natgillin/translations-raw huggingface dataset:
Maligniteter Immunosuppressiva som ustekinumab har et potentiale for at øge risikoen for maligniteter.
Malignancies Immunosuppressants like ustekinumab have the potential to increase the risk of malignancy.
4. 8).
Some patients who received STELARA in clinical studies developed cutaneous and non-cutaneous malignancies (see section 4.8).
Der er ikke udført forsøg med deltagelse af patienter, der har eller har haft maligniteter, eller forsøg, hvor der fortsat gives behandling til patienter, der udvikler en malignitet under behandlingen med STELARA.
No studies have been conducted that include patients with a history of malignancy or that continue treatment in patients who develop malignancy while receiving STELARA.
4. 8).
Hypersensitivity reactions If an anaphylactic or other serious allergic reaction occurs, administration of STELARA should be discontinued immediately and appropriate therapy instituted (see section 4.8).
Bacillus Calmette- Guérin (BCG)) ikke gives samtidig med STELARA.
3 Vaccinations It is recommended that live viral or live bacterial vaccines (such as Bacillus of Calmette and Guérin (BCG)) should not be given concurrently with STELARA.
Der er ikke udført specifikke forsøg med patienter, der for nylig var blevet vaccineret med levende vira eller levende bakterier.
Specific studies have not been conducted in patients who had recently received live viral or live bacterial vaccines.
Receptudstedere bør konsultere produktresuméet for den specifikke vaccine for yderligere oplysninger og vejledning om samtidig brug af immunosuppressiva efter vaccination.
Prescribers should consult the Summary of Product Characteristics for the specific vaccine for additional information and guidance on concomitant use of immunosuppressive agents post-vaccination.
Patienter i behandling med STELARA kan vaccineres med inaktiverede eller ikke- levende vacciner.
Patients receiving STELARA may receive concurrent inactivated or non-live vaccinations.
Samtidig immunosuppressiv behandling Sikkerheden af og effekten ved STELARA i kombination med andre immunosuppressiva, herunder biologiske lægemidler, eller lysbehandling er ikke vurderet.
Concomitant immunosuppressive therapy The safety and efficacy of STELARA in combination with other immunosuppressants, including biologics, or phototherapy have not been evaluated.
4. 5).
Caution should be exercised when considering concomitant use of other immunosuppressants and STELARA or when transitioning from other immunosuppressive biologics (see section 4.5).
Børn og unge (< 18 år) STELARA anbefales ikke til brug for børn under 18 år på grund af mangel på sikkerheds - og effektdata.
Special populations Children and adolescents (< 18 years) STELARA is not recommended for use in children below age 18 due to a lack of data on safety and efficacy.
Ældre patienter (≥ 65 år) Samlet er der ikke observeret forskelle med hensyn til effekt og sikkerhed hos patienter på 65 år eller ældre, som modtog Stelara, sammenlignet med yngre patienter.
Elderly patients (≥ 65 years) No overall differences in efficacy or safety in patients age 65 and older who received STELARA were observed compared to younger patients.
4. 2).
Hepatic and renal impairment Specific studies have not been conducted in patients with hepatic and renal impairment (see section 4.2).
I den farmakokinetiske populationsanalyse af fase III- forsøgene blev effekten af de hyppigst, samtidigt anvendte lægemidler til psoriasispatienter undersøgt (herunder paracetamol, ibuprofen, acetylsalicylsyre, metformin, atorvastatin, levothyroxin) på ustekinumabs farmokokinetik.
In the population pharmacokinetic analysis of the phase III studies, the effect of the most frequently used concomitant medicinal products in patients with psoriasis (including paracetamol, ibuprofen, acetylsalicylic acid, metformin, atorvastatin, levothyroxine) on pharmacokinetics of ustekinumab was explored.
Der var ingen indikation af interaktion ved samtidig indgift at disse lægemidler.
There were no indications of an interaction with these concomitantly administered medicinal products.
Grundlaget for denne analyse var, at mindst 100 patienter (> 5% af den undersøgte population) blev behandlet samtidigt med disse lægemidler i mindst 90% af forsøgsperioden.
The basis for this analysis was that at least 100 patients (> 5% of the studied population) were treated concomitantly with these medicinal products for at least 90% of the study period.
4. 4).
Live vaccines should not be given concurrently with STELARA (see section 4.4).
4. 4).
The safety and efficacy of STELARA in combination with other immunosuppressants, including biologics, or phototherapy have not been evaluated (see section 4.4).
Graviditet Der findes ikke tilstrækkelige data om brugen af ustekinumab hos gravide kvinder.
Pregnancy There are no adequate data from the use of ustekinumab in pregnant women.
5. 3).
Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonic/ foetal development, parturition or postnatal development (see section 5.3).
Kvinder i den fødedygtige alder skal anvende en effektiv præventionsmetode under behandlingen og op til 15 uger efter behandlingen.
Women of childbearing potential should use effective methods of contraception during treatment and up to 15 weeks after treatment.
Amning Det vides ikke, om ustekinumab udskilles i human brystmælk.
4 Lactation It is unknown whether ustekinumab is excreted in human breast milk.
Det vides ikke, om ustekinumab absorberes systemisk efter peroral indtagelse.
Animal studies have shown excretion of ustekinumab at low levels in breast milk.
Der er risiko for bivirkninger af ustekinumab hos spædbørn, der ammes.
It is not known if ustekinumab is absorbed systemically after ingestion.
Når der træffes beslutning om, hvorvidt amningen skal stoppes under behandlingen og op til 15 uger efter
Because of the potential for adverse reactions in nursing infants from ustekinumab, a decision on whether to discontinue breast-feeding during treatment and up to 15 weeks after treatment or to discontinue therapy with STELARA must be made taking into account the benefit of breast-feeding to the child and the benefit of STELARA therapy to the woman.
Der er ikke foretaget undersøgelser af virkningen på evnen til at føre motorkøretøj eller betjene maskiner.
No studies on the effects on the ability to drive and use of machines have been performed.
Nedenstående sikkerhedsdata afspejler eksponeringen for ustekinumab i 3 forsøg med 2. 266 patienter, hvoraf 1. 970 blev eksponeret i mindst 6 måneder, 1. 285 i mindst 1 år og 373 i mindst 18 måneder.
The safety data described below reflect exposure to ustekinumab in 3 studies of 2,266 patients, including 1,970 exposed for at least 6 months and 1,285 exposed for at least 1 year, and 373 for at least 18 months.
Følgende alvorlige bivirkninger blev rapporteret: • Alvorlige infektioner • Maligniteter
The following serious adverse reactions were reported: • Serious infections • Malignancies
De mest almindelige bivirkninger (> 10%) i de kontrollerede og ukontrollerede dele af de kliniske forsøg med ustekinumab mod psoriasis var nasopharyngitis og infektioner i de øvre luftveje.
The most common adverse reactions (> 10%) in controlled and uncontrolled portions of the psoriasis clinical studies with ustekinumab were nasopharyngitis and upper respiratory tract infection.
De fleste blev anset for at være milde og nødvendiggjorde ikke seponering af forsøgslægemidlet.
Most were considered to be mild and did not necessitate discontinuation of study treatment.
Tabel 1 giver en oversigt over bivirkninger fra kliniske forsøg med psoriasis.
Table 1 provides a summary of adverse reactions from psoriasis clinical studies.
Bivirkningerne er opstillet i henhold til systemorganklasse og hyppighed i henhold til følgende konvention:
The adverse reactions are classified by System Organ Class and frequency, using the following convention:
Meget almindelig (> 1/ 10) Almindelig (> 1/ 100 til < 1/ 10) Ikke almindelig (> 1/ 1. 000 til < 1/ 100) Sjælden (> 1/ 10. 000 til < 1/ 1. 000) Meget sjælden (< 1/ 10. 000), ikke kendt (kan ikke estimeres ud fra forhåndenværende data)
Very common (≥ 1/ 10), Common (≥ 1/ 100 to < 1/ 10), Uncommon (≥ 1/ 1,000 to < 1/ 100), Rare (≥ 1/ 10,000 to < 1/ 1,000), Very rare (< 1/ 10,000), not known (cannot be estimated from the available data).
Oversigt over bivirkninger i kliniske forsøg med psoriasis
Table 1 Summary of adverse reactions in psoriasis clinical studies System Organ Class
Hyppighed: bivirkning
Adverse reaction
Infektioner i de øvre luftveje, nasopharyngitis Almindelig:
Upper respiratory tract infection, nasopharyngitis Common:
Cellulitis, virusinfektion i de øvre luftveje
Cellulitis, viral upper respiratory tract infection
Depression
Depression
Faryngolaryngeale smerter, tilstoppet næse
Pharyngolaryngeal pain, nasal congestion
Træthed, erytem på injektionsstedet Ikke almindelig:
Fatigue, injection site erythema Uncommon:
Reaktioner på injektionsstedet (herunder smerter, hævelse, pruritus, induration, blødning, blå mærker og irritation)
Injection site reactions (including pain, swelling, pruritus, induration, haemorrhage, bruising and irritation)
5 Infektioner I kontrollerede forsøg med psoriasispatienter var forekomsten af infektioner eller alvorlige infektioner stort set ens for de patienter, der blev behandlet med ustekinumab, og dem, der blev behandlet med placebo.
5 Infections In controlled studies of psoriasis patients, the rates of infection or serious infection were similar between ustekinumab-treated patients and those treated with placebo.
I den placebokontrollerede periode med kliniske forsøg med psoriasispatienter var forekomsten af infektioner i opfølgningsperioden 1, 39 pr. patientår for patienter, der blev behandlet med ustekinumab, og 1, 21 hos patienter, der blev behandlet med placebo.
In the placebo-controlled period of clinical studies of psoriasis patients, the rate of infection was 1.39 per patient-year of follow-up in ustekinumab-treated patients, and 1.21 in placebo-treated patients.
4. 4).
Serious infections occurred in 0.01 per patient-year of follow-up in ustekinumab-treated patients (5 serious infections in 407 patient-years of follow-up) and 0.02 in placebo-treated patients (3 serious infections in 177 patient-years of follow-up) (see section 4.4).
Rapporterede, alvorlige infektioner omfattede cellulitis, divertikulitis, osteomyelitis, virusinfektioner, gastroenteritis, lungebetændelse og urinvejsinfektioner.
In the controlled and non-controlled portions of psoriasis clinical studies, the rate of infection was 1.24 per patient-year of follow-up in ustekinumab-treated patients, and the incidence of serious infections was 0.01 per patient-year of follow-up in ustekinumab-treated patients (24 serious infections in 2,251 patient-years of follow-up) and serious infections reported included cellulitis, diverticulitis, osteomyelitis, viral infections, gastroenteritis, pneumonia, and urinary tract infections.
I kliniske forsøg udviklede patienter med latent tuberkulose, der samtidig blev behandlet med isoniazid, ikke tuberkulose.
In clinical studies, patients with latent tuberculosis who were concurrently treated with isoniazid did not develop tuberculosis.
100 patientår i opfølgningsperioden for patienter behandlet med ustekinumab (1 patient i 406 patientår i opfølgningsperioden) sammenlignet med 0, 57 patienter behandlet med placebo (1 patient i 177 patientår i opfølgningsperioden).
Malignancies In the placebo-controlled period of the psoriasis clinical studies, the incidence of malignancies excluding non-melanoma skin cancer was 0.25 per 100 patient-years of follow-up for ustekinumab-treated patients (1 patient in 406 patient-years of follow-up) compared with 0.57 for placebo-treated patients (1 patient in 177 patient-years of follow-up).
100 patientår i opfølgningsperioden for patienter behandlet med ustekinumab (3 patienter i 406 patientår i opfølgningsperioden) sammenlignet med 1, 13 for patienter behandlet med placebo (2 patienter i 176 patientår i opfølgningsperioden).
The incidence of non-melanoma skin cancer was 0.74 per 100 patient-years of follow-up for ustekinumab-treated patients (3 patients in 406 patient-years of follow-up) compared to 1.13 for placebo-treated patients (2 patients in 176 patient-years of follow-up).
100 patientår i opfølgningsperioden for patienter behandlet med ustekinumab (8 patienter i 2. 249 patientår i opfølgningsperioden) og rapporterede maligniteter omfattede bryst -, tyktarms -, hoved - og hals -, nyre -, prostata - og thyroideacancer.
In the controlled and non-controlled portions of psoriasis clinical studies, the incidence of malignancies excluding non-melanoma skin cancers was 0.36 per 100 patient-years of follow-up for ustekinumab-treated patients (8 patients in 2,249 patient-years of follow-up) and malignancies reported included breast, colon, head and neck, kidney, prostate, and thyroid cancers.
Forekomsten af maligniteter rapporteret hos patienter behandlet med ustekinumab var sammenlignelig med den forventede forekomst hos befolkningen som helhed (incidensrate som standard = 0, 68 [95% konfidensinterval:
The rate of malignancies reported in ustekinumab-treated patients was comparable to the rate expected in the general population (standardised incidence ratio = 0.68 [95% confidence interval:
4. 4).
The incidence of non-melanoma skin cancer was 0.80 per 100 patient-years of follow-up for ustekinumab-treated patients (18 patients in 2,245 patient-years of follow-up) (see section 4.4).
Overfølsomhedsreaktioner I kliniske forsøg med ustekinumab er både udslæt og nældefeber observeret hos < 2% af patienterne.
Hypersensitivity reactions In clinical studies of ustekinumab, rash and urticaria have each been observed in < 2% of patients.
Immunogenicitet Omtrent 54% af de patienter, der blev behandlet med ustekinumab, udviklede antistoffer mod ustekinumab, sædvanligvis i lav titer.
Immunogenicity Approximately 5% of ustekinumab-treated patients developed antibodies to ustekinumab, which were generally low-titer.
Der blev ikke observeret nogen åbenbar korrelation mellem udvikling af antistoffer og reaktioner på injektionsstedet.
No apparent correlation of antibody development to injection site reactions was seen.
Imidlertid udelukker forekomsten af antistoffer ikke klinisk effekt.
Efficacy tended to be lower in patients positive for antibodies to ustekinumab; however, antibody positivity does not preclude a clinical response.
Enkeltdoser på op til 4, 5 mg/ kg er blevet indgivet intravenøst i kliniske forsøg uden dosisbegrænsende toksicitet.
Single doses up to 4.5 mg/ kg have been administered intravenously in clinical studies without dose-limiting toxicity.
6 5. 1 Farmakodynamiske egenskaber
5.1 Pharmacodynamic properties
Virkningsmekanisme Ustekinumab er et komplet humant monoklonalt IgG1κ- antistof, der binder sig med høj affinitet og specificitet til p40- proteinunderenheden af de humane cytokiner IL- 12 og IL- 23.
Mechanism of action Ustekinumab is a fully human IgG1κ monoclonal antibody that binds with high affinity and specificity to the p40 protein subunit of the human cytokines IL-12 and IL-23.
Ustekinumab hæmmer bioaktiviteten af human IL- 12 og IL- 23 ved at forhindre, at disse cytokiner binder sig til deres IL- 12Rβ1 - receptorprotein, der er udtrykt på overfladen af immunceller.
Ustekinumab inhibits the activity of human IL-12 and IL-23 by preventing these cytokines from binding to their IL-12Rβ 1 receptor protein expressed on the surface of immune cells.
Ustekinumab kan ikke binde sig til IL- 12 eller IL- 23, der allerede er bundet til celleoverfladereceptoren IL- 12Rβ1.
Ustekinumab cannot bind to IL-12 or IL-23 that is pre-bound to IL-12Rβ 1 cell surface receptors.
Det er derfor ikke sandsynligt, at ustekinumab bidrager til komplement eller antistofmedieret cytotoksicitet i den receptorbærende celle.
Thus, ustekinumab is not likely to contribute to complement- or antibody-mediated cytotoxicity of the receptor-bearing cell.
IL- 12 og IL- 23 er heterodimere cytokiner, der udskilles af aktiverede antigenpræsenterende celler, f. eks. makrofager og dendritiske celler.
IL-12 and IL-23 are heterodimeric cytokines secreted by activated antigen presenting cells, such as macrophages and dendritic cells.
IL- 12 og IL- 23 deltager i immunfunktionen ved at bidrage til aktivering af natural killer - (NK -) celler og CD4+ T- celledifferentiering og aktivering.
IL-12 and IL-23 participate in immune function by contributing to natural killer (NK) cell activation and CD4+ T-cell differentiation and activation.
Imidlertid har abnorm regulering af IL- 12 og IL- 23 været forbundet med immunmedierede sygdomme som psoriasis.
However, abnormal regulation of IL-12 and IL-23 has been associated with immune-mediated diseases, such as psoriasis.
Ustekinumab forhindrer, at IL- 12 og IL- 23 bidrager til aktivering af immunceller, f. eks. intracellulær signalering og udskillelse af cytokiner.
Ustekinumab prevents IL-12 and IL-23 contributions to immune cell activation, such as intracellular signaling and cytokine secretion.
Ustekinumab formodes derfor at afbryde signalering og cytokinkaskader, der er relevante for patologien ved psoriasis.
Thus, ustekinumab is believed to interrupt signaling and cytokine cascades that are relevant to psoriasis pathology.
Klinisk effekt og sikkerhed Sikkerheden ved og effekten af ustekinumab er blevet vurderet hos 1. 996 patienter i 2 randomiserede, dobbeltblinde, placebokontrollerede forsøg hos de patienter med moderat til svær plaque- psoriasis, som var egnede til lysbehandling eller systemisk behandling.
Clinical efficacy and safety The safety and efficacy of ustekinumabwas assessed in 1,996 patients in two randomised, double-blind, placebo-controlled studies in patients with moderate to severe plaque psoriasis and who were candidates for phototherapy or systemic therapy.
I psoriasisforsøg 1 (PHOENIX 1) blev 766 patienter vurderet.
Psoriasis Study 1 (PHOENIX 1) evaluated 766 patients.
De patienter, der var randomiseret til at få placebo i uge 0 og 4, skiftede til at få ustekinumab (enten 45 mg eller 90 mg) i uge 12 og 16 efterfulgt af indgift hver 12. uge.
Patients randomised to receive placebo at Weeks 0 and 4 crossed over to receive ustekinumab (either 45 mg or 90 mg) at Weeks 12 and 16 followed by dosing every 12 weeks.
De patienter, der oprindeligt var randomiseret til ustekinumab, og som opnåede en respons på 75 ud fra Psoriasis Area and Severity Index (en forbedring af PASI- scoren på mindst 75% i forhold til baseline) i både uge 28 og 40, blev genrandomiseret til at få ustekinumab hver 12. uge eller til placebo (dvs. ophør med behandlingen).
Patients originally randomised to ustekinumab who achieved Psoriasis Area and Severity Index 75 response (PASI improvement of at least 75% relative to baseline) at both Weeks 28 and 40 were re-randomised to receive ustekinumab every 12 weeks or to placebo (i. e., withdrawal of therapy).
De patienter, der blev genrandomiseret til placebo i uge 40, fik genoptaget behandlingen med ustekinumab med deres oprindelige dosisregime, når de oplevede et tab på mindst 50% af den forbedring af PASI- scoren, de havde opnået i uge 40.
Patients who were re-randomised to placebo at Week 40 reinitiated ustekinumab at their original dosing regimen when they experienced at least a 50% loss of their PASI improvement obtained at Week 40.
Alle patienter blev fulgt i op til 76 uger efter første indgift af forsøgsbehandlingen.
All patients were followed for up to 76 weeks following first administration of study treatment.
I psoriasisforsøg 2 (PHOENIX 2) blev 1. 230 patienter vurderet.
Psoriasis Study 2 (PHOENIX 2) evaluated 1230 patients.
61% af disse patienter udviste enten manglende respons, var intolerante over for eller havde en kontraindikation mod anden systemisk behandling.
61% of these patients were either non- responsive, intolerant, or had a contraindication to other systemic therapy.
Alle patienter blev fulgt i op til 52 uger efter første indgift af forsøgsbehandlingen.
All patients were followed for up to 52 weeks following first administration of study treatment.
I begge forsøg var der generelt overensstemmelse mellem sygdomskarakteristika ved baseline for alle behandlingsgrupper med en median PASI- score ved baseline fra 17 til 18, en median legemsoverflade (BSA) ≥ 20 ved baseline og median Dermatology Life Quality Index (DLQI) i intervallet fra 10 til 12.
In both studies, baseline disease characteristics were generally consistent across all treatment groups with a median baseline PASI score from 17 to 18 and median baseline Body Surface Area (BSA) ≥ 20, median Dermatology Life Quality Index (DLQI) range from 10 to 12.
Omtrent en tredjedel (PHOENIX 1) og en fjerdedel (PHOENIX 2) af forsøgspersonerne havde psoriasisartritis (PsA).
Approximately one third (PHOENIX 1) and one quarter (PHOENIX 2) of subjects had Psoriatic Arthritis (PsA).
Det primære effektmål i begge forsøg var andelen af patienter, der opnåede PASI 75- respons i forhold til baseline i uge 12 (se tabel 2).
The primary endpoint in both studies was the proportion of patients who achieved PASI 75 response from baseline at Week 12 (see Table 2).
Tabel 2 2)
7 Table 2 Summary of clinical response in Psoriasis Study 1 (PHOENIX 1) and Psoriasis Study 2 (PHOENIX 2)
Oversigt over klinisk respons i psoriasisforsøg 1 (PHOENIX 1) og psoriasisforsøg 2 (PHOENIX
Week 12 (2 injections)
7
Week 28 (3 injections)
Uge 12 (2 injektioner)
Psoriasis Study 1
PASI 50 - respons N (%)
PASI 50 response N (%)
PASI 75 - respons N (%)
PASI 75 response N (%)
PASI 90 - respons N (%)
PASI 90 response N (%)
PGAb af ingen eller minimal N (%)
PGAb of cleared or minimal 10 (4%) N (%)
Psoriasis - forsøg 2
Psoriasis Study 2
41 (10%)
PASI 50 response N (%) 41 (10%)
PGAb af ingen eller minimal N (%) a
PGAb of cleared or minimal 18 (4%) N (%) a
p < 0, 001 for 45 mg eller 90 mg, sammenlignet med placebo (PBO). b PGA = Lægens samlede vurdering
p < 0.001 for 45 mg or 90 mg in comparison b PGA = Physician Global Assessment
I psoriasisforsøg 1 var opretholdelsen af PASI 75 signifikant bedre ved fortsat behandling sammenlignet med behandlingsophør (p < 0, 001).
In Psoriasis Study 1 maintenance of PASI 75 was significantly superior with continuous treatment compared with treatment withdrawal (p < 0.001).
I uge 52 havde 89% af de patienter, der var genrandomiseret til vedligeholdelsesbehandling, PASI 75- respons sammenholdt med 63% af de patienter, der var genrandomiseret til placebo (behandlingsophør) (p < 0, 001).
At Week 52, 89% of patients re-randomised to maintenance treatment were PASI 75 responders compared with 63% of patients re-randomised to placebo (treatment withdrawal) (p < 0.001).
I uge 76 havde 84% af de patienter, der var genrandomiseret til vedligeholdelsesbehandling, et PASI 75 - respons sammenholdt med 19% af de patienter, der var genrandomiseret til placebo (behandlingsophør).
At week 76, 84% of patients re-randomised to maintenance treatment were PASI 75 responders compared with 19% of patients re-randomised to placebo (treatment withdrawal).
Blandt de patienter, der var genrandomiseret til placebo, og som fik genoptaget deres oprindelige behandlingsregime med ustekinumab efter tab af ≥ 50% af deres forbedring af PASI- scoren, genvandt 85% PASI 75- respons inden for 12 uger efter, at de havde genoptaget behandlingen.
In patients re-randomised to placebo, and who reinitiated their original ustekinumab treatment regimen after loss of ≥ 50% of PASI improvement 85% regained PASI 75 response within 12 weeks after re-initiating therapy.
I psoriasisforsøg 1 blev der påvist signifikante forbedringer i uge 2 og uge 12 af DLQI (Dermatology Life Quality Index) i forhold til baseline for hver behandlingsgruppe med ustekinumab sammenlignet med placebo.
In Psoriasis Study 1, at Week 2 and Week 12, significantly greater improvements from baseline were demonstrated in the DLQI in each ustekinumab treatment group compared with placebo.
Forbedringen blev opretholdt til og med uge 28.
The improvement was sustained through Week 28.