natgillin/translations-raw huggingface dataset:
What Busilvex is and what it is used for
Što je Busilvex i za što se koristi
However, for the safe use of Busilvex in patients older than 60 years only limited information is available.
No, o sigurnoj primjeni Busilvexa u bolesnika starijih od 60 godina dostupni su samo ograničeni podaci.
Particular caution should be taken if you use itraconazole and metronidazole (used for certain types of infections) or ketobemidone (used to treat pain), because this may increase the side-effects.
Osobito je potreban oprez ako upotrebljavate itrakonazol i metronidazol (upotrebljava se za određene tipove infekcija) ili ketobemidon (upotrebljava se za liječenje boli) jer to može povećati nuspojave.
The highest frequency of nausea and vomiting was 59.1% and the highest frequency of stomatitis was
Najveća učestalost mučnine i povraćanja iznosila je 59,1%, a najveća učestalost stomatitisa iznosila je
Acute GVHD was rated as serious in 3 patients.
Akutni GVHD ocijenjen je ozbiljnim u 3 bolesnika.
There was no regimen-related death through the first 100-day post-transplant and up to one year post-transplant.
Nije bilo smrti povezanih s protokolom tijekom prvih 100 dana nakon presađivanja i do godinu dana nakon presađivanja.
Busulfan is a teratogen in rats, mice and rabbits.
Busulfan je teratogen u štakora, miševa i zečeva.
Investigations: elevated liver enzymes and weight increased.
Pretrage: povišeni jetreni enzimi i povećanje težine.
The use of paracetamol during the 72 hours prior to or with Busilvex administration should be used with caution.
Upotreba paracetamola tijekom 72 sata prije ili zajedno s primjenom Busilvexa mora se primijeniti s oprezom.
HVOD occurred in: 8.2% (5/61) allogeneic patients (fatal in 2 patients) and 2.5% (1/42) of autologous patients.
HVOD se pojavio u: 8,2% (5/61) alogenih bolesnika (smrtonosno kod 2 bolesnika) i 2,5% (1/42) autolognih bolesnika.
Approximately 30% of the administered dose is excreted into the urine over 48 hours with 1% as unchanged busulfan.
Otprilike 30% primijenjene doze izlučuje se u urin tijekom 48 sati, pri čemu je 1% nepromijenjenog busulfana.
Adequate contraceptive precautions should be used when either partner is receiving Busilvex.
Moraju se primijeniti odgovarajuće mjere kontracepcije kada bilo koji od partnera prima Busilvex.
A total of 14 patients (50%) experienced a-GVHD.
Ukupno je 14 bolesnika (50%) doživjelo a-GVHD.
The terminal half-life ranged from 2.8 to 3.9 hours.
Konačni poluvijek bio je u rasponu od 2,8 do 3,9 sati.
A majority of publications reported a complete donor chimerism at day+30 for 90-100% of patients.
Većina publikacija zabilježila je potpuni donorski kimerizam na dan + 30 za 90 - 100% bolesnika.
The haematologic status should be closely monitored and vigorous supportive measures instituted as medically indicated.
Hematološki status mora se pomno pratiti i moraju se primijeniti snažne potporne mjere u skladu s medicinskom indikacijom.
Doses of 400 mg/kg/day DMA administered during organogenesis caused significant developmental anomalies.
Doze DMA 400 mg/kg/dan primijenjene tijekom organogeneze uzrokovale su značajne razvojne anomalije.
If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor before you receive treatment with Busilvex.
Ako ste trudni ili dojite, mislite da biste mogli biti trudni ili planirate imati dijete, obratite se svom liječniku prije nego primite liječenje Busilvexom.
Other medicines and Busilvex
Drugi lijekovi i Busilvex
Busulfan concentrations in the cerebrospinal fluid are comparable to those in plasma although these concentrations are probably insufficient for anti-neoplastic activity.
Koncentracije busulfana u cerebrospinalnoj tekućini usporedive su s onima u plazmi, iako su te koncentracije vjerojatno nedovoljne za antineoplastično djelovanje.
Grade 3 elevated transaminases were reported in 24% of patients.
Povišene transaminaze 3. stupnja prijavljene su u 24% bolesnika.
Busilvex is used in adults, new-born infants, children and adolescents as a treatment prior to transplantation.
Busilvex se primjenjuje u odraslih, novorođenčadi, djece i adolescenata kao liječenje prije presađivanja.
CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 60 mg/10 ml
SADRŽAJ PO TEŽINI, VOLUMENU ILI DOZNOJ JEDINICI LIJEKA 60 mg/10 ml
Busulfan is thought to be leukemogenic.
Busulfan se smatra leukemogenim.
Women of childbearing potential have to use effective contraception during and up to 6 months after treatment.
Žene reproduktivne dobi moraju koristiti učinkovitu kontracepciju tijekom i do 6 mjeseci nakon liječenja.
Two of the above four patients with serious serum hepatotoxicity were among patients with diagnosed HVOD.
Dva od gore navedena četiri bolesnika s teškom serumskom hepatotoksičnošću bili su među bolesnicima s dijagnosticiranim HVOD-om.
No pharmacokinetic explanation justifies this interaction.
Ova interakcija ne može se opravdati nikakvim farmakokinetičkim objašnjenjem.
Busilvex is available in multipacks comprising 2 packs, each containing 4 vials.
Busilvex je dostupan u višestrukim pakiranjima koja sadrže 2 pakiranja, svako s 4 bočice.
Pharmacokinetics in adults
Farmakokinetika u odraslih
It must be considered that overdose of Busilvex will also increase exposure to DMA.
Potrebno je uzeti u obzir da će predoziranje Busilvexom ujedno povećati izloženost DMA.
Busilvex can also produce symptoms of menopause and in pre-adolescent girls it can prevent the onset of puberty.
Busilvex može također uzrokovati simptome menopauze i u preadolescentnih djevojaka može spriječiti početak puberteta.
Inter and intra patient variabilities in plasma exposure were lower than 20% and 10%, respectively.
Inter- i intravarijabilnost bolesnika u plazmatskoj izloženosti bile su niže od 20%, odnosno 10%.
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.
Stalna varijacija klirensa u rasponu od 2,49 do 3,92 ml/minuta/kg utvrđena je u djece u dobi od < 6 mjeseci do 17 godina.
Busulfan belongs to a class of substances which are potentially carcinogenic based on their mechanism of action.
Busulfan pripada klasi tvari koje su potencijalno karcinogene na temelju svojih mehanizama djelovanja.
Do not freeze the diluted solution.
Ne zamrzavati razrijeđenu otopinu.
Total dose of busulfan per patient was between 6.4 mg/kg and 9.6 mg/kg.
Ukupna doza busulfana po bolesniku iznosila je između 6,4 mg/kg i 9,6 mg/kg.
In children < 9 kg, a therapeutic drug monitoring may be justified on a case by case basis, in particular in extremely young children and neonates (see section 5.2).
U djece < 9 kg praćenje terapijskog lijeka može biti opravdano ovisno o slučaju, naročito kada se radi o izrazito mladoj djeci i novorođenčadi (vidjeti dio 5.2).
As a result, the control of intravenous busulfan AUC within the therapeutic windows is not modified and a similar targeting performance between the two schedules was illustrated.
Posljedicom toga, kontrola AUC-a intravenskog busulfana unutar terapijskih okvira nije promijenjena i prikazano je slično ciljano djelovanje između dva rasporeda.
The cumulative incidence of neutrophil recovery at day 28 was 98.8% (95%CI, 85.7-99.9%).
Kumulativna incidencija oporavka neutrofila u 28. danu iznosila je 98,8% (95%-tni CI, 85,7 - 99,9%).
Busilvex may interact with other medicines.
Busilvex može međusobno djelovati s drugim lijekovima.
In both studies, all patients received a 16/16 dose regimen of Busilvex.
U oba su ispitivanja svi bolesnici primili protokol sa 16/16 doza Busilvexa.
Dose and administration: The dose of Busilvex will be calculated according to your body weight.
Doza i primjena: Doza lijeka Busilvex izračunat će se u skladu s Vašom tjelesnom težinom.
The successful engraftment achieved in all patients during phase II trials suggests the appropriateness of the targeted AUCs.
Uspješno presađivanje ostvareno je kod svih bolesnika tijekom faze II ispitivanja, što upućuje da su ciljani AUC bili odgovarajući.
Haemorrhagic cystitis including haemorrhagic cystitis induced by viral infection was reported in a range between 16% and 18.1%.
Hemoragični cistitis uključujući hemoragični cistitis induciran virusnom infekcijom prijavljen je u rasponu između 16% i 18,1%.
Repeated doses of DMA produced signs of liver toxicity, the first being increases in serum clinical enzymes followed by histopatological changes in the hepatocytes.
Ponovljene doze DMA uzrokovale su znakove toksičnosti jetre, koje su se prvo pokazale kao povećanje kliničkih enzima u serumu nakon čega su uslijedile histopatološke promjene hepatocita.
A cumulative review of the literature and safety database has been performed.
Sastavljeno je kumulativno izvješće na temelju literature i sigurnosne baze podataka.
CNS changes precede any of the more severe side effects.
Promjene SŽS-a prethode svakoj od težih nuspojava.
In human the principal toxic effects were hepatotoxicity and central nervous system (CNS) effects.
Glavni toksični učinci kod ljudi bili su hepatotoksičnost i učinci na središnji živčani sustav (SŽS).
Busulfan and DMA can impair fertility in man or woman.
Busulfan i DMA mogu narušiti plodnost u muškaraca ili žena.
Therefore Busilvex should be used with caution in this type of patients.
Stoga Busilvex treba upotrebljavati s oprezom kod ovih bolesnika.
The information presented on biotransformation and elimination is based on oral busulfan.
Informacije o biotransformaciji i eliminaciji temelje se na peroralnom busulfanu.
The treatment-related mortality/non-relapse mortality (TRM/NRM) reported until day+100 posttransplant has also been examined through a review of published data from clinical trials.
Smrtnost povezana s liječenjem/smrtnost koja nije povezana s relapsom prijavljena do dana + 100 nakon presađivanja također je ispitana putem pregleda objavljenih podataka iz kliničkih ispitivanja.
In this regard, for children < 9 kg, a monitoring of the plasma concentrations of busulfan (therapeutic drug monitoring) for dose-adjustment may improve the busulfan targeting performance, especially in extremely young children and neonates.
S obzirom na to, za djecu težine < 9 kg kontrola plazmatskih koncentracija busulfana (terapijsko praćenje lijeka) za prilagođavanje doze može poboljšati ciljano djelovanje busulfana, naročito u izrazito mlade djece i nedonoščadi.
Patients older than 50 years of age (n=23) have been successfully treated with Busilvex without doseadjustment.
Bolesnici stariji od 50 godina (n=23) uspješno su liječeni Busilvexom bez prilagođavanja doze.
It is possible that use of Busilvex may increase the risk of suffering another malignancy in the future.
Moguće je da upotreba Busilvexa može povećati opasnost od obolijevanja od druge maligne bolesti u budućnosti.
HVOD is a recognized potential complication of conditioning therapy post-transplant.
HVOD je prepoznat kao potencijalna komplikacija terapije kondicioniranja nakon presađivanja.
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.
Otpuštanje metansulfonatnih skupina u vodenom mediju stvara ugljikove ione koji mogu alkilirati DNK, što se smatra važnim biološkim mehanizmom za njegov citotoksičan učinak.
In rats, a DMA daily dose of 450 mg/kg given to rats for nine days caused inactive spermatogenesis.
U štakora je dnevna doza DMA 450 mg/kg koja je davana štakorima devet dana uzrokovala inaktivnu spermatogenezu.
Detailed information on this medicinal product is available on the website of European Medicinal Agency http://www.ema/europa.eu
Detaljnije informacije o ovom lijeku dostupne su na internetskoj stranici Europske agencije za lijekove http://www.ema/europa.eu
The other ingredients are dimethylacetamide and macrogol 400.
- Drugi sastojci su dimetilacetamid i makrogol 400.
MARKETING AUTHORISATION NUMBER(S) EU/1/03/254/002
BROJ(EVI) ODOBRENJA ZA STAVLJANJE LIJEKA U PROMET EU/1/03/254/002
What Busilvex is and what it is used for What you need to know before you use Busilvex How to use Busilvex
Što je Busilvex i za što se koristi Što morate znati prije nego počnete primjenjivati Busilvex Kako primjenjivati Busilvex
Oliguria
Oligurija
Malformations and anomalies included significant alterations in the musculoskeletal system, body weight gain, and size.
Malformacije i anomalije obuhvaćale su značajne promjene mišićno-koštanog sustava, povećanje tjelesne težine i veličine.
Detailed information on this product is available on the website of European Medicinal Agency http://www.ema.europa.eu
Detaljnije informacije o ovom lijeku dostupne su na internetskoj stranici Europske agencije za lijekove http://www.ema.europa.eu
VOD observed were neither fatal nor severe and resolved in all cases.
Zabilježena venska-okluzivna bolest nije bila niti smrtonosna niti teška i u svim slučajevima je izliječena.
39% of patients (40/103) experienced one or more episodes of infection, of which 83% (33/40) were rated as mild or moderate.
Jednu ili više epizoda infekcije doživjelo je 39% bolesnika (40/103), od čega je 83% (33/40) ocijenjeno blagima ili umjerenima.
Antiemetics should be administered prior to the first dose of Busilvex and continued on a fixed schedule according to local practice through its administration.
Antiemetike treba primijeniti prije prve doze Busilvexa i nastaviti s njihovom primjenom prema dogovorenom rasporedu u skladu s lokalnom praksom.
The increased risk of a second malignancy should be explained to the patient.
Bolesniku se mora objasniti povećani rizik od drugog malignog oboljenja.
Not relevant
Nije značajno.
Two prospective, single arm, open-label, uncontrolled phase II studies were conducted in patients with haematological disease, the majority of whom had advanced disease.
Faza II dvaju prospektivnih, nekontroliranih, otvorenih ispitivanja jedne skupine bolesnika provedena su na bolesnicima oboljelim od hematoloških bolesti, od kojih je većina imala uznapredovalu bolest.
The occurrence of infectious episodes or reactivation of opportunistic infectious agents mainly reflects the immune status of the patient receiving a conditioning regimen.
Pojava infekcija ili reaktivacija oportunističkih infektivnih uzročnika uglavnom pokazuje imunološko stanje bolesnika koji prima protokol kondicioniranja.
Busilvex should not be given by rapid intravenous, bolus or peripheral injection.
Busilvex se ne smije primjenjivati brzom intravenskom, bolusnom ili perifernom injekcijom.
Chronic GVHD (c-GVHD) was reported if serious or the cause of death, and was reported as the cause of death in 3 patients.
Kroničan GVHD (c-GVHD) prijavljen je ako je bio težak ili uzrok smrti, a kao uzrok smrti prijavljen je kod 3 bolesnika.
The most frequent infectious adverse reactions were Cytomegalovirus (CMV) reactivation [range: 30.7% - 80.0%], Epstein-Barr Virus (EBV) reactivation [range: 2.3% - 61%], bacterial infections [range: 32.0% - 38.9%] and viral infections [range: 1.3% - 17.2%].
Najčešće infekcijske nuspojave bile su reaktivacija citomegalovirusa (CMV) [raspon: 30,7% - 80,0%], reaktivacija Epstein-Barrovog virusa (EBV) [raspon: 2,3% - 61%], bakterijske infekcije [raspon: 32,0% - 38,9%] i virusne infekcije [raspon: 1,3% - 17,2%].
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.
Ukupna smrtnost i smrtnost bez relapsa na više od 100 dana nakon presađivanja bila je (8/61) 13%, odnosno (6/61) 10% u alotransplantiranih bolesnika.
No specific antidote for DMA overdose is known.
Nije poznat specifični protulijek za predoziranje s DMA.
However, more than 500 patients aged ≥ 55 years were reported in publications with FB conditioning regimens, yielding efficacy outcomes similar to younger patients.
Međutim, u publikacijama je zabilježeno da je više od 500 bolesnika u dobi od ≥ 50 godina s protokolima kondicioniranja FB-om imalo ishod djelotvornosti sličan mlađim bolesnicima.
Taking into account the PRAC Assessment Report on the PSUR(s) for busulfan, the scientific conclusions of CHMP are as follows:
Uzimajući u obzir PRAC-ovo izvješće o ocjeni periodičkog(ih) izvješća o neškodljivosti lijeka (PSUR) za busulfan, znanstveni zaključci CHMP-a su sljedeći:
Pneumonia was fatal in 1% (1/103) and life-threatening in 3% of patients.
Upala pluća bila je smrtonosna u 1% (1/103), a po život opasna u 3% bolesnika.
* veno occlusive liver disease is more frequent in paediatric population.
* vensko-okluzivna bolest jetre češća je u pedijatrijskoj populaciji.
For obese patients, dosing based on adjusted ideal body weight (AIBW) should be considered.
Za pretile bolesnike mora se razmotriti doziranje na temelju prilagođene idealne tjelesne težine (PITT).
Adverse events information is derived from two clinical trials (n=103) of Busilvex.
Informacije o nuspojavama dobivene su iz dva klinička ispitivanja (n=103) lijeka Busilvex.
Compared to the four times a day regimen, the once-daily regimen is characterized by a higher peak concentration, no drug accumulation and a wash out period (without circulating busulfan concentration) between consecutive administrations.
U usporedbi s režimom četiri puta dnevno, režim jednom dnevno obilježava viša vršna koncentracija, neakumulacija lijeka i razdoblje ispiranja (bez koncentracije busulfana u cirkulaciji) između dviju uzastopnih primjena.
A population pharmacokinetic analysis has been performed in a cohort of 205 children adequately distributed with respect to bodyweight (3.5 to 62.5 kg), biological and diseases (malignant and nonmalignant) characteristics, thus representative of the high heterogeneity of children undergoing HPCT.
U skupini od 205 djece provedena je populacijska farmakokinetička analiza koja je bila raspoređena na odgovarajući način u skladu s tjelesnom težinom (3,5 do 62,5 kg), biološkim svojstvima i svojstvima oboljenja (maligna i nemaligna) te prema tome reprezentativna za visoku heterogenost djece koja su podvrgnuta HPCT-u.
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.
Preostali lijek ne smije se ispirati u cjevima za primjenu jer brza infuzija Busilvexa nije testirana i ne preporučuje se.
Infections and infestations:
Infekcije i infestacije:
Precautions to be taken before handling or administering the medicinal product
Mjere koje treba poduzeti prije rukovanja ili primjene lijeka.
Late haemorrhagic cystitis occurring 2 weeks post-transplant are likely related to viral infection / reactivation.
Hemoragični cistitis u kasnoj fazi koji se pojavljuje 2 tjedna nakon presađivanja vjerojatno je povezan s virusnom infekcijom / reaktivacijom.
Paracetamol is described to decrease glutathione levels in blood and tissues, and may therefore decrease busulfan clearance when used in combination (see section 4.4).
Za paracetamol je opisano da smanjuje razinu glutationa u krvi i tkivima pa stoga može smanjiti klirens busulfana kada se upotrebljava u kombinaciji (vidjeti dio 4.4).
All patients should be pre-medicated with anticonvulsant medicinal products to prevent seizures reported with the use of high dose busulfan.
Svi bolesnici moraju primiti premedikaciju antikonvulzivnim lijekovima kako bi se spriječili napadaji koji su prijavljeni uz primjenu visoke doze busulfana.
For the 40% of children < 9 kg outside the target, the AUC was evenly distributed either below or above the targeted limits; i.e. 20% each < 900 and > 1500 µmol/L.min following 1 mg/kg.
Za 40% djece s težinom < 9 kg izvan cilja, AUC se ravnomjerno rasporedio ili ispod ili iznad ciljnih ograničenja; tj. po 20% < 900 i > 1500 µmol/l.min nakon 1 mg/kg.
Patients who have received prior radiation therapy, greater than or equal to three cycles of chemotherapy, or prior progenitor cell transplant may be at an increased risk (see section 4.8).
Bolesnici koji su prethodno primili terapiju zračenjem, u dozi većoj ili jednakoj trima ciklusima kemoterapije, ili su im već prije presađene progenitorske stanice mogu biti pod povećanim rizikom (vidjeti dio 4.8).
Therefore, attention should be paid to this pulmonary issue in patients with prior history of mediastinal or pulmonary radiation (see section 4.8).
Stoga je potrebno obratiti pozornost na plućne probleme u bolesnika s prethodnom anamnezom zračenja sredoprsja ili pluća (vidjeti dio 4.8).
DMA decreases fertility in male and female rodents.
DMA smanjuje plodnost u muških i ženskih glodavaca.
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.
Graft-versus host disease), koji su, iako nisu bili izravno povezani, bili glavni uzroci pobolijevanja i smrtnosti, naročito kod alogenog HPCT.
Mild/moderate fever was reported in 76% of patients.
Blaga/umjerena vrućica prijavljena je u 76% bolesnika.
Caution should be exercised when using paracetamol prior to (less than 72 hours) or concurrently with Busilvex due to a possible decrease in the metabolism of busulfan (See section 4.5).
Potreban je oprez pri primjeni paracetamola prije (manje od 72 sata) ili istodobno s Busilvexom zbog mogućeg skraćenja metabolizma busulfana (vidjeti dio 4.5).
What you need to know before you use Busilvex
Što morate znati prije nego počnete primjenjivati Busilvex
Because of the potential for tumorigenicity shown for busulfan in human and animal studies, breast-feeding should be discontinued during treatment with busulfan.
Zbog svojeg potencijala tumorogenosti koji je busulfan pokazao u ispitivanjima na ljudima i životinjama, tijekom liječenja busulfanom treba prekinuti dojenje.
Leukaemia patients treated with busulfan developed many different cytological abnormalities, and some developed carcinomas.
Bolesnici oboljeli od leukemije liječeni busulfanom razvili su mnoge različite citološke abnormalnosti, a kod nekih su se razvili karcinomi.
The FB combination allowed sufficient myeloablation modulated by the intensity of conditioning regimen through the variation of number of days of busulfan infusion.
Kombinacija s FB-om omogućila je dovoljnu mijeloablaciju moduliranu intenzitetom protokola kondicioniranja putem varijacije broja dana infuzije busulfana.
Diseases included were acute leukaemia past first remission, in first or subsequent relapse, in first remission (high risk), or induction failures; chronic melogenous leukaemia in chronic or advanced phase; primary refractory or resistant relapsed Hodgkin's disease or non-Hodgkin's lymphoma, and myelodysplastic syndrome.
Obuhvaćene bolesti bile su akutna leukemija nakon prve remisije, u prvom ili naknadnom relapsu, u prvoj remisiji (visoki rizik) ili neuspješnim indukcijama; kronična mijeloična leukemija u kroničnoj ili uznapredovaloj fazi; primarna refraktorna ili rezistento-relapsna Hodginkova bolest ili non-Hodgkingov limfom i mijelodisplastični sindrom.
Respiratory: decrease in blood oxygen.
Disanje: smanjenje kisika u krvi.
From the assessment of these articles, the causality of busulfan in the development of tooth hypoplasia is confirmed.
Na temelju ocjene tih članaka, potvrđena je uzročna povezanost busulfana za razvoj hipoplazije zuba.
No interaction was observed when busulfan was combined with 5 HT3 antiemetics such as ondansetron or granisetron.
Nisu zabilježene interakcije kada je busulfan kombiniran s antiemeticima 5 HT3 poput ondansetrona ili granisetrona.
It is recommended when treating these patients that serum transaminase, alkaline phosphatase, and bilirubin should be monitored regularly 28 days following transplant for early detection of hepatotoxicity.
Preporučuje se da se prilikom liječenja tih bolesnika redovito prate serumske transaminaze, alkalna fosfataza i bilirubin 28 dana nakon presađivanja kako bi se rano otkrila hepatotoksičnost.
The glutathione conjugate is then further metabolised in the liver by oxidation.
Konjugat glutationa potom se oksidacijom dalje metabolizira u jetri.
IBW women (kg) = 45 + 0.91x (height in cm-152).
ITT za žene (kg) = 45 + 0,91 x (visina u cm-152).
All patients experienced a profound myelosuppression.
Svi su bolesnici doživjeli tešku mijelosupresiju.