansvar og må ikke overstige 8 timer ved 2 °C- 8 °C.
If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and must not be longer than 8 hours at 2°C to 8°C.
Farveløst, 30 ml- hætteglas, type I, lukket med butylelastomerprop og aluminumsforsegling med polypropylenplasticknap.
Colourless type I 30 ml glass vial sealed with butyl elastomeric stopper and aluminium seal with polypropylene plastic button.
1 hætteglas med 100 mg azacitidin.
1 vial of 100 mg azacitidine.
Anbefalinger for sikker håndtering Vidaza er et cytotoksisk lægemiddel, og som det er tilfældet med andre potentielt toksiske stoffer, bør der udvises forsigtighed ved håndtering og klargøring af azacitidinsuspensioner.
Recommendations for safe handling Vidaza is a cytotoxic medicinal product and, as with other potentially toxic compounds, caution should be exercised when handling and preparing azacitidine suspensions.
Der skal anvendes procedurer for korrekt håndtering og destruktion af anticancer- lægemidler.
Procedures for proper handling and disposal of anticancer medicinal products should be applied.
Rekonstitutionsprocedure 1.
Reconstitution procedure 1.
Hætteglas med azacitidin; hætteglas med vand til injektionsvæske; usterile undersøgelseshandsker;
Vial(s) of azacitidine; vial(s) of water for injections; nonsterile surgical gloves; Alcohol wipes; 5 ml injection syringe(s) with needle(s).
Træk 4
4 ml of trapped
ml vand til injektionsvæske op i sprøjten og sørg for at tømme evt. luft ud af sprøjten.
water for injections should be drawn into the syringe, making sure to purge any air within the syringe.