qanastek/EMEA-V3 huggingface dataset:
The sequential enzymatic biotransformation of capecitabine to 5-FU leads to higher concentrations within tumour tissues.
Il- biotrasformazzjoni enżimatika sekwenzjali ta ’ capecitabine għal 5- FU twassal għal konċentrazzjonijiet ogħla f’ tessuti tat- tumur.
In the case of colorectal tumours, 5-FU generation appears to be in large part localised in tumour stromal cells.
Fil - każ ta ’ tumuri tal- kolon u tar- rektum, il- biċċa l- kbira tal- produzzjoni ta ’ 5- FU tidher li hija lokalizzata f’ ċelluli stromali tat- tumur.
Following oral administration of capecitabine to patients with colorectal cancer, the ratio of 5-FU concentration in colorectal tumours to adjacent tissues was 3.2 (ranged from 0.9 to 8.0).
Wara l- għoti ta ’ capecitabine mill- ħalq lill- pazjenti b’ kanċer tal- kolon u tar- rektum, il- proporzjon tal- konċentrazzjoni ta ’ 5- FU f’ tumuri tal- kolon u tar- rektum għal tessuti fil - qrib kienet ta ’ 3. 2 (li kienet tvarja minn 0. 9 għal 8. 0).
The ratio of 5-FU concentration in tumour to plasma was 21.4 (ranged from 3.9 to 59.9, n=8) whereas the ratio in healthy tissues to plasma was 8.9 (ranged from 3.0 to 25.8, n=8).
Il- proporzjon ta ’ konċentrazzjoni ta ’ 5- FU fit - tumur għal plażma kienet ta ’ 21. 4 (li kienet tvarja minn 3. 9 għal 59. 9, n=8) filwaqt li l- proporzjon f’ tessuti f’ saħħithom għal plażma kienet ta ’ 8. 9 (li kienet tvarja minn 3. 0 għal 25. 8, n=8).
Thymidine phosphorylase activity was measured and found to be 4 times greater in primary colorectal tumour than in adjacent normal tissue.
L- attività ta ’ thymidine phosphorylase kienet imkejla u nstabet li kienet 4 darbiet iżjed f’ tumur primarju tal- kolon u tar- rektum milli f’ tessut normali fil- qrib.
According to immunohistochemical studies, thymidine phosphorylase appears to be in large part localised in tumour stromal cells.
Skond studji immuno- istokimikali, jidher li l- biċċa l- kbira ta ’ thymidine phosphorylase jinstab f’ ċelluli stromali tat- tumur.
5-FU is further catabolised by the enzyme dihydropyrimidine dehydrogenase (DPD) to the much less toxic dihydro-5-fluorouracil (FUH2).
22 5- FU jkompli jiġi kkatabolizzat mill- enżima dihydropyrimidine dehydrogenase (DPD) għal dihydro- 5- fluorouracil (FUH2) li huwa ħafna inqas tossiku.
Dihydropyrimidinase cleaves the pyrimidine ring to yield 5-fluoro-ureidopropionic acid (FUPA).
Dihydropyrimidinase jkisser iċ- ċirku ta ’ pyrimidine biex jipproduċi 5- fluoro- ureidopropionic acid (FUPA).
Finally, β -ureido-propionase cleaves FUPA to α -fluoro-β - alanine (FBAL) which is cleared in the urine.
Finalment, β- ureido- propionase jkisser FUPA għal α- fluoro- β- alanine (FBAL) li jitneħħa fl- awrina.
Dihydropyrimidine dehydrogenase (DPD) activity is the rate limiting step.
L- attività ta ’ dihydropyrimidine dehydrogenase (DPD) hija l- pass li jillimita r- rata.
Deficiency of DPD may lead to increased toxicity of capecitabine (see section 4.3 and 4.4).
Defiċjenza ta ’ DPD tista ’ twassal għal żjieda fit - tossicità ta ’ capacitabine (ara sezzjoni 4. 3 u 4. 4).
Elimination: the elimination half-life (t1/ 2 in hours) of capecitabine, 5'-DFCR, 5'-DFUR, 5-FU and FBAL were 0.85, 1.11, 0.66, 0.76 and 3.23 respectively.
Il- half- life ta ’ l- eliminazzjoni (t1/ 2 f’ siegħat) ta ’ capecitabine, 5 '- DFCR, 5' - DFUR, 5- FU u FBAL kienu ta ’ 0. 85, 1. 11, 0. 66, 0. 76 u 3. 23 rispettivament.
Capecitabine and its metabolites are predominantly excreted in urine; 95.5% of administered capecitabine dose is recovered in urine.
Capecitabine u l- metaboliti tiegħu huma mneħħijin mill- ġisem l- aktar fl- awrina; 95. 5% tad- doża ta ’ capecitabine mogħtija huwa rkuprat fl - awrina.
Faecal excretion is minimal (2.6%).
It- tneħħija fil- ħmieġ hija minima (2. 6%).
The major metabolite excreted in urine is FBAL, which represents 57% of the administered dose.
Il- metabolit maġġuri mneħħi mill- ġisem fl- awrina huwa FBAL, li jirrappreżenta 57% tad- doża mogħtija.
About 3% of the administered dose is excreted in urine as unchanged drug.
Madwar 3% tad- doża mogħtija titneħħa mill - ġisem fl- awrina bħala mediċina mhix mibdula.
Phase I studies evaluating the effect of Xeloda on the pharmacokinetics of either docetaxel or paclitaxel and vice versa showed no effect by Xeloda on the pharmacokinetics of docetaxel or paclitaxel (Cmax and AUC) and no effect by docetaxel or paclitaxel on the pharmacokinetics of 5’ -DFUR.
Studji ta ’ fażi I biex jivvalutaw l- effett ta ’ Xeloda fuq il- farmakokinetika ta ’ docetaxel jew ta ’ paclitaxel u viċeversa ma wrew l- ebda effett minn Xeloda fuq il- farmakokinetika ta ’ docetaxel jew ta ’ paclitaxel (Cmax u AUC) u l- ebda effett minn docetaxel jew paclitaxel fuq il - farmakokinetika ta ’ 5 ’ - DFUR.
Pharmacokinetics in special populations:
Farmakokinetiċi f’ popolazzjonijiet speċjali:
A population pharmacokinetic analysis was carried out after Xeloda treatment of 505 patients with colorectal cancer dosed at 1250 mg/ m2 twice daily.
Analiżi farmakokinetika fuq il- popolazzjoni kienet magħmula wara l- kura b’ Xeloda f’ 505 pazjenti b’ kanċer tal- kolon u tar- rektum li ngħataw doża ta ’ 1250 mg/ m2 darbtejn kuljum.
Gender, presence or absence of liver metastasis at baseline, Karnofsky Performance Status, total bilirubin,
Is- sess, il- preżenza jew in- nuqqas ta ’ metastasi fil- fwied fil- linja bażi, Karnofsky Performance Status, bilirubin totali, albumina fis- serum, ASAT u ALAT ma kellhom l - ebda effett statistikament sinifikattiv fuq il- farmakokinetika ta ’ 5 '- DFUR, 5- FU u FBAL.
Patients with hepatic impairment due to liver metastases:
Pazjenti b’ indeboliment tal- fwied minħabba metastasi fil- fwied:
According to a pharmacokinetic study in cancer patients with mild to moderate liver impairment due to liver metastases, the bioavailability of capecitabine and exposure to 5-FU may increase compared to patients with no liver impairment.
Skond studju farmakokinetiku f’ pazjenti bil- kanċer, b’ indeboliment tal- fwied ħafif għal moderat minħabba metastasi fil- fwied, il - biodisponibiltà ta ’ capecitabine u l- espożizzjoni għal 5- FU jistgħu jiżdiedu meta mqabbla ma ’ pazjenti bl- ebda indeboliment tal- fwied.
There are no pharmacokinetic data on patients with severe hepatic impairment.
M’ hemm l- ebda informazzjoni farmakokinetika fuq pazjenti b’ indeboliment sever tal- fwied.
Based on a pharmacokinetic study in cancer patients with mild to severe renal impairment, there is no evidence for an effect of creatinine clearance on the pharmacokinetics of intact drug and 5-FU.
Ibbażat fuq studju tal- farmakokinetika f’ pazjenti bil- kanċer b’ indeboliment tal- kliewi ħafif għal sever, m’ hemm l- ebda evidenza ta ’ effett tat- tneħħija tal - krejatinina fuq il- farmakokinetika tal- mediċina intatta u ta ’ 5- FU.
Creatinine clearance was found to influence the systemic exposure to 5’ -DFUR (35% increase in AUC when creatinine clearance decreases by 50%) and to FBAL (114% increase in AUC when creatinine clearance decreases by 50%).
It- tneħħija tal- krejatinina instabet li tinfluwenza l- espożizzjoni sistematika għal 5 ’ - DFUR (żjieda ta ’ 35% fl- AUC meta t- tneħħija tal - krejatinina tonqos b’ 50%) u għal FBAL (żjieda ta ’ 114% fl- AUC meta t- tneħħija tal- krejatinina tonqos b’ 50%).
FBAL is a metabolite without antiproliferative activity.
FBAL huwa metabolit mingħajr attività kontra l- proliferazzjoni.
Based on the population pharmacokinetic analysis, which included patients with a wide range of ages (27 to 86 years) and included 234 (46%) patients greater or equal to 65, age has no influence on the pharmacokinetics of 5'-DFUR and 5-FU.
Ibbażat fuq analiżi tal- farmakokinetika tal- popolazzjoni, li kienet tinkludi pazjenti b’ firxa wiesa ’ ta ’ etajiet (minn 27 sa 86 sena) u li kienet tinkludi 234 (46%) pazjent li kellhom iżjed minn 65 sena jew kellhom 65 sena, l- età m’ għandha l- ebda influwenza fuq il- farmakokinetika ta ’ 5 '- DFUR u 5- FU.
The AUC of FBAL increased with age (20% increase in age results in a 15% increase in the AUC of FBAL).
L- AUC ta ’ FBAL żdiedet ma ’ l- età (20% żjieda fl- età tirriżulta f’ żjieda ta ’ 15% fl- AUC ta ’ FBAL).
This increase is likely due to a change in renal function.
Din iż- żjieda aktarx li hija minħabba tibdil fil- funzjoni renali.
Ethnic factors:
Fatturi etniċi:
Following oral administration of 825 mg/ m2 capecitabine twice daily for 14 days, Japanese patients (n=18) had about 36% lower Cmax and 24% lower AUC for capecitabine than Caucasian patients (n=22).
Wara l- għoti mill- ħalq ta ’ 825 mg/ m2 capecitabine darbtejn kuljum għal 14- il jum, pazjenti Ġappuniżi (n=18) kellhom Cmax għal capecitabine madwar 36% inqas u AUC 24% inqas minn pazjenti Kawkasi (n=22).
Japanese patients had also about 25% lower Cmax and 34% lower AUC for FBAL than Caucasian patients.
Pazjenti Ġappuniżi kellhom ukoll Cmax għal FBAL 25% inqas u AUC 34% inqas minn pazjenti Kawkasi.
The clinical relevance of these differences is unknown.
Ir- rilevanza klinika ta ’ dawn id- differenzi mhijiex magħrufa.
No significant differences occurred in the exposure to other metabolites (5'-DFCR, 5'-DFUR, and 5-FU).
L- ebda differenzi sinifikanti ma seħħew fl- espożizzjoni għal metaboliti oħra (5 '- DFCR, 5' - DFUR, u 5- FU).
In repeat-dose toxicity studies, daily oral administration of capecitabine to cynomolgus monkeys and mice produced toxic effects on the gastrointestinal, lymphoid and haemopoietic systems, typical for fluoropyrimidines.
Fi studji dwar it- tossiċità ta ’ dożi ripetuti, l- għoti kuljum ta ’ capecitabine mill- ħalq lil xadini cynomolgus u ġrieden, ipproduċew effetti tossiċi fuq is- sistema gastrointestinali, limfatika u emopoetika, tipika għal fluoropyrimidines.
These toxicities were reversible.
Dawn it- tossiċitajiet kienu riversibbli.
Skin toxicity, characterised by degenerative/ regressive changes, was observed with capecitabine.
Tossiċità tal- ġilda, karatterizzata minn tibdil deġenerattiv/ rigressiv, kienet osservata b’ capecitabine.
Capecitabine was devoid of hepatic and CNS toxicities.
Capecitabine kien nieqes minn tossiċitajiet epatiċi u tas- CNS.
Cardiovascular toxicity (e. g.
Tossiċità kardjovaskulari (eż. titwil ta ’ l- intervall tal- QT u
PR- and QT-interval prolongation) was detectable in cynomolgus monkeys after intravenous administration (100 mg/ kg) but not after repeated oral dosing (1379 mg/ m2/ day).
23 PR) setgħet tiġi osservata f’ xadini cynomolgus wara l- għoti fil- vini (100 mg/ kg) iżda mhux wara dożi ripetuti mill- ħalq (1379 mg/ m2/ kuljum).
A two-year mouse carcinogenicity study produced no evidence of carcinogenicity by capecitabine.
Studju ta ’ sentejn dwar il- karċinoġeniċità fil- ġrieden ma pproduċa l- ebda evidenza ta ’ karċinoġeniċità minn capecitabine.
During standard fertility studies, impairment of fertility was observed in female mice receiving capecitabine; however, this effect was reversible after a drug-free period.
Waqt studji stàndard dwar il- fertilità, indeboliment fil- fertilità ġiet osservata fi ġrieden femminili li kienu qed jingħataw capecitabine; madankollu, dan l- effett kien riversibbli wara perjodu mingħajr mediċina.
In addition, during a 13-week study, atrophic and degenerative changes occurred in reproductive organs of male mice; however these effects were reversible after a drug-free period.
Barra minn hekk, waqt studju ta ’ 13- il ġimgħa, tibdil atrofiku u deġenerattiv seħħ f’ organi riproduttivi ta ’ ġrieden maskili; madankollu dawn l- effetti kienu riversibbli wara perjodu mingħajr mediċina.
In embryotoxicity and teratogenicity studies in mice, dose-related increases in foetal resorption and teratogenicity were observed.
Fi studji dwar l- embrijutossiċità u t- teratoġeniċità fil- ġrieden, kienu osservati żidiet fl- assorbiment tal - fetu u fit- teratoġeniċità relatati mad- doża.
In monkeys, abortion and embryolethality were observed at high doses, but there was no evidence of teratogenicity.
F’ xadini, l- abort u l- mewt ta ’ l- embriju kienu osservati meta ntużaw dożi qawwija, iżda ma kien hemm l- ebda evidenza ta ’ teratoġeniċità.
Capecitabine was not mutagenic in vitro to bacteria (Ames test) or mammalian cells (Chinese hamster V79/ HPRT gene mutation assay).
Capecitabine ma kienx mutaġeniku in vitro għall- batterji (test ta ’ Ames) jew għal ċelluli mammiferi (analiżi ta ’ tibdil fil- ġeni tal- ħamster Ċiniż V79/ HPRT).
However, similar to other nucleoside analogues (ie, 5-FU), capecitabine was clastogenic in human lymphocytes (in vitro) and a positive trend occurred in mouse bone marrow micronucleus tests (in vivo).
Madankollu, bħall- analogi ta ’ nucleoside oħra (i. e., 5- FU), capecitabine kien klastoġeniku f’ limfoċiti umani (in vitro) u seħħet xejra pożittiva f’ testijiet fuq il- mikronukleu tal- mudullun tal- ġrieden (in vivo).
Tablet core: anhydrous lactose, croscarmellose sodium, hypromellose, microcrystalline cellulose, magnesium stearate.
Il- qalba tal- pillola: anhydrous lactose, croscarmellose sodium, hypromellose, microcrystalline cellulose, magnesium stearate.
Tablet coating: hypromellose, titanium dioxide (E171), yellow and red iron oxide (E172), talc.
Il- kisja tal- pillola: hypromellose, titanium dioxide (E171), iron oxide isfar u aħmar (E172), talc.
Nature:
Tip:
PVC/ PVDC blisters
Folji tal- PVC/ PVDC
Content:
Kontenut:
60 film-coated tablets (6 blisters of 10 tablets)
60 pilloli miksija b’ rita (6 folji ta ’ 10 pilloli)
6.6 Special precautions for disposal
24 6. 6 Prekawzjonijiet speċjali li għandhom jittieħdu meta jintrema
02 February 2001 Date of first renewal:
02 ta ’ Frar 2001 Data ta ’ l- ewwel tiġdid:
02 February 2006
02 ta ’ Frar 2006
Xeloda 500 mg film-coated tablets.
Xeloda Pilloli 500 mg miksija b’ rita.
500 mg capecitabine.
500 mg capecitabine.
52 mg anhydrous lactose.
52 mg anhydrous lactose.
Peach film-coated tablet of biconvex, oblong shape with the marking ‘ 500’ on the one side and ‘ Xeloda’ on the other side.
Pillola miksija b’ rita ta ’ lewn aħmar fl- isfar, ibbużżati fuq iż- żewġ naħat, ta ’ forma oblung bil- marka ‘ 500 ’ fuq naħa waħda u ‘ Xeloda ’ fuq in- naħa l- oħra.
Monotherapy Colon, colorectal and breast cancer Given as single agent, the recommended starting dose for Xeloda in the adjuvant treatment of colon cancer, in the treatment of metastatic colorectal cancer or of locally advanced or metastatic breast cancer is 1250 mg/ m2 administered twice daily (morning and evening; equivalent to 2500 mg/ m2 total daily dose) for 14 days followed by a 7-day rest period.
Monoterapija Kanċer tal- kolon, tal- kolorektum u tas- sider Mogħti bħala sustanza waħedha, d- doża rakkomandata tal- bidu ta ’ Xeloda fil- kura awżiljarja tal - kanċer tal- kolon, fil- kura ta ’ kanċer tal- kolorektum li mmetastatizza jew ta ’ kanċer tas- sider lokalment avvanzat jew li mmetastatizza hija ta ’ 1250 mg/ m2 mogħtija darbtejn kuljum (fil- għodu u
Full dose
Doża mnaqqsa Doża kollha Numru ta ’ pilloli ta ’ Doża mnaqqsa (75%) 150 mg u/ jew pilloli (50%) ta ’ 500 mg kull 1250 mg/ m2 950 mg/ m2 625 mg/ m2 għotja (kull għotja għandha tingħata filgħodu u filgħaxija)
Number of 150 mg
Erja tas - Superfiċje
Reduced dose
2 Ġisem (m)
Reduced dose
≤1. 26
tablets and/ or 500 mg tablets per
1500
(75%)
-
(50%)
3
500 mg administration (mg)
39 - 1. 52 1800 2 3
26 Table 2 Standard and reduced dose calculations according to body surface area for a starting dose of Xeloda of 1000 mg/ m2 2 Dose level 1000 mg/ m (twice daily)
≥
Number of 150 mg
2800 2
Reduced dose
5
Reduced dose
2150
(75%)
1450
(50%)
27 Tabella 2
1000 mg/ m2
Kalkulazzjonijiet għad- doża stàndard jew imnaqqsa skond l- erja tas- superfiċje tal- ġisem, għad- doża tal- bidu ta ’ Xeloda ta ’ 1000 mg/ m2 2 Livell ta ’ doża ta ’ 1000 mg/ m (darbtejn kuljum)
administration (each administration to be given morning and evening)
Doża mnaqqsa Doża kollha Numru ta ’ pilloli ta ’ Doża mnaqqsa (75%) 150 mg u/ jew pilloli (50%) ta ’ 500 mg kull 1000 mg/ m2 750 mg/ m2 500 mg/ m2 għotja (kull għotja għandha tingħata filgħodu u filgħaxija)
750 mg/ m2
Erja tas - Superfiċje
500 mg/ m2
Doża kull Doża kull għotja Doża kull għotja tal - għotja (mg) 150 mg 500 mg (mg) (mg)
Body Surface 2
2 Ġisem (m)
Dose per
≤1. 26
Dose per
1150 1 2 800
Dose per
1.
Area (m)
26 1150 1 2
150 mg
600
administration (mg)
1. 27 - 1. 38
Patients taking Xeloda should be informed of the need to interrupt treatment immediately if moderate or severe toxicity occurs Doses of Xeloda omitted for toxicity are not replaced.
Dożi ta ’ Xeloda maqbużin minħabba t- tossiċità m’ għandhomx jiġu sostitwiti.
27 Table 3 Xeloda Dose Reduction Schedule (3-weekly Cycle or Continuous Treatment)
Tabella 3 Skeda tat- Tnaqqis fid- Doża ta ’ Xeloda (Ċiklu ta ’ 3 Gradi ta ’ tossiċità *
Toxicity grades*
ġimgħat jew kura Aġġustament fid- doża
Dose changes within a treatment cycle
kontinwa) għaċ -
Dose adjustment for next cycle/ dose (% of starting dose)
Tibdiliet fid- doża f’ ċiklu ta ’ kura
• Grade 1
ċiklu/ doża li jmiss
Maintain dose level
(% tad- doża tal- bidu) • Grad 1 • Grad 2
• Grade 2
Żomm il- livell tad - doża
-1st appearance -2nd appearance -3rd appearance
- L- ewwel dehra
-4th appearance • Grade 3
- It- tieni dehra - It- tielet dehra
Discontinue treatment permanently
- Ir- raba ’ dehra
Not
Waqqaf il- kura għal kollox
-3rd appearance • Grade 4
- It- tielet dehra
Not
28
applicable
Aġġustament fid- doża għaċ - ċiklu/ doża li jmiss (% tad- doża tal- bidu) każ
-1st appearance
- L- ewwel dehra
Discontinue permanently or If physician deems it to be in the patient’ s best interest to continue, interrupt until resolved to grade 0-1
Waqqaf għal kollox jew Jekk it- tabib huwa tal- fehma li huwa fl- aħjar interess tal - pazjent li jkompli, interrompi sakemm riżolta għal grad 0- 1
*According to the National Cancer Institute of Canada Clinical Trial Group (NCIC CTG) Common Toxicity Criteria (version 1) or the Common Terminology Criteria for Adverse Events (CTCAE) of the Cancer Therapy Evaluation Program, US National Cancer Institute, version 3.0.
* Skond il- Kriterji Komuni tat- Tossiċità (verżjoni 1) tal- Grupp ta ’ Provi Kliniċi ta ’ l- Istitut Nazzjonali tal - Kanċer tal- Kanada (NCIC CTG), jew Il- Kriterji ta ’ Terminoloġija Komuni għall- Avvenimenti Avversi (CTCAE) versjoni 3. 0 tal- Programm ta ’ Valutazzjoni tat- Terapija tal- Kanċer, Istitut Nazzjonali tal- Kanċer ta ’ l - Istati Uniti.
Dose modifications for toxicity when Xeloda is used as a 3 weekly in combination with other agents should be made according to Table 3 above for Xeloda and according to the appropriate summary of product characteristics for the other agent(s).
Modifikazzjonijiet fid- doża għat- tossiċità meta Xeloda jintuża bħala ċiklu ta ’ 3 ġimgħat f’ taħlita ma ’ sustanzi oħra għandhom isiru skond Tabella 3 fuq għal Xeloda u skond is- sommarju tal- karatteristiċi tal- prodott xieraq tas- sustanza( i) l- oħra.
28 Dose modifications for toxicity when Xeloda is used continuously in combination with other agents:
Modifikazzjonijiet fid- doża għal tossiċitajiet meta Xeloda jintuża kontinwament f’ taħlita ma ’ sustanzi oħra:
Dose modifications for toxicity when Xeloda is used continuously in combination with other agents should be made according to Table 3 above for Xeloda and according to the appropriate summary of product characteristics for the other agent.
Modifikazzjonijiet fid- doża għal tossiċitajiet meta Xeloda jintuża kontinwament f’ taħlita ma ’ sustanzi oħra għandhom isiru skond Tabella 3 fuq għal Xeloda u skond is- sommarju tal- karatteristiċi tal - prodott xieraq tas- sustanza l- oħra.
Renal impairment:
29 Indeboliment tal- kliewi:
The incidence of grade 3 or 4 adverse reactions in patients with moderate renal impairment (creatinine clearance 30-50 ml/ min at baseline) is increased compared to the overall population.
L- inċidenza ta ’ reazzjonijiet avversi grad 3 jew 4 f’ pazjenti b’ indeboliment moderat tal- kliewi (tneħħija tal- krejatinina ta ’ 30- 50 ml/ min fil- linja bażi) hija ikbar meta mqabba mal- populazzjoni totali.
In patients with moderate renal impairment at baseline, a dose reduction to 75% for a starting dose of 1250mg/ m2 is recommended.
F’ pazjenti b’ indeboliment moderat tal- kliewi fil- linja bażi, tnaqqis fid- doża ta ’ 75% għal doża tal- bidu ta ’ 1250 mg/ m2 huwa rakkomandat.
In patients with moderate renal impairment at baseline, no dose reduction is required for a starting dose of 1000mg/ m2.
F’ pazjenti b ’ indeboliment moderat tal- kliewi fil- linja bażi, m’ hemm bżonn ta ’ l- ebda tnaqqis fid- doża għad- doża tal- bidu ta ’ 1000 mg/ m2.
• History of severe and unexpected reactions to fluoropyrimidine therapy, • Hypersensitivity to capecitabine or to any of the excipients or fluorouracil, • In patients with known dihydropyrimidine dehydrogenase (DPD) deficiency, • During pregnancy and lactation, • In patients with severe leucopenia, neutropenia, or thrombocytopenia, • In patients with severe hepatic impairment, • In patients with severe renal impairment (creatinine clearance below 30 ml/ min), • Treatment with sorivudine or its chemically related analogues, such as brivudine (See section 4.5), • If contraindications exist to any of the agents in the combination regimen, that agent should not be used.
• Passat mediku ta ’ reazzjonijiet serji u mhux mistennija għat- terapija bi fluoropyrimidine, • Sensitività eċċessiva għal capecitabine, jew għal xi sustanzi mhux attivi, jew għal fluorouracil, • F’ pazjenti b’ defiċjenza magħrufa ta ’ dihydropyrimidine dehydrogenase (DPD), • Waqt it- tqala u t- treddigħ, • F’ pazjenti b’ lewkopenja, newtropenja, jew tromboċitopenja severa, • F’ pazjenti b’ indeboliment sever tal- fwied, • F’ pazjenti b’ indeboliment sever tal- kliewi (tneħħija tal- krejatinina taħt 30 ml/ min), • Kura b’ sorivudine jew u bl- analogi relatati kimikament miegħu, bħal brivudine (ara sezzjoni 4. 5), • Jekk jeżistu kontra- indikazzjonijiet għal xi sustanzi fil- programm ta ’ taħlita, dik is- sustanza m’ għandiex tintuża.
29 4.4 Special warnings and precautions for use
30 4. 4 Twissijiet speċjali u prekawzjonijiet għall- użu
If Grade 2 (or higher) dehydration occurs, Xeloda treatment should be immediately interrupted and the dehydration corrected.
Jekk isseħħ deidrazzjoni ta ’ grad 2 (jew ogħla), il- kura b’ Xeloda għandha titwaqqaf minnufih u d- deidrazzjoni kkoreġuta.
Caution must be exercised in patients with diabetes mellitus or electrolyte disturbances, as these may be aggravated during Xeloda treatment.
Trid tingħata attenzjoni lill- pazjenti b’ dijabete mellitus jew disturbi fl- elettroliti, għax dawn jistgħu jiggravaw waqt il- kura b’ Xeloda.
Coumarin-derivative anticoagulation.
31 Antikoagulazzjoni b’ derivattiv ta ’ coumarin.
In a drug interaction study with single-dose warfarin administration, there was a significant increase in the mean AUC (+57%) of S-warfarin.
Fi studju dwar l- interazzjoni tal- mediċina waqt l- għoti ta ’ doża waħda ta ’ warfarin, kien hemm żjieda sinifikattiva fil- medja ta ’ l- AUC (+57%) ta ’ S- warfarin.
These results suggest an interaction, probably due to an inhibition of the cytochrome P450 2C9 isoenzyme system
Dawn ir- riżultati jissuġġerixxu interazzjoni, x’ aktarx minħabba l- impedizzjoni minn capecitabine tas - sistema ta ’ l- isoenżimi taċ- ċitokromju P450 2C9.
Phenytoin: increased phenytoin plasma concentrations resulting in symptoms of phenytoin intoxication in single cases have been reported during concomitant use of Xeloda with phenytoin.
Phenytoin: żjieda fil- konċentrazzjonijiet tal- phenytoin tal- plażma li jirriżulta f’ sintomi ta ’ intossikazzjoni tal- phenytoin f’ każijiet individwali, ġew irrapportati waqt l- użu ta ’ Xeloda flimkien ma ’ phenytoin.
Sorivudine and analogues: a clinically significant drug-drug interaction between sorivudine and 5-FU, resulting from the inhibition of dihydropyrimidine dehydrogenase by sorivudine, has been described.
32 Sorivudine u analogi: ġiet deskritta interazzjoni ta ’ sinifikanza klinika bejn sorivudine u 5- FU, li rriżultat mill- impedizzjoni ta ’ dihydropyrimidine dehydrogenase minn sorivudine.
Therefore, Xeloda must not be administered concomitantly with sorivudine or its chemically related analogues, such as brivudine (see section 4.3).
Għalhekk, Xeloda ma jistax jingħata flimkien ma ’ sorivudine jew ma ’ l- analogi relatati kimikament miegħu, bħal brivudine (ara sezzjoni 4. 3).
31 Antacid: the effect of an aluminum hydroxide and magnesium hydroxide-containing antacid on the pharmacokinetics of capecitabine was investigated.
Antaċidi: l- effett ta ’ antaċidi li fihom aluminium hydroxide u magnesium hydroxide fuq il - farmakokinetika ta ’ capecitabine kien investigat.
4.8 Undesirable effects
33 4. 8 Effetti mhux mixtieqa
The safety profiles of Xeloda monotherapy for the metastatic breast cancer, metastatic colorectal
Il- profili ta ’ sigurtà ta ’ monoterapija ta ’ Xeloda għall- popolazzjonijiet ta ’ kanċer metastatiku tas- sider, kanċer metastatiku tal- kolon u tar- rektum u ta ’ kura awżiljarja f’ kanċer tal- kolon huma komparabbli.
The following headings are used to rank the ADRs by frequency: very common (≥ 1/ 10), common (≥ 1/ 100, < 1/ 10) and uncommon (≥ 1/ 1,000, < 1/ 100).
Il- kategoriji li ġejjin huma wżati biex jikklassifikaw l- ADRs skond il- frekwenza: komuni ħafna (≥1/ 10), komuni (≥1/ 100, < 1/ 10) u mhux komuni (≥1/ 1, 000, < 1/ 100).
Within each frequency grouping, ADRs are presented in order of decreasing seriousness.
F’ kull sezzjoni ta ’ frekwenza, l - ADRs għandhom jitniżżlu skond is- serjetà tagħhom.
Table 4 Summary of related ADRs reported in patients treated with Xeloda monotherapy
Tabella 4 Sommarju ta ’ l- ADRs relatati rrapportati f’ pazjenti kkurati b’ monoterapija ta ’ Xeloda
All grades All grades
Kull grad Kull grad
Severe and/ or
Severi u/ jew ta ’ periklu għall- ħajja (grad 3- 4) jew ikkunsidrati rilevanti medikament
Lifethreatening (grade 3-4) or considered medically relevant Infections and infestations
Infezzjonijiet u
Herpes, viral infection, Nasopharyngitis, Lower respiratory tract infection
Herpes, Nasofarinġite,
Sepsis, Urinary tract infection, Cellulitis, Tonsillitis, Pharyngitis, Oral candidiasis, Influenza, Gastroenteritis, Fungal infection, Infection, Tooth abscess
l- awrina, Ċellulite, Tonsillite, Farinġite, Kandidajasi orali, Influwenza, Gastroenterite, Infezzjoni mill- moffa, Infezzjoni, Axxess f’ sinna
Neoplasm benign, malignant and unspecified
Severi u/ jew ta ’
Neutropenia, Anaemia
Newtropenija bid- deni,
Febrile neutropenia, Pancytopenia, Granulocytopenia, Thrombocytopenia, Leucopenia, Haemolytic anaemia, International Normalised Ratio (INR) increased/ Prothrombin time prolonged
tas- sistema limfatika
33
Anemija
Body System
Disturbi fis- sistema immuni
Uncommon
Sensittività eċċessiva
All grades All grades
Disturbi fil -
Severe and/ or
Anoreksja
Lifethreatening (grade 3-4) or considered medically relevant Immune system disorders
Deidratazzjoni,
-
Dijabete,
-
metaboliżmu u n -
Hypersensitivity
Tnaqqis fl- aptit,
Metabolism and nutrition disorders
Ipokalimja,
Anorexia
nutrizzjoni
Dehydration, Decreased appetite, Weight decreased
Tnaqqis fil- piż
Diabetes, Hypokalaemia, Appetite disorder, Malnutrition, Hypertriglyceridaemia,
Disturbi fl- aptit, Nutrizzjoni ħażina, Ipertrigliċeridemija
Headache, Lethargy, Dizziness, Parasthesia, Dysgeusia
Uġigħ ta ’ ras, Letarġija, Sturdament, Parasteżija, Disgewsja
Aphasia, Memory impairment, Ataxia, Syncope, Balance disorder, Sensory disorder, Neuropathy peripheral
Nuqqas tal- memorja, Ataxja, Sinkope, Disturbi fil- bilanċ, Disturbi fis- sensi, Newropatija periferali
Lacrimation increased, Conjunctivitis, Eye irritation
Tnaqqis fl- akutezza tal -
Visual acuity reduced, Diplopia
Konġuntivite, Irritazzjoni fl- għajnejn
Ear and labyrinth disorders
vista, Diplopja
Vascular disorders
Sistema tal- Ġisem
Deep vein thrombosis, Hypertension, Petechiae, Hypotension, Hot flush, Peripheral coldness
Trombożi fil- vini l - kbar, Ipertensjoni, Petekje, Fwawar, Kesħa fil- periferi
Dyspnoea, Epistaxis, Cough, Rhinorrhea
toraċiċi u medjastinali
Pulmonary embolism, Pneumothorax, Haemoptysis, Asthma, Dyspnoea exertional
Emoptisi, Ażżma, Qtugħ ta ’ nifs ma ’ l - eżerċizzju Sadd intestinali,
Gastrointestinal disorders
Fsada gastro- intestinali,
Diarrhoea, Vomiting, Nausea, Stomatitis, Abdominal pain
intestinali
Gastrointestinal haemorrhage, Constipation, Upper abdominal pain, Dyspepsia, Flatulence, Dry mouth
Uġigħ fil- parti ta ’ fuq
Intestinal obstruction, Ascites, Enteritis, Gastritis, Dysphagia, Abdominal pain lower, Oesophagitis, Abdominal discomfort, Gastrooesophageal reflux disease, Colitis, Blood in stool
Uġigħ fil- parti t’ isfel ta ’ l- addome, Osofaġite, Skumdità addominali, Marda ta ’ rifluss, gastro- osofaġali Kolite, Demm fl- ippurgar
34
Disturbi fil- ġilda u fit -
Body System
Sindrome ta ’
Very
Raxx,
Common Common
Raxx,
Uncommon
tessuti ta ’ taħt il- ġilda
All grades All grades
eritrodisasteżija
Severe and/ or
Alopeċja,
Lifethreatening (grade 3-4) or considered medically relevant Skin and subcutaneous tissue disorders
Uritkarja,
Palmar-plantar erythrodysaesthesia syndrome
palmari- plantari
Rash, Alopecia, Erythema, Dry skin, Pruritus, Skin hyper- pigmentation, Rash macular, Skin desquamation, Dermatitis, Pigmentation disorder, Nail disorder
Eritema, Ġilda xotta, Ħakk, Iperpigmentazzjoni tal - ġilda, Raxx makulari, Tqaxxir tal- ġilda, Dermatite, Disturbi fil - pigmentazzjoni, Disturbi fid- dwiefer
Skin ulcer, Rash, Urticaria, Photosensitivity reaction, Palmar erythema, Swelling face, Purpura
Reazzjoni ta ’ fotosensittività, Eritema ta ’ l- idejn, Nefħa fil- wiċċ, Purpura
Muskuloskeletal and connective tissue disorders
Disturbi muskolu -
Pain in extremity, Back pain, Arthralgia
Uġigħ fl- estremitajiet,
Joint swelling, Bone pain, Facial pain, Musculoskeletal stiffness, Muscular weakness,
Uġigħ fil- wiċċ, Egħbusija muskolu - skeletrali, Dgħjufija muskolari
Renal and urinary disorders
Severi u/ jew ta ’
Oedema, Chills, Influenza like illness, Rigors, Body temperature increased
Marda bħal l - influwenza, Rogħda, Żjieda fit- temperatura tal- ġisem
Xeloda in combination therapy:
Xeloda f’ terapija ta ’ taħlita:
35 Table 5 Summary of related ADRs reported in patients treated with Xeloda in combination treatment in addition to those seen with Xeloda monotherapy or seen at a higher frequency grouping compared to Xeloda monotherapy Body System
Sommarju ta ’ l- ADRs relatati rrapportati f’ pazjenti kkurati b’ Xeloda f’ kura ta ’ taħlita li kienu osservati minbarra dawk li dehru b’ monoterapija ta ’ Xeloda jew li dehru fi grupp ta ’ frekwenza aktar għolja meta mqabbel ma ’ monoterapija ta ’ Xeloda
- +
- + +
Herpes zoster, Urinary tract infection, Oral candidiasis, Upper respiratory tract infection, Rhinitis, Influenza, +Infection
Herpes zoster, Infezzjoni fl- apparat ta ’ l - awrina, Kandidajasi orali, Infezzjoni fl- apparat respiratorju ta ’ fuq, Rinite, Influwenza, + Infezzjoni Depressjoni tal- mudullun, +Newtropenija bid -
Blood and lymphatic system
tas- sistema limfatika
Neutropenia, +Leucopenia,
Lewkopenija, Anemija, +Deni
Bone marrow depression,
deni
disorders
newtropeniku, Tromboċitopenija Disturbi fis- sistema immuni
+ Febrile Neutropenia
Sensittività eċċessiva
Thrombocytopenia Immune system disorders Metabolism and nutrition disorders
Disturbi fil - metaboliżmu u n - nutrizzjoni
- Appetite decreased
Tnaqqis fl- aptit
Hypersensitivity Hypokalaemia, Hyponatremia, Hypomagnesaemia, Hypocalcaemia, Hyperglycaemia
Ipokalimja, Iponatrimja, Ipomagnesimja, Ipokalċimja, Ipergliċemija
- Taste disturbance, Paraesthesia and dysaesthesia, Peripheral neuropathy, Dysgeusia, Headache
- Disturb fit- togħma, Parasteżija u disasteżija, Newropatija periferali, Disgewżja, Uġigħ ta ’ ras
Sleep disorder, Anxiety Neurotoxicity, Tremor, Neuralgia, Hypersensitivity reaction
Disturbi fl- irqad, Ansjetà Newrotossiċità, Tregħid, Nevralġija, Reazzjoni ta ’ sensittività eċċessiva
Eye disorders Ear and labyrinth disorders Cardiac disorders
Disturbi fl- għajnejn
Lacrimation increased - -
Żjieda fid- dmugħ
Visual disorders, Dry eye Tinnitus, Hypoacusis Atrial fibrillation, Cardiac ischemia/ infarction
Disturbi fil- vista, Għajn tinħass xotta
Vascular disorders
Tinnitus, Ipoakusis
Lower limb oedema, Hypertension, +Embolism and thrombosis
Fibrillazzjoni atrijali, Iskemija/ infart kardijaku
Flushing, Hypotension, Hypertensive crisis
Fwawar, Pressjoni baxxa, Kriżi ipertensiva
Respiratory, thoracic and mediastinal system disorders
Disturbi respiratorji, toraċiċi u medjastinali
Sore throat, Dysaesthesia pharynx
Uġigħ fil- griżmejn, Disasteżija tal- farinġi
Hiccups, Pharyngolaryngeal pain, Dysphonia
Sulluzzu, Uġigħ faringolarinġali, Disfonija
Constipation, Dyspepsia
Stitikezza, Dispepsja
Upper gastrointestinal haemorrhage, Mouth ulceration, Gastritis, Abdominal distension, Gastroesophageal reflux disease, Oral pain, Dysphagia, Rectal haemorrhage, Abdominal pain lower
Emorraġija fl- apparat gastro- intestinali ta ’ fuq, Ulċerazzjoni fil- ħalq, Gastrite, Distensjoni addominali, marda tar- rifluss gastro- osofagali, Uġigħ fil- ħalq, Disfaġija, Emorraġija mir - rektum, Uġigħ fil- parti t’ isfel ta ’ l- addome
Hepatobiliary disorders Skin and subcutaneous tissue disorders
Iperidrosi, Raxx b’ eritema, Urtikarja, Tgħereq
For each term, the frequency count was based on ADRs of all grades.
Għal kull terminu, l- għadd tal- frekwenza kien ibbażat fuq ADRs ta ’ kull grad.
ADRs are added according to the highest incidence seen in any of the major combination trials.
L- ADRs huma miżjuda skond l- ogħla inċidenza osservata f’ wieħed mill- provi ta ’ taħlita maġġuri.
Post-Marketing Experience The following additional serious adverse reactions have been identified during post-marketing exposure:
Ir- reazzjonijiet avversi serji oħra li ġejjin ġew identifikati waqt espożizzjoni ta ’ wara t- tqegħid fis- suq:
For the capecitabine dose of 1000 mg/ m2 twice daily on days 1 to 14 every 3 weeks, a frequency of 22% to 30% of all-grade HFS was observed in capecitabine combination therapy.
Għad- doża ta ’ 1000 mg/ m2 capecitabine darbtejn kuljum fi ġranet 1 sa 14 kull 3 ġimgħat, kienet osservata frekwenza ta ’ HFS ta ’ kull grad ta ’ 22% sa 30% f’ terapija kombinata ta ’ capecitabine.
The results of a meta-analysis of 13 clinical trials with data from over 3800 patients treated with capecitabine showed that in all studies combined, the following covariates were statistically significantly associated with an increased risk of developing diarrhea: increasing capecitabine starting dose (gram), increasing duration of study treatment (weeks), increasing age (by 10 year increments), and female gender.
Ir- riżultati ta ’ meta- analiżi ta ’ 13- il prova klinika b’ tagħrif minn aktar minn 3800 pazjent kkurati b’ capecitabine wrew li fl- istudji kollha kombinati, l- kovarjanti li ġejjin kienu assoċjati b’ mod statistikament sinifikanti ma ’ żjieda fir- riskju ta ’ żvilupp ta ’ dijarea: żjieda fid- doża (grammi) tal- bidu ta ’ capecitabine, żjieda fit- tul ta ’ kura taħt studju (ġimgħat), żjieda fl- età (b’ żjidiet ta ’ 10 snin), u sess femminili.
The following covariates were statistically significantly associated with a decreased risk of developing diarrhea: increasing cumulative capecitabine dose (0.1*kg) and increasing relative dose intensity in the first six weeks
Il- kovarjanti li ġejjin kienu assoċjati b’ mod statistikament sinifikanti ma ’ tnaqqis fir- riskju ta ’ żvilupp ta ’ dijarea: żjieda fid- doża kumulattiva ta ’ capecitabine (0. 1 *) u żjieda fl- intensità tad- doża relattiva fl- ewwel sitt ġimgħat.
37 Encephalopathy:
39 Enċefalopatija:
An analysis of safety data in patients ≥ 60 years of age treated with Xeloda monotherapy and an analysis of patients treated with Xeloda plus docetaxel combination therapy showed an increase in the incidence of treatment-related grade 3 and 4 adverse reactions and treatment-related serious adverse reactions compared to patients < 60 years of age.
Analiżi ta ’ tagħrif dwar is- sigurtà f’ pazjenti b’ età ta ’ ≥ 60 sena kkurati b’ monoterapija ta ’ Xeloda u analiżi ta ’ pazjenti kkurati b’ terapija mħalta ta ’ Xeloda flimkien ma ’ docetaxel uriet żjieda fl- inċidenza ta ’ reazzjonijiet avversi ta ’ grad 3 u 4 u ta ’ reazzjonijiet avversi serji relatati mal- kura meta mqabbla ma ’ pazjenti b’ età ta ’ < 60 sena.
The results of a meta-analysis of 13 clinical trials with data from over 3800 patients treated with capecitabine showed that in all studies combined, increasing age (by 10 year increments) was statistically significantly associated with an increased risk of developing HFS and diarrhea and with a decreased risk of developing neutropenia.
Ir- riżultati ta ’ meta- analiżi ta ’ 13- il prova klinika b’ tagħrif minn aktar minn 3800 pazjent kkurati b’ capecitabine wrew li fl- istudji kollha kombinati, żjieda fl- età (b’ żjidiet ta ’ 10 snin) kienet assoċjati b’ mod statistikament sinifikanti ma ’ żjieda fir- riskju ta ’ żvilupp ta ’ HFS u dijarea u ma ’ riskju mnaqqas ta ’ żvilupp ta ’ newtropenija
Gender The results of a meta-analysis of 13 clinical trials with data from over 3800 patients treated with capecitabine showed that in all studies combined, female gender was statistically significantly associated with an increased risk of developing HFS and diarrhea and with a decreased risk of developing neutropenia.
Sess Ir- riżultati ta ’ meta- analiżi ta ’ 13- il prova klinika b’ tagħrif minn aktar minn 3800 pazjent kkurati b’ capecitabine wrew li fl- istudji kollha kombinati, sess femminili kien assoċjati b’ mod statistikament sinifikanti ma ’ żjieda fir- riskju ta ’ żvilupp ta ’ HFS u dijarea u ma ’ riskju mnaqqas ta ’ żvilupp ta ’ newtropenija
38 There is evidence that the metabolism of 5-FU in the anabolic pathway blocks the methylation reaction of deoxyuridylic acid to thymidylic acid, thereby interfering with the synthesis of deoxyribonucleic acid (DNA).
40 Hemm evidenza li l- metaboliżmu ta ’ 5- FU fis- sensiela ta ’ reazzjonijiet anaboliċi jwaqqaf ir- reazzjoni tal- methylation ta ’ deoxyuridylic acid għal thymidylic acid, u b’ hekk jinterferixxi mas- sintesi ta ’ deoxyribonucleic acid (DNA).
Colon and colorectal cancer:
Kanċer fil- kolon u kanċer fil- kolon u fir- rektum:
In the all-randomised population, Xeloda was shown to be superior to 5FU/ LV for disease-free survival (hazard ratio 0.849; 95% CI 0.739 - 0.976;, p = 0.0212), as well as for overall survival (hazard ratio 0.828; 95% CI 0.705 - 0.971; p = 0.0203).
Fil- popolazzjoni randomised kompletament, Xeloda ntwera li huwa superjuri għal 5- FU/ LV għal sopravivenza mingħajr il- marda (hazard ratio 0. 849; 95% CI 0. 739 - 0. 976; p = 0. 0212), kif ukoll għal sopravivenza totali (hazard ratio 0. 828; 95% CI 0. 705 - 0. 971; p = 0. 0203).
Currently, no comparative data are available on Xeloda monotherapy in colorectal cancer in comparison with first line combination regimens.
Bħalissa, l- ebda informazzjoni komparattiva ma hi disponibbli dwar monoterapija b’ Xeloda f’ kanċer tal- kolon u tar - rektum f’ paragun ma ’ l- ewwel għażla ta ’ kura ta ’ mediċini li jittieħdu flimkien.
Combination therapy in first-line treatment of metastatic colorectal cancer Data from a multicentre, randomised, controlled phase III clinical study (NO16966) support the use of Xeloda in combination with oxaliplatin or in combination with oxaliplatin and bevacizumab for the first-line treatment of metastatic colorectal cancer.
Terapija ta ’ taħlita għall- kura primarja ta ’ kanċer metastatiku tal- kolorektum Tagħrif minn studju kliniku multicentre, randomised, ikkontrollat ta ’ fażi III (NO16966) isostni l- użu ta ’ Xeloda f’ taħlita ma ’ oxaliplatin jew f’ taħlita ma ’ oxaliplatin u bevacizumab għall- kura primarja ta ’ kanċer metastatiku tal- kolorektum.
See Table 6 for treatment regimens.
Ara Tabella 10, għal korsijiet ta ’ kura.
39 Table 6
41 Tabella 6
Treatment Regimens in Study NO16966 (mCRC) Treatment Starting Dose 2
ta ’ Kura fl- Istudju NO16966 (mCRC) Kura Doża tal- Bidu 2
85 mg/ m IV 2
85 mg/ m IV 2 hr
hr 2
200 mg/ m2 IV 2 hr
Oxaliplatin on Day 1, every 2 weeks
Leucovorin fl- Ewwel u fit- Tieni
FOLFOX-4 + Bevacizumab
FOLFOX- 4 + 400 mg/ m2 IV bolus, Bevacizumab
200 mg/ m IV 2 hr 400 mg/ m2 IV bolus, followed by 600 mg/ m2 IV 22 hr
Ġurnata, kull ġimagħtejn
Leucovorin on Days 1 and 2, every 2 weeks 5-fluorouracil IV bolus/ infusion, each on Days 1 and 2, every 2 weeks
Bolus/ injezzjoni IV ta ’ 5 - fluorouracil, kull wieħed fl- Ewwel u fit- Tieni Ġurnata, kull ġimagħtejn
XELOX or XELOX+ Bevacizumab
XELOX jew
Oxaliplatin Capecitabine
Oxaliplatin Ġurnata, kull 3 ġimgħat Capecitabine mill- ħalq darbtejn
130 mg/ m2 IV 2 hr 1000 mg/ m2 oral twice daily
1000 mg/ m mill- ħalq
Oxaliplatin on Day 1, every 3 weeks Capecitabine oral twice daily for 2 weeks (followed by 1 week off- treatment)
minn ġimgħa waħda mingħajr kura)
In this treatment subgroup comparison, XELOX plus bevacizumab was similar compared to FOLFOX-4 plus bevacizumab in terms of progression-free survival (hazard ratio 1.01; 97.5% CI 0.84 - 1.22]).
F’ dan il- paragun ta ’ sottogrupp ta ’ kura, XELOX u bevacizumab kien simili meta mqabbel ma ’ FOLFOX- 4 u bevacizumab f’ termini ta ’ sopravivenza mingħajr progressjoni (hazard ratio 1. 01; 97. 5% CI 0. 84 - 1. 22).
The median follow up at the time of the primary analyses in the intent-to-treat population was 1.5 years; data from analyses following an additional 1 year of follow up are also included in Table 7.
Il- medjan tal- vista ta ’ wara fil- ħin tal- analiżi primarja fil- popolazzjoni b’ intenzjoni li tiġi kkurata kien ta ’ sena punt ħamsa; tagħrif minn analiżi wara sena oħra ta ’ visti ta ’ wara huwa nkluż ukoll f’ Tabella 11.
However, the on-treatment PFS analysis did not confirm the results of the general PFS and OS analysis: the hazard ratio of XELOX versus FOLFOX-4 was 1.24 with 97.5% CI 1.07 - 1.44.
Madankollu, l- analiżi tal- PFS wara l- kura ma kkonfermax ir- riżultati ta ’ l- analiżi ġenerali tal- PFS u tal- OS: il- hazard ratio ta ’ XELOX kontra FOLFOX- 4 kien ta ’ 1. 24 b’ 97. 5% CI 1. 07
Although sensitivity analyses show that differences in regimen schedules and timing of tumor assessments impact the on- treatment PFS analysis, a full explanation for this result has not been found.
Għalkemm analiżi tas- sensittività juri li differenza fl- iskeda tal- kors u fil- ħinijiet ta ’ l- istima
the non-inferiority analysis of Study NO16966 P R I M A R Y A N A L Y S IS
Riżultati NO16966
XELOX/ XELOX+P/ XELOX+BV
importanti ta ’ l- effikaċja għall- analiżi ta ’ nuqqas ta ’ inferjorità ta ’ Studju ANALIŻI PRIMARJA FOLFOX- 4/ FOLFOX- 4+P / XELOX/ XELOX+P / FOLFOX- 4+BV XELOX+BV (EPP *:
FOLFOX-4/ FOLFOX-4+P/ FOLFOX-4+BV
N=
N= 1017)
1017)
Data from a randomised, controlled phase III study (CAIRO) support the use of Xeloda at a starting dose of 1000 mg/ m2 for 2 weeks every 3 weeks in combination with irinotecan for the first-line
Tagħrif minn studju randomised u kkontrollat ta ’ fażi III (CAIRO) isostni l- użu ta ’ Xeloda f’ doża tal - bidu ta ’ 1000 mg/ m2 għal ġimagħtejn kull 3 ġimgħat flimkien ma ’ irinotecan għall- kura primarja ta ’ pazjenti b’ kanċer metastatiku tal- kolorektum.
Combination therapy in second-line treatment of metastatic colorectal cancer Data from a multicentre, randomised, controlled phase III clinical study (NO16967) support the use of Xeloda in combination with oxaliplatin for the second-line treatment of metastastic colorectal cancer.
Terapija ta ’ taħlita fil- kura tat- tieni linja ta ’ kanċer metastatiku tal- kolorektum Tagħrif minn studju kliniku b’ ħafna ċentri, randomised, ikkontrollat ta ’ fażi III (NO16967) isostni l - użu ta ’ Xeloda f’ taħlita ma ’ oxaliplatin għall- kura tat- tieni linja ta ’ kanċer metastatiku tal- kolorektum.
For the dosing schedule of XELOX and FOLFOX-4 (without addition of placebo or bevacizumab), refer to Table 6.
Għall- iskeda ta ’ dożaġġ ta ’ XELOX u FOLFOX- 4 (mingħajr iż- żjieda ta ’ plaċebo jew bevacizumab), irreferi għal Tabella 6.
XELOX was demonstrated to be non-inferior to FOLFOX-4 in terms of progression-free survival in the per-protocol population and intent-to-treat population (see Table 8).
Intwera li XELOX ma kienx inferjuri għal FOLFOX- 4 f’ termini ta ’ sopravivenza mingħajr progressjoni fil- popolazzjoni skond protokoll u fil - popolazzjoni b’ intenzjoni li jiġu kkurati (ara Tabella 8).
41 Table 8
43 Tabella 8
the non-inferiority analysis of Study NO16967 PRIMARY ANALYSIS
Riżultati importanti ta ’ NO16967
FOLFOX-4
l- effikaċja għall- analiżi ta ’ nuqqas ta ’ inferjorità ta ’ Studju ANALIŻI PRIMARJA FOLFOX- 4
(PPP*:
XELOX
N=313) (PPP*:
(PPP *:
N= 314) HR
314)
- ECF: epirubicin (50 mg/ m2 as a bolus on day 1 every 3 weeks), cisplatin (60 mg/ m2 as a two
ECF: epirubicin (50 mg / m2 bħala bolus fl- ewwel jum kull 3 ġimgħat), cisplatin (60 mg/ m2
The primary efficacy analyses in the per protocol population demonstrated non-inferiority in overall survival for capecitabine- vs 5-FU-based regimens (hazard ratio 0.86; 95% CI 08 - 0.99) and for oxaliplatin- vs cisplatin-based regimens (hazard ratio 0.92; 95% CI 0.80 - 1.1).
44 L- analiżi ta ’ effikaċja primarja f’ popolazzjoni skond il- protokoll wriet nuqqas ta ’ inferjorità fis - sopravivenza globali għal capecitabine vs korsijiet ibbażati fuq 5- FU (hazard ratio 0. 86; 95% CI 08 - 0. 99) u għal oxaliplatin vs korsijiet ibbażati fuq cisplatin (hazard ratio 0. 92; 95% CI 0. 80 - 1. 1).
42 The median overall survival was 10.0 months in cisplatin-based regimens and 10.4 months in oxaliplatin-based regimens.
Il- medjan tas- sopravvivenza globali kien ta ’ 10. 0 xhur f’ korsijiet bbażati fuq cisplatin u 10. 4 xhur f’ korsijiet bbażati fuq oxaliplatin.
Combination therapy with Xeloda and docetaxel in locally advanced or metastatic breast cancer Data from one multicentre, randomised, controlled phase III clinical trial support the use of Xeloda in combination with docetaxel for treatment of patients with locally advanced or metastatic breast cancer after failure of cytotoxic chemotherapy, including an anthracycline.
Terapija kombinata b’ Xeloda u docetaxel f’ kanċer avvanzat lokalment jew metastatiku tas- sider Tagħrif minn prova klinika waħda kkontrollata, multicentre u randomised ta ’ fażi III, tissapportja l- uża ta ’ Xeloda flimkien ma ’ docetaxel għall- kura ta ’ pazjenti b’ kanċer tas- sider avvanzat lokalment jew metastatiku wara l- falliment ta ’ kemjoterapija ċitotossika, li tinkludi anthracycline.
Monotherapy with Xeloda after failure of taxanes, anthracycline containing chemotherapy, and for whom anthracycline therapy is not indicated Data from two multicentre phase II clinical trials support the use of Xeloda monotherapy for treatment of patients after failure of taxanes and an anthracycline-containing chemotherapy regimen or for whom further anthracycline therapy is not indicated.
Monoterapija b’ Xeloda wara falliment ta ’ taxanes, kemjoterapija li fiha anthracycline, u għal dawk li terapija b’ anthracycline mhix indikata Tagħrif minn żewġ provi kliniċi, multicentre ta ’ fażi II jissapportjaw l- użu ta ’ monoterapija ta ’ Xeloda għall- kura ta ’ pazjenti wara l- falliment ta ’ taxanes u kors ta ’ kemjoterapija li fiha anthracycline jew għal dawk il- pazjenti li għalihom kura b’ anthracycline mhix indikata.
A meta-analysis of 13 clinical trials with data from over 3800 patients treated with Xeloda monotherapy or Xeloda in combination with different chemotherapy regimens in multiple indications (colon, colorectal, gastric and breast cancer), showed that patients on Xeloda who developed hand-foot syndrome (HFS) had a longer overall survival compared to patients who did not develop HFS: median overall survival 29.0 months (95% CI 26.0; 31.6) vs 15.9 months (95% CI 15.0; 17.0) with a hazard ratio of 0.59 (95% CI 0.54; 0.64).
Meta- analiżi ta ’ 13- il prova klinika b’ tagħrif minn aktar minn 3800 pazjent kkurati b’ Xeloda bħala monoterapija jew Xeloda flimkien ma ’ korsijiet ta ’ kimoterapiji differenti f’ indikazzjonijiet multipli (kanċer tal- kolon, tal- kolorektum, ta ’ l- istonku u tas- sider) wriet li pazjenti fuq Xeloda li żviluppaw is - sindrome ta ’ l- idejn u s- saqajn (HFS) kellhom sopravivenża totali itwal meta mqabbel ma ’ pazjenti li ma żviluppawx HFS: sopravivenza totali medjana 29. 0 xahar (95% CI 26. 0; 31. 6) vs 15. 9- il xahar (95% CI 15. 0; 17. 0) b’ proporzjon ta ’ periklu ta ’ 0. 59 (95% CI 0. 54; 0. 64).
5.2 Pharmacokinetic properties
45 5. 2 Tagħrif farmakokinetiku
43 Absorption: after oral administration, capecitabine is rapidly and extensively absorbed, followed by extensive conversion to the metabolites, 5'-DFCR and 5'-DFUR.
Assorbiment: wara l- għoti orali, capecitabine jiġi assorbit malajr u b’ mod estensiv, segwit minn bidla estensiva għall- metaboliti, 5 '- DFCR u 5' - DFUR.