qanastek/EMEA-V3 huggingface dataset:
While the safety profile of SPRYCEL in the elderly population was similar to that in the younger population, patients aged 65 years and older are more likely to experience fluid retention events and should be monitored closely (see section 4.8).
Filwaqt li l- profil ta ’ sigurtà ta ’ SPRYCEL fil- popolazzjoni anzjana kien simili għal dak tal- popolazzjoni iżgħar fl- età, pazjenti ta ’ 65 sena u akbar huma aktar probabbli li jesperjenzaw episodji ta ’ akkumulazzjoni ta ’ fluwidi u għandhom jiġu mmonitorjati mill- qrib (ara sezzjoni 4. 8).
QT Prolongation: in vitro data suggest that dasatinib has the potential to prolong cardiac ventricular repolarization (QT Interval) (see section 5.3).
Titwil tal- QT: tagħrif in vitro jissuġġerixxi li dasatinib għandu l- potenzjal li jtawwal ir - ripolarizzazzjoni ventrikulari kardijaka (Intervall QT) (ara sezzjoni 5. 3).
In 865 patients with leukaemia treated with dasatinib in Phase II clinical trials, the mean changes from baseline in QTc interval using Fridericia's method (QTcF) were 4 - 6 msec; the upper 95% confidence intervals for all mean changes from baseline were < 7 msec (see section 4.8).
Fi 865 pazjent bil- lewkimja, ittratti bi dasatinib fi provi kliniċi ta ’ Fażi II, il- bidliet medji mil- linja bażi fl- intervall QTc bl- użu tal - metodu Fridericia (QTcF) kienu 4- 6 msec; l- intervalli ta 'kunfidenza ta' aktar minn 95% għall- bidliet medji kollha mil- linja bażi kienu < 7 msec (ara sezzjoni 4. 8).
Of the 2,182 patients who received dasatinib in Phase II/ III clinical trials, 18 had QTc prolongation reported as an adverse event.
Mill- 2, 182 pazjent li rċivew dasatinib fi provi kliniċi ta ’ Fażi II/ III, 18 kellhom titwil tal- QTc rrapportat bħala każ avvers.
Seventeen patients (< 1%) experienced a QTcF > 500 msec.
Sbatax- il pazjent (< 1%) esperjenzaw QTcF > 500 msec.
Dasatinib should be administered with caution to patients who have or may develop prolongation of QTc.
Dasatinib għandu jingħata b' kawtela lil pazjenti li għandhom jew li jista 'jiżviluppalhom titwil tal- QTc.
These include patients with hypokalemia or hypomagnesemia, patients with congenital long QT syndrome, patients taking anti-arrhythmic medicinal products or other medicinal products which lead to QT prolongation, and cumulative high dose anthracycline therapy.
Dawn jinkludu pazjenti b' ipokalimja jew b' ipomagneżimja, pazjenti bis- sindromu ta 'QT twil konġenitali, pazjenti li jieħdu prodotti mediċinali kontra l- arritmja jew prodotti mediċinali oħra li jwasslu għal titwil tal- QT, u terapija b' doża għolja kumulattiva ta' anthracycline.
Hypokalemia or hypomagnesemia should be corrected prior to dasatinib administration.
Qabel ma jingħata dasatinib għandhom jiġu kkoreġuti ipokalimja jew ipomagneżimja.
Patients with uncontrolled or significant cardiovascular disease were not included in the clinical studies.
Pazjenti b' mard kardjovaskulari mhux ikkontrollat jew sinifikanti ma ġewx inklużi f' dawn l- istudji kliniċi.
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.
5 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.
Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.
Pazjenti li għandhom problemi ereditarji rari ta 'intolleranza għall- galactose, nuqqas ta ’ Lapp lactase jew malassorbiment tal- glucose - galactose m' għandhomx jieħdu dan il- prodott mediċinali.
Active substances that may increase dasatinib plasma concentrations In vitro studies indicate that dasatinib is a CYP3A4 substrate.
Sustanzi attivi li jistgħu jżidu l- konċentrazzjoni ta 'dasatinib fil- plażma Studji in vitro jindikaw li dasatinib huwa sottostat ta' CYP3A4.
Concomitant use of dasatinib and medicinal products which potently inhibit CYP3A4 (e. g. ketoconazole, itraconazole, erythromycin, clarithromycin, ritonavir, telithromycin) may increase exposure to dasatinib.
L- użu ta 'dasatinib flimkien ma ’ prodotti mediċinali li b' mod qawwi jinibixxu CYP3A4 (eż. ketoconazole, itraconazole, erythromycin, clarithromycin, ritonavir, telithromycin) jista' jżid l- espożizzjoni għal dasatinib.
Therefore, in patients receiving dasatinib, systemic administration of a potent CYP3A4 inhibitor is not recommended.
Għalhekk, għal pazjenti li qed jieħdu dasatinib, l- għoti sistemiku ta 'inibitur qawwi ta' CYP3A4 mhux rakkomandat.
At clinically relevant concentrations, binding of dasatinib to plasma proteins is approximately 96% on the basis of in vitro experiments.
F' konċentrazzjonijiet kliminikament rilevanti, it- twaħħil ta 'dasatinib ma' proteini tal- plażma huwa bejn wieħed u ieħor ta '96% fuq il- bażi ta' esperimenti in vitro.
No studies have been performed to evaluate dasatinib interaction with other protein-bound medicinal products.
Ma surux studji li jevalwaw l - interazzjoni ta 'dasatinib ma' prodotti mediċinali oħra mwaħħlin mal- proteini.
The potential for displacement and its clinical relevance are unknown.
Il- potenzjal għal spostament u r- rilevanza klinika tiegħu m' humiex magħrufin.
Active substances that may decrease dasatinib plasma concentrations When dasatinib was administered following 8 daily evening administrations of 600 mg rifampicin, a potent CYP3A4 inducer, the AUC of dasatinib was decreased by 82%.
Sustanzi attivi li jistgħu jnaqqsu l- konċentrazzjonijiet ta 'dasatinib fil- plażma Meta dasatinib ngħata wara tmint ijiem ta' għoti kuljum ta ’ kull filgħaxija ta’ 600 mg rifampicin, li jinduċi b’ mod qawwi CYP3A4, l- AUC ta 'dasatinib naqset bi 82%.
Other medicinal products that induce CYP3A4 activity (e. g. dexamethazone, phenytoin, carbamazepine, phenobarbital or herbal preparations containing Hypericum perforatum, also known as St.
Prodotti mediċinali oħra li jistimolaw l- attività ta 'CYP3A4 (eż. dexamethazone, phenytoin, carbamazepine, phenobarbital jew preparazzjonijiet li ġejjin mill- ħxejjex li fihom Hypericum perforatum, magħruf ukoll bħala St.
John´s Wort) may also increase metabolism and decrease dasatinib plasma concentrations.
John´s Wort) jistgħu wkoll iżidu l- metaboliżmu u jnaqqsu l- konċentrazzjonijiet ta 'dasatinib fil- plażma.
Therefore, concomitant use of potent CYP3A4 inducers with dasatinib is not recommended.
Għalhekk, l- użu ta 'sustanzi li jindiċu b’ mod qawwi CYP3A4 flimkien ma' dasatinib mhuwiex rakkomandat.
In patients in whom rifampicin or other CYP3A4 inducers are indicated, alternative medicinal products with less enzyme induction potential should be used.
F' pazjenti li jkollhom bżonn rifampicin jew xi sustanza li tinduċi CYP3A4, għandhom jintużaw prodotti mediċinali b' inqas potenzjal li jinduċu l- enżima.
Histamine-2 antagonists and proton pump inhibitors:
Antagonisti ta ’ Histamine- 2 u inibituri tal- proton pump:
Long-term suppression of gastric acid secretion by H2 antagonists or proton pump inhibitors (e. g. famotidine and omeprazole) is likely to reduce dasatinib exposure.
It- trażżin fit- tul ta 'ħruġ ta' aċidu gastriku permezz ta ’ antagonisti tar- riċetturi H2 jew ta ’ inibituri tal - proton pump (eż. famotidine u omeprazole) probabbli jnaqqas l- espożizzjoni ta 'dasatinib.
In a single-dose study in healthy subjects, the administration of famotidine 10 hours prior to a single dose of SPRYCEL reduced dasatinib exposure by 61%.
Fi studju ta 'doża waħda f' individwi b' saħħithom, l- għoti ta' famotidine 10 sigħat qabel doża waħda ta 'SPRYCEL naqqas l- espożizzjoni ta' dasatinib b' 61%.
The use of antacids should be considered in place of H2 antagonists or proton pump inhibitors in patients receiving SPRYCEL therapy (see section 4.4).
L- użu ta 'antaċidi għandu jkun ikkunsidrat minflok antagonisti tar- riċetturi H2 jew inibituri tal- proton pump f' pazjenti li qed jirċievu terapija bi SPRYCEL (ara sezzjoni 4. 4).
Antacids:
Antaċidi:
Non-clinical data demonstrate that the solubility of dasatinib is pH-dependent.
Tagħrif mhux kliniku juri li s- solubilità ta 'dasatinib tiddependi fuq il- pH.
In healthy subjects, the concomitant use of aluminium hydroxide/ magnesium hydroxide antacids with SPRYCEL reduced the AUC of a single dose of SPRYCEL by 55% and the Cmax by 58%.
F' individwi b' saħħithom, l - użu ta 'l- antaċidi aluminium hydroxide/ magnesium hydroxide flimkien ma' SPRYCEL naqqas l- AUC ta 'doża waħda ta' SPRYCEL b' 55% u Cmax bi 58%.
However, when antacids were administered 2 hours prior to a single dose of SPRYCEL, no relevant changes in dasatinib concentration or exposure were observed.
Madankollu, meta ngħataw antaċidi sagħtejn qabel doża waħda ta 'SPRYCEL, ma ġew osservati ebda bidliet rilevanti fil- konċentrazzjoni ta ’ jew fl - espożizzjoni għal dasatinib.
Thus, antacids may be administered up to 2 hours prior to or 2 hours following SPRYCEL (see section 4.4).
Għalkekk, antaċidi jistgħu jingħataw sa sagħtejn qabel jew sagħtejn wara SPRYCEL (ara sezzjoni 4. 4).
Active substances that may have their plasma concentrations altered by dasatinib Concomitant use of dasatinib and a CYP3A4 substrate may increase exposure to the CYP3A4 substrate.
Sustanzi attivi li jista 'jkollhom il- konċentrazzjoni tagħhom fil- plażma mibdula b’ dasatinib L- użu fl- istess ħin ta' dasatinib u sottostrat ta 'CYP3A4 jista' jżid l- espożizzjoni għas- sottostrat ta 'CYP3A4.
In a study in healthy subjects, a single 100 mg dose of dasatinib increased AUC and Cmax exposure to simvastatin, a known CYP3A4 substrate, by 20 and 37% respectively.
Fi studju ta 'individwi b' saħħithom, doża waħda ta' 100 mg ta 'dasatinib żiedet l- espożizzjoni ta' l- AUC u Cmax għal simvastatin, sottostrat magħruf ta 'CYP3A4, b' 20 u 37% rispettivament.
It cannot be excluded that the effect is larger after multiple doses of dasatinib.
Ma jistax jiġi eskluż li l- effett ikun akbar wara dożi multipli ta 'dasatinib.
Therefore, CYP3A4 substrates known to have a narrow therapeutic index (e. g. astemizole, terfenadine, cisapride, pimozide, quinidine, bepridil or ergot alkaloids (ergotamine, dihydroergotamine)) should be administered with caution in patients receiving dasatinib (see section 4.4).
Għalhekk, sottostrati ta 'CYP3A4 magħrufa li għandhom indiċi terawpetiku dejjaq (eż. astemizole, terfenadine, cisapride, pimozide, quinidine, bepridil jew alkalojdi ta ’ l- ergot (ergotamine, dihydroergotamine)) għandhom jingħataw b' kawtela lill- pazjenti li qed jirċievu dasatinib (ara sezzjoni 4. 4).
In vitro data indicate a potential risk for interaction with CYP2C8 substrates, such as glitazones.
Tagħrif in vitro jindika riskju potenzjali għal interazzjoni ma 'sottostrati ta' CYP2C8, bħalma huma glitazones.
Pregnancy There are no adequate data from the use of dasatinib in pregnant women.
Tqala M’ hemmx tagħrif biżżejjed dwar l- użu ta ’ dasatinib waqt it- tqala.
Studies in animals have shown reproductive toxicity (see section 5.3).
Studji fuq bhejjem urew tossiċità fuq is- sistema riproduttiva (ara sezzjoni 5. 3).
SPRYCEL should not be used during pregnancy unless clearly necessary.
SPRYCEL m’ għandux jintuża waqt it- tqala jekk m’ hemmx bżonn ċar.
If it is used during pregnancy, the patient must be informed of the potential risk to the foetus.
Jekk jintuża waqt tqala, il- pazjenta għandha tkun infurmata bir- riskju li jista 'jkun hemm għall- fetu.
6 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.
Physico-chemical and available pharmacodynamic/ toxicological data on dasatinib point to excretion in breast milk and a risk to the suckling child cannot be excluded.
Tagħrif fiżjokimiku u farmakodinamiku/ tossikoloġiku disponibbli dwar dasatinib jindika ħruġ fil- ħalib tas- sider u r- riskju għat- tarbija li qed terda 'ma jistax jiġi eskluż.
Breast-feeding should be stopped during treatment with SPRYCEL.
It- treddigħ irid jitwaqqaf waqt trattament bi SPRYCEL.
Fertility The effect of dasatinib on sperm is unknown, therefore both sexually active men and women should use effective methods of contraception during treatment.
Fertilità L- effett ta ’ dasatinib fuq l- isperma mhuwiex magħruf, u għalhekk kemm l- irġiel kif ukoll in- nisa li huma sesswalment attivi għandhom jużaw mezz ta ’ kontraċezzjoni li hu effettiv waqt il- trattament.
Patients should be advised that they may experience undesirable effects such as dizziness or blurred vision during treatment with dasatinib.
Pazjenti għandhom jiġu avżati li jistgħu jesperjenzaw xi effetti mhux mixtieqa waqt it- trattament b' dasatinib bħal sturdament jew vista mċajpra.
Therefore, caution should be recommended when driving a car or operating machines.
Għalhekk huwa rrakkomandat li wieħed joqgħod attent meta jkun qed isuq karozza jew iħaddem magni.
The data described below reflect exposure to SPRYCEL in 2,182 patients in clinical trials (starting dose 100 mg once daily, 140 mg once daily, 50 mg twice daily, or 70 mg twice daily).
L- informazzjoni deskritta hawn taħt tirrifletti l- esponiment għal SPRYCEL f’ 2, 182 pazjent fi provi kliniċi (doża tal- bidu 100 mg darba kuljum, 140 mg darba kuljum, 50 mg darbtejn kuljum, jew 70 mg darbtejn kuljum).
Of the 2,182 patients treated, 25% were ≥ 65 years of age, while 5% were ≥ 75 years of age.
Mill- 2, 182 pazjent ittrattat, 25% kellhom ≥ 65 sena, waqt li 5% kellhom ≥ 75 sena.
The median duration of therapy was 11 months (range 0.03 -31 months).
It- tul medju tat- terapija kien ta '11- il xahar (medda 0. 03- 31 xahar).
The majority of SPRYCEL-treated patients experienced adverse reactions at some time.
Il- maġġoranza tal- pazjenti ttrattati bi SPRYCEL esperjenzaw xi reazzjonijiet avversi f' xi ħin.
Most reactions were of mild-to-moderate grade.
Il- parti l - kbira tar- reazzjonijiet kienu minn ħfief sa moderati.
Treatment was discontinued for adverse reactions in 11% of patients in chronic phase CML, 12% in accelerated phase CML, 15% in myeloid blast phase CML, and 8% in lymphoid blast phase CML or Ph+ ALL.
It- trattament twaqqaf minħabba reazzjonijiet avversi fi 11% tal- pazjenti b' CML f’ fażi kronika, 12% b' CML f' fażi aċċellerata, 15% b' CML tal - majelojd blast phase, u 8% b' lymphoid blast phase CML jew Ph+ ALL.
In the Phase III dose-optimisation study in patients with chronic phase CML, the rate of discontinuation for adverse drug reaction was lower for patients treated with 100 mg once daily than for those treated with 70 mg twice daily (3% and 11%, respectively).
Fl- istudju ta ’ l- ottimizzazzjoni tad- doża ta ’ Fażi III, f’ pazjenti b’ CML ta ’ fażi kronika, ir- rata tat- twaqqif minħabba reazzjoni avversa tal- mediċina kienet aktar baxxa għall- pazjenti trattati b’ 100 mg darba kuljum milli għal dawk trattati b’ 70 mg darbtejn kuljum (3% u 11%, rispettivament).
The majority of imatinib-intolerant patients with chronic phase CML were able to tolerate treatment with dasatinib.
Il- maġġoranza tal- pazjenti b' intolleranza għal imatinib setgħu jittoleraw it- trattament b’ dasatinib.
In the Phase II single-arm study in chronic phase CML, 3 of the 99 imatinib-intolerant patients had the same grade 3 or 4 non-hematological toxicity with SPRYCEL as they did with prior imatinib; all 3 patients continued SPRYCEL treatment after dose reduction.
Fl - istudju ta ’ fergħa waħda ta ’ Fażi II b’ CML ta ’ fażi kronika, 3 mid- 99 pazjent intolleranti għal imatinib kellhom l- istess tossiċità mhux ematoloġika ta ’ grad 3 jew 4 bi SPRYCEL bħalma kellhom b’ imatinib preċedenti; it- 3 pazjenti kollha komplew it- trattament bi SPRYCEL wara tnaqqis fid- doża.
The most frequently reported adverse reactions were fluid retention (including pleural effusion), diarrhoea, headache, nausea, skin rash, dyspnoea, haemorrhage, fatigue, musculoskeletal pain, infection, vomiting, cough, abdominal pain and pyrexia (Table 3).
Ir- reazzjonijiet avversi l- aktar irrapportati kienu l- akkumulazzjoni ta 'fluwidi (inklużi effużjoni tal - plewra), dijarea, uġigħ ta' ras, nawsja, raxx tal- ġilda, dispneja, emorraġija, għeja, uġigħ muskolu - skeltrali, infezzjoni, rimettar, sogħla, uġigħ addominali u deni (Tabella 3).
Drug-related febrile neutropenia was reported in 5% of patients.
Newtropenja bid- deni relatata mal- mediċina ġiet irrapportata f' 5% tal- pazjenti.
Miscellaneous adverse reactions such as pleural effusion, ascites, pulmonary oedema and pericardial effusion with or without superficial oedema may be collectively described as “ fluid retention”.
Reazzjonijiet avversi mixxellanji bħalma huma effużjoni tal- plewra, axxite, edema pulmonari u effużjoni tal- perikardju b' edema superfiċjali jew mingħajrha jistgħu kollettivament jiġu deskritti bħala “ akkumulazzjoni ta 'fluwidi ”.
The use of dasatinib is associated with fluid retention with severe cases in 9% of patients.
L- użu ta 'dasatinib hu assoċjat ma ’ akkumulazzjoni ta ’ fluwidi b' każijiet severi f' 9% tal- pazjenti.
Severe pleural and pericardial effusion were reported in 6% and 1% of patients, respectively.
Effużjoni severa tal- plewra u tal- perikardju ġew irrapportati f' 6% u 1% tal - pazjenti, rispettivament.
Severe ascites and generalised oedema were each reported in < 1%.
Axxite severa u edema ġeneralizzata ġew irrapportati f '< 1% tal- pazjenti.
One percent of patients experienced severe non-cardiogenic pulmonary oedema.
Każijiet ta '
Fluid retention events were typically managed by supportive care measures that include diuretics or short courses of steroids.
7 akkumulazzjoni ta 'fluwidi kienu tipikament ikkontrollati b' miżuri ta' kura t' appoġġ li jinkludu dijuretiċi u korsijiet qosra ta 'sterojdi.
While the safety profile of SPRYCEL in the elderly population was similar to that in the younger population, patients aged 65 years and older are more likely to experience fluid retention events and should be monitored closely (see section 4.4).
Filwaqt li l- profil ta ’ sigurtà ta ’ SPRYCEL fil- popolazzjoni anzjana kien simili għal dik tal- popolazzjoni iżgħar fl- età, pazjenti ta ’ 65 sena u akbar huma aktar probabbli li jesperjenzaw episodji ta ’ żamma ta ’ fluwidi u għandhom jiġu mmonitorjati mill- qrib (ara sezzjoni 4. 4).
Bleeding drug-related events, ranging from petechiae and epistaxis to severe gastrointestinal haemorrhage and CNS bleeding, were reported in patients taking SPRYCEL (see section 4.4).
Każijiet ta 'fsada relatati mal- mediċina, li jvarjaw minn petechiae u epistaxis sa emorragija severa gastrointestinali u fsada ta' CNS, ġew irrapportati f’ pazjenti li jieħdu SPRYCEL (ara sezzjoni 4. 4).
Severe CNS haemorrhage occurred in < 1% of patients; 8 cases were fatal and 5 of them were associated with CTC grade 4 thrombocytopenia.
Emorraġija severa ta 'CNS ġrat f' < 1% tal- pazjenti; 8 każijiet kienu fatali u 5 minnhom kienu assoċjati ma 'tromboċitopenja ta' CTC tar- 4 grad.
Severe gastrointestinal haemorrhage occurred in 4% of patients and generally required treatment interruption and transfusions.
F' 4% tal- pazjenti kien hemm emorraġija gastrointestinali severa u ġeneralment, dawn kellhom bżonn iwaqqfu t- trattament u t- trasfużjonijiet.
Other severe haemorrhage occurred in 2%
Emorraġiji severi oħrajn seħħew fi 2% tal- pazjenti.
Most bleeding related events were typically associated with severe thrombocytopenia.
Il- biċċa l- kbira tal- każijiet relatati ma 'fsada kienu tipikament assoċjati ma' tromboċitopenja severa.
Treatment with SPRYCEL is associated with anaemia, neutropenia and thrombocytopenia.
Trattament bi SPRYCEL huwa assoċjat ma ’ anemija, newtropenja u tromboċitopenja.
Their occurrence is more frequent in patients with advanced phase CML or Ph+ ALL than in chronic phase CML (see section 4.4).
L- okkorrenza tagħhom hija aktar frekwenti f’ pazjenti b’ CML ta ’ fażi avvanzata jew Ph+ ALL milli b’ CML ta ’ fażi kronika (ara sezzjoni 4. 4).
In the Phase III dose-optimisation study in patients with chronic phase CML (median duration of treatment approximately 8 months), the incidence of pleural effusion and congestive heart failure/ cardiac dysfunction was lower in patients treated with SPRYCEL 100 mg once daily than in those treated with SPRYCEL 70 mg twice daily (Table 2a).
Fl- istudju ta ’ l- ottimizzazzjoni tad- doża ta ’ Fażi III f’ pazjenti b’ CML ta ’ fażi kronika (tul medju tat - trattament ta ’ madwar 8 xhur), l- inċidenza ta ’ effużjoni tal- plewra u insuffiċjenza tal- qalb konġestiva/ disfunzjoni tal- qalb kienet aktar baxxa fil- pazjenti trattati bi SPRYCEL 100 mg darba kuljum milli f’ dawk trattati bi SPRYCEL 70 mg darbtejn kuljum (Tabella 2a).
Myelosuppression was also reported less frequently with the 100 mg once daily (see Laboratory test abnormalities below).
Il- majelosuppressjoni ġiet irrappurtata wkoll b’ mod anqas frekwenti bil- 100 mg darba kuljum (ara l- anormalitajiet fit - testijiet tal- laboratorju hawn taħt).
Table 2a:
Tabella 2a:
Selected Adverse Drug Reactions Reported in Phase III Dose-Optimisation Study:
CML ta ’ Fażi Kronika
Chronic Phase CML 100 mg once daily 140 mg once daily 50 mg twice daily 70 mg twice daily n = 166 n = 163 n = 166 n = 167 All Grade All Grade All Grade All Grade Grades 3/ 4 Grades 3/ 4 Grades 3/ 4 Grades 3/ 4
140 mg darba 50 mg darbtejn 100 mg darba
Preferred Term
70 mg darbtejn
Diarrhoea Fluid Retention Superficial Oedema Pleural Effusion Generalised oedema
Il - Il - Il - Gradi Gradi Gradi Gradi Gradi Gradi 3/ 4 3/ 4 3/ 4 Kollha Kollha Kollha
24 21 14 7 2
Il - Gradi Gradi 3/ 4 Kollha
1 1 0 1 0
Terminu preferut
23 26 12 15 2
Dijarea
2 4 1 3 0
24
24 22 13 11 1
21
2 2 0 2 0
4 22 2
Congestive heart failure/ cardiac dysfunction
Edema superfiċjali Effużjoni tal- plewra Edema ġeneralizzata Insuffiċjenza tal- qalb konġestiva / disfunzjoni tal- qalb
Pericardial effusion Pulmonary oedema Pulmonary hypertension Haemorrhage
1
3 1 0
0 0
1 0 0
1 0
Gastrointestinal bleeding
Fsada gastro - intestinali
In the Phase III dose-optimisation study in patients with advanced phase CML and Ph+ ALL, fluid retention (pleural effusion and pericardial effusion) was reported less frequently in patients treated with SPRYCEL 140 mg once daily than in those treated with 70 mg twice daily (Table 2b).
Fl- istudju ta ’ l- ottimizzazzjoni tad- doża ta ’ Fażi III f’ pazjenti b’ CML ta ’ fażi avanzata u Ph+ALL, l - akkumulazzjoni ta ’ fluwidi (effużjoni tal- plewra u effużjoni tal- perikardju) ġiet irrappurtata b’ mod anqas frekwenti fil- pazjenti trattati b’ SPRYCEL 140 mg darba kuljum milli f’ dawk trattati b’ 70 mg darbtejn kuljum (Tabella 2b).
8 Table 2b:
8 Tabella 2b:
Selected Adverse Drug Reactions Reported in Phase Advanced Phase CML and Ph+ALL
Reazzjonijiet Avversi Magħżula tal- Mediċina Rrappurtati fi Studju ta ’ l - Ottimizzazzjoni tad- Doża ta ’ Fażi III:
III Dose-Optimisation Study:
140 mg darba kuljum 70 mg darbtejn n = 304 n = 305
140 mg once daily n = 304 All Grades Grade 3/ 4
Il- Gradi Kollha Gradi 3/ 4 Il- Gradi Kollha
70 mg twice daily n = 305 All Grades Grade 3/ 4
Gradi 3/ 4
Percent (%) of Patients
Perċentwali (%) ta ’ Pazjenti
Fluid Retention
Akkumulazzjoni ta ’ Fluwidu
Superficial oedema Pleural Effusion Generalised oedema Congestive heart failure/ cardiac dysfunction
Edema superfiċjali Effużjoni tal- plewra Edema ġeneralizzata Insuffiċjenza tal- qalb konġestiva / disfunzjoni tal - qalb
1 6 1 1
0 4
Pericardial effusion Pulmonary oedema Ascites Pulmonary hypertension
Edema pulmonari Axxite Pressjoni għolja pulmonari Emorraġija
1 1 0 0
1 0 0
0 1 0 0
1 0 0
Gastrointestinal bleeding
Fsada gastro- intestinali
In clinical trials, it was recommended that treatment with imatinib be discontinued at least 7 days before starting treatment with SPRYCEL.
Fil- provi kliniċi, kien rakkomandat li t- trattament b' imatinib jitwaqqaf ta 'lanqas 7t ijiem qabel jinbeda t- trattament bi SPRYCEL.
The following adverse reactions were reported in patients in SPRYCEL clinical trials.
Ir- reazzjonijiet avversi li ġejjin kienu rrapportati f' pazjenti fi provi kliniċi bi SPRYCEL.
These reactions are presented by system organ class and by frequency.
Dawn ir - reazzjonijiet huma ppreżentati skond is- sistema tal- klassifikazzjoni ta 'l- organi u l- frekwenza.
Frequencies are defined as: very common (≥ 1/ 10); common (≥ 1/ 100 to < 1/ 10); uncommon (≥ 1/ 1,000 to < 1/ 100); rare (≥ 1/ 10,000 to < 1/ 1,000).
Il - frekwenzi huma definiti kif ġej: komuni ħafna (≥ 1/ 10); komuni (≥ 1/ 100 sa < 1/ 10); mhux komuni (≥ 1/ 1, 000 sa < 1/ 100); rari (≥ 1/ 10, 000 sa < 1/ 1, 000).
Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
F’ kull sezzjoni ta ’ frekwenza, l- effetti mhux mixtieqa għandhom jitniżżlu skond is- serjeta ’ tagħhom bl- aktar serji imniżżlin l- ewwel segwiti minn dawk anqas serji.
Adverse drug reactions, excluding laboratory abnormalities, that were reported in ≥ 5% of patients in SPRYCEL clinical trials are shown in Table 3:
Reazzjoni avversi tal- mediċina, minbarra l- anormalitajiet tal- laboratorju, li ġew irrapportati f' ≥ 5% tal - pazjenti fil- provi kliniċi bi SPRYCEL jidhru fit- Tabella 3:
Adverse Drug Reactions (ADR) reported ≥ 5% in
rrapportati f ’ ≥ 5% fi provi kliniċi
All Patients (n= 2,182) Percent (%) of Patients
Il- Pazjenti Kollha (n= 2, 182) Perċentwali (%) ta ’ Pazjenti
Blood and lymphatic system disorders
Disturbi fid- demm u fis- sistema limfatika
Grades
Il- Gradi kollha
Grades
Gradi 3/ 4
Common: febrile neutropenia Nervous system disorders
Komuni: newtropenja bid- deni Disturbi fis- sistema nervuża
Very common: headache Common: neuropathy (including
Komuni ħafna: uġigħ ta ’ ras Komuni: newropatija (inkluża
peripheral neuropathy) Respiratory, thoracic and mediastinal disorders
newropatija periferali) Disturbi respiratorji, toraċiċi u medjastinali
Very common: pleural effusion, dyspnoea, cough Gastrointestinal disorders
Komuni ħafna: effużjoni tal- plewra, dispneja, sogħla Disturbi gastrointestinali
Very common: diarrhoea, nausea, vomiting, abdominal pain
Komuni ħafna: dijarea,
Common: gastrointestinal bleeding, mucosal inflammation (including
nawsja, rimettar, uġigħ addominali Komuni: fsada gastrointestinali, infjammazzjoni tal- mukuża (fosthom
7
22 13 10 8
< 1
1 1 1 4
dyspepsia, abdominal distension Skin and subcutaneous tissue disorders a
mukożite/ stomatite), dispepsja, nefħa addominali Disturbi fil- ġilda u fit- tessuti ta ’ taħt il - ġilda
Very common: skin rash
Komuni ħafna: raxx tal- ġilda
Common: pruritus Musculoskeletal and connective tissue disorders
Komuni: ħakk Disturbi muskolu- skeltrali u tal - connective tissue
Very common: musculoskeletal pain Common: arthralgia,
Komuni ħafna: uġigħ muskoluskeletali Komuni: artralġja,
myalgia Metabolism and nutrition disorders
mijalġja Disturbi fil- metaboliżmu u n - nutrizzjoni
Common: anorexia Infections and infestations
Komuni: anoreksja Infezzjonijiet u infestazzjonijiet Komuni ħafna: infezzjoni (fosthom
Very common: infection (including bacterial, viral, fungal, non-specific) Vascular disorders
batterika, virali, fungali, mhux speċifika) Disturbi vaskulari
Very common: haemorrhageb General disorders and administration site conditions
Komuni ħafna: emorraġija b Disturbi ġenerali u kondizzjonijiet ta ’ mnejn jingħata
Very common: superficial oedemac, fatigue, pyrexia Common: pain, asthenia, chest pain a
għeja, deni Komuni: uġigħ, astenja, uġigħ fis- sider a
Includes drug eruption, erythema, erythema multiforme, erythrosis, exfoliative rash, fungal rash, generalised erythema, genital rash, heat rash, milia, rash, rash erythematous, rash follicular, rash generalised, rash macular, rash maculo-papular, rash papular, rash pruritic, rash pustular, rash vesicular, skin exfoliation, skin irritation, and urticaria vesiculosa. b Excludes gastrointestinal bleeding and CNS bleeding; these ADRs are reported under the gastrointestinal disorders system organ class and the nervous system disorders system organ class, respectively. c Includes auricular swelling, conjunctival oedema, eye oedema, eye swelling, eyelid oedema, face oedema, gravitational oedema, lip oedema, localised oedema, macular oedema, oedema genital, oedema mouth, oedema peripheral, orbital oedema, penile oedema, periorbital oedema, pitting oedema, scrotal oedema, swelling face, and tongue oedema.
Jinkludi eruzzjoni tal- mediċina, eritema, eritema multiformi, eritrosi, raxx esfoljattiv, raxx fungali, eritema ġeneralizzata, raxx fil- ġenitali, raxx tas- sħana, milia, raxx, raxx bil- ħmura, raxx bil- follikuli, raxx ġeneralizzat, raxx bit- tbajja ’, raxx bit- tbajja ’ u l- infafet, raxx bl- infafet, raxx bil- ħakk, raxx bil- ponot, raxx vesikulari, tqaxxir tal - ġilda, irritazzjoni tal- ġilda u urtikarja vesikuloża. b Teskludi fsada gastrointestinali u fsada tas- CNS; dawn l- ADRs huma rrapportati skond disturbi gastrointestinali tas- sistema ta ’ klassifika ta ’ l- organi u disturbi fis- sistema nervuża tas- sistema ta ’ klassifika ta ’ l- organi, rispettivament. c Tinkludi nefħa fil- widnejn, edema fil- konġuntivite, edema fl- għajnejn, nefħa fl- għajnejn, edema fil- kappell ta ’ l - għajn, edema fil- wiċċ, edema tal- gravitazzjoni, edema fix- xoffa, edema lokalizzata, edema bi tbajja ’, edema fil - ġenitali, edema fil- ħalq, edema periferali, edema orbitali, edema fil- pene, edema perjorbitali, edema bi tqaxxir tal - ġilda, edema ta ’ l- iskrotu, nefħa fil- wiċċ u edema fl- ilsien.
The following adverse drug reactions were reported in patients in the SPRYCEL clinical trials at a frequency of < 5%:
Ir- reazzjonijiet avversi tal- mediċina li ġejjin ġew irrapportati f' pazjenti fi provi kliniċi bi SPRYCEL bi frekwenza ta '< 5%:
Investigations Common: weight decreased, weight increased Uncommon: blood creatine phosphokinase increased
Investigazzjonijiet Komuni: tnaqqis fil- piż, żieda fil- piż Mhux komuni: żieda fil- creatine phosphokinase fid- demm
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
10 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
Blood and lymphatic system disorders Common: pancytopenia Rare: aplasia pure red cell
Disturbi tad- demm u tas- sistema limfatika Komuni: panċitopenja Rari: aplasja taċ- ċelloli ħomor tad- demm
CNS bleeding, syncope, tremor, amnesia Rare: cerebrovascular accident, transient ischaemic attack, convulsion
Disturbi fis- sistema nervuża Komuni: sturdament, disgewżja, ħedla Mhux komuni: fsada fis- CNS, sinkope, rogħda, amnesija Rari: aċċident ċerebrovaskulari, attakk iskemiku li jgħaddi, konvulżjoni
Eye disorders Common: visual disorder (including visual disturbance, vision blurred, and visual acuity reduced), dry eye Uncommon: conjunctivitis
Disturbi fl- għajnejn Komuni: disturb fil- vista (inkluż disturb fil- vista, vista mċajpra u akutezza tal- vista mnaqqsa), għajnejn xotti Mhux komuni: konġuntivite
Ear and labyrinth disorders Common: tinnitus Uncommon: vertigo
Disturbi fil- widnejn u fis- sistema labirintika Komuni: żarżir fil- widnejn Mhux komuni: sturdament
Respiratory, thoracic and mediastinal disorders Common: pulmonary oedema, lung infiltration, pneumonitis Uncommon: bronchospasm, pulmonary hypertenstion, asthma Rare: acute respiratory distress syndrome
Disturbi respiratorji, toraċiċi u medjastinali Komuni: edema pulmonary, infiltrazzjoni tal- pulmun, pulmonite Mhux komuni: bronkospażmi, pressjoni għolja pulmonari, ażżma Rari: sindrome ta ’ għeja respiratorja akuta
Gastrointestinal disorders Common: colitis (including neutropenic colitis), gastritis, constipation, oral soft tissue disorder Uncommon: pancreatitis, upper gastrointestinal ulcer, oesophagitis, ascites, anal fissure, dysphagia
Disturbi gastro- intestinali Komuni: kolite (fosthom kolite newtropatika), gastrite, stitikezza, disturb tat- tessut artab orali Mhux komuni: pankreatite, ulċera fil- parti ta ’ fuq tas- sistema gastro- intestinali, esofaġite, axxite, fissura anali, disfaġja
Renal and urinary disorders Uncommon: renal failure, urinary frequency, proteinuria
Disturbi fil- kliewi u fis- sistema urinarja Mhux komuni: insuffiċjenza tal- kliewi, awrina frekwenti, proteinurja
Skin and subcutaneous tissue disorders Common: alopecia, dermatitis (including eczema), acne, dry skin, urticaria, hyperhidrosis Uncommon: acute febrile neutrophilic dermatosis, photosensitivity, pigmentation disorder, panniculitis, skin ulcer, bullous conditions, nail disorder, palmar-plantar erythrodysesthesia syndrome
Disturbi fil- ġilda u fit- tessuti ta ’ taħt il- ġilda Komuni: alopeċja, dermatite (inkluża ekżema), akne, ġilda niexfa, urtikarja, iperidrosi Mhux komuni: dermatożi newtrofilika akuta bid- deni, fotosensittività, disturb fil- pigmentazzjoni, panniculitis, ulċera tal- ġilda, kundizzjonijiet bullużi, disturb tad- dwiefer, palmar- plantar erythrodysesthesia syndrome
Musculoskeletal and connective tissue disorders Common: muscle inflammation, muscular weakness Uncommon: rhabdomyolysis, musculoskeletal stiffness Rare: tendonitis
Disturbi muskolu- skeltrali u tal- connective tissue Komuni: infjammazzjoni tal- muskoli, dgħjufija muskolari Mhux komuni: rabdomajoliżi, ebusija muskoluskeletali Rari: infjammazzjoni ta ’ l- għerq
Metabolism and nutrition disorders Common: appetite disturbances Uncommon: hyperuricaemia
Disturbi fil- metaboliżmu u n- nutrizzjoni Komuni: disturbi fl- aptit Mhux komuni: iperuriċemja
Infections and infestations Common: sepsis (including fatal outcome), pneumonia (including bacterial, viral, and fungal), upper respiratory tract infection/ inflammation, herpes viral infection, enterocolitis infection
Infezzjonijiet u infestazzjonijiet Komuni: sepsis (inkluż riżultat fatali), pulminite (fosthom batterika, virali, u fungali), infezzjoni/ infjammazzjoni fil- parti ta ’ fuq ta ’ l- apparat respiratorju, infezzjoni virali tal- herpes, infezzjoni ta ’ l- enterokolite
Injury, poisoning, and procedural complications Common: contusion
11 Korriment, avvelenament u komplikazzjonijiet ta ’ xi proċedura Komuni: tbenġil
Neoplasms benign, malignant and unspecified (including cysts and polyps) Uncommon: tumour lysis syndrome
Neoplażmi beninni, malinni u mhux speċifikati (fosthom ċisti u polipi) Mhux komuni: sindrome tal- lisi ta ’ tumur
Vascular disorders Common: hypertension, flushing Uncommon: hypotension, thrombophlebitis Rare: livedo reticularis
Disturbi vaskulari Komuni: pressjoni għolja, fwawar Mhux komuni: pressjoni baxxa, tromboflebite Rari: livedo reticularis
11 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
Immune System Disorders Uncommon: hypersensitivity (including erythema nodosum)
Disturbi fis- sistema immuni Mhux komuni: sensittività eċċessiva (inkluża eritema nodosum)
Hepatobiliary disorders Uncommon: hepatitis, cholestasis Rare: cholecystitis
Disturbi fil- fwied u fil- marrara Mhux komuni: epatite, kolestasi Rari: koleċistite
Reproductive system and breast disorders Uncommon: gynecomastia, irregular menstruation
Disturbi fis- sistema riproduttiva u fis- sider Mhux komuni: ginekomastja, mestrwazzjoni irregolari
Psychiatric disorders Common: depression, insomnia Uncommon: anxiety, confusional state, affect lability, libido decreased
Disturbi psikjatriċi Komuni: depressjoni, nuqqas ta ’ rqad Mhux komuni: ansjetà, stat ta ’ konfużjoni, bidliet emozzjonali, tnaqqis fil- libido
Laboratory test abnormalities:
Anormalitajiet fit- testijiet tal- laboratorju:
In CML, cytopenias (thrombocytopenia, neutropenia, and anaemia) were a consistent finding.
F' CML, instabu ċitopenja (tromboċitopenja, newtropenja, u anemija) b' mod konsistenti.
However, the occurrence of cytopenias was also clearly dependent on the stage of the disease.
Madankollu, l- okkorrenza ta 'ċitopenja kienet tiddependi wkoll biċ- ċar fuq il- fażi tal- marda.
The frequency of grade 3 and 4 haematological abnormalities is presented in Table 4.
Il - frekwenza ta ’ anormalitajiet ematoloġiċi ta ’ grad 3 u 4 hija ppreżentata fit- Tabella 4.
CTC Grades 3/ 4 Haematological Laboratory Abnormalities in Clinical Studies
Anormalitajiet Ematoloġiċi tal- Laboratorju ta ’ CTC Gradi 3/ 4 fi Studji Kliniċi
Lymphoid Blast Phase
Fażi Kronika
Haematology Parameters
Fażi Aċċellerata
Neutropenia Thrombocytopenia Anaemia a
Newtropenja Tromboċitopenja Anemija
The chronic phase data include patients treated with any dose of SPRYCEL.
Id- dejta ta ’ fażi kronika tinkludi pazjenti ttrattati bi kwalunkwe doża ta ’ SPRYCEL.
CTC grades: neutropenia (Grade 3 ≥ 0.5– 1.0 × 109/ l, Grade 4 < 0.5 × 109/ l); thrombocytopenia (Grade 3 ≥ 10– 50 × 109/ l, Grade 4 < 10 × 109/ l); anaemia (hemoglobin Grade 3 ≥ 65– 80 g/ l, Grade 4 < 65 g/ l).
Gradi CTC: newtropenja (Grad 3 ≥ 0. 5– 1. 0 × 109/ l, Grad 4 < 0. 5 × 109/ l); tromboċitopenja (Grad 3 ≥ 10– 50 × 109/ l, Grad 4 < 10 × 109/ l); anemija (emoglobina Grad 3 ≥ 65– 80 g/ l, Grad 4 < 65 g/ l).
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.
12 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.
In patients who experienced severe myelosuppression, recovery generally occurred following brief dose interruptions and/ or reductions and permanent discontinuation of treatment occurred in 1% of patients.
F' pazjenti li esperjenzaw majelosuppressjoni severa, l- irkupru ġeneralment seħħ wara waqfien mid - doża għal żmien qasir u/ jew tnaqqis u twaqqif permanenti tat- trattament seħħ f' 1% tal- pazjenti.
Most patients continued treatment without further evidence of myelosuppression.
Il - parti l- kbira tal- pazjenti komplew it- trattament mingħajr aktar evidenza ta 'majelosuppressjoni.
Biochemistry:
Bijokimika:
Grade 3 or 4 elevations of transaminases or bilirubin were reported in < 5% of patients with chronic or accelerated phase CML but elevations were reported with an increased frequency of 4 to 7% in patients with myeloid or lymphoid blast CML and Ph+ ALL.
Żidiet ta 'grad 3 jew 4 ta' transaminażi jew bilirubin ġew irrapportati f '< 5% tal- pazjenti b' CML b' fażi kronika jew aċċellerata imma ż- żidiet kienu rapportati wkoll bi frekwenza ogħla ta' 4 sa 7% f' pazjenti b' CML splussiva tal- majelojd jew tal- limfojde u Ph+ ALL.
It was usually managed with dose reduction or interruption.
Normalment ġiet ikkontrollata bi tnaqqis jew twaqqif tad- doża.
In the phase III dose optimisation studies, grade 3 or 4 elevations of transaminases or bilirubin were reported in ≤ 1% of patients with chronic phase CML with similar low
Fl- istudju ta ’ l- ottimizzazzjoni tad- doża ta ’ Fażi III, żidiet ta ’ grad 3 jew 4 ta ’ transaminases jew bilirubin ġew irrapportati f’ ≤ 1% tal- pazjenti b’ CML ta ’ fażi kronika b’ inċidenza baxxa simili fl- erba ’ gruppi ta ’ trattament; iż- żidiet kienu rrappurtati f’ 1% sa 4% tal- pazjenti b’ CML ta ’ fażi avanzata u Ph+ALL.
Approximately 5% of the dasatinib-treated patients who had normal baseline levels experienced grade 3 or 4 transient hypocalcemia at some time during the course of the study.
Bejn wieħed u ieħor 5% tal- pazjenti ttrattati b’ dasatinib li kellhom livelli normali tal- linja bażi sofrew ipokalċemja mhux permanenti ta ’ grad 3 jew 4 f' xi ħin matul il- kors ta 'l- istudju.
In general; there was no association of decreased calcium with clinical symptoms.
B' mod ġenerali; ma kien ebda assoċjazzjoni ta 'tnaqqis tal- kalċju ma' sintomi kliniċi.
Patients developing grade 3 or 4 hypocalcemia often had recovery with oral supplementation.
Pazjenti li żviluppaw ipokalċemja ta 'grad 3 jew 4 spiss fiequ b' supplimentazzjoni orali.
Grade 3 and 4 hypocalcemia and hypophosphatemia were reported in patients with all phases of CML but were reported with an increased frequency in patients with myeloid or lymphoid blast phase CML and Ph+ ALL.
Ipokalċimja u ipofosfatimja ta ’ grad 3 u 4 ġew irrapportati f’ pazjenti bil- fażijiet kollha ta ’ CML imma kienu rrapportati bi frekwenza akbar f’ pazjenti b’ CML splussiva tal- majelojd jew tal- limfojde u Ph+ALL.
Electrocardiogram:
Elettrokardjogramma:
In 5 Phase II clinical trials in patients with leukaemia, repeated baseline and on-treatment ECGs were obtained at pre-specified time points and read centrally for 865 patients receiving SPRYCEL 70 mg twice daily.
F' ħames provi kliniċi ta 'Fażi II f' pazjenti bil- lewkimja, saru ECGs ripetuti tal- linja bażi u wara t - trattament fi żminijiet speċifikati minn qabel u taw qari ċentrali għal 865 pazjent li kienu qegħdin jirċievu SPRYCEL 70 mg darbtejn kuljum.
QT interval was corrected for heart rate by Fridericia's method.
L- intervall QT ġie kkoreġut għar- rata tal- qalb bil- metodu Fridericia.
At all post-dose time points on day 8, the mean changes from baseline in QTcF interval were 4 -6 msec, with associated upper 95% confidence intervals < 7 msec.
Fil- punti kollha ta ’ wara d- doża f' jum 8, il- bidliet medji mil- linja bażi fl- intervall QTcF kienu ta ’ 4- 6 msec, b' intervalli ta 'kunfidenza assoċjati ogħla minn 95% < 7 msec.
Of the 2,182 patients who received SPRYCEL in clinical trials, 18 had QTc prolongation reported as an adverse event.
Mill- 2, 182 pazjent li rċievew SPRYCEL fi provi kliniċi, 18 kellhom prolungament tal- QTc rrapportat bħala każ avvers.
Seventeen patients (< 1%) experienced a QTcF > 500 msec (see section 4.4).
Sbatax- il pazjent (< 1%) esperjenzaw QTcF > 500 msec (ara sezzjoni 4. 4).
Experience with overdose of SPRYCEL in clinical studies is limited to isolated cases.
L- esperjenza b’ doża eċċessiva ta ’ SPRYCEL fl- istudji kliniċi hija limitata għal każijiet iżolati.
The highest reported dose ingested was 280 mg per day for one week with no associated clinical symptoms.
L- ogħla doża rrappurtata li ttieħdet kienet ta ’ 280 mg kuljum għal ġimgħa mingħajr ebda sintomu kliniku assoċjat.
Since dasatinib is associated with severe myelosuppression (see section 4.4), patients who ingested more than the recommended dose should be closely monitored for myelosuppression and appropriate supportive treatment given.
Billi dasatinib huwa assoċjat ma ’ majelosuppressjoni severa (ara sezzjoni 4. 4), il- pazjenti li jkunu belgħu aktar mid- doża rakkomandata għandhom jiġu mmonitorjati mill- qrib għal majelosuppressjoni u jingħataw trattament xieraq ta ’ sostenn.
Protein kinase inhibitor, ATC code:
Inibitur tal- proteina kinase, Kodiċi ATC:
Dasatinib inhibits the activity of the BCR-ABL kinase and SRC family kinases along with a number of other selected oncogenic kinases including c-KIT, ephrin (EPH) receptor kinases, and PDGFβ receptor.
Dasatinib jinibixxi l- attività ta 'kinase BCR- ABL u kinases tal- familja SRC flimkien ma' numru ta 'kinases onkoġeniċi oħra magħżula li jinkludu c- KIT, ephrin (EPH) receptor kinases, u r- riċettur PDGFβ.
Dasatinib is a potent, subnanomolar inhibitor of the BCR-ABL kinase with potency at concentration of 0.6-0.8 nM.
Dasatinib hu inibitur subnanomolari qawwi tal- kinase BCR- ABL b' potenza f' konċentrazzjoni ta '0. 6- 0. 8 nM.
It binds to both the inactive and active conformations of the BCR-ABL enzyme.
Hu jingħaqad ma 'konformazzjonijiet kemm attivi kif ukoll inattivi ta' l- enżima BCR - ABL.
In vitro, dasatinib is active in leukaemic cell lines representing variants of imatinib-sensitive and resistant disease.
In vitro, idasatinib hu attiv f' linji ta 'ċelluli bil- lewkimja li jirrappreżentaw varjanti ta' mard sensittiv u reżistenti għal imatinib.
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.
13 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.
Additionally, dasatinib inhibits SRC family kinases at subnanomolar concentrations.
Barra minn hekk, dasatinib jinibixxi l- kinasi tal- familja SRC f' koncentrazzjoni subnanomolari.
In vivo, in separate experiments using murine models of CML, dasatinib prevented the progression of chronic CML to blast phase and prolonged the survival of mice bearing patient-derived CML cell lines grown at various sites, including the central nervous system.
In vivo, f' esperimenti separati bl- użu ta 'mudelli tal- ġrieden ta' CML, dasatinib impedixxa l- iżvilupp ta 'CML kronika għall- fażi splussiva u tawwal is- sopravivenza tal- ġrieden li kellhom linji ta' ċelloli b' CML meħudin minn pazjenti u mkabbra f' siti differenti, inkluża is- sistema nervuża ċentrali.
Clinical trials:
Provi kliniċi:
In the Phase I study, haematologic and cytogenetic responses were observed in all phases of CML and in Ph+ ALL in the first 84 patients treated and followed for up to 27 months.
Fl- istudju ta 'Fażi I, ir- responsi ematoloġiċi u ċitoġenetiċi ġew osservati f' kull fażi ta' CML u f’ Ph+ ALL fl- ewwel 84 pazjent li ngħataw it- trattament u li kienu segwiti għal 27 xahar.
Responses were durable across all phases of CML and Ph+ ALL.
Ir- respons dam matul il- fażijiet kollha ta 'CML u Ph+ ALL.
A total of 2,182 patients were evaluated in clinical trials; of these 25% were ≥ 65 years of age and 5% were ≥ 75 years of age.
B’ kollox ġew mistħarġa 2, 182 pazjent fi provi kliniċi, minn dawn 25% kienu ≥ 65 sena u 5% kienu ≥ 75 sena.
Safety and efficacy of dasatinib have not yet been studied in paediatric patients.
Għadhom ma ġewx studjati s- sigurtà u l- effikaċja ta 'dasatinib fuq pazjenti li huma tfal.
13 Phase II clinical trials in CML:
Provi kliniċi ta ’ Fażi II f’ CML:
Four single-arm, uncontrolled, open-label phase II clinical trials were conducted to determine the safety and efficacy of dasatinib in patients with CML in chronic, accelerated, or myeloid blast phase, who were either resistant or intolerant to imatinib.
Saru erba 'provi kliniċi tal- fażi II single- arm, mhux ikkontrollati, open- label sabiex jistabbilixxu s - sigurtà u l- effikaċja ta' dasatinib f' pazjenti b' CML f' fażi kronika, aċċellerata, jew splussiva tal - majelojd, li kienu jew reżistenti jew intolleranti għal imatinib.
One randomized non-comparative trial was conducted in chronic phase patients who failed initial treatment with 400 or 600 mg imatinib.
Prova waħda mhux komparattiva fejn l - pazjenti ntgħażlu b' mod każwali saret f' pazjenti f' fażi kronika li fuqhom, it- trattament tal- bidu b' 400 jew 600 mg ta 'imatinib ma ħadimx.
The starting dose was 70 mg dasatinib twice daily.
Id- doża tal- bidu ta ’ dasatinib kienet ta '70 mg darbtejn kuljum.
Dose modifications were allowed for improving activity or management of toxicity (see section 4.2).
Kienu permessi modifikazzjonijiet fid- doża sabiex itejbu l- attività jew jikkontrollaw it- tossiċità (ara sezzjoni 4. 2).
The efficacy of dasatinib is based on haematological and cytogenetic response rates.
L- effikaċja ta 'dasatinib hi bbażata fuq rati ta' responsi ematoloġiċi u ċitoġenetiċi.
Durability of response and estimated survival rates provide additional evidence of dasatinib clinical benefit.
Id- durabilità tar- rispons u r- rati stmati ta ’ sopravivenza jipprovdu evidenza addizzjonali tal- benefiċċju kliniku ta ’ dasatinib.
Chronic Phase CML:
CML ta 'Fażi kronika:
Two clinical trials were conducted in patients resistant or intolerant to imatinib; the primary efficacy endpoint in these trials was Major Cytogenetic Response (MCyR).
Żewġ provi kliniċi saru f' pazjenti li huma reżistenti jew intolleranti għal imatinib; il- punt aħħari primarju ta 'effikaċja f' dawn il- provi kien Respons Ċitoġeniku Maġġuri (MCyR):