qanastek/EMEA-V3 huggingface dataset:
Patients with severe hepatic organ impairment should be carefully monitored for adverse
Pazjenti b’ indeboliment sever ta ’ l- organu epatiku għandhom ikunu mmonitorjati bl - attenzjoni għal avvenimenti avversi.
No specific modification to the starting dose is recommended for patients with hepatic impairment prior to starting treatment; subsequent dose modifications should be based on haematology laboratory values.
L- ebda tibdil speċifiku fid- doża tal- bidu mhu rakkomandat f’ pazjenti b’ indeboliment epatiku qabel il- bidu tal- kura; tibdil sussegwenti fid- doża għandu jkun ibbażat fuq il- valuri ematoloġiċi tal- laboratorju.
Vidaza is contraindicated in patients with advanced malignant hepatic tumours (see sections 4.3 and 4.4).
Vidaza hu kontra- indikat f’ pazjenti b’ tumuri epatiċi malinni avvanzati (ara sezzjonijiet 4. 3 u 4. 4).
No specific dose adjustments are recommended for the elderly.
L- ebda aġġustamenti speċifiċi fid- doża mhuma rakkomandati fl- anzjani.
Because elderly patients are more likely to have decreased renal function, it may be useful to monitor renal function.
Minħabba li pazjenti anzjani huma aktar mistennija li jkollhom tnaqqis fil- funzjoni renali, jista ’ jkun utli li jsir monitoraġġ tal- funzjoni renali.
Vidaza is not recommended for use in children below 18 years due to insufficient data on safety and efficacy.
Vidaza mhuwiex rakkomandat għall- użu fit- tfal ta ’ taħt it- 18- il sena minħabba li m’ hemmx biżżejjed informazzjoni dwar is- sigurtà u l- effikaċja.
Laboratory tests Liver function tests and serum creatinine should be determined prior to initiation of therapy and prior to each treatment cycle.
Testijiet tal- laboratorju Testijiet tal- funzjoni tal- fwied u l- krejatinina fis- serum għandhom jiġu stabbiliti qabel il- bidu tat - terapija u qabel kull ċiklu ta ’ kura.
Complete blood counts should be performed prior to initiation of therapy and as needed to monitor response and toxicity, but at a minimum, prior to each treatment cycle.
L- għadd komplet taċ- ċelluli tad- demm għandu jinkiseb qabel il - bidu tat- terapija u skond il- bżonn biex isir monitoraġġ tar- rispons u tat- tossiċità, iżda mill- inqas, qabel kull ċiklu ta ’ kura.
Method of administration Reconstituted Vidaza should be injected subcutaneously into the upper arm, thigh or abdomen.
Kif għandu jingħata Vidaza rikostitwit għandu jkun injettat taħt il- ġilda fin- naħa ta ’ fuq tad- driegħ, koxxa jew addome.
Injection sites should be rotated.
Il - postijiet fejn tingħata l- injezzjoni għandhom jinbidlu.
New injections should be given at least 2.5 cm from the previous site and never into areas where the site is tender, bruised, red, or hardened.
Injezzjonijiet ġodda għandhom jingħataw mill - inqas 2. 5 ċm mill- post ta ’ qabel u qatt f’ żoni fejn il- ġilda tkun ratba, imbenġla, ħamra, jew iebsa.
Detailed instructions for the reconstitution and administration procedure for Vidaza are provided in section 6.6.
Struzzjonijiet dettaljati għar- rikostituzzjoni u l- proċedura ta ’ l- għoti għal Vidaza jinsabu f’ sezzjoni 6. 6.
Advanced malignant hepatic tumours (see section 4.4).
Tumuri epatiċi malinni avvanzati (ara sezzjoni 4. 4).
Haematological toxicity Treatment with azacitidine is associated with anaemia, neutropenia and thrombocytopenia, particularly during the first 2 cycles (see section 4.8).
Tossiċità ematoloġika Il- kura b’ azacitidine hi assoċjata ma ’ anemija, newtropenija u tromboċitopenija, speċjalment matul l - ewwel 2 ċikli (ara sezzjoni 4. 8).
Complete blood counts should be performed as needed to monitor response and toxicity, but at least prior to each treatment cycle.
L- għadd komplet taċ- ċelluli tad- demm għandu jinkiseb skond il - bżonn biex isir monitoraġġ tar- rispons u tat- tossiċità, iżda mill- inqas, qabel kull ċiklu ta ’ kura.
After administration of the recommended dose for the first cycle, the dose for subsequent cycles should be reduced or its administration delayed based on nadir counts and haematological response (see section 4.2).
Wara l - għoti tad- doża rakkomandata għall- ewwel ċiklu, id- doża għal ċikli sussegwenti għandha titnaqqas jew l- għoti tagħha jiġi ttardjat skond l- għadd tan- nadir u r- rispons ematoloġiku (ara sezzjoni 4. 2).
Patients should be advised to promptly report febrile episodes.
Il - pazjenti għandhom jingħataw parir biex jirrappurtaw immedjatament episodji ta ’ deni.
Patients and physicians are also advised to be observant for signs and symptoms of bleeding.
Il- pazjenti u t - tobba huma avżati wkoll biex ikunu viġilanti għal sinjali u sintomi ta ’ ħruġ ta ’ demm.
Hepatic impairment No formal studies have been conducted in patients with hepatic impairment.
Indeboliment epatiku Ma saru l- ebda studji formali fuq pazjenti b’ indeboliment epatiku.
Patients with extensive tumour burden due to metastatic disease have been rarely reported to experience progressive hepatic coma and death during azacitidine treatment, especially in such patients with baseline serum albumin < 30 g/ l.
Pazjenti b’ tagħbija estensiva tat - tumur minħabba mard metastatiku kienu rarament irrappurtati li ġarrbu koma epatika progressiva u mewt matul il- kura b’ azacitidine, speċjament f’ pazjenti bħal dawn li jkollhom albumina fis- serum fil - linja bażi ta ’ < 30 g/ l.
Azacitidine is contraindicated in patients with advanced malignant hepatic tumours (see section 4.3).
Azacitidine hu kontra- indikat f’ pazjenti b’ tumuri epatiċi malinni avvanzati (ara sezzjoni 4. 3).
Renal impairment Renal abnormalities ranging from elevated serum creatinine to renal failure and death were reported rarely in patients treated with intravenous azacitidine in combination with other chemotherapeutic agents.
4 Indeboliment renali Anormalitajiet renali li jvarjaw minn livelli għolja ta ’ krejatinina fis- serum sa insuffiċjenza renali u mewt kienu rrappurtati b’ mod rari f’ pazjenti kkurati b’ azacitidine mogħti ġol- vina flimkien ma ’ sustanzi kemoterapewtiċi oħra.
If
Flimkien ma ’ dan, l- aċidożi tubulari renali, definita bħala tnaqqis fil - livell tal- bicarbonate fis- serum għal < 20 mmol/ l flimkien ma ’ awrina alkalina u ipokalemija (potassium fis- serum < 3 mmol/ l) żviluppat f’ 5 pazjenti b’ lewkimja majeloġena kronika (CML) ikkurati b’ azacitidine u etoposide.
4 unexplained reductions in serum bicarbonate (< 20 mmol/ l) or elevations of serum creatinine or BUN occur, the dose should be reduced or administration delayed (see section 4.2).
Jekk iseħħ tnaqqis inspjegabbli fil- livelli tal- bicarbonate fis- serum (< 20 mmol/ l) jew żidiet tal- krejatinina fis- serum jew BUN, id- doża għandha titnaqqas jew l- għoti jiġi ttardjat (ara sezzjoni 4. 2).
Patients with renal impairment should be closely monitored for toxicity since azacitidine and/ or its metabolites are primarily excreted by the kidney (see section 4.2).
Pazjenti b’ indeboliment renali għandhom ikunu mmonitorjati mill- qrib għat- tossiċità minħabba li azacitidine u/ jew il- metaboliti tiegħu jitneħħew primarjament mill- kliewi (ara sezzjoni 4. 2).
Cardiac and pulmonary disease Patients with a history of severe congestive heart failure, clinically unstable cardiac disease or pulmonary disease were excluded from the pivotal clinical study and therefore the safety and efficacy of Vidaza in these patients has not been established.
Mard kardijaku u pulmonari Pazjenti bi storja ta ’ insuffiċjenza konġestiva severa tal- qalb, mard tal- qalb li jkun klinikament instabbli jew mard pulmonari kienu esklużi mill- istudju kliniku ta ’ importanza kbira u għalhekk is - sigurtà u l- effikaċja ta ’ Vidaza f’ dawn il- pazjenti ma kinitx stabbilita.
Based on in vitro data, azacitidine metabolism does not appear to be mediated by cytochrome P450 isoenzymes (CYPs), UDP-glucuronosyltransferases (UGTs), sulfotransferases (SULTs), and glutathione transferases (GSTs); interactions related to these metabolizing enzymes in vivo are therefore considered unlikely.
Ibbażat fuq dejta in vitro, ma jidhirx li l- metaboliżmu ta ’ azacitidine hu medjat mill- isoenzimi ta ’ cytochrome P450 (CYPs), UDP- glucuronosyltransferases (UGTs), sulfotransferases (SULTs), u glutathione transferases (GSTs); l- interazzjonijiet relatati ma ’ dawn l- enzimi li jimmetabolizzaw in vivo huma għalhekk ikkunsidrati li mhumiex mistennija.
Clinically significant inhibitory or inductive effects of azacitidine on cytochrome P450 enzymes are unlikely (see section 5.2).
Effetti inibitorji jew induttivi ta ’ azacitidine fuq l- enzimi ta ’ cytochrome P450 li huma klinikament sinifikanti mhumiex mistennija (ara sezzjoni 5. 2).
No formal clinical drug interaction studies with azacitidine have been conducted.
Ma saru l- ebda studji kliniċi formali dwar l- interazzjoni tal- mediċina b’ azacitidine.
Pregnancy There are no adequate data on the use of azacitidine in pregnant women.
Tqala M’ hemmx tagħrif biżżejjed dwar l- użu ta ’ azacitidine waqt it- tqala.
Studies in mice have shown reproductive toxicity (see section 5.3).
Studji fuq il- ġrieden urew ħsara fuq is- sistema riproduttiva (ara sezzjoni 5. 3).
Based on results from animal studies and its mechanism of action, azacitidine should not be used during pregnancy, especially during the first trimester, unless clearly necessary.
Ibbażat fuq riżultati minn studji fuq l- annimali u l- mekkaniżmu tiegħu ta ’ l- azzjoni, azacitidine m’ għandux jintuża waqt it- tqala, speċjalment matul l- ewwel trimestru, ħlief jekk ma tkunx meħtieġa b’ mod ċar.
The advantages of treatment should be weighed against the possible risk for the foetus in every individual case.
Il - vantaġġi tal- kura għandhom jintiżnu kontra r- riskju possibbli lill- fetu f’ kull każ individwali.
Men and women of childbearing potential must use effective contraception during and up to 3 months after treatment.
Irġiel u nisa li potenzjalment jista ’ jkollhom it- tfal għandhom jużaw kontraċezzjoni effettiva matul u sa 3 xhur wara l- kura.
Lactation It is not known whether azacitidine or its metabolites are excreted in human milk.
Treddigħ Mhux magħruf jekk azacitidine jew il- metaboliti tiegħu jitneħħewx fil- ħalib tal- bniedem.
Due to the potential serious adverse reactions in the nursing child, breast-feeding is contraindicated during azacitidine therapy.
Minħabba l - potenzjal ta ’ reazzjonijiet avversi serji fit- tarbija li tkun qed terda ’, it- treddigħ hu kontra- indikat matul it- terapija b’ azacitidine.
Fertility There are no human data on the effect of azacitidine on fertility.
Fertilità M’ hemm l- ebda dejta umana fuq l- effett ta ’ azacitidine fuq il- fertilità.
In animals, adverse effects of azacitidine on male fertility have been documented (see section 5.3).
Fl- annimali, l- effetti avversi ta ’ azacitidine fuq il- fertilità fl- irġiel kienu dokumentati (ara sezzjoni 5. 3).
Men should be advised not to father a child while receiving treatment and must use effective contraception during and up to 3 months after treatment.
L- irġiel għandhom jingħataw parir biex ma jkollhomx tfal waqt li jkunu qed jirċievu l- kura u li għandhom jużaw kontraċezzjoni effettiva matul u sa 3 xhur wara l- kura.
Before starting treatment, male patients should be advised to seek counselling on sperm storage.
Qabel il- bidu tal- kura, il- pazjenti rġiel għandhom jiġu avżati biex jieħdu parir dwar il- ħażna ta ’ l- isperma.
No studies of the effects on the ability to drive and use machines have been performed.
Ma sarux studji dwar l- effetti fuq il- ħila biex issuq u tħaddem magni.
Patients should be advised that they may experience undesirable effects such as fatigue, during treatment.
Il- pazjenti għandhom ikunu avżati li jista ’ jkollhom effetti mhux mixtieqa bħal għeja kbira, matul il- kura.
Therefore, caution should be recommended when driving a car or operating machines.
Għalhekk, il- kawtela għandha tkun rakkomandata meta wieħed isuq karozza jew iħaddem il- magni.
Adverse reactions considered to be possibly or probably related to the administration of Vidaza have occurred in 97% of patients.
Reazzjonijiet avversi li huma kkunsidrati li huma possibbilment jew probabbilment relatati ma ’ l- għoti ta ’ Vidaza seħħew f’ 97% tal- pazjenti.
5 The most commonly reported adverse reactions with azacitidine treatment were haematological reactions (71.4%) including thrombocytopenia, neutropenia and leukopenia (usually Grade 3-4), gastrointestinal events (60.6%) including nausea, vomiting (usually Grade 1-2) or injection site reactions (77.1%; usually Grade 1-2).
L- iktar reazzjonijiet avversi rrappurtati b’ mod komuni bil- kura ta ’ azacitidine kienu reazzjonijiet ematoloġiċi (71. 4%) li jinkludu tromboċitopenja, newtropenja u lewkopenja (normalment Grad 3- 4), avvenimenti gastro- intestinali (60. 6%) li jinkludu nawsja, rimettar (normalment Grad 1- 2) jew reazzjonijiet fejn tingħata l- injezzjoni (77. 1%; normalment Grad 1- 2).
The most common serious adverse reactions (> 2%) noted from the pivotal study (AZA PH GL 2003 CL 001) and also reported in the supporting studies (CALGB 9221 and CALGB 8921) included febrile neutropenia (8.0%) and anaemia (2.3%).
L- iktar reazzjonijiet avversi serji komuni (> 2%) osservati mill- istudju ta ’ importanza kbira (AZA PH GL 2003 CL 001) u rrappurtati wkoll fi studji ta ’ appoġġ (CALGB 9221 u CALGB 8921) kienu jinkludu newtropenija bid- deni (8. 0%) u anemija (2. 3%).
Other less frequently reported serious adverse reactions (< 2%) included neutropenic sepsis, pneumonia, thrombocytopenia and haemorrhagic events (e. g. cerebral haemorrhage).
Reazzjonijiet avversi serji oħrajn li kienu rrappurtati inqas frekwentment (< 2%) kienu jinkludu sepsis newtropenika, pnewmonja, tromboċitopenja u avvenimenti emorraġiċi (eż. emorraġija ċerebrali).
The table below contains the adverse reactions for which a causal relationship with azacitidine treatment could reasonably be established.
It- tabella t’ hawn taħt fiha r- reazzjonijiet avversi li għalihom relazzjoni kawżali bil- kura b’ azacitidine setgħet tkun stabbilita b’ mod raġonevoli.
Frequencies given are based on the observations during the pivotal clinical study or two supporting clinical studies.
Il- frekwenzi mogħtija huma bbażati fuq l- osservazzjonijiet matul l- istudju kliniku ta ’ importanza kbira jew iż- żewġ studji kliniċi ta ’ appoġġ.
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); very rare (< 1/ 10,000); not known (cannot be estimated from the available data).
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), rari ħafna (< 1/ 10, 000), mhux magħrufa (ma tistax tittieħed stima mid- data disponibbli).
System Organ Class
Sistema tal - Klassifika tal - Organi
pneumonia, nasopharyngitis
pnewmonja,
neutropenic sepsis, upper respiratory tract infection, urinary tract infection, sinusitis, pharyngitis, rhinitis, herpes simplex
sepsis newtropenika,
Blood and lymphatic system disorders
Infestazzjonijiet
febrile neutropenia, neutropenia, leukopenia, thrombocytopenia, anaemia
infezzjoni fl- apparat respiratorju ta ’ fuq, infezzjoni fl- apparat ta ’ l - awrina, sinusite, farinġite, rinite, herpes simplex
bone marrow failure, pancytopenia
Disturbi tad -
Immune system disorders
newtropenja bid- deni,
hypersensitivity reactions
insuffiċjenza tal- mudullun,
Metabolism and nutrition disorders
demm u tas - sistema limfatika Disturbi fis - sistema immuni
anorexia
newtropenja, lewkopenja, tromboċitopenja, anemija
hypokalemia
panċitopenja
confusional state, anxiety, insomnia
reazzjonijiet minħabba sensittività eċċessiva
Nervous system disorders Eye disorders
Disturbi fil - metaboliżmu u n - nutrizzjoni Disturbi psikjatriċi
dizziness, headache
anoreksja
intracranial haemorrhage, lethargy eye haemorrhage, conjunctival haemorrhage
ipokalemja stat ta ’ konfużjoni, ansjetà, nuqqas ta ’ rqad
Vascular disorders
Disturbi fis -
hypertension, hypotension, haematoma
sturdament, uġigħ ta ’
Respiratory, thoracic and mediastinal disorders
emorraġija intrakranjali,
dyspnoea
sistema nervuża
dyspnoea exertional, pharyngolaryngeal pain
letarġija
6 System Organ Class
6 Sistema tal - Klassifika tal - Organi Disturbi fl - għajnejn Disturbi vaskulari
Uncommon
qtugħ ta ’ nifs
diarrhoea, vomiting, constipation, nausea, abdominal pain
stitikezza, nawsja,
gastrointestinal haemorrhage, haemorrhoidal haemorrhage, stomatitis, gingival bleeding, dyspepsia
murliti, stomatite, ħruġ ta ’ demm tal- ħanek, dispepsja
petechiae, pruritus, rash, ecchymosis
tbenġil, ħakk, raxx,
purpura, alopecia, erythema, rash macular
purpura, alopeċja, eritema,
Musculoskeletal, and connective tissue disorders
Disturbi muskolu - skeletrali u tal - connective tissue
myalgia, musculoskeletal pain
fis- sider, eritema fis- sit
Renal and urinary disorders
ematoma, ebusija, raxx,
haematuria
mnejn jingħata
General disorders and administration site conditions
ħakk, infjammazzjoni, tibdil
fatigue, pyrexia, chest pain, injection site erythema, injection site pain, injection site reaction (unspecified)
fis- sit ta ’ l- injezzjoni, reazzjoni fis- sit ta ’ l - injezzjoni (mhux speċifikata)
injection site: bruising, haematoma, induration, rash, pruritus, inflammation, discoloration, nodule and haemorrhage. malaise
fil- kulur, formazzjoni ta ’ għoqod u emorraġija. telqa
weight decreased
tnaqqis fil- piż
Haematologic adverse reactions The most commonly reported adverse reactions associated with azacitidine treatment were haematological including thrombocytopenia, neutropenia and leukopenia, and were usually Grade 3 or 4.
Reazzjonijiet ematoloġiċi avversi L- iktar reazzjonijiet avversi li kienu rrappurtati b’ mod komuni assoċjati mal- kura b’ azacitidine kienu ematoloġiċi li jinkludu tromboċitopenja, newtropenja u lewkopenja, u kienu normalment ta ’ Grad 3 jew 4.
There is a greater risk of these events occurring during the first 2 cycles, after which they occur with less frequency in patients with restoration of haematological function.
Hemm riskju ikbar li dawn l- avvenimenti jseħħu matul l- ewwel 2 ċikli, u wara jseħħu b’ inqas frekwenza f’ pazjenti u b’ restorazzjoni tal- funzjoni ematoloġika.
Most haematological adverse reactions were managed by routine monitoring of complete blood counts and delaying azacitidine administration in the next cycle, prophylactic antibiotics and/ or growth factor support (e. g.
Il- biċċa l- kbira tar- reazzjonijiet avversi ematoloġiċi kienu mmaniġġjati bil- monitoraġġ ta ’ rutina ta ’ l- għadd komplet taċ- ċelluli tad - demm u billi l- għoti ta ’ azacitidine jiġi ttardjat fiċ- ċiklu li jmiss, antibijotiċi profilattiċi u/ jew sapport tal- fattur tat- tkabbir (eż.
G-CSF) for neutropenia and transfusions for anaemia or thromobocytopenia as required.
G- CSF) għan- newtropenja u trasfużjonijiet għall- anemija jew tromboċitopenja kif meħtieġ.
Infections Myelosupression may lead to neutropenia and an increased risk of infection.
Infezzjonijiet Il- majelosoppressjoni tista ’ twassal għan- newtropenja u għal żieda fir- riskju ta ’ infezzjoni.
Serious adverse reactions such as neutropenic sepsis (0.8%) and pneumonia (2.5%) were reported in patients receiving azacitidine.
Reazzjonijiet avversi serji bħal sepsis newtropenika (0. 8%) u pnewmonja (2. 5%) kienu rrappurtati f’ pazjenti li kienu qed jirċievu azacitidine.
Infections may be managed with the use of anti-infectives plus growth factor support (e. g.
L- infezzjonijiet jistgħu jiġu mmaniġġjati bl- użu ta ’ mediċini kontra l- infezzjoni flimkien mas- sapport tal- fattur tat- tkabbir (eż.
G-CSF) for neutropenia.
G- CSF) għan- newtropenja.
Bleeding Bleeding may occur with patients receiving azacitidine.
7 Ħruġ ta ’ demm Il- ħruġ ta ’ demm jista ’ jseħħ f’ pazjenti li jkunu qed jirċievu azacitidine.
Serious adverse reactions such as gastrointestinal haemorrhage (0.8%) and intracranial haemorrhage (0.5%) have been reported.
Reazzjonijiet avversi serji bħal emorraġija gastro- intestinali (0. 8%) u emorraġija intrakranjali (0. 5%) kienu rrappurtati.
Patients should be monitored for signs and symptoms of bleeding, particularly those with pre-existing or treatment-related thrombocytopenia.
Il - pazjenti għandhom ikunu mmonitorjati għall- sinjali u sintomi ta ’ ħruġ ta ’ demm, speċjalment dawk bi tromboċitopenja li kienet teżisti minn qabel jew li tkun marbuta mal- kura.
Hypersensitivity Serious hypersensitivity reactions (0.25%) have been reported in patients receiving azacitidine.
Sensittività eċċessiva Reazzjonijiet serji ta ’ sensittività eċċessiva (0. 25%) kienu rrappurtati f’ pazjenti li kienu qed jirċievu azacitidine.
In case of an anaphylactic-like reaction, treatment with azacitidine should be immediately discontinued and appropriate symptomatic treatment initiated.
Fil- każ ta ’ reazzjoni qisha anafilattika, il- kura b’ azacitidine għandha titwaqqaf immedjatament u kura sintomatika adatta għandha tinbeda.
Skin and subcutaneous tissue adverse reactions The majority of skin and subcutaneous adverse reactions were associated with the injection site.
Reazzjonijiet avversi tat- tessut tal- ġilda u ta ’ taħt il- ġilda Il- maġġoranza tar- reazzjonijiet avversi tal- ġilda u ta ’ taħt il- ġilda kienu assoċjati mas- sit ta ’ l - injezzjoni.
The majority of adverse reactions occurred during the first
L- ebda waħda minn dawn ir- reazzjonijiet avversi ma wasslet għat- twaqqif temporanju jew permanenti ta ’ azacitidine, jew għat- tnaqqis tad- doża ta ’ azacitidine fl- istudju ta ’ importanza kbira.
7 2 cycles and tended to decrease with subsequent cycles.
Il - maġġoranza tar- reazzjonijiet avversi seħħew matul l- ewwel 2 ċikli u kellhom tendenza li jonqsu f’ ċikli sussegwenti.
Subcutaneous adverse reactions such as injection site rash/ inflammation/ pruritus, rash, erythema and skin lesion may require management with concomitant medicinal products, such as antihistamines, corticosteroids and non-steroidal anti- inflammatory drugs (NSAIDs).
Reazzjonijiet avversi ta ’ taħt il- ġilda bħal raxx/ infjammazzjoni/ ħakk fis- sit ta ’ l - injezzjoni, raxx, eritema u leżjonijiet tal- ġilda jistgħu jkunu jeħtieġu mmaniġġjar bi prodotti mediċinali fl- istess ħin, bħal antistamini, kortikosterojdi u mediċini anti- infjammatorji mhux sterojdi (NSAIDs).
Gastrointestinal adverse reactions The most commonly reported gastrointestinal adverse reactions associated with azacitidine treatment included constipation, diarrhoea, nausea and vomiting.
Reazzjonijiet avversi gastro- intestinali Ir- reazzjonijiet avversi gastro- intestinali li kienu rrappurtati l- iktar komuni assoċjati mal- kura b’ azacitidine kienu jinkludu stitikezza, dijarea, nawsja u rimettar.
These adverse reactions were managed symptomatically with anti-emetics for nausea and vomiting; antidiarrhoeals for diarrhoea, and laxatives and/ or stool softeners for constipation.
Dawn ir- reazzjonijiet avversi kienu mmaniġġjati b’ mod sintomatiku b’ mediċini kontra n- nawsja għan- nawsja u rimettar; mediċini kontra d- dijarea għad- dijarea, u lassattivi u/ jew mediċini li jrattbu l- ippurgar għall- istitikezza.
One case of overdose with azacitidine was reported during clinical trials.
Każ wieħed ta ’ doża eċċessiva b’ azacitidine kien rrappurtat matul provi kliniċi.
A patient experienced diarrhoea, nausea, and vomiting after receiving a single intravenous dose of approximately 290 mg/ m2, almost 4 times the recommended starting dose.
Pazjent wieħed kellu d- dijarea, nawsja, u rimettar wara li rċieva doża waħda ġol- vina ta ’ madwar 290 mg/ m2, kważi 4 darbiet tad- doża tal- bidu rakkomandata.
In the event of overdose, the patient should be monitored with appropriate blood counts and should receive supportive treatment, as necessary.
Fil- każ ta ’ doża eċċessiva, il- pazjent għandu jkun mmonitorjat b’ għadd adattat taċ- ċelluli tad- demm u għandu jirċievi kura ta ’ appoġġ, kif meħtieġ.
There is no known specific antidote for azacitidine overdose.
M’ hemm l- ebda antidot speċifiku magħruf għal doża eċċessiva b’ azacitidine.
Antineoplastic agent, Pyrimidine analogues; ATC code:
Sustanza antineoplastika, Analogi ta ’ pyrimidine; Kodiċi ATC:
Mechanism of action Azacitidine is believed to exert its antineoplastic effects by multiple mechanisms including cytotoxicity on abnormal haematopoietic cells in the bone marrow and hypomethylation of DNA.
Mekkaniżmu tal- azzjoni Hu maħsub li azacitidine jeżerċita l- effetti antineoplastiċi tiegħu permezz ta ’ mekkaniżmi multipli li jinkludu ċitotossiċità fuq ċelluli ematopojetiċi anormali fil- mudullun u hypomethylation tad- DNA.
The cytotoxic effects of azacitidine may result from multiple mechanisms, including inhibition of DNA, RNA and protein synthesis, incorporation into RNA and DNA, and activation of DNA damage pathways.
L - effetti ċitotossiċi ta ’ azacitidine jistgħu jirriżultaw minn mekkaniżmi multipli, li jinkludu l- inibizzjoni tad- DNA, RNA u s- sintesi tal- proteina, l- inkorporazzjoni fl- RNA u DNA, u l- attivazzjoni tal- passaġġi tal- ħsara tad- DNA.
Non-proliferating cells are relatively insensitive to azacitidine.
Iċ- ċelluli li ma jipproliferawx huma relattivament insensittivi għal azacitidine.
Incorporation of azacitidine into DNA results in the inactivation of DNA methyltransferases, leading to hypomethylation of DNA.
L - inkorporazzjoni ta ’ azacitidine fid- DNA tirriżulta fl- inattivazzjoni ta ’ DNA methyltransferases, li twassal għal hypomethylation tad- DNA.
DNA hypomethylation of aberrantly methylated genes involved in normal cell cycle regulation, differentiation and death pathways may result in gene re-expression and restoration of cancer- suppressing functions to cancer cells.
L- importanza relattiva tal- hypomethylation tad -
The relative importance of DNA hypomethylation versus cytotoxicity or other activities of azacitidine to clinical outcomes has not been established.
8 DNA kontra ċ- ċitotossiċità jew attivitajiet oħrajn ta ’ azacitidine għar- riżultati kliniċi ma kinux stabbiliti.
Clinical efficacy and safety The efficacy and safety of Vidaza were studied in an international, multicenter, controlled, open-label, randomised, parallel-group, Phase 3 comparative study (AZA PH GL 2003 CL 001) in patients with: intermediate-2 and high-risk MDS according to the International Prognostic Scoring System (IPSS), refractory anaemia with excess blasts (RAEB), refractory anaemia with excess blasts in transformation (RAEB-T) and modified chronic myelomonocytic leukaemia (mCMML) according to the French American British (FAB) classification system.
MDS intermedja- 2 u ta ’ riskju għoli skond l- International Prognostic Scoring System (IPSS), anemija refrettarja b’ blasts eċċessivi (RAEB), anemija refrettarja b’ blasts eċċessivi li qed jinbidlu (RAEB- T) u lewkimja majelomonoċitika kronika modifikata (mCMML) skond is- sistema tal - klassifikazzjoni French American British (FAB).
RAEB-T patients (21-30% blasts) are now considered to be AML patients under the current WHO classification system.
Pazjenti b’ RAEB- T (21- 30% blasts) issa huma kkunsidrati li huma pazjenti tal- AML taħt is- sistema kurrenti tal- klassifikazzjoni tal- WHO.
Azacitidine plus best supportive care (BSC) (n = 179) was compared to conventional care regimens (CCR).
Azacitidine flimkien mal- aħjar kura ta ’ appoġġ (BSC) (n = 179) kien imqabbel ma ’ korsjiet ta ’ kura konvenzjonali (CCR).
CCR consisted of BSC alone (n = 105), low-dose cytarabine plus BSC (n = 49) or standard induction chemotherapy plus BSC (n = 25).
CCR kienet tikkonsisti f’ BSC waħidha (n = 105), cytarabine f’ doża baxxa flimkien ma ’ BSC (n = 49) jew kimoterapija ta ’ l- induzzjoni standard flimkien ma ’ BSC (n = 25).
Patients were pre-selected by their physician to 1 of the 3 CCR prior to randomisation.
Il - pazjenti ntgħażlu minn qabel mit- tabib tagħhom għal 1 mit- 3 CCR qabel ir- randomisation.
Patients received this pre-selected regimen if not randomised to Vidaza.
Il- pazjenti rċivew dan il- kors magħżul minn qabel jekk ma kinux randomised għal Vidaza.
As part of the inclusion criteria, patients were required to have an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2.
Bħala parti mill - kriterja ta ’ l- inklużjoni, il- pazjenti kienu jeħtieġu li jkollhom stat tal- prestazzjoni Eastern Cooperative Oncology Group (ECOG) ta ’ 0- 2.
Patients with secondary MDS were excluded from the study.
Pazjenti b’ MDS sekondarja kienu esklużi mill- istudju.
The primary endpoint of the study was overall survival.
Il- punt aħħari primarju ta ’ l- istudju kienet is- sopravivenza totali.
Vidaza was administered at a subcutaneous dose of 75 mg/ m2 daily for 7 days, followed by a rest period of 21 days (28-day treatment cycle) for a median of 9 cycles
Vidaza ngħata taħt il- ġilda f’ doża ta ’ 75 mg/ m2 kuljum għal 7 ijiem, segwit minn perjodu ta ’ serħan ta ’ 21 jum (ċiklu tal- kura ta ’ 28 jum) għall- medjan ta ’ 9 ċikli (medda = 1- 39) u medja ta ’ 10. 2 ċikli.
Within the Intent to Treat population (ITT), the median age was 69 years (range 38 to 88 years).
Fi ħdan il- popolazzjoni b’ Intenzjoni li Jigu Kkurati (ITT), l- età medjana kienet ta ’ 69 sena (medda 38 sa 88 sena).
In the ITT analysis of 358 patients (179 azacitidine and 179 CCR), Vidaza treatment was associated with a median survival of 24.46 months versus 15.02 months for those receiving CCR treatment, a difference of 9.4 months, with a stratified log-rank p-value of 0.0001.
Fl- analiżi ITT ta ’ 358 pazjent (179 azacitidine u 179 CCR), il- kura b’ Vidaza kienet assoċjata ma ’ medjan ta ’ sopravivenza ta ’ 24. 46 xahar kontra 15. 02 xahar għall- dawk li kienu qed jirċievu l- kura CCR, differenza ta ’ 9. 4 xhur, b’ valur p stratifikat log- rank ta ’ 0. 0001.
The hazard ratio for the treatment effect was 0.58 (95% CI:
Il- proporzjon tal- periklu għall - effett tal- kura kien ta ’ 0. 58 (95% CI:
0.43, 0.77).
0. 43; 0. 77).
The two-year survival rates were 50.8% in patients receiving azacitidine versus 26.2% in patients receiving CCR (p < 0.0001).
Ir- rati tas- sopravivenza fuq medda ta ’ sentejn kienu 50. 8% f’ pazjenti li kienu qed jirċievu azacitidine kontra 26. 2% f’ pazjenti li kienu qed jirċievu CCR (p < 0. 0001).
Log-Rank p = 0.0001 HR = 0.58 [95% CI:
Log- Rank p = 0. 0001 HR 0. 58 [95% CI:
0.43-0.77] Deaths:
0. 43- 0. 77] Imwiet:
AZA = 82, CCR = 113 Proportion Surviving
AZA = 82, CCR = 113 Proporzjon li għexu
Time (months) from Randomization # at risk
Żmien (xhur) mir- Randomization # f’ riskju
KEY:
KEY:
AZA = azacitidine; CCR = conventional care regimens; CI = confidence interval; HR = hazard ratio
AZA = azacitidine; CCR = (conventional care regimens) korsjiet ta ’ kura konvenzjonali; CI = (confidence interval) intervall tal- kunfidenza; HR = (hazard ratio) proporzjon tal- periklu
The survival benefits of Vidaza were consistent regardless of the CCR treatment option (BSC alone, low-dose cytarabine plus BSC or standard induction chemotherapy plus BSC) utilised in the control arm.
9 Il- benefiċċji tas- sopravivenza ta ’ Vidaza kienu konsistenti irrispettivament mill- għażla tal- kura CCR (BSC waħidha, doża baxxa ta ’ cytarabine flimkien ma ’ BSC jew kimoterapija ta ’ l- induzzjoni standard flimkien ma ’ BSC) użati fil- parti tal- kontroll ta ’ l- istudju.
When IPSS cytogenetic subgroups were analysed, similar findings in terms of median overall survival were observed in all groups (good, intermediate, poor cytogenetics, including monosomy 7).
Meta s- sotto- gruppi ċitoġeniċi IPSS kienu analizzati, sejbiet simili fir- rigward ta ’ medjan tas - sopravivenza totali kienu osservati fil- gruppi kollha (ċitoġeniċi tajbin, intermedji, batuti, li jinkludu monosomija 7).
On analyses of age subgroups, an increase in median overall survival was observed for all groups (< 65 years, ≥ 65 years and ≥ 75 years).
Meta saret analiżi tas- sotto- gruppi ta ’ l- età, żieda fil- medjan tas- sopravivenza totali kienet osservata għall- gruppi kollha (< 65 sena, ≥ 65 sena u ≥ 75 sena).
Vidaza treatment was associated with a median time to death or transformation to AML of 13.0 months versus 7.6 months for those receiving CCR treatment, an improvement of 5.4 months with a stratified log-rank p-value of 0.0025.
Il- kura b’ Vidaza kienet assoċjata ma ’ żmien medjan sal- mewt jew trasformazzjoni għal AML ta ’ 13. 0 - il xahar kontra 7. 6 xhur għal dawk li kienu qed jirċievu kura CCR, titjib ta ’ 5. 4 xhur b’ valur p stratifikat log- rank ta ’ 0. 0025.
Vidaza treatment was also associated with a reduction in cytopenias, and their related symptoms.
Il- kura b’ Vidaza kienet wkoll assoċjata ma ’ tnaqqis fiċ- ċitopenji, u s- sintomi relatati tagħhom.
Vidaza treatment led to a reduced need for red blood cell (RBC) and platelet transfusions.
Il- kura b’ Vidaza wasslet għal tnaqqis fil- ħtieġa ta ’ trasfużjonijiet ta ’ ċelluli tad- demm ħomor (RBC) u plejtlits.
Of the patients in the azacitidine group who were RBC transfusion dependent at baseline, 45.0% of these patients became RBC transfusion independent during the treatment period, compared with 11.4% of the patients in the combined CCR groups (a statistically significant (p < 0.0001) difference of 33.6% (95% CI:
Mill- pazjenti fil- grupp ta ’ azacitidine li kienu dipendenti fuq it- trasfużjonijiet tar- RBC fil - linja bażi, 45. 0% minn dawn il- pazjenti saru indipendenti mit- trasfużjonijiet tar- RBC matul il- perjodu tal- kura meta mqabbla ma ’ 11. 4% tal- pazjenti fil- gruppi tas- CCR kombinati (differenza statistikament sinifikanti (p < 0. 0001) ta ’ 33. 6% (95% CI:
22.4, 44.6).
22. 4; 44. 6)).
In patients who were RBC transfusion dependent at baseline and became independent, the median duration of RBC transfusion independence was 13 months in the azacitidine group.
F’ pazjenti li kienu dipendenti fuq it - trasfużjonijiet tar- RBC fil- linja bażi u saru indipendenti, it- tul medjan ta ’ l- indipendenza mit - trasfużjonijiet tar- RBC kien ta ’ 13- il xahar fil- grupp ta ’ azacitidine.
9 Response was assessed by the investigator or by the Independent Review Committee (IRC).
Ir- rispons kien evalwat mill- investigatur jew mill- Kumitat Indipendenti ta ’ l- Evalwazzjoni (IRC).
Overall response (complete remission [CR] + partial remission [PR]) as determined by the investigator was 29% in the azacitidine group and 12% in the combined CCR group (p = 0.0001).
Ir - rispons totali (tnaqqis sħiħ tal- mard [CR] + tnaqqis parzjali tal- mard [PR]) kif stabbilit mill - investigatur kien ta ’ 29% fil- grupp ta ’ azacitidine u 12% fil- grupp tas- CCR kombinati (p = 0. 0001).
Overall response (CR + PR) as determined by the IRC in AZA PH GL 2003 CL 001 was 7% (12/ 179) in the azacitidine group compared with 1% (2/ 179) in the combined CCR group (p = 0.0113).
Ir- rispons totali (CR + PR) kif stabbilit mill- IRC fl- istudju AZA PH GL 2003 CL 001 kien ta ’ 7% (12/ 179) fil- grupp ta ’ azacitidine meta mqabbel ma ’ 1% (2/ 179) fil- grupp tas- CCR kombinati (p = 0. 0113).
The differences between the IRC and investigator assessments of response were a consequence of the International Working Group (IWG) criteria requiring improvement in peripheral blood counts and maintenance of these improvements for a minimum of 56 days.
Id- differenzi bejn l- evalwazzjonijiet tar- rispons tal- IRC u l- investigatur kienu konsegwenza tal- kriterja tal- International Working Group (IWG) li kienet teħtieġ titjib fl- għadd periferali taċ- ċelluli tad- demm u l- manteniment ta ’ dan it- titjib għal minimu ta ’ 56 jum.
A survival benefit was also demonstrated in patients that had not achieved a complete/ partial response following azacitidine treatment.
Intwera wkoll benefiċċju tas- sopravivenza f’ pazjenti li ma kinux laħqu rispons sħiħ/ parzjali wara l- kura b’ azacitidine.
Haematological improvement (major or minor) as determined by the IRC was achieved in 49% of patients receiving azacitidine compared with 29% of patients treated with combined CCR (p < 0.0001).
Titjib ematoloġiku (maġġuri jew minuri) kif stabbilit mill- IRC intlaħaq f’ 49% tal - pazjenti li kienu qed jirċievu azacitidine meta mqabbla ma ’ 29% tal- pazjenti kkurati b’ CCR kombinati (p < 0. 0001).
In patients with one or more cytogenetic abnormalities at baseline, the percentage of patients with a major cytogenetic response was similar in the azacitidine and combined CCR groups.
F’ pazjenti b’ anormalità ċitoġenika waħda jew aktar fil- linja bażi, il- perċentwali ta ’ pazjenti b’ rispons ċitoġeniku maġġuri kien simili fil- gruppi kkurati b’ azacitidine u bis- CCR kombinati.
Minor cytogenetic response was statistically significantly (p = 0.0015) higher in the azacitidine group (34%) compared with the combined CCR group (10%).
Ir- rispons ċitoġeniku minuri kien statistikament sinifikanti (p = 0. 0015) ogħla fil- grupp ta ’ azacitidine (34%) meta mqabbel mal- grupp ikkurat bis- CCR kombinati (10%).
The pharmacokinetics of azacitidine were studied following single 75 mg/ m2 doses given by subcutaneous and intravenous administration.
Il- farmakokinetika ta ’ azacitidine kienet studjata wara dożi waħidhom ta ’ 75 mg/ m2 mogħtija taħt il - ġilda u ġol- vina.
Absorption Azacitidine was rapidly absorbed after subcutaneous administration with peak plasma azacitidine concentrations of 750 ± 403 ng/ ml occurring at 0.5 h (the first sampling point) after dosing.
Assorbiment Azacitidine kien assorbit b’ mod mgħaġġel wara l- għoti taħt il- ġilda b’ konċentrazzjonijiet massimi ta ’ azacitidine fil- plażma ta ’ 750 ± 403 ng/ ml li jseħħu wara 0. 5 siegħa (l- ewwel darba li jittieħed kampjun) wara d- dożaġġ.
The absolute bioavailability of azacitidine after subcutaneous relative to intravenous administration was approximately 89% based on area under the curve (AUC).
Il- bijodisponibilità assoluta ta ’ azacitidine wara l- għoti taħt il- ġilda meta mqabbla mal- għoti ġol- vina kienet ta ’ madwar 89% ibbażati fuq l- erja taħt il- kurva (AUC).
Distribution Following intravenous administration, the mean volume of distribution was 76 ± 26 l, and systemic clearance was 147 ± 47 l/ h.
Distribuzzjoni Wara l- għoti ġol- vina, il- medja tal- volum tad- distribuzzjoni kienet ta ’ 76 ± 26 l, u t- tneħħija sistemika kienet ta ’ 147 ± 47 l/ siegħa.
Metabolism Based on in vitro data, azacitidine metabolism does not appear to be mediated by cytochrome P450 isoenzymes (CYPs), UDP-glucuronosyltransferases (UGTs), sulfotransferases (SULTs), and glutathione transferases (GSTs).
10 Metaboliżmu Ibbażat fuq dejta in vitro, ma jidhirx li l- metaboliżmu ta ’ azacitidine hu medjat mill- isoenzimi ta ’ cytochrome P450 (CYPs), UDP- glucuronosyltransferases (UGTs), sulfotransferases (SULTs), u glutathione transferases (GSTs).
Metabolism of azacitidine is by spontaneous hydrolysis and by deamination mediated by cytidine deaminase.
Il- metaboliżmu ta ’ azacitidine isir permezz ta ’ idrolisi spontanja u b’ deaminazzjoni medjata minn cytidine deaminase.
In human liver S9 fractions, formation of metabolites was independent of NADPH implying any metabolism would be catalysed by cytosolic enzymes.
Fi frazzjonijiet S9 ta ’ fwied uman, il- formazzjoni tal- metaboliti kienet indipendenti minn NADPH li timplika li kwalunkwe metaboliżmu ser ikun ikkatalizzat minn enzimi ċitosoliċi.
In vitro studies of azacitidine with cultured human hepatocytes indicate that at concentrations of 1.0 µM to 100 µM (i. e. up to approximately 30-fold higher than clinically achievable concentrations), azacitidine does not induce cytochrome P450 isoenzymes (CYP) 1A2, 2C19, or 3A4 or 3A5.
Studji in vitro ta ’ azacitidine b’ epatoċiti umani kolturati jindikaw li f’ konċentrazzjonijiet ta ’ 1. 0 µM sa 100 µM (i. e. sa madwar 30 darba ogħla minn konċentrazzjonijiet li jintlaħqu klinikament), azacitidine ma jinduċix l- isoenzimi ta ’ cytochrome P450 (CYP) 1A2, 2C19, jew 3A4 jew 3A5.
In a study to assess inhibition of a series of P450 isoenzymes (CYP 1A2, 2C9, 2C19, 2D6, 2E1 and 3A4) incubated with 100 µM azacitidine, IC50 values could not be determined, therefore, enzyme inhibition by azacitidine at clinically achievable plasma concentrations is unlikely.
Fi studju biex jevalwa l- inibizzjoni ta ’ serje ta ’ isoenzimi ta ’ P450 (CYP 1A2, 2C9, 2C19, 2D6, 2E1 u 3A4) inkubati b’ 100 µM ta ’ azacitidine, il- valuri IC50 ma setgħux ikunu stabbliti, u għalhekk, l - inibizzjoni tal- enzimi b’ azacitidine f’ konċentrazzjonijiet fil- plażma li jintlaħqu klinikamentat mhijiex mistennija.
The potential to inhibit CYP2B6 or 2C8 has not been studied.
Il- potenzjal li jinibixxi CYP2B6 jew 2C8 ma kienx studjat.
Excretion Azacitidine is cleared rapidly from plasma with a mean elimination half-life (t½) after subcutaneous administration of 41 ± 8 minutes.
Tneħħija Azacitidine jitneħħa malajr mill- plażma b’ half- life medja tal- eliminazzjoni (t½) wara l- għoti taħt il - ġilda ta ’ 41 ± 8 minuti.
Urinary excretion is the primary route of elimination of azacitidine and/ or its metabolites.
It- tneħħija mill- awrina hi r- rotta primarja tat- tneħħija ta ’ azacitidine u/ jew tal - metaboliti tiegħu.
Following intravenous and subcutaneous administration of 14C-azacitidine, 50-85% of the administered radioactivity was recovered in urine, while < 1% was recovered in faeces.
Wara l- għoti ġol- vina u taħt il- ġilda ta ’ 14C- azacitidine, 50- 85% tar- radjuattività mogħtija kienet irkuprata fl- awrina filwaqt li < 1% kienet irkuprata fl- ippurgar.
10 Special populations The effects of renal or hepatic impairment (see section 4.2), gender, age, or race on the pharmacokinetics of azacitidine have not been formally studied.
Popolazzjonijiet speċjali L- effetti ta ’ indeboliment epatiku jew renali (ara sezzjoni 4. 2), sess, età, jew razza fuq il - farmakokinetiċi ta ’ azacitidine ma kinux studjati formalment.
Pharmacogenomics The effect of known cytidine deaminase polymorphisms on azacitidine metabolism has not been formally investigated.
Pharmakoġenomika L- effett ta ’ cytidine deaminase polymorphisms magħrufa fuq il- metaboliżmu ta ’ azacitidine ma kienx investigat formalment.
Azacitidine induces both gene mutations and chromosomal aberrations in bacterial and mammalian cell systems in vitro.
Azacitidine jinduċi kemm mutazzjonijiet tal- ġeni kif ukoll aberazzjonijiet kromosomali f’ sistemi ta ’ ċelluli batterjali u mammiferi in vitro.
The potential carcinogenicity of azacitidine was evaluated in mice and rats.
Il- karċinoġeneċità potenzjali ta ’ azacitidine kienet evalwata fil - ġrieden u fil- firien.
Azacitidine induced tumours of the haematopoietic system in female mice, when administered intraperitoneally 3 times per week for 52 weeks.
Azacitidine ikkawża tumuri tas- sistema ematopojetika fil- ġrieden nisa, meta ngħata mill- peritonew 3 darbiet fil- ġimgħa għal 52 ġimgħa.
An increased incidence of tumours in the lymphoreticular system, lung, mammary gland, and skin was seen in mice treated with azacitidine administered intraperitoneally for 50 weeks.
Kienet osservata żieda fl- inċidenza ta ’ tumuri fis- sistema limforetikulari, fil- pulmun, fil- glandola mammarja, u fil- ġilda fil- ġrieden ikkurati b’ azacitidine mogħti mill- peritonew għal 50 ġimgħa.
A tumorigenicity study in rats revealed an increased incidence of testicular tumours.
Studju dwar it- tumoroġeneċità fil- firien żvela żieda fl- inċidenza ta ’ tumuri testikulari.
Early embryotoxicity studies in mice revealed a 44% frequency of intrauterine embryonal death (increased resorption) after a single intraperitoneal injection of azacitidine during organogenesis.
Studji dwar l- embrijotossiċità bikrija fil- ġrieden żvelaw frekwenza ta ’ 44% ta ’ mewt embrijonali fl - utru (żieda fl- assorbiment) wara injezzjoni waħda mill- peritonew ta ’ azacitidine matul l- organoġenesi.
Developmental abnormalities in the brain have been detected in mice given azacitidine on or before closure of the hard palate.
Anormalitajiet tal- iżvilupp fil- moħħ kienu osservati fil- ġrieden li ngħataw azacitidine waqt jew qabel l- għeluq tal- palat iebes.
In rats, azacitidine caused no adverse effects when given pre-implantation, but it was clearly embryotoxic during when given during organogenesis.
Fil- firien, azacitidine ma kkawża l- ebda effetti avversi meta ngħata qabel l - impjant, iżda kien embrijotossiku b’ mod ċar meta ngħata matul l- organoġenesi.
Foetal abnormalities caused during organogenesis included:
Anormalitajiet fetali kkawżati matul l- organoġenesi kienu jinkludu:
CNS anomalies (exencephaly/ encephalocele), limb anomalies (micromelia, club foot, syndactyly, oligodactyly) and others (micrognathia, gastroschisis, oedema, and rib abnormalities).
Anomaliji tas- Sistema Nervuża Ċentrali (CNS) (exencephaly/ enċefaloċele), anomaliji fir- riġlejn jew fid- dirgħajn (mikromelia, saqajn mgħawġa, syndactyly, oligodactyly) u oħrajn (mikrognatija, gastroschisis, edema, u anormalitajiet fil- kustilji).
Administration of azacitidine to male mice prior to mating with untreated female mice resulted in decreased fertility and loss of offspring during subsequent embryonic and postnatal development.
L- għoti ta ’ azacitidine lil ġrieden irġiel qabel it- tgħammir ma ’ ġrieden nisa mhux ikkurati rriżulta fi tnaqqis tal- fertilità u t- telf tal- frieħ matul l- iżvilupp embrijoniku sussegwenti u wara t- twelid.
Treatment of male rats resulted in decreased weight of the testes and epididymides, decreased sperm counts, decreased pregnancy rates, an increase in abnormal embryos and increased loss of embryos in mated females (see section 4.4).
Il- kura ta ’ firien rġiel irriżultat fi tnaqqis fil- piż tat- testikoli u tal- epididimu, tnaqqis fl- għadd ta ’ l- isperma, tnaqqis fir- rati tat- tqala, żieda f’ embriji anormali u żieda fit- telf ta ’ embriji fi ġrieden nisa mgħammra (ara sezzjoni 4. 4).
This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.
6. 2 Inkompatibilitajiet
Unopened powder vial:
Il- kunjett tat- trab mhux miftuħ:
Chemical and physical in-use stability of the reconstituted medicinal product has been demonstrated at 25°C for 45 minutes and at 2°C to 8°C for 8 hours.
L- istabbiltà kimika u fiżika waqt l- użu tal- prodott mediċinali rikostitwit intweriet f’ temperatura ta ’ 25°C għal 45 minuta u f’ temperatura ta ’ minn 2°C sa 8°C għal 8 sigħat.
From a microbiological point of view, the reconstituted product should be used immediately.
Mill- aspett mikrobijoloġiku, il- prodott rikostitwit għandu jintuża immedjatament.
If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and must not be longer than 8 hours at 2°C to 8°C.
Jekk ma jintużax immedjatament, iż- żmien tal- ħażna waqt l- użu u l- kundizzjonijiet ta ’ qabel l- użu huma r - responsabbiltà ta ’ l- utent u m’ għandhomx ikunu itwal minn 8 sigħat f’ temperatura ta ’ minn 2°C sa 8°C.
Colourless type I 30 ml glass vial sealed with butyl elastomeric stopper and aluminium seal with polypropylene plastic button.
Kunjett tal- ħġieġ bla kulur ta ’ tip I ta ’ 30 ml issiġillat b’ tapp tal- butyl elastomeriku u siġill tal - aluminju b’ buttuna tal- plastik tal- polypropylene.
1 vial of 100 mg azacitidine.
Daqs tal- pakkett: kunjett 1 ta ’ 100 mg azacitidine.
Recommendations for safe handling Vidaza is a cytotoxic medicinal product and, as with other potentially toxic compounds, caution should be exercised when handling and preparing azacitidine suspensions.
Rakkomandazzjonijiet għal immaniġġjar sigur Vidaza hu prodott mediċinali ċitotossiku u, bħal fil- każ ta ’ prodotti oħra potenzjalment tossiċi, għandha tintuża l- kawtela meta timmaniġġja u tipprepara suspensjonijiet ta ’ azacitidine.
Procedures for proper handling and disposal of anticancer medicinal products should be applied.
Il- proċeduri għall- immaniġġjar u rimi kif suppost ta ’ prodotti mediċinali kontra l- kanċer għandhom jiġu segwiti.
If reconstituted azacitidine comes into contact with the skin, immediately and thoroughly wash with soap and water.
Jekk azacitidine rikostitwit imiss mal- ġilda, aħsel immedjatament u bir- reqqa bis- sapun u bl- ilma.
If it comes into contact with mucous membranes, flush thoroughly with water.
Jekk imiss mal- membrani mukużi, laħlaħ bir- reqqa bl- ilma.
Reconstitution procedure 1.
Proċedura tar- rikostituzzjoni 1.
The following supplies should be assembled:
L- oġġetti li ġejjin għandhom jitlestew:
Vial(s) of azacitidine; vial(s) of water for injections; nonsterile surgical gloves; Alcohol wipes; 5 ml injection syringe(s) with needle(s).
Biċċiet tat- tajjar bl- alkoħol; siringa( i) għall- injezzjoni ta ’ 5 ml bil- labra (labar).
4 ml of trapped
4 ml ta ’ ilma għall- injezzjonijiet għandhom jinġibdu ġos- siringa, filwaqt li taċċerta ruħek li tneħħi xi arja li tkun inqabdet ġos- siringa.