natgillin/translations-raw huggingface dataset:
Derfor bør den behandlende læge vurdere de potentielle fordele og risici forbundet med at fortsætte behandlingen hos patienter, som ikke udviser hæmatologisk og/ eller klinisk forbedring efter 2 behandlingscykler.
Therefore, the potential benefit and risks associated with continued therapy in patients who do not show haematological and/ or clinical improvement after 2 treatment cycles should be assessed by the treating physician.
4. 5 og 4. 8).
Patients with cardiac disease and those taking medicinal products known to affect blood pressure or cardiac function should be closely monitored during treatment with clofarabine (see sections 4.5 and 4.8).
Der er ingen erfaring med patienter med nyreinsufficiens (serum- kreatinin ≥ 2 x ULN for aldersgruppen), og clofarabin udskilles hovedsageligt via nyrerne.
There is no experience in patients with renal insufficiency (serum creatinine ≥ 2 x ULN for age) and clofarabine is predominately excreted via the kidneys.
4. 2 og 4. 3).
Therefore, clofarabine should be used with caution in patients with mild to moderate renal insufficiency (see sections 4.2 and 4.3).
4. 2 og 5. 2).
However, these limited data indicate that clofarabine may accumulate in patients with decreased creatinine clearance (see sections 4.2 and 5.2).
4. 5 og 4. 8).
The concomitant use of medicinal products that have been associated with renal toxicity and those eliminated by tubular secretion should be avoided particularly during the 5 day clofarabine administration period (see sections 4.5 and 4.8).
Derfor bør clofarabin anvendes med forsigtighed til patienter med mild til moderat nedsættelse af leverfunktionen (se pkt.
Therefore, clofarabine should be used with caution in patients with mild to moderate hepatic impairment (see sections 4.2 and 4.3).
4. 5 og 4. 8).
The concomitant use of medicinal products that have been associated with hepatic toxicity should be avoided wherever possible (see sections 4.5 and 4.8).
Enhver patient, som for tredje gang får en svær toksicitetsreaktion (NCI- CTC grad 3- toksicitet), en svær toksicitetsreaktion, der ikke aftager i løbet af 14 dage (bortset fra kvalme og opkastning), eller en
4 Any patient who experiences a severe toxicity (US NCI CTC Grade 3 toxicity) on a third occasion, a severe toxicity that does not recover within 14 days (excluding nausea and vomiting), or a life-threatening or disabling toxicity (US NCI CTC Grade 4 toxicity) should be withdrawn from treatment with clofarabine (see section 4.2).
Det svarer til 3, 08 mmol (eller 70, 77 mg) natrium, og der bør tages højde for dette hos patienter på diæt med kontrolleret natriumindhold.
This is equivalent to 3.08 mmol (or 70.77 mg) of sodium and should be taken into consideration for patients on a controlled sodium diet.
Der er endnu ikke udført formelle interaktionsforsøg med clofarabin.
No formal interaction studies have been performed to date with clofarabine.
Der er dog ikke kendskab til klinisk signifikante interaktioner med andre lægemidler eller laboratorieundersøgelser.
However, there are no known clinically significant interactions with other medicinal products or laboratory tests.
Clofarabin metaboliseres ikke i påviselig grad via cytochrom P450 - (CYP450 -) enzymsystemet.
Clofarabine is not detectably metabolised by the cytochrome P450 (CYP) enzyme system.
Derfor er det usandsynligt, at clofarabin skulle reagere med aktive stoffer, der hæmmer eller inducerer CYP450- enzymer.
Therefore, it is unlikely to interact with active substances which inhibit or induce cytochrome P450 enzymes.
Endvidere er det usandsynligt, at clofarabin skulle hæmme et af de 5 største humane CYP- isoformer (1A2, 2C9, 2C19, 2D6 og 3A4) eller inducere 2 af disse isoformer (1A2 og 3A4) ved de plasma- koncentrationer, der opnås efter en intravenøs infusion af 52 mg/ m2/ dag.
In addition, clofarabine is unlikely to inhibit any of the major 5 human CYP isoforms (1A2, 2C9, 2C19, 2D6 and 3A4) or to induce 2 of these isoforms (1A2 and 3A4) at the plasma concentrations achieved following intravenous infusion of 52 mg/ m2/ day.
Clofarabin udskilles hovedsageligt via nyrerne, og leveren er et muligt målorgan for toksicitet.
Clofarabine is predominately excreted via the kidneys and the liver is a potential target organ for toxicity.
Samtidig brug af lægemidler, som er sat i forbindelse med nyretoksicitet, eller som udskilles via nyretubili, bør derfor undgås, hvilket især gælder under de fem dages aktiv behandling med clofarabin (se pkt.
Hence, the concomitant use of medicinal products that have been associated with renal toxicity and those eliminated by tubular secretion should be avoided particularly during the 5 day clofarabine administration period (see sections 4.4, 4.8 and 5.2).
4. 4 og 4. 8).
In addition, the concomitant use of medicinal products that have been associated with hepatic toxicity should be avoided wherever possible (see sections 4.4 and 4.8).
4. 4 og 4. 8).
Patients taking medicinal products known to affect blood pressure or cardiac function should be closely monitored during treatment with clofarabine (see sections 4.4 and 4.8).
5. 3).
Studies in animals have shown reproductive toxicity including teratogenicity (see section 5.3).
Evoltra bør derfor ikke anvendes under graviditet, og især ikke i løbet af det første trimester, med mindre det er klart nødvendigt (dvs. kun hvis den potentielle fordel for moderen opvejer den potentielle risiko for fostret).
Therefore, Evoltra should not be used during pregnancy, especially not during the first trimester, unless clearly necessary (i. e. only if the potential benefit to the mother outweighs the risk to the foetus).
4. 3).
However, because of the potential for serious adverse reactions in nursing infants, breastfeeding should be discontinued prior to, during and following treatment with Evoltra (see section 4.3).
Fertile kvinder og seksuelt aktive mænd skal anvende sikker prævention under behandlingen.
Females of childbearing potential and sexually active males must use effective methods of contraception during treatment.
5. 3).
Dose related toxicities on male reproductive organs have been observed in mice, rats and dogs, and toxicities on female reproductive organs have been observed in mice (see section 5.3).
4. 7 Virkninger på evnen til at føre motorkøretøj eller betjene maskiner
5 4.7 Effects on ability to drive and use machines
De foreliggende oplysninger er baseret på data fra kliniske forsøg, hvor 132 patienter (> 1 og < 21 år) enten med ALL eller akut myeloid leukæmi (AML) fik mindst én dosis clofarabin.
The information provided is based on data generated from clinical trials in which 132 patients (> 1 and < 21 years old) with either ALL or acute myeloid leukaemia (AML) received at least one dose of clofarabine.
115 (87%) af disse patienter fik den anbefalede dosis clofarabin på 52 mg/ m2/ dag, idet 14 patienter fik under 52 mg/ m2/ dag og 3 patienter fik over 52 mg/ m2/ dag.
One hundred and fifteen (87%) of these patients received the recommended clofarabine dose of 52 mg/ m2/ day with 14 patients receiving less than 52 mg/ m2/ day and 3 patients receiving more than 52 mg/ m2/ day.
129 patienter (98% af den samlede population) fik mindst én bivirkning, der af investigator ansås for at være relateret til clofarabin.
One hundred and twenty nine patients (98% of the total population) experienced at least one adverse event considered by the study investigator to be related to clofarabine.
De hyppigst rapporterede bivirkninger var kvalme (61% af patienterne), opkastning (61%), febril neutropeni 32%), hovedpine (24%), pyreksi (21%), pruritus (21%) og dermatitis (20%).
Those most frequently reported were nausea (61% of patients), vomiting (61%), febrile neutropenia (32%), headache (24%), pyrexia (21%), pruritus (21%) and dermatitis (20%).
Selv om 76 patienter (58%) fik mindst én alvorlig bivirkning, der kunne henføres til clofarabin, var der kun 2 patienter, der indstillede behandlingen på grund af en bivirkning, som i begge tilfælde var hyperbilirubinæmi, hvilket den ene fik efter at have fået clofarabin i doser på 52 mg/ m2/ dag og den anden i doser på 70 mg/ m2/ dag.
Although 76 patients (58%) experienced at least one serious clofarabine-related adverse event, only 2 patients discontinued treatment because of an adverse reaction; both with hyperbilirubinaemia, one after receiving 52 mg/ m2/ day and one after 70 mg/ m2/ day clofarabine.
Én patient fik clofarabin- relateret akut systemisk vaskulær lækage- syndrom, hvilket var en medvirkende årsag til hjertestop, én patient døde af respirationshæmning og hepatocellulær skade, én patient af septisk shock og multiorgansvigt og én af multiorgansvigt.
However, the deaths of 4 patients were considered by the study investigator to be related to treatment with clofarabine: one patient experienced clofarabine-related acute vascular leak syndrome that contributed to cardiac arrest; one patient died from respiratory distress and hepatocellular damage; one patient from septic shock and multi-organ failure; and one patient from multi-organ failure.
Bivirkninger, der anses for at være relateret til clofarabin og rapporteredes i kliniske forsøg med hyppighed ≥ 1/ 100 (d. v. s. hos > 1/ 132 patienter) (Meget almindelig = ≥ 1/ 10, Almindelig = ≥ 1/ 100, < 1/ 10) Infektiøse og parasitære sygdomme
Adverse events considered to be related to clofarabine reported at frequencies ≥ 1/ 100 (i. e. in > 1/ 132 patients) in clinical trials (Very common = ≥ 1/ 10; Common = ≥ 1/ 100 to < 1/ 10) Infections and infestations
Septisk shock *, sepsis, bakteriæmi, pneumoni, herpes zoster, herpes simplex, infektion omkring implantat, oral kandidose
Septic shock*, sepsis, bacteraemia, pneumonia, herpes zoster, herpes simplex, implant infection, oral candidiasis
Godartede og ondartede svulster (herunder cyster og polypper)
Neoplasms benign and malignant (including cysts and polyps)
Tumorlysesyndrom *
Tumour lysis syndrome*
Meget almindelig:
Blood and the lymphatic system disorders Very common:
Febril neutropeni Almindelig:
Febrile neutropenia Common:
Forstyrrelser i immunsystemet Stofskiftesygdomme og ernæringsbetingede sygdomme Psykiske sygdomme
Neutropenia Immune system disorders Metabolism and nutrition disorders
Overfølsomhed Almindelig:
Hypersensitivity Common:
Dehydrering, anoreksi, nedsat appetit, vægttab Meget almindelig:
Very common:
Angst Almindelig:
Anxiety Common:
Agitation, irritabilitet, rastløshed
Agitation, irritability, restlessness
Perifer neuropati, paræstesier, somnolens, svimmelhed, tremor
Peripheral neuropathy, paraesthesia, somnolence, dizziness, tremor
Sygdomme i det ydre og det indre øre Hjertesygdomme Karsygdomme
Ear and labyrinth disorders Cardiac disorders Vascular disorders
Hørenedsættelse Almindelig:
Hearing impaired Common:
Perikardiel ekssudation *, takykardi * Meget almindelig:
Pericardial effusion*, tachycardia* Very common:
Ansigtsrødmen * Almindelig:
Flushing* Common:
Hypotension *, hæmatom
Hypotension*, haematoma
Systemisk vaskulær lækage syndrom *, og mediastinum Gastrointestinale sygdomme
6 Respiratory, thoracic and mediastinal disorders Gastrointestinal disorders
takypnø, epistaxis, dyspnø, hoste Meget almindelig:
Capillary leak syndrome*, tachypnoea, epistaxis, dyspnoea, cough Very common:
Opkastning, diaré, kvalme Almindelig:
Vomiting, diarrhoea, nausea Common:
Hæmatemese, blødning i munden, smerter i abdomen, smerter i epigastriet, gingival blødning, mundsår, proktalgi, stomatitis
Haematemesis, mouth haemorrhage, abdominal pain, upper abdominal pain, gingival bleeding, mouth ulceration, proctalgia, stomatitis
Gulsot, hyperbilirubinæmi *, forhøjet alanin - og aspartat- aminotransferaser (ALAT * og ASAT *)
Jaundice, hyperbilirubinaemia*, increases in alanine (ALT)* and aspartate (AST)* aminotransferases
Dermatitis, pruritus Almindelig:
Dermatitis, pruritus Common:
Eksfoliativ dermatitis, petekkier, kontusion, palmar- plantar erytrodysæstesi (PPE ~ Hand - and Foot - syndrom), generaliseret udslæt, erytem, pruritus - lignende udslæt, alopeci, makulo- papulært udslæt, hudsygdom, lokaliseret eksfoliation, erytematøst hududslæt, hyperpigmentering af hud, øget svedtendens, tør hud
Exfoliative dermatitis, petechiae, contusion, palmar-plantar erythrodysaesthesia syndrome, generalised rash, erythema, pruritic rash, alopecia, maculo-papular rash, skin disorder, localised exfoliation, erythematous rash, skin hyperpigmentation, increased sweating, dry skin
Sygdomme i bevægeapparatet og bindevæv
Musculoskeletal, connective tissue and bone disorders Renal and urinary disorders General disorders and administration site conditions * = see below
Almindelig:
Chest wall pain, bone pain, neck and back pain, limb pain, myalgia, arthralgia Common:
Hæmaturi * Meget almindelig:
Haematuria* Very common:
Pyreksi, slimhindeinflammation, træthed Almindelig:
Pyrexia, mucosal inflammation, fatigue Common:
Multiorgansvigt, smerter, rigor, ødem, perifert ødem, forandringer i mental status, hedetur, utilpashed
Multi-organ failure, pain, rigors, oedema, peripheral oedema, mental status changes, feeling hot, feeling abnormal
Infektiøse og parasitære sygdomme:
Infections and infestations adverse events:
45% af patienterne havde haft en eller flere vedvarende infektioner før behandlingen med clofarabin.
Forty five percent of patients had one or more ongoing infections prior to receiving treatment with clofarabine.
81% af patienterne fik dog mindst én hændelse i form af en infektiøs eller parasitær sygdom, efter at de var begyndt at få clofarabin (se pkt.
However, 81% of patients experienced at least one infections and infestations adverse event after receiving clofarabine (see section 4.4).
39 hændelser hos 22/ 132 patienter ansås for at være relateret til clofarabin, og disse ansås for alvorlige: infektion omkring implantat (1 tilfælde), sepsis (1 tilfælde) og septisk shock (2 tilfælde, hvor 1 patient døde (se ovenfor)).
Thirty nine events in 22/ 132 patients were considered to be related to clofarabine of which implant infection (1 event), sepsis (1 event) and septic shock (2 events; 1 patient died (see above)) were considered to be serious.
Systemisk inflammatorisk respons- syndrom (SIRS) eller systemisk vaskulær lækage- syndrom:
Systemic Inflammatory Response Syndrome (SIRS) or capillary leak syndrome:
4. 4).
SIRS, capillary leak syndrome or tumour lysis syndrome were reported as an adverse event in 10% (13/ 132) of patients (see section 4.4).
Disse bivirkninger ansås for at være relateret til clofarabin hos 11 patienter:
These events were considered to be related to clofarabine in 11 patients:
SIRS (2 tilfælde, som begge blev anset for alvorlige), systemisk vaskulær lækage- syndrom (3 tilfælde, som alle var alvorlige) og tumorlysesyndrom (7 tilfælde, hvoraf 4 var alvorlige).
SIRS (2 events; both were considered to be serious), capillary leak syndrome (3 events; all of which were serious) and tumour lysis syndrome (7 events; 4 of which were serious).
Hjertesygdomme:
Cardiac disorders adverse events:
47% af patienterne fik mindst én hændelse i form af hjertesygdom.
Forty seven percent of patients experienced at least one cardiac disorders adverse event.
4. 4).
Fifteen events in 12/ 132 patients were considered to be related to clofarabine, none of which were serious and the most frequently reported being tachycardia (7 events; see section 4.4).
De fleste af disse tilfælde af takykardi var dog forbigående og med sinusrytme og rapporteredes hos patienter, som havde konfunderende anæmi og/ eller infektioner.
However, the majority of these tachycardia events were transient, of sinus rhythm and reported in patients who had confounding anaemia and/ or infections.
Perikardiel ekssudation og perikarditis optrådte som bivirkning hos 8% (hos 10/ 132) af patienterne.
Pericardial effusion and pericarditis were reported as an adverse event in 8% (10/ 132) of patients.
Disse tilfælde blev efterfølgende alle vurderet til at være relateret til clofarabin: perikardiel ekssudation (9 tilfælde, hvoraf 1 var alvorlig) og perikarditis (1 hændelse, der ikke var alvorlig).
These events were all subsequently assessed as being related to clofarabine: pericardial effusion (9 events; 1 of which was serious) and pericarditis (1 event; not serious).
Hos de fleste patienter (8/ 10) ansås perikardiel ekssudation og perikarditis for at være asymptomatisk og uden eller kun med ubetydelig klinisk signifikans ifølge vurdering af ekkokardiografi.
In the majority of patients (8/ 10), the pericardial effusion and pericarditis were deemed to be asymptomatic and of little or no clinical significance on echocardiographic assessment.
Perikardiel ekssudation var imidlertid klinisk signifikant hos 2 patienter, som i en vis grad var hæmodynamisk kompromitterede.
However, the pericardial effusion was clinically significant in 2 patients with some associated haemodynamic compromise.
Karsygdomme:
Vascular disorders adverse events:
58% af patienterne fik mindst én hændelse i form af karsygdom.
Fifty eight percent of patients experienced at least one vascular disorders adverse event.
4. 4).
Twenty six events in 24/ 132 patients were considered to be related to clofarabine, the most frequently reported being flushing (15 events; not serious) and hypotension (5 events; one of which was considered to be serious; see section 4.4).
De fleste af disse hypotensive hændelser forekom dog hos patienter, som havde konfunderende svære infektioner.
However, the majority of these hypotensive events were reported in patients who had confounding severe infections.
Nyre - og urinvejssygdomme:
7 Renal and urinary disorders adverse events:
36% af patienterne fik mindst én nyre - og urinvejssygdom.
Thirty six percent of patients experienced at least one renal and urinary disorders adverse event.
Endvidere oplevede 9/ 132
Five adverse events in 4/ 132 patients were considered to be related to clofarabine, none of which were serious; haematuria (4 events) and acute renal failure (1 event).
4. 3 og 4. 4).
In addition, 9/ 132 patients receiving clofarabine had at least severely elevated creatinine (at least US NCI CTC Grade 3 elevated creatinine) and increased blood creatinine was reported as an adverse event that was not related to clofarabine on 2 occasions (see sections 4.3 and 4.4).
Lever - og galdevejssygdomme:
Hepato-biliary disorders adverse events:
Leveren er et potentielt målorgan for clofarabintoksicitet, og 26% af patienterne oplevede mindst ét tilfælde af sygdom i lever - og galdeveje (se pkt.
The liver is a potential target organ for clofarabine toxicity and 26% of patients experienced at least one hepato-biliary disorders adverse event (see sections 4.3 and 4.4).
Akut cholecystitis (1 tilfælde), cholelithiase (1 tilfælde), hepatocellulær skade (1 tilfælde, hvor patienten døde (se ovenfor)) og hyperbilirubinæmi (2 tilfælde, hvor patienterne indstillede behandlingen (se ovenfor)).
Fourteen events in 10/ 132 patients were considered to be related to clofarabine of which acute cholecystitis (1 event), cholelithiasis (1 event), hepatocellular damage (1 event; patient died (see above)) and hyperbilirubinaemia (2 events; patients discontinued therapy (see above)) were considered to be serious.
Endvidere havde 55/ 129 patienter, der fik clofarabin, i hvert fald svært forhøjet ALAT (mindst NCI - CTC- grad 3), 38/ 102 havde forhøjet ASAT og 19/ 131 patienter forhøjet bilirubin.
In addition, 55/ 129 patients receiving clofarabine had at least severely (at least US NCI CTC Grade 3) elevated ALT, 38/ 102 elevated AST and 19/ 131 elevated bilirubin levels.
Alle 5 hændelser ansås for at være alvorlige og relateret til clofarabin.
Increased ALT and increased AST were reported as an adverse event on 2 occasions each and increased blood bilirubin was reported as an adverse event on 1 occasion; all 5 events were considered to be severe and related to clofarabine.
De fleste forhøjelser af ALAT og ASAT forekom inden for 1 uge efter administration af clofarabin og var forbigående (de varede typisk < 2 uger).
The majority of elevations in ALT and AST occurred within 1 week of clofarabine administration and were transient (typically of < 2 weeks duration).
Selv om det forekom mindre hyppigt, syntes forhøjet bilirubin at vare længere.
Although less common, elevations in bilirubin appeared to be more persistent.
Symptomerne på overdosering forventes dog at omfatte kvalme, opkastning, diaré og svær knoglemarvsdepression.
However, possible symptoms of overdose are expected to include nausea, vomiting, diarrhoea and severe bone marrow depression.
Hidtil er den højeste døgndosis administreret til mennesker 70 mg/ m2 5 dage i træk (2 pædiatriske ALL- patienter).
To date, the highest daily dose administered to human beings is 70 mg/ m2 for 5 consecutive days (2 paediatric ALL patients).
Antineoplastiske midler
Antineoplastic agents
Virkemåde:
Mechanism of action:
Clofarabin er en purin nukleosid antimetabolit.
Clofarabine is a purine nucleoside anti-metabolite.
Dets tumorbekæmpende virkning menes at kunne henføres til 3 virkemåder: • DNA- polymerase α- hæmning, der afslutter DNA- kædens elongering og/ eller DNA - syntese/ reparation. • Hæmning af ribonukleotidreduktase med reduktion af cellulære deoxynukleotidphosphat- pools (dNTP- pools). • Nedbrydning af mitokondriel membranintegritet med frigivelse af cytochrom C og andre proapoptotiske faktorer, der medfører programmeret celledød selv hos lymfocytter som ikke er i deling.
Its antitumour activity is believed to be due to 3 mechanisms: • DNA polymerase α inhibition resulting in termination of DNA chain elongation and/ or DNA synthesis / repair. • Ribonucleotide reductase inhibition with reduction of cellular deoxynucleotide triphosphate (dNTP) pools.
Clofarabin må først diffundere eller transporteres til målceller, hvor det fortløbende phosphoryleres til mono - og biphosphat af intracellulære kinaser og til sidst til det aktive konjugat clofarabin -
8 • Disruption of mitochondrial membrane integrity with the release of cytochrome C and other proapoptotic factors leading to programmed cell death even in non-dividing lymphocytes.
8 5 ’ - triphosphat.
Clofarabine must first diffuse or be transported into target cells where it is sequentially phosphorylated to the mono- and bi-phosphate by intracellular kinases, and then finally to the active conjugate, clofarabine 5’ -triphosphate.
Endvidere besidder clofarabin større modstandsevne over for cellulær nedbrydning af adenosin - deaminase og mindre modtagelighed for phosphorolytisk spaltning end andre aktive stoffer i denne klasse, mens clofarabintriphosphats affinitet til DNA- polymerase α and ribonukleotidreduktase svarer til eller overstiger affiniteten til deoxyadenosintriphosphat.
In addition, clofarabine possesses greater resistance to cellular degradation by adenosine deaminase and decreased susceptibility to phosphorolytic cleavage than other active substances in its class whilst the affinity of clofarabine triphosphate for DNA polymerase α and ribonucleotide reductase is similar to or greater than that of deoxyadenosine triphosphate.
In vitro- forsøg har vist, at clofarabin hæmmer cellevækst i og er cytotoksisk over for en lang række hurtigt prolifererende hæmatologiske og faste tumorcellelinier.
In vitro studies have demonstrated that clofarabine inhibits cell growth in and is cytotoxic to a variety of rapidly proliferating haematological and solid tumour cell lines.
Clofarabin var også virksomt mod hvilende lymfocytter og makrofage.
It was also active against quiescent lymphocytes and macrophages.
Med henblik på systematisk evaluering af de responser, som er set hos patienter, har et ublindet uafhængigt responsvurderingsudvalg (Independent Response Review Panel – IRRP) bestemt følgende responsrater baseret på definitioner udarbejdet af Children’ s Oncology Group:
To enable systematic evaluation of the responses seen in patients, an unblinded Independent Response Review Panel (IRRP) determined the following response rates based on definitions produced by the Children’ s Oncology Group: