qanastek/EMEA-V3 huggingface dataset:
In a post-hoc analysis, patients with favourable clinical status at baseline (low pain intensity, good QoL and good PS) may derive more benefit from Tarceva.
F’ analiżi post- hoc, pazjenti bi stat kliniku favorevoli f’ linja bażi (intensità ta ’ uġigħ baxxa, QoL tajjeb u PS tajjeb) jistgħu jieħdu aktar benefiċċju minn Tarceva.
The benefit is mostly driven by the presence of a low pain intensity score.
Il- benefiċċju huwa miksub l- aktar mill - preżenza ta ’ riżultat ta ’ intensità ta ’ uġigħ baxxa.
In a post-hoc analysis, patients on Tarceva who developed a rash had a longer overall survival compared to patients who did not develop rash (median OS 7.2 months vs 5 months, HR:0.61).
F’ analiżi post- hoc, pazjenti fuq Tarceva li żviluppaw raxx kellhom sopravivenza totali itwal meta mqabbla ma ’ pazjenti li ma żvilluppaw raxx (OS medjan 7. 2 xhur vs 5 xhur, HR: 0. 61).
90% of patients on Tarceva developed rash within the first 44 days.
90% tal- pazjenti fuq Tarceva żviluppaw raxx fl- ewwel 44 ġurnata.
The median time to onset of rash was 10 days.
Il- ħin medjan ta ’ bidu ta ’ raxx kien ta ’ għaxart ijiem.
A fter oral administration, erlotinib peak plasma levels are obtained in approximately 4 hours after oral dosing.
Wara l- għotja mill- ħalq, erlotinib jilħaq l- għola livelli fil- plażma wara madwar 4 sigħat mid- dożaġġ orali.
A study in normal healthy volunteers provided an estimate of the absolute bioavailability of 59%.
Studju f’ volontiera normali u b’ saħħithom ipprovda estimu tal- bijodisponibiltà assoluta ta ’ 59%.
The exposure after an oral dose may be increased by food.
L- espożizzjoni wara doża mill- ħalq tista ’ tiżdied bl- ikel.
Erlotinib has a mean apparent volume of distribution of 232 l and distributes into tumour tissue of humans.
Erlotinib għandu volum medju apparenti ta ’ distribuzzjoni ta ’ 232 l u jiddistribwixxi ruħu fit- tessut tat- tumur fil- bnedmin.
In a study of 4 patients (3 with non-small cell lung cancer [NSCLC], and 1 with laryngeal cancer) receiving 150 mg daily oral doses of Tarceva, tumour samples from surgical excisions on Day 9 of treatment revealed tumour concentrations of erlotinib that averaged 1,185 ng/g of tissue.
Fi studju ta ’ 4 pazjenti (3 b’ kanċer tal- pulmun mhux taċ- ċellola żgħira [NSCLS], u wieħed b’ kanċer tal- larinġi) li ngħataw dożi kuljum ta ’ 150 mg ta ’ Tarceva mill - ħalq, kampjuni tat- tumur li ttieħdu minn operazzjoni fil- Ġurnata numru 9 tal- kura wrew konċetrazzjoni fit- tumur ta ’ erlotinib b’ medja ta ’ 1, 185 ng/ g tat- tessut.
This corresponded to an overall average of 63% (range 5-161%) of the steady state observed peak plasma concentrations.
Dan jikkorrispondi għall- medja totali ta ’ 63% (raġġ 5- 161%) ta ’ l- għola konċentrazzjonijiet fil- plażma osservati fi stat stabbli.
The primary active metabolites were present in tumour at concentrations averaging 160 ng/g tissue, which corresponded to an overall average of 113% (range 88-130%) of the observed steady state peak plasma concentrations.
Il - metaboliti attivi prinċipali kienu preżenti fit- tumur f’ konċentrazzjonijiet fit- tessut b’ medja ta ’ 160 ng/ g, li tikkorrespondi għal medja totali ta ’ 113% (raġġ 88- 130%) ta ’ l- għola konċentrazzjonijiet fil - plażma osservati fi stat stabbli.
Plasma protein binding is approximately 95%.
Twaħħil mal- proteini fil- plażma kien ta ’ madwar 95%.
Erlotinib binds to serum albumin and alpha-1 acid glycoprotein (AAG).
Erlotinib jeħel ma ’ l- albumina tas- serum u ma ’ alpha- 1 acid glycoprotein (AAG).
Erlotinib is metabolised in the liver by the hepatic cytochromes in humans, primarily CYP3A4 and to a lesser extent by CYP1A2.
Erlotinib huwa metabolizzat fil- fwied minn ċitokromi epatiċi fil- bnedmin, primarjament CYP3A4 u ftit anqas minn CYP1A2.
Extrahepatic metabolism by CYP3A4 in intestine, CYP1A1 in lung, and 1B1 in tumour tissue potentially contribute to the metabolic clearance of erlotinib.
Metaboliżmu mhux mill- fwied, minn CYP3A4 fil- musrana, CYP1A1 fil- pulmun, u 1B1 fit- tessut tat- tumur potenzjalment jikkontribwixxu għat- tneħħija metabolika ta ’ erlotinib.
There are three main metabolic pathways identified:
Hemm tliet passaġġi prinċipali ta ’ metaboliżmu identifikati:
1) O-demethylation of either side chain or both, followed by oxidation to the carboxylic acids; 2) oxidation of the acetylene moiety followed by hydrolysis to the aryl carboxylic acid; and 3) aromatic hydroxylation of the phenyl-acetylene moiety.
1) O- demethylation ta ’ waħda mill- katini tal- ġnub jew tat- tnejn, u wara ossidazzjoni għal carboxylic acids; 2) ossidazzjoni tal- parti acetylene u wara idroliżi għal aryl carboxylic acid; u 3) hydroxylation aromatika tal- parti phenyl- acetylene.
The primary metabolites OSI-420 and OSI-413 of erlotinib produced by O-demethylation of either side chain have comparable potency to erlotinib in non-clinical in vitro assays and in vivo tumour models.
13 waħda mill- katini tal- ġnub għandhom qawwa komparabbli ma ’ erlotinib f’ testijiet mhux kliniċi in vitro u mudelli tat- tumur in vivo.
They are present in plasma at levels that are < 10% of erlotinib and display similar pharmacokinetics as erlotinib.
Huma preżenti fil- plażma f’ livelli li huma < 10% ta ’ erlotinib u juru farmakokinetika simili għal dik ta ’ erlotinib.
Erlotinib is excreted predominantly as metabolites via the faeces (> 90%) with renal elimination accounting for only a small amount (approximately 9%) of an oral dose.
Erlotinib jitneħħa primarjament bħala metaboliti ġol- ħmieġ (> 90%), bi tneħħija mill - kliewi tammonta għal biss kwantità żgħira (madwar 9%) tad- doża mill- ħalq.
Less than 2% of the orally administered dose is excreted as parent substance.
Anqas minn 2% tad - doża mogħtija mill- ħalq titneħħa bħala s- sustanza oriġinali.
A population pharmacokinetic analysis in 591 patients receiving single agent Tarceva shows a mean apparent clearance of 4.47 l/hour with a median half-life of 36.2 hours.
Analiżi tal- farmakokinetika ta ’ popolazzjoni f’ 591 pazjent li ngħataw Tarceva waħdu wriet medja apparenti ta 'tneħħija ta ’ 4. 47 l/ siegħa b ’ half- life medjana ta ’ 36. 2 sigħat.
Therefore, the time to reach steady state plasma concentration would be expected to occur in approximately 7-8 days.
Għalhekk, il- ħin sabiex tintlaħaq konċentrazzjoni ta ’ stat stabbli fil- plażma huwa maħsub li hu ta ’ madwar 7- 8 tijiem.
Pharmacokinetics in special populations:
Farmakokinetika f’ popolazzjoni speċjali:
Based on population pharmacokinetic analysis, no clinically significant relationship between predicted apparent clearance and patient age, bodyweight, gender and ethnicity were observed.
Ibbażat fuq analizi tal- farmakokinetika tal- popolazzjoni, ma ġiet osservata l- ebda relazzjoni klinikament sinnifikanti bejn it- tneħħija apparenti stmata u l- eta ’ tal- pazjent, piż, sess u etniċità.
Patient factors, which correlated with erlotinib pharmacokinetics, were serum total bilirubin, AAG and current smoking.
Fatturi tal- pazjent, li jikkorrelaw mal- farmakokinetika ta ’ erlotinib, kienu total tal- bilirubina fis- serum, AAG u jekk il- pazjent hux qed ipejjep.
Increased serum concentrations of total bilirubin and AAG concentrations were associated with a reduced erlotinib clearance.
Żieda fil- konċetrazzjonijiet fis- serum tat- total tal- bilirubina u konċetrazzjonijiet ta ’ AAG kienu assoċjati ma ’ tnaqqis fit- tneħħija ta ’ erlotinib.
The clinical relevance of these differences is unclear.
Ir- rilevanza klinika ta ’ dawn id- differenzi mhux ċara.
However, smokers had an increased rate of erlotinib clearance.
Iżda, dawk li qed ipejpu kellhom żieda fir- rata ’ ta ’ tneħħija ta ’ erlotinib.
This was confirmed in a pharmacokinetic study in non-smoking and currently cigarette smoking healthy subjects receiving a single oral dose of 150 mg erlotinib.
Dan kien ikkonfermat fi studju farmakokinetika f’ soġġetti f’ saħħithom li ma jpejpux u dawk li bħalissa qed ipejpu, li ngħataw doża waħda mill- ħalq ta ’ 150 mg erlotinib.
The geometric mean of the Cmax was 1056 ng/mL in the non-smokers and 689 ng/mL in the smokers with a mean ratio for smokers to non-smokers of 65.2% (95% CI:
Il- medja ġejometrika ta ’ Cmax kien ta ’ 1056 ng/ mL f’ dawk li ma jpejpux u 689 ng/ mL f’ dawk li jpejpu b ’ ratio medju ta ’ dawk li jpejpu għal dawk li ma jpejpux ta ’ 65. 2% (95% CI:
44.3 to 95.9, p = 0.031).
44. 3 sa ’ 95. 9, p = 0. 031).
The geometric mean of the AUC0-inf was 18726 ng•h/mL in the non-smokers and 6718 ng•h/mL in the smokers with a mean ratio of 35.9% (95% CI:
Il- medja ġejometrika ta ’ AUC0- inf kien ta ’ 18726 ng• h/ mL f’ dawk li ma jpejpux u 6718 ng• h/ mL f’ dawk li jejpu b’ ratio medju ta ’ 35. 9% (95% CI:
23.7 to 54.3, p < 0.0001).
23. 7 sa ’ 54. 3, p < 0. 0001).
The geometric mean of the C24h was 288 ng/mL in the non-smokers and 34.8 ng/mL in the smokers with a mean ratio of 12.1% (95% CI:
Il- medja ġejometrika ta ’ C24h kienet ta ’ 288 ng/ mL f’ dawk li ma jpejpux u 34. 8 ng/ mL f’ dawk li jpejpu b ’ ratio medju ta ’ 12. 1% (95% CI:
4.82 to 30.2, p = 0.0001).
4. 82 sa ’ 30. 2, p = 0. 0001).
In the pivotal Phase III NSCLC trial, current smokers achieved erlotinib steady state trough plasma concentration of 0.65 µg/mL (n=16) which was approximately 2-fold less than the former smokers or patients who had never smoked (1.28 µg/mL, n=108).
Fi prova pivitali ta ’ Fażi III dwar NSCLC, dawk li kienu qed ipejpu f’ dak iż- żmien laħqu l- inqas konċentrazzjoni ta ’ erlotinib fil- plażma fi stat fiss b’ valur ta ’ 0. 65 µg/ mL (n=16) li kien madwar darbtejn inqas minn dak ta ’ pazjenti li qabel kienu jpejpu iżda waqfu jew pazjenti li qatt ma pejpu (1. 28 µg/ mL, n=108).
In a phase I dose escalation study in NSCLC patients who were
Dan l- effett kien akkumpanjat minn żjieda ta ’ 24% fit- tneħħija apparenti ta ’ erlotinib mill- plażma.
13 current smokers, pharmacokinetic analyses at steady-state indicated a dose proportional increase in erlotinib exposure when the Tarceva dose was increased from 150 mg to the maximum tolerated dose of 300 mg.
Fi studju ta ’ fażi I dwar żjieda fid- doża f’ pazjenti b’ NSCLC li kienu qed ipejpu f’ dak iż- żmien, analiżi farmakokinetika fi stat fiss indikat żjieda proporzjonali mad- doża fl - espożizzjoni għal erlotinib meta d- doża ta ’ Tarceva kienet miżjuda minn 150 mg għad- doża massima ttollerata ta ’ 300 mg.
Steady-state trough plasma concentrations at a 300 mg dose in current smokers in this study was 1.22 µg/mL (n=17).
F’ dan l- istudju l- inqas konċentrazzjoni fil- plażma fi stat fiss b’ doża ta ’ 300 mg f’ dawk li jpejpu kienet 1. 22 µg/ mL (n=17).
Based on the results of pharmacokinetic studies, current smokers should be advised to stop smoking while taking Tarceva, as plasma concentrations could be reduced otherwise.
Ibbażat fuq ir- riżultati ta ’ l- istudji farmakokinetiċi, dawk li bħalissa qed ipejpu għandhom jingħataw parir biex jiefqu jpejpu waqt li qed jieħdu Tarceva, għax jekk ma jgħamlux hekk il- konċetrazzjonijiet fil- plażma jistgħu jonqsu.
Based on population pharmacokinetic analysis, the presence of an opioid appeared to increase exposure by about 11%.
Ibbażati fuq analiżi tal- farmakokinetika ta ’ popolazzjoni, il- preżenza ta ’ opioid wassal għal żieda ta ’ madwar 11% fl- espożizzjoni.
A second population pharmacokinetic analysis was conducted that incorporated erlotinib data from 204 pancreatic cancer patients who received erlotinib plus gemcitabine.
Sar analiżi tal- farmakokinetika tal- popolazzjoni ieħor li nkorpora riżultati ta ’ erlotinib minn 204 pazjent b’ kanċer tal- frixa li rċevew erlotinib flimkien ma ’ gemcitabine.
This analysis demonstrated that covariants affecting erlotinib clearance in patients from the pancreatic study were very similar to those seen in the prior single agent pharmacokinetic analysis.
Dan l- analiżi wera li l - kovarjanti li affetwaw it- tneħħija f’ pazjenti mill- istudju tal- frixa kienu simili ħafna għal dawk li ntwerew fl- analiżi tal- farmakokinetika ta ’ qabel b’ sustanza waħda.
No new covariate effects were identified.
Ma ġewx identifikati effetti ta ’ kovarjanti ġodda.
Co-administration of gemcitabine had no effect on erlotinib plasma clearance.
L- għotja flimkien ta ’ gemcitabine ma kellha l- ebda effett fuq it- tneħħija ta ’ erlotinib mill- plażma.
There have been no specific studies in paediatric or elderly patients.
Ma sarux studji speċifiċi f’ pazjenti pedjatriċi u anzjani.
Erlotinib is primarily cleared by the liver.
Erlotinib jitneħħa primarjament mill- fwied.
In patients with solid tumours and with moderately impaired hepatic function (Child-Pugh score 7-9), geometric mean erlotinib AUC0-t and Cmax was 27000 ng•h/mL and 805 ng/mL, respectively, as compared to 29300 ng•h/mL and 1090 ng/mL in patients with adequate hepatic function including patients with primary liver cancer or hepatic metastases.
14 AUC0- t u Cmax ta ’ erlotinib kienet 27000 ng• h/ mL u 805 ng/ mL, rispettivament, kif imqabbel ma ’ 29300 ng• h/ mL u 1090 ng/ mL f’ pazjenti b’ funzjoni tal- fwied adegwata, inkluż pazjenti b’ kanċer primarju tal- fwied jew b’ metastasi fil- fwied.
Although the Cmax was statistically significant lower in moderately hepatic impaired patients, this difference is not considered clinically relevant.
Għalkemm f’ pazjenti b’ indeboliment moderat tal- fwied Cmax kienet inqas b’ mod sinifikanti statistikament, din id- differenza mhux ikkunsidrata ta ’ rilevanza klinika.
No data are available regarding the influence of severe hepatic dysfunction on the pharmacokinetics of erlotinib.
M’ hemmx tagħrif disponibbli dwar l- influwenza ta ’ funzjoni ħażina tal- fwied severa fuq il - farmakokinetika ta ’ erlotinib.
In population pharmacokinetic analysis, increased serum concentrations of total bilirubin were associated with a slower rate of erlotinib clearance.
F’ analiżi tal- farmakokinetika tal- popolazzjoni, żieda fil - konċetrazzjonijiet fis- serum tat- total ta ’ bilirubina kienet assoċjata ma ’ tneħħija aktar bil- mod ta ’ erlotinib.
Erlotinib and its metabolites are not significantly excreted by the kidney, as less than 9% of a single dose is excreted in the urine.
Erlotinib u l- metaboliti tiegħu mhux imneħħija b’ mod sinnifikattiv mill- kliewi, għax anqas minn 9% ta ’ doża waħda titneħħa fl- awrina.
In population pharmacokinetic analysis, no clinically significant relationship was observed between erlotinib clearance and creatinine clearance, but there are no data available for patients with creatinine clearance < 15 ml/min.
F’ analiżi tal- farmakokinetika tal - popolazzjoni, ma ġiet osservata l- ebda relazzjoni klinikament sinnifikanti bejn it- tneħħija ta ’ erlotinib u t- tneħħija ta ’ kreatinina, iżda m’ hemmx tagħrif disponibbli dwar pazjenti li għandhom tneħħija ta ’ kreatinina < 15 ml/ min.
Chronic dosing effects observed in at least one animal species or study included effects on the cornea (atrophy, ulceration), skin (follicular degeneration and inflammation, redness, and alopecia), ovary (atrophy), liver (liver necrosis), kidney (renal papillary necrosis and tubular dilatation), and gastrointestinal tract (delayed gastric emptying and diarrhoea).
Effetti kroniċi ta ’ dożaġġ, osservati ta ’ l- inqas fi speċi ta ’ annimali waħda jew fi studju, inkludew effetti fuq il- korneja (atrofija, ulċerazzjoni), ġilda (deġenerazzjoni follikulari u infjammazjoni, ħmura u twaqqigħ tax- xahar), ovarji (atrofija), fwied (nekrożi tal- fwied), kliewi (nekrozi papillari tal- kliewi u dilatazzjoni tat- tubi), u fil- passaġġ gastro- intestinali (l- istonku jdum aktar biex jitbattal u dijarea).
Red blood cell parameters were decreased and white blood cells, primarily neutrophils, were increased.
Parametri taċ- ċelloli ħomor tad- demm naqsu u ċ- ċelloli bojod tad- demm, primarjament in- newtrofili, żdiedu.
There were treatment-related increases in ALT, AST and bilirubin.
Kien hemm żdiediet f’ ALT, AST u bilirubina relatati mal- kura.
These findings were observed at exposures well below clinically relevant exposures
Dawn is- sejbiet ġew osservati f’ espożizzjonijiet ħafna anqas minn espożizzjonijiet klinikament relevanti.
Based on the mode of action, erlotinib, has the potential to be a teratogen.
Ibbażat fuq il- mod ta ’ azzjoni, erlotinib, għandu l- potenzjal li jkun teratoġeniku.
Data from reproductive toxicology tests in rats and rabbits at doses near the maximum tolerated dose and/or maternally toxic doses showed reproductive (embryotoxicity in rats, embryo resorption and foetotoxicity in rabbits) and developmental (decrease in pup growth and survival in rats) toxicity, but was not teratogenic and did not impair fertility.
Tagħrif minn testijiet dwar it- tossiċità riproduttiva fil- firien u fniek b’ dożi li jqarrbu d- doża massima tollerata u/ jew dożi li ħuma tossiċi għall- omm, wrew tossiċità riproduttiva (tossiċità fl- embriju tal- firien, l- embriju jiġi assorbit lura u tossiċità fil- fetu fil- fniek) u tossiċità fl- iżvilupp (tnaqqis fit- tkabbir tal- ferħ u sopravivenza fil- firien), iżda ma kienx teratoġeniku u ma tellifx il- fertilità.
These findings were observed at clinically relevant exposures.
Dawn is- sejbiet ġew osservati f’ espożizzjonijiet klinikament rilevanti.
Erlotinib tested negative in conventional genotoxicity studies.
Erlotinib ta ’ riżultat negattiv fi studji konvenzjonali ta ’ ġenotossiċità.
Lactose monohydrate Cellulose, microcrystalline (E460) Sodium starch glycolate Type A Sodium laurilsulfate Magnesium stearate (E470 b)
Lactose monohydrate Cellulose, microcrystalline (E460) Sodium starch glycolate Type A Sodium laurilsulfate Magnesium stearate (E470 b)
Hydroxypropyl cellulose (E463) Titanium dioxide (E171) Macrogol Hypromellose (E464)
Hydroxypropyl cellulose (E463) Titanium dioxide (E171) Macrogol Hypromellose (E464)
Printing ink yellow:
Shellac (E904)
Shellac (E904) Iron oxide yellow (E172)
15 Iron oxide isfar (E172)
This medicinal product does not require any special storage conditions.
Dan il- prodott mediċinali ma jeħtieġ l- ebda prekawzjonijiet speċjali għall- ħażna.
PVC blister sealed with aluminium foil containing 30 tablets.
Strixxi tal- PVC issiġillati b’ folja ta ’ l- aluminju li fihom 30 pillola.
19 September 2005
19 ta ’ Settembru 2005
Tarceva 100 mg film-coated tablets
Tarceva 100 mg pilloli miksija b’ rita.
Tarceva 100 mg One film-coated tablet contains 100 mg erlotinib (as erlotinib hydrochloride).
Tarceva 100 mg Pillola miksija b’ rita li fiha 100 mg erlotinib (bħala erlotinib hydrochloride)
Film-coated tablet White to yellowish, round, biconvex tablets with ‘Tarceva 100’ and logo printed in grey on one side.
Pillola miksija b’ rita Pilloli bojod għal safranin, tondi, ibbuzzati fuq iż- żewġ naħat, b ’ ‘ Tarceva 100 ’ u logo stampati bil - griż fuq naħa waħda.
Non-small cell lung cancer (NSCLC):
Kanċer tal- pilmun mhux taċ- ċellola żgħira (NSCLC):
When prescribing Tarceva, factors associated with prolonged survival should be taken into account.
Meta jiġi preskritt Tarceva, wieħed irid jikkonsidra l- fatturi assoċjati ma’ sopravivenza itwal.
When dose adjustment is necessary, reduce in 50 mg steps (see section 4.4).
17 Meta jkun hemm bżonn aġġustament tad- doża, naqqas bi kwantità ta ’ 50 mg kull darba (ara sezzjoni 4. 4.).
17 Tarceva is available in strengths of 25 mg, 100 mg and 150 mg.
Tarceva huwa disponibbli bħala pilloli b’ qawwiet ta ’ 25 mg, 100 mg u 150 mg.
The safety and efficacy of erlotinib has not been studied in patients with severe hepatic impairment.
Is- sigurtà u l - effikaċja ta ’ erlotinib ma kienux studjati f’ pażjenti b ’ indeboliment sever tal- fwied.
Use of Tarceva in patients with severe renal impairment is not recommended.
L- użu ta ’ Tarceva f’ pazjenti b’ indeboliment sever renali mhux rakkomandat.
Severe hypersensitivity to erlotinib or to any of the excipients.
Sensittività eċċessiva qawwija għal erlotinib jew għal xi sustanzi mhux attivi
18 In patients who develop acute onset of new and/or progressive unexplained pulmonary symptoms such as dyspnoea, cough and fever, Tarceva therapy should be interrupted pending diagnostic evaluation.
18 parenkima tal- pulmun ġà eżistenti, mard metastatiku tal- pulmun, jew infezzjonijiet tal- pulmon, kienu frekwenti.
Diarrhoea has occurred in approximately 50% of patients on Tarceva and moderate or severe diarrhoea should be treated with e.g. loperamide.
Dijarea seħħet f’ madwar 50% tal- pazjenti fuq Tarceva u dijarea moderata jew qawwija għandha tiġi kkurata b ’ e. ż. loperamide.
Some cases were secondary to severe dehydration due to diarrhoea, vomiting and/or anorexia, while others were confounded by concomitant chemotherapy.
Uħud mill- każijiet kienu sekondarji għall- deidrazzjoni qawwija minħabba dijarea, rimettar u/ jew anoressija, filwaqt li oħrajn irriżultaw wkoll minħabba l- użu fl- istess ħin ta ’ kemjoterapija.
Caution should be exercised when ciprofloxacin or potent CYP1A2 inhibitors (e.g. fluvoxamine) are combined with erlotinib.
Għandu jkun hemm kawtela meta ciprofloxacin jew inibituri qawwija ta ’ CYP1A2 (e. ż. fluvoxamine) jitħaltu flimkien ma ’ erlotinib.
Pretreatment or coadministration of Tarceva did not alter the clearance of the prototypical CYP3A4 substrates, midazolam and erythromycin, but did appear to decrease the oral bioavailability of midazolam by up to 24%.
Kura minn qabel jew għotja fl- istess ħin ta ’ tarceva ma bidlux it- tneħħija tas- substrati prototipiċi ta ’ CYP3A4, midazolam u erythromycin, iżda dehru li jnaqqsu il- biodisponibiltà orali ta ’ midazolam b’ sa 24%.
In another clinical study, erlotinib was shown not to affect pharmacokinetics
Fi studju kliniku ieħor, erlotinib intwera li ma affettwax il- farmakokinetika ta ’ paclitaxel, susbtrat ta ’ CYP3A4/ 2C8, mogħti fl- istess ħin.
Gilbert’s disease) may exhibit increased serum concentrations of bilirubin and must be treated with caution.
Pazjenti b’ ammont żgħir ta ’ UGT1A1 jew mard ġenetiku ta ’ glukuronidazzjoni (e. ż. il- marda ta ’ Gilbert) jistgħu juru żieda tal- konċentrazzjoni fis- serum ta ’ bilirubina u jridu jiġu kkurati b’ attenzjoni.
Therefore, caution should be used when erlotinib is combined with a potent CYP3A4 inhibitor, e.g. azole antifungals (i.e. ketoconazole, itraconazole, voriconazole), protease inhibitors, erythromycin or clarithromycin.
Għalhekk, l- użu ta ’ erlotinib flimkien ma ’ inibitur qawwi ta ’ CYP3A4 e. ż. azole antifungals (ketoconazole, itraconazole, voriconazole), inibituri tal- protease, erythromycin jew clarithromycin, trid issir b’ attenzjoni.
Reduced exposure may also occur with other inducers e.g. phenytoin, carbamazepine, barbiturates or St.
Espożizzjoni mnaqqsa tistà tiġri wkoll b’ indutturi oħra e. ż. phenytoin, carbamazepine, barbiturates jew St.
The refore, patients who are still smoking should be encouraged to stop smoking as early as possible before initiation of treatment with Tarceva, as plasma erlotinib concentrations are reduced otherwise.
L- effett
The clinical effect of the decreased exposure has not been formally assessed but it is likely to be clinically significant.
20 kliniku ta ’ tnaqqis fl- espożizzjoni għadu ma ġiex assessjat formalment iżda huwa probabbli li huwa klinikament sinnifikanti.
Concomitant administration of inhibitors of Pgp, e.g. cyclosporine and verapamil, may lead to altered distribution and/or altered elimination of erlotinib.
L- ġħotja flimkien ta ’ inibituri ta ’ Pgp, e. ż. cyclosporine u verapamil, tista ’ twassal għal tibdil fid- distribuzzjoni u/ jew tibdil fl- eliminazzjoni ta ’ erlotinib.
20 erlotinib with omeprazole, a proton pump inhibitor (PPI), decreased the erlotinib exposure [AUC] and maximum concentration [Cmax] by 46% and 61%, respectively.
L- għotja flimkien ta ’ erlotinib ma ’ omeprazole, inibitur tal- pompi tal- protoni (PPI), naqqsu l- espożizzjoni għal erlotinib [AUC] u l- konċentrazzjoni massima [Cmax] b ’ 46% u 61%, rispettivament.
However, when Tarceva was dosed in a staggered manner 2 hours before or 10 hours after ranitidine 150 mg b.i.d., erlotinib exposure [AUC] and maximum concentrations [Cmax] decreased only by 15% and 17%, respectively.
Madankollu, meta Tarceva kien iddożat waħdu, sagħtejn qabel jew 10 sigħat wara ranitidine 150 mg b. i. d., l- espożizzjoni għal erlotinib [AUC] u l- konċentrazzjonijiet massimi [Cmax] naqsu biss bi 15% u 17%, rispettivament.
If the use of ranitidine is considered, it should be used in a staggered manner; i.e.
Jekk jiġi kkunsidrat l- użu ta ’ ranitidine, dan għandu jintuża waħdu; i. e.
Studies in animals have shown some reproductive toxicity (see section 5.3).
Studji fuq l- animali urew xi tossiċitáfuq is- sistema riproduttiva (ara sezzjoni 5. 3).
4.8 Undesirable effects
21 4. 8 Effetti mhux mixtieqa
Most were Grade 1/2 in severity and manageable without intervention.
Ħafna kienu Grad 1/ 2 fis- severità u kienu kkontrollati mingħajr l- ebda intervent.
Grade 3/4 rash and diarrhoea occurred in 9% and 6%, respectively in Tarceva-treated patients and each resulted in study discontinuation in 1% of patients.
Raxx u dijarea ta ’ Grad 3/ 4 seħħew f’ 9% u 6%, rispettivament tal- pazjenti kkurati b’ Tarceva u f’ kull każ kien hemm 1% tal- pazjenti li waqqfu l- istudju minħabba f’ dan.
In study BR. 21, the median time to onset of rash was 8 days, and the median time to onset of diarrhoea was 12 days.
Fi studju BR. 21, il- ħin medjan sakemm deher ir- raxx kien ta ’ tmint ijiem, u il- ħin medjan sakemm deheret id- dijarrea kien ta ’ 12- il ġurnata.
21 Adverse events occurring more frequently (≥3%) in Tarceva-treated patients than in the placebo group in the pivotal study BR.21, and in at least 10% of patients in the Tarceva group, are summarised by National Cancer Institute-Common Toxicity Criteria (NCI-CTC) Grade in Table 1.
Effetti avversi li seħħew aktar ta ’ spiss (≥3%) f’ pazjenti kkurati b’ Tarceva milli dawk fil- grupp plaċebo fl- istudju pivotal BR. 21, u f’ minn ta ’ l- inqas 10% tal- pazjenti fil- grupp b’ Tarceva, huma miġbura skond il- Grad National Cancer Institute- Common Toxicity Criteria (NCI- CTC) f ’ Tabella 1.
Conjunctivitis Keratoconjunctivitis sicca Respiratory, thoracic and mediastinal disorders
Konġuntivite Keratokonġuntivite sikka Disturbi respiratoriu, toraċiċi u medjastinali
* Severe infections, with or without neutropenia, have included pneumonia, sepsis, and cellulitis. ** Can lead to dehydration, hypokalemia and renal failure. *** Rash included dermatitis acneiform.
22 ** Tista ’ twassal għal deidrazzjoni, ipokalimja u insuffiċjenza renali. *** Raxx inkluda dermatite acneiform.
In the Tarceva plus gemcitabine arm, Grade 3/4 rash and diarrhoea were each reported in 5% of patients.
Fil- grupp ta ’ Tarceva flimkien ma ’ gemcitabine, raxx ta ’ Grad 3/ 4, u dijarea, kienu rrappurtati f’ 5% tal- pazjenti.
22 Adverse events occurring more frequently (≥3%) in Tarceva 100 mg plus gemcitabine-treated patients than in the placebo plus gemcitabine group in the pivotal study PA.3, and in at least 10% of patients in the Tarceva 100 mg plus gemcitabine group, are summarised by National Cancer Institute-Common Toxicity Criteria (NCI-CTC) Grade in Table 2.
Fl- istudju pivitali PA. 3, effetti avversi li seħħew aktar ta ’ spiss (≥3%) f’ pazjenti kkurati b’ Tarceva 100 mg flimkien ma ’ gemcitabine milli fil- grupp ikkurati bi plaċebo flimkien ma ’ gemcitabine, u li seħħew f’ minn ta ’ l- anqas 10% tal- pazjenti fil- grupp b’ Tarceva 100 mg flimkien ma ’ gemcitabine, huma miġbura skond il- Grad National Cancer Institute- Common Toxicity Criteria (NCI- CTC) f ’ Tabella 2.
Very common ADRs in study PA.3 (100 mg cohort)
ADRs komuni ħafna fl- istudju PA. 3 (100 mg ko- orti)
Erlotinib N = 259 Any
Erlotinib N = 259 Kull
3
Grad 3 4
Headache Neuropathy Respiratory ,thoracic and mediastinal disorders
Uġigħ ta ’ ras Newropatija Disturbi respiratorji, toraċiċi u medjastinali
Pyrexia Fatigue Rigors
Erlotinib N = 259
3 6 73 12
3
23 The following terms are used to rank the undesirable effects by frequency: very common (> 1/10); common (> 1/100, < 1/10); uncommon (> 1/1,000, < 1/100); rare (> 1/10,000, < 1/1000); very rare (< 1/10,000) including isolated reports.
Dawn it- termini li ġejjin qed jintużaw sabiex l- effetti mhux mixtieqa jitniżżlu skond il- frekwenza: komuni ħafna (> 1/ 10); komuni (> 1/ 100, < 1/ 10); mhux komuni (> 1/ 1000, < 1/ 100); Rari (> 1/ 10000, < 1/ 1000); rari ħafna (< 1/ 10, 000) inkluż rapporti iżolati.
Very common ADR’s are presented in Tables 1 and 2, ADR’s in other frequency categories are summarized below.
ADRs komuni ħafna huma ppreżentati f’ Tabelli 1 u 2, ADRs f’ kategoriji ta ’ frekwenzi oħra huma miġbura taħt.
Hirsutism, eyelash/eyebrow changes and brittle and loose nails.
Xagħar eċċessiv, tibdil fix- xagħar ta ’ l- għajnejn/ ħuġbejn u dwiefer fraġili u laxki.
Rare cases of hepatic failure (including fatalities) have been reported during use of Tarceva.
Każijiet rari ta ’ insuffiċjenza renali (inkluż imwiet) ġew irrappurtati waqt l - użu ta ’ Tarceva.
Eye disorders:
24 Disturbi fl- għajnejn:
Respiratory, thoracic and mediastinal disorders:
Disturbi respiratorji, toraċiċi u medjastanjali:
24 Erlotinib is an epidermal growth factor receptor/human epidermal growth factor receptor type 1 (EGFR also known as HER1) tyrosine kinase inhibitor.
Erlotinib huwa riċettur tal- fattur ta ’ żvilupp epidermiku / inibitur tyrosine kinase tal- fattur ta ’ żvilupp epidermiku ta ’ tip 1 uman (EGFR magħruf ukoll bħala HER1).
In non-clinical models, inhibition of EGFR phosphotyrosine results in cell stasis and/or death.
F’ mudelli mhux kliniċi, inibizzjoni ta ’ EGFR phosphotyrosine jirriżulta fi stasi ċellolari u/ jew mewt.
The primary endpoint was survival.
L- mira primarja kienet sopravivenza.
The effect on overall survival was explored across different patient subsets.
25 L- effett fuq is- sopravivenza totali ġie studjat f’ subsets differenti ta ’ pazjenti.
In the 45% of patients with known EGFR-expression status, the hazard ratio was 0.68 (CI 0.49-0.94) for patients with EGFR-positive tumours and 0.93 (CI 0.63-1.36) for patients with EGFR-negative tumours (defined by IHC using EGFR pharmDx kit and defining EGFR-negative as less than 10% tumour cells staining).
F ’ 45% tal- pazjenti li kien mgħaruf l- istat ta ’ espressjoni ta ’ EGFR, il- hazard ratio kien ta ’ 0. 68 (CI 0. 49- 0. 94) għall- pazjenti li kellhom tumuri posittivi għal EGFR u 0. 93 (CI 0. 63- 1. 36) għall- pazjenti b ’ tumuri negattivi għal EGFR (iddefiniti minn IHC bl- użu ta ’ kitt EGFR pharmDx u b’ EGFR- negattiv iddefinit bħala anqas minn 10% taċ- ċelloli tat- tumur jieħdu l- kulur).
25 A survival benefit of Tarceva was also observed in patients who did not achieve an objective tumour response (by RECIST).
Benefiċċju ta ’ sopravivenza ta ’ Tarceva ġie osservat ukoll f’ pazjenti li ma laħqux l- iskop ta ’ rispons mit- tumur (minn RECIST).
Patients were randomised to receive Tarceva or placebo once daily on a continuous schedule plus gemcitabine IV (1000 mg/m2, Cycle 1 - Days 1, 8, 15, 22, 29, 36 and 43 of an 8 week cycle; Cycle 2 and subsequent cycles - Days 1, 8 and 15 of a 4 week cycle [approved dose and schedule for pancreatic cancer, see the gemcitabine SPC]).
L- pazjenti kienu magħżula bl - addoċċ biex jingħataw Tarceva jew plaċebo darba kuljum fuq skeda kontinwa flimkien ma ’ gemcitabine IV (1000 mg/ m2, Ċiklu 1 - Ġranet 1, 8, 15, 22, 29, 36 u 43 ta ’ ċiklu ta ’ 8 ġimgħat; Ċiklu 2 u ċikli ta ’ wara - Ġranet 1, 8 u 15 ta ’ ċiklu ta ’ 4 ġimgħat [doża u skeda approvata għall- kanċer tal - frixa, ara l- SPC ta ’ gemcitabine]).
Baseline demographic and disease characteristics of the patients were similar between the 2 treatment groups, 100 mg Tarceva plus gemcitabine or placebo plus gemcitabine, except for a slightly larger proportion of females in the erlotinib/gemcitabine arm compared with the placebo/gemcitabine arm:
Il- linja bażi tal- karatteristiċi demografiċi u tal- marda tal- pazjenti kienu simili bejn iż- żewġ gruppi ta ’ kura, ta ’ Tarceva 100mg flimkien ma ’ gemcitabine jew plaċebo flimkien ma ’ gemcitabine, għajr għal proporzjon kemmxejn akbar ta ’ nisa fil- grupp ta ’ erlotinib/ gemcitabine meta mqabbel mal- grupp plaċebo/ gemcitabine:
Baseline Females Baseline ECOG performance status (PS) = 0 Baseline ECOG performance status (PS) = 1 Baseline ECOG performance status (PS) = 2 Metastatic disease at baseline
26 Linja bażi Nisa Linja bażi ta ’ ECOG performance status (PS) = 0 Linja bażi ta ’ ECOG performance status (PS) = 1 Linja bażi ta ’ ECOG performance status (PS) = 2 Marda metastatika f’ linja bażi
Placebo 44% 32% 51% 17% 76%
Tarceva 51% 31% 51% 17% 77%
Placebo + gemcitabine (n = 2 60) Median OS = 6.0 months
Placebo + gemcitabine (n = 260) OS medjan = 6. 4 xhur
Overall Survival – Patients with Distant Metastases 1.0
27 Sopravivenza Totali – Pazjenti b’ Metastasi Distanti 1. 0
0.1 gemcitabine (n = 197) Median OS = 5.06 months 0.0
gemcitabine OS medjan =
A bsorption:
Assorbiment:
After oral administration, erlotinib peak plasma levels are obtained in approximately 4 hours after oral dosing.
Wara l- għotja mill- ħalq, erlotinib jilħaq l- għola livelli fil- plażma wara madwar 4 sigħat mid- dożaġġ orali.
In a study of 4 patients (3 with non-small cell lung cancer [NSCLC], and 1 with laryngeal cancer) receiving 150 mg daily oral doses of Tarceva, tumour samples from surgical excisions on Day 9 of treatment revealed tumour concentrations of erlotinib that averaged 1,185 ng/g of tissue.
Fi studju ta ’ 4 pazjenti (3 b’ kanċer tal- pulmun mhux taċ- ċellola żgħira [NSCLC], u wieħed b’ kanċer tal- larinġi) li ngħataw dożi kuljum ta ’ 150 mg ta ’ Tarceva mill - ħalq, kampjuni tat- tumur li ttieħdu minn operazzjoni fil- Ġurnata numru 9 tal- kura wrew konċetrazzjoni fit- tumur ta ’ erlotinib b’ medja ta ’ 1, 185 ng/ g tat- tessut.
Extrahepatic metabolism by CYP3A4 in intestine, CYP 1A1 in lung, and 1B1 in tumour tissue potentially contribute to the metabolic clearance of erlotinib.
Metaboliżmu mhux mill- fwied, minn CYP3A4 fil- musrana, CYP1A1 fil- pulmun, u 1B1 fit- tessut tat- tumur potenzjalment jikkontribwixxu għat- tneħħija metabolika ta ’ erlotinib.
The re are three main metabolic pathways identified:
Hemm tliet passaġġi prinċipali ta ’ metaboliżmu identifikati:
The primary metabolites OSI-420 and OSI-413 of erlotinib produced by O-demethylation of either side chain have comparable potency to erlotinib in non-clinical in vitro assays and in vivo tumour models.
28 waħda mill- katini tal- ġnub għandhom qawwa komparabbli ma ’ erlotinib f’ testijiet mhux kliniċi in vitro u mudelli tat- tumur in vivo.
In the pivot al Phase III NSCLC trial, current smokers achieved erlotinib steady state trough plasma concentration of 0.65 µg/mL (n=16) which was approximately 2-fold less than the former smokers or patients who had never smoked (1.28 µg/mL, n=108).
Fi prova pivitali ta ’ Fażi III dwar NSCLC, dawk li kienu qed ipejpu f’ dak iż- żmien laħqu l- inqas konċentrazzjoni ta ’ erlotinib fil- plażma fi stat fiss b’ valur ta ’ 0. 65 µg/ mL (n=16) li kien madwar darbtejn inqas minn dak ta ’ pazjenti li qabel kienu jpejpu iżda waqfu jew pazjenti li qatt ma pejpu (1. 28 µg/ mL, n=108).
28 current smokers, pharmacokinetic analyses at steady-state indicated a dose proportional increase in erlotinib exposure when the Tarceva dose was increased from 150 mg to the maximum tolerated dose of 300 mg.
Fi studju ta ’ fażi I dwar żjieda fid- doża f’ pazjenti b’ NSCLC li kienu qed ipejpu f’ dak iż- żmien, analiżi farmakokinetika fi stat fiss indikat żjieda proporzjonali mad- doża fl - espożizzjoni għal erlotinib meta d- doża ta ’ Tarceva kienet miżjuda minn 150 mg għad- doża massima ttollerata ta ’ 300 mg.
In patients with solid tumours and with moderately impaired hepatic function (Child-Pugh score 7-9), geometric mean erlotinib AUC0-t and Cmax was 27000 ng•h/mL and 805 ng/mL, respectively, as compared to 29300 ng•h/mL and 1090 ng/mL in patients with adequate hepatic function including patients with primary liver cancer or hepatic metastases.
29 29300 ng• h/ mL u 1090 ng/ mL f’ pazjenti b’ funzjoni tal- fwied adegwata, inkluż pazjenti b’ kanċer primarju tal- fwied jew b’ metastasi fil- fwied.
Printing ink grey:
Linka griża għall- istampar:
Shellac (E904) Iron oxide yellow (E172) Iron oxide black (E172) Titanium dioxide (E171)
30 Iron oxide iswed (E172) Titanium dioxide (E171)
Tarceva 150 mg film-coated tablets
Tarceva 150 mg pilloli miksija b’ rita.
Tarceva 150 mg One film-coated tablet contains 150 mg erlotinib (as erlotinib hydrochloride).
Tarceva 150 mg Pillola miksija b’ rita li fiha 150 mg erlotinib (bħala erlotinib hydrochloride)
Film-coated tablet White to yellowish, round, biconvex tablets with ‘Tarceva 150’ and logo printed in brown on one side.
Pillola miksija b’ rita Pilloli bojod għal safranin, tondi, ibbuzzati fuq iż- żewġ naħat, b ’ ‘ Tarceva 150 ’ u logo stampati bil - kannella fuq naħa waħda.
No n-small cell lung cancer (NSCLC):Tarceva is indicated for the treatment of patients with locally advanced or metastatic non-small cell lung cancer after failure of at least one prior chemotherapy regimen.
Tarceva huwa indikat għall- kura ta ’ pazjenti b’ kanċer tal- pulmun mhux taċ- ċellola żgħira avvanzat lokalment jew li mmetastatizza, wara li falla imqar kors wieħed minn qabel ta ’ kemjoterapija.
When dose adjustment is necessary, reduce in 50 mg steps (see section 4.4).
32 Meta jkun hemm bżonn aġġustament tad- doża, naqqas bi kwantità ta ’ 50 mg kull darba (ara sezzjoni 4. 4.).
32 Tarceva is available in strengths of 25 mg, 100 mg and 150 mg.
Tarceva huwa disponibbli bħala pilloli b’ qawwiet ta ’ 25 mg, 100 mg u 150 mg.
Based on pharmacokinetic data no dose adjustments appear necessary in patients with mild or moderate renal impairment (see section 5.2).
Skond data farmakokinetika, ma jidhirx li hemm bżonn ta ’ aġġustament fid- doża f’ pazjenti b’ indeboliment ħafif għal moderati renali (ara sezzjoni 5. 2).
33 In patients who develop acute onset of new and/or progressive unexplained pulmonary symptoms such as dyspnoea, cough and fever, Tarceva therapy should be interrupted pending diagnostic evaluation.
33 parenkima tal- pulmun ġà eżistenti, mard metastatiku tal- pulmun, jew infezzjonijiet tal- pulmon, kienu frekwenti.
The refore, in such patients, periodic liver function testing should be considered.
Għalhekk, f’ dawn il- pazjenti, għandu jiġi kkunsidrat ittestjar perjodiku tal- funzjoni tal - fwied.
The clinical effect of the decreased exposure has not been formally assessed but it is likely to be clinically significant.
35 kliniku ta ’ tnaqqis fl- espożizzjoni għadu ma ġiex assessjat formalment iżda huwa probabbli li huwa klinikament sinnifikanti.
35 erlotinib with omeprazole, a proton pump inhibitor (PPI), decreased the erlotinib exposure [AUC] and maximum concentration [Cmax] by 46% and 61%, respectively.
L- għotja flimkien ta ’ erlotinib ma ’ omeprazole, inibitur tal- pompi tal- protoni (PPI), naqqsu l- espożizzjoni għal erlotinib [AUC] u l- konċentrazzjoni massima [Cmax] b ’ 46% u 61%, rispettivament.
The re are no studies in pregnant women using erlotinib.
Ma sarux studji b’ erlotinib f’ nisa tqal.
Grade 3/4 rash and diarrhoea occurred in 9% and 6%, respectively in Tarceva-treated patients and each resulted in study discontinuation in 1% of patients.
Raxx u dijarea ta ’ Grad 3/ 4 seħħew f’ 9% u 6% rispettivament tal- pazjenti kkurati b’ Tarceva u f’ kull każ kien hemm 1% tal- pazjenti li waqqfu l- istudju minħabba f’ dan.
36 Adverse events occurring more frequently (≥3%) in Tarceva-treated patients than in the placebo group in the pivotal study BR.21, and in at least 10% of patients in the Tarceva group, are summarised by National Cancer Institute-Common Toxicity Criteria (NCI-CTC) Grade in Table 1.
Effetti avversi li seħħew aktar ta ’ spiss (≥3%) f’ pazjenti kkurati b’ Tarceva milli dawk fil- grupp plaċebo fl- istudju pivotal BR. 21, u f’ minn ta ’ l- inqas 10% tal- pazjenti fil- grupp b’ Tarceva, huma miġbura skond il- Grad National Cancer Institute- Common Toxicity Criteria (NCI- CTC) f ’ Tabella 1.
Anorexia Eye disorders
Anoreksja Disturbi f l- għajnejn
Rash*** Pruritus Dry skin General disorders and administration site conditions
Raxx ***
4 5
4
* Severe infections, with or without neutropenia, have included pneumonia, sepsis, and cellulitis. ** Can lead to dehydration, hypokalemia and renal failure. *** Rash included dermatitis acneiform.
37 ** Tista ’ twassal għal deidrazzjoni, ipokalimja u insuffiċjenza renali. *** Raxx inkluda dermatite acneiform.
37 Adverse events occurring more frequently (≥3%) in Tarceva 100 mg plus gemcitabine-treated patients than in the placebo plus gemcitabine group in the pivotal study PA.3, and in at least 10% of patients in the Tarceva 100 mg plus gemcitabine group, are summarised by National Cancer Institute-Common Toxicity Criteria (NCI-CTC) Grade in Table 2.
Fl- istudju pivitali PA. 3, effetti avversi li seħħew aktar ta ’ spiss (≥3%) f’ pazjenti kkurati b’ Tarceva 100 mg flimkien ma ’ gemcitabine milli fil- grupp ikkurati bi plaċebo flimkien ma ’ gemcitabine, u li seħħew f’ minn ta ’ l- anqas 10% tal- pazjenti fil- grupp b’ Tarceva 100 mg flimkien ma ’ gemcitabine, huma miġbura skond il- Grad National Cancer Institute- Common Toxicity Criteria (NCI- CTC) f ’ Tabella 2.
0 0
38
38 The following terms are used to rank the undesirable effects by frequency: very common (> 1/10); common (> 1/100, < 1/10); uncommon (> 1/1,000, < 1/100); rare (> 1/10,000, < 1/1000); very rare (< 1/10,000) including isolated reports.
Dawn it- termini li ġejjin qed jintużaw sabiex l- effetti mhux mixtieqa jitniżżlu skond il- frekwenza: komuni ħafna (> 1/ 10); komuni (> 1/ 100, < 1/ 10); mhux komuni (> 1/ 1000, < 1/ 100); Rari (> 1/ 10000, < 1/ 1000); rari ħafna (< 1/ 10, 000) inkluż rapporti iżolati.
Eye disorders:
39 Disturbi fl- għajnejn:
Very rare:
Konġuntivite fi studju PA. 3. Rari ħafna:
Conjunctivitis in study PA.3.
Ulċeri tal- korneja kienu
Corneal ulcerations have been reported very rarely in patients receiving Tarceva as a complication of mucocutaneous inflammation.
rrappurtati b’ mod rari ħafna bħala kumplikazzjoni ta ’ infjammazzjoni mukokutanja f’ pazjenti li qed jirċievu Tarceva.
39 Erlotinib is an epidermal growth factor receptor/human epidermal growth factor receptor type 1 (EGFR also known as HER1) tyrosine kinase inhibitor.
Erlotinib huwa riċettur tal- fattur ta ’ żvilupp epidermiku / inibitur tyrosine kinase tal- fattur ta ’ żvilupp epidermiku ta ’ tip 1 uman (EGFR magħruf ukoll bħala HER1).
The effect on overall survival was explored across different patient subsets.
40 L- effett fuq is- sopravivenza totali ġie studjat f’ subsets differenti ta ’ pazjenti.
40 A survival benefit of Tarceva was also observed in patients who did not achieve an objective tumour response (by RECIST).
Benefiċċju ta ’ sopravivenza ta ’ Tarceva ġie osservat ukoll f’ pazjenti li ma laħqux l- iskop ta ’ rispons mit- tumur (minn RECIST).
Baseline demographic and disease characteristics of the patients were similar between the 2 treatment groups, 100 mg Tarceva plus gemcitabine or placebo plus gemcitabine, except for a slightly larger proportion of females in the erlotinib/gemcitabine arm compared with the placebo/gemcitabine arm:
Il- linja bażi tal- karatteristiċi demografiċi u tal- marda tal- pazjenti kienu simili bejn iż- żewġ gruppi ta ’ kura, ta ’ Tarceva flimkien ma ’ gemcitabine jew plaċebo flimkien ma ’ gemcitabine, għajr għal proporzjon kemmxejn akbar ta ’ nisa fil- grupp ta ’ erlotinib/ gemcitabine meta mqabbel mal- grupp plaċebo/ gemcitabine:
Baseline Females Baseline ECOG performance status (PS) = 0 Baseline ECOG performance status (PS) = 1 Baseline ECOG performance status (PS) = 2 Metastatic disease at baseline
41 Linja bażi Nisa Linja bażi ta ’ ECOG performance status (PS) = 0 Linja bażi ta ’ ECOG performance status (PS) = 1 Linja bażi ta ’ ECOG performance status (PS) = 2 Marda metastatika f’ linja bażi
Survival Probability
42 Sopravivenza Totali – Pazjenti Kollha 10 0. 9 Probabbiltà ta ’ Sopravivenza
Overall Survival – Patients with Distant Metastases 1.0
Sopravivenza Totali – Pazjenti b’ Metastasi Distanti 1. 0
0.1 gemcitabine (n = 197) Median OS = 5.06 months 0.0
gemcitabine (n = 197) OS medjan = 5. 06 xhur
6
0 6
42 5.2 Pharmacokinetic properties
5. 2 Tagħrif farmakokinetiku
Distribution:
43 Distribuzzjoni:
Erlotinib is metabolised in the liver by the hepatic cytochromes in humans, primarily CYP3A4 and to a lesser extent by CYP 1A2.
Erlotinib huwa metabolizzat fil- fwied minn ċitokromi epatiċi fil- bnedmin, primarjament CYP3A4 u ftit anqas minn CYP1A2.
The primary metabolites OSI-420 and OSI-413 of erlotinib produced by O-demethylation of either side chain have comparable potency to erlotinib in non-clinical in vitro assays and in vivo tumour models.
Il - metaboliti prinċipali OSI- 420 u OSI- 413 ta ’ erlotinib riżultat ta ’ O- demethylation ta ’ waħda mill - katini tal- ġnub għandhom qawwa komparabbli ma ’ erlotinib f’ testijiet mhux kliniċi in vitro u mudelli tat- tumur in vivo.
This effect was accompanied by a 24% increase in apparent erlotinib plasma clearance.
Dan l- effett kien akkumpanjat minn żjieda ta ’ 24% fit- tneħħija apparenti ta ’ erlotinib mill- plażma.
In a phase I dose escalation study in NSCLC patients who were current smokers, pharmacokinetic analyses at steady-state indicated a dose proportional increase in
Fi studju ta ’ fażi I dwar żjieda fid- doża f’ pazjenti b’ NSCLC li kienu qed ipejpu f’ dak iż- żmien, analiżi farmakokinetika fi stat fiss indikat żjieda proporzjonali mad- doża fl - espożizzjoni għal erlotinib meta d- doża ta ’ Tarceva kienet miżjuda minn 150 mg għad- doża massima ttollerata ta ’ 300 mg.
Based on the results of pharmacokinetic studies, current smokers should be advised to stop smoking while taking Tarceva, as plasma concentrations could be reduced otherwise.
44 Ibbażat fuq ir- riżultati ta ’ l- istudji farmakokinetiċi, dawk li bħalissa qed ipejpu għandhom jingħataw parir biex jiefqu jpejpu waqt li qed jieħdu Tarceva, għax jekk ma jgħamlux hekk il- konċetrazzjonijiet fil- plażma jistgħu jonqsu.
In patients with solid tumours and with moderately impaired hepatic function (Child-Pugh score 7-9), geometric mean erlotinib AUC0-t and Cmax was 27000 ng•h/mL and 805 ng/mL, respectively, as compared to 29300 ng•h/mL and 1090 ng/mL in patients with adequate hepatic function including patients with primary liver cancer or hepatic metastases.
F’ pazjenti b’ tumuri solidi u b’ indeboliment moderat tal- funzjoni tal- fwied (punteġġ Child- Pugh 7- 9), il- medja ġeometrika ta ’ l - AUC0- t u Cmax ta ’ erlotinib kienet 27000 ng• h/ mL u 805 ng/ mL, rispettivament, kif imqabbel ma ’ 29300 ng• h/ mL u 1090 ng/ mL f’ pazjenti b’ funzjoni tal- fwied adegwata, inkluż pazjenti b’ kanċer primarju tal- fwied jew b’ metastasi fil- fwied.
Carcinogenicity studies have not been performed.
Studji ta ’ karċinoġeniċità ma sarux.
A mild phototoxic skin reaction was observed in rats after UV irradiation.
Reazzjoni fototossika ħafifa tal- ġilda ġiet osservata fil- firien wara rradjazzjoni bil- UV.
Printing ink brown Shellac (E904) Iron oxide red (E172)
Shellac (E904) Iron oxide aħmar (E172)
47 A.
47 ANNESS II
Roche Pharma AG Emil-Barell-Strasse 1 D-79639 Grenzach-Wyhlen Germany
Roche Pharma AG Emill- Barell- Strasse 1 D- 79639 Grenzach- Wyhlen Il- Ġermanja
49 A.
49 ANNESS III
50 PARTICULARS TO APPEAR ON THE OUTER PACKAGING AND THE IMMEDIATE PACKAGING
TIKKETTA
Tarceva 25 mg film-coated tablets Erlotinib
Tarceva 25 mg pilloli miksija b’ rita Erlotinib
Each tablet contains 25 mg of erlotinib (as erlotinib hydrochloride).
Kull pillola fiha 25 mg ta ’ erlotinib (bħala erlotinib hydrochloride).
For oral use Read the package leaflet before use
Għall- użu mill- ħalq Aqra l- fuljett ta ’ tagħrif qabel l- użu
52 MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS
53 TAGĦRIF MINIMU LI GĦANDU JIDHER FUQ L- ISTRIXXI JEW FUQ IL- FOLJI
Tarceva 100 mg film-coated tablets Erlotinib
Tarceva 100 mg pilloli miksija b’ rita Erlotinib
Each tablet contains 100 mg of erlotinib (as erlotinib hydrochloride).
Kull pillola fiha 100 mg ta ’ erlotinib (bħala erlotinib hydrochloride).
55 MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS
56 TAGĦRIF MINIMU LI GĦANDU JIDHER FUQ L- ISTRIXXI JEW FUQ IL- FOLJI
56 PARTICULARS TO APPEAR ON THE OUTER PACKAGING AND THE IMMEDIATE PACKAGING
57 TAGĦRIF LI GĦANDU JIDHER FUQ IL- PAKKETT TA ’ BARRA U IL- PAKKETT LI JMISS MAL- PRODOTT
Tarceva 150 mg film-coated tablets Erlotinib
Tarceva 150 mg pilloli miksija b’ rita Erlotinib
Each tablet contains 150 mg of erlotinib (as erlotinib hydrochloride).
Kull pillola fiha 150 mg ta ’ erlotinib (bħala erlotinib hydrochloride)
58 MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS
59 TAGĦRIF MINIMU LI GĦANDU JIDHER FUQ L- ISTRIXXI JEW FUQ IL- FOLJI