natgillin/translations-raw huggingface dataset:
Nedenstående tabel viser de bivirkninger, hvor forskellen i hyppighed sammenlignet med kontrolarmen er mindst 2%, og som optrådte hyppigere hos patienter, der havde fået mindst én infusion med MabThera i forhold til dem, der havde fået placebo i fase III- studiet og den kombinerede population i fase II - studierne.
ADRs, which occurred with at least a 2% difference compared to the control arm and more frequently by patients who had received at least one infusion of MabThera than among patients that had received placebo in the phase III trial and the combined population included in phase II studies, are listed in the Table below.
Frekvenserne er defineret som meget almindelig ≥ 1/ 10 og almindelig (≥ 1/ 100 til < 1/ 10).
Frequencies are defined as very common (≥ 1/ 10) and common (≥ 1/ 100 to < 1/ 10).
Inden for hver hyppighedsgruppe er bivirkningerne angivet efter faldende alvorlighed.
Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness
De mest almindelige bivirkninger, der blev anset for at være relateret til administration af 2 x 1000 mg MabThera i fase- II og fase- III studier, var akutte infusionsreaktioner.
The most frequent adverse reactions considered due to receipt of 2x1000 mg MabThera in Phase II and III studies were acute infusion reactions.
Infusionsreaktioner forekom hos 15% af patienterne efter den første infusion af rituximab og 5% efter placebo.
Infusion reactions occurred in 15% patients following the first infusion of rituximab and 5% in placebo patients.
Infusionsreaktionerne faldt til 2% efter den anden infusion i både rituximab - og placebogruppen.
Infusion reactions decreased to 2% following the second infusion in both rituximab and placebo groups.
4. 4)
The safety information collected during post marketing experience reflects the expected adverse reaction profile as seen in clinical trials for MabThera (see section 4.4).
som fik MabThera i kliniske studier eller i forbindelse med post- marketing overvågning.
Summary of Adverse Drug Reactions Reported in Clinical Trials or During Postmarketing Surveillance Occurring in Patients with Rheumatoid Arthritis receiving MabThera
Systemorgan - klasser
System Organ Infections and Infestations
Meget almindelig
Class Very Common Common any infection, upper urinary tract respiratory tract infections infection
øvre luftvejsinfek - tioner
Immune System Disorders General disorders and administration site conditions
reaktioner (kvalme, kulderystelse, rinit, nældefeber, hedeture),
*Infusion related reactions (nausea, chills, rhinitis, urticaria hot flush) hypertension, rash, pyrexia, pruritus, throat irritation and hypotension
reaktioner (generelt ødem, bronkospasme, hiven efter vejret, larynxødem angioødem, generel kløe,
*Infusion related reactions (generalized oedema, bronchospasm, wheezing, laryngeal oedema, angioneurotic oedema, generalized pruritis, anaphylaxis, anaphylactoid reaction)
hypertension, udslæt,
Metabolism and Nutritional Disorders
anafylaksi, anafylaktoide
hypercholesterolemia
Almene symptomer og reaktioner på administrationss tedet
Nervous System disorders Gastrointestinal Disorders
Nervesystemet Mave - tarmkanalen
Paraesthesia, migraine dyspepsia
Paræstesi, migræne Dyspepsi
Musculo skeletal disorders
artralgier / muskuloskeletale smerter, osteoartrit
arthralgia / musculoskeletal pain, osteoarthritis
* Reaktioner, som forekommer inden for 24 timer efter infusion.
*Reactions occurring during or within 24 hours of infusion.
Infusionsrelaterede reaktioner kan forekomme i forbindelse med hypersensitivitet og/ eller virkningsmekanismen.
Infusion related reactions may occur as a result of hypersensitivity and/ or to the mechanism of action.
15 Følgende hændelser er blevet rapporteret som bivirkninger, set i kliniske forsøg, og med samme frekvens i MabThera- armen som i kontrolarmen: nedre luftvejsinfektioner/ pneumoni, smerter i øvre del af abdomen, muskelkramper og astenia.
The following terms have been reported as adverse events during clinical trials, however, were reported at a similar incidence in the MabThera-arms compared to control arms: lower respiratory tract infections/ pneumonia, abdominal pain upper, muscle spasms and asthenia.
Gentagne behandlinger De begrænsede kliniske data fra gentagen behandling af RA- patienter synes at vise en bivirkningsprofil, som ligner den ved første behandling.
Multiple Courses The limited clinical trial data on multiple courses of treatment of RA patients seem to be associated with a similar ADR profile to that observed following first exposure.
På baggrund af tilgængelige data kan forværring af infusions - eller allergiske reaktioner og manglende B- celle- depletering efter rituximab ikke udelukkes hos HACA- positive patienter efter gentagen eksponering for rituximab.
However, worsening of infusion or allergic reactions and failure to B cell deplete following rituximab cannot be excluded in HACA positive patients after repeated exposure to rituximab on the basis of available data.
Hyppigheden af akutte infusionsreaktioner efter senere behandlingsforløb var generelt lavere end hyppigheden efter den første infusion med MabThera.
The incidence of acute infusion reactions following subsequent treatment courses was generally lower than the incidence following the first infusion of MabThera.
I et forsøg, der sammenlignede effekten af glukokortikoidbehandling, blev disse hændelser observeret hos 5/ 149 (3%) af patienterne efter deres første infusion med rituximab- placebo og hos 42/ 192 (22%) af patienterne, der modtog deres første infusion med 1000 mg rituximab.
15 Infusion-related reactions Symptoms suggesting an acute infusion reaction (e. g. pruritis, fever, urticaria/ rash, chills, pyrexia, rigors, sneezing, angioneurotic edema, throat irritation, cough and bronchospasm, with or without associated hypotension or hypertension) were observed in 79/ 540 (15%) patients following their first exposure to MabThera; In a study comparing the effect of glucocorticoid regimen, these events were observed in 5/ 149 (3%) of patients following their first rituximab placebo infusion and 42/ 192 (22%) of patients receiving their first infusion of 1000 mg rituximab.
Præmedicinering med intravenøse glukokortikoider reducerede signifikant hyppigheden og sværhedsgraden af disse hændelser.
Premedication with intravenous glucocorticoid significantly reduced the incidence and severity of these events.
Af de patienter, der fik 1000 mg rituximab uden præmedicinering med glukokortikoider, oplevede henholdsvis 18/ 65 (28%) en akut infusionsreaktion, sammenlignet med 24/ 127 (19%) af patienterne, der blev præmedicinerede med intravenøse glukokortikoider.
Of the patients who received 1000 mg rituximab without premedication with glucocorticoids, 18/ 65 (28%) experienced an acute infusion reaction, compared with 24/ 127 (19%) in patients given intravenous glucocorticoid premedication, respectively.
Infektioner Hyppigheden af infektioner var omtrent 0, 9 pr. patientår hos patienter behandlet med MabThera.
Infections The rate of infection was approximately 0.9 per patient year in MabThera treated patients.
Infektionerne blev som regel lokaliseret i de øvre luftveje eller urinvejene.
The infections consisted mostly of upper respiratory tract infections and urinary tract infections.
Hyppigheden af klinisk signifikante infektioner, af hvilke nogle var fatale, var 0, 05 pr. patientår hos patienter behandlet med MabThera.
The incidence of clinically significant infection, some of which were fatal, was 0.05 per patient year in MabThera treated patients.
Tilfælde af progressiv multifokal leukoencefalopati med dødelig udgang er rapporteret efter anvendelse af MabThera i forbindelse med behandling for autoimmune sygdomme, som inkluderer reumatoid arthritis og ikke- godkendte indikationer som systemisk lupus erythematosus (SLE) og vaskulitis.
This includes Rheumatoid Arthritis and off-label autoimmune diseases, including Systemic Lupus Erythematosus (SLE) and Vasculitis.
Alle rapporterede tilfælde havde flere risikofaktorer for PML, enten den underliggende sygdom og/ eller langvarig behandling med immunsuppressiva eller behandling med kemoterapi.
All the reported cases had multiple risk factors for PML, including either the underlying disease and or long-term immunosuppressive therapy or chemotherapy.
Maligne sygdomme De kliniske data og i særdeleshed antallet af gentagne behandlinger er for begrænsede til at vurdere den potentielle incidens af maligne sygdomme efter eksponering for rituximab.
Malignancies The clinical data, particularly the number of repeated courses, are too limited to assess the potential incidence of malignancies following exposure to rituximab, although present data do not seem to suggest any increased risk.
Tilgængelige data tyder dog ikke på en forøget risiko.
Long-term safety evaluations are ongoing.
Kardiovaskulære Kardiale hændelser blev observeret hos 11% af patienterne i kliniske studier med MabThera.
Cardiovascular Cardiac events were observed in 11% patients in clinical studies with MabThera.
I placebokontrollerede forsøg blev alvorlige kardiale hændelser rapporteret med samme hyppighed hos MabThera - og placebobehandlede patienter (2%).
In placebo controlled studies, serious cardiac events were reported equally in MabThera and placebo treated patients (2%).
Der er ingen erfaringer vedrørende overdosering i de kliniske undersøgelser.
There has been no experience of overdose in human clinical trials.
Højere enkeltdoser end 1000 mg er imidlertid ikke blevet undersøgt i kontrollerede kliniske undersøgelser.
However, single doses higher than 1000 mg have not been tested in controlled clinical trials.
Monoklonale antistoffer, ATC kode:
Pharmacotherapeutic group: monoclonal antibodies, ATC code:
Rituximab bindes specifikt til det transmembrane antigen, CD20, et non- glycosyleret phosphoprotein som findes på præ- B og modne B lymfocytter.
Rituximab binds specifically to the transmembrane antigen, CD20, a non-glycosylated phosphoprotein, located on pre-B and mature B lymphocytes.
Antigenet udtrykkes på > 95% af alle B- celle non - Hodgkin lymfomer.
The antigen is expressed on > 95% of all B cell non-Hodgkin’ s lymphomas.
CD20 findes på både normale og på maligne B- celler, men ikke på tidlige forstadier, pro- B- celler, normale plasmaceller eller andet normalt væv.
CD20 is found on both normal and malignant B cells, but not on haematopoietic stem cells, pro- B cells, normal plasma cells or other normal tissue.
Rituximabs Fab domæne bindes til CD20 antigenet på B lymfocytter og Fc domainet kan rekruttere immuneffektor funktioner til at mediere B- celle lysis.
16 The Fab domain of rituximab binds to the CD20 antigen on B lymphocytes and the Fc domain can recruit immune effector functions to mediate B cell lysis.
Rituximabs binding til CD 20 antigenet på B lymfocytter har vist også at inducere celledød via apoptose.
Rituximab binding to CD 20 antigen on B lymphocytes has also been demonstrated to induce cell death via apoptosis.
Det perifere B- celle tal faldt til under normalområdet efter den første dosis af MabThera.
Peripheral B cell counts declined below normal following completion of the first dose of MabThera.
Hos patienter behandlet for hæmatologiske maligne sygdomme begyndte B- celle regenerering inden for 6 måneders behandling og nåede normale niveauer mellem 9 og 12 måneder efter afsluttet behandling.
In patients treated for hematological malignancies, B cell repletion began within 6 months of treatment returning to normal levels between 9 and 12 months after completion of therapy.
Hos patienter med reumatoid arthritis sås øjeblikkelig B- celle depletering i perifert blod efter to infusioner af 1000 mg MabThera med 14 dages interval.
In rheumatoid arthritis patients, immediate depletion of B cells in the peripheral blood was observed following two infusions of 1000 mg MabThera separated by a 14 day interval.
Tegn på gendannelse af B- celler blev observeret hos størstedelen af patienterne ved uge 40, uanset om MabThera blev anvendt som monoterapi eller i kombination med methotrexat.
Peripheral blood B cell counts begin to increase from week 24 and evidence for repopulation is observed in the majority of patients by week 40, whether MabThera was administered as monotherapy or in combination with methotrexate.
Klinisk erfaring ved non- Hodgkin lymfom og kronisk lymfatisk leukæmi
Clinical Experience in Non-Hodgkin’ s lymphoma and in chronic lymphocytic leukaemia
Follikulær non- Hodgkin lymfom
Follicular non-Hodgkin's lymphoma
Monoterapi Induktionsbehandling, 1 dosis ugentligt til ialt 4 doser I det pivotale studie fik 166 patienter med recidiverende eller kemoterapi- resistent lavmalignt eller follikulært B- celle NHL 375 mg/ m2 MabThera som intravenøs infusion én gang om ugen i fire uger.
Monotherapy Initial treatment, weekly for 4 doses In the pivotal study, 166 patients with relapsed or chemoresistant low-grade or follicular B cell NHL received 375 mg/ m2 of MabThera as an intravenous infusion once weekly for four weeks.
41% - 56%) med 6% komplet respons (CR) og 42% partielt respons (PR).
The overall response rate (ORR) in the intent-to-treat (ITT) population was 48% (CI95% 41% - 56%) with a 6% complete response (CR) and a 42% partial response (PR) rate.
Den mediane tid indtil progression var 13, 0 måneder for responderende patienter.
The projected median time to progression (TTP) for responding patients was 13.0 months.
I en subgruppeanalyse var den samlede responsrate højere hos patienter med histologisk subtype IWF B, C og D sammenlignet med subtype IWF A (58% vs.
In a subgroup analysis, the ORR was higher in patients with IWF B, C, and D histological subtypes as compared to IWF A subtype (58% vs.
12%), højere hos patienter hvis største læsions længste diameter var < 5 cm vs. > 7 cm (53% vs.
12%), higher in patients whose largest lesion was< 5 cm vs. > 7 cm in greatest diameter (53% vs.
38%) og højere hos patienter med kemoterapifølsomt relaps sammenlignet med kemoterapi- resistent relaps (defineret som en responsvarighed < 3 måneder) (50% vs.
38%), and higher in patients with chemosensitive relapse as compared to chemoresistant (defined as duration of response < 3 months) relapse (50% vs.
Den samlede responsrate hos patienter, som tidligere var behandlet med autolog knoglemarvstransplantation var 78% versus 43% hos patienter uden autolog knoglemarvstransplantation.
ORR in patients previously treated with autologous bone marrow transplant (ABMT) was 78% versus 43% in patients with no ABMT.
Hverken alder, køn, lymfomgrad, initial diagnose, tilstedeværelse eller fravær af udbredt sygdom, normal eller høj LDH, eller tilstedeværelse af ekstranodal sygdom havde statistisk signifikant effekt (Fisher’ s exact test) på responset på MabThera.
Neither age, sex, lymphoma grade, initial diagnosis, presence or absence of bulky disease, normal or high LDH nor presence of extranodal disease had a statistically significant effect (Fisher’ s exact test) on response to MabThera.
40% af patienterne med involvering af knoglemarven responderede sammenlignet med 59% af patienterne uden involvering af knoglemarven (p=0, 0186).
40% of patients with bone marrow involvement responded compared to 59% of patients with no bone marrow involvement (p=0.0186).
Dette fund kunne ikke bekræftes af en trinvis logistisk regressionsanalyse i hvilken følgende faktorer blev identificeret som prognostiske faktorer: histologisk type, bcl- 2 positivitet ved baseline, resistens overfor sidste kemoterapi og udbredt sygdom.
This finding was not supported by a stepwise logistic regression analysis in which the following factors were identified as prognostic factors: histological type, bcl-2 positivity at baseline, resistance to last chemotherapy and bulky disease.
Induktionsbehandling, 1 dosis ugentligt til ialt 8 doser I et enkelt- arms multicenterstudie fik 37 patienter med recidiveret elle kemoterapi- resistent lavmalignt eller follikulært B- celle NHL 375 mg/ m2 MabThera som intravenøs infusion ugentligt i otte doser.
Initial treatment, weekly for 8 doses In a multi-centre, single-arm study, 37 patients with relapsed or chemoresistant, low grade or follicular B cell NHL received 375 mg/ m2 of MabThera as intravenous infusion weekly for eight doses.
41% - 73%; CR 14% og PR 43%) med
The ORR was 57% (95% Confidence interval (CI); 41% – 73%; CR 14%, PR 43%) with a projected median TTP for responding patients of 19.4 months (range 5.3 to 38.9 months).
Den samlede responsrate var 36% (95% konfidensinterval:
Initial treatment, bulky disease, weekly for 4 doses In pooled data from three studies, 39 patients with relapsed or chemoresistant, bulky disease (single lesion ≥ 10 cm in diameter), low grade or follicular B cell NHL received 375 mg/ m2 of MabThera as intravenous infusion weekly for four doses.
4, 5 – 26, 8 måneder).
The ORR was 36% (CI95% 21% – 51%; CR 3%, PR 33%) with a median TTP for responding patients of 9.6 months (range 4.5 to 26.8 months).
Genbehandling, 1 dosis ugentligt til ialt 4 doser I et enkelt- arms multicenterstudie blev 58 patienter med recidiveret elle kemoterapi- resistent lavmalignt eller follikulært B- celle NHL, som havde opnået et objektivt klinisk respons efter en tidligere serie med MabThera, genbehandlet med 375 mg/ m2 MabThera som intravenøs infusion ugentligt i fire doser.
Re-treatment, weekly for 4 doses In a multi-centre, single-arm study, 58 patients with relapsed or chemoresistant low grade or follicular B cell NHL, who had achieved an objective clinical response to a prior course of MabThera, were re- treated with 375 mg/ m2 of MabThera as intravenous infusion weekly for four doses.
Tre patienter havde fået to serier med MabThera før inklusion og fik således den tredje serie i studiet.
Three of the patients had received two courses of MabThera before enrollment and thus were given a third course
To patienter blev genbehandlet to gange under studiet.
17 in the study.
Den samlede responsrate for de 60 genbehandlinger i studiet var 38% (95% konfidensinterval:
Two patients were re-treated twice in the study.
5, 4 måneder - 26, 6 måneder).
For the 60 re-treatments on study, the ORR was 38% (CI95% 26% – 51%; 10% CR, 28% PR) with a projected median TTP for responding patients of 17.8 months (range 5.4 – 26.6).
Det svarer til, hvad der blev opnået efter den første serie med MabThera (12, 4 måneder).
This compares favourably with the TTP achieved after the prior course of MabThera (12.4 months).
Induktionsbehandling i kombination med kemoterapi I et åbent, randomiseret studie blev 322 tidligere ubehandlede patienter med follikulært lymfom randomiseret til enten CVP- kemoterapi (cyklophosphamid 750 mg/ m2, vincristin 1, 4 mg/ m2 op til maksimalt 2 mg på dag 1 og prednisolon 40 mg/ m2 på dag 1- 5) hver 3. uge i 8 serier eller til MabThera 375 mg/ m2 i kombination med CVP (R- CVP).
Initial treatment, in combination with chemotherapy In an open-label randomised trial, a total of 322 previously untreated patients with follicular lymphoma were randomised to receive either CVP chemotherapy (cyclophosphamide 750 mg/ m2, vincristine 1.4 mg/ m2 up to a maximum of 2 mg on day 1, and prednisolone 40 mg/ m2/ day on days 1 -5) every 3 weeks for 8 cycles or MabThera 375 mg/ m2 in combination with CVP (R-CVP).
I alt 321 patienter fik behandling (162 patienter fik R- CVP og 159 fik CVP) og blev analyseret for effekt.
A total of 321 patients (162 R-CVP, 159 CVP) received therapy and were analysed for efficacy.
R- CVP var signifikant bedre end CVP mht. det primære endepunkt, tid til behandlingssvigt (27 måneder vs.
R-CVP led to a significant benefit over CVP for the primary endpoint, time to treatment failure (27 months vs.
6, 6 måneder), p < 0, 0001, log rank test).
6.6 months, p < 0.0001, log-rank test).
Andelen af patienter med tumorrespons (CR, Cru, PR) var signifikant højere (p < = 0, 0001), chi square test) i R- CVP- gruppen (80, 9%) end i CVP- gruppen (57, 2%).
The proportion of patients with a tumour response (CR, CRu, PR) was significantly higher (p < 0.0001 Chi-Square test) in the R-CVP group (80.9%) than the CVP group (57.2%).
Behandling med R- CVP forlængede signifikant tiden til sygdomsprogression eller død, sammenlignet med CVP; 33, 6 måneder i forhold til 14, 7 måneder (p < 0, 0001, log- rank test).
Treatment with R-CVP significantly prolonged the time to disease progression or death compared to CVP, 33.6 months and 14.7 months, respectively (p < 0.0001, log-rank test).
Den mediane responsvarighed var 37, 7 måneder i R- CVP- gruppen, og den var 13, 5 måneder i i CVP- gruppen (p < 0, 0001), log rank test).
The median duration of response was 37.7 months in the R-CVP group and was 13.5 months in the CVP group (p < 0.0001, log-rank test).
Forskellen i den samlede overlevelse viste en stærk klinisk forskel (p=0, 029, log rank test stratificeret ved center): overlevelsesrater på 53 måneder var 80, 9% for patienter i R- CVP- gruppen i forhold til 71, 1% for patienter i CVP- gruppen.
The difference between the treatment groups with respect to overall survival showed a significant clinical difference (p=0.029, log-rank test stratified by center): survival rates at 53 months were 80.9% for patients in the R-CVP group compared to 71.1% for patients in the CVP group
Resultaterne fra tre andre randomiserede studier, hvor MabThera blev anvendt i kombination med andre kemoterapibehandlinger end CVP (CHOP, MCP, CHVP/ Interferon- α), har også vist signifikante forbedringer i responsrater, tidsafhængige parametre samt samlet overlevelse.
Results from three other randomized trials using MabThera in combination with chemotherapy regimen other than CVP (CHOP, MCP, CHVP/ Interferon-α) have also demonstrated significant improvements in response rates, time-dependent parameters as well as in overall survival.
Nøgleresultater fra alle fire studier er opsummeret i tabel 3.
Key results from all four studies are summarized in table 3.
18 Tabel 3
18 Table 3
Opsummering af nøgleresultater fra fire fase- III randomiserede studier, der evaluerer fordelene ved MabThera med forskellige kemoterapibehandlinger ved follikulært lymfom
Summary of key results from four phase III randomized studies evaluating the benefit of MabThera with different chemotherapy regimens in follicular lymphoma
Behandling, Median ORR,% CR, Median OS rates, n FU,% TTF/ PFS /% måneder EFS måneder CVP, 159 53 57 10 Median 53- måneder R- CVP, 162 81 41 TTP:
FU, ORR,% TTF/ PFS/ EFS N%
71. 1
rates,
14. 7 80. 9 33. 6 p=0. 029 P < 0. 0001
P < 0.0001
GLSG’ 00 OSHO- 39
2.6 years
CHOP, 205 18 90 17 Median 18- måneder R- CHOP, 96 20 TTF:
17
2. 6 år 90 223 Ikke opnået 95 p < 0. 001 p = 0. 016 MCP, 96 47 75 25 Median 48- måneder R- MCP, 105 92 50 PFS:
Not reached p < 0.001
28. 8 74 Ikke opnået 87 p < 0. 0001 p = 0. 0096
p < 0.0001
CHVP- IFN, 42 85 49 Median 42- måneder 183 94 76 EFS:
183
36 84 R- CHVP - Ikke opnået 91 IFN, 175 p < 0. 0001 p = 0. 029
p < 0.0001
EFS – Eventfri overlevelse TTP – Tid til progression eller død PFS – Progressionsfri overlevelse TTF – Tid til behandlingssvigt OS rates – Overlevelsesrater ved analysetiden
EFS – Event Free Survival TTP – Time to progression or death PFS – Progression-Free Survival TTF – Time to Treatment Failure OS rates – survival rates at the time of the analyses
Vedligeholdelsesbehandling I et prospektivt, ublindet, internationalt, multicenter fase III forsøg, blev 465 patienter med refraktær/ relaps af follikulært NHL i første omgang randomiseret til induktionsbehandling med enten CHOP (cyclophosphamid, doxorubicin, vincristin, prednisolon; n=231) eller MabThera plus CHOP (R- CHOP, n=234).
Maintenance therapy In a prospective, open label, international, multi-centre, phase III trial, 465 patients with relapsed/ refractory follicular NHL were randomised in a first step to induction therapy with either CHOP (cyclophosphamide, doxorubicin, vincristine, prednisolone; n=231) or MabThera plus CHOP (R-CHOP, n=234).
De to behandlingsgrupper var ligeligt fordelt med hensyn til baseline - karakteristika og sygdomsstatus.
The two treatment groups were well balanced with regard to baseline characteristics and disease status.