qanastek/EMEA-V3 huggingface dataset:
It cannot be excluded that sorafenib may increase the concentrations of concomitantly administered substrates of CYP2C9.
Ma jistax jiġi eskluż li sorafenib jista ’ jżid il- konċentrazzjonijiet ta ’ substrati ta ’ CYP2C9 li jingħataw fl- istess waqt.
The concomitant treatment with Nexavar and warfarin, a CYP2C9 substrate, did not result in changes in mean PT-INR compared to placebo.
Kura fl- istess waqt b’ Nexavar u warfarin, substrat ta ’ CYP2C9, ma wassalx għall- bidliet f’ PT- INR medju meta mqabbel mal- plaċebo.
However, patients taking warfarin or phenprocoumon should have their INR checked regularly (see section 4.4).
Madankollu, pazjenti li qed jieħdu warfarin jew phenprocoumon għandu jkollhom l- INR tagħhom iċċekkjat regolarment (ara sezzjoni 4. 4).
CYP2B6 and CYP2C8 substrates:
4 Substrati ta ’ CYP2B6 u CYP2C8:
Sorafenib inhibited CYP2B6 and CYP2C8 in vitro, but the clinical relevance of this inhibition has not been evaluated.
Sorafenib jinibixxi CYP2B6 u CYP2C8 in vitro, iżda r- rilevanza klinika ta ’ din l- inibizzjoni ma ġietx evalwata.
It cannot be excluded that sorafenib may increase the concentrations of concomitantly administered substrates of CYP2B6 (e. g. bupropion, cyclophosphamide, efavirenz, ifosfamide, methadone) and CYP2C8 (e. g. paclitaxel, amodiaquine, repaglinide).
Ma jistax jiġi eskluż li sorafenib jista ’ jżid il - konċentrazzjonijiet ta ’ substrati ta ’ CYP2B6 (e. ż. bupropion, cyclophosphamide, efavirenz, ifosfamide, methadone) u ta ’ CYP2C8 (e. ż. paclitaxel, amodiaquine, repaglinide) mogħtija fl- istess ħin.
UGT1A1 and UGT1A9 substrates:
Substrati ta ’ UGT1A1 u UGT1A9:
In vitro, sorafenib inhibited glucuronidation via UGT1A1 and UGT1A9.
In vitro, sorafenib inibixxa l- glukoronidazzjoni permezz ta ’ UGT1A1 u UGT1A9.
The clinical relevance of this finding is unknown (see below and section 4.4).
Ir- rilevanza klinika ta ’ din is- sejba mhix magħrufa (ara isfel u sezzjoni 4. 4).
CYP isoforms selective substrates:
Substrati selettivi ta ’ isoformi ta ’ CYP:
Concomitant administration of sorafenib and midazolam, dextromethorphan or omeprazole, which are substrates for cytochromes CYP3A4, CYP2D6 and CYP2C19 respectively, did not alter the exposure of these agents.
L- għotja ta ’ sorafenib flimkien ma ’ midazolam, dextromethorphan jew omeprazole, li huma substrati għal ċitokromji CYP3A4, CYP2D6 u CYP2C19 rispettivament, ma biddlitx l- espożizzjoni ta ’ dawn l- aġenti.
This indicates that sorafenib is neither an inhibitor nor an inducer of these cytochrome P450 isoenzymes.
Dan jindika li sorafenib la huwa inibitur u lanqas induttur ta ’ dawn l- isożimi taċ- ċitokromju P450.
Therefore, clinical pharmacokinetic interactions of sorafenib with substrates of these enzymes are unlikely.
Għalhekk, interazzjonijiet farmakokinetiċi kliniċi ta ’ sorafenib ma ’ substrati ta ’ dawn l- isożimi mhumiex probabbli.
4 In vitro studies of CYP enzyme induction:
Studji in vitro ta ’ l- induzzjoni ta ’ l- enżima CYP:
CYP1A2 and CYP3A4 activities were not altered after treatment of cultured human hepatocytes with sorafenib, indicating that sorafenib is unlikely to be an inducer of CYP1A2 and CYP3A4.
Dan jindika li sorafenib x’ aktarx mhux induttur ta ’ CYP1A2 u CYP3A4.
P-gp-substrates:
Substrati ta ’ P- gp:
In vitro, sorafenib has been shown to inhibit the transport protein p-glycoprotein (P- gp).
In vitro, sorafenib intwera li jinibixxi l- ġarr tal- proteina p- glycoprotein (P- gp).
Increased plasma concentrations of P-gp substrates such as digoxin cannot be excluded with concomitant treatment with sorafenib.
Żjieda fil- konċentrazzjonijiet tal- plażma ta ’ substrati ta ’ P- gp bħal digoxin ma tistax tiġi eskluża b’ kura flimkien ma ’ sorafenib.
Combination with other anti-neoplastic agents:
Kombinazzjoni ma ’ aġenti oħra anti- neoplastiċi:
In clinical studies Nexavar has been administered with a variety of other anti-neoplastic agents at their commonly used dosing regimens including gemcitabine, oxaliplatin, doxorubicin, and irinotecan.
Fi studji kliniċi, Nexavar ingħata ma ’ varjetà ta ’ aġenti anti- neoplastiċi fil- korsijiet ta ’ dożaġġ li ġeneralment jiġu wżati, inkluż gemcitabine, oxaliplatin, doxorubicin, u irinotecan.
Sorafenib had no effect on the pharmacokinetics of gemcitabine or oxaliplatin.
Sorafenib ma kellu l- ebda effett fuq il- farmakokinetika ta ’ gemcitabine jew ta ’ oxaliplatin.
Concomitant treatment with Nexavar resulted in a 21% increase in the AUC of doxorubicin.
Kura flimkien ma ’ Nexavar wassal għal żjieda ta ’ 21% fl- AUC ta ’ doxorubicin.
When administered with irinotecan, whose active metabolite SN-38 is further metabolised by the UGT1A1 pathway, there was a 67 - 120% increase in the AUC of SN-38 and a 26 - 42% increase in the AUC of irinotecan.
Meta ingħata ma ’ irinotecan, li l- metabolita attiv tiegħu SN- 38 jiġi mmetabolizzat aktar mir- rotta UGT1A1, kien hemm żjieda ta ’ 67 - 120% fl- AUC ta ’ SN- 38 u żjieda ta ’ 26 - 42% fl- AUC ta ’ irinotecan.
The clinical significance of these findings is unknown (see section 4.4).
Is- sinifikat kliniku ta ’ dawn is- sejbiet mhux magħruf (ara sezzjoni 4. 4).
Docetaxel (75 or 100 mg/ m2 administered once every 21 days) when co-administered with sorafenib (200 mg twice daily or 400 mg twice daily administered on Days 2 through 19 of a 21-day cycle with a 3-day break in dosing around administration of docetaxel) resulted in a 36-80% increase in docetaxel AUC and a 16-32% increase in docetaxel Cmax.
Docetaxel (75 jew 100 mg/ m2 mogħti darba kull 21 ġurnata) meta jingħata flimkien ma ’ sorafenib (200 mg darbtejn kuljum jew 400 mg darbtejn kuljum mogħtija fi Ġranet 2 sa 19 minn ċiklu ta ’ 21 - ġurnata b’ pawża ta’ 3- ijiem fid- dożaġġ waqt l- għotja ta ’ docetaxel) wassal għall- żjieda ta ’ 36 - 80% fl- AUC ta ’ docetaxel AUC u żjieda ta ’ 16 - 32% f’ Cmax ta ’ docetaxel.
Caution is recommended when sorafenib is co-administered with docetaxel (see section 4.4).
Kawtela hija rakkomandata meta sorafenib jingħata flimkien ma ’ docetaxel (ara sezzjoni 4. 4).
There are no data on the use of sorafenib in pregnant women.
Ma hemmx tagħrif dwar l- użu ta ’ sorafenib f’ nisa tqal.
Studies in animals have shown reproductive toxicity including malformations (see section 5.3).
Studji fl- annimali wrew tossiċità riproduttiva inkluż malformazzjonijiet (ara sezzjoni 5. 3).
In rats, sorafenib and its metabolites were demonstrated to cross the placenta and sorafenib is anticipated to cause harmful effects on the foetus.
Fil- firien, sorafenib u l- metaboliti tiegħu intwerew li jgħaddu mill- plaċenta u sorafenib mistenni li jikkawża effetti ħżiena fuq il- fetu.
Nexavar should not be used during pregnancy unless clearly necessary, after careful consideration of the needs of the mother and the risk to the foetus.
Nexavar m’ għandux jintuża waqt it- tqala ħlief meta hemm bżonn speċifiku, wara konsiderazzjoni b’ attenzjoni tal - bżonnijiet ta ’ l- omm u r- riskji għall- fetu.
Women of childbearing potential must use effective contraception during treatment.
Nisa b’ potenzjal li jkollhom it- tfal għandhom jużaw kontraċezzjoni effettiva waqt il- kura.
Results from animal studies further indicate that sorafenib can impair male and female fertility (see section 5.3).
Riżultati minn studji fl- annimali komplew jindikaw li sorafenib jista ’ jtellef il- fertilità tar- raġel u l- mara (ara sezzjoni 5. 3).
It is not known whether sorafenib is excreted in human milk.
Mhux magħruf jekk sorafenib jitneħħa fil- ħalib uman.
In animals, sorafenib and/ or its metabolites were excreted in milk.
Fl- annimali, sorafenib u/ jew il- metaboliti tiegħu kienu mneħħija fil- ħalib.
Because sorafenib could harm infant growth and development (see section 5.3), women must not breast-feed during sorafenib treatment.
Minħabba li sorafenib jista ’ jagħmel ħsara lit- tkabbir u l- iżvilupp tat- tarbija (ara sezzjoni 5. 3), in- nisa m’ għnadhomx ireddgħu waqt kura b’ sorafenib.
There is no evidence that Nexavar affects the ability to drive or to operate machinery.
M’ hemmx evidenza li Nexavar jaffettwa l- ħila biex issuq jew tħaddem magni.
The most common adverse reactions were diarrhoea, rash, alopecia and hand-foot syndrome (corresponds to palmar plantar erythrodysaesthesia syndrome in MedDRA).
L- aktar effetti avversi komuni kienu dijarrea, raxx, alopeċja u sindrome ta ’ l- id u s- sieq (li jikkorrespondi għas- sindromu ta ’ eritrodisasteżija palmari- plantari f’ MedDRA).
Adverse reactions reported in at least 5% of patients in any treatment group – study 11213 in renal cell carcinoma (see study 1 in section 5.1).
Reazzjonijiet avversi rrappurtati f’ ta ’ l- inqas 5% tal- pazjenti f’ kull grupp ta ’ kura – studju 11213 fuq karċinoma taċ- ċellula renali (ara studju 1 f’ sezzjoni 5. 1).
System organ
Sistema tal -
Placebo N=451
Plaċebo N=451
class Metabolism and
klassifika tal - organi Disturbi fil -
Preferred term
ppreferut
all grades grade 3 grade 4 all grades grade 3 grade 4
grad 4 kull grad grad 3
nutrition disorders Nervous system
metaboliżmu u n- nutrizzjoni Disturbi fis -
anorexia
0% 5% < 1%
headache
0% 3% 0%
0%
2% 0% 2% < 1% < 1% 0%
12% 2% < 1% 1% < 1% 6% 0% 0% 2% 0% 38% 2% 0% 9% < 1% 16% < 1% 0% 12% < 1% 10% < 1% 0% 6% < 1% 6% 0% 0% 3% 0%
< 1% 1% < 1% 0% 2% 0% 0% 9% < 1% 0% 12% < 1% 0% 6% < 1% 0% 3% 0%
0% 0% 0% 0% 0% 0%
0% 0% 0% 0% 0% 0%
rash alopecia hand foot syndrome**
raxx alopeċja sindromu ta ’ l- id u
pruritus erythema dry skin skin exfoliation
ħakk eritema ġilda xotta tqaxxir tal- ġilda
17% < 1% 0% 4% 0% 15% 0% 0% 4% 0% 11% 0% 0% 2% 0% 7% < 1% 0% 2% 0%
0% 4% 0% 0% 4% 0% 0% 2% 0% 0% 2% 0%
Musculoskeletal and connective
Disturbi muskolu -
arthralgia
artralġja uġigħ fl -
6% < 1% 0% 3% 0%
0% 3% 0%
tissue disorders General disorders and
skeltrali u tal - connective tissue
pain in extremity fatigue
estremitajiet
6% < 1% 0% 2% 0% 15% 2% 0% 11% < 1%
0% 2% 0%
administration site conditions
Disturbi ġenerali u kondizzjonijiet
asthenia
0% 11% < 1%
Adverse reactions reported in at least 5% of patients in any treatment group – study 100554 in hepatocellular carcinoma (see study 3 in section 5.1).
Reazzjonijiet avversi rrappurtati f’ ta ’ l- inqas 5% tal- pazjenti f’ kull grupp ta ’ kura – studju 100554 fuq karċinoma epatoċellulari (ara studju 3 f’ sezzjoni 5. 1).
Placebo N= 302
Plaċebo N= 302
term
ppreferut
all grades
kull grad
grade 4 all grades grade 3
grad 4 kull grad grad 3
nutrition disorders
metaboliżmu u n- nutrizzjoni
anorexia
anoressija
0% 3% < 1%
0% 3% < 1%
gastrointestinal disorders
Disturbi gastro - intestinali
diarrhoea nausea abdominal
dijarrea tqalligħ uġigħ fl -
0% 11% 2% 0% 8% 1%
0% 11% 2% 0% 8% 1%
pain
addome
Skin and
Disturbi fil- ġilda
vomiting hand foot
rimettar sindromu ta ’
subcutaneous
u fit- tessuti ta ’ taħt il- ġilda
syndrome**
l- id u s - sieq **
0% 2% 0%
0% 2% 0%
alopecia rash pruritus dry skin
alopeċja raxx ħakk ġilda xotta
0% 2% 0% 0% 8% 0% 0% 7% < 1% 0% 4% 0%
0% 2% 0% 0% 8% 0% 0% 7% < 1% 0% 4% 0%
General disorders and
Disturbi ġenerali u kondizzjonijiet
fatigue
għeja
< 1% 13% 3%
< 1% 13% 3%
administration site conditions
ta 'mnejn jingħata Investigazzjoniji
asthenia
astejna
< 1% 2% < 1%
< 1% 2% < 1%
Investigations
et Disturbi respiratorji,
Respiratory, thoracic and
telf ta ’ piż
0% < 1% 0%
0% < 1% 0%
mediastinal disorders
toraċiċi u medjastinali
hoarseness
ħanqa
Adverse reactions reported in multiple clinical trials are listed below in Table 3, by system organ class (in MedDRA) and frequency.
Reazzjonijiet avversi rrappurtati fi provi kliniċi multipli huma mniżżla f’ Tabella 3 isfel, skond is - sistema tal- klassifikazzjoni tal- organi (f’ MedDRA) u l- frekwenza.
Frequencies are defined as: very common (≥ 1/ 10), common (≥ 1/ 100, < 1/ 10), uncommon (≥ 1/ 1,000, < 1/ 100).
Il- frekwenzi huma mniżżla bħala: komuni ħafna (≥1/ 10), komuni (≥1/ 100 sa < 1/ 10), mhux komuni (≥1/ 1, 000 sa < 1/ 100).
Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
F’ kull grupp ta ’ frekwenza, l- effetti li huma l- aktar serji huma mniżżlin l- ewwel, segwiti minn dawk anqas serji.
7 Table 3:
7 Tabella 3:
All adverse reactions reported in patients in multiple clinical trials
Kull reazzjoni avversa rrappurtata f’ pazjenti minn provi kliniċi multipli
Infections and infestations
Sistema tal - klassifikazzjoni tal - organi
≥ 1/ 10
Komuni Ħafna ≥ 1/ 10
≥ 1/ 100, < 1/ 10
Komuni ≥1/ 100, < 1/ 10
≥ 1/ 1,000, < 1/ 100 folliculitis infection
Mhux Komuni ≥1/ 1, 000, < 1/ 100
Blood and lymphatic system disorders
Infezzjonijiet u infestazzjonijiet
lymphopenia
follikulite infezzjoni
leucopenia neutropenia anaemia thrombocytopenia
Disturbi tad- demm u tas- sistema limfatika
Immune system disorders
limfopenja
hypersensitivity reactions (including skin reactions and urticaria)
lewkopenja newtropenja anemija tromboċitopenja
Endocrine disorders
Disturbi fis- sistema immuni Disturbi fis- sistema endokrinarja
hypothyroidism
reazzjonijiet ta ’ ipersesittività (inkluż reazzjonijiet tal- ġilda u urtikarja) ipotirojdiżmu iponatrimja
hypophosphataemia
ipofosfatimja
hyponatraemia dehydration
diżidratazzjoni
depression
depressjoni
Nervous system disorders Ear and labyrinth disorders
Disturbi fis- sistema nervuża Disturbi fil- widnejn u fis- sistema labirintika
peripheral sensory neuropathy tinnitus
newropatija sensittività periferali żanżin fil- widnejn
reversible posterior leukoencephalopathy*
lewkoenċelopatija posterjuri riversibbli *
myocardial ischaemia and infarction* congestive heart failure*
iskemija u infart mijokardjali * insuffiċjenza tal- qalb konġestiva *
haemorrhage (inc. gastrointestinal*, respiratory tract* and cerebral haemorrhage*) hypertension
emorraġġija (ink. emorraġġija gastro - intestinali *, fil - passaġġ respiratorju * u ċerebrali *) ipertensjoni
hypertensive crisis*
kriżi ipertensiva *
hoarseness
stitikezza
rhinorrhoea
intestinali
Gastrointestinal disorders Hepatobiliary disorders
Disturbi fil- fwied u fil- marrara
diarrhoea nausea vomiting
rimettar
constipation stomatitis (including dry mouth and glossodynia) dyspepsia dysphagia
ħalq xott u glossodinja) dispepsja disfaġija
gastro oesophageal reflux disease pancreatitis gastritis gastrointestinal perforations* increase in bilirubin and jaundice cholecystitis cholangitis
pankrejatite gastrite perforazzjoni gastro - intestinali * żjieda fil- bilirubin u suffejra, koleċistite, kolanġite
8 System organ class
8 Sistema tal - klassifikazzjoni tal - organi
≥ 1/ 1,000, < 1/ 100
Mhux Komuni ≥1/ 1, 000, < 1/ 100
Skin and subcutaneous tissue disorders
raxx Disturbi fil- gilda u fit- tessuti ta ’ taħt il -
rash alopecia hand foot syndrome** erythema pruritus
sindromu ta ’ l- id u s -
dry skin dermatitis exfoliative acne skin desquamation
tqaxxir tal- ġilda
eczema erythema multiforme minor keratoacanthoma/ squamous cell cancer of the skin
keratoacantoma/ kanċ er taċ- ċelluli skwamużi tal- ġilda
arthralgia myalgia
artralġja mijalġja
renal failure
insuffiċjenza renali
Reproductive system and breast disorders
Disturbi fis- sistema riproduttiva u tas - sider
gynaecomastia
ginekomastja
fatigue pain (including mouth, abdominal, bone, tumour pain and headache)
fl- għadam, uġigħ tat - tumur u uġigħ ta ’ ras)
asthenia fever influenza like illness
Investigazzjonijiet
Investigations
tnaqqis fil- piż
increased amylase increased lipase
żjieda fil- lipase
weight decreased transient increase in transaminases
żjieda temporanja fit - transaminases
transient increase in blood alkaline phosphatase, INR abnormal, prothrombin level abnormal
alkaline phosphatase fid- demm, INR anormali, livell anormali ta ’ prothrombin
* The adverse reactions may have a life-threatening or fatal outcome. ** hand foot syndrome corresponds to palmar plantar erythrodysaesthesia syndrome in MedDRA
* Reazzjonijiet avversi li jista ’ jkollhom riżultat li jista ’ jipperikola l- ħajja jew jikkawża l- mewt. ** sindromu ta ’ l- id u s- sieq jikkorrespondi għas- sindromu eritrodisasteżija palmari- plantari fil - MedDRA
Laboratory test abnormalities Increased lipase and amylase were very commonly reported.
Anormalitajiet fit- testijiet tal- laboratorju Żjieda fil- lipase u amylase kienu rrappurtati b’ mod komuni ħafna.
CTCAE Grade 3 or 4 lipase elevations occurred in 11% and 9% of patients in the Nexavar group in study 1 (RCC) and study 3 (HCC), respectively, compared to 7% and 9% of patients in the placebo group.
L- elevazzjonijiet tal- lipase CTCAE ta ’ Grad 3 jew 4 seħħew f’ 11% u f’ 9% tal- pazjenti fil- grupp ta ’ Nexavar fi studji 1 (RCC) u f’ studju 3 (HCC), rispettivament, meta mqabbla ma ’ 7% u ma ’ 9% tal- pazjenti fil- grupp tal- plaċebo.
CTCAE Grade 3 or 4 amylase elevations were reported in 1% and 2% of patients in the Nexavar group in study 1 and study 3, respectively, compared to 3% of patients in each placebo group.
Elevazzjonijiet ta ’ amylase CTCAE ta ’ Grad 3 jew 4 ġew irrappurtati f’ 1% u f’ 2% tal- pazjenti fil - grupp b’ Nexavar fi studju 1 u studju 3 rispettivament, meta mqabbla ma ’ 3% tal- pazjenti f’ kull grupp plaċebo.
Clinical pancreatitis was reported in 2 of 451 Nexavar treated patients (CTCAE Grade 4) in study 1, 1 of 297 Nexavar treated patients in study 3 (CTCAE Grade 2), and 1 of 451 patients (CTCAE Grade 2) in the placebo group in study 1.
Pakrejatite klinika kienet irrappurtata f’ 2 minn 451 pazjent kkurat b’ Nexavar (CTCAE ta ’ Grad 4) f’ studju 1, 1 minn 297 tal- pazjenti kkurati b’ Nexavar f’ studju 3 (CTCAE ta ’ Grad 2), u 1 minn 451 pazjent (CTCAE ta ’ Grad 2) fil- grupp tal- plaċebo ta ’ studju 1.
Hypophosphataemia was a very common laboratory finding, observed in 45% and 35% of Nexavar treated patients compared to 12% and 11% of placebo patients in study 1 and study 3, respectively.
Ipofosfatimja kienet sejba tal- laboratorju komuni ħafna, osservata f’ 45% u f’ 35% tal- pazjenti kkurati b’ Nexavar meta mqabbla ma ’ 12% u ma ’ 11% tal- pazjenti bil- plaċebo fi studju 1 u studju 3 rispettivament.
CTCAE Grade 3 hypophosphataemia (1 – 2 mg/ dl) in study 1 occurred in 13% of Nexavar treated patients and 3% of patients in the placebo group, in study 3 in 11% of Nexavar treated patients and 2% of patients in the placebo group.
Ipofosfatemija CTCAE ta ’ Grad 3 (1 – 2 mg/ dl) f’ studju 1 seħhet fi 13% tal- pazjenti kkurati b’ Nexavar u 3% tal- pazjenti fil- grupp tal- plaċebo, f’ studju 3 11% tal- pazjenti kkurati b’ Nexavar u 2% tal- pazjenti fil- grupp plaċebo.
There were no cases of CTCAE Grade 4 hypophosphataemia (< 1 mg/ dl) reported in either Nexavar or placebo patients in study 1, and 1 case in the placebo group in study 3.
Ma kienx hemm każijiet ta ’ ipofosfatemija CTCAE ta ’ Grad 4 (< 1 mg/ dl) rrappurtati jew fil- pazjenti b’ Nexavar jew bil- plaċebo f’ studju 1, u każ wieħed fil - grupp plaċebo f’ studju 3.
The aetiology of hypophosphataemia associated with Nexavar is not known.
L- etjoloġija ta ’ ipofosfatemija assoċjata ma ’ Nexavar mhix magħrufa.
CTCAE Grade 3 or 4 laboratory abnormalities occurring in ≥ 5% of Nexavar treated patients included lymphopenia and neutropenia.
Anomaliji tal- laboratorju ta ’ CTCAE ta ’ Grad 3 jew 4 seħhew f’ ≥ 5% tal- pazjenti kkurati b’ Nexavar inkluż limfopenja u newtropenja
9 4.9 Overdose
9 4. 9 Doża eċċessiva
There is no specific treatment for Nexavar overdose.
M’ hemmx kura speċifika għall- doża eċċessiva ta ’ Nexavar.
The highest dose of sorafenib studied clinically is 800 mg twice daily.
L- għola doża ta ’ sorafenib studjata klinikament kienet 800 mg darbtejn kuljum.
The adverse events observed at this dose were primarily diarrhoea and dermatological events.
L- effetti avversi osservati f’ din id- doża kienu primarjament dijarrea u episodji dermatoloġiċi.
In the event of suspected overdose Nexavar should be withheld and supportive care instituted where necessary.
F’ każ ta ’ suspett ta ’ doża eċċessiva Nexavar għandu jitwaqqaf u meta meħtieġ, għandha tinbeda kura ta ’ support.
Protein kinase inhibitors, ATC code:
Inibituri tal- proteina kinase, Kodiċi ATC:
Sorafenib is a multikinase inhibitor which has demonstrated both anti-proliferative and anti- angiogenic properties in vitro and in vivo.
Sorafenib huwa inibitur ta ’ multikinase li in vitro u in vivo wera kemm kwalitajiet anti- proliferattivi kif ukoll anti- anġjoġeniċi.
Mechanism of action and pharmacodynamic effects Sorafenib is a multikinase inhibitor that decreases tumour cell proliferation in vitro.
Mekkaniżmu ta ’ azzjoni u effetti farmakodinamiċi Sorafenib huwa inibitur ta ’ multikinase li in vitro jnaqqas il- proliferazzjoni taċ- ċelloli tat- tumur.
Sorafenib inhibits tumour growth of a broad spectrum of human tumour xenografts in athymic mice accompanied by a reduction of tumour angiogenesis.
Flimkien ma ’ tnaqqis fl- anġjoġenesi tat- tumur, sorafenib jinibixxi t- tkabbir tat- tumur f’ varjeta kbira ta ’ tumori umani trapjantati fi ġrieden atimiċi.
Sorafenib inhibits the activity of targets present in the tumour cell (CRAF, BRAF, V600E BRAF, c-KIT, and FLT-3) and in the tumour vasculature (CRAF, VEGFR-2, VEGFR-3, and PDGFR-ß).
Sorafenib jinibixxi l- attività ta ’ miri preżenti fiċ- ċellola tat- tumur (CRAF, BRAF, V600E BRAF, c- KIT, u FLT- 3) u fil- vaskulatura tat- tumur (CRAF, VEGFR- 2, VEGFR- 3, u PDGFR- ß).
RAF kinases are serine/ threonine kinases, whereas c-KIT, FLT-3, VEGFR-2, VEGFR-3, and PDGFR-ß are receptor tyrosine kinases.
RAF kinases huma serine/ threonine kinases, filwaqt li c- KIT, FLT- 3, VEGFR- 2, VEGFR- 3, u PDGFR- ß huma tyrosine kinases tar- riċettur.
The clinical safety and efficacy of Nexavar have been studied in patients with hepatocellular carcinoma (HCC) and in patients with advanced renal cell carcinoma (RCC).
L- effikaċja u s- sigurtà klinika ta ’ Nexavar ġew studjati f’ pazjenti b’ karċinoma epatoċellulari (HCC) u f’ pazjenti b’ karċinoma avvanzat taċ- ċellula renali (RCC).
Hepatocellular carcinoma Study 3 (study 100554) was a Phase III, international, multi-centre, randomised, double blind, placebo-controlled study in 602 patients with hepatocellular carcinoma.
Karċinoma epatoċellulari Studju 3 (studju 100554) kien studju ta ’ Fażi III, internazzjonali, b’ ħafna ċentri, randomised, double blind u kkontrollat bil- plaċebo f’ 602 pazjent b’ karċinoma epatoċellulari.
Demographics and baseline disease characteristics were comparable between the Nexavar and the placebo group with regard to ECOG status (status 0:
Demografika u linja bażi tal - karatteristiċi tal- marda kienu komparabbli bejn il- grupp ta ’ Nexavar u tal- plaċebo fir- rigward ta ’ l- istat ECOG (stat 0:
54%; status 1:
54%; stat 1:
39%; status 2:
39%; stat 2:
7%), TNM stage (stage I: < 1% vs. < 1%; stage II:
7%), stadju TNM (stadju I: < 1% vs. < 1%; stadju II:
8.3%; stage III:
8. 3%; stadju III:
37.8% vs.
37. 8% vs.
43.6%; stage IV:
43. 6%; stadju IV:
50.8% vs.
50. 8% vs.
46.9%), and BCLC stage (stage B:
46. 9%), u stadju BCLC (stadju B:
16.8%; stage C:
16. 8%; stadju C:
83.2%; stage D: < 1% vs.
83. 2%; stadju D: < 1% vs.
The study was stopped after a planned interim analysis of OS had crossed the prespecified efficacy boundary.
L- istudju twaqqaf wara li analiżi interim ippjanata ta ’ OS kienet qabżet il- livell ta ’ effikaċja speċifikat minn qabel.
This OS analysis showed a statistically significant advantage for Nexavar over placebo for OS (HR:
Din l- analiżi ta ’ OS wriet vantaġġ statistikament sinifikanti għal Nexavar fuq plaċebo għal OS (HR:
0.69, p = 0.00058, see Table 4).
0. 69, p = 0. 00058, ara Tabella 4).
In the prespecified stratification factors (ECOG status, presence or absence of macroscopic vascular invasion and/ or extrahepatic tumour spread) the hazard ratio consistently favoured Nexavar over placebo.
Fil- fatturi ta ’ stratifikazzjoni ECOG speċifikati minn qabel (stat ECOG, preżenza jew nuqqas ta ’ invażjoni vaskulari makroskopika u/ jew firxa tat- tumur barra mill- fwied) il- proporzjon ta ’ periklu iffavurixxa b’ mod konsistenti Nexavar fuq plaċebo.
The descriptive subgroup analysis suggested a potentially less pronounced treatment effect for the subgroups of patients below 65 years of age and those with metastatic disease.
L- analiżi deskrittiva tas- sottogrupp issuġġeriet effett ta ’ kura potenzjalment inqas qawwi għas- sottogruppi ta ’ pazjenti ta ’ età inqas minn 65 sena u għal dawk b’ marda metastatika.
There are limited data from this study in patients with Child Pugh B liver impairment and only one patient with Child Pugh C had been included.
Hemm tagħrif limitat minn dan l - istudju f’ pazjenti b’ indeboliment tal- fwied Child Pugh B u kien inkluż pażjent wieħed biss b’ Child Pugh C.
Efficacy Results from study 3 (study 100554) in hepatocellular carcinoma
Riżultati ta ’ Effikaċja minn studju 3 (studju 100554) dwar karċinoma epatoċellulari
Placebo (N=303)
Plaċebo (N=303)
P-value
Valur P
Overall Survival (OS) [median, weeks (95% CI)]
Sopravvivenza Globali (OS) [medjan, ġimgħat (95% CI)]
Time to Progression (TTP) [median, weeks (95% CI)]**
Ħin sal- Progressjoni (TTP) [medjan, ġimgħat (95% CI)] **
CI=Confidence interval, HR=Hazard ratio (Nexavar over placebo) *statistically significant as the p-value was below the prespecified O’ Brien Fleming stopping boundary of 0.0077 **independent radiological review
CI=Intervall ta ’ Kunfidenza, HR=Proporzjon ta ’ Periklu (Nexavar fuq plaċebo) * statistikament sinifikanti minħabba li l- valur p kien inqas mil- livell ta ’ waqfien O’ Brien Fleming speċifikat minn qabel ta ’ 0. 0077 ** analiżi radjoloġika indipendenti
Renal cell carcinoma The safety and efficacy of Nexavar in the treatment of advanced renal cell carcinoma (RCC) were investigated in two clinical studies:
Karċinoma taċ- ċellula renali Is- sigurtà u l- effikaċja ta ’ Nexavar fil- kura ta ’ karċinoma avvanzata taċ- ċelloli renali (RCC) kienu nvestigati f’ żewġ studji kliniċi:
Study 1 (study 11213) was a Phase III, multi-centre, randomised, double blind, placebo-controlled study in 903 patients.
Studju 1 (studju 11213) kien studju ta ’ Fażi III, f’ iktar minn sit wieħed, randomised, double blind u kkontrollat bil- plaċebo f’ 903 pazjent.
Only patients with clear cell renal carcinoma and low and intermediate risk MSKCC (Memorial Sloan Kettering Cancer Center) were included.
Kienu nklużi biss pazjenti b’ karċinoma taċ- ċelloli renali ċara u b’ riskju MSKCC (Memorial Sloan Kettering Cancer Center) baxx u intermedju.
The primary endpoints were overall survival and progression-free survival (PFS).
Il- miri primarji kienu sopravivenza totali u sopravivenza bla progressjoni (PFS).
Approximately half of the patients had an ECOG performance status of 0, and half of the patients were in the low risk MSKCC prognostic group.
Madwar nofs il- pazjenti kellhom stat ta ’ eżekuzzjoni ta ’ ECOG ta ’ 0, u nofs il- pazjenti kienu fil- grupp pronostiku b’ riskju baxx skond MSKCC.
PFS was evaluated by blinded independent radiological review using RECIST criteria.
PFS kien evalwat skond kriterji RECIST minn reviżjoni radjoloġika indipendenti għamja.
The PFS analysis was conducted at 342 events in 769 patients.
L- analiżi ta ’ PFS kienet kondotta fuq 342 episodju f’ 769 pazjent.
The median PFS was 167 days for patients randomised to Nexavar compared to 84 days for placebo patients (HR = 0.44; 95% CI:
Il- PFS medjan kien 167 ġurnata għall- pazjenti randomized għal Nexavar meta mqabbla ma ’ 84 ġurnata f’ pazjenti bil- plaċebo (HR = 0. 44; 95% CI:
0.35 - 0.55; p < 0.000001).
0. 35 - 0. 55; p < 0. 000001).
Age, MSKCC prognostic group, ECOG PS and prior therapy did not affect the treatment effect size.
Eta ’, grupp pronjostiku MSKCC, ECOG PS u terapija minn qabel ma affettwatx id- daqs ta ’ l- effett tal- kura.
An interim analysis (second interim analysis) for overall survival was conducted at 367 deaths in 903 patients.
Analiżi fl- intervall (it- tieni analiżi fl- intervall) għas- sopravivenza totali kien kondott fuq 367 mewt f’ 903 pazjent.
The nominal alpha value for this analysis was 0.0094.
Il- valur nominali alfa għal dan l- analiżi kien 0. 0094.
The median survival was 19.3 months for patients randomised to Nexavar compared to 15.9 months for placebo patients (HR = 0.77; 95% CI:
Is- sopravivenza medjana kienet 19. 3 xhur għall- pazjenti randomised għal Nexavar meta mqabbla ma ’ 15. 9 xhur għall- pazjenti fuq il - plaċebo (HR = 0. 77; 95% CI:
At the time of this analysis, about 200 patients had crossed-over to sorafenib from the placebo group.
Fiż- żmien ta ’ dan l- analiżi, madwar 200 pazjent qalbu mill- grupp plaċebo għal sorafenib.
Study 2 was a Phase II, discontinuation study in patients with metastatic malignancies, including RCC.
Studju 2 kien studju ta ’ Fażi II b’ waqfien fil- kura f’ pazjenti b’ tumuri malinni metastatiċi, inkluż RCC.
Patients with stable disease on therapy with Nexavar were randomised to placebo or continued Nexavar therapy.
Pazjenti b’ marda stabbli fuq terapija b’ Nexavar kienu randomised għall- plaċebo jew komplew it - terapija b’ Nexavar.
Progression-free survival in patients with RCC was significantly longer in the Nexavar group (163 days) than in the placebo group (41 days) (p = 0.0001, HR = 0.29).
Sopravivenza bla progressjoni f’ pazjenti b’ RCC kienet sinifikatament itwal fil - grupp b’ Nexavar (163 ġurnata) milli fil- ġrupp bil- plaċebo (41 ġurnata) (p = 0. 0001, HR = 0. 29).
Absorption and distribution:
Assorbiment u distribuzzjoni:
After administration of Nexavar tablets the mean relative bioavailability is 38 - 49% when compared to an oral solution.
Wara amministrazzjoni ta ’ pilloli Nexavar il- biodisponibiltà relattiva medja hija ta ’ 38 - 49% meta mqabbla ma ’ soluzzjoni li tittieħed mill- ħalq.
The absolute bioavailability is not known.
Il- biodisponibilità assoluta mhux magħrufa.
Following oral administration sorafenib reaches peak plasma concentrations in approximately 3 hours.
Wara amministrazzjoni li tittieħed mill- ħalq, sorafenib jilħaq l- għola konċetrazzjonijiet fil- plażma wara madwar 3 sigħat.
When given with a high-fat meal sorafenib absorption was reduced by 30% compared to administration in the fasted state.
Meta ngħata flimkien ma ’ ikla b’ ħafna xaħam l- assorbiment ta ’ sorafenib naqas bi 30% meta mqabbel ma ’ amministrazzjoni fi stat sajjem.
Mean Cmax and AUC increased less than proportionally beyond doses of 400 mg administered twice daily.
Il- valur medju ta ’ Cmax u AUC żdiedu inqas minn proporzjalment b’ dożi ta ’ aktar minn 400 mg mogħtija darbtejn kuljum.
In vitro binding of sorafenib to human plasma proteins is 99.5%.
It- twaħħil in vitro ta ’ sorafenib ma ’ proteini tal- plażma umana huwa 99. 5%.
Multiple dosing of Nexavar for 7 days resulted in a 2.5- to 7-fold accumulation compared to single dose administration.
Dożaġġ multiplu ta ’ Nexavar għal 7 ijiem irriżulta f’ akkumulazzjoni ta ’ 2. 5 - sa 7- darbiet meta mqabbel ma ’ għotja ta ’ doża waħda.
Steady state plasma sorafenib concentrations are achieved within 7 days, with a peak to trough ratio of mean concentrations of less than 2.
Konċetrazzjonijiet fil- plażma fi stat stabbli ta ’ sorafenib intlaħqu
11 Metabolism and elimination:
Metaboliżmu u eliminazzjoni:
Sorafenib is metabolised primarily in the liver and undergoes oxidative metabolism, mediated by CYP 3A4, as well as glucuronidation mediated by UGT1A9.
Il- half- life ta ’ eliminazzjoni ta ’ sorafenib hija ta ’ madwar 25 - 48 siegħa, Sorafenib huwa metabolizzat primarjament fil- fwied u jgħaddi minn metaboliżmu ossidattiv, medjat minn CYP 3A4, kif ukoll glukuronidazzjoni medjata minn UGT1A9.
Sorafenib accounts for approximately 70 - 85% of the circulating analytes in plasma at steady state.
Sorafenib jirrappreżenta madwar 70 - 85% ta ’ l- analiti preżenti fl- plażma fi stat stabbli.
Eight metabolites of sorafenib have been identified, of which five have been detected in plasma.
Ġew identifikati tmin metaboliti ta ’ sorafenib, li ħamsa minnhom kienu osservatifil- plażma.
The main circulating metabolite of sorafenib in plasma, the pyridine N-oxide, shows in vitro potency similar to that of sorafenib.
Il- metabolita prinċipali ta ’ sorafenib li qed jiċċirkola fil- plażma, pyridine N- oxide, juri potenza in vitro simili għal dik ta ’ sorafenib.
This metabolite comprises approximately 9 - 16% of circulating analytes at steady state.
Dan il- metabolita jammonta għal madwar 9 - 16% ta ’ l- analiti li qed jiċċirkolaw fi stat stabbli.
Unchanged sorafenib, accounting for 51% of the dose, was found in faeces but not in urine, indicating that biliary excretion of unchanged drug might contribute to the elimination of sorafenib.
Wara amministrazzjoni mill- ħalq ta ’ doża ta ’ 100 mg ta ’ formulazzjoni ta ’ soluzzjoni ta ’ sorafenib, 96% tad- doża kienet irkuprata f’ 14- il ġurnata, b’ 77% tad- doża mneħħija fil- feċi, u 19% tad- doża mneħħija fl- awrina bħala metaboliti ta ’ glukuronidazzjoni. Sorafenib mhux mibdul, li jammonta għal 51% tad- doża, instab fil- feċi iżda mhux fl- urina, u b’ hekk jindika li tneħħijja biljari tal- mediċina mhux mibdula tista ’ tikkontribwixxi għall- eliminazzjoni ta ’ sorafenib.
Pharmacokinetics in special populations:
Farmakokinetika f’ popolazzjonijiet speċjali:
Analyses of demographic data suggest that there is no relationship between pharmacokinetics and age (up to 65 years) gender or body weight.
Analiżi ta ’ tagħrif demografiku jissuġġerixxi li m’ hemmx relazzjoni bejn il- farmakokinetika u l- età (sa 65 sena), sess jew piż tal- ġisem.
No studies have been conducted to investigate the pharmacokinetics of sorafenib in paediatric patients.
Ma sarux studji biex jinvestigaw il- farmakokinetika ta ’ sorafenib f’ pazjenti pedjatriċi.
Race:
Rażża:
There are no clinically relevant differences in pharmacokinetics between Caucasian and Asian subjects.
Ma hemm l- ebda differenzi klinikament rilevanti fil- farmakokinetika bejn individwi Kawkasi u Asjatiċi.
In four Phase I clinical trials, steady state exposure to sorafenib was similar in patients with mild or moderate renal impairment compared to the exposures in patients with normal renal function.
F’ erba ’ provi kliniċi ta ’ Fażi I, l- espożizzjoni ta ’ sorafenib fi stat stabbli kienet simili f’ pazjenti b’ indeboliment renali ħafif jew moderat meta mqabbel ma ’ espożizzjonijiet f’ pazjenti b’ funzjoni renali normali.
In a clinical pharmacology study (single dose of 400 mg sorafenib), no relationship was observed between sorafenib exposure and renal function in subjects with normal renal function, mild, moderate or severe renal impairment.
Fi studji kliniku farmakoloġiku (doża waħda ta ’ 400 mg ta ’ sorafenib), ma kienet osservata l- ebda relazzjoni bejn l- esponiment ta ’ sorafenib u l- funzjoni renali f’ individwi b’ funzjoni renali normali, indeboliment renali ħafif, moderat jew sever.
No data is available in patients requiring dialysis.
M’ hemmx tagħrif f’ pazjenti li jinħtieġ d- dijalisi.
In hepatocellular carcinoma patients with mild or moderate hepatic impairment, exposure values were comparable and within the range of exposures observed in patients without hepatic impairment.
F’ pazjenti b’ karċinoma epatoċellolari b’ indeboliment epatiku ħafif jew moderat, il- valuri ta ’ espożizzjoni kienu komparabbli u fir- raġġ ta ’ espożizzjonijiet osservati f’ pazjenti mingħajr indeboliment epatiku.
There are no data for patients with Child-Pugh C (severe) hepatic impairment.
M’ hemmx tagħrif dwar pazjenti b’ indeboliment epatiku Child- Pugh C (sever).
Sorafenib is mainly eliminated via the liver, and exposure might be increased in this patient population.
Sorafenib jiġi mneħħi prinċipalment mill- fwied, u l- espożizzjoni tista ’ tiżdied f’ din il - popolazzjoni ta ’ pazjenti.
The preclinical safety profile of sorafenib was assessed in mice, rats, dogs and rabbits.
Il- profil ta ’ sigurtà preklinikali ta ’ sorafenib kien studjat fil- ġrieden, firien, klieb u fniek.
Repeat-dose toxicity studies revealed changes (degenerations and regenerations) in various organs at exposures below the anticipated clinical exposure (based on AUC comparisons).
Studji dwar it- tossiċità ta ’ doża ripetuta wrew tibdil (deġenerazzjonijiet u riġenerazzjonijiet) f’ bosta organi f’ espożizzjonijiet inqas mill- espożizzjoni klinika antiċipata (ibbażat fuq paraguni ta ’ AUC).
After repeated dosing to young and growing dogs effects on bone and teeth were observed at exposures below the clinical exposure.
Wara dożaġġ ripetut fi klieb żgħar u li qed jikbru, kienu osservati effetti fuq l- għadam u s- snien f’ espożizzjonijiet inqas mill- espożizzjoni klinika.
Changes consisted in irregular thickening of the femoral growth plate, hypocellularity of the bone marrow next to the altered growth plate and alterations of the dentin composition.
Il- bidliet ikkonsistew minn tħaxxin irregolari tal - platt tat- tkabbir femorali, ipoċellolarità tal- mudullun ta ’ l- għadam ħdejn il- platt tat- tkabbir alterat u alterazzjonijiet fil- kompożizzjoni tad- dentin.
Similar effects were not induced in adult dogs.
Effetti simili ma kienux indotti fi klieb adulti.
The standard program of genotoxicity studies was conducted and positive results were obtained as an increase in structural chromosomal aberrations in an in vitro mammalian cell assay (Chinese hamster ovary) for clastogenicity in the presence of metabolic activation was seen.
12 Ġie kondott il- programm stàndard ta ’ studji dwar il- ġenotossiċità, u riżultati pożittivi kienu miksuba bħala żjieda fl- aberrazzjonijiet strutturali fil- kromożomi f’ analiżi taċ- ċelloli mammiferi in vitro (ovarju ta ’ ħamster Ċiniż) għal klastoġeniċità fil- preżenza ta ’ attivazzjoni metabolika.
Sorafenib was not genotoxic in the Ames test or in the in vivo mouse micronucleus assay.
Sorafenib ma kienx ġenotossiku fit- test Ames jew fl- analiżi in vivo tal- mikronukleju tal- ġrieden.
One intermediate in the manufacturing process, which is also present in the final drug substance (< 0.15%), was positive for mutagenesis in an in vitro bacterial cell assay (Ames test).
Intermedjarju wieħed fil- proċess ta ’ manifattura, li huwa preżenti ukoll fis- sustanza mediċinali finali (< 0. 15%), kien pożittiv għall- mutaġenisi f’ analiżi in vitro f’ ċelloli tal- batterja (Ames test).
Furthermore, the sorafenib batch tested in the standard genotoxicity battery included 0.34% PAPE.
Barra minn hekk, il - lott ta ’ sorafenib ittestjat fil- batterija ġenotossika stàndard inkluda 0. 34% ta ’ PAPE.
Carcinogenicity studies have not been conducted with sorafenib.
Ma sarux studji dwar il- karċinoġeniċità b’ sorafenib.
12 No specific studies with sorafenib have been conducted in animals to evaluate the effect on fertility.
Ma sarux studji speċifiċi b’ sorafenib fl- annimali biex jivvalutaw l- effett fuq il- fertilità.
An adverse effect on male and female fertility can however be expected because repeat-dose studies in animals have shown changes in male and female reproductive organs at exposures below the anticipated clinical exposure (based on AUC).
Iżda, effett avvers fuq il- fertilità fl- irġiel u n- nisa huwa mistenni minħabba li studji ta ’ doża ripetuta fl- annimali wrew tibdil fl- organi riproduttivi fl- irġiel u n- nisa f’ espożizzjonijiet inqas mill- espożizzjoni klinika mistennija (ibbażat fuq l- AUC).
Typical changes consisted of signs of degeneration and retardation in testes, epididymides, prostate, and seminal vesicles of rats.
Tibdiliet tipiċi ikkonsistew f’ sinjali ta ’ deġenerazzjoni u ritardazzjoni fit- testikoli, epididimi, prostata, u l- bużżieqa seminali tal- firien.
Female rats showed central necrosis of the corpora lutea and arrested follicular development in the ovaries.
Firien nisa wrew nekrożi ċentrali tal - corpora lutea u twaqqif fl- iżvilupp follikolari fl- ovarji.
Dogs showed tubular degeneration in the testes and oligospermia.
Klieb urew deġenerazzjoni tubolari fit- testikoli u oligospermja.
Sorafenib has been shown to be embryotoxic and teratogenic when administered to rats and rabbits at exposures below the clinical exposure.
Sorafenib intwera li huwa embrijotossiku u teratoġeniku meta ingħata lill- firien u fniek f’ espożizzjonijiet inqas mill- espożizzjoni klinika.
Observed effects included decreases in maternal and foetal body weights, an increased number of foetal resorptions and an increased number of external and visceral malformations.
Effetti osservati nkluduew tnaqqis fil- piżijiet tal - ġisem ta ’ l- omm u tal- fetu, żjieda fin- numru ta ’ risorbimenti tal- fetu u żjieda fin- numru ta ’ malformazzjonijiet esterni u fil- vixxri.
Core: croscarmellose sodium microcrystalline cellulose hypromellose sodium laurilsulfate magnesium stearate
Qalba: croscarmellose sodium microcrystalline cellulose hypromellose sodium laurilsulfate magnesium stearate
Coating: hypromellose macrogol (3350) titanium dioxide (E 171) ferric oxide red (E 172)
Rita: hypromellose macrogol (3350) titanium dioxide (E 171) ferric oxide aħmar (E 172)
112 (4 x 28) tablets in transparent (PP/ Aluminium) blister packs.
112 (4 x 28) pilloli ġo folji trasparenti (PP/ Aluminium).
July 2006
Lulju 2006
Bayer Schering Pharma AG 51368 Leverkusen Germany
Bayer Schering Pharma AG 51368 Leverkusen Il- Ġermanja
The MAH commits to performing the studies and additional pharmacovigilance activities detailed in the Pharmacovigilance Plan.
L- MAH jikkommetti ruħu li jwettaq l- istudji u l- attivitajiet ta ’ farmakoviġilanza kif mniżzla fil- Pjan ta ’ Farmakoviġilanza.
An updated Risk Management Plan, as per the CHMP Guideline on Risk Management Systems for medicinal products for human use, should be submitted at the same time as the PSURs, within 60 days of an important (Pharmacovigilance or Risk minimisation) milestone being reached or when the results of a study becoming available or at the request of the Competent authority.
Pjan imġedded ta ’ Mmaniġġjar tar- Riskji, skond il- Linji Gwida ta ’ CHMP dwar is- Sistemi ta ’ Mmaniġġjar tar- Riskji għall- prodotti mediċinali għall- użu fil- bniedem, għandu jiġi sottomess fl- istess waqt bħal PSURs, f’ 60 ġurnata minn meta ntlaħaq għan importanti (tnaqqis ta ’ Farmakoviġilanza jew Riskju) jew meta r- riżultati ta ’ studju jsiru disponibbli jew wara rikjesta mill- awtorità Kompetenti.
{OUTER CARTON}
{KARTUNA TA ’ BARRA}
Nexavar 200 mg film-coated tablets sorafenib
Nexavar 200 mg pilloli miksija b’ rita sorafenib
Each tablet contains 200 mg of sorafenib (as tosylate).
Kull pillola fiha 200 mg ta ’ sorafenib (bħala tosylate).
112 film-coated tablets
112 pillola miksija b’ rita
Oral use.
Għall- użu mill- ħalq.
Do not store above 25 °C.
Taħżinx f’ temperatura ’ l fuq minn 25°C.
Nexavar 200 mg tablets Sorafenib
Pilloli Nexavar 200 mg Sorafenib
MON TUE WED THU FRI SAT SUN
TNE TLI ERB ĦAM ĠIM SIB ĦAD
What Nexavar is and what it is used for 2.
X’ inhu Nexavar u għalxiex jintuża 2.
Before you take Nexavar 3.
Qabel ma tieħu Nexavar 3.
How to take Nexavar 4.
Kif għandek tieħu Nexavar 4.
How to store Nexavar 6.
Kif taħżen Nexavar 6.
WHAT NEXAVAR IS AND WHAT IT IS USED FOR
X’ INHU NEXAVAR U GĦALXIEX JINTUŻA
Nexavar is used to treat liver cancer (hepatocellular carcinoma).
Nexavar jintuża għall- kura ta ’ kanċer fil- fwied (karċinoma epatoċellulari).
Nexavar is also used to treat kidney cancer (advanced renal cell carcinoma) at an advanced stage when standard therapy has not helped to stop your disease or is considered unsuitable.
Nexavar jintuża wkoll biex jikkura il- kanċer tal- kliewi (karċinoma avvanzata taċ- ċellola renali) fi stadju avvanzat meta terapija stàndard ma għinitx twaqqaf il- marda tiegħek jew hija kkunsidrata mhix xierqa.
Nexavar is a so- called multikinase inhibitor.
Nexavar huwa ’ l hekk msejjaħ inibitur ta ’ multikinase.
It works by slowing down the rate of growth of cancer cells and cutting off the blood supply that keeps cancer cells growing.
Jaħdem billi jbaxxi ir- rata ta ’ tkabbir taċ- ċelloli tal- kanċer u billi jaqta ’ il- provista tad- demm li żżomm iċ- ċelloli tal- kanċer jikbru.
BEFORE YOU TAKE NEXAVAR
QABEL MA TIEĦU NEXAVAR
Do not take Nexavar
Tieħux Nexavar
The
- Jekk inti allerġiku (tbati minn sensittività eċċessiva) għal sorafenib jew sustanzi oħra ta ’
ingredients are listed at the end of this leaflet.
Is- sustanzi l- oħra huma mniżżla fl- aħħar tal- fuljett.
Take special care with Nexavar
Oqgħod attent ħafna b’ Nexavar
- If you experience skin problems.
- Jekk ikollok problemi fil- ġilda.
Nexavar can cause rashes and skin reactions, especially on the
Nexavar jista ’ jikkawża raxx u reazzjonijiet fil- ġilda,
hands and feet.
speċjalment fl- idejn u fis- saqajn.
These can usually be treated by your doctor.
Dawn ħafna drabi jistgħu jkunu kkurati mit- tabib tiegħek.
If not, your doctor may interrupt treatment or stop it altogether.
Jekk le, it- tabib tiegħek jista ’ jinterrompi l- kura jew iwaqqafha għal kollox.
- If you have high blood pressure.
- Jekk għandek pressjoni tad- demm għolja.
Nexavar can raise blood pressure, and your doctor will usually
Nexavar jista ’ jgħolli l- pressjoni tad- demm, u
monitor your blood pressure and may give you a medicine to treat your high blood pressure.
normalment it- tabib tiegħek jissorvelja il- pressjoni tad- demm u jista ’ jagħtik mediċina biex jikkuralek il- pressjoni għolja tad- demm.
- If you get any bleeding problems, or are taking warfarin or phenprocoumon.
- Jekk ikollok xi problemi ta ’ fsada jew qed tieħu warfarin jew phenprocoumon.
Treatment with
Kura
Nexavar may lead to a higher risk of bleeding.
b’ Nexavar tista ’ twassal għall- riskju għola ta ’ fsada.
If you are taking warfarin or phenprocoumon, medicines which thin the blood to prevent blood clots, there may be a greater risk of bleeding.
Jekk qed tieħu warfarin jew phenprocoumon, mediċini li jraqqu d- demm biex jipprevjenu emboli tad- demm, jista ’ jkun hemm riskju akbar ta ’ fsada.
- If you get chest pain or heart problems.
- Jekk ikollok uġigħ fis- sider jew problemi fil- qalb.
Your doctor may decide to interrupt treatment or stop it
It- tabib tiegħek jista ’ jiddeċidi li jinterrompi
altogether.
l- kura jew iwaqqafha għal kollox.
- If you are going to have surgery, or if you had an operation recently.
- Jekk ha tagħmel operazzjoni, jew jekk reċentament għamilt operazzjoni.
Nexavar might affect the
Nexavar jista ’
way your wounds heal.
jaffettwa il- mod kif ifiequ l- feriti.
You will usually be taken off Nexavar if you are having an operation.
Normalment kura b’ Nexavar titwaqqaf jekk se tagħmel operazzjoni.
Your doctor will decide when to start with Nexavar again.
It- tabib tiegħek jiddeċidi meta terġa ’ tibda tieħu Nexavar.
- If you have severe liver impairment.
- Jekk qed tieħu irinotecan jew qed tingħata docetxel, li huma wkoll mediċini għall- kanċer.
You may experience more severe side effects when taking
- Jekk għandek indeboliment sever tal- fwied.
this medicine.
meta tieħu din il- mediċina.
- If you have poor kidney function.
- Jekk għandek funzjoni tal- kliewi ħażina.
Your doctor will monitor your fluid and electrolyte balance.
It- tabib tiegħek se jissorvelja il- bilanċ ta ’ fluwidu u
Nexavar may reduce fertility in both men and women.
Nexavar jista ’ jnaqqas il- fertilità kemm fl- irġiel kif ukoll fin- nisa.
If you are concerned, talk to a
Jekk inkwetat, kellem
doctor.
lil tabib.
- Holes in the gut wall (gastrointestinal perforation) may occur during treatment (see Possible Side
- Toqob fil- ħajt tal- musrana (perforazzjoni gastro- intestinali) jistgħu jseħħu waqt kura (ara
Effects, section 4).
Peffetti Sekondarji li Jista ’ Jkollu, sezzjoni 4).
In this case your doctor will interrupt the treatment.
F’ dan il- każ it- tabib tiegħek ser iwaqqaf il- kura.
Tell your doctor if any of these affect you.
Għid lit- tabib tiegħek jekk xi wieħed minn dawn jaffettwak.
You may need treatment for them, or your doctor may decide to change your dose of Nexavar, or stop treatment altogether.
Jista ’ jkollok bżonn kura għalihom, jew it- tabib tiegħek jista ’ jiddeċidi li jbiddillek id- doża ta ’ Nexavar, jew iwaqqaf il- kura għal kollox.
See also Possible Side Effects, section 4.
Ara wkoll Effetti Sekondari li jista ’ jkollu sezzjoni 4.
Taking other medicines Some medicines may affect Nexavar, or be affected by it.
Meta tieħu mediċini oħra Xi mediċini jistgħu jaffettwaw Nexavar, jew jiġu affttwati minnu.
Tell your doctor or pharmacist if you are taking anything in this list:
Għid lit- tabib jew lill- ispiżjar tiegħek jekk qiegħed tieħu xi wieħed minn din il- lista:
- Rifampicin, an antibiotic
- Rifampicin, anti- bijotiku
- St John’ s wort, a herbal treatment for depression
- St John’ s wort, kura mill- ħxejejx għad- depressjoni
- Phenytoin, carbamazepine or phenobarbital, treatments for epilepsy and other conditions
- Phenytoin, carbamazepine jew phenobarbital, kura għall- epilessija u kundizzjonijiet oħra
- Dexamethasone, a corticosteroid used for various conditions
- Dexamethasone, kortikosterojd użat f’ diversi kundizzjonijiet
- Warfarin or phenprocoumon, anticoagulants used to prevent blood clots
- Warfarin jew phenprocoumon, antikoagulanti wżati biex jipprevjenu emboli tad- demm