natgillin/translations-raw huggingface dataset:
(44- 20) 74 18 84 00 Fax (44- 20) 74 18 86 68 E- mail: mail@ emea. europa. eu http: // www. emea. europa. eu ©EMEA 2007 Reproduction and/ or distribution of this document is authorised for non commercial purposes only provided the EMEA is acknowledged Hvordan blev Aldurazyme undersøgt?
(44-20) 74 18 84 00 Fax (44-20) 74 18 86 68 E-mail: mail@emea. europa. eu http: / /www. emea. europa. eu ©EMEA 2007 Reproduction and/ or distribution of this document is authorised for non commercial purposes only provided the EMEA is acknowledged How has Aldurazyme been studied?
Aldurazyme er blevet undersøgt hos 45 patienter i alderen fem år og derover med den bekræftede diagnose mucopolysaccharidosis I (MPS I).
Aldurazyme has been studied in 45 patients aged five years and over with a confirmed diagnosis of MPS I.
Undersøgelsen sammenlignede virkningen af Aldurazyme med placebo (en uvirksom behandling).
The study compared the effect of Aldurazyme to that of placebo (a dummy treatment).
lungefunktionen (forceret vitalkapacitet) og den afstand, patienterne kunne gå på seks minutter før og efter 26 ugers behandling, men undersøgelsen blev videreført i fire år.
The main measure of effectiveness was the lung function (forced vital capacity, FVC) and the distance the patients could walk over six minutes before and after 26 weeks of treatment, but the study continued for up to four years.
Undersøgelsen så navnlig på lægemidlets sikkerhed, men målte også dets effekt (effekt på reduceringen af GAG- niveauet i urinen og leverens størrelse).
The study was looking mainly at the safety of the medicine, but it also measured its effectiveness (looking at its effect on reducing levels of GAGs in the urine and on the size of the liver).
Hvilke fordele viser undersøgelserne, at der er ved Aldurazyme?
What benefit has Aldurazyme shown during the studies?
Denne virkning blev opretholdt i op til fire år.
This effect was maintained for up to four years.
60%, og halvdelen af de behandlede børn havde en lever af normal størrelse ved undersøgelsens slutning.
In children under five years of age, Aldurazyme reduced the levels of GAGs in the urine by about 60% and half of the children treated had a liver of a normal size at the end of the study.
De fleste af bivirkningerne ved Aldurazyme var snarere infusionsrelaterede reaktioner end reaktioner forårsaget af selve lægemidlet.
Most of the side effects seen with Aldurazyme are reactions caused by the infusion rather than the medicine itself.
De var som regel milde til moderate i intensitet og aftog med tiden.
These are generally mild to moderate in intensity and decrease with time.
De hyppigste bivirkninger ved Aldurazyme hos patienter over fem år (som ses hos flere end 1 ud af 10 patienter) er hovedpine, kvalme, mavesmerter, udslæt, artropati (ledskader), artralgi (ledsmerter), rygsmerter, smerter i ekstremiteterne (hænder og fødder), rødme, pyrexi (feber) og reaktioner på infusionsstedet.
The most common side effects with Aldurazyme in patients over the age of five (seen in more than 1 patient in 10) are headache, nausea (feeling sick), abdominal (tummy) pain, rash, arthropathy (damage to the joints), arthralgia (joint pain), back pain, pain in the extremities (hands and feet), flushing, pyrexia (fever) and reactions at the site of the infusion.
Hos patienter under fem år er almindeligt forekommende bivirkninger forhøjet blodtryk, faldende iltsaturation (en målestok for lungefunktionen), hjertebanken, feber og kulderystelser.
In patients under five years of age, the very common side effects are increased blood pressure, decreased oxygen saturation (a measure of lung function), tachycardia (fast heart rate), pyrexia and chills.
Den fuldstændige liste over de indberettede bivirkninger ved Aldurazyme fremgår af indlægssedlen.
For the full list of all side effects reported with Aldurazyme, see the Package Leaflet.
Aldurazyme må ikke anvendes af personer, som kan få en stærk allergisk reaktion (anafylaktisk reaktion) over for laronidase eller et af de øvrige indholdsstoffer.
Aldurazyme should not be used in people who may have a severe allergic reaction (anaphylactic reaction) to laronidase or any of the other ingredients.
Udvalget for Humanmedicinske Lægemidler (CHMP) besluttede, at Aldurazyme er effektivt til at kontrollere symptomerne på MPS I.
The Committee for Medicinal Products for Human Use (CHMP) decided that Aldurazyme gives effective control of the symptoms of MPS I.
Udvalget besluttede, at fordelene ved Aldurazyme var større end risiciene for en langsigtet enzymsubstitutionsbehandling af patienter med den bekræftede diagnose mucopolysaccharidosis I.
The Committee decided that Aldurazyme’ s benefits are greater than its risks for long-term enzyme replacement therapy in patients with a confirmed diagnosis of MPS I.
Udvalget anbefalede derfor udstedelse af markedsføringstilladelse for Aldurazyme.
The Committee recommended that Aldurazyme be given marketing authorisation.
Aldurazyme er blevet godkendt under ” særlige omstændigheder ”, da det ikke har været muligt at indhente fyldestgørende oplysninger om Aldurazyme, da sygdommen er sjælden.
This means that, because the disease is rare, it has not been possible to obtain complete information about Aldurazyme.
Hvert år gennemgår Det Europæiske Lægemiddelagentur (EMEA) alle nye oplysninger, der måtte foreligge, og opdaterer dette sammendrag efter behov.
Every year, the European Medicines Agency (EMEA) will review any new information that may become available and this summary will be updated as necessary.
Hvilke oplysninger afventes der stadig for Aldurazyme?
What information is still awaited for Aldurazyme?
Firmaet, som fremstiller Aldurazyme, vil overvåge patienterne ved at se på infusionsrelaterede reaktioner og udviklingen af antistoffer.
The company that makes Aldurazyme will monitor patients receiving Aldurazyme, looking at reactions to the infusion and the development of antibodies.
Andre oplysninger om Aldurazyme:
Other information about Aldurazyme:
Europa- Kommissionen udstedte en markedsføringstilladelse med gyldighed i hele Den Europæiske Union for Aldurazyme til Genzyme Europe B. V. den 10. juni 2003.
The European Commission granted a marketing authorisation valid throughout the European Union for Aldurazyme to Genzyme Europe B. V. on 10 June 2003.
Den fuldstændige EPAR for Aldurazyme findes her.
The record of Aldurazyme’ s designation as an orphan medicine is available here The full EPAR for Aldurazyme can be found here.
EU- nummer EU/ 1/ 03/ 253/ 001
EU/ 1/ 03/ 253/ 001
Særnavn Aldurazyme
Aldurazyme
Styrke 100 E/ ml
100 U/ ml
Lægemiddelform Koncentrat til infusionsvæske, opløsning
Concentrate for solution for infusion
Emballage Hætteglas
Vial (glass)
Indhold (koncentration) 5 ml (100 E/ ml)
5 ml (100 U/ ml)
100 E/ ml
100 U/ ml
5 ml (100 E/ ml)
5 ml (100 U/ ml)
Aldurazyme 100 E/ ml koncentrat til opløsning til infusion.
Aldurazyme 100 U/ ml concentrate for solution for infusion
0, 58 mg) laronidase.
1 ml contains 100 U (approximately 0.58 mg) of laronidase.
Den aktive enhed (E) defineres som hydrolysen af én mikromol substrat (4- MUI) pr. minut.
The activity unit (U) is defined as the hydrolysis of one micromole of substrate (4-MUI) per minute.
Laronidase er en rekombinant form af human α- L- iduronidase og fremstilles ved hjælp af rekombinant DNA- teknologi med cellekultur fra hamsterovarier (CHO).
Laronidase is a recombinant form of human α -L-iduronidase and is produced by recombinant DNA technology using mammalian Chinese Hamster Ovary (CHO) cell culture.
Hvert hætteglas med 5 ml indeholder 1, 29 mm natrium.
Each vial of 5 ml contains 1.29 mmol sodium.
Alle hjælpestoffer er anført under pkt 6. 1.
For a full list of excipients, see section 6.1.
Koncentrat til opløsning til infusion.
Concentrate for solution for infusion.
5. 1).
Aldurazyme is indicated for long-term enzyme replacement therapy in patients with a confirmed diagnosis of Mucopolysaccharidosis I (MPS I; α -L-iduronidase deficiency) to treat the non- neurological manifestations of the disease (see section 5.1).
Behandling med Aldurazyme skal overvåges af en læge med erfaring i behandling af patienter med MPS I eller andre arvelige metaboliske sygdomme.
Aldurazyme treatment should be supervised by a physician experienced in the management of patients with MPS I or other inherited metabolic diseases.
Indgivelse af Aldurazyme skal udføres i hensigtsmæssige, kliniske omgivelser, hvor genoplivningsudstyr til akut opståede situationer skal være let tilgængeligt.
Administration of Aldurazyme should be carried out in an appropriate clinical setting where resuscitation equipment to manage medical emergencies would be readily available.
Den anbefalede dosering for Aldurazyme er 100 E/ kg kropsvægt, der indgives én gang om ugen som en intravenøs infusion.
The recommended dosage regimen of Aldurazyme is 100 U/ kg body weight administered once every week as an intravenous infusion.
Den indledende infusionshastighed på 2 E/ kg/ t kan øges i trin for hver 15 minutter, hvis det tåles, til maksimalt 43 E/ kg/ t.
The initial infusion rate of 2 U/ kg/ h may be incrementally increased every fifteen minutes, if tolerated, to a maximum of 43 U/ kg/ h.
3- 4 timer.
The total volume of the administration should be delivered in approximately 3-4 hours.
6. 6, der indeholder yderligere anvisninger.
For information on pre-treatment, see section 4.4 and for further instructions, see section 6.6.
Aldurazymes sikkerhed og virkning hos patienter, der er mere end 65 år, er ikke fastslået, og ingen dosering kan anbefales til disse patienter.
The safety and efficacy of Aldurazyme in patients older than 65 years have not been established and no dosage regimen can be recommended in these patients.
Aldurazymes sikkerhed og virkning hos patienter med nyre - og leverinsufficiens er ikke vurderet, og ingen dosering kan anbefales til disse patienter.
The safety and efficacy of Aldurazyme in patients with renal or hepatic insufficiency have not been evaluated and no dosage regimen can be recommended in these patients.
4. 4 og 4. 8).
Severe hypersensitivity (e. g. anaphylactic reaction) to the active substance or to any of the excipients (see sections 4.4 and 4.8).
4. 8).
Patients treated with Aldurazyme may develop infusion-associated reactions (IARs), defined as any related adverse event occurring during the infusion or until the end of the infusion day (see section 4.8).
Disse patienter bør derfor specifikt fortsat overvåges nøje og kun modtage infusion af Aldurazyme i et hensigtsmæssigt klinisk miljø, hvor genoplivningsudstyr til brug i nødstilfælde er umiddelbart tilgængeligt.
Severe infusion associated reactions have been reported in patients with pre-existent severe underlying upper airway involvement and therefore specifically these patients should continue to be closely monitored and only be infused with Aldurazyme in an appropriate clinical setting where resuscitation equipment to manage medical emergencies would be readily available.
Der skal tages nøje hensyn til patientens kliniske status inden indgivelse af Aldurazyme.
Careful consideration should be given to the patient’ s clinical status prior to administration of Aldurazyme.
På basis af den kliniske fase 3 undersøgelse forventes næsten alle patienter at udvikle IgG- antistoffer over for laronidase, for det meste inden for 3 måneder efter behandlingens påbegyndelse.
Based on the Phase 3 clinical trial, almost all patients are expected to develop IgG antibodies to laronidase, mostly within 3 months of initiation of treatment.
4. 3 og 4. 8).
Patients who have developed antibodies or symptoms of IARs should be treated with caution when administering Aldurazyme (see sections 4.3 and 4.8).
I kliniske undersøgelser kunne IAR normalt styres ved at nedsætte infusionshastigheden og ved at (for) behandle patienten med antihistaminer og/ eller antipyretika (paracetamol eller ibuprofen), hvorved patienten blev i stand til at fortsætte behandlingen.
In clinical studies IARs were usually manageable by slowing the rate of infusion and by (pre-) treating the patient with antihistamines and/ or antipyretics (paracetamol or ibuprofen), thus enabling the patient to continue treatment.
60 minutter før infusionens start for at minimere den eventuelle forekomst af infusionsrelaterede reaktioner.
With initial administration of Aldurazyme or upon re-administration following interruption of treatment, it is recommended that patients be administered pretreatment medicines(antihistamines and/ or antipyretics) approximately 60 minutes prior to the start of the infusion, to minimise the potential occurrence of IARs.
Hvis der er klinisk indikation herfor, bør medicinering før behandling ved efterfølgende infusioner med Aldurazyme overvejes.
If clinically indicated, administration of pretreatment medications with subsequent infusions of Aldurazyme should be considered.
I tilfælde af en mild eller moderat infusionsrelateret reaktion (IAR) skal behandling med antihistaminer og paracetamol/ ibuprofen overvejes og/ eller reduktion af infusionshastigheden til halvdelen af den infusionshastighed, hvor reaktionen optrådte.
In case of a mild or moderate IAR, treatment with antihistamines and paracetamol/ ibuprofen should be considered and/ or a reduction in the infusion rate to half the infusion rate at which the reaction occurred.
I tilfælde af en enkelt, svær IAR skal infusionen afbrydes, til symptomerne er fjernet, og behandling med antihistaminer og paracetamol/ ibuprofen skal overvejes.
In case of a single severe IAR, the infusion should be stopped until the symptoms are resolved and treatment with antihistamines and paracetamol/ ibuprofen should be considered.
Infusionen kan genoptages med en reduktion af infusionshastigheden til 1/ 2 til 1/ 4 af den infusionshastighed, hvor reaktionen optrådte.
The infusion can be restarted with a reduction of the infusion rate to 1/ 2 – 1/ 4 the rate of the infusion at which the reaction occurred.
I tilfælde af en tilbagevendende, moderat IAR eller genudsættelse efter en enkelt, svær IAR skal der overvejes forbehandling (antihistaminer og paracetamol/ ibuprofen og/ eller kortikosteroider) og en reduktion af infusionshastigheden til 1/ 2 til 1/ 4 af den infusionshastighed, hvor den foregående reaktion optrådte.
In case of a recurrent moderate IAR or re-challenge after a single severe IAR, pretreatment should be considered (antihistamines and paracetamol/ ibuprofen and/ or corticosteroids) and a reduction of the infusion rate to 1/ 2 – 1/ 4 the rate of the infusion at which the previous reaction occurred.
6. 6).
3 This medicinal product contains sodium and is administered in 0.9% sodium chloride intravenous solution (see section 6.6).
På basis af dets metabolisme er det ikke sandsynligt, at laronidase vil medføre Cytochrome P450- fremkaldte interaktioner.
Based on its metabolism, laronidase is an unlikely candidate for Cytochrome P450 mediated interactions.
Der foreligger ikke tilstrækkelige data om brugen af Aldurazyme hos gravide.
There are inadequate data on the use of Aldurazyme in pregnant women.
5. 3).
Animal studies do not indicate direct or indirect harmful effects on pregnancy, embryonal/ foetal development, parturition and postnatal development (see section 5.3).
Derfor bør Aldurazyme ikke anvendes under graviditet, medmindre det klart er nødvendigt.
Therefore Aldurazyme should not be used during pregnancy unless clearly necessary.
Laronidase kan udskilles i mælken.
Laronidase may be excreted in milk.
Størstedelen af de relaterede bivirkninger i de kliniske undersøgelser blev klassificeret som infusionsrelaterede reaktioner (IAR), som opstod for 53% af patienterne i fase 3- undersøgelsen (behandlet i op til 4 år) og for 35% af patienterne i undersøgelsen af patienter under 5 år (op til 1 års behandling).
The majority of the related adverse events in the clinical trials were classified as infusion-associated reactions (IARs), experienced by 53% of the patients in the Phase 3 study (treated for up to 4 years) and 35% of the patients in the under 5 study (up to 1 year of treatment).
Størstedelen af IAR’ erne var milde eller moderate i styrke.
The majority of the IARs were mild or moderate in intensity.
De hyppigste uønskede hændelser (ADR’ er) var: hovedpine, kvalme, mavesmerter, udslæt, arthralgi, rygsmerter, smerter i ekstremiteter, flushing, pyrexi, reaktioner på infusionsstedet, forhøjet blodtryk, nedsat iltmætning, takykardi og kulderystelser.
The most frequent adverse drug reactions (ADRs) were: headache, nausea, abdominal pain, rash, arthralgia, backpain, pain at extremity, flushing, pyrexia, infusion site reactions, blood pressure increased, oxygen saturation decreased tachycardia and chills.
ADR' er, der er indberettet under fase 3 undersøgelsen og dennes forlængelse med i alt 45 patienter i alderen 5 år og ældre, der blev behandlet i op til 4 år, er anført nedenfor med anvendelse af følgende frekvenskategorier: meget almindelig (≥ 1/ 10); almindelig (≥ 1/ 100 til < 1/ 10).
ADRs to Aldurazyme reported during the Phase 3 study and its extension in a total of 45 patients age 5 years and older and treated up to 4 years are listed below using the following categories of frequency: very common (≥ 1/ 10); common (≥ 1/ 100 to < 1/ 10).
MedDRA
MedDRA MedDRA
Foretrukken term iht.
Frequency
MedDRA
System Organ Class
Frekvens
Preferred Term
forhøjet legemstemperatur, nedsat iltmætning
oxygen saturation decreased
Hjerte
common
takykardi
headache
almindelig
very common
meget hovedpine
common
Nervesystemet
disorders
paræstesi, svimmelhed
respiratory distress, dyspnoea, cough
almindelig almindelig
common
respirationsbesvær, dyspnø, hoste kvalme, mavesmerter
vomiting, diarrhoea rash
almindelig meget
common very common
Mave- tarmkanalen Hud og subkutane væv
Skin and subcutaneous tissue disorders angioneurotic edema, swelling face,
opkastning, diaré Udslæt angioneurotisk ødem, hævet ansigt, urticaria, pruritus, koldsved, alopeci, hyperhidrosis
urticaria, pruritus, cold sweat, alopecia, hyperhidrosis arthropathy, arthralgia, back pain,
almindelig almindelig meget almindelig almindelig
common
artropati, arthralgi, rygsmerter, smerter i
Musculoskeletal and connective tissue ain extremity disorders
meget
very common
kstremiteter muskelsmerter flushing
musculoskeletal pain flushing Vascular disorders hypotension, pallor, peripheral coldness
almindelig almindelig meget
common very common common
Vaskulære sygdomme
pyrexia, Infusion site reaction
hypotension, bleghed, perifer kuldefølelse pyreksi, reaktioner på infusionsstedet
chills, feeling hot, feeling cold, fatigue, influenza like illness
almindelig almindelig meget
common
Almene symptomer og reaktioner på administrationsstedet
system disorders
kulderystelser, følelse af varme, følelse af kulde, træthed, influenzalignende sygdom
anaphylactic reaction
Immunsystemet Psykiske forstyrrelser
Psychiatric disorders
anafylaktisk reaktion hvileløshed
restlessness
De fleste ADR’ er var milde til moderate i styrke.
Most of the ADRs were mild to moderate in severity.
Erfaringer efter markedsføringen med infusionsrelaterede reaktioner afslørede regelmæssig indberetning af tilfælde af pyrexi, kulderystelser og opkastning, for det meste af mild til moderat intensitet.
Post-marketing experience of infusion associated reactions revealed reporting of pyrexia, chills and vomiting, mostly mild to moderate in intensity.
4. 4).
Additionally, a few patients who had a prior history of severe MPS I- related upper airway and pulmonary involvement, experienced severe reactions including bronchospasm, respiratory arrest, and facial oedema (see section 4.4).
Pædiatrisk population Uønskede hændelser, der blev indberettet under fase 2 undersøgelsen med i alt 20 patienter i alderen 5 år eller yngre, hovedsagligt af den alvorlige fænotype og behandlet med Aldurazyme i op til 12 måneder, er anført nedenfor.
Paediatric population ADRs to Aldurazyme reported during a Phase 2 study in a total of 20 patients, under 5 years of age and mainly of the severe phenotype, treated up to 12 months are listed below.
Undersøgelser
System Organ Class
forhøjet blodtryk
Preferred term
meget almindelig
Investigations
nedsat iltmætning
blood pressure increased
meget almindelig
Very common
takykardi
oxygen
Almene symptomer og reaktioner på
saturation decreased tachycardia
meget almindelig
Very common Very common
kulderystelser
pyrexia chills
I et fase 4- forsøg fik 33 MPS I- patienter 1 af 4 dosisregimener:
5 In a phase 4 study 33 MPS1 patients received 1 of 4 dose regimens:
100 E/ kg i. v. hver uge (anbefalet dosis), 200 E/ kg i. v. hver uge, 200 E/ kg i. v. hver 2. uge eller 300 E/ kg i. v. hver 2. uge.
100 U/ Kg IV every week (recommended dose), 200 U/ Kg IV every week, 200 U/ Kg IV every 2 weeks or 300 U/ Kg IV every 2 weeks.
Gruppen på den anbefalede dosis havde det færreste antal patienter, som fik ADR’ er og IAR’ er.
The recommended dose group had the fewest number of patients who experienced ADRs and IARs.
Typen af IAR’ er svarede til den, der blev observeret i andre kliniske forsøg.
The type of IARs was similar to those seen in other clinical studies.
Immunogenicitet Stort set alle patienter udviklede IgG- antistoffer mod laronidase.
Immunogenicity Almost all patients developed IgG antibodies to laronidase.
Ved afslutningen af fase 3- undersøgelsen (eller på tidspunktet for frafald i undersøgelsen) havde 13/ 45 patienter ingen påviselige antistoffer ifølge en radioimmunpræcipitations- analyse (RIP), hvilken omfattede 3 patienter, som aldrig havde serokonverteret.
By the end of the Phase 3 study (or at time of early study withdrawal), 13/ 45 patients had no detectable antibodies by radioimmunoprecipitation (RIP) assay, including 3 patients that had never seroconverted.
Patienter, som ikke havde lave antistofniveauer, havde et kraftigt fald i GAG- niveauet i urin, hvorimod patienter med høje antistoftitre udviste et variabelt fald i GAG- niveauet i urin.
Patients with absent to low antibody levels showed a robust reduction in urinary GAG level, whereas patients with high antibody titers showed variable reduction in urinary GAG.
Den kliniske betydning af dette fund kendes ikke, da der ikke var nogen konsekvente forbindelser mellem IgG- antistofniveauet og de kliniske effekt- endpoints.
The clinical significance of this finding is unknown since there were no consistent relationships between IgG antibody level and clinical efficacy endpoints.
Desuden blev 60 patienter i fase 2 - og fase 3- undersøgelserne testet for in- vitro neutraliserende virkning.
In addition 60 patients in the Phase 2 and 3 studies were tested for in-vitro neutralising effects.
Fire patienter (tre i fase 3 undersøgelsen og en i fase 2 undersøgelsen) udviste marginal til lav hæmning in vitro af laronidase- enzymatisk aktivitet, der ikke syntes at påvirke den kliniske effekt og/ eller reduktion af GAG i urinen.
Four patients (three in the Phase 3 study and one in the Phase 2 study) showed marginal to low level in vitro inhibition of laronidase enzymatic activity, which did not appear to impact clinical efficacy and/ or urinary GAG reduction.
Tilstedeværelsen af antistoffer syntes ikke at være relateret til forekomsten af infusionsrelaterede reaktioner, selvom reaktionernes indtræden typisk faldt sammen med dannelsen af IgG- antistoffer.
The presence of antibodies did not appear to be related to the incidence of IARs, although the onset of IARs typically coincided with the formation of IgG antibodies.
Forekomsten af IgE- antistoffer var ikke fuldt udforsket.
The occurrence of IgE antibodies was not fully explored.
Farmakoterapeutisk klassifikation: enzymer ATC- kode:
Enzymes, ATC code:
Sygdomme i forbindelse med oplagring af mucopolysakkarid skyldes mangel på de specifikke lysosomal- enzymer, der er nødvendige for glykosaminoglycanernes (GAG) katabolisme.
Mucopolysaccharide storage disorders are caused by the deficiency of specific lysosomal enzymes required for the catabolism of glycosaminoglycans (GAGs).