natgillin/translations-raw huggingface dataset:
Studiets primære endepunkt var varigt tumor- og symptomatisk respons, defineret som tumorrespons vurderet ved uvildig gennemgang og komplet resolution eller stabilisering af prospektivt indsamlede symptomer på MCD i mindst 18 uger uden behandlingssvigt.
The primary endpoint of the study was durable tumour and symptomatic response, defined as tumour response assessed by independent review and complete resolution or stabilisation of prospectively collected MCD symptoms, for at least 18 weeks without treatment failure.
Et åbent, ikke-randomiseret fase 2-multicenterstudie vurderede sikkerhed og virkning ved længerevarende behandling med siltuximab hos 60 patienter med MCD, som tidligere havde deltaget i studie 1 (41 patienter) eller studie 2 (19 patienter).
An open-label, multicentre, non-randomised Phase 2 study assessed the safety and efficacy of extended treatment with siltuximab in 60 patients with MCD who were previously enrolled in Study 1 (41 patients) or Study 2 (19 patients).
Hæmoglobinrespons defineredes som en ændring fra baseline på ≥ 15 g/l (0,9 mmol/l) i uge 13.
Haemoglobin response was defined as a change from baseline of ≥ 15 g/L (0.9 mmol/L) at Week 13.
Inspicer hætteglassene for partikelindhold og misfarvning før tilberedning af dosis.
Inspect the vials for particulate matter and discolouration prior to dose preparation.
De vigtigste resultater for virkning fra studie 1 fremgår af tabel 3.
Key efficacy results from Study 1 are summarised in Table 3.
• Aktivt stof: siltuximab.
• The active substance is siltuximab.
• Den anbefalede dosis er 11 mg pr. kg legemsvægt, der gives en gang hver 3. uge.
• The recommended dose is 11 milligrams per kilogram of body weight, given once every
Infusionen skal afsluttes inden for 6 timer efter tilsætning af den rekonstituerede opløsning til infusionsposen.
The infusion should be completed within 6 hours of the addition of the reconstituted solution to the infusion bag.
Tegn omfatter: hoste, influenzalignende symptomer, utilpashed, rød eller varm hud, feber.
Signs include: cough, flu-like symptoms, feeling unwell, red or hot skin, fever.
Siltuximab (9,2 og 46 mg/kg/uge) medførte ikke toksicitet i reproduktionsorganerne hos cynomolgusaber.
Siltuximab (9.2 and 46 mg/kg/week) did not produce any toxicity of the reproductive tract in cynomolgus monkeys.
Gennem binding til IL6 blokerer siltuximab dets aktivitet og stopper unormal cellevækst.
By binding to IL-6, siltuximab blocks its activity and stops abnormal cell growth.
• hvis du har en sygdom som f.eks. et mavesår eller betændelse i en eller flere divertikler (divertikulitis), der kan øge risikoen for at få en rift i din mave eller tarm (gastrointestinal perforering).
• you have a condition such as stomach ulcer or diverticulitis that may increase the risk of getting a tear in the stomach or gut (gastrointestinal perforation).
Den procentvise ændring fra baseline i MCD-relaterede symptomer og den samlede symptomscore relateret til sygdommen for hver behandlingscyklus blev beregnet.
The percent change from baseline in MCD-related signs and symptoms and MCD-related overall symptom score at each cycle was calculated.
Symptomer relateret til MCD blev indsamlet prospektivt.
MCD-related signs and symptoms were prospectively collected.
Overproduktion af IL-6 i kroniske inflammatoriske sygdomme og maligniteter er sat i forbindelse med anæmi og kakeksi og der er fremsat en hypotese om, at det spiller en central rolle ved fremning af proliferation af plasmaceller og systemiske manifestationer hos patienter med CD.
Overproduction of IL-6, in chronic inflammatory diseases and malignancies has been linked to anaemia and cachexia and has been hypothesised to play a central role in driving plasma cell proliferation and systemic manifestations in patients with CD.
Siltuximabs immunogenicitet blev evalueret ved hjælp af metoderne antigen-bridging enzym-immunoassay (EIA) og elektrokemiluminiscens- (ECL-) baseret immunoassay (ECLIA).
The immunogenicity of siltuximab has been evaluated using antigen-bridging enzyme immunoassay (EIA) and electrochemiluminescence (ECL)-based immunoassay (ECLIA)
Det er veldokumenteret, at IL-6 stimulerer eksprimering af C-reaktivt protein (CRP) i akutfasen.
It is well established that IL-6 stimulates the acute-phase expression of C-reactive protein (CRP).
(IR; IR)b
(N/A; N/A)b
• SYLVANT udleveres i et hætteglas af glas, der indeholder et hvidt pulver til koncentrat til infusionsvæske, opløsning (pulver til koncentrat).
• SYLVANT is supplied as a glass vial containing a white powder for concentrate for solution for infusion (powder for concentrate).
Symptomerne på denne sygdom kan omfatte træthed, natlige svedudbrud, en prikkende fornemmelse og manglende appetit.
Symptoms of this disease may include feeling tired, sweating at night, having a tingling feeling, and loss of appetite.
Den ordinerende læge bør også udvise forsigtighed ved samtidig administration af siltuximab og lægemidler, der er substrater for CYP3A4, hvis en nedsættelse af virkningen ville være uønsket (f.eks. orale kontraceptiva).
Prescribers should also exercise caution when siltuximab is co-administered with medicinal products that are CYP3A4 substrates where a decrease in effectiveness would be undesirable (e.g., oral contraceptives).
* Bedste understøttende behandling a 95 % konfidensinterval for forskellen i procentdele b IR = “Ikke relevant”, der var ingen respondere, hvorfor 95 % CI ikke er relevant c 95 % konfidensinterval for hazard ratio d Fuldstændigt symptomatisk respons defineres som 100 % reduktion i den samlede symptomscore for MCD ved baseline, der blev opretholdt i mindst 18 uger før behandlingssvigt
* Best Supportive Care a 95% confidence interval for the for the difference in proportions b N/A = “Not applicable”, there were no responders therefore 95% CI is not applicable c 95% confidence interval for the hazard ratio d Complete symptomatic response is defined as a 100% reduction in the baseline MCD overall symptom score sustained for at least 18 weeks prior to treatment failure
Behandlingen med SYLVANT bør pauseres, hvis patienten har en svær infektion eller en svær ikke-hæmatologisk bivirkning, og den kan genoptages med samme dosis, når patienten er kommet sig.
The SYLVANT therapy should be withheld if the patient has a severe infection or any severe non-haematological toxicity and can be restarted at the same dose after recovery.
I overensstemmelse med halveringstiden efter den første dosis nåede serumkoncentrationer steady state ved den sjette infusion (med 3 ugers interval) med gennemsnitlige (± SD) maksimale og bundkoncentrationer på henholdsvis 332 ± 139 og 84 ± 66 mikrog/ml.
Consistent with half-life after the first dose, serum concentrations reached steady-state levels by the sixth infusion (intervals every 3 weeks) with mean (± SD) peak and trough concentrations of 332 ± 139 and 84 ± 66 mcg/mL, respectively.
Der er rapporteret gastrointestinal (GI) perforering med siltuximab i kliniske studier, omend ikke i studier af MCD.
Gastrointestinal (GI) perforation has been reported in siltuximab clinical trials although not in MCD trials.
Siltuximabs populationsfarmakokinetik blev analyseret for at evaluere virkningerne af demografiske kendetegn.
The population PK of siltuximab were analysed to evaluate the effects of demographic characteristics.
I kliniske studier blev siltuximab associeret med en infusionsrelaret reaktion eller overfølsomhedsreaktion hos 5,1 % (svær reaktion hos 0,8 %) af de patienter, der fik siltuximab som monoterapi.
In clinical studies, siltuximab was associated with an infusion related reaction or hypersensitivity reaction in 5.1% (severe reaction in 0.8%) of patients treated with siltuximab monotherapy.
Siltuximabs påvirkning af fertilitet er ikke evalueret hos mennesket.
Effects of siltuximab on fertility have not been evaluated in humans.
Det skal besluttes, om amning skal ophøre eller behandling med siltuximab seponeres, idet der tages højde for fordelene ved amning for barnet i forhold til de terapeutiske fordele for moderen.
A decision must be made whether to discontinue breast-feeding or discontinue/abstain from siltuximab therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.
Indehaveren af markedsføringstilladelsen skal fremsende data i tabelform til CHMP hver 12. måned i lighed med cyklus for fremsendelse af periodiske, opdaterede sikkerhedsberetninger (PSUR'er), og tabellen må kun omfatte data for de patienter, der er kandidater til behandling med siltuximab.
The MAH should provide tabulated data to the CHMP every 12 months in line with the periodic safety update report (PSUR) cycle including data for only those patients who are candidates for treatment with siltuximab.
IL-6 har vist sig at være involveret i forskellige normale fysiologiske processer såsom induktion af produktion af immunoglobulin, initiering af akutfase proteinsyntese i leveren og stimulering af den hæmatopoietiske prækursor for cellevækst og -differentiering.
IL-6 has been shown to be involved in diverse normal physiologic processes such as induction of immunoglobulin secretion, initiation of hepatic acute phase protein synthesis, and stimulation of hematopoietic precursor cell proliferation and differentiation.
Siltuximab virker gennem neutralisering af IL-6-bioaktivitet, som kan måles indirekte ved suppression af CRP.
The mechanism of action of siltuximab is neutralisation of IL-6 bioactivity, which can be measured indirectly by suppression of CRP.
Under intravenøs infusion af SYLVANT kan der opnås bedring af lette til moderate infusionsreaktioner, hvis infusionen gives langsommere eller stoppes helt.
During intravenous infusion of SYLVANT, mild to moderate infusion reactions may improve following slowing of or stopping the infusion.
Under eller efter infusionen bør behandling seponeres hos patienter, der har svære overfølsomhedsreaktioner relateret til infusionen (f.eks. anafylaksi).
During or following infusion, treatment should be discontinued in patients who have severe infusion related hypersensitivity reactions (e.g., anaphylaxis).
Ligesom med andre immunglobulin G-antistoffer passerer siltuximab placenta, hvilket er observeret i studier med aber.
As with other immunoglobulin G antibodies, siltuximab crosses the placenta as observed in studies in monkeys.
Efter administration af gentagne doser i den anbefalede dosering var clearance af siltuximab tidsuafhængigt, og der sås moderat systemisk akkumulering (et akumulationsindeks på 1,7).
Following the repeat dose administration at the recommended dose, siltuximab clearance was found to be time-invariant, and systemic accumulation was moderate (accumulation index of 1.7).
Kriterier for genbehandling
Retreatment criteria
Dokumentation fra studier udført med siltuximab og andre IL6-hæmnere indikerer, at siltuximab har et lavt potentiale for karcinogenicitet.
Evidence from studies conducted with siltuximab and other IL-6 inhibitors suggest that the potential for siltuximab to cause carcinogenicity is low.
Ud over studie 1 foreligger der også effektdata for patienter med CD fra et fase 1-studie med en enkelt arm (studie 2).
Study 2 In addition to Study 1, efficacy data are available in patients with CD from a single arm Phase 1 study
Brug ikke lægemidlet efter den udløbsdato, der står på pakningen efter EXP. Udløbsdatoen er den sidste dag i den nævnte måned.
Do not use this medicine after the expiry date which is stated on the label after EXP.
Siltuximabs påvirkning af CYP450-enzymaktivitet kan vare ved i flere uger efter behandlingsstop.
The effect of siltuximab on CYP450 enzyme activity can persist for several weeks after stopping therapy.
Dyrestudier af siltuximab indikerer ikke skadelige virkninger på graviditeten eller på den embryoføtale udvikling (se pkt.
Studies in animals with siltuximab have shown no adverse effect on pregnancy or on embryofetal development (see section 5.3).
• Ikke anvendt lægemiddel samt affald heraf skal bortskaffes i henhold til lokale retningslinjer.
• Any unused product or waste material should be disposed of in accordance with local requirements.
• Anvend en aseptisk teknik.
• Use aseptic technique.
Udvalgte effektresultater fra studie 1 i den hyaline vaskulære undergruppe er gengivet i tabel 4.
Select efficacy results from Study 1 in the hyaline vascular subgroup are summarised in Table 4.
Det er ukendt, om silituximab udskilles i human mælk.
It is unknown whether siltuximab is excreted in human milk.
Ud fra et mikrobiologisk synspunkt skal lægemidlet anvendes med det samme, med mindre metoden for åbning/rekonstitution/fortynding udelukker risiko for mikrobiel forurening.
From a microbiological point of view, unless the method of opening/reconstitution/dilution precludes the risk of microbial contamination, the product should be used immediately.
Siltuximab er et monoklonalt antistof (en særlig type protein), der binder selektivt til et antigen (et målprotein) i kroppen, det såkaldte interleukin-6 (IL6).
Siltuximab is a monoclonal antibody (a specialised type of protein) that binds selectively to an antigen (a target protein) in the body called interleukin-6 (IL-6).
Virkningen af status for anti-siltuximab-antistoffer er ikke undersøgt, da antallet af patienter, der var positive for anti-siltuximab-antistoffer, var utilstrækkeligt.
The effect of anti-siltuximab antibody status was not examined, as there were insufficient numbers of anti-siltuximab antibody positive patients.
a SYLVANT kan øge hæmoglobinniveauet hos patienter med MCD.
a SYLVANT may increase haemoglobin levels in MCD patients
Inden for hver angivet hyppighed anføres bivirkningerne efter, hvor alvorlige de er.
Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.
Artralgi, smerter i ekstremiteter
Arthralgia, pain in extremity
• ledsmerter, smerter i arme eller ben
• joint pain, arm or leg pain
Derfor vil administration af siltuximab sammen med substrater for CYP450, der har et snævert terapeutisk indeks, potentielt kunne ændre terapeutiske virkninger og toksicitet af disse lægemidler på grund af ændringen af CYP450-metabolismen.
Therefore, administering siltuximab with CYP450 substrates that have a narrow therapeutic index has the potential to change therapeutic effects and toxicity of these medicinal products due to alteration in the CYP450 pathways.
Multicentrisk Castlemans sygdom fører til udvikling af godartede tumorer (svulster der ikke skyldes kræft) i kroppens lymfeknuder.
Multicentric Castleman's disease causes benign tumours (non-cancerous growths) to develop in the lymph nodes in the body.
Tabel 3: Endepunkter for effekt fra studie 1 Endepunkter for effekt
Table 3: Efficacy endpoints from study 1 Efficacy endpoints
I kliniske studier sås ingen større aldersrelaterede forskelle i farmakokinetik (PK) eller i sikkerhedsprofil.
No major age-related differences in pharmacokinetics (PK) or in safety profile were observed in clinical studies.
Behandlingen med SYLVANT gives af en læge eller sygeplejerske, og det er ikke sandsynligt, at du får for meget.
As this medicine will be given to you by your doctor or nurse, it is unlikely that you will be given too much.
I studie 1 blev der observeret en statistisk signifikant forskel ved uvildig gennemgang af varige responsrater for tumorer og symptomer i siltuximabarmen sammenlignet med placeboarmen (henholdsvis 34 % og 0 %; 95 % CI: 11,1, 54,8, p = 0,0012).
In Study 1 a statistically significant difference in independently reviewed durable tumour and symptomatic response rate in the siltuximab arm compared with the placebo arm (34% vs. 0%, respectively; 95% CI: 11.1, 54.8; p = 0.0012) was observed.
Scoring for ECOG-funktionsniveau (0/1/2) ved baseline var henholdsvis 42 %/45 %/13 % i siltuximabarmen og 39 %/62 %/0 % i placeboarmen.
ECOG performance status score (0/1/2) at baseline was 42%/45%/13% in the siltuximab arm and 39%/62%/0% in the placebo arm, respectively.
SYLVANT anvendes til behandling af multicentrisk Castlemans sygdom (MCD) hos voksne patienter, der ikke er smittet med human immundefektvirus (hiv) eller human herpesvirus-8 (HHV-8).
SYLVANT is used to treat multicentric Castleman's disease (MCD) in adult patients who do not have human immunodeficiency virus (HIV) or human herpesvirus-8 (HHV-8) infection.
Når bioaktivt IL-6 bindes af siltuximab, kan det resultere i øget metabolisme af substrater for CYP450, eftersom CYP450-enzymaktivitet normaliseres.
Binding bioactive IL-6 by siltuximab may result in increased metabolism of CYP450 substrates, because CYP450 enzyme activity will normalise.
Immunsystemet Almindelige
Immune system disorders common
Komplet symptomatisk respons defineredes som en 100 % reduktion af den samlede symptomscore ved baseline for MCD, der varede ved i mindst 18 uger før behandlingssvigt
Complete symptom response was defined as a 100% reduction from the baseline overall in the MCD-related overall symptom score sustained for at least 18 weeks prior to treatment failure.
Ved langtidsbehandling af MCD-patienter med siltuximab ved den anbefalede dosering på 11 mg/kg hver 3. uge forekom der infusionsrelaterede reaktioner eller overfølsomhedsreaktioner med en hyppighed på 6,3 % (svær reaktion hos 1,3 %).
In long-term treatment of MCD patients with siltuximab at the recommended dosage of 11 mg/kg every 3 weeks, infusion related reactions or hypersensitivity reactions occurred at a frequency of 6.3% (1.3% for severe reactions).
Hos patienter med baseline-ALATop til 3,7 gange den øvre grænse for normalområdet, baseline-albumin i området 15 til 58 g/l og baseline-bilirubin i området 1,7 til 42,8 mg/dl sås ingen betydningsfuld påvirkning af siltuximabs farmakokinetik.
For patients with baseline alanine transaminase up to 3.7 times the upper limit of normal baseline albumin ranging from 15 to 58 g/L, and baseline bilirubin ranging from 1.7 to 42.8 mg/dL there was no meaningful effect on siltuximab PK.
Det er især vigtigt, at du fortæller det til lægen eller apotekspersonalet, hvis du tager et af følgende lægemidler:
In particular, tell your doctor or pharmacist if you are taking any of the following medicines:
Siltuximab passerede placenta under drægtigheden, hvorved føtale serumkoncentrationer på drægtighedsdag (GD) 140 svarede til koncentrationerne hos moderdyret.
Siltuximab crossed the placenta during gestation whereby fetal serum concentrations of siltuximab at gestation day (GD) 140 were similar to maternal concentrations.
Vægtstigning a Alle patienter med Castlemans sygdom, som fik siltuximab i den anbefalede dosering på 11 mg/kg hver 3. uge [inklusive patienter der skiftede behandling (crossover) (N = 87)]
Weight increased a All patients with CD treated with siltuximab at recommended dose of 11 mg/kg every 3 weeks [including crossover patients (N = 87)]
Det skal du vide, før du begynder at bruge SYLVANT Du må ikke få SYLVANT:
What you need to know before you are given SYLVANT You should not be given SYLVANT if:
Af disse patienter havde 31 % radiologisk respons baseret på en uvildig gennemgang, og 88 % responderede klinisk som defineret i protokollen.
In this study, 16 of the 35 MCD patients were hyaline vascular subtype; 31% of these patients had a radiologic response based on independent review and 88% showed clinical benefit response as defined in the protocol.
Efter initiering eller seponering af SYLVANT hos patienter i behandling med lægemidler, der er substrater for CYP450 og har et snævert terapeutisk indeks, ambefales monitorering af virkningen (f.eks. ved warfarin) eller koncentrationen af lægemidlet (f.eks. ciclosporin eller theophyllin).
Upon initation or discontinuation of siltuximab in patients being treated with concomitant medicinal products that are CYP450 substrates and have a narrow therapeutic index, monitoring of the effect (e.g., warfarin) or concentration of medicinal product (e.g., cyclosporine or theophylline) is recommended.
Incidensen af påviselige anti-siltuximab-antistoffer var samlet set 0,9 % (4/432) og 2,1 % (4/189) for patienter med mindst én prøve testet med den høj lægemiddel tolerante ECLIA-analysemetode.
The incidence rate of detectable anti-siltuximab antibodies was 0.9% (4/432) overall and 2.1% (4/189) in patients with at least once sample tested with the high medicinal product tolerant ECLIA assay.
Histidinhydrochloridmonohydrat Polysorbat 80
Histidine hydrochloride monohydrate Polysorbate 80
Siltuximab bør ikke anvendes under graviditeten eller til kvinder i den fertile alder der ikke anvender kontraception.
Siltuximab is not recommended during pregnancy and in women of childbearing potential not using contraception.
Der er ikke påvist ændret sikkerheds- eller virkningsprofil hos de patienter, der udviklede antistoffer mod siltuximab.
No evidence of altered safety or efficacy was identified in the patients who developed antibodies to siltuximab.
Under behandlingen bør måling af IL-6-koncentrationer i serum eller plasma ikke anvendes som farmakodynamisk markør, da siltuximab-neutraliserede antistof-IL-6-komplekser interfererer med aktuelle immunologiske metoder til kvantificering af IL-6.
Measurement of IL-6 concentrations in serum or plasma during treatment should not be used as a pharmacodynamic marker, as siltuximab-neutralised antibody-IL-6 complexes interfere with current immunological-based IL-6 quantification methods.
Den anbefalede dosering af siltuximab er 11 mg/kg indgivet over 1 time som intravenøs infusion, der administreres hver 3. uge indtil behandlingsvigt.
The recommended dose is 11 mg/kg siltuximab given over 1 hour as an intravenous infusion administered every 3 weeks until treatment failure.
I løbet af et embryoføtalt udviklingsstudie, hvor siltuximab blev administreret intravenøst til drægtige cynomolgusaber (drægtighedsdag 20-118) i doser på 9,2 og 46 mg/kg/uge blev der ikke observeret toksicitet hos moderdyr eller foster.
During an embryo-fetal development study where siltuximab was administered intravenously to pregnant cynomolgus monkeys (gestation day 20 - 118) at doses of 9.2 and 46 mg/kg/week, no maternal or fetal toxicity was observed.
Pædiatrisk population Siltuximabs sikkerhed og virkning er ikke klarlagt hos pædiatriske patienter.
Paediatric population The safety and efficacy of siltuximab have not been established in paediatric patients.
Hos de 16 patienter med MCD, der fik 11 mg/kg hver 3. uge, var den samlede tumorresponsrate ifølge en uvildig gennemgang 43,8 % med 6,3 % komplet respons.
16 patients with MCD treated with 11 mg/kg every 3 weeks, overall tumour response rate by independent review was 43.8% with 6.3% complete response.
Den mediane varighed af behandling med siltuximab var 5,52 år (interval: 0,8 til 10,8 år).
Median duration of siltuximab treatment was 5.52 years (range: 0.8 to 10.8 years); more than 50% of patients received siltuximab treatment for ≥5 years.
Pakningsstørrelser og yderligere oplysninger SYLVANT indholder
Contents of the pack and other information What SYLVANT contains
Tabel 4: Udvalgte endepunkter for effekt for den hyaline vaskulære undergruppe fra studie 1
Table 4: Select efficacy endpoints for hyaline vascular subgroup from study 1 Efficacy endpoints
Langsomt tilsæt den samlede mængde rekonstitueret SYLVANT-opløsning til 250 ml-infusionsposen.
Slowly add the total volume of reconstituted SYLVANT solution to the 250 mL infusion bag.
Metabolisme og ernæring Meget almindelige
Metabolism and nutrition disorders very common
Biomarkører
Biomarkers
Der sås en mindre reduktion af T-celleafhængigt antistofrespons og et fald i størrelsen på miltens germinalcentre efter Keyhole limpet hemocyanin- (KLH-)immunisering, som ansås for at være farmakologisk respons på IL6-hæmning og uden toksikologisk betydning.
A slight reduction in T-cell dependent antibody response and a reduction in the size of the splenic germinal centers following Keyhole limpet hemocyanin (KLH) immunisation was observed which were considered to be pharmacological responses of IL-6 inhibition and not of toxicological significance.