qanastek/EMEA-V3 huggingface dataset:
No interaction was observed when busulfan was combined with fluconazole (antifungal agent) or 5 HT3 antiemetics such as ondansetron or granisetron.
Ma kienet osservata l- ebda interazzjoni meta l- busulfan ingħaqad ma 'flukonażol (aġent antifungali) jew antijemitiċi 5 - HT3 bħal ngħidu aħna ondansetron jew granisetron.
Pregnancy HPCT is contraindicated in pregnant women; therefore, Busilvex is contraindicated during pregnancy.
HPCT m’ għandux jingħata lil nisa tqal; mela, Busilvex m' għandux jingħata waqt it- tqala.
Busulfan has caused embryofoetal lethality and malformations in pre-clinical studies. (see section 5.3)
Busulfan ikkaġuna l- mewt ta ’ l- embriju/ fetu u l- malformazzjonijiet fi studji pre- klinikali (ara sezzjoni 5. 3)
There are no adequate data from the use of either busulfan or DMA in pregnant woman.
M’ hemmx dejta biżżejjed dwar l- użu tal- busulfan jew id- DMA f’ nisa tqal.
A few cases of congenital abnormalities have been reported with low-dose oral busulfan, not necessarily attributable to the active substance, and third trimester exposure may be associated with impaired intrauterine growth.
Ftit każi ta ’ annormalitajiet konġenitali kienu rrapportati bid- doża baxxa mill- ħalq ta ’ busulfan, imma mhumiex bilfors attribwiti għas- sustanza attiva, u l- esponiment tat- tielet trimestru għandu mnejn ikun assoċjat ma ’ żvilupp imfixkel intrajuterin.
Women of childbearing potential have to use effective contraception during and up to 6 months after treatment.
Nisa li jistgħu joħorġu tqal għandhom jużaw kontraċettiv effettiv waqt u sa 6 xhur wara t- trattament.
Lactation It is not known whether busulfan and DMA are excreted in human milk.
Treddigħ Mhux magħruf jekk il- busulfan u d- DMA jitkeċċewx fil- ħalib uman.
Because of the potential for tumorigenicity shown for busulfan in human and animal studies, breast-feeding should be discontinued at the start of therapy.
Peress li studji fuq nies u annimali wrew li hemm potenzjali ta ’ tumoriġeniċità fil- każ ta ’ busulfan, it- treddigħ għandu jitwaqqaf fil- bidu tat- terapija.
Fertility Busulfan and DMA can impair fertility in man or woman.
Fertilità Busulfan u DMA jistgħu jgħarrqu l- fertilità ta ’ raġel jew mara.
Therefore it is advised not to father child during the treament and up to 6 months after treatment and to seek advice on cryo-conservation of sperm prior to treatment because of the possibility of irreversible infertility (see section 4.4).
Għalhekk hu rrikkmandat biex ma tkunx missier wild waqt it- trattament u sa 6 xhur wara t- trattament u li tfittex parir dwar krijo - konservazzjoni ta ’ sperma qabel it- trattament minħabba il- possibbiltà ta ’ infertilità irriversibbli (ara sezzjoni 4. 4).
Not relevant
Mhux relevanti.
4.8 Undesirable effects
4. 8 Effetti mhux mixtieqa.
Averse events in adults Adverse events information is derived from two clinical trials (n=103) of Busilvex.
Effetti avversi fl- adulti Tagħrif dwar każijiet avversi inkisbu minn żewġ studji kliniċi (n=103) tal- Busilvex.
Serious toxicities involving the haematologic, hepatic and respiratory systems were considered as expected consequences of the conditioning regimen and transplant process.
Tossiċitajiet serji li kienu jinvolvu s- sistemi ematoloġiċi, epatiċi u respiratorji kienu meqjusa bħala konsegwenzi mistennija tar- regimen kondizzjonarju u l- proċess tat- trapjant.
These include infection and Graft-versus host disease (GVHD) which although not directly related, were the major causes of morbidity and mortality, especially in allogeneic HPCT.
Dawn jinkludi l- infezzjoni u l- marda tat- trapjant- kontra r- riċevitur (GVHD) li għalkemm mhumiex direttament relattati, kienu l- kawżi maġġuri tal- morbidità u l- mortalità, speċjalment fil- każ ta ’ HPCT alloġeniku.
Blood and the lymphatic system disorders:
Marda tad- demm u tas- sistema limfatika:
Myelo-suppression and immuno-suppression were the desired therapeutic effects of the conditioning regimen.
Il- mijelosuppressjoni u l- immunosuppressjoni kienu l- effetti terapewtiċi mixtieqa tar- regimen kondizzjonarju.
Therefore all patients experienced profound cytopenia: leukopenia 96%, thrombocytopenia 94%, and anemia 88%.
Għalhekk il- pazjenti kollha esperjenzaw ċitopenija profonda: lewkopenja 96%, tromboċitopenja 94%, u anemja 88%.
The median time to neutropenia was 4 days for both autologous and allogeneic patients.
Il- ħin medjan għan- newtropenija kien ta ’ 4 ġranet kemm
The median duration of neutropenia was 6 days and 9 days for autologous and allogeneic patients.
It- tul ta ’ żmien medjan tan- newtropenija kien ta ’ 6 ġranet u 9 ġranet għall- pazjenti awtologużi u pazjenti alloġenejiċi.
6 The incidence of acute graft versus host disease (a-GVHD) data was collected in OMC-BUS-4 study(allogeneic)(n=61).
Mard tas- sistema immuni Id- dejta dwar l- inċidenza ta ’ mard akut tat- trapjant kontra r- riċevitur (a- GVHD) inġabar fi studju (alloġenejiku) (n=61) OMC- BUS- 4.
A total of 11 patients (18%) experienced a-GVHD.
Total ta '11- il pazjent (18%) mardu bil- a- GVHD.
The incidence of a- GVHD grades I-II was 13% (8/ 61), while the incidence of grade III-IV was 5% (3/ 61).
L- inċidenza tal- gradi ta ’ a- GVHD I- II kienu 13% (8/ 61), waqt li l- inċidenza ta ’ grad III- IV kien ta ’ 5% (3/ 61).
Acute GVHD was rated as serious in 3 patients.
GVHD akuta kienet ikklasifikata bħala serja fi 3 pazjenti.
Chronic GVHD (c-GVHD) was reported if serious or the cause of death, and was reported as the cause of death in 3 patients.
GVHD kronika (c- GVHD) kienet irrapportata jekk kienet serja jew kienet il- kawża tal- mewt, u kienet irrapportata bħala l- kawża tal - mewt fi 3 pazjenti.
39% of patients (40/ 103) experienced one or more episodes of infection, of which 83% (33/ 40) were rated as mild or moderate.
Infezzjonijiet u infestazzjonijiet 39% tal- pazjenti (40/ 103) kellhom episodju wieħed jew aktar ta ’ infezzjoni, li minnhom 83% (33/ 40) kienu kklasifikati bħala ħfief jew moderati.
Pneumonia was fatal in 1% (1/ 103) and life-threatening in 3% of patients.
Il- Pnewmonja kienet fatali f’ 1% (1/ 103) u kienet meqjusa bħala theddida għall- ħajja fi 3% tal- pazjenti.
Other infections were considered severe in 3% of patients.
Infezzjonijiet oħra kienu meqjusa bħala severi fi 3% tal- pazjenti.
Fever was reported in 87% of patients and graded as mild/ moderate in 84% and severe in 3%.
Id- deni kien irrapportat f’ 87% tal- pazjenti u kklassifikat bħala ħafif/ moderat f’ 84% u sever fi 3%.
47% of patients experienced chills which were mild/ moderate in 46% and severe in 1%.
47% tal- pazjenti ħassew kesħa li kienet ħafifa/ moderata fi 46% tal- pazjenti u severa f' 1%.
Hepato-biliary disorders:
Mard tal- fwied u tal- marrara:
15% of SAEs involved liver toxicity.
15% tas- SAEs kienu jinvolvu tossiċità fil- fwied.
HVOD is a recognized potential complication of conditioning therapy post-transplant.
HVOD kienet rikonoxxuta bħala komplikazzjoni potenzjali tat- terapija kondizzjonarja ta ’ wara t- trapjant.
Six of 103 patients (6%) experienced HVOD.
Sitta minn 103 pazjent (6%) mardu bil- HVOD.
HVOD occurred in:
HVOD laqtet:
8.2% (5/ 61) allogeneic patients (fatal in 2 patients) and 2.5% (1/ 42) of autologous patients.
8. 2% (5/ 61) tal- pazjenti alloġenejiċi (2 pazjenti kienu fatali) u 2. 5% (1/ 42) tal- pazjenti awtologużi.
Elevated bilirubine (n=3) and elevated AST (n=1) were also observed.
Bilirubin elavat (n=3) u AST elevat (n=1) kienu wkoll osservati.
Two of the above four patients with serious serum hepatotoxicity were among patients with diagnosed HVOD.
Tnejn mill- erba ’ pazjenti t’ hawn fuq li kellhom epatotossiċità tas- serum serja kienu fost dawk il- pazjenti b’ HVOD iddijanjostikata.
One patient experienced a fatal case of acute respiratory distress syndrome with subsequent respiratory failure associated with interstitial pulmonary fibrosis in the Busilvex studies.
Pazjent bata minn każ fatali ta 'sindrom akut ta' periklu respiratorju b' difett sussegwenti respiratorju assoċjat ma ’ fibrożi pulmonari interstitjali fl- istudji tal- Busilvex.
In addition the literature review reports alterations of cornea and lens of the eye with oral busulfan.
Barra minn dan, il- kotba tar- revizjoni irrapportaw tibdil fil- kornea u l- lenti ta ’ l- għajn kaġun tal- busulfan li jittieħed mill- ħalq.
Adverse events in paediatric patients Adverse events information are derived from the clinical study in paediatrics (n=55).
Każijiet avversi f’ pazjenti pedjatriċi Tagħrif dwar każijiet avversi jistgħu jinkisbu mill- istudju kliniku fil- pedjatriċi (n=55).
Serious toxicities involving the hepatic and respiratory systems were considered as expected consequences of the conditioning regimen and transplant process.
Tossiċitajiet serji li kienu jinvolvu s- sistemi epatiċi u respiratorji kienu meqjusa bħala konsegwenzi mistennija tar- regimen kondizzjonarju u l- proċess tat- trapjant.
The incidence of acute graft versus host disease (a-GVHD) data was collected in allogeneic patients (n=28).
Mard tas- sistema immuni Id- dejta dwar l- inċidenza ta ’ mard akut tat- trapjant kontra r- riċevitur (a- GVHD) inġabar minn pazjenti alloġenejiċi (n=28).
A total of 14 patients (50%) experienced a-GVHD.
Total ta '14- il pazjent (50%) mardu bil- a- GVHD.
The incidence of a-GVHD grades I-II was 46.4% (13/ 28), while the incidence of grade III-IV was 3.6% (1/ 28).
L- inċidenza tal- gradi ta ’ a- GVHD I- II kienu 46. 4% (13/ 28), waqt li l- inċidenza ta ’ grad III- IV kien ta ’ 3. 6% (1/ 28).
Chronic GVHD was reported only if it is the cause of death: one patient died 13 months post-transplant.
GVHD kronika kienet irrapportata biss jekk kienet il- kawża tal- mewt: pazjent wieħed miet 13- il xahar wara t- trapjant.
Infections (documented and non documented febrile neutropenia) were experienced in 89% of patients (49/ 55).
Infezzjonijiet u infestazzjonijiet 89% tal- pazjenti (49/ 55) kellhom infezzjonijiet ta ’ (newtropenija febrili dokumentata u mhux dokumentata).
Mild/ moderate fever was reported in 76% of patients.
Deni ħafif/ moderat kien irrapportat f' 76% tal- pazjenti.
Grade 3 elevated transaminases were reported in 24% of patients.
Transaminasi elevati grad 3 kien irrapportat f’ 24% tal- pazjenti.
Veino occlusive disease (VOD) was reported in 15% (4/ 27) and 7% (2/ 28) of the autologous and allogenic transplant respectively.
Mard okklużżiv tal- vini (VOD) kien irrapportat f’ 15% (4/ 27) u 7% (2/ 28) tat- trapjant awtologuż u dak alloġenejiku rispettivament.
VOD observed were neither fatal nor severe and resolved in all cases.
VOD li kienu osservati la kienu fatali u lanqas severi u kienu riżolti kollha.
Within each frequency grouping, adverse events are presented in order of decreasing seriousness.
Reazzjonijiet avversi li kienu rrapportati kemm fl- adulti kif ukoll f’ pazjenti pedjatriċi bħala aktar minn każ iżolat huma elenkati hawn taħt u kienu kklasifikati skond is- sistema tal- klassifika tal- organi u
7 Infections and infestations
7 skond il- frekwenza.
Rhinitis Pharyngitis
Komuni ħafna Rinite Farinġite
Blood and lymphatic system disorders
Disturbi tas- sistema tad- demm u limfatika
Neutropenia Thrombocytopenia Febrile neutropenia Anaemia Pancytopenia
Newtropenija Tromboċitopenija Newtropenja bid - deni Anemija Panċitopenija Newtropenija febrili
Immune system disorders
Disturbi fis- sistema immunitarja
Allergic reaction
Reazzjoni allerġika
Metabolism and nutrition disorders
Disturbi tal- metaboliżmu u nutrizzjoni
Anorexia Hyperglycaemia Hypocalcaemia Hypokalaemia Hypomagnesaemia Hypophosphatemia
Anoreksja Ipergliċemija Ipokalċemija Ipokalemija Ipomagnesemija Ipofosfatemija
Hyponatraemia
Iponatremija
Anxiety Depression Insomnia
Ansjetà Depressjoni Insomnja
Confusion
Konfużjoni
Delirium Nervousness Hallucination Agitation
Delirjum Nervożità Alluċinazzjoni Aġitazzjoni
Headache Dizziness
Uġigħ ta ’ ras Sturdament
Seizure Encephalopathy Cerebral haemorrhage
Aċċessjoni Enċefalopatija Emorraġija ċerebrali
Cardiac disorders
Disturbi fil- qalb
Tachycardia
Takikardija
Arrhythmia Atrial fibrillation Cardiomegaly Pericardial effusion Pericarditis
Arritmija Fibrillazzjoni atrijali Kardjomegali Effużjoni perikardjali Perikardite
Ventricular extrasystoles Bradycardia
Ekstrasistoli ventrikulari Bradicardija
Vascular disorders
Disturbi vaskulari
Hypertension Hypotension Thrombosis Vasodilatation
Ipertensjoni Ipotensjoni Vasodilatatazzjoni Trombożi
Femoral artery thrombosis Capillary leak syndrome
Trombożi ta ’ l- arterja femorali Sindrom ta ’ nixxija kapillari
Respiratory thoracic and mediastinal disorders
Disturbi respiratorji, toraċiċi u medjastinali
Dyspnoea Epistaxis Cough Hiccup
Dispneja Epistassi Sogħla Sulluzzu
Hyperventilation Respiratory failure Alveolar haemorrhages Asthma Atelectasis Pleural effusion
Iperventilazzjoni Difett respiratorju Emorraġiji Alveolari Ażma Atelektasi Effużżjoni Plewrali
Hypoxia
Ipossja
8 Hepato-biliary disorders
8 Disturbi gastrointestinali
Skin and subcutaneous tissue disorders
Stomatite Dijarea Dardir Irrimettar Dispepsja Uġigħ fl- istonku Axxite Stitikezza Skomfort anali
Rash Pruritis Alopecia
Ilejus Ematemesi Esofagite
Skin desquamation Erythema Pigmentation disorder
Emorraġija gastro - intestinali
Musculoskeletal and connective tissue disorders
Disturbi fil- fwied u fil- marrara:
Myalgia Back pain
Epatomegalija Suffejra
Arthralgia Renal and urinary disorders
Disturbi tal- ġilda u tat- tessuti ta ’ taħt il- ġilda
Dysuria Oligurea
Raxx Prurite Alopeċija
Haematuria Moderate renal insufficiency
Deskwamazzjoni tal- ġilda Eritema Mard tal - pigmentazzjoni Tqaxxir tal- ġilda
General disorders and administration site conditions
Disturbi muskolu- skeltrali u tat - tessut konnettiv
Asthenia Chills Fever Chest pain
Majalġja Uġigħ fid- dahar Artralġja
Oedema Oedema general
Disturbi fil- kliewi u fis- sistema urinarja
Pain
Disurija Oligureja
Pain or inflammation at injection site
Ematurija Insuffiċjenza moderata tal- kliewi
Mucositis Investigations
Disturbi ġenerali u kondizzjonijiet Astenja ta 'mnejn jingħata
Transaminases increased Bilirubin increased GGT increased Alkaline phosphatases increased Weight increased
Kesħa Deni Uġigħ fis- sider Edema Edema ġenerali Uġigħ Uġigħ jew infjammazzjoni fis- sit ta ’ l- injezzjoni Mukositi
Bun increase Decrease ejection fraction
Investigazzjonijiet
Abnormal breath sounds Creatinine elevated
Żieda fil- BUN Tnaqqis fil- frazzjoni ta ’ tfigħ ‘ il- barra
The principal toxic effect is profound myeloablation and pancytopenia but the central nervous system, liver, lungs, and gastrointestinal tract may also be affected.
L- effett prinċipali tossiku hu l- panċitopenija u mijeloablazzjoni profonda imma s- sistema ċentrali nervuża, il- fwied, il- pulmuni u l- kanal gastro- intestinali għandhom mnejn ikunu milquta wkoll.
There is no known antidote to Busilvex other than haematopoietic progenitor cell transplantation.
Jekk ma jkunx hemm it- trapjant taċ- ċelluli ematopojetiċi proġenitriċi, id- dożaġġ irrakkomandat ta ’ Busilvex
In the absence of haematopoietic progenitor cell transplantation, the recommended dosage of Busilvex would constitute an overdose of busulfan.
9 jikkonstitwixxi doża eċċessiva ta ’ busulfan.
The haematologic status should be closely monitored and vigorous supportive measures instituted as medically indicated.
L- istatus ematoloġiku għandu jkun mgħasses bir- reqqa u għandu jkun hemm miżuri vigurużi ta ’ appoġġ hekk kif inhu indikat medikalment.
There have been two reports that busulfan is dialyzable, thus dialysis should be considered in the case of an overdose.
Kien hemm żewġ rapporti li busulfan hu dijaliżabbli, b' hekk id- dijalisi għandu jkun meqjus bħala każ ta 'doża eċċessiva.
Since, busulfan is metabolized through conjugation with glutathione, administration of glutathione might be considered.
Ġaladarba, il- busulfan hu metabolizzat permezz tal- konjugazzjoni mal- glutatijon, l- għoti tal- glutatijon għandu mnejn ikun investigat.
9 It must be considered that overdose of Busilvex will also increase exposure to DMA.
Wieħed irid jiftakar li doża eċċessiva ta ’ Busilvex ser iżżied ukoll l- esponiment għad- DMA.
In human the principal toxic effects were hepatotoxicity and central nervous system (CNS) effects.
Fil- każ tal- bnedmin l- effetti prinċipali tossiċi kienu epatotossiċità u l- effetti tas- sistema ċentrali nervuża.
CNS changes precede any of the more severe side effects.
It - tibdil ta ’ CNS jiġu qabel kwalunkwe effetti severi oħra.
No specific antidote for DMA overdose is known.
S’ issa m’ hemm l- ebda antidot għal doża eċċessiva ta ’ DMA.
In case of overdose, management would include general supportive care.
Jekk tingħata doża eċċessiva, l- immaniġġjar għandu jinkludu trattament ġenerali ta 'appoġġ.
5 PHARMACOLOGICAL PROPERTIES
TAGĦRIF FARMAKOLOĠIKU
Alkyl sulfonates, ATC code:
Sulfonati alkili, ATC code:
L01AB01.
L01AB01 Kodiċi ATC:
Busulfan is a potent cytotoxic agent and a bifunctional alkylating agent.
Busulfan hu aġent qawwi ċitotossiku u aġent alkilatinku bifunzjonali.
In aqueous media, release of the methanesulphonate groups produces carbonium ions which can alkylate DNA, thought to be an important biological mechanism for its cytotoxic effect.
F’ medja milwiema, il- ħruġ tal- gruppi metanesulfonati jipproduċi ijoni tal- karbonjum li jistgħu idaħħlu alkil fid- DNA, li hu maħsub li hu mekkaniżmu importanti bijoloġiku minħabba l- effett tiegħu ċitotossiku.
Clinical trials in adults Documentation of the safety and efficacy of Busilvex in combination with cyclophosphamide in the BuCy2 regimen prior to conventional allogeneic and/ or autologous HPCT derive from two clinical trials (OMC-BUS-4 and OMC-BUS-3).
Studji kliniċi fl- adulti Id- dokumentazzjoni tas- sigurtà u l- effikaċja tal- Busilvex flimkien mal- ċiklofosfamid fir- regimen BuCy2 qabel ll- HPCT alloġenejiku konvenzjonali u/ jew awtologuż huma bbażati fuq żewġ studji kliniċi (OMC- BUS- 4 u OMC- BUS- 3).
Two prospective, single arm, open-label, uncontrolled phase II studies were conducted in patients with haematological disease, the majority of whom had advanced disease.
Saru żewġ studji prospettivi, driegħ waħda, miftuħin, mhux ikkontrollati fażi II fuq pazjenti li jbatu minn marda ematoloġikali, u rriżulta li l- biċċa l- kbira tagħhom kienu jinsabu fl- istat avvanz tal- marda.
Diseases included were acute leukemia past first remission, in first or subsequent relapse, in first remission (high risk), or induction failures; chronic melogenous leukemia in chronic or advanced phase; primary refractory or resistant relapsed Hodgkin’ s disease or non-Hodgkin’ s lymphoma, and myelodysplastic syndrome.
Il- mard kien jinkludi l- lewkimja akuta li għaddiet l- ewwel stadju ta ’ remissjoni, fl- ewwel rikaduta jew dik sussegwenti, fl- ewwel remissjoni (riskju għoli), jew fallimenti induttivi; il- lewkimja melogenuża kronika fil- fażi kronika jew avvanzata, il- marda primarja refraktorja jew reżistenti reċidivanti ta ’ Hodgkin jew limfoma li mhix ta ’ Hodgkin u sindrom mijelodisplastiku.
Patients received doses of 0.8 mg/ kg busulfan every 6 hours infusion for a total 16 doses followed by cyclophosphamide at 60 mg/ kg once per day for two days (BuCy2 regimen).
Pazjenti li ngħataw dożi ta ’ 0. 8 mg/ kg ta ’ busulfan f’ infużjoni kull 6 sigħat għal total ta '16- il doża u wara ngħataw ċ- ċiklofosfamid f’ doża ta ’ 60 mg/ kg darba kuljum għal jumejn (BuCy2 regimen).
The primary efficacy parameters in these studies were myeloablation, engraftment, relapse, and survival.
Il- parametri effikaċi primarji f’ dawn l- istudji kienu l- mijeloablazzjoni, tilqim, rikaduta, baqgħu ħajjin.
In both studies, all patients received a 16/ 16 dose regimen of Busilvex.
Fiż- żewġ studji, il- pazjenti kollha rċevew 16/ 16 regimen ta ’ doża tal- Busilvex.
No patients were discontinued from treatment due to adverse reactions related to Busilvex.
Ma kien hemm l- ebda pazjent li twaqqaflu t- trattament minħabba reazzjonijiet avversi marbuta mal- Busilvex.
All patients experienced a profound myelosuppression.
Il- pazjenti kollha kellhom mijelosuppressjoni profonda.
The time to Absolute Neutrophil Count (ANC) greater than 0.5x109 / l was 13 days (range 9-29 days) in allogenic patients (OMC-BUS 4), and 10 days (range 8-19 days) in autologous patients (OMC-BUS 3).
Il- ħin għall- Għadd Asolut Newtrofil (ANC) akbar minn 0. 5 x 109/ 1 kien 13- il ġurnata (minn 9 sa 29 ġurnata) f’ pazjenti alloġenejiċi (OMC- BUS 4), u 10 ġranet (minn 8 sa 19- il ġurnata) f’ pazjenti awtologużi (OMC- BUS 3).
All evaluable patients engrafted.
Il- pazjenti kollha li setgħu jiġu evalwati ġew imlaqqma.
There is no primary nor secondary graft rejection.
Ma kienx hemm rifjut primarju jew sekondarju tat- tilqim.
Overall mortality and non- relapse mortality at more than 100 days post-transplant was (8/ 61) 13% and (6/ 61) 10% in allotransplanted patients, respectively.
Kollox ma 'kollox, il- mortalità u l- mortalità fejn ma kienx hemm rikaduta ta ’ aktar minn 100 ġurnata wara t - trapjant kien (8/ 61) 13% u (6/ 61) 10% f’ pazjenti allotrapjantati, rispettivament.
During the same period there was no death in autologous recipients.
Matul l- istess perijodu ma kien hemm l- ebda mewt f' riċevuturi awtologużi.
Clinical trials in paediatric patients Documentation of the safety and efficacy of Busilvex in combination with cyclophosphamide in the BuCy4 or with melphalan in the BuMel regimen prior to conventional allogeneic and/ or autologous HPCT derives from clinical trial F60002 IN 101 G0.
Id- dokumentazzjoni dwar is- sigurtà u l- effikaċja tal- Busilvex flimkien mas- ċiklofosfamid fir- regimen BuCy4 jew mal- melfalan fir- regimen BuMel qabel l- HPCT konvenzjonali alloġenejiku u/ jew awtologuż irriżultaw minn studju kliniku F60002 IN 101 G0.
The patients received the dosing mentioned in section 4.2.
Il- pazjenti rċevew id- dożaġġ imsemmi fis- sezzjoni 4. 2.
All patients experienced a profound myelosuppression.
10 Il- pazjenti kollha kellhom mijelosuppressjoni profonda.
The time to Absolute Neutrophil Count (ANC) greater than 0.5x109/ l was 21 days (range 12-47 days) in allogenic patients, and 11 days (range 10-15 days) in autologous patients.
Il- ħin għall- Għadd Assolut Newtrofil (ANC) akbar minn 0. 5x109/ 1 kien 21- il ġurnata (minn 12 sa 47- il ġurnata) f’ pazjenti alloġenejiċi, u 11- il ġurnata (minn 10 sa 15- il ġurnata) f’ pazjenti awtologużi.
All children engrafted.
It- tfal kollha tlaqqmu.
There is no primary or secondary graft rejection.
Ma kienx hemm rifjut primarju jew sekondarju tat- tilqim.
93% of allogeneic patients showed complete chimerism.
93% tal- pazjenti alloġenejiċi wrew kimeriżmu komplet.
There was no regimen-related death through the first 100-day post-transplant and up to one year post-transplant.
Ma kien hemm l- ebda mewt relattata mar- regimen matul l- ewwel 100 ġurnata wara t- trapjant u sa sena wara t - trapjant.
10 The pharmacokinetics of Busilvex has been investigated.
Il- farmakokinetiċi tal- Busilvex kienu investigati.
The information presented on metabolism and elimination is based on oral busulfan.
It- tagħrif li kien ippreżentat dwar il- metaboliżmu u t- tkeċċija hu bbażat fuq il- busulfan mogħti mill- ħalq.
Pharmacokinetics in adults Absorption The pharmacokinetics of intravenous busulfan was studied in 124 evaluable patients following a 2- hour intravenous infusion for a total of 16 doses over four days.
Il- farmakokinetiċi ta ’ busulfan mogħti ġol- vini kien studjat f’ 124 pazjent evalwabbli wara infużjoni minn ġol- vina ta ’ 2 sigħat għal total ta ’ 16- il doża fuq firxa ta ’ erbat ijiem.
Immediate and complete availability of the dose is obtained after intravenous infusion of busulfan.
Id- disponibilità immedjata u kompleta tad- doża inkisbet wara l- infużjoni minn ġol- ġilda tal- busulfan.
Similar blood exposure was observed when comparing plasma concentrations in adult patients receiving oral and intravenous busulfan at 1 mg/ kg and 0.8 mg/ kg respectively.
Esponiment simili għad - demm kien osservat meta tqabblu konċentrazzjonijiet tal- plażma f' pazjenti adulti li rċevew busulfan mogħti mill- ħalq u mogħti ġol- vini f’ 1 mg/ kg u 0. 8 mg/ kg rispetttivament.
Low inter (CV=21%) and intra (CV=12%) patient variability on busulfan exposure was demonstrated through a population pharmacokinetic analysis, performed on 102 patients.
Varjabilità baxxa inter (CV=21%) u intra (CV=12%) fil- pazjenti dwar esponiment għal- busulfan intwera permezz ta ’ analiżi farmakokinetika tal- popolazzjoni, li sar fuq 102 pazjent.
Distribution Terminal volume of distribution Vz ranged between 0.62 and 0.85 l/ kg.
Il- volum terminali tad- distribuzzjoni Vz kienet bejn 0. 62 u 0. 85 l/ kg.
Busulfan concentrations in the cerebrospinal fluid are comparable to those in plasma although these concentrations are probably insufficient for anti-neoplastic activity.
Il- konċentrazzjonijiet tal- Busulfan fil- fluwidu ċerebrospinali hu paragonabbli ma ’ dawk fil- plażma għalkemm dawn il- konċentrazzjonijiet mhumiex probabbilment biżżejjed fil- każ ta 'attività anti - nejoplastika.
Reversible binding to plasma proteins was around 7% while irreversible binding, primarily to albumin, was about 32%.
Irbit riversibbli ma ’ proteini tal- plażmatiċi kien madwar 7% waqt l- irbit irreversibbli, primarjament ma ’ l- albumin, kien madwar 32%.
Metabolism Busulfan is metabolised mainly through conjugation with glutathione (spontaneous and glutathione-S- transferase mediated).
Busulfan hu prinċipalment metaboliżżat permezz tal- konjugazzjoni mal- glutatijon (spontanju u medjat mill- glutatijon- S- transferas).
The glutathione conjugate is then further metabolised in the liver by oxidation.
Il- glutatijonn konjugat hu metaboliżżat aktar fil- fwied permezz tal -- ossidazjoni.
None of the metabolites is thought to contribute significantly to either efficacy or toxicity.
L- ebda metabolit mhu maħsub li jikkontribwixxi b’ mod sinifikanti għall- effikaċja jew it- tossiċità.
Elimination Total clearance in plasma ranged 2.25 - 2.74 ml/ minute/ kg.
It- tneħħija totali fil- plażma kienet minn 2. 25 sa 2. 74 ml/ minuta/ kg.
The terminal half-life ranged from 2.8 to 3.9 hours.
In- nofs ħajja terminali kienet minn 2. 8 sa 3. 9 sigħat.
Approximately 30% of the administered dose is excreted into the urine over 48 hours with 1% as unchanged busulfan.
Madwar 30% tad- doża mogħtija hi mkeċċija fl- awrina fuq firxa ta '48 sigħat b' 1% bħala busulfan mhux mibdul.
Elimination in faeces is negligible.
L- eliminazzjoni fil- ħara hi negliġibbli.
Irreversible protein binding may explain the incomplete recovery.
L- irbit irreversibbli tal- proteini għandu mnejn jispjega għala dak li jkun ma jfiqx għal kollox.
Contribution of long-lasting metabolites is not excluded.
Il- kontribuzzjoni għall- metaboliti li jdumu ħafna mhix eskluża.
Pharmacokinetic linearity The dose proportional increase of busulfan exposure was demonstrated following intravenous busulfan up to 1 mg/ kg.
Il- linerjarità farmakokinetika Iż- żieda ta ’ l- esponiment għall- busulfan huwa proporzjonali għad- doża u dan kien muri wara l- għoti tal- busulfan minn ġol- vina sa 1 mg/ kg.
Pharmacokinetic/ pharmacodynamic relationships The literature on busulfan suggests a therapeutic window between 900 and 1500 µMol. minute for AUC.
Relazzjonijiet farmakokinetiċi/ farmakodinamiċi Il- letteratura dwar il- busulfan tissuġġerixxi li hemm tieqa terapewtika bejn 900 u 1500 µMol. minuta AUC.
During clinical trials with intravenous busulfan, 90% of patients AUCs were below the upper AUC limit (1500 µMol. minute) and at least 80% were within the targeted therapeutic window (900- 1500 µMol. minute).
Matul l- istudji kliniċi bil- busulfan mogħti ġol- vini, 90% ta ’ l- AUCs tal- pazjenti kienu aktar baxxi mill- ogħla limitu AUC (1500 µMol. minuta) u ta ’ l- anqas 80% kienu fi ħdan it- tieqa terapewtika mmirata (minn 900 sa 1500 µMol. minuta).
Special populations The effects of renal dysfunction on intravenous. busulfan disposition have not been assessed.
Popolazzjonijiet speċjali L- effetti ta ’ l- anormalità tal- kliewi fuq id- disponibilità tal- busulfan mogħti ġol- vini li jingħata minn ġol- vina ma ġewx assessjati.
The effects of hepatic dysfunction on intravenous busulfan disposition have not been assessed.
11 L- effetti ta ’ l- anormalità epatika fuq id- disponibilità tal- busulfan li jingħata ġol- vini ma ġewx assessjati.
Nevertheless the risk of liver toxicity may be increased in this population.
Madankollu r- riskju ta ’ tossiċità tal- fwied għandu mnejn jiżdied f’ din il- popolazzjoni.
No age effect on busulfan clearance was evidenced from available intravenous busulfan data in patients over 60 years.
Skond id- dejta li jeżistu dwar il- busulfan li jingħata ġol- vini lill- pazjent li għandhom iżjed minn 60 sena, ma jidhirx li l- età għandha x’ taqsam mat- tkeċċija tal- busulfan.
Pharmacokinetics in paediatric patients A continuous variation of clearance ranging from 2.49 to 3.92 ml/ minute/ kg has been established in children from < 6 months up to 17 years old.
Farmakokinetiċi f’ pazjenti pedjatriċi Kien hemm varjazzjoni kontinwa ta 'tkeċċija minn 2. 49 sa 3. 92 ml/ minuta/ kg fi tfal minn < 6 xhur sa 17- il sena.
The terminal half life ranged from 2.26 to 2.52 h.
In- nofs ħajja terminali kienet mifruxa minn 2. 26 sa 2. 52 h.
The dosing recommended in section 4.2. allows to achieve a similar AUC whatever the children's age, the targeted range of AUCs being the one used for adults.
Id- dożaġġ rrakkomandat f’ sezzjoni 4. 2 jippermetti li jintlaħaq AUC simili hu x’ inhu l- età tat- tfal, il- firxa mmirata ta ’ l- AUCs hi dik użata għall- adulti.
Inter and intra patient variabilities in plasma exposure were lower than 20% and 10%, respectively.
Varjabilitajiet inter u intra pazjent fl- esponiment għall- plażma kienu aktar baxxi minn 20% u 10% rispettivament.
11 Pharmacokinetic/ pharmacodynamic relationships:
Relazzjonijiet farmakokinetiċi/ farmakodinamiċi:
The successful engraftment achieved in all patients during phase II trials suggests the appropriateness of the targeted AUCs.
It- trapjant irnexxa fil- każ tal- pazjenti kollha matul l- istudji tal- fażi II u dan jissuġġerixxi l- validità ta 'l- AUCs immirati.
Occurrence of VOD was not related to overexposure.
Meta kien hemm il- VOD dan ma kienx marbut ma ’ esponiment eċċessiv.
PK/ PD relationship was observed between stomatitis and AUCs in autologous patients and between bilirubin increase and AUCs in a combined autologous and allogeneic patient analysis.
Ir - relazzjoni PK/ PD kien osservat bejn l- istomatite u l- AUCs f’ pazjenti awtologużi u bejn żjieda fil - bilirubin u l- AUCs f’ analiżi magħdud ta ’ pazjenti li għamlu trapjant awtologuż u alloġenejiku.
Busulfan is mutagenic and clastogenic.
Busulfan hu mutaġeniku u klastoġeniku.
Busulfan was mutagenic in Salmonella typhimurium, Drosophila melanogaster and barley.
Busulfan kien mutaġeniku f’ Salmonella typhimurium, Drosophila melanogaster u x- xgħir.
Busulfan induced chromosomal aberrations in vitro (rodent and human cell) and in vivo (rodents and humans).
Busulfan ikkaġuna aberrazzjonijiet kromosomali in vitro (f’ ċellula ta ’ annimali gerriema u umana) u in vivo (annimali gerriema u bnedmin).
Various chromosome aberrations have been observed in cells from patients receiving oral busulfan.
Aberrazzjonijiet kromosomali varji kienu osservati f’ ċelluli ta ’ pazjenti li kienu qegħdin jingħataw il- busulfan mill - ħalq.
Busulfan belongs to a class of substances which are potentially carcinogenic based on their mechanism of action.
Busulfan jappartjeni għal dik il- klassi ta ’ sostanzi li huma potenzjalment karċinoġeniċi skond il- mekkaniżmu tagħhom ta ’ l- azzjoni.
On the basis of human data, busulfan has been classified by the IARC as a human carcinogen.
Skond tagħrif dwar il- bnedmin, busulfan ġie kklasifikat mill - IARC bħala karċinoġen uman.
WHO has concluded that there is a causal relationship between busulfan exposure and cancer.
Il- WHO ikkonkluda li hemm relazzjoni kawżali bejn l- esponiment għall- busulfan u l- kanċer.
The available data in animals support the carcinogenic potential of busulfan.
It- tagħrif li għandna dwar l- annimali jappoġġja l- potenzjal karċinoġeniku ta ’ busulfan.
Intravenous administration of busulfan to mice significantly increased the incidences of thymic and ovarian tumours.
L- għoti minn ġol- vina tal- busulfan lill- ġrieden żied b’ mod sinifikanti l- inċidenzi tat - tumuri timiċi u dawk ovarjani.
Busulfan is teratogen in rats, mice and rabbits.
Busulfan hu teratoġeniku fil- firien, ġrieden u l- fniek.
Malformations and anomalies included significant alterations in the musculoskeletal system, body weight gain, and size.
Il- malformazzjonijiet u l- anomaliji kienu jinkludu tibdil sinifikanti fis- sistema musko- skeletali, żjieda fil- piż tal- ġisem, u daqs.
In pregnant rats, busulfan produced sterility in both male and female offspring due to the absence of germinal cells in testes and ovaries.
Fil- każ ta ’ firien tqal, il- busulfan ikkaġuna sterilità kemm fil- frieħ maskili u dawk feminili minħabba n- nuqqas ta 'ċelluli ġerminali fit- testes u l- ovarji.
Busulfan was shown to cause sterility in rodents.
Kien stabbilit li l- Busulfan jikkaġuna sterilità fil- firien.
Busulfan depleted oocytes of female rats, and induced sterility in male rats and hamster.
Il - Busulfan battal l- ooċiti tal- firien nisa, u għamel il- firien u l- ħamster irġiel sterili.
Repeated doses of DMA produced signs of liver toxicity, the first being increases in serum clinical enzymes followed by histopatological changes in the hepatocytes.
Dożi ripetuti ta ’ DMA ipproduċew sinjali ta ’ tossiċità fil- fwied, l- ewwel kien hemm żjieda fl- enżimi klinikali tas- serum u wara kien hemm tibdil istopatoloġiku fl- epatoċiti.
Higher doses can produce hepatic necrosis and liver damage can be seen following single high exposures.
Dożi ogħla jistgħu jipproduċu nekrożi epatika u wieħed jista ’ jara l- ħsara fil- fwied wara esponimenti waħdanin b’ doża għolja.
DMA is teratogenic in rats.
Id- DMA hi teratoġenika fil- firien.
Doses of 400 mg/ kg/ day DMA administered during organogenesis caused significant developmental anomalies.
Dożi ta ’ 400 mg/ kg/ kuljum ta ’ DMA mogħtija matul l- organuġenesi ikkaġunaw anomaliji sinifikanti ta ’ l- iżvilupp.
The malformations included serious heart and/ or major vessels anomalies: a common truncus arteriosis and no ductus arteriosis, coarctation of the pulmonary trunk and the pulmonary arteries, intraventricular defects of the heart.
Il- malformazzjonijiet jinkludu anomaliji serji fil- qalb u/ jew fil- vini/ arterji maġġuri: arterjosi komuni taz- zokk tal- ġisem u l- ebda arterjosi tal- kanal, koarktazjoni taz- zokk pulmonari u l- arteriji pulmonari, difetti intraventrikulari tal- qalb.
Other frequent anomalies included cleft palate, anasarca and skeletal anomalies of the vertebrae and ribs.
Anomaliji oħra frekwenti jinkludu palat mixquq, anasarka, anomaliji skeletali tal- vertibri u tal- kustilji.
DMA decreases fertility in male and female rodents.
Id- DMA inaqqas il- fertilità ta ’ l- annimali gerriema rġiel u nisa.
A single s. c. dose of 2.2 g/ kg administered on gestation day 4 terminated pregnancy in 100% of tested hamster.
Doża waħda s. c. ta ’ 2. 2 g/ kg mogħtija fir- raba 'ġurnata tat- tqala ikkawżat l- abort f’ 100% tal- ħamsters li ġew ittestjati.
In rats, a DMA daily dose of 450 mg/ kg given to rats for nine days caused inactive spermatogenesis.
Fil- firien, doża ta ’ kuljum ta ’ DMA ta ’ 450 mg/ kg li ngħatat lil firien għal disgħat ijiem ikkaġunat spermatoġenesi inattiva.
6 PHARMACEUTICAL PARTICULARS
TAGĦRIF FARMAĊEWTIKU
Dimethylacetamide Macrogol 400.
12 Dimethylacetamide Makrogol 400.
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.
Minħabba li ma sarux studji li juru liema huma l- prodotti li ma jaqblux miegħu, dan il- prodott mediċinali m’ għandux jitħallat ma ’ prodotti mediċinali oħra ħlief dawk imsemmija f ’ sezzjoni 6. 6.
Do not use polycarbonate syringes with Busilvex.
Tużax is- sirinġi polikarbonati mal- Busilvex.
2 years 12 Diluted solution
Kunjetti: sentejn Soluzzjoni maħlula
Chemical and physical in-use stability after dilution in glucose 5% or sodium chloride 9 mg/ ml (0.9%) solution for injection has been demonstrated for:
Kien hemm stabilità kemikali u fiżika meta tintuża u wara lis- sustanza kienet miżjuda bl- ilma f’ soluzzjoni tal- glukows 5% jew f’ soluzzjoni ta ’ klorid tas- sodju 9 mg/ ml (0. 9%) għall- injezzjoni:
- 8 hours (including infusion time) after dilution when stored at 20 °C ± 5 °C
- 8 sigħat (inkluż il- ħin ta ’ l- infużjoni) wara lis- sustanza kienet miżjuda bl- ilma meta tkun,
- 12 hours after dilution when stored at 2 °C-8 °C followed by 3 hours stored at 20 °C ± 5 °C
- 12- il siegħa wara lis– sustanza tkun miżjuda bl- ilma meta tkun maħżuna f’ temperatura minn 2°C
(including infusion time).
sa 8°C u wara tkun maħżuna għal 3 sigħat f’ 20°C ± 5°C (inkluż il- ħin ta ’ l- infużjoni).
From a microbiological point of view, the product should be used immediately after dilution.
Mill- lant mikrobijoloġikali, il- prodott għandu jintuża immedjatament wara li jkun miżjud bl- ilma.
If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than the above mentioned conditions when dilution has taken place in controlled and validated aseptic conditions.
6. 4 Prekawzjonijiet speċjali għall- ħażna
Storein a refrigerator (2 ° C-8 °C).
Aħżen fi friġġ (2°C- 8°C).
Do not freeze the diluted solution.
Tagħmilx fil- friża soluzzjoni dilwita.
For storage conditions of the diluted medicinal product see section 6.3
Għall- kundizzjonijiet ta ’ ħżin tal- prodott mediċinali dilwit ara sezzjoni 6. 3.
10 ml of concentrate for solution for infusion in clear glass vials (type I) with a butyl rubber stopper covered by a purple flip-off aluminium seal cap.
10 ml ta ’ konċentrat għal soluzzjoni għall- infużjoni f’ kunjetti tal- ħġieġ ċari (tip I) b’ tapp tal- gomma tal- butyl mgħottijin b’ għatu vjola li jinfetaħ b’ daqqa ta ’ saba ’ ssiġillat ta ’ l- aluminju.
Pack size:
Daqs tal- pakkett:
8 vials per box
8 kunjetti kull kaxxa
6.6 Special precautions for disposal and other handling
6. 6 Prekawzjonijiet speċjali għar- rimi u mmaniġġjar ieħor
Preparation of Busilvex Procedures for proper handling and disposal of anticancer medicinal products should be considered.
Il- proċeduri għall- immaniġġjar sew u r- rimi ta ’ prodotti mediċinali antikanċer għandhom ikunu meqjusa.
All transfer procedures require strict adherence to aseptic techniques, preferably employing a vertical laminar flow safety hood
Il- proċeduri kollha ta ’ trasferiment jirrikjedu osservanza stretta ta 'tekniċi aseptiċi, preferabbilment barnuża tas- sigurtà vertikali bi fluss laminari.
As with other cytotoxic compounds, caution should be exercised in handling and preparing the Busilvex solution:
L- istess bħal fil- każ ta 'taħlit ieħor ċitotossiku, wieħed għandu joqgħod attent meta jkun qed jimmaniġġja u jipprepara t- taħlita Busilvex:
- The use of gloves and protective clothing is recommended.
- L- użu ta ’ l- ingwanti u ħwejjeġ protettivi hu rrakkomandat.
- If Busilvex or diluted Busilvex solution contacts the skin or mucosa, wash them thoroughly with
- Jekk il- Busilvex jew it- taħlita Busilvex miżjuda bl- ilma tmiss mal- ġilda jew il- mukoża, aħsilhom
water immediately.
sewwa bl- ilma immedjatament.
Calculation of the quantity of Busilvex to be diluted and of the diluent
Kalkulazzjoni tal- kwantità ta ’ Busilvex li għandha tkun miżjuda bl- ilma u tad- dilwent.
Busilvex must be diluted prior to use with either sodium chloride 9 mg/ ml (0.9%) solution for injection or glucose solution for injection 5%.
Busilvex għandu jkun miżjud bl- ilma qabel ma jintuża jew b’ soluzzjoni tal- klorid tas- sodju ta ’ 9 mg/ ml (0. 9%) għall- injezzjoni jew soluzzjoni tal- glukows ta ’ 5% għall- injezzjoni.
The quantity of the diluent must be 10 times the volume of Busilvex ensuring the final concentration of busulfan remains at approximately 0.5 mg/ ml.
Il- kwantità ta ’ dilwent irid ikun 10 darbiet il- volum tal- Busilvex u wieħed irid jara li l- konċentrazzjoni finali tal- busulfan tibqa 'madwar 0. 5 mg/ ml.
By example:
Pereżempju:
The amount of Busilvex and diluent to be administered would be calculated as follows: for a patient with a Y kg body weight:
L- ammont ta ’ Busilvex u d- dilwent li ser jingħata għandu jkun ikkalkulat kif ġej: għal pazjent li għandu piż tal- ġisem Y kg:
Quantity of Busilvex:
• Kwantità ta ’ Busilvex:
Y (kg) x D (mg/kg) = A ml of Busilvex to be diluted
Y (kg) x D (mg/ kg) = A ml ta ’ Busilvex li għandu jkun miżjud bl- ilma 6 (mg/ ml)
Y: body weight of the patient in kg D: dose of Busilvex (see section 4.2)
Y: piż tal- ġisem tal- pazjent f’ kg D: doża ta ’ Busilvex (ara sezzjoni 4. 2) • Kwantità ta ’ dilwent:
(A ml Busilvex) x (10) = B ml of diluent
(A ml ta ’ Busilvex) x (10) = B ml tad- dilwent
To prepare the final solution for infusion, add (A) ml of Busilvex to (B) ml of diluent (sodium chloride 9 mg/ml (0.9%) solution for injection or glucose solution for injection 5%)
Biex tipprepara s- soluzzjoni finali għall- infużjoni, żid (A) ml ta 'Busilvex ma' (B) ml tad- dilwent (soluzzjoni ta ’ klorid tas- sodju ta ’ 9 mg/ ml (0. 9%) għall- injezzjoni jew is- soluzzjoni tal- glukows għall- injezzjoni ta ’ 5%)
Preparation of the solution for infusion
Preparazzjoni tas- soluzzjoni għall- infużjoni
• Busilvex must be prepared by a healthcare professional using sterile transfer techniques.Using a non polycarbonate syringe fitted with a needle:
Uża sirinġa polikarbonata iffittjata b’ labra:
- the calculated volume of Busilvex must be removed from the vial.
- l- volum ikkalkulat tal- Busilvex għandu jitneħħa mill- kunjett.
- the contents of the syringe must be dispensed into an intravenous bag (or syringe) which
- is- sustanza tas- siringa għandu jiġi żvojtat f' borża li tintuża għal ġol- vini (jew siringa) li diġà
already contains the calculated amount of the selected diluent.
fiha l- ammont ikkalkulat tad- dilwent magħżul.
Busilvex must always be added to the diluent, not the diluent to Busilvex.
Busilvex għandu dejjem jiżdied mad- dilwent, mhux id- dilwent ma 'Busilvex.
Busilvex must not be put into an intravenous bag that does not contain sodium chloride 9 mg/ml (0.9%) solution for injection or glucose solution for injection 5%.
Busilvex m’ għandux jitpoġġa ġo borza li tintuża għal ġol- vini li ma fihiex soluzzjoni ta ’ klorid tas- sodju ta ’ 9 mg/ ml (0. 9%) għall- injezzjoni jew soluzzjoni ta ’ glukows ta ’ 5% għall- injezzjoni.
• The diluted solution must be mixed thoroughly by inverting several times
• Is- soluzzjoni dilwita għandha tiġi mħallta sewwa billi taqleb ta ’ taħt fuq diversi drabi.
After dilution, 1 ml of solution for infusion contains 0.5 mg of busulfan
Wara li tkun miżjuda bl- ilma, 1 ml tas- soluzzjoni għall- infużjoni fiha 0. 5 mg ta ’ busulfan.
Diluted Busilvex is a clear colourless solution
Meta l- Busilvex ikun miżjud bl- ilma, dan ikun soluzzjoni ċara bla kulur.
Instructions for use Prior to and following each infusion, flush the indwelling catheter line with approximately 5 ml of sodium chloride 9 mg/ml (0.9%) solution for injection or glucose (5%) solution for injection.
Qabel u wara kull infużjoni, ifflaxxja il- linja tal- kateter li suppost jinżamm fil- pazjent għal żmien twil b’ madwar 5 ml ta ’ soluzzjoni ta ’ klorid tas- sodju ta ’ 9 mg/ ml (0. 9%) għall- injezzjoni jew soluzzjoni tal- glukows (5%) għall- injezzjoni.
The residual medicinal product must not be flushed in the administration tubing as rapid infusion of Busilvex has not been tested and is not recommended.
Il- prodott mediċinali m’ għandux jiġi fflaxxjat fit- tubi ta ’ l- amministrazzjoni għax qatt ma sar test ta ’ l - infużjoni rapida tal- Busilvex u dan mhux irrakkomandat.
The entire prescribed Busilvex dose should be delivered over two hours.
14 Id- doża kollha preskritta tal- Busilvex għandha tingħata fuq firxa ta ’ sagħtejn.
Small volumes may be administered over 2 hours using electric syringes.
Volumi żgħar għandhom mnejn jingħataw fuq firxa ta ’ 2 sigħat permezz ta ’ l- użu ta ’ sirinġi ta ’ l- elettriku.
In this case infusion sets with minimal priming space should be used (i.e 0.3-0.6 ml), primed with medicinal product solution prior to beginning the actual Busilvex infusion and then flushed with sodium chloride 9 mg/ml (0.9%) solution for injection or glucose (5%) solution for injection.
F' dan il- każ infużjoni issettjata bi spazju minimali pprajmjat għandha tintuża (i. e. 0. 3- 0. 6 ml), ippramjat b' soluzzjoni ta 'droga qabel il- bidu ta ’ l- infużjoni attwali tal- Busilvex u mbagħad tkun ifflaxxjata b’ soluzzjoni tal- klorid tas- sodju ta ’ 9 mg/ ml (0. 9%) għall- injezzjoni jew soluzzjoni tal- glukows (5%) għall- injezzjoni.
Busilvex must not be infused concomitantly with another intravenous solution.
Busilvex m’ għandux jiġi infużat konkomitament ma ’ taħlit likwidi ieħor mill- ġol vini.
Polycarbonate syringes must not be used with Busilvex.
Is- sirinġi polikarbonati m’ għandhomx jiġu użati mal- Busilvex.
For single use only.
Użahom darba waħda biss.
Only a clear solution without any particles should be used.
Soluzzjoni ċara biss għandha tintuża mingħajr fdal.
Any unused product or waste material should be disposed of in accordance with local requirements for cytotoxic medicinal products.
Kull fdal tal- prodott jew prodott li ma jkunx intuża jew skart li jibqa ’ wara l- użu tal- prodott għandu jintrema kif jitolbu l- liġijiet lokali dwar prodotti mediċali ċitotossiċi.
14 7 MARKETING AUTHORISATION HOLDER
ID- DETENTUR TA ’ L- AWTORIZZAZZJONI GĦAT- TQEGĦID FIS- SUQ
Pierre Fabre Médicament 45, Place Abel Gance F-92654 Boulogne Billancourt Cedex France
Pierre Fabre Médicament 45, Place Abel Gance F- 92654 Boulogne Billancourt Cedex Franza
8 MARKETING AUTHORISATION NUMBER(S)
NUMRU( I) TA ’ L- AWTORIZZAZZJONI GĦAT- TQEGĦID FIS- SUQ
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
DATA TA ’ L- EWWEL AWTORIZZAZZJONI/ TIĠDID TA ’ L- AWTORIZZAZZJONI
Date of first authorisation:
Data ta ’ l- ewwel awtorizzazzjoni:
09 July, 2003 Date of latest renewal:
09 ta ’ Lulju 2003 Data ta ’ l- aħħar tiġdid:
08 July, 2008
08 ta ’ Lulju 2008
10 DATE OF REVISION OF THE TEXT
DATA TA ’ META ĠIET RIVEDUTA L- KITBA
15 ANNEX II
15 ANNESS II
MANUFACTURING AUTHORISATION HOLDER RESPONSIBLE FOR BATCH RELEASE
DETENTUR TA ’ L- AWTORIZZAZZJONI TAL - MANIFATTURA RESPONSABBLI GĦALL- ĦRUĠ TAL- LOTT
16 A MANUFACTURING AUTHORISATION HOLDER RESPONSIBLE FOR BATCH RELEASE
16 A DETENTUR TA ’ L- AWTORIZZAZZJONI TAL- MANIFATTURA RESPONSABBLI GĦALL- ĦRUĠ TAL- LOTT
Pierre Fabre Médicament Production Site Aquitaine Pharm International Avenue du Béarn -Idron F-64320 France
Pierre Fabre Médicament Production Site Aquitaine Pharm International Avenue du Béarn - Idron F- 64320 Franza
B CONDITIONS OF THE MARKETING AUTH ORISATION
B KUNDIZZJONIJIET TA ’ L- AWTORIZZAZZJONI GĦAT- TQEGĦID FIS- SUQ
• CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE IMPOSED ON THE MARKETING AUTHORISATION HOLDER
• KUNDIZZJONIJIET JEW RESTRIZZJONIJIET FUQ IL- FORNIMENT U L- UŻU IMPOSTI FUQ ID- DETENTUR TA ’ L- AWTORIZZAZZJONI GĦAT- TQEGĦID FIS- SUQ
Summary of Product Characteristics, 4.2)
Sommarju tal - Karatteristiċi tal- Prodot, sezzjoni 4. 2)
17 ANNEX III
17 ANNESS III
LABELLING
18 A. TIKKETTA
19 PARTICULARS TO APPEAR ON THE OUTER PACKAGING {Box containing 8 vials of 10ml)
19 TAGĦRIF LI GĦANDU JIDHER FUQ IL- PAKKETT TA ’ BARRA
Busilvex 6 mg/ml concentrate for solution for infusion busulfan
Busilvex 6 mg/ ml konċentrat għal soluzzjoni għall- infużjoni busulfan
STATEMENT OF ACTIVE SUBSTANCE
DIKJARAZZJONI TAS- SUSTANZA ATTIVA
One ml of concentrate contains 6 mg of busulfan and provides 0.5 mg/ml of busulfan after dilution
Ml wieħed ta ’ konċentrat fih 6 mg ta 'busulfan u jipprovdi 0. 5 mg/ ml ta ’ busulfan wara lis- sustanza tkun miżjuda bl- ilma
Each vial contains Dimethylacetamide and Macrogol 400
Kull kunjett fih Dimetilaċetamid u Makrogol 400
Concentrate for solution for infusion Box of 8 single use vials of 10 ml 60 mg per vial
60 mg kull kunjett
Intravenous use (IV) Must be diluted before use Read the package leaflet before use
Użu għal ġol- vini (IV) Irid ikun imħallat bl- ilma qabel ma tużah Aqra l- fuljett ta ’ tagħrif qabel l- użu
OTHER SPECIAL WARNING IF NECESSARY
TWISSIJA SPEĊJALI OĦRA, JEKK MEĦTIEĠA
Cytotoxic agent, special handling instructions
Aġent citotossiku, struzzjonijiet speċjali dwar kif timmaniġġjah
SPECIAL STORAGE CONDITIONS
20 Aħżen fi friġġ (2°C – 8°C)
Any unused product or waste material should be disposed of in accordance with local requirements
Kull fdal tal- prodott li ma jkunx intuża jew skart li jibqa wara l- użu tal- prodott għandu jintrema kif jitolbu l- liġijiet lokali.