natgillin/translations-raw huggingface dataset:
4. 8).
Since mitotane increases plasma levels of steroid binding proteins, free cortisol and corticotropin (ACTH) determinations are necessary for optimal dosing of steroid substitution (see section 4.8).
Shock, svært traume eller infektion:
Shock, severe trauma or infection:
Mitotan bør temporært afbrydes umiddelbart efter shock, svært traume eller infektion, da adrenal suppression er dets primære virkning.
Mitotane should be temporarily discontinued immediately following shock, severe trauma or infection, since adrenal suppression is its prime action.
Monitorering af plasmaniveauer:
Monitoring of plasma levels:
Mitotanplasmaniveauer bør monitoreres med henblik på justering af dosis af mitotan, navnlig hvis høje startdoser anses for nødvendige.
Mitotane plasma levels should be monitored in order to adjust the mitotane dose, particularly if high starting doses are considered necessary.
4. 2).
Dose adjustments may be necessary to achieve the desired therapeutic levels in the window between 14 and 20 mg/ l and avoid specific adverse reactions (see section 4.2).
Nedsat lever - eller nyrefunktion:
Hepatic or renal impairment:
Der er utilstrækkelige data til at understøtte anvendelsen af mitotan hos patienter med kraftigt nedsat lever - eller nyrefunktion.
There are insufficient data to support the use of mitotane in patients with severe hepatic or renal impairment.
4. 2).
In patients with mild or moderate hepatic or renal impairment, caution should be exercised and monitoring of mitotane plasma levels is particularly recommended (see section 4.2).
Mitotan vævsakkumulation:
Mitotane tissue accumulation:
Fedtvæv kan fungere som reservoir for mitotan, hvilket medfører en øget halveringstid og mulig akkumulering af mitotan.
Fat tissue can act as a reservoir for mitotane, resulting in a prolonged half-life and potential accumulation of mitotane.
Monitorering af mitotanplasmaniveauer (f. eks. hver anden måned) er derfor også nødvendig efter seponering af behandling, da der kan forekomme længerevarende frigørelse af mitotan.
Therefore, monitoring of mitotane plasma levels (e. g. every two months) is also necessary after interruption of treatment, as prolonged release of mitotane can occur.
Forsigtighed og nøje monitorering af mitotanplasmaniveauet anbefales kraftigt ved behandling af overvægtige patienter.
Caution and close monitoring of mitotane plasma levels are highly recommended when treating overweight patients.
Forstyrrelser i centralnervesystemet:
Central nervous system disorders:
Længerevarende, løbende indgivelse af høje doser af mitotan kan lede til reversibel hjerneskade og funktionsnedsættelse.
Long-term continuous administration of high doses of mitotane may lead to reversible brain damage and impairment of function.
4. 8).
Behavioural and neurological assessments should be made at regular intervals, especially when mitotane plasma levels exceed 20 mg/ l (see section 4.8).
Blødningstid:
Bleeding time:
4. 8).
Prolonged bleeding time has been reported in patients treated with mitotane and this should be taken into account when surgery is considered (see section 4.8).
Warfarin og coumarin- lignende antikoagulantia:
Warfarin and coumarin-like anticoagulants:
4. 5).
Physicians should closely monitor patients for a change in anticoagulant dose requirements when administering mitotane to patients on coumarin-like anticoagulants (see section 4.5).
Stoffer, der metaboliseres af cytokrom P450:
Substances metabolised through cytochrome P450:
Mitotan er en hepatisk enzym- inducer og bør anvendes med forsigtighed i tilfælde af samtidig anvendelse af lægemidler influeret af hepatisk enzyminduktion
Mitotane is a hepatic enzyme inducer and it should be used with caution in case of concomitant use of medicinal products influenced by hepatic enzyme
4. 5).
3 induction (see section 4.5).
Kvinder i den fødedygtige alder:
Women of childbearing potential:
4. 6).
Women of childbearing potential must use effective contraception during treatment with mitotane (see section 4.6).
Hos børn og unge kan der observeres neuro- psykologisk retardering under behandling med mitotan.
In children and adolescents, neuro-psychological retardation can be observed during mitotane treatment.
Spironolacton:
Spironolactone:
4. 3).
Mitotane must not be given in combination with spironolactone, since this active substance may block the action of mitotane (see section 4.3).
Warfarin og coumarinlignende antikoagulantia:
Warfarin and coumarin-like anticoagulants:
Mitotan er blevet rapporteret at fremme metaboliseringen af warfarin ved hepatisk mikrosomal enzyminduktion, hvilket kan medføre behov for øget dosis af warfarin.
Mitotane has been reported to accelerate the metabolism of warfarin through hepatic microsomal enzyme induction, leading to an increase in dose requirements for warfarin.
Lægerne bør derfor monitorere patienterne tæt med henblik på eventuel ændring af dosis af antikoagulans, når der gives mitotan til patienter på coumarinlignende antikoagulantia.
Therefore, physicians should closely monitor patients for a change in anticoagulant dose requirements when administering mitotane to patients on coumarin-like anticoagulants.
Substanser metaboliseret via cytokrom P450:
Substances metabolised through cytochrome P450:
Mitotan har vist sig at have en induktiv virkning på cytokrom P450 enzymer.
Mitotane has been shown to have an inductive effect on cytochrome P450 enzymes.
Plasmakoncentrationerne af stoffer metaboliseret via cytokrom P450 kan derfor ændres.
Therefore, the plasma concentrations of the substances metabolised via cytochrome P450 may be modified.
På grund af manglende information om de specifikke involverede P450 isoenzymer bør der udvises forsigtighed, når der samtidig ordineres aktive substanser, der metaboliseres i dette system, såsom bl. a. antikonvulsiva, rifabutin, rifampicin, griseofulvin og perikon (Hypericum perforatum).
John’ s wort (Hypericum perforatum).
Lægemidler med indvirkning på centralnervesystemet:
Medicinal products active on central nervous system:
4. 8).
Mitotane can cause central nervous system undesirable effects at high concentrations (see section 4.8).
Madvarer med højt fedtindhold:
Fat-rich food:
Data med forskellige formuleringer af mitotan antyder, at administration sammen med madvarer med højt fedtindhold fremmer absorptionen af mitotan.
Data with various mitotane formulations suggest that administration with fat-rich food enhances absorption of mitotane.
Hormonbindende protein:
Hormone binding protein:
Mitotan har vist sig at øge plasmaniveauer af hormonbindende protein (f. eks. kønshormonbindende globulin (SHBG) og kortikosteroidbindende globulin (CBG)).
Mitotane has been shown to increase plasma levels of hormone binding proteins (e. g. sex hormone-binding globulin (SHBG) and corticosteroid-binding globulin (CBG)).
Graviditet Data for anvendelse af mitotan hos et begrænset antal gravide indikerer abnormiteter i binyrerne hos fostret.
Pregnancy Data on a limited number of exposed pregnancies indicate abnormalities on the adrenals of the foetus after exposure to mitotane.
5. 3).
Animal studies with similar substances have shown reproductive toxicity (see section 5.3).
Lysodren bør kun gives til en gravid kvinde, hvis der er klart behov for det, og hvis den kliniske fordel klart opvejer enhver potentiel risiko for fostret.
Lysodren should be given to a pregnant woman only if clearly needed and if the clinical benefit clearly outweighs any potential risk to the foetus.
Kvinder i den fødedygtige alder skal anvende sikker kontraception under behandling og efter seponering af behandlingen, så længe mitotan kan detekteres i plasma.
Women of childbearing potential must use effective contraception during treatment and after discontinuation of treatment as long as mitotane plasma levels are detectable.
Den forlængede elimination af mitotan efter seponering af Lysodren bør tages i betragtning.
The prolonged elimination of mitotane from the body after discontinuation of Lysodren should be considered.
Amning Grundet mitotans lipofile natur vil det sandsynligvis blive udskilt i modermælken.
Lactation Due to the lipophilic nature of mitotane, it is likely to be excreted in breast milk.
4. 3) og efter seponering af behandlingen, så længe mitotan kan detekteres i plasma.
Breast-feeding is contraindicated while taking mitotane (see section 4.3) and after treatment discontinuation as long as mitotane plasma levels are detectable.
5 4. 7 Virkninger på evnen til at føre motorkøretøj eller betjene maskiner
4 4.7 Effects on ability to drive and use machines
Lysodren har en væsentlig indflydelse på evnen til at køre og betjene maskiner.
Lysodren has a major influence on the ability to drive and use machines.
Mere end 80% af patienter behandlet med mitotan har udvist mindst én type bivirkning.
More than 80% of patients treated with mitotane have shown at least one type of undesirable effect.
Frekvensgrupperne er defineret efter følgende konvention:
Frequency groupings are defined according to 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).
Bivirkningsfrekvens identificeret ud fra litteraturdata:
Frequency of adverse reactions identified from literature data Adverse reaction
Bivirkning Organklasse
System Organ Class
Forhøjede leverenzymer Forhøjet plasmakolesterol Forhøjede plasmatriglycerider
Elevated liver enzymes Plasma cholesterol increased Plasma triglycerides increased
Nedsat blodurinsyre
Blood uric acid decreased
Leukopeni Blødningstid forlænget
Leucopoenia Bleeding time prolonged
Ataksi Paræstesi Vertigo Søvnighed
Ataxia Paresthesia Vertigo Sleepiness
Mental svækkelse Polyneuropati Bevægelsesforstyrrelse Svimmelhed Hovedpine
Mental impairment Polyneuropathy Movement disorder Dizziness Headache
Makulopati Retinal toksicitet Diplopi Uklar linse Nedsat syn Sløret syn
Maculopathy Retinal toxicity Diplopia Lens opacity Visual impairment Vision blurred
Mucositis Opkastning
Mucositis Vomiting Diarrhoea Nausea Epigastric discomfort
Diarré Kvalme Epigastrisk ubehag
Salivary hypersecretion
Det endokrine system Metabolisme og ernæring
Endocrine disorders Metabolism and nutrition disorders
Binyrebarkinsufficiens Anoreksi Hyperkolesterolæmi Hypertriglyceridæmi
Adrenal insufficiency Anorexia Hypercholesterolemia Hypertriglyceridaemia
Thyroideasvækkelse Hypourikæmi
Thyroid impairment Hypouricaemia
Infektioner og parasitære sygdomme
5 Infections and infestations
Hypertension
Hypertension Orthostatic hypotension Flushing
Almene symptomer og reaktioner på administrationsstedet
General disorders and Asthenia administration site conditions
Lever og galdeveje
Hepatobiliary disorders Reproductive system Gynaecomastia and breast disorders Psychiatric disorders Confusion
Leverskade (hepatocellulær/ cholestatis k/ blandet)
Liver damage (hepatocellular/ cholestatic / mixed)
Gastrointestinale forstyrrelser er oftest rapporteret (10 til 100% af patienterne) og er reversible, når dosis bliver reduceret.
Gastrointestinal disorders are the most frequently reported (10 to 100% of patients) and are reversible when the dose is reduced.
Bivirkninger ved nervesystemet forekommer hos cirka 40% af patienter.
Nervous system undesirable effects occur in approximately 40% of patients.
Alvorlige bivirkninger synes forbundet med den kumulative eksponering for mitotan og vil sandsynligvis forekomme, når mitotanplasmaniveauet er på 20 mg/ l eller derover.
Serious undesirable effects appear linked to the cumulative exposure to mitotane and are most likely to occur when mitotane plasma levels are at 20 mg/ l or above.
4. 4).
Nervous system undesirable effects appear reversible after cessation of mitotane treatment and decrease in plasma levels (see section 4.4).
Hududslæt, der er blevet rapporteret hos 5 til 25% af patienterne, synes ikke at være dosisrelaterede.
Skin rashes which have been reported in 5 to 25% of patients do not seem to be dose related.
Leukopeni er blevet rapporteret hos 8 til 12% af patienterne.
Leucopoenia has been reported in 8 to 12% of patients.
Selvom den nøjagtige mekanisme ved sådan en virkning er ukendt, og dens forbindelse med mitotan eller med den underliggende lidelse er usikker, bør det tages i betragtning, når der overvejes operation.
Prolonged bleeding time appears a frequent finding (90%): although the exact mechanism of such an effect is unknown and its relation with mitotane or with the underlying disease is uncertain, it should be taken into account when surgery is considered.
Aktiviteten af leverenzymer (gamma- GT, aminotransferase, alkalisk fosfatase) er almindeligvis øget.
The activity of liver enzymes (gamma-GT, aminotransferase, alkaline phosphatase) is commonly increased.
Autoimmun hepatitis er blevet rapporteret hos 7% af patienterne uden anden information om mekanismen.
Autoimmune hepatitis has been reported in 7% of patients with no other information on mechanism.
Muligheden for mitotan- induceret leverskade kan derfor ikke udelukkes.
Therefore, the possibility of mitotane-induced liver damage cannot be excluded.
Hos pœdiatriske patienter Neuro- psykologisk retardering kan observeres under behandling med mitotan.
Paediatric patients Neuro-psychological retardation may be observed during mitotane treatment.
Hypothyroidisme og vækstbegrænsning kan også observeres.
Hypothyroidism and growth retardation may be also observed.
Mitotan overdosering kan lede til svækkelse af centralnervesystemet, især hvis mitotanplasmaniveauet er over 20 mg/ l.
Mitotane overdose may lead to central nervous system impairment especially if mitotane plasma levels are above 20 mg/ l.
Det anbefales at øge frekvensen af monitorering af mitotanplasmaniveauet (f. eks. hver anden uge) hos patienter, der er i risiko for overdosering (f. eks. ved nyre - eller leverskade, hos overvægtige patienter eller patienter med nyligt vægttab).
It is recommended to increase frequency of mitotane plasma level monitoring (e. g. every two weeks) in patients at risk of overdose (e. g. in case of renal or hepatic impairment, obese patients or patients with a recent weight loss).
7 5.
6 5.
5. 1 Farmakadynamiske egenskaber
5.1 Pharmacodynamic properties
Antineoplastiske midler ATC kode:
Other antineoplastic agents, ATC code:
Virkningsmekanisme Mitotan er en adrenal cytotoksisk aktiv substans, selvom det tilsyneladende også kan medføre adrenal hæmning uden cellulær destruktion.
Mechanism of action Mitotane is an adrenal cytotoxic active substance, although it can apparently also cause adrenal inhibition without cellular destruction.
Administrationen af mitotan ændrer den ekstra- adrenale metabolisme af kortisol hos mennesket, ledende til en reduktion i målbare 17- hydroxy kortikosteroider, også selvom plasmaniveauer af kortikosteroider ikke falder.
The administration of mitotane alters the extra-adrenal metabolism of cortisol in humans, leading to a reduction in measurable 17-hydroxy corticosteroids, even though plasma levels of corticosteroids do not fall.
Mitotan medfører tilsyneladende øget formation af 6- beta- hydroxyl kolesterol.
Mitotane apparently causes increased formation of 6-beta- hydroxy cholesterol.
Klinisk effekt Mitotan er ikke blevet undersøgt i et omfattende klinisk udviklingsprogram.
Clinical efficacy Mitotane has not been studied in a comprehensive clinical development program.
Blandt de sidste finder tre undersøgelser kun sådan en øgning hos patienter, hos hvem mitotanplasmaniveauet er over 14 mg/ l.
Among the latter, three studies find such an increase only in patients in whom mitotane plasma is above 14 mg/ l.
Udtrykt i total eller delvis tumor - og/ eller metastaseregression, har elve undersøgelser vist nogen grad af forbedring og nogle gange til tider længerevarende remissioner.
In terms of total or partial tumour and/ or metastasis regression, eleven studies have shown some degree of improvement and sometimes occasional prolonged remissions.
I adskillige undersøgelser mangler imidlertid de objektive kriterier for evaluering af tumorrespons eller er ikke rapporteret.
However, in several studies, the objective criteria for evaluating tumour response are missing or not reported.
Der er ikke desto mindre undersøgelser, der giver nøjagtig information om tumorregression eller forsvinden og demonstrerer, at tærsklen på 14 mg/ l synes nødvendig for at inducere en objektiv tumorregression.
There are nevertheless some studies which provide accurate information on tumour regression or disappearance and demonstrate that the threshold of 14 mg/ l appears necessary to induce an objective tumour regression.
Klinisk information kommer hovedsagelig fra en prospektiv afprøvning (n= 24 patienter) hos børn og unge, som ved diagnose var i alderen fra 5 måneder til 16 år (aldersmedian:
Paediatric patients Clinical information comes mainly from a prospective trial (n= 24 patients) in children and adolescents aged at diagnosis from 5 months to 16 years (median age:
4 år), der havde en ikke - resektérbar primærtumor, eller som udviste et tumor tilbagefald eller en metastatisk sygdom; de fleste af børnene (75%) fremstod med endokrine symptomer.
4 years) who had an unresectable primary tumour or who presented a tumour recurrence or a metastasic disease; most of the children (75%) presented with endocrine symptoms.
Der var tilbagefald hos 40% af børnene; overlevelsesraten efter 5 år var 49%.
There were recurrences in 40% of children; the survival rate at 5 years was 49%.
Absorption I en undersøgelse udført med 8 patienter med adrenalt carcinom behandlet med mitotan 2 til 3 g dagligt, blev der fundet en yderst signifikant korrelation mellem plasma mitotankoncentrationen og den totale mitotandosis.
Absorption In a study performed in 8 patients with adrenal carcinoma treated with 2 to 3 g daily of mitotane, a highly significant correlation was found between plasma mitotane concentration and the total mitotane dose.
Målt plasma mitotankoncentration (14 mg/ l) blev nået hos alle patienter indenfor 3 til 5 måneder, og den totale mitotandosis strakte sig mellem 283 og 387 g (median værdi:
The target plasma mitotane concentration (14 mg/ l) was reached in all patients within 3 to 5 months and the total mitotane dose ranged between 283 and 387 g (median value:
Tærsklen på 20 mg/ l blev nået for kumulative mængder mitotan på cirka 500 g.
The threshold of 20 mg/ l was reached for cumulative amounts of mitotane of approximately 500 g.
I en anden undersøgelse fik 3 patienter med adrenalt carcinom Lysodren i henhold til en præcis protokol, der tillod hurtig introduktion af en høj dosis, hvis produktet blev godt tolereret:
In another study, 3 patients with adrenal carcinoma received Lysodren according to a precise protocol allowing fast introduction of a high dose if the product was well tolerated:
3 g (som 3 indtagelser) på dag 1, 4, 5 g på dag 2, 6 g på dag 3, 7, 5 g på dag 4 og 9 g på dag 5.
3 g (as 3 intakes) on day 1, 4.5 g on day 2, 6 g on day 3, 7.5 g on day 4 and 9 g on day 5.
Denne dosis Lysodren blev fortsat eller nedsat som funktion af bivirkninger og plasma mitotanniveauer.
This dose of Lysodren was continued or decreased in function of side effects and plasma mitotane levels.
Hos to af de 3 patienter blev plasmaniveauer på mere end 14 mg/ l opnået indenfor 15 dage og hos en af dem, blev niveauer over 20 mg/ l opnået indenfor cirka 30 dage.
In two of the 3 patients, plasma levels of more than 14 mg/ l were achieved within 15 days and in one of them levels above 20 mg/ l were achieved within approximately 30 days.
Derudover fortsatte, i begge undersøgelser, hos nogle patienter, plasma mitotanniveauer med at stige på trods af vedligeholdelse eller en nedgang i den daglige dosis mitotan.
In addition, in both studies, in some patients, the plasma mitotane levels continued to rise despite maintenance or a decrease of the daily dose of mitotane.
8 Fordeling Obduktionsdata fra patienter viser, at mitotan bliver fundet i de fleste af kroppens væv, med fedt som det primære sted for opbevaring.
7 Distribution Autopsy data from patients show that mitotane is found in most tissues of the body, with fat as the primary site of storage.
Metabolisme Metabolismeundersøgelser hos mennesket har identificeret den tilhørende syre, 1, 1 - (o, p '- dichlordiphenyl) eddikesyre (o, p ’ - DDA), som den væsentlige cirkulerende metabolit, sammen med mindre mængder af 1, 1 - (o, p' - dichlordiphenyl) - 2, 2 dichlorethen (o, p ’ - DDE) analogen af mitotan.
Metabolism Metabolism studies in man have identified the corresponding acid, 1,1-(o, p'-dichlorodiphenyl) acetic acid (o, p’ -DDA), as the major circulating metabolite, together with smaller quantities of the 1,1-(o, p'- dichlorodiphenyl)-2,2 dichloroethene (o, p’ -DDE) analogue of mitotane.
Intet uændret mitotan er blevet fundet i galde eller i urin, hvor o, p ’ - DDA prædominerer, sammen med adskillige af dens hydroxylerede metabolitter.
No unchanged mitotane has been found in bile or in urine, where o, p’ -DDA predominates, together with several of its hydroxylated metabolites.
4. 5.
For induction with cytochrome P450, see section 4.5.
Udskillelse Efter intravenøs administration blev 25% af dosis udskilt som metabolitter inden for 24 timer.
Excretion After intravenous administration, 25% of the dose was excreted as metabolites within 24 hours.
Ikke- kliniske data på den almene toksicitet af mitotan er begrænset.
Non-clinical data on the general toxicity of mitotane is limited.
Majsstivelse Mikrokrystallinsk cellulose (E 460) Macrogol 3350 Silica, kolloid, vandfri
Maize starch Microcrystalline cellulose (E 460) Macrogol 3350 Silica colloidal anhydrous
Firkantet, ugennemsigtig, hvid HDPE flaske indeholdende 100 tabletter.
Square opaque white HDPE bottle containing 100 tablets.
6. 6 Regler for destruktion og anden håndtering
8 6.6 Special precautions for disposal and other handling
9 Dette lægemiddel bør ikke håndteres af personer udover patienten og hans/ hendes plejepersonale og især ikke af gravide kvinder.
This medicinal product should not be handled by persons other than the patient and his/ her caregivers, and especially not by pregnant women.
Ikke anvendte lægemidler samt affald heraf bør destrueres i henhold til lokale retningslinjer for cytotoksiske lægemidler.
Any unused product or waste material should be disposed of in accordance with local requirements for cytotoxic medicinal products.
Laboratoire HRA Pharma 15 rue Béranger 75003 Paris Frankrig
Laboratoire HRA Pharma 15 rue Béranger 75003 Paris France
DAT0 FOR FØRSTE MARKEDSFØRINGSTILLADELSE/ FORNYELSE AF TILLADELSEN
DATE OF FIRST AUTHORISATION/ RENEWAL OF THE AUTHORISATION
Detaljeret information om dette lægemiddel findes på EMEA’ s (European Medicines Agency) website 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/
10 BILAG II
9 ANNEX II
VIRKSOMHEDSGODKENDELSE
10 A MANUFACTURING AUTHORISATION HOLDER RESPONSIBLE FOR BATCH RELEASE
Via del Murillo Km 2, 800 04010 Sermoneta (Latina) Italien
2.800 04010 Sermoneta (Latina) Italy
ETIKETTERING
13 PARTICULARS TO APPEAR ON THE OUTER PACKAGING AND ON THE IMMEDIATE PACKAGING
INSTRUKTIONER FOR ANVENDELSEN
PACKAGE LEAFLET
- Spørg lægen eller på apoteket, hvis der er mere, De vil vide.
- If you have further questions, please ask your doctor or pharmacist.
- Lægen har ordineret Lysodren til Dem personligt.
- This medicine has been prescribed for you.
Lysodrens virkning og hvad De skal bruge det til 2.
What Lysodren is and what it is used for 2.
Det skal De vide, før De begynder at tage Lysodren 3.
Before you take Lysodren 3.
Sådan skal De tage Lysodren 4.
How to take Lysodren 4.
Sådan opbevarer De Lysodren 6.
How to store Lysodren 6.
LYSODRENS VIRKNING OG HVAD DE SKAL BRUGE DET TIL
WHAT LYSODREN IS AND WHAT IT IS USED FOR