qanastek/EMEA-V3 huggingface dataset:
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).
Pazjenti li qed jieħdu prodotti mediċinali li huma magħrufa li jaffettwaw l- pressjoni tad- demm jew funzjoni kardijaka għandhom ikunu monitorjati sewwa matul it- trattament b’ clofarabine (ara sezzjonijiet 4. 4 u 4. 8).
There are no data on the use of clofarabine in pregnant women.
M’ hemm l- ebda tagħrif dwar l- użu ta ’ clofarabine minn nisa tqal.
Studies in animals have shown reproductive toxicity including teratogenicity (see section 5.3).
Studju fuq bhejjem urew tossiċità fis- sistema riproduttiva inkluża t- teratoġeniċità (ara sezzjoni 5. 3).
Clofarabine may cause serious birth defects when administered during pregnancy.
Clofarabine għandu mnejn jikkawża difetti serji tat- twelid meta jingħata matul it- tqala.
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).
Għalhekk, Evoltra m’ għandhiex tintuża matul it - tqala, aktar u aktar matul l- ewwel trimestru, għajr meta tkun verament meħtieġa, (p. e. meta l - benefiċċju potenzjali għall- omm ikun akbar mir- riskju għall- fetu).
If a patient becomes pregnant during treatment with clofarabine, they should be informed of the possible hazard to the foetus.
Jekk il- pazjenta issir tqila matul it - trattament b ’ clofarabine, għandhom ikunu informati dwar il- perikulu li jista ’ jkun hemm għall- fetu.
It is unknown whether clofarabine or its metabolites are excreted in human breast milk.
Mhux magħruf jekk clofarabine jew il- metaboliti tiegħu jinżilx fil- ħalib uman tas- sider.
The excretion of clofarabine in milk has not been studied in animals.
L- inżul ta ’ clofarabine fil- ħalib ma ġiex studjat fil- bhejjem.
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).
5 serji fi tfal li huma mreddgħa, it- treddiegħ għandu jitwaqqaf qabel, matul u wara t- trattament b’ Evoltra (ara sezzjoni 4. 3).
Females of childbearing potential and sexually active males must use effective methods of contraception during treatment.
Nisa li jistgħu joħorġu tqal u rġiel li huma sesswalment attivi iridu jużaw meżżi effettivi ta ’ kontraċezzjoni matul it- trattament.
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).
Tossiċitajiet marbuta mad- doża fuq organi riproduttivi maskili kienu osservati fil- ġrieden, firien u klieb, u tossiċitajiet fuq organi riproduttivi femminili kienu osservati fil- ġrieden (ara sezzjoni 5. 3).
As the effect of clofarabine treatment on human fertility is unknown, reproductive planning should be discussed with patients as appropriate.
Peress li l- effett tat- trattament b ’ clofarabine fuq il- fertilità umana mhux magħruf, l- ippjanar riproduttiv għandu jkun diskuss mal- pazjenti b’ mod adattat.
5 4.7 Effects on ability to drive and use machines
4. 7 Effetti fuq il- ħila biex issuq u tħaddem magni
No studies on the effects of clofarabine on the ability to drive and use machines have been performed.
Ma saru l- ebda studji fuq l- effetti ta ’ clofarabine fuq il- ħila biex issuq u tħaddem il- magni.
However, patients should be advised that they may experience undesirable effects such as dizziness, light-headedness or fainting spells during treatment and told not to drive or operate machines in such circumstances.
Imma, il - pazjenti għandhom jingħataw parir li huma għandhom mnejn iħossu ċerti effetti mhux mixtieqa bħal sturdament, iħossuhom sturduti, każijiet ta ’ ħass ħażin matul it- trattament u għandhom jgħidulhom biex ma jsuqux jew iħaddmu magni f' dawn iċ- ċirkustanzi.
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.
It- tagħrif ipprovdut hu bbażat fuq tagħrif ġenerat minn provi kliniċi li fihom 132 pazjent (> 1 u < 21 sena) b' jew b' ALL jew lewkimja mijelojda akuta (AML) ingħataw ta ’ l- anqas doża waħda ta ’ clofarabine.
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.
Mija u ħmistax (87%) minn dawn il- pazjenti ngħataw id- doża rrakkomandata ta ’ clofarabine ta ’ 52 mg/ m2/ kuljum u b' 14- il pazjent ngħataw inqas minn 52 mg/ m2/ kuljum u 3 pazjenti ngħataw aktar minn 52 mg/ m2/ kuljum.
Patients with advanced stages of ALL or AML may have confounding medical conditions that make causality of adverse events difficult to assess due to the variety of symptoms related to the underlying disease, its progression and the co-administration of numerous medicinal products.
Pazjenti li kienu jinsabu fi stati avvanzati ta ’ ALL jew AML għandhom mnejn ikollhom kondizzjonijiet mediċi li huma impossibbli tisseparahom li jagħmlu l- każwalità ta ’ każi avversi diffiċli biex tassessjahom minħabba varjetà ta ’ sintomi li għandhom x’ jaqsmu ma ’ l- marda fondamentali, l - progress tagħha u l- għotja flimkien ta 'prodotti mediċinali numerużi.
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.
Mija u disgħa u għoxrin pazjent (98% tal- popolazzjoni totali) esperjenzaw ta ’ l- anqas każ wieħed avvers li kien meqjus mill- investigatur ta ’ l- istudju li għandu x’ jaqsam ma ’ clofarabine.
Those most frequently reported were nausea (61% of patients), vomiting (61%), febrile neutropenia (32%), headache (24%), pyrexia (21%), pruritus (21%) and dermatitis (20%).
L- iktar komuni kienu dardir (61% tal- pazjenti), ramettar (61%), newtropenija febrili (32%), uġigħ ta ’ ras (24%), deni (21%), prurite (21%) u dermatite (20%).
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.
Għalkemm 76 pazjent (58%) esperjenzaw ta ’ l - anqas każ wieħed avvers serju marbut ma ’ clofarabine, 2 pazjenti biss ma komplewx it- trattament minħabba reazzjoni avversa; it- tnejn bil- iperbilirubinemja, wieħed wara li rċieva 52 mg/ m2/ kuljum u l - ieħor wara li rċieva 70 mg/ m2/ kuljum ta ’ clofarabine.
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.
Biss, il- mewt ta ’ 4 pazjenti kienet meqjusa mill - investigatur ta ’ l- istudju li hi marbuta mat- trattament b ’ clofarabine: pazjent esperjenza sindrom tat - tnixxija vaskulari akuta li kienet marbuta ma 'clofarabine li wasslet għall- arrest kardijaku; pazjent miet minn problema respiratorja u ħsara epatoċellulari; pazjent minn xokk setptiku u falliment multi - organiku: pazjent minn falliment multi- organiku.
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
Każijiet avversi meqjusa bħala marbuta ma ’ clofarabine rrapportati fi frekwenzi ≥ 1/ 100 (p. e. f ’ > 1/ 132 pazjenti) fi studji kliniċi (Komuni ħafna = ≥ 1/ 10; Komuni = ≥ 1/ 100 sa < 1/ 10) Infezzjonijiet u infestazzjonijiet
Septic shock*, sepsis, bacteraemia, pneumonia, herpes zoster, herpes simplex, implant infection, oral candidiasis
Xokk septiku *, sepsi, bakteremja, pnewmonja, erpi żoster, erpi simplex, infezzjoni ta ’ impjant, kandidjasi orali
Neoplasms benign and malignant (including cysts and polyps)
Neoplażmi beninni u malinni (inklużi ċisti u polipi) Disturbi tad- demm u tas- sistema
Tumour lysis syndrome*
Sindrom tal- lysis ta ’ tumur Komuni ħafna:
Febrile neutropenia Common:
limfatika:
Neutropenia Immune system disorders Metabolism and nutrition disorders
Disturbi fis- sistema immuni Disturbi fil- metaboliżmu u n -
Hypersensitivity Common:
Newtropenja Komuni:
Anxiety Common:
Sensittività eċċessiva Komuni:
Agitation, irritability, restlessness
Dejidrazzjoni, anoreksja, inqas aptit,
Nervous system disorders
nutrizzjoni
Very common:
6 Komuni ħafna:
Headache Common:
Ansjetà Disturbi psikjatriċi Komuni:
Peripheral neuropathy, paraesthesia, somnolence, dizziness, tremor
Aġitazzjoni, irritabilità, bla kwiet f ’ ġismu Komuni ħafna:
Ear and labyrinth disorders Cardiac disorders Vascular disorders
Uġigħ ta ’ ras Disturbi fis- sistema nervuża Komuni:
Hearing impaired Common:
Newropatija periferali, parestesja, ħedla ta ’ rqad, sturdament, rogħda Komuni: nuqqas ta’ smigħ Disturbi fil- widnejn u fis- sistema labirintika Komuni:
Pericardial effusion*, tachycardia* Very common:
Effużjoni perikardjali *, takikardja * Disturbi fil- qalb Komuni ħafna:
Flushing* Common:
Ħmura fil- wiċċ * Disturbi vaskulari Komuni:
Hypotension*, haematoma
Ipotensjoni *, ematoma Komuni:
6 Respiratory, thoracic and mediastinal disorders Gastrointestinal disorders
Sindrom ta ’ nixxija kapillari *, Disturbi respiratorji, toraċiċi u medjastinali Disturbi gastro- intestinali Disturbi fil- fwied u fil- marrara:
Capillary leak syndrome*, tachypnoea, epistaxis, dyspnoea, cough Very common:
takipneja, epistassi, dispnea, sogħla Komuni ħafna:
Vomiting, diarrhoea, nausea Common:
Irramettar, dijarea, dardir Komuni:
Haematemesis, mouth haemorrhage, abdominal pain, upper abdominal pain, gingival bleeding, mouth ulceration, proctalgia, stomatitis
Ematemesi, emorraġija fil- ħalq, uġigħ fl- addome, uġigħ fil- parti ta ’ fuq ta ’ l- addome, fsad fil- ħanek, ulċerazzjoni fil- ħalq, proktalġja, stomatite Komuni:
Jaundice, hyperbilirubinaemia*, increases in alanine (ALT)* and aspartate (AST)* aminotransferases
Dermatite, prurite
Skin and subcutaneous tissue disorders
ġilda Disturbi muskolu- skeltrali u tal -
Very common:
Komuni:
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
Uġigħ fil- qafas tas- sider, uġigħ fl -
Musculoskeletal, connective tissue and bone disorders Renal and urinary disorders General disorders and administration site conditions * = see below
connective tissue u tal- għadam
Common:
Ematurja Komuni ħafna:
Chest wall pain, bone pain, neck and back pain, limb pain, myalgia, arthralgia Common:
Deni, infjammazzjoni mukosali, Disturbi ġenerali u kondizzjonijiet ta ’ mnejn jingħata * = ara hawn taħt
Haematuria* Very common:
għejja Komuni:
Multi-organ failure, pain, rigors, oedema, peripheral oedema, mental status changes, feeling hot, feeling abnormal
Falliment multi- organiku, uġigħ, ebusija, edema, edema periferali, tibdil fl- istatus mentali, tħoss sħana, tħossok anormali
Infections and infestations adverse events:
Każi avversi ta ’ infezzjonijiet u infestazzjonijiet:
Forty five percent of patients had one or more ongoing infections prior to receiving treatment with clofarabine.
Ħamsa u erbgħin fil- mija tal- pazjenti kellhom wieħed jew aktar minn infezzjoni kontinwa qabel ma rċevew trattament b’ clofarabine.
However, 81% of patients experienced at least one infections and infestations adverse event after receiving clofarabine (see section 4.4).
Imma, 81% tal - pazjenti esperjenzaw ta ’ l- anqas każ wieħed avvers ta 'infezzjonijiet u infestazzjonijiet wara li ngħataw clofarabine (ara sezzjoni 4. 4).
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.
Disgħa u tletin każ f’ 22/ 132 pazjenti kienu meqjusa li kienu marbuta ma ’ clofarabine li minnhom infezzjoni ta ’ l- impjant (każ wieħed), sepsis (każ wieħed), xokk septiku (2 każi; pazjent wieħed miet (ara hawn fuq)) kienu meqjusa serji.
Systemic Inflammatory Response Syndrome (SIRS) or capillary leak syndrome:
Sindrom ta ’ Rispons Infjammattorju Sistemiku (SIRS) jew sindrom ta ’ nixxija kapillari:
SIRS, capillary leak syndrome or tumour lysis syndrome were reported as an adverse event in 10% (13/ 132) of patients (see section 4.4).
SIRS, sindrom ta ’ nixxija kapillari jew sindrom tal- lysis tat- tumur kienu rrapportati bħala każ avvers f' 10% (13/ 132) tal- pazjenti (ara sezzjoni 4. 4).
These events were considered to be related to clofarabine in 11 patients:
Dawn il- każi kienu meqjusa li kienu marbuta ma 'clofarabine fi 11- il pazjent:
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).
SIRS (2 każi; it- tnejn kienu meqjusa bħala serji), sindrom ta ’ nixxija kapillari (3 każi; kollha kienu serji), u sindrom ta ’ lysis ta 'tumur (7 każi; 4 minnhom kienu serji).
Cardiac disorders adverse events:
7 Każi avversi ta ’ disturbi fil- qalb:
Forty seven percent of patients experienced at least one cardiac disorders adverse event.
Sebgħa u erbgħin fil- mija tal- pazjenti esperjenzaw ta ’ l- anqas każ wieħed avvers ta ’ disturbi fil- qalb.
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).
Ħmistax- il każ f’ 12/ 132 pazjenti kienu meqjusa marbutin ma ’ clofarabine, l- ebda wieħed minnhom ma kien serju u l- aktar wieħed komuni kien takikardja (7 każi; ara sezzjoni 4. 4).
However, the majority of these tachycardia events were transient, of sinus rhythm and reported in patients who had confounding anaemia and/ or infections.
Imma, il- biċċa l- kbira ta ’ dawn il- każi ta ’ takikardja kienu temporanji, ta ’ sinus ritmiku u kien irrapportati f’ pazjenti li kellhom anemija u/ jew infezzjonijiet li hu impossibbli tisseparahom.
Pericardial effusion and pericarditis were reported as an adverse event in 8% (10/ 132) of patients.
Effużjoni perikardjali u perikardite kienu rrapportati bħala każ avvers fi 8% (10/ 132) tal- pazjenti.
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).
Dawn il- każi kienu sussegwentement assessjati bħala marbuta ma 'clofarabine: effużjoni perikardjali (9 każi: wieħed minnhom kien serju) u perikardite (każ wieħed; mhux serju).
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.
Fil- każ tal- biċċa l- kbira tal- pazjenti (8/ 10), l- effużjoni perikardjali u l- perikardite kienu meqjusa li kienu asimptomatiċi u ta ’ importanza żgħira jew ta ’ l- ebda sinifikat kliniku skond assessjament ekocardjografiku.
However, the pericardial effusion was clinically significant in 2 patients with some associated haemodynamic compromise.
Imma, effużjoni perikardjali kienet klinkalment sinifikanti f’ 2 pazjenti b' xi kompromess emodinamiku assoċjat.
Vascular disorders adverse events:
Każi avversi ta ’ disturbi vaskulari:
Fifty eight percent of patients experienced at least one vascular disorders adverse event.
Tmienja u ħamsin fil- mija tal- pazjenti esperjenzaw ta ’ l- anqas każ avvers wieħed ta ’ disturbi vaskulari.
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).
Sitta u għoxrin każ f’ 24/ 132 pazjenti kienu meqjusa marbuta ma ’ clofarabine, l- aktar wieħed komuni kien ħmura fil- wiċċ (15- il każ; mhux serju) u ipotensjoni (5 każi, wieħed minnhom kien meqjus serju; ara sezzjoni 4. 4).
However, the majority of these hypotensive events were reported in patients who had confounding severe infections.
Imma, l- biċċa l- kbira ta ’ dawn il- każi ipotensivi kienu rrapportati f’ pazjenti li kellhom infezzjonijiet severi li huma impossibbli tisseparahom.
7 Renal and urinary disorders adverse events:
Każi avversi ta ’ disturbi fil- kliewi u fis- sistema urinarja:
Thirty six percent of patients experienced at least one renal and urinary disorders adverse event.
Sitta u tletin fil- mija tal- pazjenti esperjenzaw ta ’ l- anqas każ avvers wieħed ta ’ disturbi fil- kliewi u tas- sistema urinarja.
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).
Ħames każi avversi f' 4/ 132 pazjenti kienu meqjusa bħala marbuta ma ’ clofarabine, l- ebda wieħed minnhom ma ’ kien serju; ematurja (4 każi) u falliment akut renali (1 każ).
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).
Barra minn dan, 9/ 132 pazjent li kienu qed jingħataw clofarabine kellhom ta ’ l- anqas kreatinina elevata b’ mod qawwi (ta ’ l- anqas kreatinina elevata ta ’ Grad 3 ta ’ CTC tal- NCI ta ’ l- US) u żieda tal- kreatinina fid- demm kienet irrapportata bħala każ avvers li ma kienx marbut ma ’ clofarabine f’ 2 okkażjonijiet (ara sezzjonijiet 4. 3 u 4. 4).
Hepato-biliary disorders adverse events:
Każi avversi ta ’ disturbi fil- fwied u fil- marrara:
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).
Il- fwied hu potenzjalment organi bersall għat- tossiċità ta ’ clofarabine u 26% tal- pazjenti batew minn ta 'l- anqas każ wieħed avvers ta' disturbi fil- fwied u fil - marrara (ara sezzjonijiet 4. 3 u 4. 4).
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.
Erbatax- il każ f’ 10/ 132 pazjent kienu meqjusa bħala marbuta ma ’ clofarabine li minnhom kien hemm koleċistite akuta (1 każ), kolelitjasis (1 każ), ħsara epatoċelluri (1 każ; il- pazjent miet (ara hawn fuq)) u iperbilirubinemja (2 każi; pazjent ma kompliex it- terapija (ara hawn fuq) kienu meqjusa serji.
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.
Barra minn dan, 55/ 129 pazjenti li ngħataw clofarabine kellhom ta ’ l- anqas ALT elevat b’ mod qawwi (ta ’ l- anqas Grad 3 ta ’ CTC tal- NCI ta ’ l- US), 38/ 102 AST elevat u 19/ 131 livelli elevati tal- bilirubin.
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.
ALT ogħla u AST ogħla kienu rrapportati bħala każi avversi f' 2 okkażjonijiet u bilirubin ogħla fid - demm kien irrapportat bħala każ avvers f' okkazjoni waħda: il- 5 każi kollha kienu meqjusa severi u marbuta ma ’ clofarabine.
The majority of elevations in ALT and AST occurred within 1 week of clofarabine administration and were transient (typically of < 2 weeks duration).
Il- biċċa l- kbira ta ’ elevazzjonijiet f’ ALT u AST ġraw fi żmien ġimgħa min meta ngħata l- clofarabine u kienu temporanji (tipikament dewma ta ’ < 2 ġimgħat).
Although less common, elevations in bilirubin appeared to be more persistent.
Għalkemm kienu anqas komuni, l- elevazzjonijiet fil- bilirubin dehru aktar persistenti.
However, possible symptoms of overdose are expected to include nausea, vomiting, diarrhoea and severe bone marrow depression.
Imma, possibilment is- sintomi ta ’ doża eċċessiva huma mistennija li jinkludu dardir, irramettar, dijarea, u dipressjoni severa tal- mudulun tal- għadma.
To date, the highest daily dose administered to human beings is 70 mg/ m2 for 5 consecutive days (2 paediatric ALL patients).
S’ issa l- ogħla doża ta ’ kuljum li ngħatat lill- bnedmin kienet 70 mg/ m2 għal 5 ġranet konsekuttivi (2 pazjenti ALL pedjatriċi).
The toxicities observed in these patients included vomiting, hyperbilirubinaemia, elevated transaminase levels and maculo-papular rash.
It- tossiċitajiet osservati f’ dawn il- pazjenti kienu jinkludu rramettar, iperbilirubinemja, u livelli elevati ta ’ transaminasi u raxx makulo- papulari.
No specific antidotal therapy exists.
8 M’ hemm l- ebda terapija speċifika antidotali.
Immediate discontinuation of therapy, careful observation and initiation of appropriate supportive measures are recommended.
Il- waqfien immedjat tat- terapija, osservanza bir- reqqa u bidu ta 'mizuri appoġġjati adattati huma rrakkomandati.
Antineoplastic agents
Aġenti antineoplastiċi
ATC code:
Ċodiċi ATC:
This medicinal product has been authorised under “ Exceptional Circumstances”.
Dan il- prodott mediċinali kien awtorizzat taħt “ Ċirkustanzi Eċċezzjonali ”.
This means that due to the rarity of the disease it has not been possible to obtain complete information on this medicinal product.
Dan ifisser li minħabba li l - marda hi rari ma kienx possibbli li tinkiseb informazzjoni kompleta dwar dan il- prodott mediċinali.
The European Medicines Agency (EMEA) will review any new information which may become available every year and this SPC will be updated as necessary.
L - Aġenzija Ewropea dwar il- mediċini (EMEA) ser tirrevedi kull tip ta ’ informazzjoni ġdida li toħroġ kull sena u ser taġġorna dan is- Sommarju tal- Karatteristiċi tal- Prodott skond il- bżonn.
Clofarabine is a purine nucleoside anti-metabolite.
Clofarabine hu anti- metabolit purin nukleosijd.
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.
L- attività tiegħu ta ’ kontra t - tumuri hi maħsuba li hi riżultat ta '3 mekkaniżmi: • Inibizzjoni tad- DNA polymerase α li jwassal għat- tmiem ta ’ l- elongazzjoni tal- katina tad- DNA u/ jew sinteżi/ tiswija tad- DNA. • Inibizzjoni ta ’ Ribonucleotide reductase bi tnaqqis ta ’ għadajjar ta ’ cellular deoxynucleotide triphosphate (dNTP). • Tħarbit ta ’ l- integrità tar- rita mitokondrjali bil- ħruġ ta ’ cytochrome C u fatturi oħra proapoptotiċi li jirriżultaw fil- mewt programmata taċ- ċellula anki fl- limpoċiti li ma jkunux diviżi.
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.
L- ewwelnettt clofarabine irid jinxtered jew ikun trasportat f' ċelluli bersall fejn ikun b’ mod sekwenzjali fosforilatat għal mono - u bi- fosfat bil- kinasi intraċellulari, u fl- aħħar għal konjugat attiv, clofarabine 5 '- triphosphate.
Clofarabine has high affinity for one of the activating phosphorylating enzymes, deoxycytidine kinase, which exceeds that of the natural substrate, deoxycytidine.
Clofarabine għandu affinità għolja ma ’ wieħed mill- enżimi attivanti li jiffosforilizzaw, deoxycytidine kinase, li hu akbar mis- sottostrat naturali, deoxycytidine.
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.
Barra minn dan, clofarabine fih reżistenza akbar għad- degradazzjoni ċellulari b’ adenosin deaminejs u suxxettibilità mnaqqsa għal qsim fosforolitiku minn sustanzi attivi oħra fil- klassi tiegħu waqt li l - affinità ta ’ clofarabine triphosphate għad- DNA polymerejs α u ribonukleotijd reduktejs hi simili għal jew akbar minn dik ta ’ deoxyadenosine triphosphate.
Pharmacodynamic effects:
Effetti farmakodinamiċi:
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.
Studji in vitro wrew li clofarabine jinibixxi l- iżvilupp taċ- ċelluli fil - u hu ċitotossiku għal varjetà ta ’ linji ċellulari ta ’ tumur solidi u dawk ematoloġikali li joktru malajr.
It was also active against quiescent lymphocytes and macrophages.
Kien attiv wkoll kontra limfoċiti passivi u makrofaġi.
In addition, clofarabine delayed tumour growth and, in some cases, caused tumour regression in an assortment of human and murine tumour xenografts implanted in mice.
Barra minn dan, clofarabine dewwem l- iżvilupp tat - tumur u f’ xi każi, ikkawża rigress tat- tumur f’ assortiment ta ’ ksenograffi ta ’ tumuri umani u murini li kienu mpjantati fil- ġrieden.
Clinical efficacy and safety:
Effikaċja u sigurtà klinikali:
Clinical efficacy:
Effikaċja klinikali:
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:
Biex jiffaċilita l- evalwazzjoni sistematika tar- risponsi li dehru fil- pazjenti, Panel tar- Reviżjoni tar- Rispons Indipendenti (IRRP) mhux għami, iddetermina dawn ir- rati ta ’ risponsi li ġejjin ibbażati fuq id- definizzjonijiet ipproduċuti mill- Grupp ta 'l- Onkoloġija tat- Tfal:
CR = Complete Remission
9 RK = Remissjoni Kompleta RKp – Remissjoni Kompleta fin -
Patients who met each of the following criteria: • No evidence of circulating blasts or extramedullary disease • An M1 bone marrow (≤ 5% blasts) • Recovery of peripheral counts (platelets ≥ 100 x 109/ l and ANC ≥ 1.0 x 109/ l)
Pazjenti li ssodisfaw kull wieħed mill- kriterji li ġejjin: • L- ebda xhieda ta ’ ċelluli primittivi ċirkulanti jew mard ekstramedullari • Mudullun tal- għadam M1 (≤ 5% ċelluli primittivi) • Rikopru ta ’ kownts periferali (plejtlits ≥ 100 x 109/ l u ANC ≥ 1. 0 x 109/ l) • Pazjenti li jissodisfaw il- kriterji kollha tal- RK barra mil -
CRp = Complete Remission in the Absence of Total Platelet Recovery PR = Partial Remission
Nuqqas ta ’ Rkupru Komplet ta ’ Pjastrini
• Patients who met all of the criteria for a CR except for recovery of platelet counts to > 100 x 109/ l Patients who met each of the following criteria: • Complete disappearance of circulating blasts • An M2 bone marrow (≥ 5% and ≤ 25% blasts) and appearance of normal progenitor cells • An M1 marrow that did not qualify for CR or CRp
irkupru tal- kownts tal- plejtlits għal > 100 x 109/ l
Overall Remission (OR) Rate
RP = Remissjoni Parzjali Rata ta ’ Remissjoni Totali (RT)
• (Number of patients with a CR + Number of patients with a CRp) ÷ Number of eligible patients who received clofarabine
Pazjenti li ssodisfaw kull wieħed mill- kriterji li ġejjin: • Kien hemm assenza kompleta ta ’ ċelluli primittivi ċirkulanti • Mudullun tal- għadma M2 (≥ 5% u ≤ 25% ċelluli primittivi) u d- dehra ta 'ċelluli normali proġenitriċi • Mudullun M1 li ma jikkwalifikax għal RK jew RKp • (Numru ta ’ pazjenti b’ RK + Numru ta ’ pazjenti li għandhom RKp) ÷ Numru ta ’ pazjenti eliġibbli li rċevew il - clofarabine
The safety and efficacy of clofarabine were evaluated in a phase I, open-label, non-comparative, dose-escalation study in 25 paediatric patients with relapsed or refractory leukaemia (17 ALL; 8 AML) who had failed standard therapy or for whom no other therapy existed.
Is- sigurtà u l- effikaċja ta ’ clofarabine kienu evalwati fi studju ta ’ fażi I, open- label, mhux- komparattiv, eskalazzjoni ta ’ doża f’ 25 pazjent pedjatriku li kellhom lewkimja rkaduta jew refrattarja (17 ALL; 8 AML) li ma għaddewx mit- terapija standard jew li fil- każ tagħhom ma kienx hemm terapija oħra.
Dosing commenced at 11.25 with escalation to 15, 30, 40, 52 and 70 mg/ m2/ day by intravenous infusion for 5 days every 2 to 6 weeks depending on toxicity and response.
Id - dożaġġ beda fil- 11. 25 b’ eskalazzjoni għal 15, 30, 40, 52 u 70 mg/ m2/ kuljum b’ infużjoni għal ġol- vini għal 5 ġranet minn kull 2 sa 6 ġimgħat dejjem jiddependi mit- tossiċità u r- rispons.
Thirteen of these patients (9 ALL, 4 AML) were treated with the 52 mg/ m2/ day clofarabine regimen.
Tlettax minn dawn il- pazjenti (9 ALL, 4 AML) kienu kkurati b’ regimen ta ’ 52 mg/ m2/ kuljum ta ’ clofarabine.
Of the 17 ALL patients, 4 achieved a complete remission (24%; CR) and 1 a partial remission (6%; PR) at varying doses.
Mis- 17 ALL pazjent, 4 kellhom remissjoni kompleta (24%; RK) u 1 remissjoni parzjali (6% RP) f' dożi varji.
Dose-limiting toxicities in this study were hyperbilirubinaemia, elevated transaminase levels and maculo-papular rash experienced at 70 mg/ m2/ day (2 ALL patients; see section 4.9).
Tossiċitajiet limitati mid- doża f’ dan l- istudju kienu iperbilirubinemja, livelli elevati ta ’ transaminasi u raxx makulo- papulari li nħassu f’ 70 mg/ m2/ kuljum (2 ALL pazjenti; ara sezzjoni 4. 9).
The maximum tolerated dose identified in the phase I study described above of 52 mg/ m2/ day clofarabine was
Studju multi- ċentriku, fażi II, open- label, mhux- komparattiv ta ’ clofarabine sar biex jiddetermina r - rata tar- remissjoni totali (RT) f’ pazjenti li ngħataw trattament intensiv minn qabel (≤ 21 sena meta saret dijanjosi inizjali) b’ ALL rikaduta jew refrattorja definit permezz ta ’ l- użu tal- klassifika Franċiża - Amerikana- Brittanika.
9 administered by intravenous infusion for 5 consecutive days every 2 to 6 weeks.
Id- doża massima ttolerata identifikata fl- istudju ta 'fażi I deskritt hawn fuq ta' 52 mg/ m2/ kuljum ta ’ clofarabine ġiet mogħtija permezz ta ’ infużjoni għal ġol- vini għal 5 ġranet konsekuttivi minn kull 2 sa 6 ġimgħat.
The table below summarises the key efficacy results for this study.
Il- tabella t’ hawn taħt tagħti fil- qosor ir- riżultati prinċipali ta ’ effikaċja ta ’ dan l- istudju.
Patients with ALL must not have been eligible for therapy of higher curative potential and must have been in second or subsequent relapse and/ or refractory i. e. failed to achieve remission after at least two prior regimens.
Pazjenti bil- ALL ma setgħux kienu eliġibbli għat- terapija għal- potenzjal kurattiv ogħla u jridu jkunu fit- tieni rikaduta jew dawk sussegwenti u/ jew refrattorji i. e. ma rnexxilhomx li jkollhom remissjoni wara ta 'l- anqas żewġ reġimeni ta' qabel.
Before enrolling in the trial, 58 of the 61 patients (95%) had received 2 to 4 different induction regimens and 18/ 61 (30%) of these patients had undergone at least 1 prior haematological stem cell transplant (HSCT).
Qabel ma nkitbu għal din il- prova, 58 minn 61 pazjent (95%) kienu rċevew minn 2 sa 4 reġimeni differenti ta ’ induzzjoni u 18/ 61 (30%) minn dawn il- pazjenti kienu rċevew minn qabel ta 'l- anqas trapjant wieħed ta' ċelluli steminali ematoloġikali (HSCT).
The median age of treated patients (37 males, 24 females) was 12 years old.
L- età medjana ta ’ pazjenti li ngħataw it- trattament (37 maskili, 24 feminili) kienet ta '12- il sena.
Administration of clofarabine resulted in a dramatic and rapid reduction in peripheral leukaemia cells in 31 of the 33 patients (94%) who had a measurable absolute blast count at baseline.
L- għoti ta 'clofarabine wassal għal tnaqqis drammatiku u ta ’ malajr fiċ- ċelluli periferali tal- lewkimja f’ 31 minn 33 pazjent (94%) li kellhom kownt taċ- ċelluli primittivi assoluti li kien jista ’ jitkejjel fil - linjabażi.
The 12 patients who achieved an overall remission (CR + CRp) had a median survival time of 66.6 weeks as of the data collection cut-off date.
It- 12- il pazjent li kisbu remissjoni totali (RK + RKp) kellhom ħin medjan ta ’ sopravivenza ta ’ 66. 6 ġimgħa mid- data meta twaqqaf il- ġbir tat- tagħrif.
Responses were seen in different immunophenotypes of ALL, including pre-B cell and T-cell.
Ir- risponsi kienu investigati f’ immunofenotipi differenti ta ’ ALL, inklużi pre- B cellula u T- cellula.
Although transplantation rate was not a study endpoint, 10/ 61 patients (16%) went on to receive a HSCT after treatment with clofarabine (3 after achieving a CR, 2 after a CRp, 3 after a PR, 1 patient that was considered a treatment failure by the IRRP and 1 that was considered not evaluable by the IRRP).
Għalkemm ir- rata ta ’ trapjanti ma kienx l- għan aħħari ta 'l- istudju, 10/ 61 pazjenti (16%) komplew sejrin u rċevew HSCT wara t - trattament bil- clofarabine (3 wara li kisbu RK, 2 wara RKp, 3 wara RP, pazjent 1 li kien meqjus li m’ għaddiex mit- trattament mill- IRRP u 1 kien meqjus li ma jistax jiġi evalwat mill- IRRP).
Response durations are confounded in patients who received a HSCT.
Huwa diffiċli tissepara d- dewmien tar- rispons fil- każ ta ’ pazjenti li rċevew HSCT.
Efficacy results from the pivotal study in patients (≤ 21 years old at initial diagnosis) with relapsed or refractory ALL after at least two prior regimens Response
10 Riżultati ta ’ l- effikaċja minn studju pivotali f’ pazjenti (≤ 21 sena fid- dijanjosi inizjali) b’ ALL rikadut jew refrattarju wara ta 'l- anqas żewġ reġimeni li ngħataw minn qabel Kategorija tar - rispons
patients (n = 61)
Pazjenti Dewmien medjan tar - ITT * remissjoni (ġimgħat) (n = 61) (95% CI ***)
remission (weeks) (95% CI)
Ħin medjan ta ’ progressjoni (ġimgħat) ** (95% CI ***)
progression (weeks)** (95% CI)
Is- sopravivenza totali medjana (ġimgħat) (95% CI ***)
survival (weeks) (95% CI)
12 28. 6 (20%) (9. 7 sa 58. 6)
Overall remission (CR + CRp) CR
37. 0 (15. 4 sa 61. 9)
12 (20%) 7 (12%)
66. 6 (53. 7 sa 89. 4)
28.6 (9.7 to 58.6) 47.9 (6.1 to -)
7 47. 9 (12%) (6. 1 sa -)
37.0 (15.4 to 61.9) 56.1 (13.7 to -)
56. 1 (13. 7 sa -)
66.6 (53.7 to 89.4) 66.6 (66.6 to 89.4)
66. 6 (66. 6 sa 89. 4)
CRp
RKp
5 (8%)
5 28. 6 (8%) (4. 6 sa 35. 4)
37.0 (9.1 to 39.4)
37. 0 (9. 1 sa 39. 4)
53.7 (9.1 to -)
53. 7 (9. 1 sa -)
6 (10%)
6 5. 2 (10%) (2. 3 sa -)
8.6 (6.3 to -)
8. 6 (6. 3 sa -)
33.0 (18.1 to -)
33. 0 (18. 1 sa -)
CR + CRp + PR Treatment failure
RK + RKp + RP Falliment tat -
18 (30%) 33 (54%)
18 11. 7 (30%) (6. 1 sa 47. 9) 33 N/ A
11.7 (6.1 to 47.9) N/ A
20. 4 (10. 6 sa 56. 1)
66.6 (42.0 to 89.4) 7.6
66. 6 (42. 0 sa 89. 4)
Not evaluable
trattament Ma jistax jiġi evalwat
10 (16%)
(54%) 10 N/ A (16%)
(3.4 to 5.1)
4. 0 (3. 4 sa 5. 1)
(6.7 to 12.6)
7. 6 (6. 7 sa 12. 6)
All patients
Il- pazjenti kollha
61 (100%)
61 N/ A (100%)
5.4 (4.0 to 6.1)
5. 4 (4. 0 sa 6. 1)
12.9 (7.9 to 18.1)
12. 9 (7. 9 sa 18. 1)
*ITT = intention to treat. **Patients alive and in remission at the time of last follow up were censored at that time point for the analysis.
* ITT = intenzjoni li jingħata kura ** Pazjenti ħajjin u f’ remissjoni fil- perijodu ta ’ l- aħħar follow- up kienu ċċensurati minn dak il - punt tal- ħin għall- analiżi *** Confidence interval
Clinical safety:
Sigurtà klinika:
See section 4.8.
Ara sezzjoni 4. 8.
The pharmacokinetics of clofarabine were studied in 40 patients aged between 2 to 19 years old with relapsed or refractory ALL or AML.
Il- farmakokinetiċi ta ’ clofarabine kienu studjati f’ 40 pazjent ta ’ bejn 2 sa 19- il sena li kellhom ALL jew AML rikadut jew refrattorju.
The patients were enrolled into a single phase I (n = 12) or two phase II (n = 14 / n = 14) safety and efficacy studies, and received multiple doses of clofarabine by intravenous infusion (see section 5.1).
Il- pazjenti kienu miktuba f’ fażi waħda I (n = 12) jew żewġ fażijiet II (n = 14 / n= 14) ta 'studji tas- sigurtà u effikaċja, u rċevew aktar minn doża waħda ta ’ clofarabine permezz ta ’ infużjoni għal ġol- vini (ara sezzjoni 5. 1).
10 Pharmacokinetics in patients aged between 2 to 19 years old with relapsed or refractory ALL or AML following administration of multiple doses of clofarabine by intravenous infusion Parameter
Farmakokinetiċi f’ pazjenti li kellhom bejn 2 sa 19- il sena b’ ALL jew AML rikadut jew refrattorju wara l- għoti ta ’ aktar minn doża waħda ta ’ clofarabine permezz ta ’ infużjoni għal ġol- vini Parametru Distribuzzjoni:
Estimates based on other
Volum ta ’ distribuzzjoni (rata stabbli)
non-compartmental analysis (n = 14 / n = 14)
Estimi bbażati fuq analiżi non - kompartmentali (n= 14 / n = 14) 172 1/ m2
analysis
bbażati fuq analiżi ieħor
Volume of distribution (steady state) Plasma protein binding Serum albumin Elimination:
Irbit tal- proteina fil- plażma Serum albumin Tneħħija:
47.1% 27.0%
47. 1% 27. 0%
Half-life of clofarabine triphosphate
β half- life ta ’ clofarabine Half- life ta ’ clofarabine triphosphate Tneħħija sistematika Tneħħija renali
2
5. 2 sigħat 28. 8 1/ h/ m2 10. 8 1/ h/ m2
> 24 hours
> 24 siegħa
Renal clearance Dose excreted in urine
Doża mneħħija fl- awrina
Multivariate analysis showed that the pharmacokinetics of clofarabine are weight dependent and although white blood cell (WBC) count was identified as having an impact on clofarabine pharmacokinetics, this did not appear sufficient to individualise a patient’ s dosage regimen based on their WBC count.
L- analiżi multivarjata wera li l- farmakokinetiċi ta ’ clofarabine jiddependi mill- piż u għalkemm il - kownt tal- lewkoċiti (WBC) kien identifikat li kellu impatt fuq il- farmakokinetiċi tal- clofarabine, dan ma kienx jidher li kien biżżejjed biex jindividwalizza ir- regimen tad- dożaġġ tal- pazjenti ibbażat fuq il - kownt tagħhom ta ’ WBC.
Intravenous infusion of 52 mg/ m2 clofarabine produced equivalent exposure across a wide range of weights.
Infużjoni għal ġol- vini ta ’ 52 mg/ m2 ta ’ clofarabine ipproduċiet esponiment ekwivalenti li kien mifrux fuq firxa wiesgħa ta 'piżijiet.
However, Cmax is inversely proportional to patient weight and, therefore, small children may have a higher Cmax at the end of infusion than a typical 40 kg child given the same dose of clofarabine per m2.
Għalhekk, wieħed
Accordingly, longer infusion times should be considered in children weighing < 20 kg (see section 4.2).
11 għandu jqies jekk tfal li jiżnu < 20 kg (ara sezzjoni 4. 2) għandhomx jingħataw ħinijiet itwal ta 'infużjoni.
Clofarabine is eliminated by a combination of renal and non-renal excretion.
Clofarabine jiġi mkeċċi permezz ta ’ tneħħija renali u dik mhux renali.
After 24 hours, about 60% of the dose is excreted unchanged in the urine.
Wara 24 siegħa, madwar 60% tad- doża titkeċċa kif inhi fl- awrina.
Clofarabine clearance rates appear to be much higher than glomerular filtration rates suggesting filtration and tubular secretion as kidney elimination mechanisms.
Ir- rati tat- tneħħija ta ’ clofarabine jidhru li huma ħafna ogħla mir - rati tal- filtrazzjoni glomerulari li jissuġġerixxi li l- filtrazzjoni u t- tnixxija tubulari huma mekkaniżmi tat- tneħħija mill- kliewi.
However, as clofarabine is not detectably metabolised by the cytochrome P450 (CYP) enzyme system, pathways of non-renal elimination currently remain unknown.
Biss, peress li clofarabine mhux metabolizzat b' mod li jidher bis- sistema ta ’ l - enżim cytochrome P450 (CYP), s' issa għadna ma nafux fejn huma l- passaġġi tat- tneħħija li ma jinvolvux il- kliewi.
No apparent difference in pharmacokinetics was observed between patients with ALL or AML, or between males and females.
Ma ġiet osservata l- ebda differenza apparenti fil- farmakokinetiċi bejn pazjenti bil- ALL jew AML; jew bejn maskili u feminili.
No relationship between clofarabine or clofarabine triphosphate exposure and either efficacy or toxicity has been established in this population.
Ma kienet stabbilita l- ebda relazzjoni bejn esponiment għal clofarabine jew clofarabine triphosphate u jew l- effikaċja jew it- tossiċità f’ din il- popolazzjoni.
Special populations:
Populazzjonijiet speċjali
Adults (> 21 and < 65 years old):
Adulti (> 21 u < 65 sena):
There are currently insufficient data to establish the safety and efficacy of clofarabine in adult patients.
Bħalissa m' hemmx tagħrif suffiċjenti biex tkun stabbilita s- sigurtà u l - effikaċja ta ’ clofarabine f’ pazjenti adulti.
However, the pharmacokinetics of clofarabine in adults with relapsed or refractory AML following administration of a single dose of 40 mg/ m2 clofarabine by intravenous infusion over 1 hour were comparable to those described above in patients aged between 2 to 19 years old with relapsed or refractory ALL or AML following administration of 52 mg/ m2 clofarabine by intravenous infusion over 2 hours for 5 consecutive days.
Imma, il- farmakokinetiċi ta ’ clofarabine fl- adulti b’ AML rikadut jew refrattarju wara l- għoti ta ’ doża waħda ta ’ 40 mg/ m2 ta ’ clofarabine permezz ta ’ infużjoni għal ġol- vini fuq perijodu ta ’ siegħa kienu komparabbli ma ’ dawk deskritti hawn fuq f’ pazjenti ta ’ bejn is- sentejn u 19- il sena b' ALL jew AML rikadut jew refrattarju wara l- għoti ta ’ 52 mg/ m2 ta ’ clofarabine permezz ta ’ infużjoni għal ġol- vini fuq perijodu ta ’ sagħtejn għal 5 ġranet konsekuttivi.
Elderly patients (≥ 65 years old):
Pazjenti anzjani (≥ 65 sena):
There are currently insufficient data to establish the safety and efficacy of clofarabine in elderly patients.
Bħalissa m' hemmx tagħrif suffiċjenti biex tkun stabbilita s- sigurtà u l - effikaċja ta ’ clofarabine f’ pazjenti anzjani.
There is no experience in patients with renal insufficiency (serum creatinine ≥ 2 x ULN for age) and clofarabine is predominately excreted via the kidneys (see sections 4.3 and 4.4).
M’ hemmx esperjenza dwar l- użu f’ pazjenti li jbatu minn insuffiċjenza renali (kreatinina tas- serum ≥ 2 x ULN għall- età) u clofarabine fil- biċċa l- kbira tal- każi jitneħħa mill - kliewi (ara sezzjonijiet 4. 3 u 4. 4).
To date, there are limited data on the pharmacokinetics of clofarabine in patients with decreased creatinine clearance.
S’ issa, hemm tagħrif limitat dwar il- farmakokinetiċi ta ’ clofarabine f’ pazjenti li jesperjenzaw tneħħija mnaqqsa ta 'kreatinina.
However, these data indicate that clofarabine may accumulate in such patients (see figure below and sections 4.2 and 4.4).
Imma, dan it- tagħrif jindika li l- clofarabine għandu mnejn jakkumula f’ dawn il- pazjenti (ara l- figura hawn taħt u f’ sezzjoni 4. 2 u 4. 4).
11 Clofarabine AUC0-24 hours by baseline estimated creatinine clearance in patients aged between 2 to 19 years old with relapsed or refractory ALL or AML (n = 11 / n = 12) following administration of multiple doses of clofarabine by intravenous infusion (Creatinine clearance estimated using Schwartz formula) 3000
12 Clofarabine AUC0- 24 sigħat bit- tneħħija kkalkulata tal- kreatinina skond il- linjabażi f' pazjenti ta 'bejn 2 sa 19- il sena li għandhom ALL jew AML rikaduti jew refrattarji (n= 11 / n= 12) wara l- għoti ta ’ aktar minn doża waħda ta ’ clorabine permezz ta ’ infużjoni għal ġol- vini (Tneħħija tal- kreatinina stimata permezz ta ’ l- użu tal- formula Schwartz) 3000
Clofarabine
2500 Clofarabine AUC 0- 24 hours
Estimated creatinine clearance (ml/ min)
Estimated creatinine clearance (ml/ min)
Patients with hepatic impairment:
Clofarabine AUC 0- 24 hours (ng* h/ ml) = Clofarabine AUC 0- 24 sigħat (ng* h/ ml) Estimated creatinine clearance (ml/ min) = Tneħħija ta ’ kreatinina stimata (ml/ min)
There is no experience in patients with hepatic impairment (serum bilirubin > 1.5 x ULN plus AST and ALT > 5 x ULN) and the liver is a potential target organ for toxicity (see sections 4.3 and 4.4).
Pazjenti li jbatu minn indeboliment epatiku Mhemmx esperjenza dwar l- użu f’ pazjenti li jbatu minn indeboliment epatiku (serum bilirubin > 1. 5 x ULN kif ukoll AST u ALT > 5 x ULN) u l- fwied hu organu potenzjali bersall għat- tossiċità (ara sezzjonijiet 4. 3 u 4. 4).
Toxicology studies of clofarabine in mice, rats and dogs showed that rapidly proliferating tissues were the primary target organs of toxicity.
Studji tossikoloġiċi ta ’ clofarabine fi ġrieden, firien u klieb urew lit- tessuti li jipproliferaw malajr kienu l- organi primarji tal- bersall tat- tossiċità.
Cardiac effects were observed in rats consistent with cardiomyopathy and contributed to signs of cardiac failure after repeated cycles of treatment.
L- effetti kardijaċi kienu osservati f' firien konsistenti ma ’ kardjomijopatija u kkontribwew għal sinjali ta ’ falliment kardijaku wara ċikli rripetuti ta 'trattament.
The incidence of these toxicities was dependent on both the dose of clofarabine administered and the duration of treatment.
L- inċidenza ta ’ dawn it- tossiċitajiet kienu jiddependu kemm fuq id- doża ta ’ clofarabine mogħtija u fuq kemm dam it- trattament.
They were reported at exposure levels (Cmax) approximately 7 to 13 fold (after 3 or more dosing cycles) or 16 to 35 fold (after one or more dosing cycles) higher than clinical exposures.
Kienu rrapportati f‘ livelli ta ’ esponiment (Cmax) madwar minn 7 sa 13- il darba (wara 3 ċikli jew aktar ta ’ dożaġġ) jew minn 16 sa 35 darba (wara ċiklu wieħed jew aktar ta ’ dożaġġ) ogħla mill- esponimenti kliniki.
The minimal effects seen at lower doses suggest that there is a threshold for toxicities on the heart and nonlinear plasma pharmacokinetics in the rat may play a role in the observed effects.
L- effetti minimi li kienu osservati f’ livelli aktar baxxi ta ’ dożi jissuġerixxu li hemm livell minimu ta ’ tossiċitajiet fuq il- qalb u l- farmakokinetiċi nonlineari fil- plażma fil- far għandhom mnejn jkollhom rwol fl- effetti osservati.
Glomerulonephropathy was reported in rats at exposure levels 3 to 5 fold higher than the clinical AUC after 6 dosing cycles of clofarabine.
Kien hemm rapporti ta ’ glomerulonefropatija fi firien fil- livell ta ’ esponiment li kienu minn 3 sa 5 darbiet ogħla mill- AUC klinikali wara 6 ċikli ta ’ dożaġġ ta ’ clofarabine.
It was characterised by minor thickening of the glomerular basement membrane with only slight tubular damage and was not associated with changes in serum chemistry.
Kien ikkaratterizzat minn ħxuna minuri tal- glomerular bejsment membrejn bi ħsara minima tubulari u ma kinitx assoċjata mat - tibdil fil- kimika tas- serum.
Hepatic effects were observed in rats following chronic administration of clofarabine.
Effetti epatiċi kienu osservati fil- firien wara l- għoti kroniku ta ’ clofarabine.
These likely represent the superimposition of degenerative and regenerative changes as a result of treatment cycles, and were not associated with changes in serum chemistry.
Dawn x' aktarx jirrappreżentaw is- superimpozizzjoni ta 'tibdil deġenerattiv u riġenerattiv bħala riżultat taċ- ċikli ta' trattament, u ma kinux assoċjati ma ’ tibdil fil- kimika tas- serum.
Histological evidence of hepatic effects was seen in dogs following acute administration of high doses, but was also not accompanied by changes in serum chemistry.
Xhieda istoloġikali ta ’ effetti epatiċi kienet osservata fil- klieb wara l- għoti akut ta 'dożi għolja, imma dan ma kienx akkumpanjat ma ’ tibdil fil- kimika tas- serum.
Dose related toxicities on male reproductive organs were observed in mice, rats and dogs.
Tossiċitajiet marbuta mad- doża fuq organi riproduttivi maskili kienu osservati fil- ġrieden, firien u klieb.
These effects included bilateral degeneration of the seminiferous epithelium with retained spermatids and atrophy of interstitial cells in rats at exaggerated exposure levels (150 mg/ m2/ day), and cell degeneration of the epididymis and degeneration of the seminiferous epithelium in dogs at clinically relevant exposure levels (> 7.5 mg/ m2/ day clofarabine).
13 (150 mg/ m2/ kuljum) u deġenerazzjoni ta ’ cellula ta ’ l- epididimis u deġenerazzjoni ta ’ l- epiteljum seminiferus fil- klieb f’ livelli ta ’ esponiment relevanti kliniku (≥ 7. 5 mg/ m2/ kuljum ta ’ clofarabine).
12 Delayed ovarian atrophy or degeneration and uterine mucosal apoptosis were observed in female mice at the only dose used of 225 mg/ m2/ day clofarabine.
Atrofija ovarjana postposta jew deġenerazzjoni u apoptożi mukosali uterina kienu osservati fi ġrieden feminili fil- livell ta ’ l- unika doża li ntużat ta ’ 225 mg/ m2/ kuljum ta ’ clofarabine.