qanastek/EMEA-V3 huggingface dataset:
1- An open-label, randomised, non-comparative multicenter study was conducted in patients who failed initial treatment with 400 or 600 mg imatinib.
1 - Sar studju mhux komparattiv, open- label, fejn l- pazjenti ntgħażlu b’ mod każwali b' aktar minn ċentru wieħed fuq pazjenti li fuqhom, it- trattament tal- bidu b' 400 jew 600 mg ta 'imatinib ma ħadimx.
They were randomised (2:1) to either dasatinib (70 mg twice daily) or imatinib (400 mg twice daily).
Il- pazjenti ntgħażlu b' mod każwali (2: 1) biex jingħataw jew dasatinib (70 mg darbtejn kuljum) jew imatinib (400 mg darbtejn kuljum).
Crossover to the alternative treatment arm was allowed if patients showed evidence of disease progression or intolerance that could not be managed by dose modification.
Kien permess li l- pazjenti jibdlu għall- fergħa l- oħra tat- trattament jekk il- pazjenti wrew evidenza ta 'żvilupp fil- marda jew intolleranza li ma setgħetx tkun ikkontrollata b' modifikazzjoni tad- doża.
The primary endpoint was MCyR at 12 weeks.
Il- punt ta ’ tmiem primarju kien MCyR wara 12- il ġimgħa.
Results are available for 150 patients:
Ir- riżultati huma disponibbli għal 150 pazjent:
101 were randomised to dasatinib and 49 to imatinib (all imatinib-resistant).
101 kienu magħżula għal dasatinib u 49 għal imatinib (kollha reżistenti għal imatinib).
The median time from diagnosis to randomisation was 64 months in the dasatinib group and 52 months in the imatinib group.
Iż- żmien medju mid- dijanjosi sa meta ntgħażlu l- pazjenti b' mod każwali kien ta '64 xahar fil- grupp ta' dasatinib u 52 xahar fil- grupp ta 'imatinib.
All subjects were extensively pretreated.
L- individwi kollha kellhom trattament estensiv qabel.
Prior complete haematologic response (CHR) to imatinib was achieved in 93% of the overall patient population.
Respons ematoloġiku komplet minn qabel (CHR) għal imatinib inkiseb f' 93% tal - popolazzjoni kollha tal- pazjenti.
A prior MCyR to imatinib was achieved in 28% and 29% of the patients in the dasatinib and imatinib arms, respectively.
MCyR minn qabel għal imatinib kien miksub fi 28% u 29% tal - pazjenti fil- fergħat ta ’ dasatinib u imatinib, rispettivament.
Median duration of treatment was 23 months for dasatinib (with 44% of patients treated for > 24 months to date) and 3 months for imatinib (with 10% of patients treated for > 24 months to date).
It- tul medju tat- trattament kien ta ’ 23 xahar għal dasatinib (b' 44% tal- pazjenti ttrattati għal > 24 xahar sa llum) u 3 xhur għal imatinib (b' 10% tal- pazjenti ttrattati għal > 24 xahar sa llum).
Ninety-three percent of patients in the dasatinib arm and 82% of patients in the imatinib arm achieved a CHR prior to crossover.
Tlieta u disgħin fil- mija tal- pazjenti fil- fergħa ta 'dasatinib u 82% tal- pazjenti fil- fergħa ta' imatinib kisbu CHR qabel il- crossover.
At 3 months, a MCyR occurred more often in the dasatinib arm (36%) than in the imatinib arm (29%).
Wara 3 xhur, McyR ġara aktar spiss fil- fergħa ta ’ dasatinib (36%) u milli fil- fergħa ta ’ imatinib (29%).
Notably, 22% of patients reported a complete cytogenetic response (CCyR) in the dasatinib arm while only 8% achieved a CCyR in the imatinib arm.
B’ mod partikolari, 21% tal- pazjenti rrapportaw respons ċitoġeniku komplet (CCyR) fil- fergħa ta ’ dasatinib waqt li 8% biss kisbu CCyR fil- fergħa ta ’ imatinib.
With longer treatment and follow-up (median of 24 months), MCyR was achieved in 53% of the dasatinib-treated patients (CCyR in 44%) and 33% of the imatinib-treated patients (CCyR in 18%) prior to crossover.
Bi trattament u follow- up itwal (medjan ta ’ 24 xahar), inkiseb MCyR fi 53% tal- pazjenti ttrattati b’ dasatinib (CCyR f’ 44%) u 33% tal- pazjenti ttrattati b’ imatinib (CCyR fi 18%) qabel il- crossover.
Among patients who had received imatinib 400 mg prior to study entry, MCyR was achieved in 61% of patients in the dasatinib arm and 50% in the imatinib arm.
Fost il- pazjenti li rċevew imatinib 400 mg qabel id- dħul fl- istudju, MCyR inkiseb f’ 61% tal- pazjenti fil- fergħa ta ’ dasatinib u 50% fil- fergħa ta ’ imatinib.
Based on the Kaplan-Meier estimates, the proportion of patients who maintained MCyR for 1 year was 92% (95% CI:
14 Abbażi ta ’ l- istimi Kaplan- Meier, il- proporzjon ta ’ pazjenti li żammew MCyR għal sena kien 92% (95% CI:
[85%-100%]) for dasatinib (CCyR 97%, 95% CI:
[85% - 100%]) għal dasatinib (CCyR 97%, 95% CI:
[92%-100%]) and 74% (95% CI:
[92% - 100%]) u 74% (95% CI:
[49%-100%]) for imatinib (CCyR 100%).
[49% - 100%]) għal imatinib (CCyR 100%).
The proportion of patients who maintained MCyR for 18 months was 90% (95% CI:
Il- proporzjon ta ’ pazjenti li żammew MCyR għal 18- il xahar kien 90% (95% CI:
[82%-98%]) for dasatinib (CCyR 94%, 95% CI:
[82% - 98%]) għal dasatinib (CCyR 94%, 95% CI:
[87%-100%]) and 74% (95% CI:
[87% - 100%]) u 74% (95% CI:
Based on the Kaplan-Meier estimates, the proportion of patients who had progression-free survival (PFS) for 1 year was 91% (95% CI:
Abbażi ta ’ l - estimi Kaplan- Meier, il- proporzjon ta ’ pazjenti li kellhom sopravivenza ħielsa mill - progressjoni (PFS) għal sena kien ta ’ 91% (95% CI:
[85%-97%]) for dasatinib and 73% (95% CI:
[85% - 97%]) għal dasatinib u 73% (95% CI:
[54%-91%]) for imatinib.
[54% - 91%]) għal imatinib.
The proportion of patients who had PFS at 2 years was 86% (95% CI:
Il- proporzjon ta ’ pazjenti li kellhom PFS wara sentejn kien ta ’ 86% (95% CI:
[78%-93%]) for dasatinib and 65% (95% CI:
[78% - 93%]) għal dasatinib u 65% (95% CI:
[43%-87%]) for imatinib.
[43% - 87%]) għal imatinib.
A total of 43% of the patients in the dasatinib arm, and 82% in the imatinib arm had treatment failure, defined as disease progression or cross-over to the other treatment (lack of response, study drug intolerance, etc.).
Total ta ’ 43% tal- pazjenti fil- fergħa ta ’ dasatinib, u 82% fil- fergħa ta ’ imatinib ma ħadimx it - trattament fuqhom, definit bħala progress tal- marda jew cross- over għat- trattament l- ieħor (nuqqas ta ’ rispons, intolleranza għall- mediċina ta ’ l- istudju, eċċ.).
The rate of major molecular response (defined as BCR-ABL/ control transcripts ≤ 0.1% by RQ-PCR in peripheral blood samples) prior to crossover was 29% for dasatinib and 12% for imatinib.
Ir- rata ta ’ rispons molekulari maġġuri (definit bħala BCR- ABL/ transcripts ta ’ kontroll ≤ 0. 1% b’ RQ - PCR f’ kampjuni periferali tad- demm) qabel il- crossover kienet 29% għal dasatinib u 12% għal imatinib.
14 2- An open-label, single-arm, multicenter study was conducted in patients resistant or intolerant to imatinib (i. e. patients who experienced significant toxicity during treatment with imatinib that precluded further treatment).
2 - Sar studju open- label, b' fergħa waħda, f' ċentri varji fuq pazjenti reżistenti jew intolleranti għal imatinib (jiġifieri pazjenti li sofrew tossiċità sinifikanti waqt it- trattament b’ imatinib tant li twaqqfilhom t- trattament).
A total of 387 patients received dasatinib 70 mg twice daily (288 resistant and 99 intolerant).
Total ta ’ 387 pazjent rċevew dasatinib 70 mg darbtejn kuljum (288 reżistenti u 99 intolleranti għal imatinib).
The median time from diagnosis to start of treatment was 61 months.
Iż- żmien medju mid- dijanjożi sal- bidu tat- trattament kien ta ’ 61 xahar.
The majority of the patients (53%) had received prior imatinib treatment for more than 3 years.
Il- maġġoranza tal - pazjenti (53%) kienu ħadu trattament b’ imatinib qabel għal aktar minn tliet snin.
Most resistant patients (72%) had received > 600 mg imatinib.
Il- pazjenti l- aktar reżistenti (72%) kienu rċevew > 600 mg imatinib.
In addition to imatinib, 35% of patients had received prior cytotoxic chemotherapy, 65% had received prior interferon, and 10% had received a prior stem cell transplant.
Barra imatinib, 35% tal- pazjenti kienu rċevew kimoterapija ċitotossika qabel, 65% kienu ħadu interferon qabel, u 10% kienu għamlu trapjant taċ - ċelloli stemma qabel.
Thirty-eight percent of patients had baseline mutations known to confer imatinib resistance.
Tmienja u tletin fil- mija tal- pazjenti kellhom mutazzjonijiet fil- linja bażi magħrufa li tikkawża reżistenza għal imatinib.
Median duration of treatment on dasatinib was 24 months with 51% of patients treated for > 24 months to date.
It- tul medju tat- trattament b’ dasatinib kien ta ’ 24 xahar b’ 51% tal- pazjenti ttrattati għal > 24 xhur sa llum.
Efficacy results are reported in Table 5.
Ir- riżultati ta ’ l- effikaċja jidhru f' Tabella 5.
MCyR was achieved in 55% of imatinib-resistant patients and 82% of imatinib-intolerant patients.
MCyR inkiseb f’ 55% tal- pazjenti reżistenti għal imatinib u fi 82% ta ’ pazjenti intolleranti għal imatinib.
With a minimum of 24 months follow-up, 21 of the 240 patients who had achieved a MCyR had progressed and the median duration of MCyR had not been reached.
B' mill- anqas 24 xahar ta ’ follow- up, 21 mill- 240 pazjent li kienu laħqu MCyR kellhom progress u ż - żmien medju ta 'kemm idum MCyR ma ntlaħaqx.
Based on the Kaplan-Meier estimates, 95% (95% CI:
Abbażi ta ’ l- estimi Kaplan- Meier, 95% (95% CI:
[92%-98%]) of the patients maintained MCyR for 1 year and 88% (95% CI:
[92% - 98%]) tal- pazjenti żammew MCyR għal sena u 88% (95% CI:
[83%-93%]) maintained MCyR for 2 years.
[83% - 93%]) żammew MCyR għal sentejn.
The proportion of patients who maintained CCyR for 1 year was 97% (95% CI:
Il- proporzjon ta ’ pazjenti li żammew CCyR għal sena kien 97% (95% CI:
[94%-99%]) and for 2 years was 90% (95% CI:
[94% - 99%]) u għal sentejn kien ta ’ 90% (95% CI:
Fifty-five percent of the imatinib-resistant patients with no prior MCyR to imatinib (n= 288) achieved a MCyR with dasatinib.
Ħamsa u ħamsin fil- mija tal- pazjenti reżistenti għal imatinib mingħajr MCyR preċedenti għal imatinib (n= 288) laħqu MCyR b’ dasatinib.
There were 45 different BCR-ABL mutations in 38% of patients enrolled in this trial.
Kien hemm 45 mutazzjonijiet BCR- ABL differenti fi 38% tal- pazjenti mniżżlin fil- prova.
Complete haematologic response or MCyR was achieved in patients harboring a variety of BCR-ABL mutations associated with imatinib resistance except T315I.
Rispons ematoloġiku sħiħ jew MCyR inkiseb f’ pazjenti b’ varjetà ta ’ mutazzjonijiet BCR- ABL assoċjati ma ’ reżistenza għal imatinib għajr T315I.
The rates of MCyR at 2 years were similar whether patients had any baseline BCR-ABL mutation, P-loop mutation, or no mutation (63%, 61% and 62%, respectively).
Ir- rati ta ’ MCyR wara sentejn kienu simili kemm jekk il- pazjenti kellhom xi mutazzjoni BCR- ABL tal- linja bażi, mutazzjoni P- loop, jew ebda mutazzjoni (63%, 61% u 62%, rispettivament).
Among imatinib-resistant patients, the estimated rate of PFS was 88% (95% CI:
Fost il- pazjenti reżistenti għal imatinib, ir- rati stmati ta ’ PFS kienu ta ’ 88% (95% CI:
[84%-92%]) at 1 year and 75% (95% CI:
[84% - 92%]) wara sena u 75% (95% CI:
[69%-81%]) at 2 years.
[69% - 81%]) wara sentejn.
Among imatinib-intolerant patients, the estimated rate of PFS was 98% (95% CI:
Fost il- pazjenti intolleranti għal imatinib, ir- rata stmata ta ’ PFS kienet ta ’ 98% (95% CI:
[95%-100%]) at 1 year and 94% (95% CI:
[95% - 100%]) wara sena u 94% (95% CI:
[88%-99%]) at 2 years.
[88% - 99%]) wara sentejn.
The rate of major molecular response at 24 months was 45% (35% for imatinib-resistant patients and 74% for imatinib-intolerant patients).
Ir- rata ta ’ rispons molekulari maġġuri wara 24 xahar kienet ta ’ 45% (35% għal pazjenti reżistenti għal imatinib u 74% għal pazjenti intolleranti għal imatinib).
Accelerated Phase CML:
CML b’ Fażi Aċċellerata:
An open-label, single-arm, multicenter study was conducted in patients intolerant or resistant to imatinib.
Sar studju open- label, single- arm, f’ aktar minn ċentru wieħed f’ pazjenti intolleranti jew reżistenti għal imatinib.
A total of 174 patients received dasatinib 70 mg twice daily (161 resistant and 13 intolerant to imatinib).
Total ta ’ 174 pazjenti rċevew dasatinib 70 mg darbtejn kuljum (161 reżistenti u 13 intolleranti għal imatinib).
The median time from diagnosis to start of treatment was 82 months.
Iż- żmien medju mid- dijanjożi sal- bidu tat- trattament kien ta ’ 82 xahar.
Median duration of treatment on dasatinib was 14 months with 31% of patients treated for > 24 months to date.
15 It- tul medju tat- trattament b’ dasatinib kien ta ’ 14- il xahar b’ 31% tal- pazjenti ttrattati għal > 24 xahar sa llum.
The rate of major molecular response (assessed in 41 patients with a CCyR) was 46% at 24 months.
Ir- rata ta ’ rispons molekulari maġġuri (evalwata f’ 41 pazjent b’ CCyR) kienet ta ’ 46% wara 24 xahar.
Further efficacy results are reported in Table 5.
Riżultati addizzjonali dwar l- effikaċja huma rrapportati fit- Tabella 5.
Myeloid Blast Phase CML:
Myeloid Blast Phase CML:
A total of 109 patients received dasatinib 70 mg twice daily (99 resistant and 10 intolerant to imatinib).
Total ta ’ 109 pazjent irċevew dasatinib 70 mg darbtejn kuljum (99 reżistenti u 10 intolleranti għal imatinib).
The median time from diagnosis to start of treatment was 48 months.
Iż- żmien medju mid- dijanjożi sal- bidu tat- trattament kien ta ’ 48 xahar.
Median duration of treatment on dasatinib was 3.5 months with 12% of patients treated for > 24 months to date.
It- tul medju tat - trattament b’ dasatinib kien ta ’ 3. 5 xhur bi 12% tal- pazjenti ttrattati għal > 24 xahar sa llum.
The rate of major molecular response (assessed in 19 patients with a CCyR) was 68% at 24 months.
Ir- rata ta ’ rispons molekulari maġġuri (evalwata f’ 19- il pazjent b’ CCyR) kienet ta ’ 68% wara 24 xahar.
Clinical trials in Lymphoid Blast Phase CML and Ph+ ALL:
Provi kliniċi f’ Lymphoid Blast Phase CML u Ph+ ALL:
An open-label, single-arm, multicenter study was conducted in patients with lymphoid blast phase CML or Ph+ ALL who were resistant or intolerant to prior imatinib therapy.
Sar studju open- label, single- arm, f’ aktar minn ċentru wieħed fuq pazjenti b’ lymphoid blast phase CML jew Ph+ ALL li kienu reżistenti jew intolleranti għal terapija b’ imatinib preċedenti.
A total of 48 patients with lymphoid blast CML received dasatinib 70 mg twice daily (42 resistant and 6 intolerant to imatinib).
Total ta ’ 48 pazjent b’ lymphoid blast CML irċevew dasatinib 70 mg darbtejn kuljum (42 reżistenti u 6 intolleranti għal imatinib).
The median time from diagnosis to start of treatment was 28 months.
Iż- żmien medju mid- dijanjożi sal- bidu tat- trattament kien ta ’ 28 xahar.
Median duration of treatment on dasatinib was 3 months with 2% treated for > 24 months to date.
It - tul medju tat- trattament b’ dasatinib kien ta ’ 3 xhur bi 2% ttrattati għal > 24 xahar sa llum.
The rate of major molecular response (all 22 treated patients with a CCyR) was 50% at 24 months.
Ir- rata ta ’ rispons molekulari maġġuri (it- 22 pazjent kollha ttrattati b’ CCyR) kienet ta ’ 50% wara 24 xahar.
In addition, 46 patients with Ph+ ALL received dasatinib 70 mg twice daily (44 resistant and 2 intolerant to imatinib).
Barra minn hekk, 46 pazjent b’ Ph+ ALL irċevew dasatinib 70 mg darbtejn kuljum (44 reżistenti u 2 intolleranti għal imatinib).
Median duration of
Iż- żmien medju mid- dijanjożi sal- bidu tat- trattament kien ta ’ 18- il xahar.
15 treatment on dasatinib was 3 months with 7% of patients treated for > 24 months to date.
It- tul medju tat- trattament b’ dasatinib kien ta ’ 3 xhur b’ 7% tal- pazjenti ttrattati għal > 24 xahar sa llum.
Further efficacy results are reported in Table 5.
Ir- rata ta ’ rispons molekulari maġġuri (il- 25 pazjent kollha ttrattati b’ CCyR) kienet ta ’ 52% wara 24 xahar.
Table 5:
Riżultati addizzjonali dwar l- effikaċja huma rrapportati fit- Tabella 5.
Efficacy in Phase II SPRYCEL Single-Arm
16 Effikaċja fi provi kliniċi single arm ta ’ Fażi II ta ’ SPRYCELa Tabella 5:
Clinical Studiesa Myeloid Lymphoid
Myeloid Blast
Chronic
Lymphoid Blast
Accelerated
Kronika
Blast Blast
Aċċellerata
Haematologic Response Rateb (%) MaHR (95% CI)
(95% CI)
n/ a
applikabbli
CHR (95% CI) NEL (95% CI)
CHR (95% CI)
91% (88– 94) n/ a
91% (88– 94)
Duration of MaHR (%; Kaplan-Meier Estimates)
Tul ta ’ MaHR (%; Stimi Kaplan- Meier) mhux
1 Year 2 Year
71% (55- 87)
c
Sentejn
n/ a n/ a
applikabbli
79% (71-87) 60% (50-70)
60% (50- 70)
71% (55-87) 41% (21-60)
41% (21- 60)
29% (3-56) 10% (0-28)
10% (0- 28)
32% (8-56) 24% (2-47)
24% (2- 47)
Cytogenetic Response (%) MCyR (95% CI) CCyR (95% CI)
Rispons Ċitoġenetikuc (%) MCyR (95% CI)
Survival (%; Kaplan-Meier Estimates) Progression-Free
Sopravivenza (%; Stimi Kaplan- Meier) Ħielsa minn progressjoni
1 Year 2 Year
Sena Sentejn
Overall a
Ġenerali a
Numbers in bold font are the results of primary endpoints. b Haematologic response criteria (all responses confirmed after 4 weeks):
Numbri b’ tipa skura huma r- riżultati ta ’ punti ta ’ tmiem primarji. b Kriterji ta ’ respons ematoloġiku (ir- responsi kollha kkonfermati wara 4 ġimgħat):
Major haematologic response:
Respons ematoloġiku maġġuri:
(MaHR) = complete haematologic response (CHR) + no evidence of leukemia (NEL).
(MaHR) = respons ematoloġiku sħiħ (CHR) + ebda evidenza ta ’ lewkemja (NEL).
CHR (chronic CML):
CHR (CML kronika):
WBC ≤ institutional ULN, platelets < 450,000/ mm3, no blasts or promyelocytes in peripheral blood, < 5% myelocytes plus metamyelocytes in peripheral blood, basophils in peripheral blood < 20%, and no extramedullary involvement.
Ċelloli tad- demm bojod (WBC) ≤ ULN istituzzjonali, plejtlits < 450, 000/ mm3, ebda blasts jew promajeloċiti f’ demm periferali, < 5% majeloċiti miżjud b’ metamajeloċiti fid- demm periferali, < 20% bażofili fid- demm periferali, u ebda involviment ekstramedullari.
CHR (advanced CML/ Ph+ ALL):
CHR (CML/ Ph+ ALL avvanzata):
WBC ≤ institutional ULN, ANC ≥ 1000/ mm3, platelets ≥ 100,000/ mm3, no blasts or promyelocytes in peripheral blood, bone marrow blasts ≤ 5%, < 5% myelocytes plus metamyelocytes in peripheral blood, basophils in peripheral blood < 20%, and no extramedullary involvement.
WBC ≤ ULN istituzzjonali, ANC ≥ 1, 000/ mm3, plejtlits ≥ 100, 000/ mm3, ebda blasts jew promajeloċiti f’ demm periferali, blasts fil- mudullun ≤ 5%, < 5% majeloċiti u b’ metamajeloċiti fid- demm periferali, < 20% bażofili fid- demm periferali, u ebda involviment ekstamedullari.
NEL: same criteria as for CHR but ANC ≥ 500/ mm3 and< 1000/mm3, or platelets ≥ 20,000/mm3 and ≤ 1 00,000/mm3. c Cytogenetic response criteria: complete (0% Ph+ metaphases) or partial (> 0%– 35%).
NEL: l- istess kriterji bħal ta ’ CHR iżda ANC ≥ 500/ mm3 u < 1, 000/ mm3, jew platelets ≥ 20, 000/ mm3 u ≤ 100, 000/ mm3. c Kriterji ta ’ respons ċitoġenetiċi: totali (0% Ph+ metafażi) jew parzjali (> 0% – 35%).
MCyR (0% – 35%) combines both complete and partial responses. n/ a = not applicable CI = confidence interval ULN = upper limit normal range.
MCyR (0% – 35%) jikkombina kemm respons sħiħ kif ukoll parzjali. n/ a = mhux applikabbli CI = intervall ta ’ kunfidenza ULN = medda normali tal- limitu ta ’ fuq.
The outcome of patients with bone marrow transplantation after dasatinib treatment has not been fully evaluated.
Ir- riżultati tal- pazjenti bi trapjant tal- mudullun wara l- kura b' dasatinib għadhom ma ġewx evalwati għal kollox.
Phase III Clinical Trials Two randomised, open-label studies were conducted to evaluate the efficacy of dasatinib administered once daily compared with dasatinib administered twice daily:
Provi Kliniċi ta ’ Fażi III Saru żewġ studji open label, fejn il- pazjenti ntgħażlu b’ mod każwali, biex tiġi evalwata l- effikaċja ta ’ dasatinib mogħti darba kuljum meta mqabbel ma ’ dasatinib mogħti darbtejn kuljum:
1- In the study of chronic phase CML, the primary endpoint was MCyR in imatinib-resistant patients.
1 - Fl- istudju ta ’ CML ta ’ fażi kronika, il- punt aħħari primarju kien l- MCyR f’ pazjenti reżistenti għal imatinib.
The main secondary endpoint was MCyR by total daily dose level in the imatinib-resistant patients.
Il- punt aħħari sekondarju prinċipali kien l- MCyR bil- livell tad- doża totali ta ’ kuljum fil - pazjenti reżistenti għal imatinib.
Other secondary endpoints included duration of MCyR, progression-free survival, and overall survival.
Punti aħħarija sekondarji oħra kienu jinkludu t- tul tal- MCyR, is - sopravivenza mingħajr progressjoni tal- marda, u s- sopravivenza globali.
A total of 670 patients, of whom 498 were imatinib-resistant, were randomised to the dasatinib 100 mg once daily, 140 mg once daily, 50 mg twice daily, or 70 mg twice daily group.
Total ta ’ 670 pazjent, li minnhom 498 kienu reżistenti għal imanitib, ġew magħżula b’ mod każwali għall- grupp ta ’ dasatinib 100 mg darba kuljum, 140 mg darba kuljum, 50 mg darbtejn kuljum, jew 70 mg darbtejn kuljum.
Median duration of treatment was approximately 8 months (range < 1– 15 months).
It - perjodu medju ta ’ trattament kien ta ’ madwar 8 xhur (medda < 1– 15- il xahar).
16 Response rates are presented in Table 6.
17 Ir- rati ta ’ respons huma ppreżentati f’ Tabella 6.
Efficacy was achieved across all dasatinib treatment groups with the once daily schedule demonstrating comparable efficacy (non-inferiority) to the twice daily schedule on the primary efficacy endpoint (difference in MCyR 2.8%; 95% confidence interval [-6% - 11.6%]).
L- effikaċja nkisbet fil- gruppi kollha ta ’ trattament b’ dasatinib, bl- iskeda ta ’ darba kuljum li turi effikaċja komparabbli (mhux inferjuri) għall- iskeda ta ’ darbtejn kuljum fuq il- punt aħħari primarju ta ’ l- effikaċja (differenza fil- MCyR 2. 8%; 95% intervall ta ’ kunfidenza [- 6% - 11. 6%]).
The main secondary endpoint of the study also showed comparable efficacy (non-inferiority) between the 100 mg total daily dose and the 140 mg total daily dose (difference in MCyR -0.8%; 95% confidence interval [-9.6% - 8.0%]).
Il- punt aħħari sekondarju prinċipali wkoll wera effikaċja komparabbli (mhux inferjuri) bejn id- doża totali ta ’ 100 mg kuljum u d- doża totali ta ’ 140 mg kuljum (differenza fil- MCyR - 0. 8%; 95% intervall ta ’ kunfidenza [- 9. 6% - 8. 0%]).
Durations of MCyR, progression-free survival, and overall survival were similar across the four treatment groups.
It- tulijiet tal- MCyR, is- sopravivenza mingħajr progressjoni tal- marda, u is- sopravivenza globali kienu simili fl- erba ’ gruppi ta ’ trattament.
The median overall survival had not been reached for any of the four treatment groups.
Iż- żmien medju ta ’ sopravivenza globali ma ntlaħaqx għall- ebda wieħed mill- erba ’ gruppi ta ’ trattament.
Efficacy of SPRYCEL in Phase III Dose-Optimisation Study: Chronic 100 mg once daily 50 mg twice daily 140 mg once daily n = 167 n = 168 n = 167
CML ta ’ Fażi Kronika 50 mg darbtejn 140 mg darba 70 mg darbtejn 100 mg darba kuljum kuljum kuljum kuljum n = 167 n = 168 n = 167 n = 168
Phase CML 70 mg twice daily n = 168
Perċentwali (%) ta ’ Pazjenti a
Percent (%) of Patients a Haematologic Response Rate (%) CHR
Rata ta ’ Respons Ematoloġiku (%) CHR
Cytogenetic Response (%) MCyR All Patients (95% CI) Imatinib-
Respons Ċitoġeniku (%) MCyR Il- Pazjenti Kollha (95% CI) Pazjenti reżistenti
resistant patients (n/ N) CCyR
għal imatinib (n/ N) CCyR
All Patients Imatinib-
Il- Pazjenti Kollha Pazjenti reżistenti
resistant patients (n/ N) a
għal Imatinib (n/ N) a
Haematologic response criteria (all responses confirmed after 4 weeks):
Kriterji ta ’ respons ematoloġiku (ir- responsi kollha kkonfermati wara 4 ġimgħat):
WBC ≤ institutional ULN, platelets < 450,000/ mm3, no blasts or promyelocytes in peripheral blood, < 5% myelocytes plus metamyelocytes in peripheral blood, basophils in peripheral blood< 20%, and no extramedullary involvement. b Cytogenetic response criteria: complete (0% Ph+ metaphases) or partial (> 0%–35%).
WBC ≤ ULN istituzzjonali, platelets < 450, 000/ mm3, ebda blasts jew promajeloċiti f’ demm periferali, < 5% majeloċiti miżjud b’ metamajeloċiti fid- demm periferali, < 20% bażofili fid- demm periferali, u ebda involviment ekstramedullari. b Kriterji ta ’ respons ċitoġeniku: sħiħ (0% Ph+ metafażijiet) jew parzjali (> 0% – 35%).
MCyR (0% – 35%) combines both complete and partial responses.
MCyR (0% – 35%) jikkombina kemm responsi sħaħ kif ukoll parzjali.
2- In the study of advanced phase CML and Ph+ALL, the primary endpoint was MaHR.
2 - Fl- istudju ta ’ CML ta ’ fażi avanzata u Ph+ALL, il- punt aħħari primarju kien MaHR.
A total of 611 patients were randomised to either the dasatinib 140 mg once daily or 70 mg twice daily group.
Total ta ’ 611- il pazjent ġew magħżula b’ mod każwali għall- grupp ta ’ dasatinib 140 mg darba kuljum jew għall- grupp ta ’ dasatinib 70 mg darbtejn kuljum.
Median duration of treatment was approximately 6 months (range < 1-16 months).
Il- perjodu medju ta ’ trattament kien ta ’ madwar 6 xhur (medda < 1- 16- il xahar).
The once daily schedule demonstrated comparable efficacy (non-inferiority) to the twice daily schedule on the primary efficacy endpoint (difference in MaHR 0.2%; 95% confidence interval [-7.8% - 8.1%]).
L- iskeda ta ’ darba kuljum uriet effikaċja komparabbli (mhux inferjuri) ma ’ l- iskeda ta ’ darbtejn kuljum fuq il- punt aħħari primarju ta ’ l- effikaċja (differenza fil- MaHR 0. 2%; 95% intervall ta ’ kunfidenza [- 7. 8% - 8. 1%]).
However, with a follow-up of 6 months, the duration of response seems to favor the twice daily schedule across the different phases of advanced disease, particularly phases with lymphoid transformation.
Madankollu, b’ follow- up ta ’ 6 xhur, il- perjodu ta ’ rispons donnu jiffavorixxi l- iskeda ta ’ darbtejn kuljum matul il- fażijiet kollha ta ’ mard avanzat, b’ mod partikulari fażijiet bi trasformazzjoni tal- limfojde.
Therefore 70 mg twice daily remains the recommended dose schedule in imatinib-resistant or intolerant patients with advanced phase CML and Ph+ALL.
Għalhekk 70 mg darbtejn kuljum tibqa ’ l- iskeda ta ’ dożaġġ rakkomandata f’ pazjenti reżistenti għal imatinib jew pazjenti b’ CML ta ’ fażi avanzata u Ph+ALL.
The pharmacokinetics of dasatinib were evaluated in 229 adult healthy subjects and in 84 patients.
Il- farmakokinetiċi ta ’ dasatinib ġew evalwati f’ 229 adult b’ saħħtu u f’ 84 pazjent.
Dasatinib is rapidly absorbed in patients following oral administration, with peak concentrations between 0.5-3 hours.
Dasatinib huwa assorbit malajr f’ pazjenti li jkunu qegħdin jieħduh mill- ħalq, b’ konċentrazzjonijiet  massimi bejn 0. 5- 3 sigħat.
Following oral administration, the increase in the mean exposure (AUC τ) is
Wara għoti mill- ħalq, iż- żieda fl- espożizzjoni medja (AUCτ) hija bejn
17 approximately proportional to the dose increment across doses ranging from 25 mg to 120 mg twice daily.
18 wieħed u ieħor proporzjonali għaż- żieda fid- doża f’ dożi minn 25 mg sa 120 mg darbtejn kuljum.
The overall mean terminal half-life of dasatinib is approximately 5-6 hours in patients.
Il - half- life terminali medju globali ta ’ dasatinib huwa bejn wieħed u ieħor 5- 6 sigħat f’ pazjenti.
Data from healthy subjects administered a single, 100 mg dose of dasatinib 30 minutes following a high-fat meal indicated a 14% increase in the mean AUC of dasatinib.
Tagħrif minn individwi b’ saħħithom mogħtija doża waħda ta ’ 100 mg ta ’ dasatinib 30 minuta wara ikla b’ ammont kbir ta ’ xaħam indika żieda ta ’ 14% fl- AUC medju ta ’ dasatinib.
A low-fat meal 30 minutes prior to dasatinib resulted in a 21% increase in the mean AUC of dasatinib.
Ikla b’ ammont baxx ta ’ xaħam 30 minuta qabel dasatinib irriżultat f’ żieda ta ’ 21% fl- AUC medju ta ’ dasatinib.
The observed food effects do not represent clinically relevant changes in exposure.
L- effetti ta ’ l- ikel osservati ma jirrappreżentawx bidliet klinikament rilevanti fl- espożizzjoni.
In patients, dasatinib has a large apparent volume of distribution (2,505 l) suggesting that the medicinal product is extensively distributed in the extravascular space.
F’ pazjenti, dasatinib għandu volum ta ’ distribuzzjoni apparenti kbir (2, 505 l) u dan jissuġġerixxi li l - prodott mediċinali huwa distribwit b’ mod estensiv fl- ispazju ekstravaskulari.
At clinically relevant concentrations of dasatinib, binding to plasma proteins was approximately 96% on the basis of in vitro experiments.
F’ konċentrazzjonijiet li huma klimikament rilevanti ta ’ dasatinib, it- twaħħil ma ’ proteini tal- plażma kien bejn wieħed u ieħor 96% fuq il- bażi ta ’ esperimenti in vitro.
Dasatinib is extensively metabolized in humans with multiple enzymes involved in the generation of the metabolites.
Dasatinib jiġi metabolizzat sewwa b’ mod estensiv b’ bosta enżimi involuti fil- ġenerazzjoni tal - metaboliti.
In healthy subjects administered 100 mg of [14C]-labelled dasatinib, unchanged dasatinib represented 29% of circulating radioactivity in plasma.
F’ individwi b’ saħħithom mogħtija 100 mg ta ’ dasatinib ittikkettat b ’ [14C], dasatinib mhux mibdul irrappreżenta 29% tar- radjuattività li kienet qegħda tiċċirkola fil- plażma.
Plasma concentration and measured in vitro activity indicate that metabolites of dasatinib are unlikely to play a major role in the observed pharmacology of the product.
Il- konċentrazzjoni fil - plażma u attività in vitro imkejjla jindikaw li l- metaboliti ta ’ dasatinib m’ humiex mistennija li jkollhom rwol maġġuri fil- farmakoloġija osservata tal- prodott.
CYP3A4 is a major enzyme responsible for the metabolism of dasatinib.
CYP3A4 huwa enżima maġġuri responsabbli għall- metaboliżmu ta ’ dasatinib.
Elimination is predominantly in the faeces, mostly as metabolites.
Eliminazzjoni sseħħ b’ mod predominanti fl- ippurgar, l- aktar bħala metaboliti.
Following a single oral dose of [14C]-labelled dasatinib, approximately 89% of the dose was eliminated within 10 days, with 4% and 85% of the radioactivity recovered in the urine and faeces, respectively.
Wara doża orali waħda ta ’ dasatinib ittikkettat b ’ [14C], bejn wieħed u ieħor 89% tad- doża ġiet eliminata fi żmien 10t ijiem, b’ 4% u 85% tar- radjuattività rkuprata fl- awrina u fl- ippurgar, rispettivament.
Unchanged dasatinib accounted for 0.1% and 19% of the dose in urine and faeces, respectively, with the remainder of the dose as metabolites.
Dasatinib mhux mibdul ammonta għal 0. 1% u 19% tad- doża fl- awrina u fl- ippurgar, rispettivament, bil- bqija tad- doża bħala metaboliti.
Hepatic and renal impairment:
Indeboliment epatiku u renali:
Dasatinib and its metabolites are minimally excreted via the kidney.
Dasatinib u l- metaboliti tiegħu jitneħħew minimament permezz tal- kilwa.
Exposure to dasatinib may be expected to increase if liver function is impaired (see section 4.4).
L- espożizzjoni għal dasatinib tista ’ tkun mistennija li tiżdied jekk il- funzjoni tal- fwied ma tkunx qiegħda taħdem tajjeb (ara sezzjoni 4. 4).
The non-clinical safety profile of dasatinib was assessed in a battery of in vitro and in vivo studies in mice, rats, monkeys, and rabbits.
Il- profil tas- sigurtà mhux kliniku ta ’ dasatinib ġie vvalutat f’ sensiela ta ’ studji in vitro u in vivo fi ġrieden, firien, xadini, u fniek.
The primary toxicities occurred in the gastrointestinal, haematopoietic, and lymphoid systems.
It- tossiċitajiet primarji seħħew fis- sistemi gastrointestinali, ematopojetiċi, u tal- limfojde.
Gastrointestinal toxicity was dose-limiting in rats and monkeys, as the intestine was a consistent target organ.
It- tossiċità gastrointestinali kienet ta ’ limitazzjoni għad- doża fil- firien u fix- xadini, minħabba li l- intestini kienu organu konsistentament fil- mira.
In rats, minimal to mild decreases in erythrocyte parameters were accompanied by bone marrow changes; similar changes occurred in monkeys at a lower incidence.
Fil- firien, tnaqqis minimu għal ħafif f’ parametri eritroċiti kien akkompanjat b’ bidliet fil- mudullun; tibdil simili seħħ f’ xadini f’ inċidenza iktar baxxa.
Lymphoid toxicity in rats consisted of lymphoid depletion of the lymph nodes, spleen, and thymus, and decreased lymphoid organ weights.
It- tossiċità tal - limfojde fil- firien kienet tikkonsisti minn tnaqqis tal- limfojde tal- lymph nodes, tal- milsa, u tat- timu, u tnaqqis fil- piżijiet ta ’ l- organi tal- limfojde.
Changes in the gastrointestinal, haematopoietic and lymphoid systems were reversible following cessation of treatment.
Tibdil fis- sistemi gastrointestinali, ematopojetiċi, u tal - limfojde kienu riversibbli wara l- waqfien tat- trattament.
Renal changes in monkeys treated for up to 9 months were limited to an increase in background kidney mineralization.
Tibdil renali fix- xadini ttrattati sa 9 xhur kien limitat għal żieda fil- mineralizzazzjoni tal- kliewi fl - isfond.
Cutaneous haemorrhage was observed in an acute, single-dose oral study in monkeys but was not observed in repeat-dose studies in either monkeys or rats.
Emorraġija fil- ġilda ġiet osservata fi studju orali, ta ’ doża waħda, akut f’ xadini, iżda din ma ġietx osservata fi studji b’ doża ripetuta fix- xadini jew fil- firien.
In rats, dasatinib inhibited platelet aggregation in vitro and prolonged cuticle bleeding time in vivo, but did not invoke spontaneous haemorrhage.
Fil- firien, dasatinib inibixxa l - aggregazzjoni tal- platelets in vitro u tawwal il- ħin tal- fsada ta ’ l- epiderme in vivo, iżda ma wassalx għal emorraġija spontanja.
Dasatinib activity in vitro in hERG and Purkinje fiber assays suggested a potential for prolongation of cardiac ventricular repolarization (QT interval).
L- attività in vitro ta ’ Dasatinib f’ analiżi hERG u Purkinje fiber issuġġeriet potenzjal għal titwil tar - ripolarizzazzjoni ventrikulari kardijaka (intervall QT).
However, in an in vivo single-dose study in conscious telemetered monkeys, there were no changes in QT interval or ECG wave form.
Madankollu, fi studju ta ’ doża waħda in vivo f’ xadini telemetrati f’ sensihom, ma kien hemm ebda bidla fl- intervall QT jew fil- forom ta ’ mewġ ta ’ l - ECG.
18 Dasatinib was not mutagenic in in vitro bacterial cell assays (Ames test) and was not genotoxic in an in vivo rat micronucleus study.
19 Dasatinib ma kienx mutaġeniku f’ analiżi ta ’ ċelloli batterjali in vitro (Ames test) u ma kienx ġenotossiku fi studju mikronukleju fuq il- firien in vivo.
Dasatinib was clastogenic in vitro to dividing Chinese Hamster Ovary (CHO) cells.
Dasatinib kien klastoġeniku in vitro għal diviżjoni ta ’ ċelloli ovarji tal- Ovarju tal- Ħamster Ċiniż (CHO).
Dasatinib did not affect male or female fertility in a conventional rat fertility and early embryonic development study, but induced embryolethality at dose levels approximating human clinical exposures.
Dasatinib ma affettwax il- fertilità ta ’ l- irġiel jew tan- nisa fi studju konvenzjonali dwar il- fertilità tal - firien u dwar l- iżvilupp embrijoniku bikri, iżda wassal għal embrijoletalità f’ livelli ta ’ dożi li joqorbu għall- espożizzjonijiet kliniċi umani.
In embryofoetal development studies, dasatinib likewise induced embryolethality with associated decreases in litter size in rats, as well as foetal skeletal alterations in both rats and rabbits.
Fi studji dwar l- iżvilupp embrijofetali, dasatinib, bl- istess mod, wassal għal embrijoletalità bi tnaqqis fid- daqs tal- boton fil- firien, kif ukoll għal tibdil skeletrali tal- fetu kemm fil- firien kif ukoll fil- fniek.
These effects occurred at doses that did not produce maternal toxicity, indicating that dasatinib is a selective reproductive toxicant from implantation through the completion of organogenesis.
Dawn l- effetti seħħew f’ dożi li ma pproduċewx tossiċità fl- omm u dan jindika li dasatinib huwa tossikant selettiv għas- sistema riproduttiva mill- impjantazzjoni sa tmiem l- organoġeneżi.
In mice, dasatinib induced immunosuppression, which was dose-related and effectively managed by dose reduction and/ or changes in dosing schedule.
Fil- ġrieden, dasatinib wassal għal immunosuppressjoni, li kienet relatata mad- doża u ġiet ikkontrollata b’ mod effettiv bi tnaqqis tad- doża u/ jew tibdil fl- iskeda tad- dożaġġ.
Dasatinib had phototoxic potential in an in vitro neutral red uptake phototoxicity assay in mouse fibroblasts.
Dasatinib kellu potenzjal fototossiku f’ analiżi ta ’ neutral red uptake phototoxicity in vitro f’ fibroblasti tal- ġrieden.
Dasatinib was considered to be non-phototoxic in vivo after a single oral administration to female hairless mice at exposures up to 3-fold the human exposure following administration of the recommended therapeutic dose (based on AUC).
Dasatinib kien ikkunsidrat li mhuwiex fototossiku in vivo wara l- għoti ta ’ darba lil ġrieden nisa bla xagħar f’ espożizzjonijiet sa 3 darbiet dawk tal- espożizzjoni umana wara l- għoti tad- doża terapewtika rakkomandata (ibbażata fuq l- AUC).
No carcinogenesis studies were conducted with dasatinib.
Ma saru ebda studji dwar il- karċinoġenesi b’ dasatinib.
Lactose monohydrate Cellulose, microcrystalline Croscarmellose sodium Hydroxypropyl cellulose Magnesium stearate
Lactose monohydrate Cellulose, microcrystalline Croscarmellose sodium Hydroxypropyl cellulose Magnesium stearate
Hypromellose Titanium dioxide Macrogol 400
Hypromellose Titanium dioxide Macrogol 400
Alu/ Alu blisters (calendar blisters and unit dose blisters) and high-density polyethylene (HDPE) bottle with child resistant closure of polypropylene.
Folji tal- Alu/ Alu (folji indikati bil- ġranet u folji ta ’ doża waħda) u flixkun tal- polyethylene ta ’ densità għolja( HDPE) b’ tapp tal- polypropylene li t- tfal isibu diffiċli biex jiftħuh.
Cartons containing 56 film-coated tablets in 4 blisters of 14 film-coated tablets each.
Kaxex tal- kartun li fihom 56 pillola miksija b’ rita f’ 4 folji ta ’ 14- il pillola miksija b’ rita f’ kull waħda.
Cartons containing 60 film-coated tablets in perforated unit dose blisters.
20 Kaxex tal- kartun li fihom 60 pillola miksija b’ rita f’ folji ta ’ doża waħda perforati.
19 Cartons containing one bottle with 60 film-coated tablets.
Kaxex tal- kartun li fihom flixkun wieħed b’ 60 pillola miksijin b’ rita.
The tablets consist of a core tablet, surrounded by a film coating to prevent exposure of health care professionals to the active substance.
Il- pilloli huma magħmulin mill- qalba tal- pillola, mdawwra b’ kisja b’ rita sabiex l- espożizzjoni tal - professjonisti tal- kura tas- saħħa għas- sustanza attiva tkun impeduta.
However, if the tablets are unintentionally crushed or broken, health care professionals should wear disposable chemotherapy gloves for appropriate disposal in order to minimize the risk of dermal exposure.
Madankollu, jekk dawn il- pilloli jitfarrku jew jinqasmu mhux intenzjonalment, il- professjonisti tal- kura tas- saħħa għandhom jilbsu ngwanti tal- kimoterapija li jintremew wara l- użu sabiex jitnaqqas kemm jista ’ jkun ir- riskju ta ’ espożizzjoni fuq il- ġilda.
BRISTOL-MYERS SQUIBB PHARMA EEIG Uxbridge Business Park Sanderson Road Uxbridge UB8 1DH United Kingdom
BRISTOL- MYERS SQUIBB PHARMA EEIG Uxbridge Business Park Sanderson Road Uxbridge UB8 1DH Ir- Renju Unit
EU/ 1/ 06/ 363/ 004 - 56 film-coated tablets (blisters) EU/ 1/ 06/ 363/ 007 - 60 x 1 film-coated tablets (unit-dose blisters) EU/ 1/ 06/ 363/ 001 - 60 film-coated tablets (bottle)
EU/ 1/ 06/ 363/ 004 - 56 pillola miksijin b’ rita (folji) EU/ 1/ 06/ 363/ 007 - 60 x 1 pillola miksijin b’ rita (folji b’ doża waħda) EU/ 1/ 06/ 363/ 001 - 60 pillola miksijin b’ rita (flixkun)
Detailed information on this product is available on the website of the European Medicines Agency (EMEA) http: / /www. emea. europa. eu.
Informazzjoni dettaljata dwar dan il- prodott tinsab fuq il- website ta ’ l- Aġenzija Ewropeja dwar il - Mediċini (EMEA): http: // www. emea. europa. eu.
SPRYCEL 50 mg film-coated tablets
SPRYCEL 50 mg pilloli miksijin b’ rita
Each film-coated tablet contains 50 mg dasatinib (as monohydrate).
Kull pillola miksija b’ rita fiha 50 mg dasatinib (bħala monoidrat).
Excipients: each tablet contains 67.5 mg of lactose monohydrate.
Sustanzi mhux attivi: kull pillola fiha 67. 5 mg ta ’ lactose monohydrate.
White to off-white, biconvex, oval tablet with "BMS" debossed on one side and "528" on the other side.
Pillola ovali, tvarja minn bajda għal offwajt, ibbuzzata fuq iż- żewġ naħat, b '"BMS" imnaqqxa fuq naħa waħda u "528" fuq in- naħa l- oħra.
21 Dose escalation:
22 Żieda fid- doża:
Paediatric patients:
23 Pazjenti pedjatriċi:
22 Hepatic impairment: no clinical trials were conducted with SPRYCEL in patients with moderate to severe hepatic impairment (trials excluded patients with ALT and/ or AST > 2.5 times the upper limit of the normal range and/ or total bilirubin > 2 times the upper limit of the normal range).
Indeboliment epatiku: ma sarux provi kliniċi bi SPRYCEL f' pazjenti b' indeboliment epatiku minn moderat sa sever (il- provi eskludew pazjenti b' ALT u/ jew AST > 2. 5 darbiet l- ogħla limitu tal- medda normali u/ jew bilirubin totali > darbtejn l- ogħla limitu tal- medda normali).
Important adverse reactions Myelosuppression: treatment with dasatinib is associated with anaemia, neutropenia and thrombocytopenia.
24 Reazzjonijiet avversi importanti Majelosuppressjoni: trattament b’ dasatinib hu assoċjat ma 'anemija, newtropenja u tromboċitopenja.
23 reversible and usually managed by withholding dasatinib temporarily or by dose reduction (see sections 4.2 and 4.8).
Il- majelosuppressjoni kienet ġeneralment riversibbli u normalment ikkontrollata bil- waqfien temporanju ta 'dasatinib jew bi tnaqqis tad- doża (ara sezzjonijiet 4. 2 u 4. 8).
Lactose This medicinal product contains 135 mg of lactose monohydrate in a 100 mg daily dose and 189 mg of lactose monohydrate in a 140 mg daily dose.
25 Lactose Dan il- prodott mediċinali fih 135 mg ta ’ lactose monohydrate f’ doża ta ’ kuljum ta ’ 100 mg u 189 mg ta 'lactose monohydrate f' doża ta' kuljum ta '140 mg.
24 4.5 Interaction with other medicinal products and other forms of interaction
4. 5 Prodotti mediċinali oħra li ma jaqblux ma ’ dan il- prodott u affarijiet oħra li jistgħu jibdlu l- effett farmaċewtiku tal- prodott
4.6 Pregnancy and lactation
26 4. 6 Tqala u treddigħ
25 Lactation There is insufficient/ limited information on the excretion of dasatinib in human or animal breast milk.
Treddigħ L- informazzjoni dwar il- ħruġ ta 'dasatinib fil- ħalib tas- sider uman jew ta' annimali oħra mhix suffiċjenti jew hi limitata.
Fluid retention events were typically managed by supportive care measures that include diuretics or short courses of steroids.
27 akkumulazzjoni ta 'fluwidi kienu tipikament ikkontrollati b' miżuri ta' kura t' appoġġ li jinkludu dijuretiċi u korsijiet qosra ta 'sterojdi.
0 0 0
Edema pulmonari Pressjoni għolja pulmonari Emorraġija
27 Table 2b:
28 Tabella 2b:
Selected Adverse Drug Reactions Reported in Phase III Dose-Optimisation Study:
Reazzjonijiet Avversi Magħżula tal- Mediċina Rrappurtati fi Studju ta ’ l - Ottimizzazzjoni tad- Doża ta ’ Fażi III:
Advanced Phase CML and Ph+ALL 140 mg once daily 70 mg twice daily n = 304 n = 305 All Grades Grade 3/ 4 All Grades Grade 3/ 4
CML ta ’ Fażi Avanzata u Ph+ALL
Preferred Term
140 mg darba kuljum 70 mg darbtejn n = 304 n = 305
Percent (%) of Patients
Il- Gradi Kollha Gradi 3/ 4 Il- Gradi Kollha
Diarrhoea
Gradi 3/ 4
Adverse Drug Reactions (ADR) reported ≥ 5%
rrapportati f ’ ≥ 5% fi provi kliniċi
Grades 3/ 4
Gradi 3/ 4
Cardiac disorders Common: congestive heart failure/ cardiac dysfunction, pericardial effusion, arrhythmia (including tachycardia), palpitations Uncommon: myocardial infarction, pericarditis, ventricular arrhythmia (including ventricular tachycardia), angina pectoris, cardiomegaly Rare: cor pulmonale, myocarditis, acute coronary syndrome
30 Disturbi fil- qalb Komuni: insuffiċjenza tal- qalb konġestiva/ disfunzjoni tal- qalb, effużjoni tal- perikardju, arritmja (inkluż takikardija), palpitazzjonijiet Mhux komuni: infart mijokardijaku, perikardite, arritmja ventrikulari (fosthom takikardija ventrikulari), anġina pettorali, kardjomegalija Rari: cor pulmonali, mijokardite, sindrome koronarju akut
Injury, poisoning, and procedural complications Common: contusion
31 Korriment, avvelenament u komplikazzjonijiet ta ’ xi proċedura Komuni: tbenġil
30 General disorders and administration site conditions Common: generalised oedema, chills Uncommon: malaise Rare: temperature intolerance
Disturbi ġenerali u kondizzjonijiet ta ’ mnejn jingħata Komuni: edema ġeneralizzata, irjiħat Mhux komuni: telqa Rari: intolleranza tat- temperatura
In the Phase III dose-optimisation study in patients with chronic phase CML, the frequency of neutropenia, thrombocytopenia and anaemia was lower in the SPRYCEL 100 mg once daily than in the SPRYCEL 70 mg twice daily group.
32 Fl- istudju ta ’ l- ottimizzazzjoni tad- doża ta ’ Fażi III f’ pazjenti b’ CML ta ’ fażi kronika, il- frekwenza ta ’ newtropenja, tromboċitopenija u anemija kienet aktar baxxa fil- grupp ta ’ SPRYCEL 100 mg darba kuljum milli fil- grupp ta ’ SPRYCEL 70 mg darbtejn kuljum.
These non-clinical studies show that dasatinib can overcome imatinib resistance resulting from BCR-ABL overexpression, BCR-ABL kinase domain mutations, activation of alternate signaling pathways involving the SRC family kinases (LYN, HCK), and multidrug resistance gene overexpression.
33 imatinib li jirriżulta minn espressjoni żejda ta ’ BCR- ABL, mutazzjonijiet fid- domain tal- kinase BCR - ABL, attivazzjoni ta 'passaġġi tas- sinjalazzjoni alternattivi li jinvolvu l- kinasi tal- familja SRC (LYN, HCK), u espressjoni żejda tal- ġene tar- reżistenza għal ħafna mediċini.
32 Phase II clinical trials in CML:
Provi kliniċi ta ’ Fażi II f’ CML:
Based on the Kaplan-Meier estimates, the proportion of patients who maintained MCyR for 1 year was 92% (95% CI:
34 Abbażi ta ’ l- istimi Kaplan- Meier, il- proporzjon ta ’ pazjenti li żammew MCyR għal sena kien 92% (95% CI:
33 2- An open-label, single-arm, multicenter study was conducted in patients resistant or intolerant to imatinib (i. e. patients who experienced significant toxicity during treatment with imatinib that precluded further treatment).
2 - Sar studju open- label, b' fergħa waħda, f' ċentri varji fuq pazjenti reżistenti jew intolleranti għal imatinib (jiġifieri pazjenti li sofrew tossiċità sinifikanti waqt it- trattament b’ imatinib tant li twaqqfilhom t- trattament).
Median duration of treatment on dasatinib was 14 months with 31% of patients treated for > 24 months to date.
35 It- tul medju tat- trattament b’ dasatinib kien ta ’ 14- il xahar b’ 31% tal- pazjenti ttrattati għal > 24 xahar sa llum.
34 treatment on dasatinib was 3 months with 7% of patients treated for > 24 months to date.
It- tul medju tat- trattament b’ dasatinib kien ta ’ 3 xhur b’ 7% tal- pazjenti ttrattati għal > 24 xahar sa llum.
Efficacy in Phase II SPRYCEL Single-Arm
36 Effikaċja fi provi kliniċi single arm ta ’ Fażi II ta ’ SPRYCELa Tabella 5:
35 Response rates are presented in Table 6.
37 Ir- rati ta ’ respons huma ppreżentati f’ Tabella 6.
36 approximately proportional to the dose increment across doses ranging from 25 mg to 120 mg twice daily.
38 wieħed u ieħor proporzjonali għaż- żieda fid- doża f’ dożi minn 25 mg sa 120 mg darbtejn kuljum.
37 Dasatinib was not mutagenic in in vitro bacterial cell assays (Ames test) and was not genotoxic in an in vivo rat micronucleus study.
39 Dasatinib ma kienx mutaġeniku f’ analiżi ta ’ ċelloli batterjali in vitro (Ames test) u ma kienx ġenotossiku fi studju mikronukleju fuq il- firien in vivo.
Cartons containing 60 film-coated tablets in perforated unit dose blisters.
40 Kaxex tal- kartun li fihom 60 pillola miksija b’ rita f’ folji ta ’ doża waħda perforati.
38 Cartons containing one bottle with 60 film-coated tablets.
Kaxex tal- kartun li fihom flixkun wieħed b’ 60 pillola miksijin b’ rita.
EU/ 1/ 06/ 363/ 005 - 56 film-coated tablets (blisters) EU/ 1/ 06/ 363/ 008 - 60 x 1 film-coated tablets (unit-dose blisters) EU/ 1/ 06/ 363/ 002 - 60 film-coated tablets (bottle)
EU/ 1/ 06/ 363/ 005 - 56 pillola miksijin b’ rita (folji) EU/ 1/ 06/ 363/ 008 - 60 x 1 pillola miksijin b’ rita (folji b’ doża waħda) EU/ 1/ 06/ 363/ 002 - 60 pillola miksijin b’ rita (flixkun)
SPRYCEL 70 mg film-coated tablets
SPRYCEL 70 mg pilloli miksijin b’ rita
Each film-coated tablet contains 70 mg dasatinib (as monohydrate).
Kull pillola miksija b’ rita fiha 70 mg dasatinib (bħala monoidrat).
Excipients: each tablet contains 94.5 mg of lactose monohydrate.
Sustanzi mhux attivi: kull pillola fiha 94. 5 mg ta ’ lactose monohydrate.
White to off-white, biconvex, round tablet with "BMS" debossed on one side and "524" on the other side.
Pillola tonda, tvarja minn bajda għal offwajt, ibbuzzata fuq iż- żewġ naħat, b '"BMS" imnaqqxa fuq naħa waħda u "524" fuq in- naħa l- oħra.
40 Dose escalation:
42 Żieda fid- doża:
Paediatric patients:
43 Pazjenti pedjatriċi: