natgillin/translations-raw huggingface dataset:
In case of concomitant use of agents that may increase panobinostat plasma concentrations, such as strong CYP3A4 inhibitors, dose adjustment is required (see sections 4.5 and 4.2). 
U slučaju istodobne primjene tvari koje mogu povećati koncentracije panobinostata u plazmi, kao što su snažni CYP3A4 inhibitori, potrebno je prilagoditi dozu (vidjeti dijelove 4.5 i 4.2).
There are no clinical studies on the use of Farydak in pregnant patients. 
Nema kliničkih ispitivanja primjene Farydaka u trudnih bolesnica.
Panobinostat may be started at a dose of 15 mg, and if tolerated in the first cycle escalated to 20 mg in the second cycle. 
Primjena panobinostata može se započeti u dozi od 15 mg, a ako se podnosi u prvom ciklusu može se povećati do 20 mg u drugom ciklusu.
- Do not take this medicine after the expiry date, which is stated on the carton and blister foil. 
- Ovaj lijek se ne smije upotrijebiti nakon isteka roka valjanosti navedenog na kutiji i foliji blistera.
Resume at the same dose 
Nastaviti u istoj dozi
Some of these infections (e.g. pneumonia) have been severe (e.g. leading to sepsis, or respiratory or multi-organ failure) and have had fatal outcomes (see section 4.8). 
Neke od tih infekcija (npr. pneumonija) bile su teške (npr. dovele do sepse, ili respiratornog ili multiorganskog zatajenja) te su imale smrtne ishode (vidjeti dio 4.8).
If this is unavoidable, patients should be closely monitored and further dose reduction or discontinuation may be considered as clinically indicated (see section 4.5). 
Ako je to neizbježno, bolesnike treba pažljivo pratiti te razmotriti dodatno smanjenje doze ili prekid terapije ako je to klinički indicirano (vidjeti dio 4.5).
Cycles 1-8 (3-week cycles) 
1.-8. ciklus (3-tjedni ciklusi)
These medicines should be used with care or may need to be avoided during your treatment with Farydak. 
Ti se lijekovi moraju koristiti oprezno ili ćete ih možda trebati izbjegavati tijekom liječenja Farydakom.
Due to the potential risk of death or malformation to the foetus, you should use the following methods of contraception while taking Farydak: 
Zbog potencijalnog rizika od smrti ili anomalije fetusa, morate koristiti sljedeće metode kontracepcije dok uzimate Farydak:
Pertinent metabolic pathways involved in the biotransformation of panobinostat are reduction, hydrolysis, oxidation and glucuronidation processes. 
Relevantni metabolički putevi uključeni u biotransformaciju panobinostata su procesi redukcije, hidrolize, oksidacije i glukuronidacije.
Hard capsule 6 capsules 12 capsules 24 capsules 
12 kapsula 24 kapsule
• difficulty in breathing with blueness around the mouth, which could lead to loss of consciousness (sign of serious lung problems) 
• poteškoće s disanjem uz plavilo oko usana, što može dovesti do gubitka svijesti (znak ozbiljnih problema s plućima)
All 55 patients were previously treated with bortezomib and at least one IMiD (lenalidomide: 98.2%, thalidomide: 69.1%). 
Svih 55 bolesnika prethodno je bilo liječeno bortezomibom i najmanje jednim imunomodulacijskim lijekom (lenalidomid: 98,2%, talidomid: 69,1%).
• The patient compliance card shall contain instructions on the following key messages: o How to become familiar with the compliance card: this section provides a general overview of the compliance card and its purpose. 
• Kartica za praćenje suradljivosti bolesnika treba sadržavati upute za sljedeće ključne poruke: o Kako se upoznati s karticom za praćenje suradljivosti: taj dio pruža opće informacije o kartici za praćenje suradljivosti i navodi njezinu svrhu.
Treatment with Farydak should be initiated by a physician experienced in the use of anti-cancer therapies. 
Liječenje Farydakom treba započeti liječnik koji ima iskustva u primjeni terapija protiv raka.
- Store in the original package in order to protect from moisture. 
- Čuvati u originalnom pakiranju radi zaštite od vlage.
Grade on day of treatment 
Stupanj neutropenije na dan liječenja
Inhibition of HDAC activity results in increased acetylation of histone proteins, an epigenetic alteration that results in a relaxing of chromatin, leading to transcriptional activation. 
Inhibicija aktivnosti HDAC-a rezultira povećanom acetilacijom histonskih proteina, epigenetskom promjenom koja rezultira opuštanjem kromatina, što dovodi do transkripcijske aktivacije.
Panobinostat is rapidly and almost completely absorbed with Tmax reached within 2 hours of oral administration in patients with advanced cancer. 
Panobinostat se brzo i gotovo potpuno apsorbira pri čemu se Tmax postiže u roku od 2 sata od peroralne primjene u bolesnika s uznapredovalim rakom.
Gastrointestinal toxicity, primarily diarrhoea, nausea and vomiting, is among the most frequently reported adverse reactions. 
Gastrointestinalna toksičnost, prvenstveno proljev, mučnina i povraćanje, među najčešće su prijavljenim nuspojavama.
In vitro, panobinostat caused the accumulation of acetylated histones and other proteins, inducing cell cycle arrest and/or apoptosis of some transformed cells. 
In vitro je panobinostat uzrokovao akumulaciju acetiliranih histona i drugih proteina, uključujući zaustavljanje staničnog ciklusa i/ili apoptozu nekih transformiranih stanica.
- The active substance of Farydak is panobinostat. 
- Djelatna tvar Farydaka je panobinostat.
For patients >75 years of age, depending on the patient's general condition and concomitant diseases, an adjustment of the starting doses or schedule of the components of the combination regimen may be considered. 
>75 godina, ovisno o bolesnikovom općem stanju i istodobno prisutnim bolestima, može se razmotriti prilagođavanje početnih doza ili rasporeda komponenti kombiniranog režima.
Panobinostat may increase the QTc interval (see section 4.4). 
Panobinostat bi mogao produljiti QTc interval (vidjeti dio 4.4).
The primary endpoint of the study was to assess overall response rate (ORR) after 8 cycles of therapy 
Primarni ishod ispitivanja bio je procijeniti ukupnu stopu odgovora (eng. overall response rate, ORR)
Patients should be monitored for signs and symptoms of infections during treatment with panobinostat; if a diagnosis of infection is made, appropriate anti-infective treatment should be instituted promptly and interruption or discontinuation of Farydak considered. 
U bolesnika treba pratiti postoje li znakovi i simptomi infekcija tijekom liječenja panobinostatom; ako se utvrdi dijagnoza infekcije, potrebno je odmah započeti odgovarajuće antiinfekcijsko liječenje te razmotriti privremeni ili trajni prekid primjene Farydakom.
• palpitations 
• palpitacije
Patients should be instructed to avoid star fruit, grapefruit, grapefruit juice, pomegranates and pomegranate juice, as these are known to inhibit cytochrome P450 3A enzymes and may increase the bioavailability of panobinostat. 
Bolesnike treba uputiti da izbjegavaju karambolu (zvjezdano voće), grejp, sok od grejpa, šipak (nar) i sok od nara, budući da je za njih poznato da inhibiraju enzime citokroma P450 3A i mogu povećati bioraspoloživost panobinostata.
CTC grade 3 fatigue was reported in 15.7% of the patients, and grade 4 in 1.3%. 
Umor 3. stupnja prema CTC-u bio je prijavljen u 15,7% bolesnika, a 4. stupnja u 1,3%.
Talk to your doctor or pharmacist before taking Farydak: - if you have liver problems or have ever had liver disease. 
Obratite se svom liječniku ili ljekarniku prije nego uzmete Farydak: - ako imate problema s jetrom ili ako ste ikada imali bolest jetre.
Gastrointestinal toxicity is very common in patients treated with panobinostat. 
Gastrointestinalna toksičnost vrlo je česta u bolesnika liječenih panobinostatom.
Therefore a complete blood count must be performed before initiating therapy with panobinostat, with frequent monitoring during treatment (in particular before each injection of bortezomib as per bortezomib SmPC). 
Stoga se mora napraviti kompletna krvna slika prije početka terapije panobinostatom, uz učestalo praćenje tijekom liječenja (osobito prije svake injekcije bortezomiba u skladu sa Sažetkom opisa svojstava lijeka za bortezomib).
The bortezomib and dexamethasone prescribing information should be consulted prior to the start of the combination treatment to assess whether a dose reduction is required. 
Potrebno je pročitati informacije o propisivanju za bortezomib i deksametazon prije početka kombiniranog liječenja kako bi se procijenilo je li potrebno smanjenje doze.
If you are a sexually active man, you should use condoms during treatment with Farydak. 
Ako ste seksualno aktivan muškarac, morate koristiti kondome tijekom liječenja Farydakom.
Panobinostat shows more cytotoxicity towards tumour cells compared to normal cells. 
Panobinostat pokazuje više citotoksičnosti prema tumorskim stanicama u usporedbi s normalnim stanicama.
Frequency of monitoring of these patients should be increased during treatment with panobinostat, particularly during the dose escalation phase. 
Učestalost praćenja tih bolesnika treba povećati tijekom liječenja panobinostatom, osobito tijekom faze povećanja doze.
How to use the Farydak blister 
Kako koristiti Farydak blister
In addition, increased expression of the tumour suppressor gene p21CDKNIA (cyclin dependent kinase inhibitor 1/p21) gene, a key mediator of G1 arrest and differentiation, was triggered with panobinostat exposure. 
Uz to, povećana ekspresija tumor supresorskog gena p21CDKNIA (inhibitor kinaze 1/p21 ovisan o ciklinu), ključnog posrednika zaustavljanja i diferencijacije G1 faze, bila je potaknuta izloženošću panobinostatu.
The median PFS (95% CI) was 12.0 months (10.3, 12.9) and 8.1 months (7.6, 9.2), respectively. 
Medijan PFS-a (95% CI) bio je 12,0 mjeseci (10,3, 12,9) odnosno 8,1 mjesec
• increased blood level of the waste product creatinine 
• povećana razina otpadnog proizvoda kreatinina u krvi
Liver function should be monitored prior to treatment and regularly during treatment. 
Funkciju jetre treba pratiti prije liječenja te redovito tijekom liječenja.
Unchanged panobinostat accounted for <2.5% of the dose in urine and <3.5% of the dose in faeces. 
Nepromijenjeni panobinostat činio je <2,5% doze u mokraći i <3,5% doze u stolici.
Carcinogenicity studies have not been performed with panobinostat. 
Ispitivanja kancerogenosti nisu provođena s panobinostatom.
The median time to onset for grade 3 and 4 thrombocytopenia was one month and the median time to recovery was 12 days. 
Medijan vremena do nastupa trombocitopenije 3. i 4. stupnja bio je mjesec dana, a medijan vremena do oporavka bio je 12 dana.
- Do not take this medicine if you notice any damage to the packaging or if there are any signs of tampering. 
- Ovaj lijek se ne smije upotrijebiti ako primijetite da je pakiranje oštećeno ili postoje vidljivi znakovi neovlaštenog otvaranja.
Censoring Times PAN+BTZ+Dex (n/N=44/73) PBO+BTZ+Dex (n/N=54/74) 
Vremena cenzuriranja PAN+BTZ+Dex (n/N=44/73) PBO+BTZ+Dex (n/N=54/74)
Localised and systemic infections, including pneumonia, other bacterial infections, invasive fungal infections such as aspergillosis or candidiasis, and viral infections including hepatitis B virus and herpes simplex, have been reported in patients taking panobinostat. 
Lokalizirane i sistemske infekcije, uključujući upalu pluća, druge bakterijske infekcije, invazivne gljivične infekcije kao što su aspergiloza ili kandidijaza, te virusne infekcije uključujući hepatitis B virus i herpes simplex, prijavljene su u bolesnika koji su uzimali panobinostat.
In the event of grade 3 nausea or grade 3 or 4 vomiting despite administration of an anti-emetic, panobinostat should be temporarily discontinued and resumed at a reduced dose on recovery to grade 1. 
U slučaju mučnine 3. stupnja ili povraćanja 3. ili 4. stupnja usprkos primjeni antiemetika, potrebno je privremeno prekinuti primjenu panobinostata te nastaviti u smanjenoj dozi nakon oporavka do 1. stupnja.
Adverse drug reactions are listed according to system organ classes in MedDRA. 
Nuspojave na lijek su navedene prema klasifikaciji organskih sustava u MedDRA-i.
Based on preclinical and clinical data, panobinostat has the potential to prolong the QT interval. 
Na temelju pretkliničkih i kliničkih podataka, panobinostat ima potencijal produljivanja QT intervala.
Pooled clinical data from over 500 patients treated with panobinostat alone in multiple indications and at different dose levels have shown that the incidence of CTC grade 3 QTc prolongation (QTcF >500 msec) was approximately 1% overall and 5% or more at a dose of 60 mg or higher; no episodes of torsades de pointes were observed. 
Objedinjeni klinički podaci dobiveni od više od 500 bolesnika liječenih samo panobinostatom za više indikacija i u različitim dozama pokazali su da je incidencija produljenja QTc-a 3. stupnja prema CTC-u (QTcF >500 msec) bila otprilike 1% ukupno te 5% ili više pri dozi od 60 mg ili većoj; nisu bile uočene epizode torsades de pointes.
There is no relevant use of panobinostat in paediatric patients below the age of 18 years in the indication multiple myeloma (see section 5.2). 
Nema relevantne primjene panobinostata u pedijatrijskih bolesnika mlađih od 18 godina za indikaciju multiplog mijeloma (vidjeti dio 5.2).
Gastrointestinal toxicity 
Gastrointestinalna toksičnost
QTcF should be <480 msec prior to initiation of treatment with Farydak. 
QTcF treba biti <480 msec prije početka liječenja Farydakom.
HDACs catalyse the removal of acetyl groups from the lysine residues of histones and some non-histone proteins. 
HDAC-i kataliziraju uklanjanje acetilnih skupina iz lizinskih ostataka histona i nekih nehistonskih proteina.
Overall panobinostat exposure and inter-patient variability remained unchanged with or without food, whereas Cmax was reduced by <45% and Tmax prolonged by 1 to 2.5 hours with food (i.e. both normal and high-fat breakfasts). 
Ukupna izloženost panobinostatu i varijabilnost među bolesnicima ostale su nepromijenjene uz obrok ili bez njega, dok se Cmax smanjio za <45%, a Tmax produljio za 1 do 2,5 sata uz obrok (tj. i uz normalan doručak i uz doručak bogat masnoćama).
However, thrombocytopenia is reversible (median time to recovery of 12 days) and can usually be managed by dose adjustment and interruption with or without platelet transfusion (see section 4.4). 
Međutim, trombocitopenija je reverzibilna (medijan vremena do oporavka od 12 sati) i obično se može zbrinuti prilagođavanjem doze i privremenim prekidom terapije uz transfuziju trombocita ili bez nje (vidjeti dio 4.4).
Panobinostat has demonstrated mutagenic potential in the Ames assay, endo-reduplication effects in human peripheral blood lymphocytes in vitro, and DNA damage in an in vivo COMET study in mouse lymphoma L5178Y cells, that are attributed to the pharmacological mode of action. 
Panobinostat je pokazao mutageni potencijal u Amesovom testu, endoreduplikacijske učinke u limfocitima ljudske periferne krvi in vitro i oštećenje DNK u in vivo ispitivanju COMET na stanicama L5178Y mišjeg limfoma, koji se pripisuju farmakološkom načinu djelovanja.
Your doctor may need to change your dose, temporarily stop or completely stop your treatment with Farydak in case you experience side effects. 
Liječnik će Vam možda morati promijeniti dozu, privremeno ili trajno prekinuti liječenje Farydakom ako osjetite nuspojave.
In the phase III study, thrombocytopenia typically recovered to baseline by the start of the next 21-day cycle (see Figure 1). 
U ispitivanju faze III trombocitopenija se obično oporavila na početnu vrijednost do početka sljedećeg 21-dnevnog ciklusa (vidjeti Sliku 1).
Potential contributing factors may include prior history of chemotherapy, stem cell transplant, the nature of the disease and neutropenia or lymphopenia associated with Farydak treatment. 
Potencijalni čimbenici koji tome doprinose mogu uključivati prethodnu kemoterapiju, transplantaciju matičnih stanica, prirodu bolesti te neutropeniju ili limfopeniju povezanu s liječenjem Farydakom.
If you accidentally take more capsules than you should, or if someone else accidentally takes your medicine, talk to a doctor or go to a hospital straight away. 
Ako slučajno uzmete više kapsula nego što ste trebali, ili ako netko drugi slučajno uzme
• The dose should be omitted, if QTcF is ≥480 msec or above 60 msec from baseline. 
• Dozu treba propustiti ako je QTcF ≥480 msec ili iznad 60 msec u odnosu na početnu vrijednost.
• swollen ankles (a sign of a low level of albumin in the blood which is known as hypoalbuminaemia) 
• otečeni gležnjevi (znak niske razine albumina u krvi koja se naziva hipoalbuminemija)
Bortezomib may be started at 1.3 mg/m2 once weekly on days 1 and 8, and dexamethasone at 20 mg on days 1 and 8. 
Bortezomib se može započeti u dozi od 1,3 mg/m2 jedanput na tjedan i to 1. i 8. dana, a deksametazon u dozi od 20 mg 1. i 8. dana.
Sexually active men taking Farydak and their female partners should use a highly effective method of contraception during the man's treatment and for six months after his last dose of Farydak. 
Seksualno aktivni muškarci koji uzimaju Farydak i njihove partnerice trebaju koristiti vrlo učinkovitu metodu kontracepcije tijekom liječenja muškarca te šest mjeseci nakon njegove zadnje doze Farydaka.
The primary target organs of toxicity following administration of panobinostat in rats and dogs were identified as the erythropoietic, myelopoietic and lymphatic systems. 
Primarni ciljni organi toksičnosti nakon primjene panobinostata u štakora i pasa utvrđeni su kao eritropoetski, mijelopoetski i limfni sustav.
Prostatic atrophy accompanied by reduced secretory granules, testicular degeneration, oligospermia and increased epididymal debris were observed in dogs at exposures corresponding to 0.41-0.69 of the human clinical AUC and not fully reversible after a 4 week recovery period. 
Atrofija prostate popraćena smanjenim sekretornim granulama, degeneracijom testisa, oligospermijom i povećanim ostacima u epididimisu bila je uočena u pasa pri izloženostima koje odgovaraju 0,41-0,69 klinički uočenog AUC-a kod ljudi i nije bila potpuno reverzibilna nakon razdoblja oporavka od 4 tjedna.
Prophylactic anti-emetics should be administered at the discretion of the physician and in accordance with local medical practice (see section 4.4). 
Profilaktičke antiemetike treba primjenjivati prema odluci liječnika te u skladu s lokalnom medicinskom praksom (vidjeti dio 4.4).
Due to its cytostatic/cytotoxic mode of action, panobinostat can influence the quality of sperm formed during treatment. 
Zbog svog citostatičnog/citotoksičnog načina djelovanja, panobinostat može utjecati na kvalitetu sperme koja nastaje za vrijeme liječenja.
Women of childbearing potential taking panobinostat in combination with bortezomib and dexamethasone must use highly effective contraception for three months after stopping treatment (see sections 4.5 and 4.6 and bortezomib and dexamethasone SmPC). 
Žene reproduktivne dobi koje uzimaju panobinostat u kombinaciji s bortezomibom i deksametazonom moraju koristiti vrlo učinkovitu kontracepciju tri mjeseca nakon prekida liječenja (vidjeti dijelove 4.5 i 4.6 te Sažetak opisa svojstava lijeka za bortezomib i deksametazon).
Of note, whereas grade 3 and grade 4 neutropenia were observed in 28% and 7% of patients, respectively, febrile neutropenia was observed in 1% of patients (see section 4.8). 
Valja napomenuti da dok je neutropenija 3. odnosno 4. stupnja bila uočena u 28% odnosno 7% bolesnika, febrilna neutropenija bila je uočena u 1% bolesnika (vidjeti dio 4.8).
Limited experience with overdose has been reported during clinical studies. 
Tijekom kliničkih ispitivanja zabilježeno je ograničeno iskustvo s predoziranjem.
Multiple myeloma is a disorder of plasma cells (a type of blood cell) that grow out of control in the bone marrow. 
Multipli mijelom je poremećaj plazma stanica (vrsta krvne stanice) koje nekontrolirano rastu u koštanoj srži.
Omit dose Resume at reduced dose or with the same dose but with a once-weekly schedule 
Nastaviti u smanjenoj dozi ili u istoj dozi, ali po rasporedu jedanput na tjedan
Take Farydak on days 1, 3 and 5 and on days 8, 10 and 12. 
Uzmite Farydak 1., 3. i 5. dana te 8., 10. i 12. dana.
Prophylactic anti-emetics (e.g. prochlorperazine) may be considered at the discretion of the physician and in accordance with local medical practice. 
Profilaktički antiemetici (npr. proklorperazin) mogu se razmotriti prema odluci liječnika te u skladu s medicinskom praksom.
If continuous treatment with a strong CYP3A4 inhibitor is required, a dose escalation from 10 mg to 15 mg panobinostat may be considered based on patient tolerability. 
Ako je potrebno kontinuirano liječenje snažnim CYP3A4 inhibitorom, može se razmotriti povećanje doze panobinostata s 10 mg na 15 mg ovisno o bolesnikovoj podnošljivosti.
For patients >75 years of age, depending on the patient's general condition and concomitant diseases, an adjustment of the starting doses or schedule of the components of the combination regimen may be considered (see section 4.2). 
>75 godina, ovisno o bolesnikovom općem stanju i istodobno prisutnim bolestima, može se razmotriti prilagođavanje početnih doza ili rasporeda komponenti kombiniranog režima (vidjeti dio 4.2).
Avoid panobinostat use in patients who are taking CYP2D6 substrates with a narrow therapeutic index (including, but not limited to, pimozide). 
Treba izbjegavati primjenu panobinostata u bolesnika koji uzimaju CYP2D6 supstrate s uskim terapijskim indeksom (uključujući, između ostalih, pimozid).
Patients should be advised to contact their physician if severe gastrointestinal toxicity occurs and dose adjustment or discontinuation may be required (see section 4.4). 
Bolesnike treba uputiti da se obrate svom liječniku ako se pojavi teška gastrointestinalna toksičnost, a moglo bi biti potrebno prilagoditi dozu ili prekinuti primjenu (vidjeti dio 4.4).
Please refer to Table 1 for cycles 1 to 8 and Table 2 for cycles 9-16. 
Provjerite Tablicu 1 za 1. do 8. ciklus te Tablicu 2 za 9.-16. ciklus.
QTcF >480 and <500 msec was recorded in 1.3% of patients and change from baseline of >60 msec was observed in 0.8% of patients. 
QTcF >480 i <500 msec bio je zabilježen u 1,3% bolesnika, a promjena u odnosu na početnu vrijednost >60 msec bila je uočena u 0,8% bolesnika.
However, treatment discontinuation due to these reactions was reported in a relatively small proportion of patients, with diarrhoea at 4.5% and nausea and vomiting at 0.5% each. 
Međutim, prekid liječenja uzrokovan tim nuspojavama bio je prijavljen u relativno malom udjelu bolesnika, zbog proljeva u 4,5%, a zbog mučnine i povraćanja u po 0,5%.
In patients with hepatic impairment receiving concomitant medicinal products which are strong CYP3A4 inhibitors, treatment with panobinostat should be avoided due to lack of experience and safety data in this patient population. 
U bolesnika s oštećenjem jetre koji istodobno primaju lijekove koji su snažni CYP3A4 inhibitori, liječenje panobinostatom treba izbjegavati zbog nedostatka iskustva i sigurnosnih podataka u toj bolesničkoj populaciji.
Farydak is always used together with two other medicines: bortezomib and dexamethasone. 
Farydak se uvijek koristi zajedno s još dva lijeka: bortezomibom i deksametazonom.
The treatment was discontinued in 2.9% of patients due to fatigue and asthenia. 
Liječenje je bilo prekinuto u 2,9% bolesnika zbog umora i astenije.
For patients experiencing severe adverse drug reactions other than thrombocytopenia, gastrointestinal toxicity, neutropenia or QTc prolongation, the recommendation is the following: 
Za bolesnike u kojih dođe do teških nuspojava osim trombocitopenije, gastrointestinalne toksičnosti, neutropenije ili produljenja QTc-a, preporuka je sljedeća:
Reduce bortezomib dose to 0.7 mg/m2 in the first treatment cycle. 
Smanjiti dozu bortezomiba na 0,7 mg/m2 u prvom ciklusu liječenja.
Consider dose escalation to 1.0 mg/m2 or further dose reduction to 0.5 mg/m2 in subsequent cycles based on patient tolerability. 
Razmotriti povećanje doze do 1,0 mg/m2 ili daljnje smanjenje doze do 0,5 mg/m2 u naknadnim ciklusima na temelju bolesnikove podnošljivosti.