natgillin/translations-raw huggingface dataset:
30%) af alvorlige og livstruende fødselsdefekter såsom: ektromeli (ameli, fokomeli, hemimeli) af over - og/ eller underekstremiteter, mikroti med misdannelse af ydre øregang (blind eller manglende), misdannelser af mellem og indre øre (mindre hyppigt), okulære misdannelser (anoftalmi, microftalmi), medfødte hjertesygdomme, nyremisdannelser.
Thalidomide is a powerful human teratogen, inducing a high frequency (about 30%) of severe and live-threatening birth defects such as: ectromelia (amelia, phocomelia, hemimelia) of the upper and/ or lower extremities, microtia with abnormality of the external acoustic meatus (blind or absent), middle
Andre mindre hyppige misdannelser er også blevet beskrevet.
Other less frequent abnormalities have also been described.
Kvinder i den fertile alder:
Women of childbearing potential:
4. 4).
Women of childbearing potential must use one effective method of contraception for 4 weeks before therapy, during therapy, and during 4 weeks after thalidomide therapy (see section 4.4).
Hvis graviditet forekommer hos en kvinde, der behandles med thalidomid, skal behandlingen straks ophøre, og patienten skal henvises til vurdering og rådgivning hos en læge, der er specialist i eller har erfaring med teratologi.
If pregnancy occurs in a woman treated with thalidomide, treatment must be stopped immediately and the patient should be referred to a physician specialised or experienced in teratology for evaluation and advice.
7 Mandlige patienter med kvindelige partnere i den fertile alder:
Male patients with female partners of childbearing potential:
Da thalidomid kan findes i sæd, skal mandlige patienter benytte kondom i behandlingsperioden og i 1 uge efter pausering og/ eller behandlingsophør ved samleje med en gravid kvinde eller en kvinde i den fertile alder, der ikke benytter effektiv prævention.
As thalidomide is found in semen, male patients must use condoms during treatment and for 1 week after dose interruption and/ or cessation of treatment when having sexual intercourse with a pregnant woman or with a woman with childbearing potential who is not using effective contraception.
Hvis graviditet forekommer hos en partner af en mandlig patient, der tager thalidomid, skal den kvindelige partner henvises til vurdering og rådgivning hos en læge, der er specialist i eller har erfaring med teratologi.
If pregnancy occurs in a partner of male patient taking thalidomide, the female partner should be referred to a physician specialised or experienced in teratology for evaluation and advice.
Det er uklart, om thalidomid udskilles i human modermælk.
It is unknown whether thalidomide is excreted in human breast milk.
Dyreforsøg har vist udskillelse af thalidomid i mælken.
Animal studies have shown excretion of thalidomide in breast milk.
Amning bør derfor ophøre ved behandling med thalidomid.
Therefore breast-feeding should be discontinued during therapy with thalidomide.
4. 7 Virkning på evnen til at føre motorkøretøjer eller betjene maskiner
4.7 Effects on ability to drive and use machines
Der er ikke udført undersøgelser vedrørende virkningen på evnen til at føre motorkøretøjer eller betjene maskiner.
No studies on the effects on the ability to drive and use machines have been performed.
4. 8).
However thalidomide may cause somnolence and blurred vision (see section 4.8).
De mest almindeligt observerede bivirkninger forbundet med anvendelse af thalidomid kombineret med melphalan og prednison er: neutropeni, leukopeni, obstipation, somnolens, paræstesi, perifer neuropati, anæmi, lymfopeni, trombocytopeni, svimmelhed, dysæstesi, tremor og perifert ødem.
The most commonly observed adverse reactions associated with the use of thalidomide in combination with melphalan and prednisone are: neutropenia, leukopenia, constipation, somnolence, paraesthesia, peripheral neuropathy, anaemia, lymphopenia, thrombocytopenia, dizziness, dysaesthesia, tremor and peripheral oedema.
4. 2., 4. 4 og 4. 5).
The clinically important adverse reactions associated with the use of thalidomide in combination with melphalan and prednisone or dexamethasone include: deep vein thrombosis and pulmonary embolism, peripheral neuropathy, severe skin reactions including Stevens Johnson Syndrome and toxic epidermal necrolysis, syncope, bradycardia, and dizziness (see sections 4.2, 4.4 and 4.5).
Tabel 2 indeholder kun bivirkninger, der har en beviselig sammenhæng med thalidomidbehandling.
Table 2 contains only the adverse reactions for which a causal relationship with medicinal product treatment could reasonably be established.
Hyppighederne er baseret på observationer fra det afgørende kliniske sammenligningsstudie af virkningen af thalidomid i kombination med melphalan og prednison hos patienter med tidligere ubehandlet myelomatose.
Frequencies given are based on the observations during a pivotal comparative clinical study investigating the effect of thalidomide in combination with melphalan and prednisone in previously untreated multiple myeloma patients.
Ud over de bivirkninger, som blev observeret i undersøgelsen, angives også bivirkninger forbundet med thalidomid i kombination med dexamethason samt bivirkninger baseret på erfaringer med lægemidlet efter markedsføringen jf. tabel 2.
In addition to the adverse reactions noted in the pivotal study, adverse reactions related to thalidomide in combination with dexamethasone and also those based on post-marketing experience with the medicinal product are provided after Table 2.
Hyppighederne defineres som: meget almindelig (≥ 1/ 10), almindelig (≥ 1/ 100 til < 1/ 10), ikke almindelig (≥ 1/ 1000 til < 1/ 100), sjælden (≥ 1/ 10, 000 til < 1/ 1000), meget sjælden (< 1/ 10, 000, vides ikke (kan ikke vurderes ud fra de tilgængelige data)).
Frequencies are defined as: very common (≥ 1/ 10), common (≥ 1/ 100 to < 1/ 10); uncommon (≥ 1/ 1000 to < 1/ 100); rare (≥ 1/ 10,000 to < 1/ 1000); very rare (< 1/ 10,000, not known (cannot be estimated from the available data)).
Hyppighed af bivirkninger forbundet med thalidomid i kombination med melphalan og prednison
Frequency of adverse reactions with thalidomide in combination with melphalan and prednisone
Systemorganklasse Hjerte
System Organ Class Cardiac disorders
Neutropeni Leukopeni Anæmi Lymfopeni Trombocytopeni 8
Neutropenia Leukopenia Anaemia Lymphopenia Thrombocytopenia
Perifer neuropati * Tremor Svimmelhed Paræstesi Dysæstesi Somnolens
Peripheral neuropathy* Tremor Dizziness Paraesthesia Dysaesthesia Somnolence
Abnorm koordinationsevne
Abnormal coordination
Lungeemboli * Interstitiel lungesygdom Bronkopneumopati Dyspnø
Pulmonary embolism* Interstitial lung disease Bronchopneumopathy Dyspnea
Opkast Mundtørhed
Vomiting Dry mouth
Toksisk hududslæt Udslæt Tør hud
Toxic skin eruption Rash Dry skin
Infektioner og parasitære sygdomme Karsygdomme
Infections and infestations Vascular disorders
Pneumoni Dyb venøs trombose *
Pneumonia Deep vein thrombosis*
Feber Asteni Utilpashed
Pyrexia Asthenia Malaise
Psykiske forstyrrelser * - Se detaljeret afsnit herunder
Psychiatric disorders * - See detailed section below
Forvirring Depression
Confusional state Depression
Ud over de ovennævnte bivirkninger har thalidomid i kombination med dexamethason i andre kliniske undersøgelser som en meget almindelig bivirkning haft træthed; som almindelige bivirkninger: forbigående iskæmi, synkope, svimmelhed, hypotension, humørsvingninger, angst, sløret syn, kvalme og dyspepsi; og som usædvanlige bivirkninger: cerebral apopleksi, divertikelperforation, peritonit, ortostatisk hypotension samt bronkitis.
In addition to the adverse reactions outlined above thalidomide in combination with dexamethasone in other clinical studies led to the very common adverse reaction of fatigue; common adverse reactions of transient ischaemic event, syncope, vertigo, hypotension, mood altered, anxiety, blurred vision, nausea and dyspepsia; and uncommon adverse reactions of cerebrovascular accident, diverticular perforation, peritonitis, orthostatic hypotension and bronchitis.
Yderligere bivirkninger, som ikke observeredes i det sammenlignende studie, men som er knyttet til erfaringer med thalidomid efter markedsføringen omfatter: toksisk epidermal nekrolyse, ileus, hypothyreose og seksuel dysfunktion.
Additional adverse reactions related to post-marketing experience with thalidomide and not seen in the pivotal study include: toxic epidermal necrolysis, intestinal obstruction, hypothyroidism and sexual dysfunction.
Hæmatologiske bivirkninger er sammenlignet med behandlingen i kontrolgruppen, hvor behandlingen i sig selv havde betydelige virkninger på blod - og lymfesystem (tabel 3).
Adverse reactions for haematological disorders are provided compared to the comparator arm, as the comparator has a significant effect on these disorders (Table 3)
Tabel 3:
9 Table 3:
5. 1)
Comparison of haematological disorders for the melphalan, prednisone (MP) and melphalan, prednisone, thalidomide (MPT) combinations in study IFM 99-06 (see section 5.1)
MP (n=193) Grad 3 og 4 *
MP (n=193) Grades 3 and 4*
Neutropeni Leukopeni Anæmi Lymfopeni Trombocytopeni * WHO- kriterier
Neutropenia Leukopenia Anaemia Lymphopenia Thrombocytopenia * WHO Criteria
Teratogenicitet:
Teratogenicity:
4. 4 og 4. 6).
Thalidomide must not be used at any time during pregnancy (see sections 4.4 and 4.6).
4. 4).
An increased risk of DVT and PE has been reported in patients treated with thalidomide (see section 4.4).
9 Perifer neuropati:
Peripheral neuropathy:
4. 4).
Peripheral neuropathy is a very common, potentially severe, adverse reaction of treatment with thalidomide that may result in irreversible damage (see section 4.4).
Forekomsten af neuropatiske hændelser, der fører til afbrydelse, dosisreduktion eller ophør med behandlingen øges med den kumulerede dosis og behandlingens varighed.
Incidence of neuropathy events leading to discontinuation, dose reduction or interruption increases with cumulative dose and duration of therapy.
Der kan forekomme symptomer nogen tid efter, at behandlingen med thalidomid er ophørt, og disse kan forsvinde langsomt eller slet ikke.
Symptoms may occur some time after thalidomide treatment has been stopped and may resolve slowly or not at all.
18 tilfælde af overdosering er beskrevet i litteraturen med doser op til 14, 4 g.
Eighteen cases of overdose have been reported in the literature concerning doses up to 14.4 g.
I tilfælde af overdosering monitoreres patientens vitale tegn, og relevant understøttende behandling gives til opretholdelse af blodtryk og respiration.
In the event of an overdose, the patient’ s vital signs should be monitored and appropriate supportive care given to maintain blood pressure and respiratory status.
Farmakoterapeutisk klassifikation: immunsupprimerende læge middel, ATC- kode:
Pharmacotherapeutic group: immunosuppressive agent, ATC code:
Thalidomid har et kiralt center og benyttes klinisk som racemisk blanding af (+) - (R) - og (-) - (S) - thalidomid.
Thalidomide has a chiral centre and is used clinically as a racemate of (+)-(R)- and (-)-(S)- thalidomide.
Data fra in vitro- undersøgelser samt kliniske forsøg synes at pege i retning af, at de immunmodulerende, antiinflammatoriske og antineoplastiske virkninger af thalidomid er forbundet med supprimering af en for kraftig tumornekrosefaktor- alfa( TNF- α) - produktion, nedregulering af udvalgte celleoverflade- adhæsionsmolekyler involveret i leukocytmigration samt antiangiogenetisk aktivitet.
Data from in vitro studies and clinical trials suggest that the immunomodulatory, anti-inflammatory and anti-neoplastic effects of thalidomide may be related to suppression of excessive tumour necrosis factor-alpha (TNF-α) production, down-modulation of selected cell surface adhesion molecules involved in leukocyte migration and anti-angiogenic activity.
Thalidomid er endvidereet centralt aktivt, non- barbiturat hypnotisk sedativ.
Thalidomide is also a non-barbiturate centrally active hypnotic sedative.
Resultater fra IFM 99- 06, som var et fase 3, randomiseret, ublindet, parallelgruppe, multicenterforsøg har påvist en øget overlevelse, når thalidomid benyttes i kombination med melphalan og prednison i 12 cyklusser af 6 ugers varighed til behandling af nydiagnosticerede patienter med myelomatose.
In
I denne undersøgelse var patienterne 65- 75 år; 41% (183/ 447) af patienterne var 70 år eller derover.
10 this study the age range of patients was 65-75 years, with 41% (183/ 447) of patients 70 years old or older.
Mediandosisen af thalidomid var 217 mg og > 40% af patienterne modtog 9 cyklusser.
The median dose of thalidomide was 217 mg and > 40% of patients received 9 cycles.
Melphalan og prednison blev givet i doser på henholdsvis 0, 25 mg/ kg/ dag og 2 mg/ kg/ dag på dag 1 til 4 af hver 6 - ugerscyklus.
Melphalan and prednisone were dosed at 0.25 mg/ kg/ day and 2 mg/ kg/ day respectively on days 1 to 4 of each 6 weeks cycle.
Ud over per protokol- analysen blev der foretaget en opdatering af IFM 99- 06- studiet, som leverede yderligere 15 måneders opfølgningsdata.
Further to the per protocol analysis, an update was conducted for the IFM 99-06 study providing an additional 15 months follow-up data.
Den mediane samlede overlevelse (OS) var 51, 5 ± 4, 5 og 33, 2 ± 3, 2 måneder i henholdsvis MPT - og MP - gruppenrne (97, 5% KI 0, 42 - 0, 84).
The median overall survival (OS) was 51.6 ± 4.5 and 33.2 ± 3.2 months in the MPT and MP groups, respectively (97.5% CI 0.42 to 0.84).
Denne 18 måneders forskel var statistisk signifikant med en hazard ratio på 0, 59 for reduktion af risikoen for dødsfald i MPT- armen, et 97, 5% konfidensinterval på 0, 42- 0, 84 og en p- værdi på < 0, 001 (se figur 1).
This 18 month difference was statistically significant with a hazard ratio of reduction of risk of death in the MPT arm of 0.59, 97.5% confidence interval of 0.42-0.84 and p-value of < 0.001 (see Figure 1).
10 Figur 1:
Figure 1:
Samlet overlevelse i henhold til behandling
Overall survival according to treatment
Proportion
Proportion
0. 4 Overlevelsestid
0.4
O/ N+
O/ N +
median ± se (måned) 33. 2 ± 3. 2 51. 6 ± 4. 5
median ± se (month)
MP - T
MP -T
Tid fra randomisering (måned) (måned) Tid fra randomisering (month) Time from randomization
Time from randomization (month)
Absorptionen af thalidomid er langsom efter peroral administration.
Absorption of thalidomide is slow after oral administration.
De maksimale plasmakoncentrationer nås 2- 5 timer efter indgivelsen.
The maximum plasma concentrations are reached 2-5 hours after administration.
Plasmaproteinbindingen af (+) - (R) og (-) - (S) enantiomerer blev påvist at være henholdsvis 55% og 65%.
The plasma protein binding of the (+)-(R) and (-)-(S) enantiomers was found to be 55% and 65% respectively.
4. 4).
Therefore, because of the known severe teratogenic effects of the product, during treatment with thalidomide and for 1 week after stopping the treatment, male patients must use condoms if their partner is pregnant or is of childbearing potential not using effective contraception (see section 4.4).
På nuværende tidspunkt er thalidomids præcise stofskiftevej og endelige udfald ikke fuldstændig kendt hos mennesker.
At the present time, the exact metabolic route and fate of thalidomide is not completely known in humans.
Tilgængelige data indikerer, at lægemidlet hovedsageligt nedbrydes ved ikke - enzymatisk hydrolyse.
Available data indicate that the medicinal product is eliminated mainly by non-enzymatic hydrolysis.
En meget lille del af thalidomid katalyseres af cytochrom P450 i levermetabolismen.
There is minimal cytochrome P450 catalysed hepatic metabolism of thalidomide.
Der findes in vitro- data, der angiver at prednison kan fremkalde enzyminduktion, hvilket muligvis kan reducere den systemiske eksponering af samtidigt anvendte medikamenter.
There are in vitro data indicating that prednisone may give rise to enzyme induction which could reduce the
Den gennemsnitlige halveringstid for thalidomid i plasma efter peroral administration af doser på mellem 50 mg og 400 mg var 5, 5 til 7, 3 timer.
The mean elimination half-life of thalidomide in plasma following single oral doses between 50 mg and 400 mg was 5.5 to 7.3 hours.
Den totale systemiske eksponering (AUC) er proportional med dosis under enkeltdosisbetingelser.
Total systemic exposure (AUC) is proportional to dose at single- dose conditions.
Der er ikke observeret tegn på akkumulering eller induktion af metabolismen.
No time dependency of the pharmacokinetics has been observed.
Nedsat lever - og nyrefunktion:
Hepatic and renal insufficiency:
Thalidomids farmakokinetik hos patienter med nedsat nyre - eller leverfunktion er ikke kendt.
The pharmacokinetics of thalidomide in patients with impaired renal or hepatic function is unknown.
Efter et års dosering blev der hos hanhunde observeret reversible galdepropper i canaliculi ved eksponering, der var over 1, 9 gange større end human eksponering.
In the male dog, after one year of dosing, reversible bile plugs in canaliculi were observed at exposures greater than 1.9 fold the human exposure.
Nedsat trombocyttal fandtes i forsøg med mus og rotter.
Decreased platelet counts were noted in the mouse and rat studies.
Sidstnævnte synes at være relateret til thalidomid og forekom ved eksponering, der var over 2, 4 gange større end human eksponering.
The latter appears to be related to thalidomide and occurred at exposures greater than 2.4 fold the human exposure.
I et etårigt hundeforsøg blev der observeret forstørrelse og/ eller blålig misfarvning af mælkekirtlerne og forlænget østrus hos tæver ved eksponering på henholdsvis 1, 8 gange og større end 3, 6 gange human eksponering.
In a one-year dog study, enlarged and/ or blue discoloration of mammary glands and prolonged estrus were observed in females at exposures equal to 1.8 or greater than 3.6-fold the human exposure, respectively.
15, 13 og 39 gange den anslåede kliniske AUC ved anbefalet startdosis.
No evidence of carcinogenicity was observed at exposures approximately 15, 13 and 39 times the estimated clinical AUC at the recommended starting dose in mice, male rats and female rats respectively.
Dyreforsøg har vist forskelle i arternes følsomhed overfor thalidomids teratogene virkninger.
Animal studies have demonstrated differences in species susceptibility to the teratogenic effects of thalidomide.
Et forsøg på kaniner viste ingen påvirkning af fertilitetsindeks hos hverken hanner eller hunner, skønt testikeldegeneration blev observeret hos hannerne.
A study in rabbits demonstrated no effect on fertility indices in males or females although testicular degeneration was observed in males.
En peri - og postnatal toksicitetsundersøgelse udført på kaniner med thalidomid indgivet ved doser på op til 500 mg/ kg/ dag medførte aborter, forøget antal dødfødsler og reduceret levedygtighed af ungerne under amning.
A peri and postnatal toxicity study performed in rabbits with thalidomide administered at doses up to 500 mg/ kg/ day resulted in abortions, increased stillbirths and decreased pup viability during lactation.
Indhold af kapsel:
Capsule contents:
Vandfri laktose Mikrokrystallinsk cellulose Crospovidon (type A) Povidon (K90) Stearinsyre Kolloid, vandfri silica
Anhydrous lactose Microcrystalline cellulose Crospovidone (Type A) Povidone (K90) Stearic acid Colloidal anhydrous silica
Schellak Sort jernoxid (E172) Propylenglycol
Shellac Black iron oxide (E172) Propylene glycol
PVC/ PE/ Aclar/ aluminium blisterpakning med 14 kapsler.
PVC/ PE/ Aclar/ aluminium blister containing 14 capsules
28 kapsler (to blistere) i et brevkort.
28 capsules (two blisters) in a wallet card.
Celgene Europe Ltd Riverside House Riverside Walk Windsor SL4 1NA Storbritannien Tlf.: +44 (0) 1753 240600 Fax: +44 (0) 1753 240899
Celgene Europe Ltd Riverside House Riverside Walk Windsor SL4 1NA United Kingdom Tel: +44 (0)1753 240600 Fax: +44 (0)1753 240899
Detaljeret information om dette lægemiddel er tilgængelig på Det europæiske Lægemiddelagenturs (EMEAs) hjemmeside: http: // www. emea. europa. eu
Detailed information on this medicinal product is available on the website of the European Medicines Agency (EMEA): http: / /www. emea. europa. eu.
Tafarnaubach Industrial Estate Tredegar Gwent NP22 3AA Storbritannien
Tafarnaubach Industrial Estate Tredegar Gwent NP22 3AA United Kingdom
Lægemidlet må kun udleveres efter begrænset recept (jf. bilag I:
Medicinal product subject to restricted medical prescription. (see Annex 1:
4. 2).
Summary of Product Characteristics, section 4.2.).
Indehaveren af markedsføringstilladelsen udarbejder detaljerne for et kontrolleret distributionssystem med de kompetente, nationale myndigheder og skal følge et sådant program nationalt for at sikre, at: o Alle læger og apotekere, der påtænker at ordinere og sælge Thalidomide Celgene, før lanceringen modtager et Kære Sundhedspersonale- brev som beskrevet herunder. o Alt sundhedspersonale, der påtænker at ordinere (og efter aftale med den kompetente nationale myndighed, sælge) Thalidomide Celgene, før ordinering forsynes med undervisningsmateriale til sundhedspersonale, der indeholder følgende: o Brochure til sundhedspersonale o Patientbrochurer o Patientkort o Produktresumé, indlægsseddel og etikettering
The MAH shall agree the details of a controlled distribution system with the National Competent Authorities and must implement such programme nationally to ensure that: o Prior to launch, all doctors and pharmacists who intend to prescribe or dispense Thalidomide Celgene receive a Dear Healthcare Professional letter as described below. o Prior to prescribing all healthcare professionals who intend to prescribe (and in agreement with the National Competent Authority, dispense) Thalidomide Celgene are provided with an Educational Healthcare Professional’ s Kit containing the following: o Healthcare professional booklet o Patient booklets o Patient cards o Summary of Product Characteristics, Package Leaflet and Labelling
Indehaveren af markedsføringstilladelsen skal aftale den endelige tekst i Kære Sundhedspersonale- brevet og indholdet af undervisningsmaterialet til sundhedspersonalet med de kompetente, nationale myndigheder i hvert medlemsland forud for markedsføring af produktet samt sikre, at det indeholder de nøgleelementer, der er beskrevet herunder.
The MAH should agree the final text of the Dear Healthcare Professional letter and the contents of the Educational Healthcare Professional’ s Kit with the National Competent Authority in each Member State prior to marketing of the product and ensure that the materials contain the key elements as described below.
Indehaveren af markedsføringstilladelsen skal også før lancering af produktet aftale
The MAH should also agree with each Member State prior to the launch of the product: o The most appropriate strategies to monitor the off label use within national territories
15 følgende med medlemsstaterne: o De mest hensigtmæssige strategier til at monitorere off- label- brug inden for nationale grænser o Indsamling af detaljerede oplysninger, der som minimum omfatter patientdemografi og indikation, til nøje overvågning af off- label- brug inden for de nationale grænser o implementering af nationale tiltag til vurdering af effektiviteten og overholdelsen af PSF.
16 o The collection of detailed data with at least patient demographics and indication in order to monitor closely the off-label use within national territory o The set-up of national measures to assess the effectiveness of and compliance with the PPP.
Indehaveren af markedsføringstilladelsen skal underrette EMEA og de relevante repræsentanter for patienter og ofre i det pågældende land om den foreslåede lanceringsdato forud for lanceringen i hver medlemsstat.
The MAH shall notify the EMEA and the appropriate national patients and victims representatives of the proposed launch date before launch in each Member State.