qanastek/EMEA-V3 huggingface dataset:
The free drug clearance of imatinib is probably similar between patients with renal impairment and those with normal renal function, since renal excretion represents only a minor elimination pathway for imatinib (see sections 4.2 and 4.4).
Il- clearance tal- mediċina ħielsa ta ’ imatinib hija probabli simili bejn pazjenti li jkollhom indeboliment tal- kliewi u dawk b’ funzjoni tal- kliewi normali, peress li l- eliminazzjoni renali tirrappresenta mezz ta ’ eliminazzjoni minuri għal imatinib (ara sezzjonijiet 4. 2 u 4. 4).
Although the results of pharmacokinetic analysis showed that there is considerable inter-subject variation, the mean exposure to imatinib did not increase in patients with varying degrees of liver dysfunction as compared to patients with normal liver function (see sections 4.2, 4.4 and 4.8).
Għalkemm ir- riżultati ta ’ l- analiżi farmakokinetika wriet li hemm varjazzjoni konsiderevoli bejn is - suġġetti, il- medja ta ’ l- esponiment għal imatinib ma żdiedetx fil- pazjenti li kellhom gradi varji ta ’ funzjonijiet ħżiena tal- fwied meta mqabbla ma ’ pazjenti b’ funzjoni tal- fwied normali (ara sezzjonijiet 4. 2, 4. 4 u 4. 8).
22 5.3 Preclinical safety data
23 5. 3 Tagħrif ta ’ qabel l- użu kliniku dwar is- sigurtà tal- mediċina
The preclinical safety profile of imatinib was assessed in rats, dogs, monkeys and rabbits.
Il- profil tas- sigurtà ta ’ imatinib, qabel l- użu kliniku, kien stmat fil- firien, fil- klieb, f’ xadini u fil- fniek.
Multiple dose toxicity studies revealed mild to moderate haematological changes in rats, dogs and monkeys, accompanied by bone marrow changes in rats and dogs.
Studji fuq l- effett tossiku minn dożi ripetuti wrew xi tibdil ematoloġiku, ħafif sa moderat, fil- firien, fil - klieb u fix- xadini, flimkien ma ’ xi effetti fuq il- mudullun fil- firien u fil- klieb.
The liver was a target organ in rats and dogs.
Il- fwied jidher li kien organu li jintlaqat mill- mediċina fil- firien u fil- klieb.
Mild to moderate increases in transaminases and slight decreases in cholesterol, triglycerides, total protein and albumin levels were observed in both species.
Kien hemm żiediet żgħar għal moderati fil- livelli tat- transaminases u kien hemm xi tnaqqis żgħir fil- livelli tal- kolesterol, tat - triglycerides, proteini totali, u ta ’ l- albumina fiż- żewġ speċi.
No histopathological changes were seen in rat liver.
Ma kienx hemm tibdil isto- patoloġiku fil - fwied tal- far.
Severe liver toxicity was observed in dogs treated for 2 weeks, with elevated liver enzymes, hepatocellular necrosis, bile duct necrosis, and bile duct hyperplasia.
Fi klieb li kienu kurati għal ġimgħatejn kien hemm effett tossiku qawwi fuq il- fwied, b’ żieda fil- livelli ta ’ l- enzimi tal- fwied, nekrożi taċ- ċelluli tal- fwied, nekrożi tat- tubu tal- bajl, u iperplażja tat- tubu tal- bajl.
Renal toxicity was observed in monkeys treated for 2 weeks, with focal mineralisation and dilation of the renal tubules and tubular nephrosis.
F’ xadini li kienu ħadu l- kura għal ġimgħatejn kien hemm effett tossiku fuq il- kliewi, b’ mineralizzazzjoni fokali u twessigħ tat- tubi ż- żgħar tal- kliewi u nefrożi tubulari.
Increased blood urea nitrogen (BUN) and creatinine were observed in several of these animals.
Kien hemm żiediet fil- livelli tan- nitroġenu ta ’ l- ureja fid- demm u tal- kreatinina f’ ħafna minn dawn l- annimali.
In rats, hyperplasia of the transitional epithelium in the renal papilla and in the urinary bladder was observed at doses ≥ 6 mg/ kg in the 13-week study, without changes in serum or urinary parameters.
Fil- firien, kien hemm iperplażja ta ’ l- epitelju transizzjonali fil- papilla renali u fil- bużżieqa ta ’ l- awrina meta ntużaw dożi ta ’ ≥ 6 mg/ kg fl- istudju li sar fuq 13- il ġimgħa, mingħajr ma kien hemm xi tibdil fil - parametri tas- serum jew ta ’ l- awrina.
An increased rate of opportunistic infections was observed with chronic imatinib treatment.
Kien hemm rata ogħla ta ’ infezzjonijiet opportunistiċi meta imatinib ingħata fit- tul.
In a 39-week monkey study, no NOAEL (no observed adverse effect level) was established at the lowest dose of 15 mg/ kg, approximately one-third the maximum human dose of 800 mg based on body surface.
Fi studju li sar fuq ix- xadini, fuq 39- il ġimgħa, ma ġiex stabbilit in- NOAEL (livell fejn ma jkunux osservati effetti avversi), bl- aktar doża baxxa ta ’ 15 mg/ kg, li tiġi bejn wieħed u ieħor terz ta ’ l- ogħla doża possibbli fil- bniedem li hija 800 mg jekk wieħed jibbażaha fuq l- erja tas- superfiċje tal- ġisem.
Treatment resulted in worsening of normally suppressed malarial infections in these animals.
Il - kura wasslet biex infezzjonijiet tal- malarja li s- soltu jkunu mrażżna f’ dawn l- annimali, minnflok ikomplu jiħżienu.
Imatinib was not considered genotoxic when tested in an in vitro bacterial cell assay (Ames test), an in vitro mammalian cell assay (mouse lymphoma) and an in vivo rat micronucleus test.
Imatinib ma kienx meqjus li kellu effett ġenotossiku meta gie ttestjat f’ assay ta ’ ċelluli ta ’ batterji in vitro (test Ames), u f’ assay ta ’ ċelluli mammiferi in vitro (limfoma fil- ġurdien) u f’ test in vivo fuq il - mikronukleju fil- far.
Positive genotoxic effects were obtained for imatinib in an in vitro mammalian cell assay (Chinese hamster ovary) for clastogenicity (chromosome aberration) in the presence of metabolic activation.
F’ analiżi in vitro għal klastoġeniċità (aberrazzjoni tal- kromożomi), li saret fuq ċelluli mammiferi (l- ovarju tal- ħamster Ċiniż) irriżulta li imatinib kellu effett tossiku fuq il- ġeni fil - presenza ta ’ attivazzjoni metabolika.
Two intermediates of the manufacturing process, which are also present in the final product, are positive for mutagenesis in the Ames assay.
Żewġ sustanzi li huma intermedjarji fil- proċess tal- manifattura, u li jinstabu wkoll fil- prodott finali, jirriżulta li jwasslu għal tibdil ġenetiku, skond l- assayi Ames.
One of these intermediates was also positive in the mouse lymphoma assay.
Fl - assay fuq il- limfoma fil- ġurdien, wieħed minn dawn l- intermedjarji kien posittiv ukoll.
In a study of fertility, in male rats dosed for 70 days prior to mating, testicular and epididymal weights and percent motile sperm were decreased at 60 mg/ kg, approximately equal to the maximum clinical dose of 800 mg/ day, based on body surface area.
Fi studju fuq il- fertilità, f’ firien ta ’ sess maskili li ngħataw il- mediċina għal 70 jum qabel ma tgħammru, irriżulta li kien hemm tnaqqis fil- piż tat- testikoli u ta ’ l- epididimu u anke tnaqqis fil - perċentwal ta ’ sperma b’ mobilità tajba, meta ntużat doża ta ’ 60 mg/ kg, li hi bejn wieħed u ieħor ekwivalenti għall- ogħla doża klinika possibbli ta ’ 800 mg/ jum, jekk wieħed iqis l- erja tas- superfiċje tal- ġisem.
This was not seen at doses ≤ 20 mg/ kg.
Dan ma rriżultax meta d- dożi li ntużaw kienu ta ’ ≤ 20 mg/ kg.
A slight to moderate reduction in spermatogenesis was also observed in the dog at oral doses ≥ 30 mg/ kg.
Kien hemm ukoll xi tnaqqis żgħir sa moderat fil- produzzjoni ta ’ l- isperma, fil- kelb, b’ dożi mill- ħalq ta ’ ≥ 30 mg/ kg.
When female rats were dosed 14 days prior to mating and through to gestational day 6, there was no effect on mating or on number of pregnant females.
Meta firien tas- sess feminili ngħataw il- kura minn 14- il jum qabel ma tgħammru sas- 6 jum tat- tqala, ma kien hemm l- ebda effett fuq it- tgħammir jew fuq in- numru ta ’ firien li ħarġu tqal.
At a dose of 60 mg/ kg, female rats had significant post- implantation foetal loss and a reduced number of live foetuses.
B’ doża ta ’ 60 mg/ kg, il - firien tas- sess feminili kellhom numru sinifikanti ta ’ feti li ntilfu wara l- impjant tal- bajda u numru iżgħar ta ’ feti ħajjin.
This was not seen at doses ≤ 20 mg/ kg.
Ma kienx hemm l- istess effett meta d- dożi kienu ≤ 20 mg/ kg.
In an oral pre- and postnatal development study in rats, red vaginal discharge was noted in the 45 mg/ kg/ day group on either day 14 or day 15 of gestation.
Fi studju fuq l- effett li trattament mill- ħalq jista ’ jkollu fuq l- iżvilupp kemm qabel kif ukoll wara t - twelid fil- far, kien hemm tisfija ħamra mill- vaġina f’ dak il- grupp li ħa doża ta ’ 45 mg/ kg/ jum u dan ġara jew fl- 14- il jum jew fil- 15- il jum tat- tqala.
At the same dose, the number of stillborn pups as well as those dying between postpartum days 0 and 4 was increased.
Bl- istess doża, n- numru ta ’ wild li twieldu mejtin kif ukoll in- numru ta ’ dawk li mietu fil- jiem bejn 0- 4 wara t- twelid, kienu ogħla.
In the F1 offspring, at the same dose level, mean body weights were reduced from birth until terminal sacrifice and the number of litters achieving criterion for preputial separation was slightly decreased.
B’ doża ta ’ l- istess livell, il- piżijiet medji tal- wild F1, kienu inqas mit- twelid sa ma kellhom jinqatlu, u n- numru ta ’ boton li laħqu l- kriterju tas- separazzjoni tal- prepuzju kien ukoll kemm kemm inqas.
F1 fertility was not affected, while an increased number of resorptions and a decreased number of viable foetuses was noted at 45 mg/ kg/ day.
Il- fertilità tal- grupp F1 ma kienetx affettwata, filwaqt li n- numru ta ’ feti li naqsu mill- piż żdied u numru iżgħar ta ’ feti baqgħu ħajjin b’ doża ta ’ 45 mg/ kg/ jum.
The no observed effect level (NOEL) for both the maternal animals and the F1 generation was 15 mg/ kg/ day (one quarter of the maximum human dose of 800 mg).
Il- livell li fih ma kienx hemm effett kemm fl- ommijiet kif ukoll fil - ġenerazzjoni F1 kien ta ’ 15 mg/ kg/ jum (kwart ta ’ l- ogħla doża possibbli fil- bniedem, li hija 800 mg).
Imatinib was teratogenic in rats when administered during organogenesis at doses ≥ 100 mg/ kg, approximately equal to the maximum clinical dose of 800 mg/ day, based on body surface area.
24 Imatinib kellu effett teratoġeniku fil- far, meta ngħata fiż- żmien l- organoġenesi f’ dożi ta ’ ≥ 100 mg/ kg, li jiġu bejn wieħed u ieħor ekwivalenti għall- ogħla doża klinika ta ’ 800 mg/ jum, jekk wieħed jikkunsidra l- erja tas- superfiċje tal- ġisem.
Teratogenic effects included exencephaly or encephalocele, absent/ reduced frontal and absent parietal bones.
L- effetti teratoġeniċi kienu jinkludu exencephaly jew encephalocele, u assenza/ daqs iżgħar ta ’ l- għadam tal- ġbin u assenza ta ’ l- għadam parjetali.
These effects were not seen at doses ≤ 30 mg/ kg.
Dawn l - effetti ma dehrux b’ dożi ta ’ ≤ 30 mg/ kg.
23 In the 2-year rat carcinogenicity study administration of imatinib at 15, 30 and 60 mg/ kg/ day resulted in a statistically significant reduction in the longevity of males at 60 mg/ kg/ day and females at ≥ 30 mg/ kg/ day.
Fi studju dwar l- effett kanċeroġenu fil- far li dam sentejn, meta imatinib ingħata b’ 15, 30 u 60 mg/ kg/ jum wassal għal tnaqqis statistikament sinifikanti fit- tul tal- ħajja tal- firien maskili b’ 60 mg/ kg/ jum u fil- firien femminili b ’ ≥30 mg/ kg/ jum.
Histopathological examination of decedents revealed cardiomyopathy (both sexes), chronic progressive nephropathy (females) and preputial gland papilloma as principal causes of death or reasons for sacrifice.
Eżami istopatoloġiku tad- dixxendenti wera kardjomijopatija (iż- żewġ sessi), avvanz ta ’ nefropatija kronika (firien femminili) u papilloma tal - glandola tal- prepuzju bħala il- kawża prinċipali tal- mewt jew għax kellhom jinqatlu.
Target organs for neoplastic changes were the kidneys, urinary bladder, urethra, preputial and clitoral gland, small intestine, parathyroid glands, adrenal glands and non- glandular stomach.
L- organi li ntlqatu b’ tibdil neoplastiku kienu l- kliewi, il- bużżieqa ta ’ l- awrina, l- uretra, il- glandoli prepuzzjali u tal - klitoris, l- imsaren iż- żgħar, il- glandoli tal- paratajrojd, il- glandoli adrenali u l- istonku mingħajr glandoli.
Papilloma/ carcinoma of the preputial/ clitoral gland were noted from 30 mg/ kg/ day onwards, representing approximately 0.5 or 0.3 times the human daily exposure (based on AUC) at 400 mg/ day or 800 mg/ day, respectively, and 0.4 times the daily exposure in children (based on AUC) at 340 mg/ m2/ day.
Papilloma/ karċinoma tal- glandola tal- prepuzju/ klitoris dehru mat- 30 mg/ kg/ jum ‘ l quddiem, li jiġi madwar 0. 5 jew 0. 3- il darba ta ’ l- esponiment ta ’ kuljum fil- bniedem (bażat fuq l- AUC) b’ 400 mg/ jum jew 800 mg/ jum, rispettivament, u 0. 4- il darba l- esponiment fit- tfal (bażat fuq l- AUC) b’ 340 mg/ m2/ jum.
The no observed effect level (NOEL) was 15 mg/ kg/ day.
Il- livell fejn ma jkunx osservat effett (NOEL) kien 15 mg/ kg/ jum.
The renal adenoma/ carcinoma, the urinary bladder and urethra papilloma, the small intestine adenocarcinomas, the parathyroid glands adenomas, the benign and malignant medullary tumours of the adrenal glands and the non-glandular stomach papillomas/ carcinomas were noted at 60 mg/ kg/ day, representing approximately 1.7 or 1 times the human daily exposure (based on AUC) at 400 mg/ day or 800 mg/ day, respectively, and 1.2 times the daily exposure in children (based on AUC) at 340 mg/ m2/ day.
L - adenoma/ karċinoma tal- kliewi, il- bużżieqa ta ’ l- awrina u papilloma ta ’ l- uretra, l- adenokarċinomi ta ’ l - imsaren, l- adenomi tal- glandoli paratajrojd, it- tumuri benini u malinni tal- mudullun tal- glandoli adrenali u tal- papillomi/ karċinomi ta ’ l- istonku mingħajr il- glandoli dehru b’ 60 mg/ kg/ jum, li jiġu madwar 1. 7- il darba jew darba 1 l- esponiment ta ’ kuljum fil- bniedem (bażat fuq l- AUC) b’ 400 mg/ jum jew 800 mg/ jum, rispettivament, u 1. 2- il darba l- esponiment ta ’ kuljum fit- tfal (bażat fuq l- AUC) b’ 340 mg/ m2/ jum.
The no observed effect level (NOEL) was 30 mg/ kg/ day.
Il- livell fejn ma jkunx osservat effett (NOEL) kien 30 mg/ kg/ jum.
The mechanism and relevance of these findings in the rat carcinogenicity study for humans are not yet clarified.
Il- mekkaniżmu u r- rilevanza ta ’ dawn is- sejbiet fl- istudju ta ’ karċinoma fil- far għall- bnedmin għadhom ma ġewx iċċarati.
Non-neoplastic lesions not identified in earlier preclinical studies were the cardiovascular system, pancreas, endocrine organs and teeth.
Leżjonijiet mhux neoplastiċi li ma kienux identifikati fi studji ta ’ qabel l- użu kliniku kienu s- sistema kardjovaskolari, il- pankreas, l- organi endokrini u s- snien.
The most important changes included cardiac hypertrophy and dilatation, leading to signs of cardiac insufficiency in some animals.
L- aktar bidliet importanti kienu ipertrofija kardijaka u dilatazzjoni li wasslu għal sinjali ta ’ insuffiċjenza tal- qalb f’ xi annimali.
Cellulose microcrystalline Crospovidone Magnesium stearate Silica colloidal, anhydrous
Cellulose microcrystalline Crospovidone Magnesium stearate Silica colloidal, anhydrous
Gelatin Iron oxide, yellow (E172) Titanium dioxide (E171)
Gelatin Iron oxide, yellow (E172) Titanium dioxide (E171)
Printing ink:
Inka tal- kitba:
Iron oxide, red (E172) Shellac Soya lecithin
Iron oxide, red (E172) Shellac Soya lecithin
24 6.4 Special precautions for storage
6. 4 Prekwazjonijiet speċjali għall- ħażna
PVC/ aluminium blisters
Folji ta ’ l- aluminium/ PVC
Packs containing 30 capsules.
Pakketti li fihom 30 kapsula.
Novartis Europharm Limited Wimblehurst Road Horsham West Sussex, RH12 5AB UNITED KINGDOM
Novartis Europharm Limited Triq Wimblehurst Horsham West Sussex, RH12 5AB Ir- Renju Unit
07.11.2001 Date of first renewal:
07. 11. 2001 Data ta ’ l- ewwel tiġdid:
Glivec 100 mg hard capsules
Glivec 100 mg kapsuli iebsin
Each capsule contains 100 mg imatinib (as mesilate).
Kull kapsula fiha 100 mg ta ’ imatinib (bħala mesilate).
White to yellow powder in an orange to greyish-orange opaque capsule, marked “ NVR SI”.
Trab li l- kulur tiegħu jvarja minn abjad għal isfar, f’ kapsula li ma jgħaddix dawl minnha b’ kulur li jvarja minn oranġjo sa oranġjo fil- griż, u li hija mmarkata “ NVR SI ”.
Except in newly diagnosed chronic phase CML, there are no controlled trials demonstrating a clinical benefit or increased survival for these diseases.
27 fil- fażi kronika li tkun għada kif ġiet dijanjostikata, m’ hemmx studji kontrollati li juru li hemm xi vantaġġ kliniku jew li tiżdied is- sopravivenza f ’ dan il- mard.
26 haematological malignancies and malignant sarcomas, as appropriate.
It- terapija għandha tibda tingħata minn tabib li għandu esperjenza fil- kura ta ’ pazjenti b’ mard ematoloġiku malinn u sarkomi malinni, kif jixraq.
Dose increases from 340 mg/ m2 daily to 570 mg/ m2 daily (not to exceed the total dose of 800 mg) may be considered in children in the absence of severe adverse drug reaction and severe non-leukaemia- related neutropenia or thrombocytopenia in the following circumstances: disease progression (at any time); failure to achieve a satisfactory haematological response after at least 3 months of treatment; failure to achieve a cytogenetic response after 12 months of treatment; or loss of a previously achieved haematological and/ or cytogenetic response.
28 Żidiet fid- dożi minn 340 mg/ m2 kuljum għal 570 mg/ m2 kuljum (sabiex ma tinqabiżx id- doża totali ta ’ 800 mg) tista ’ titqies fi tfal jekk ma jkollhomx effetti avversi severi u newtropinja jew tromboċitopenja severi li ma jkunux relatati ma ’ lewkimja taħt dawn iċ- ċirkostanzi: avvanz tal- marda (ikun f’ liema żmien ikun) meta ma jkunx hemm rispons ematoloġiku sodisfaċenti wara mill- inqas 3 xhur ta ’ kura; meta ma jkunx hemm rispons ċitoġenetiku wara mill- inqas 12- il xahar ta ’ kura, jew meta jkun hemm telf ta ’ rispons ematoloġiku u/ jew ċitoġenetiku li jkun( u) inkiseb( bu) qabel.
27 Treatment schedule:
Kemm iddum il- kura:
Posology for DFSP The recommended dose of Glivec is 800 mg/ day for patients with DFSP.
29 Pożoloġija għal DFSP Id- doża ta ’ Glivec rakkomandata għal pazjenti b’ DFSP hija 800 mg/ jum.
Haematological adverse reactions Dose reduction or treatment interruption for severe neutropenia and thrombocytopenia are 28 recommended as indicated in the table below.
Effetti emataloġiċi avversi Huwa rakkomandat li d- doża titnaqqas jew inkella l- kura tieqaf għal xi żmien f’ każ li jkun hemm newtropenja jew tromboċitopenja severi u dan għandu jsir kif indikat fit- tabella li jmiss.
Elderly patients:
31 L- użu fl- anzjani:
30 John’ s Wort) may significantly reduce exposure to Glivec, potentially increasing the risk of therapeutic failure.
John’ s Wort) jista ’ jwassal biex inaqqas l- ammont ta ’ Glivec effettiv fiċ- ċirkolazzjoni, u b’ hekk iżid r- riskju li l- kura fil- fatt ma taħdimx.
Active substances that may have their plasma concentration altered by Glivec Imatinib increases the mean Cmax and AUC of simvastatin (CYP3A4 substrate) 2- and 3.5-fold, respectively, indicating an inhibition of the CYP3A4 by imatinib.
33 Sustanzi attivi li jistgħu jkollhom il- konċentrazzjoni tagħhom fil- plażma mibdula minħabba f’ Glivec Imatinib iżid is- Cmax intermedju u l- AUC ta ’ simvastatin (sustanza li fuqa jaħdem is- CYP3A4) b ’ 2 - u bi 3. 5- il darba, rispettivament, u dan jindika li imatinib jinibixxi is- CYP3A4.
33 When imatinib was combined with high dose chemotherapy in Ph+ ALL patients, transient liver toxicity in the form of transaminase elevation and hyperbilirubinaemia were observed.
Meta imitanib kien kombinat ma ’ dożi għolja ta ’ kimoterapija f’ pazjenti b’ Ph+ ALL, tossiċità mumentanja tal- fwied dehret bħala żieda fil- livelli ta ’ transaminases u bilirubin fid- demm.
Herpes zoster, herpes simplex, nasopharyngitis, pneumonia7, sinusitis, cellulites, upper respiratory tract infection, influenza, urinary tract infection, gastroenteritis, sepsis
Infezzjonijiet u infestazzjonijiet Herpes zoster, herpes simplex, nasofarinġite, pnewmonja7, sinużite, ċellulite, Mhux komuni: infezzjoni tan- naħa ta ’ fuq tal- passaġġ respiratorju, influwenza, infezzjoni tal - passaġġ ta ’ l- awrina, gastro- enterite, sepsi Rari:
36 Laboratory test abnormalities Haematology In CML, cytopenias, particularly neutropenia and thrombocytopenia, have been a consistent finding in all studies, with the suggestion of a higher frequency at high doses ≥ 750 mg (phase I study).
Anormalitajiet fit- testijiet tal- laboratorju Ematoloġija Fil- każ ta ’ CML, ċitopenji, l- aktar newtropinja u tromboċitopinja, dejjem kienu sejbiet konsistenti, f’ kull studju li sar, u kien hemm anke indikazzjonijiet li l- frekwenza tagħhom kienet tiżdied meta kienu jintużaw dożi kbar ta ’ ≥ 750 mg (fl- istudju ta ’ fażi I).
Biochemistry Severe elevation of transaminases (< 5%) or bilirubin (< 1%) was seen in CML patients and was usually managed with dose reduction or interruption (the median duration of these episodes was approximately one week).
38 Biokimika Żieda qawwija fil- livelli tat- transaminases (< 5%) jew tal- bilirubin (< 1%) kienet evidenti f’ pazjenti b’ CML u s- soltu kienet kontrollata bi tnaqqis fid- doża jew inkella billi kien imwaqqaf għal ftit żmien it– trattament (it- tul medjan ta ’ dawn l- episodji kien ta ’ bejn wieħed u ieħor, ġimgħa).
Except in newly diagnosed chronic phase CML, there are no controlled trials demonstrating a clinical benefit, such as improvement in disease-related symptoms or increased survival.
39 dijanjostikata, ma hemmx provi b’ kontroll li juru xi benefiċċju mill- aspett kliniku, bħal xi titjib fis - sintomi li għandhom x’ jaqsmu mal- marda jew xi żieda fis- sopravivenza.
The percentage of some adverse reactions was higher in the 40 patients in whom the dose was increased to 800 mg daily compared to the population of patients before dose increase (n=551).
41 reazzjonijiet avversi kien ogħla fl- 40 pazjent li kellhom id- doża miżjuda għall- 800 mg kuljum imqabbla mal- popolazzjoni tal- pazjenti qabel żdiedet id- doża (n=551).
40 response was also higher in the patients treated at 600 mg (33%) as compared to the patients treated at 400 mg (16%, p=0.0220).
Ir- rata tar- rispons kienet ukoll ogħla fil- pazjenti li ħadu doża ta ’ 600 mg (33%) meta mqabbla mal- pazjenti li kienu ħadu doża ta ’ 400 mg (16%, p=0. 0220).
% of patients (CI95%) 1 Haematological response Complete haematological response (CHR)
% tal- pazjenti (CI95%) 42 Rispons ematoloġiku1 Rispons ematoloġiku komplet (CHR)
41 majority of patients who achieved a CCyR developed the CCyR between months 3 and 10 with a median time to response based on the Kaplan-Meier estimate of 5.6 months.
Il- maġġoranza tal- pazjenti li kisbu CCyR żviluppaw is- CCyR bejn it- 3 u l- 10 xahar b’ ħin medjan għar- rispons bażat fuq l- istima Kaplan- Meier ta ’ 5. 6 xhur.
All patients received imatinib and consolidation chemotherapy (see Table 5) after induction and the levels of bcr-abl transcripts were identical in the two arms at 8 weeks.
43 pazjenti kollha rċevew imatinib u terapija konsolidata (ara Tabella 5) wara induzzjoni u l- livelli ta ’ bcr- abl transcripts kienu identiċi fiż- żewġ friegħi mat- 8 ġimgħa.
n (%) 1(0.7)
kollha (n=147) mg (n=73) mg (n=74) n (%) 1 (0. 7)
44 In two clinical studies (study B2222 and an intergroup study S0033) the daily dose of Glivec was escalated to 800 mg in patients progressing at the lower daily doses of 400 mg or 600 mg.
F’ żewġ studji kliniċi (studju B2222 u studju b’ grupp intern S0033), id- doża ta ’ Glivec kienet miżjuda għall 800 mg kuljum fil- pazjenti li kienu għaddejin tajjeb bid- dożi aktar baxxi ta ’ 400 mg u 600 mg kuljum.
Clinical studies in DFSP One phase II, open label, multicentre clinical trial (study B2225) was conducted including 12 patients with DFSP treated with Glivec 800 mg daily.
46 Studji kliniċi f’ DFSP Prova klinika waħda ta ’ Fażi II, open label, f’ ħafna ċentri (studju B2225) kien imwettaq b’ 12- il pazjent b’ DFSP kurata b’ Glivec 800 mg kuljum.
45 Imatinib was shown in vitro to be a competitive inhibitor of marker substrates for CYP2C9, CYP2D6 and CYP3A4/ 5.
Ir- riżultati in vitro wrew li imatinib jinibixxi b’ mod kompetittiv lis- sustanzi markaturi li fuqhom jaħdmu l- enzimi CYP2C9, CYP2D6 u CYP3A4/ 5.
46 5.3 Preclinical safety data
48 5. 3 Tagħrif ta ’ qabel l- użu kliniku dwar is- sigurtà tal- mediċina
Imatinib was teratogenic in rats when administered during organogenesis at doses ≥ 100 mg/ kg, approximately equal to the maximum clinical dose of 800 mg/ day, based on body surface area.
49 Imatinib kellu effett teratoġeniku fil- far, meta ngħata fiż- żmien l- organoġenesi f’ dożi ta ’ ≥ 100 mg/ kg, li jiġu bejn wieħed u ieħor ekwivalenti għall- ogħla doża klinika ta ’ 800 mg/ jum, jekk wieħed jikkunsidra l- erja tas- superfiċje tal- ġisem.
47 In the 2-year rat carcinogenicity study administration of imatinib at 15, 30 and 60 mg/ kg/ day resulted in a statistically significant reduction in the longevity of males at 60 mg/ kg/ day and females at ≥ 30 mg/ kg/ day.
Fi studju dwar l- effett kanċeroġenu fil- far li dam sentejn, meta imatinib ingħata b’ 15, 30 u 60 mg/ kg/ jum wassal għal tnaqqis statistikament sinifikanti fit- tul tal- ħajja tal- firien maskili b’ 60 mg/ kg/ jum u fil- firien femminili b ’ ≥30 mg/ kg/ jum.
Papilloma/ carcinoma of the preputial/ clitoral gland were noted from 30mg/ kg/ day onwards, representing approximately 0.5 or 0.3 times the human daily exposure (based on AUC) at 400 mg/ day or 800 mg/ day, respectively, and 0.4 times the daily exposure in children (based on AUC) at 340 mg/ m2/ day.
Papilloma/ karċinoma tal- glandola tal- prepuzju/ klitoris dehru mat- 30 mg/ kg/ jum ‘ l quddiem, li jiġi madwar 0. 5 jew 0. 3- il darba ta ’ l- esponiment ta ’ kuljum fil- bniedem (bażat fuq l- AUC) b’ 400 mg/ jum jew 800 mg/ jum, rispettivament, u 0. 4- il darba l- esponiment fit- tfal (bażat fuq l- AUC) b’ 340 mg/ m2/ jum.
Gelatin Iron oxide, red (E172) Iron oxide, yellow (E172) Titanium dioxide (E171)
Gelatin Iron oxide, red (E172) Iron oxide, yellow (E172) Titanium dioxide (E171)
6.3 Shelf life
50 6. 3 Żmien kemm idum tajjeb il- prodott mediċinali
48 6.4 Special precautions for storage
6. 4 Prekwazjonijiet speċjali għall- ħażna
Packs containing 24, 48, 96, 120 and 180 capsules.
Pakketti li fihom 24, 48, 96, 120 u 180 kapsuli.
Glivec 100 mg film-coated tablets
Glivec 100 mg pilloli miksija b’ rita
Each film-coated tablet contains 100 mg imatinib (as mesilate).
Kull pillola miksija b’ rita fiha 100 mg ta ’ imatinib (bħala mesilate).
Very dark yellow to brownish-orange film-coated tablet, round with “ NVR” on one side and “ SA” and score on the other side.
Pillola miksija b’ rita ta ’ kulur li jvarja minn isfar skur ħafna għal oranġjo fil- kannella, tonda u mmarkata “ NVR ” fuq naħa u “ SA ” u rig mnejn taqsam fuq l- oħra.
Except in newly diagnosed chronic phase CML, there are no controlled trials demonstrating a clinical benefit or increased survival for these diseases.
52 fil- fażi kronika li tkun għada kif ġiet dijanjostikata, m’ hemmx studji kontrollati li juru li hemm xi vantaġġ kliniku jew li tiżdied is- sopravivenza f ’ dan il- mard.
50 4.2 Posology and method of administration
4. 2 Pożoloġija u metodu ta ’ kif għandu jingħata
Therapy should be initiated by a physician experienced in the treatment of patients with haematological malignancies and malignant sarcomas, as appropriate.
It- terapija għandha tibda tingħata minn tabib li għandu esperjenza fil- kura ta ’ pazjenti b’ mard ematoloġiku malinn u sarkomi malinni, kif jixraq.
For doses of 400 mg and above (see dosage recommendation below) a 400 mg tablet (not divisible) is available.
Għal dożi ta ’ 400 mg jew aktar (ara d- dużaġġ rakkomandat hawn taħt) teżisti pillola ta ’ 400 mg (li m’ għandhiex tiġi maqsuma).
The prescribed dose should be administered orally with a meal and a large glass of water to minimise the risk of gastrointestinal irritations.
Id- doża li tkun ordnata għandha tingħata mill- ħalq, darba kuljum flimkien ma ’ l- ikel u tazza ilma kbira biex jitnaqqas ir- riskju ta ’ irritazzjonijiet gastro- intestinali.
For patients unable to swallow the film-coated tablets, the tablets may be dispersed in a glass of mineral water or apple juice.
F’ pazjenti li ma jkunux jistgħu jibilgħu l- pilloli miksija b’ rita, din tista ’ tinfirex f’ tazza ilma minerali jew meraq tat- tuffieħ.
The required number of tablets should be placed in the appropriate volume of beverage (approximately 50 ml for a 100 mg tablet, and 200 ml for a 400 mg tablet) and stirred with a spoon.
Numru ta ’ pilloli li jkun hemm bżonn jittieħdu għandhom jitqegħedu f’ volum xieraq tax- xarba (bejn wieħed u ieħor 50 ml għall- pillola ta ’ 100 mg, u 200 ml għall- pillola ta ’ 400 mg) u mħawwda b’ kuċċarina.
The suspension should be administered immediately after complete disintegration of the tablet(s).
Is- suspensjoni għandha tingħata mill- ewwel, hekk kif il- pillola( i) ddub( jdubu) għall- kollox.
Treatment can be given as a once daily dose or alternatively the daily dose may be split into two administrations – one in the morning and one in the evening.
53 kuljum jew inkella id- doża ta ’ kuljum tista ’ tinqasam f’ darbtejn – waħda filgħodu u waħda filgħaxija.
Dose increases from 340 mg/ m2 daily to 570 mg/ m2 daily (not to exceed the total dose of 800 mg) may be considered in children in the absence of severe adverse drug reaction and severe non-leukaemia- related neutropenia or thrombocytopenia in the following circumstances: disease progression (at any 51 time); failure to achieve a satisfactory haematological response after at least 3 months of treatment; failure to achieve a cytogenetic response after 12 months of treatment; or loss of a previously achieved haematological and/ or cytogenetic response.
Żidiet fid- dożi minn 340 mg/ m2 kuljum għal 570 mg/ m2 kuljum (sabiex ma tinqabiżx id- doża totali ta ’ 800 mg) tista ’ titqies fi tfal jekk ma jkollhomx effetti avversi severi u newtropinja jew tromboċitopenja severi li ma jkunux relatati ma ’ lewkimja taħt dawn iċ- ċirkostanzi: avvanz tal- marda (ikun f’ liema żmien ikun) meta ma jkunx hemm rispons ematoloġiku sodisfaċenti wara mill- inqas 3 xhur ta ’ kura; meta ma jkunx hemm rispons ċitoġenetiku wara mill- inqas 12- il xahar ta ’ kura, jew meta jkun hemm telf ta ’ rispons ematoloġiku u/ jew ċitoġenetiku li jkun( u) inkiseb( bu) qabel.
Treatment schedule:
Kemm iddum il- kura:
At the time of analysis, the treatment duration was a median of 7 months (7 days to 13 months).
Meta saret l- analiżi, il- kura kienet iddum medja ta ’ 7 xhur (minn 7 ijiem sa
Posology for DFSP The recommended dose of Glivec is 800 mg/ day for patients with DFSP.
Pożoloġija għal DFSP Id- doża ta ’ Glivec rakkomandata għal pazjenti b’ DFSP hija 800 mg/ jum.
52 If elevations in bilirubin > 3 x institutional upper limit of normal (IULN) or in liver transaminases > 5 x IULN occur, Glivec should be withheld until bilirubin levels have returned to < 1.5 x IULN and transaminase levels to < 2.5 x IULN.
IULN) jew tat- transaminases tal- fwied għal > 5 x l- IULN, Glivec m’ għandux jingħata sakemm il- livell tal- bilirubin jinżel lura għal < 1. 5 x l- IULN u dak tat - transaminase għal < 2. 5 x l- IULN.
Haematological adverse reactions Dose reduction or treatment interruption for severe neutropenia and thrombocytopenia are recommended as indicated in the table below.
Effetti emataloġiċi avversi Huwa rakkomandat li d- doża titnaqqas jew inkella l- kura tieqaf għal xi żmien f’ każ li jkun hemm newtropenja jew tromboċitopenja severi u dan għandu jsir kif indikat fit- tabella li jmiss.
If cytopenia persists for 4 weeks and is still unrelated to leukaemia, stop Glivec until ANC ≥ 1 x 109/ l and platelets ≥ 20 x 109/ l, then resume treatment at 300 mg.
Jekk iċ- ċitopenja tippersisti għal
Paediatric accelerated phase CML and blast
a ANC < 0. 5 x 109/ l
ANC < 0.5 x 109/ l and/ or
CML fil- fażi aċċelerata u/ jew pedjatrika u blast crisis
If cytopenia persists for 4 weeks and is still unrelated to leukaemia, stop Glivec until ANC ≥ 1 x 109/ l and platelets ≥ 20 x 109/ l, then resume treatment at
Jekk iċ- ċitopenja tippersisti għal 4 ġimgħat u għada mhix relatata mal - lewkimja, waqqaf Glivec sakemm ANC ≥ 1 x 109/ l u l- plejtlets ≥ 20 x 109/ l, imbagħad erġa ibda l- kura b’ 200 mg/ m2.
DFSP (at dose 800 mg)
DFSP ANC < 1. 0 x 109/ l (doża ta ’ 800 mg) u/ jew
However, in these patients caution is recommended.
56 Madankollu, f’ dawn il- pazjenti hija rakkomandata l- kawtela.
Elderly patients:
L- użu fl- anzjani:
54 phenytoin, carbamazepine, rifampicin, phenobarbital or Hypericum perforatum, also known as St.
L- użu fl- istess żmien, ta ’ imatinib ma ’ prodotti mediċinali li jinduċu is- CYP3A4 (ez., dexamethasone, phenytoin, carbamazepine, rifampicin, phenobarbital, jew Hypericum perforatum, magħruf ukoll bħala St.
John’ s Wort) may significantly reduce exposure to Glivec, potentially increasing the risk of therapeutic failure.
John’ s Wort) jista ’ jwassal biex inaqqas l- ammont ta ’ Glivec effettiv fiċ- ċirkolazzjoni, u b’ hekk iżid r- riskju li l- kura fil- fatt ma taħdimx.
As cardiac adverse events have been reported uncommonly with imatinib, a careful assessment of the benefit/ risk of imatinib therapy should be considered in the HES/ CEL population before treatment initiation.
Mard
Myelodysplastic/ myeloproliferative diseases with PDGFR gene re-arrangements could be associated with high eosinophil levels.
57 majelodisplastiku/ majeloproliferattiv b’ tibdil fil- ġene PDGFR jistgħu jkunu assoċjati ma ’ livelli għoljin ta ’ eżinofils.
Evaluation by a cardiology specialist, performance of an echocardiogram and determination of serum troponin should therefore be considered in patients with HES/ CEL, and in patients with MDS/ MPD associated with high eosinophil levels before imatinib is administered.
Stima minn speċjalista kardjologu, ekokardjogramma u kejl tat- troponin fis- serum għandhom għaldaqstant ikunu konsidrati f’ pazjenti b’ HES/ CEL, u f’ pazjenti b’ MDS/ MPD assoċjati ma ’ livelli għolja ta ’ eżinofils qabel ma ’ jingħata imatinib.
However, the occurrence of these cytopenias is likely to be related to the stage of the disease being treated and they were more frequent in patients with accelerated phase CML or blast crisis as compared to patients with
Biss, dan it- tnaqqis fl- għadd taċ- ċelluli x’ aktarx li jkollu x’ jaqsam mal- fażi tal- marda li tkun qed tiġi ttrattata u jidher ukoll li dawn kienu aktar frekwenti f’ pazjenti fil- fażi l- imgħaġġla ta ’ CML jew f ’ blast crisis meta mqabbla ma ’ pazjenti li kienu fil- fażi kronika ta ’ CML.
Treatment with Glivec may be interrupted or the dose may be reduced, as recommended in section 4.2.
Il- kura b’ Glivec tista ’ titwaqqaf għal ftit jew id- doża tiġi mnaqqsa, hekk kif irakkomandat f’ sezzjoni 4. 2.
Active substances that may have their plasma concentration altered by Glivec Imatinib increases the mean Cmax and AUC of simvastatin (CYP3A4 substrate) 2- and 3.5-fold, respectively, indicating an inhibition of the CYP3A4 by imatinib.
58 Sustanzi attivi li jistgħu jkollhom il- konċentrazzjoni tagħhom fil- plażma mibdula minħabba f’ Glivec Imatinib iżid is- Cmax intermedju u l- AUC ta ’ simvastatin (sustanza li fuqa jaħdem is- CYP3A4) b ’ 2 - u bi 3. 5- il darba, rispettivament, u dan jindika li imatinib jinibixxi is- CYP3A4.
56 Caution should therefore be exercised when using Glivec and paracetamol concomitantly, especially with high doses of paracetamol.
Għaldaqstant għandha tintuża kawtela meta jkunu qed jintużaw Glivec u paracetamol flimkien, l- aktar meta l- aktar b’ dożi għoljin ta ’ paracetamol.
57 When imatinib was combined with high dose chemotherapy in Ph+ ALL patients, transient liver toxicity in the form of transaminase elevation and hyperbilirubinaemia were observed.
Meta imitanib kien kombinat ma ’ dożi għolja ta ’ kimoterapija f’ pazjenti b’ Ph+ ALL, tossiċità mumentanja tal- fwied dehret bħala żieda fil- livelli ta ’ transaminases u bilirubin fid- demm.
Rare:
60
Table 2
62 Tabella 2
60 Laboratory test abnormalities Haematology In CML, cytopenias, particularly neutropenia and thrombocytopenia, have been a consistent finding in all studies, with the suggestion of a higher frequency at high doses ≥ 750 mg (phase I study).
Anormalitajiet fit- testijiet tal- laboratorju Ematoloġija Fil- każ ta ’ CML, ċitopenji, l- aktar newtropinja u tromboċitopinja, dejjem kienu sejbiet konsistenti, f’ kull studju li sar, u kien hemm anke indikazzjonijiet li l- frekwenza tagħhom kienet tiżdied meta kienu jintużaw dożi kbar ta ’ ≥ 750 mg (fl- istudju ta ’ fażi I).
Biochemistry Severe elevation of transaminases (< 5%) or bilirubin (< 1%) was seen in CML patients and was usually managed with dose reduction or interruption (the median duration of these episodes was approximately one week).
63 Biokimika Żieda qawwija fil- livelli tat- transaminases (< 5%) jew tal- bilirubin (< 1%) kienet evidenti f’ pazjenti b’ CML u s- soltu kienet kontrollata bi tnaqqis fid- doża jew inkella billi kien imwaqqaf għal ftit żmien it– trattament (it- tul medjan ta ’ dawn l- episodji kien ta ’ bejn wieħed u ieħor, ġimgħa).
Except in newly diagnosed chronic phase CML, there are no controlled trials demonstrating a clinical benefit, such as improvement in disease-related symptoms or increased survival.
64 dijanjostikata, ma hemmx provi b’ kontroll li juru xi benefiċċju mill- aspett kliniku, bħal xi titjib fis - sintomi li għandhom x’ jaqsmu mal- marda jew xi żieda fis- sopravivenza.
The percentage of some adverse reactions was higher in the 40 patients in whom the dose was increased to 800 mg daily compared to the population of patients before dose increase (n=551).
66 reazzjonijiet avversi kien ogħla fl- 40 pazjent li kellhom id- doża miżjuda għall- 800 mg kuljum imqabbla mal- popolazzjoni tal- pazjenti qabel żdiedet id- doża (n=551).
64 response was also higher in the patients treated at 600 mg (33%) as compared to the patients treated at 400 mg (16%, p=0.0220).
Ir- rata tar- rispons kienet ukoll ogħla fil- pazjenti li ħadu doża ta ’ 600 mg (33%) meta mqabbla mal- pazjenti li kienu ħadu doża ta ’ 400 mg (16%, p=0. 0220).
% of patients (CI95%) 1 Haematological response Complete haematological response (CHR)
% tal- pazjenti (CI95%) 67 Rispons ematoloġiku1 Rispons ematoloġiku komplet (CHR)
65 majority of patients who achieved a CCyR developed the CCyR between months 3 and 10 with a median time to response based on the Kaplan-Meier estimate of 5.6 months.
Il- maġġoranza tal- pazjenti li kisbu CCyR żviluppaw is- CCyR bejn it- 3 u l- 10 xahar b’ ħin medjan għar- rispons bażat fuq l- istima Kaplan- Meier ta ’ 5. 6 xhur.
All patients received imatinib and consolidation chemotherapy (see Table 5) after induction and the levels of bcr-abl transcripts were identical in the two arms at 8 weeks.
68 pazjenti kollha rċevew imatinib u terapija konsolidata (ara Tabella 5) wara induzzjoni u l- livelli ta ’ bcr- abl transcripts kienu identiċi fiż- żewġ friegħi mat- 8 ġimgħa.
(q 12 h), days 2-3, for 4 cycles
Alternar bejn kors ta ’
Maintenance Study AUS01
kimoterapija:
VCR 1.3 g/ m2 i. v., day 1; prednisolone 60 mg/ m2 oral, days 1-5
Kimoterapija b’ doża għolja ta ’ MTX
Induction- consolidation therapy
69
Hyper-CVAD regimen:
(24 h), jum 1, u Ara- C 2 g/ m2 i. v.
(3 h, q 12 h), days 1-3; vincristine 2 mg i. v., days 4, 11; doxorubicine 50 mg/ m2 i. v.
(3 h, q 12 h), jiem 1- 3; Terapija ta ’ vincristine 2 mg i. v., jiem 4, 11; doxorubicine 50 mg/ m2 i. v.
(24 h), day 1, Ara-C 1 g/ m2 i. v.
(24 h), induzzjoni - jum 4; DEX 40 mg/ jum f’ jiem 1- 4 u 11- 14, alternati b’ MTX 1 g/ m2 i. v. aċċertament (24 h), jum 1, Ara- C 1 g/ m2 i. v.
68 In two clinical studies (study B2222 and an intergroup study S0033) the daily dose of Glivec was escalated to 800 mg in patients progressing at the lower daily doses of 400 mg or 600 mg.
F’ żewġ studji kliniċi (studju B2222 u studju b’ grupp intern S0033), id- doża ta ’ Glivec kienet miżjuda għall 800 mg kuljum fil- pazjenti li kienu għaddejin tajjeb bid- dożi aktar baxxi ta ’ 400 mg u 600 mg kuljum.
Clinical studies in DFSP One phase II, open label, multicentre clinical trial (study B2225) was conducted including 12 patients with DFSP treated with Glivec 800 mg daily.
71 Studji kliniċi f’ DFSP Prova klinika waħda ta ’ Fażi II, open label, f’ ħafna ċentri (studju B2225) kien imwettaq b’ 12- il pazjent b’ DFSP kurata b’ Glivec 800 mg kuljum.
Absorption Mean absolute bioavailability for imatinib is 98%.
Assorbiment Il- firxa mal- ġisem assoluta medja għal imatinib hija ta ’ 98%.
There was high between-patient variability in plasma imatinib AUC levels after an oral dose.
Il- varjabilità minn pazjent għall- ieħor tal- livelli ta ’ l- AUC ta ’ imatinib fil- plażma wara li tkun ingħatat doża mill- ħalq, kienet kbira.
69 Imatinib was shown in vitro to be a competitive inhibitor of marker substrates for CYP2C9, CYP2D6 and CYP3A4/ 5.
Ir- riżultati in vitro wrew li imatinib jinibixxi b’ mod kompetittiv lis- sustanzi markaturi li fuqhom jaħdmu l- enzimi CYP2C9, CYP2D6 u CYP3A4/ 5.
70 5.3 Preclinical safety data
73 5. 3 Tagħrif ta ’ qabel l- użu kliniku dwar is- sigurtà tal- mediċina
Imatinib was teratogenic in rats when administered during organogenesis at doses ≥ 100 mg/ kg, approximately equal to the maximum clinical dose of 800 mg/ day, based on body surface area.
74 Imatinib kellu effett teratoġeniku fil- far, meta ngħata fiż- żmien l- organoġenesi f’ dożi ta ’ ≥ 100 mg/ kg, li jiġu bejn wieħed u ieħor ekwivalenti għall- ogħla doża klinika ta ’ 800 mg/ jum, jekk wieħed jikkunsidra l- erja tas- superfiċje tal- ġisem.
71 In the 2-year rat carcinogenicity study administration of imatinib at 15, 30 and 60 mg/ kg/ day resulted in a statistically significant reduction in the longevity of males at 60 mg/ kg/ day and females at ≥ 30 mg/ kg/ day.
Fi studju dwar l- effett kanċeroġenu fil- far li dam sentejn, meta imatinib ingħata b’ 15, 30 u 60 mg/ kg/ jum wassal għal tnaqqis statistikament sinifikanti fit- tul tal- ħajja tal- firien maskili b’ 60 mg/ kg/ jum u fil- firien femminili b ’ ≥30 mg/ kg/ jum.
Cellulose microcrystalline Crospovidone Hypromellose Magnesium stearate Silica, colloidal anhydrous
Cellulose microcrystalline Crospovidone Hypromellose Magnesium stearate Silica, colloidal anhydrous
Tablet coat:
Il- kisja tal- pillola:
Iron oxide, red (E172) Iron oxide, yellow (E172) Macrogol Talc Hypromellose
Iron oxide, red (E172) Iron oxide, yellow (E172) Macrogol Talc Hypromellose
6.3 Shelf life
75 6. 3 Żmien kemm idum tajjeb il- prodott mediċinali
72 6.4 Special precautions for storage
6. 4 Prekwazjonijiet speċjali għall- ħażna
PVC/ alu blisters
Folji ta ’ l- alu/ PVC
Packs containing 20, 60, 120 or 180 film-coated tablets
Pakketti li fihom 20, 60, 120 jew 180 pilloli miksija b’ rita.
11.11.2003 Date of first renewal:
11. 11. 2003 Data ta ’ l- ewwel tiġdid:
Glivec 400 mg film-coated tablets
Glivec 400 mg pilloli miksija b’ rita
Each film-coated tablet contains 400 mg imatinib (as mesilate).
Kull pillola miksija b’ rita fiha 400 mg ta ’ imatinib (bħala mesilate).
Very dark yellow to brownish-orange, ovaloid, biconvex film-coated tablet with bevelled edges, debossed with “ NVR” on one side and “ SL” on the other side.
Pillola konvessa fuq żewġ naħat, ovali b’ truf imżerżqin, miksija b’ rita ta ’ kulur li jvarja minn isfar skur ħafna għal oranġjo fil- kannella, mnaqqxa b ’ “ NVR ” fuq naħa u “ SL ” fuq l- oħra.
Except in newly diagnosed chronic phase CML, there are no controlled trials demonstrating a clinical benefit or increased survival for these diseases.
77 fil- fażi kronika li tkun għada kif ġiet dijanjostikata, m’ hemmx studji kontrollati li juru li hemm xi vantaġġ kliniku jew li tiżdied is- sopravivenza f ’ dan il- mard.
74 4.2 Posology and method of administration
4. 2 Pożoloġija u metodu ta ’ kif għandu jingħata
For doses other than 400 mg and 800 mg (see dosage recommendation below) a 100 mg divisible tablet is available.
Għal dożi oħra apparti dawk ta ’ 400 mg jew 800 mg (ara d- dużaġġ raikkomandat hawn taħt), teżisti pillola ta ’ 100 mg li tista ’ tiġi maqsuma.
Treatment can be given as a once daily dose or alternatively the daily dose may be split into two administrations – one in the morning and one in the evening.
78 kuljum jew inkella id- doża ta ’ kuljum tista ’ tinqasam f’ darbtejn – waħda filgħodu u waħda filgħaxija.
Dose increases from 340 mg/ m2 daily to 570 mg/ m2 daily (not to exceed the total dose of 800 mg) may be considered in children in the absence of severe adverse drug reaction and severe non-leukaemia- related neutropenia or thrombocytopenia in the following circumstances: disease progression (at any 75 time); failure to achieve a satisfactory haematological response after at least 3 months of treatment; failure to achieve a cytogenetic response after 12 months of treatment; or loss of a previously achieved haematological and/ or cytogenetic response.
Żidiet fid- dożi minn 340 mg/ m2 kuljum għal 570 mg/ m2 kuljum (sabiex ma tinqabiżx id- doża totali ta ’ 800 mg) tista ’ titqies fi tfal jekk ma jkollhomx effetti avversi severi u newtropinja jew tromboċitopenja severi li ma jkunux relatati ma ’ lewkimja taħt dawn iċ- ċirkostanzi: avvanz tal- marda (ikun f’ liema żmien ikun) meta ma jkunx hemm rispons ematoloġiku sodisfaċenti wara mill- inqas 3 xhur ta ’ kura; meta ma jkunx hemm rispons ċitoġenetiku wara mill- inqas 12- il xahar ta ’ kura, jew meta jkun hemm telf ta ’ rispons ematoloġiku u/ jew ċitoġenetiku li jkun( u) inkiseb( bu) qabel.
76 If elevations in bilirubin > 3 x institutional upper limit of normal (IULN) or in liver transaminases > 5 x IULN occur, Glivec should be withheld until bilirubin levels have returned to < 1.5 x IULN and transaminase levels to < 2.5 x IULN.
IULN) jew tat- transaminases tal- fwied għal > 5 x l- IULN, Glivec m’ għandux jingħata sakemm il- livell tal- bilirubin jinżel lura għal < 1. 5 x l- IULN u dak tat - transaminase għal < 2. 5 x l- IULN.
However, in these patients caution is recommended.
81 Madankollu, f’ dawn il- pazjenti hija rakkomandata l- kawtela.
78 phenytoin, carbamazepine, rifampicin, phenobarbital or Hypericum perforatum, also known as St.
L- użu fl- istess żmien, ta ’ imatinib ma ’ prodotti mediċinali li jinduċu is- CYP3A4 (ez., dexamethasone, phenytoin, carbamazepine, rifampicin, phenobarbital, jew Hypericum perforatum, magħruf ukoll bħala St.
Myelodysplastic/ myeloproliferative diseases with PDGFR gene re-arrangements could be associated with high eosinophil levels.
82 majelodisplastiku/ majeloproliferattiv b’ tibdil fil- ġene PDGFR jistgħu jkunu assoċjati ma ’ livelli għoljin ta ’ eżinofils.
Active substances that may have their plasma concentration altered by Glivec Imatinib increases the mean Cmax and AUC of simvastatin (CYP3A4 substrate) 2- and 3.5-fold, respectively, indicating an inhibition of the CYP3A4 by imatinib.
83 Sustanzi attivi li jistgħu jkollhom il- konċentrazzjoni tagħhom fil- plażma mibdula minħabba f’ Glivec Imatinib iżid is- Cmax intermedju u l- AUC ta ’ simvastatin (sustanza li fuqa jaħdem is- CYP3A4) b ’ 2 - u bi 3. 5- il darba, rispettivament, u dan jindika li imatinib jinibixxi is- CYP3A4.
80 Caution should therefore be exercised when using Glivec and paracetamol concomitantly, especially with high doses of paracetamol.
Għaldaqstant għandha tintuża kawtela meta jkunu qed jintużaw Glivec u paracetamol flimkien, l- aktar meta l- aktar b’ dożi għoljin ta ’ paracetamol.
81 When imatinib was combined with high dose chemotherapy in Ph+ ALL patients, transient liver toxicity in the form of transaminase elevation and hyperbilirubinaemia were observed.
Meta imitanib kien kombinat ma ’ dożi għolja ta ’ kimoterapija f’ pazjenti b’ Ph+ ALL, tossiċità mumentanja tal- fwied dehret bħala żieda fil- livelli ta ’ transaminases u bilirubin fid- demm.
Rare:
85
Table 2
87 Tabella 2
84 Laboratory test abnormalities Haematology In CML, cytopenias, particularly neutropenia and thrombocytopenia, have been a consistent finding in all studies, with the suggestion of a higher frequency at high doses ≥ 750 mg (phase I study).
Anormalitajiet fit- testijiet tal- laboratorju Ematoloġija Fil- każ ta ’ CML, ċitopenji, l- aktar newtropinja u tromboċitopinja, dejjem kienu sejbiet konsistenti, f’ kull studju li sar, u kien hemm anke indikazzjonijiet li l- frekwenza tagħhom kienet tiżdied meta kienu jintużaw dożi kbar ta ’ ≥ 750 mg (fl- istudju ta ’ fażi I).
Biochemistry Severe elevation of transaminases (< 5%) or bilirubin (< 1%) was seen in CML patients and was usually managed with dose reduction or interruption (the median duration of these episodes was approximately one week).
88 Biokimika Żieda qawwija fil- livelli tat- transaminases (< 5%) jew tal- bilirubin (< 1%) kienet evidenti f’ pazjenti b’ CML u s- soltu kienet kontrollata bi tnaqqis fid- doża jew inkella billi kien imwaqqaf għal ftit żmien it– trattament (it- tul medjan ta ’ dawn l- episodji kien ta ’ bejn wieħed u ieħor, ġimgħa).