qanastek/EMEA-V3 huggingface dataset:
Patients with Renal Impairment (Standard Cockcroft and Gault formula or Glomerular Filtration Rate measured Tc99m-DPTA serum clearance method):
(Formula Standard Cockcroft & Gault jew Metodu tat- tneħħija mis- serum Tc99m- DPTA biex tiġi kkalkulata r- Rata ta ’ Filtrazzjoni Glomerulari):
Pemetrexed is primarily eliminated unchanged by renal excretion.
Pemetrexed primarjament jiġi eliminat bla ebda modifikazzjoni permezz ta ’ tneħħija mill- kliewi.
In clinical studies, patients with creatinine clearance of ≥ 45 ml/ min required no dose adjustments other than those recommended for all patients.
Fi studji klinici, pazjenti bi tneħħija tal - krejatinina ta ’ ≥ 45 ml/ min ma kellhomx bżonn ta ’ aġġustamenti fid- doża ħlief dawk rakkomandati għall- pazjenti kollha.
There are insufficient data on the use of pemetrexed in patients with creatinine clearance below 45 ml/ min; therefore the use of pemetrexed is not recommended (see section 4.4).
M’ hemmx tagħrif biżżejjed dwar l- użu ta ’ pemetrexed f’ pazjenti bi tneħħija tal - krejatinina ta ’ inqas minn 45 ml/ min; għalhekk l- użu ta ’ pemetrexed m’ huwiex rakkomandat (ara sezzjoni 4. 4).
Patients with Hepatic Impairment:
Pazjenti b’ Indeboliment tal- Fwied:
No relationships between AST (SGOT), ALT (SGPT), or total bilirubin and pemetrexed pharmacokinetics were identified.
Ma kienet identifikata l- ebda relazzjoni bejn l- AST (SGOT), l - ALT (SGPT), jew it- total ta ’ bilirubina u l- farmakokinetika ta ’ pemetrexed.
However patients with hepatic impairment such as bilirubin > 1.5 times the upper limit of normal and/ or transaminase > 3.0 times the upper limit of normal (hepatic metastases absent) or > 5.0 times the upper limit of normal (hepatic metastases present) have not been specifically studied.
Madankollu, ma ġewx studjati speċifikament pazjenti b’ indeboliment tal- fwied bħal każijiet ta ’ bilirubina > 1. 5 darbiet il - limitu massimu tan- normal u/ jew transaminase > 3. 0 darbiet il- limitu massimu tan- normal (mingħajr metastażi fil- fwied) jew > 5. 0 darbiet il- limitu massimu tan- normal (b’ metastażi fil- fwied).
4 Breast-feeding must be discontinued during pemetrexed therapy (see section 4.6).
4 It- treddigħ għandu jieqaf matul it- terapija b’ pemetrexed (ara Sezzjoni 4. 6).
Concomitant yellow fever vaccine (see section 4.5).
Vaċċin tal- yellow fever fl- istess żmien (ara Sezzjoni 4. 5).
Pemetrexed can suppress bone marrow function as manifested by neutropenia, thrombocytopenia and anaemia (or pancytopenia) (see section 4.8).
Pemetrexed jista ’ jissopprimi l- funzjoni tal- mudullun kif manifestat min- newtropenja, mit - tromboċitopenja u mill- anemija (jew panċitopenja) (ara sezzjoni 4. 8).
Myelosuppression is usually the dose-limiting toxicity.
Il- majelosoppressjoni normalment hija it- tossiċità li tillimita d- doża.
Patients should be monitored for myelosuppression during therapy and pemetrexed should not be given to patients until absolute neutrophil count (ANC) returns to ≥ 1500 cells/ mm3 and platelet count returns to ≥ 100,000 cells/ mm3.
Waqt it- terapija, l- pazjenti għandhom ikunu monitorati għall- majelosoppressjoni u pemetrexed m’ għandux jingħata lill- pazjenti qabel l- għadd assolut ta ’ newtrofili (ANC) ma jerġa ’ jkun ≥ 1500 ċellula/ mm3 u l- għadd ta ’ plejtlits ma jerġa ’ jkun ≥ 100, 000 ċellula/ mm3.
Dose reductions for subsequent cycles are based on nadir ANC, platelet count and maximum non-haematologic toxicity seen from the previous cycle (see section 4.2).
It- tnaqqis tad- doża għaċ- ċikli sussegwenti huwa bbażat fuq l- għadd l- iktar baxx ta ’ ANC, fuq l- għadd tal- plejtlits u l- ogħla tossiċità li mhijiex ematoloġika li tkun ġiet osservata fiċ- ċiklu ta ’ qabel (ara sezzjoni 4. 2).
Less toxicity and reduction in Grade 3/ 4 haematologic and non-haematologic toxicities such as neutropenia, febrile neutropenia and infection with Grade 3/ 4 neutropenia were reported when pre-treatment with folic acid and vitamin B12 was administered.
Ġie rrappurtat li t- tossiċità kienet inqas u kien hemm tnaqqis fit- tossiċitajiet kemm ematoloġiċi ta ’ grad 3/ 4 kif ukoll f’ dawk mhux ematoloġiċi bħan- newtropenja, newtropenja bid- deni, u infezzjoni b’ newtropenja ta ’ Grad 3/ 4, f’ pazjenti li ngħataw folic acid u vitamina B12 qabel ma bdiet il- kura.
Therefore, all patients treated with pemetrexed must be instructed to take folic acid and vitamin B12 as a prophylactic measure to reduce treatment-related toxicity (see section 4.2).
Għalhekk, il- pazjenti kollha kkurati b’ pemetrexed għandhom jingħatawlhom istruzzjonijiet biex jieħdu folic acid u vitamina B12 bħala miżura profilattika biex tonqos it- tossiċità relatata mal- kura (ara sezzjoni 4. 2).
Skin reactions have been reported in patients not pre-treated with a corticosteroid.
Ġew irrappurtati reazzjonijiet fil- ġilda ta ’ pazjenti li ma ħadux kortikosterojdi qabel ma bdiet il- kura.
Pre-treatment with dexamethasone (or equivalent) can reduce the incidence and severity of skin reactions (see section 4.2).
Dexamethasone (jew l- ekwivalenti) mogħti qabel il- kura jista ’ jnaqqas l- inċidenza u l- gravità ta ’ reazzjonijiet fil- ġilda (ara sezzjoni 4. 2).
An insufficient number of patients has been studied with creatinine clearance of below 45 ml/ min.
Ġew studjati numru insuffiċjenti ta ’ pazjenti bi tneħħija tal - krejatinina ta ’ inqas minn 45 ml/ min.
Therefore, the use of pemetrexed in patients with creatinine clearance of < 45 ml/ min is not recommended (see section 4.2).
Għalhekk, l- użu ta ’ pemetrexed mhux rakkomandat f’ pazjenti bi tneħħija tal - krejatinina ta ’ < 45 ml/ min (ara sezzjoni 4. 2).
Patients with mild to moderate renal insufficiency (creatinine clearance from 45 to 79 ml/ min) should avoid taking non-steroidal anti-inflammatory drugs (NSAIDs) as ibuprofen, and aspirin (> 1.3 g daily) for 2 days before, on the day of, and 2 days following pemetrexed administration (see section 4.5).
Pazjenti b’ insuffiċjenza renali minn ħafifa għal moderata (tneħħija ta ’ krejatinina bejn 45 u 79 ml/ min) għandhom jevitaw li jieħdu mediċini anti- infjammatorji li mhumiex sterojdi (NSAIDs) bħal ibuprofen, u aspirina (> 1. 3 g kuljum) minn jumejn qabel, dakinhar, u sa jumejn wara l- għoti ta ’ pemetrexed (ara sezzjoni 4. 5).
All patients eligible for pemetrexed therapy should avoid taking NSAIDs with long elimination half- lives for at least 5 days prior to, on the day of, and at least 2 days following pemetrexed administration (see section 4.5).
Il- pazjenti kollha li jkunu eliġibbli biex jieħdu t- terapija b’ pemetrexed m’ għandhomx jieħdu NSAIDs b’ half- life ta ’ eliminazzjoni twila għal mill- inqas 5 ijiem qabel, dakinhar, u sa mill- inqas jumejn wara l- għoti ta ’ pemetrexed (ara sezzjoni 4. 5).
Serious renal events, including acute renal failure, have been reported with pemetrexed alone or in association with other chemotherapeutic agents.
Kienu rappurtati komplikazzjonijiet renali serji, fosthom insuffiċjenza renali akuta, kemm bl- użu ta ’ pemetrexed waħdu kif ukoll meta ntuża flimkien ma ’ sustanzi kimoterapewtiċi oħra.
Many of the patients in whom these occurred had underlying risk factors for the development of renal events including dehydration or pre-existing hypertension or diabetes.
Fejn seħħew dawn il- każijiet, ħafna pazjenti kellhom fatturi oħra ta ’ riskju għall- iżvilupp ta ’ dawn il - komplikazzjonijiet, li kienu jinkludu d- diżidratazzjoni jew l- eżistenza qabel ma bdiet il- kura ta ’ pressjoni għolja jew tad- dijabete.
The effect of third space fluid, such as pleural effusion or ascites, on pemetrexed is unknown.
L- effett fuq pemetrexed ta ’ l- akkumulazzjoni ta ’ fluwidu fit- tielet spazju, bħall- effużjoni plewrali jew l- axxite, mhix magħrufa.
In patients with clinically significant third space fluid, consideration should be given to draining the effusion prior to pemetrexed administration.
F’ pazjenti li jkollhom akkumulazzjoni klinikament sinifikanti ta ’ fluwidu fit - tielet spazju, għandu jiġi kkunsidrat jekk għandiex titneħħa l- effużjoni qabel ma jingħata pemetrexed.
Due to the gastrointestinal toxicity of pemetrexed given in combination with cisplatin, severe dehydration has been observed.
Kienet osservata diżidratazzjoni gravi minħabba t- tossiċità gastrointestinali ikkawżata minn pemetrexed meta jingħata flimkien ma ’ cisplatin.
Therefore, patients should receive adequate antiemetic treatment and appropriate hydration prior to and/ or after receiving treatment.
Għalhekk, il- pazjenti għandhom jirċievu kura anti - emetika adegwata, kif ukoll idratazzjoni xierqa qabel u/ jew wara li jirċievu l- kura.
Serious cardiovascular events, including myocardial infarction and cerebrovascular events have been uncommonly reported during clinical studies with pemetrexed, usually when given in combination with another cytotoxic agent.
Każijiet kardjovaskulari serji, fosthom infart mijokardijaku u każijiet ċerebrovaskulari, ma kinux rappurtati ta ’ sikwit fi studji kliniċi b’ pemetrexed, u dawn ħafna drabi seħħew meta pemetrexed ingħata flimkien ma ’ sustanza ċitotossika oħra.
Most of the patients in whom these events have been observed had pre- existing cardiovascular risk factors (see section 4.8).
Il- parti l- kbira tal- pazjenti b’ dawn il- każijiet kellhom fatturi ta ’ riskju kardjovaskulari li kienu jeżistu qabel ma bdiet il- kura (ara sezzjoni 4. 8).
Immunodepressed status is common in cancer patients.
5 L- immunodipressjoni hija komuni f’ pazjenti li jkollhom kanċer.
As a result, concomitant use of live attenuated vaccines (except yellow fever which is contraindicated) is not recommended (see section 4.3 and 4.5).
Għalhekk, mhux rakkomandat li jingħataw vaċċini ħajjin attenwati (ħlief fil- każ tal- yellow fever li huwa kontra- indikat) fl- istess żmien (ara sezzjonijiet 4. 3 u 4. 5).
5 Pemetrexed can have genetically damaging effects.
Pemetrexed jista ’ jkollu effetti li jagħmlu ħsara fuq livell ġenetiku.
Sexually mature males are advised not to father a child during the treatment and up to 6 months thereafter.
Hu rakkomandat li rġiel li huma maturi sesswalment m’ għandhomx jippruvaw għat- tfal waqt il- kura u sa 6 xhur wara.
Contraceptive measures or abstinence are recommended.
Huma rakkomandati miżuri ta ’ kontraċezzjoni jew l- astinenza.
Owing to the possibility of pemetrexed treatment causing irreversible infertility, men are advised to seek counselling on sperm storage before starting treatment.
Minħabba li l- kura b’ pemetrexed tista ’ tikkawża infertilità irriversibbli, hu rakkomandat li l- irġiel għandhom jieħdu parir jekk għandhomx jaħżnu l- isperma qabel jieħdu l- kura.
Women of childbearing potential must use effective contraception during treatment with pemetrexed (see section 4.6).
In- nisa li jista ’ jkollhom it- tfal għandhom jużaw kontraċezzjoni effettiva meta jieħdu l- kura b’ pemetrexed (ara sezzjoni 4. 6).
Cases of radiation pneumonitis have been reported in patients treated with radiation either prior, during or subsequent to their pemetrexed therapy.
Każijiet ta ’ pulmonite kawża ta ’ radjazzjoni ġew irrapportati f’ pazjenti li ġew mogħtija r- radjazzjoni qabel, waqt jew wara l- kura b’ pemetrexed.
Particular attention should be paid to these patients and caution exercised with use of other radiosensitising agents.
Attenzjoni partikulari għandha tingħata lil dawn il- pazjenti u għandha tintuża l- kawtela meta jingħataw sustanzi oħra li jżidu s- sensittività għar- radjazzjoni.
Cases of radiation recall have been reported in patients who received radiotherapy weeks or years previously.
Ġew irrapportati każijiet fejn reġgħu dehru l- effetti tar- radjazzjoni f’ pazjenti li kienu rċevew ir - radjoterapija ġimgħat jew snin qabel.
Pemetrexed is mainly eliminated unchanged renally by tubular secretion and to a lesser extent by glomerular filtration.
Pemetrexed primarjament jiġi eliminat bla ebda modifikazzjoni mill- kliewi permezz ta ’ sekrezzjoni tubulari u fuq skala iżgħar permezz ta ’ filtrazzjoni glomerulari.
Concomitant administration of nephrotoxic drugs (e. g. aminoglycoside, loop diuretics, platinum compounds, cyclosporin) could potentially result in delayed clearance of pemetrexed.
Jekk jingħataw mediċini nefrotossiċi (eż. aminoglikosidi, dijuretiċi li jaħdmu fuq il- liwja tubulari, komposti tal- platinu, cyclosporin) fl - istess żmien, dawn jistgħu jwasslu għal dewmien fit- tneħħija ta ’ pemetrexed.
This combination should be used with caution.
L- użu ta ’ dawn il - mediċini flimkien ma ’ pemetrexed għandha ssir b’ kawtela.
If necessary, creatinine clearance should be closely monitored.
Jekk ikunu neċċessarji, it- tneħħija tal - krejatinina għandha tiġi osservata bir- reqqa.
Concomitant administration of substances that are also tubularly secreted (e. g. probenecid, penicillin) could potentially result in delayed clearance of pemetrexed.
L- għoti fl- istess żmien ta ’ sustanzi li wkoll ikollhom sekrezzjoni tubulari (eż. probenecid, penicillin) jista ’ jwassal għal dewmien fit- tneħħija ta ’ pemetrexed.
Caution should be made when these drugs are combined with pemetrexed.
L- attenzjoni hi meħtieġa meta dawn il - mediċini jingħataw flimkien ma ’ pemetrexed.
If necessary, creatinine clearance should be closely monitored.
Jekk ikunu neċċessarji, it- tneħħija tal- krejatinina għandha tiġi osservata bir- reqqa.
In patients with normal renal function (creatinine clearance > 80 ml/ min), high doses of non-steroidal anti-inflammatory drugs (NSAIDs, such as ibuprofen > 1600 mg/ day) and aspirin at higher dosage (> 1.3 g daily) may decrease pemetrexed elimination and, consequently, increase the occurrence of pemetrexed adverse events.
F’ pazjenti li jkollhom il- kliewi jaħdmu normali (tneħħija tal- krejatinina ≥ 80 ml/ min), dożi għolja ta ’ mediċini anti- infjammatorji li mhumiex sterojdi (NSAIDs, bħal ibuprofen > 1600 mg/ kuljum) kif ukoll doża għolja ta ’ aspirina (≥ 1. 3 g kuljum) jistgħu jnaqqsu l- eliminazzjoni ta ’ pemetrexed u, b’ hekk, tiżdied l- inċidenza ta ’ każijiet avversi ta ’ pemetrexed.
Therefore, caution should be made when administering higher doses of NSAIDs or aspirin at higher dosage, concurrently with pemetrexed to patients with normal function (creatinine clearance > 80 ml/ min).
Għalhekk, għandha tingħata attenzjoni meta jingħataw dożi għolja ta ’ NSAIDs jew ta ’ aspirina flimkien ma ’ pemetrexed lil pazjenti b’ funzjoni tal- kliewi normali (tneħħija tal- krejatinina ≥ 80 ml/ min).
In patients with mild to moderate renal insufficiency (creatinine clearance from 45 to 79 ml/ min), the concomitant administration of pemetrexed with NSAIDs (e. g. ibuprofen) or aspirin at higher dosage should be avoided for 2 days before, on the day of, and 2 days following pemetrexed administration (see section 4.4).
Ibuprofen) jew aspirina f’ dożi għoljin għandu jkun evitat minn jumejn qabel, dakinhar u sa jumejn wara l- għoti ta ’ pemetrexed (ara sezzjoni 4. 4).
In the absence of data regarding potential interaction with NSAIDs having longer half-lives as piroxicam or rofecoxib, the concomitant administration with pemetrexed should be avoided for at least 5 days prior to, on the day of, and at least 2 days following pemetrexed administration (see section 4.4).
Fin- nuqqas ta ’ tagħrif dwar l- interazzjoni potenzjali ma ’ NSAIDs li jkollhom half- life itwal bħal piroxicam jew rofecoxib, l- għoti ta ’ pemetrexed fl- istess żmien għandu jkun evitat mill- anqas minn 5 ijiem qabel, dakinhar u sa mill- inqas jumejn wara l- għoti ta ’ pemetrexed (ara sezzjoni 4. 4).
Pemetrexed undergoes limited hepatic metabolism.
Pemetrexed ikollu metaboliżmu limitat fil- fwied.
Results from in vitro studies with human liver microsomes indicated that pemetrexed would not be predicted to cause clinically significant inhibition of the metabolic clearance of drugs metabolised by CYP3A, CYP2D6, CYP2C9, and CYP1A2.
Studji in vitro b’ mikrożomi tal- fwied umani juru li mhux previst li pemetrexed jikkawża l- inibizzjoni klinikament sinifikanti tat- tneħħija metabolika ta ’ mediċini li jkunu metabolizzati b’ CYP3A, CYP2D6, CYP2C9, u CYP1A2.
Interactions common to all cytotoxics:
Interazzjonijiet komuni għaċ- ċitotossiċi kollha:
Due to the increased thrombotic risk in patients with cancer, the use of anticoagulation treatment is frequent.
Minħabba r- riskju akbar ta ’ trombożi f’ pazjenti bil- kanċer, l- użu ta ’ kura antikoagulanti hija frekwenti.
The high intra-individual variability of the coagulation status during diseases and the possibility of interaction between oral anticoagulants and anticancer chemotherapy require increased frequency of INR (International Normalised Ratio) monitoring, if it is decided to treat the patient with oral anticoagulants.
6 bżonn ta ’ monitoraġġ ta ’ l- INR (International Normalised Ratio) aktar spiss, jekk ikun deċiż li l - pazjent għandu jingħatalu kura b’ antikoagulanti orali.
Yellow fever vaccine: risk of fatal generalised vaccinale disease (see section 4.3).
Użu fl- istess zmien kontra- indikat: il- vaċċin tal- yellow fever: riskju ta ’ mard vaċċinali ġeneralizzat li jwassal għall- mewt (ara sezzjoni 4. 3).
Live attenuated vaccines (except yellow fever, for which concomitant use is contraindicated): risk of systemic, possibly fatal, disease.
Użu fl- istess żmien mhux rakkomandat: vaċċini ħajjin attenwati (ħlief għal dak tal- yellow fever, fejn l - użu fl- istess żmien huwa kontra- indikat): riskju ta ’ mard sistemiku, li jista ’ jwassal għall- mewt.
The risk is increased in
Uża vaċċin inattivat jekk ikun jeżisti (poljomajelite) (ara sezzjoni 4. 4).
6 subjects who are already immunosuppressed by their underlying disease.
4. 6 Tqala u Treddigħ
There are no data from the use of pemetrexed in pregnant women but pemetrexed, like other anti-metabolites, is suspected to cause serious birth defects when administered during pregnancy.
M’ hemmx tagħrif dwar l- użu ta ’ pemetrexed f’ nisa tqal iżda, bħal antimetaboliti oħra, hemm suspett li pemetrexed jikkawża difetti serji konġeniti meta jingħata waqt it- tqala.
Animal studies have shown reproductive toxicity (see section 5.3).
Studji fuq l- annimali wrew tossiċità fuq is- sistema riproduttiva (ara sezzjoni 5. 3).
Pemetrexed should not be used during pregnancy unless clearly necessary, after a careful consideration of the needs of the mother and the risk for the foetus (see section 4.4).
Pemetrexed m’ għandux jintuża waqt it- tqala sakemm mhux verament neċċessarju, wara kunsiderazzjoni xierqa tal- ħtiġijiet ta ’ l- omm u r- riskju għall- fetu (ara sezzjoni 4. 4).
Women of childbearing potential must use effective contraception during treatment with pemetrexed.
Nisa li jista ’ jkollhom it- tfal għandhom jużaw kontraċezzjoni effettiva waqt il- kura b’ pemetrexed.
Pemetrexed can have genetically damaging effects.
Pemetrexed jista ’ jkollu effetti li jagħmlu ħsara fuq livell ġenetiku.
It is not known whether pemetrexed is excreted in human milk and adverse reactions on the suckling child cannot be excluded.
Mhux magħruf jekk pemetrexed jgħaddix fil- ħalib uman u wieħed ma jistax jeskludi li jkun hemm xi reazzjonijiet avversi fit- tarbija li titredda ’.
Breast-feeding must be discontinued during pemetrexed therapy (see section 4.3).
It- treddigħ għandu jieqaf waqt it- terapija b’ pemetrexed (ara sezzjoni 4. 3).
However, it has been reported that pemetrexed may cause fatigue.
Madankollu, kien irrappurtat li pemetrexed jista ’ jikkawża l- għeja.
Therefore patients should be cautioned against driving or operating machines if this event occurs.
Għalhekk, il- pazjenti għandhom ikunu mwissija biex fil- każ li jiġri dan, ma jsuqux jew iħaddmu magni.
The table below provides the frequency and severity of undesirable effects that have been reported in > 5% of 168 patients with mesothelioma who were randomised to receive cisplatin and pemetrexed and 163 patients with mesothelioma randomised to receive single agent cisplatin.
It- tabella hawn taħt tati l- frekwenza u s- severità ta ’ l- effetti mhux mixtieqa li ġew irrapportati f ’ > 5% tal- 168 pazjent b’ mesoteljoma li ntgħażlu bl- addoċċ biex jirċievu cisplatin u pemetrexed u 163 pazjent b’ mesoteljoma li ntgħażlu bl- addoċċ biex jirċievu cisplatin waħdu.
In both treatment arms, these chemonaive patients were fully supplemented with folic acid and vitamin B12.
Fiż- żewġ fergħat ta ’ kura, dawn il - pazjenti, li ma kienu ħadu ebda kimoterapija oħra, ngħataw folic acid u vitamina B12 bħala suppliment.
Very common (≥ 1/ 10), Common (≥ 1/ 100 and < 1/ 10), Uncommon (≥ 1/ 1000 and < 1/ 100), Rare (≥ 1/ 10,000 and < 1/ 1000), Very Rare (<  1/ 10,000) and Not known (cannot be estimated from available data-spontaneous reports)
Komuni ħafna (> 1/ 10), Komuni (> 1/ 100 sa < 1/ 10), Mhux komuni (> 1/ 1000 sa < 1/ 100), Rari (> 1/ 10, 000 sa < 1/ 1000), Rari ħafna (< 1/ 10, 000) u Mhijiex magħrufa (ma tistax tiġi stimata mir- rapporti ta ’ informazzjoni spontanja li hemm disponibbli).
Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
F’ kull sezzjoni ta ’ frekwenza, l- effetti mhux mixtieqa huma mniżżlin f’ ordni ta ’ l- iżjed serju sa l- inqas serju.
7 System Organ
7 Sistema tal - klassifika ta ’ l -
Event*
Avveniment *
Pemetrexed/ cisplatin (N = 168)
Pemetrexed/ cisplatin (N = 168)
Class
organi
All
Grad ta ’ Kull
Grade All
Kull Grad ta ’ Kull
All Grade All
Grad ta ’
Grade
Grad Ta ’
Grades
Tossiċità Grad 3- 4 Ta ’
Grades 3-4 Grades
Tossiċità 3- 4
3-4
Tossiċità (%)
Toxicity Toxicity (%) (%)
(%) Tossiċità (%)
Blood and Lymphatic System
Disturbi fid - Demm u fis - Sistema
Neutrophils/ Granulocytes decreased
Tnaqqis fin - newtrofili / granuloċiti
56.0 23.2
23. 2
13.5 3.1
3. 1
Disorders
Limfatika
Leukocytes decreased
Tnaqqis fil - lewkoċiti
53.0 14.9
14. 9
16.6 0.6
16. 6
Haemoglobin decreased
Tnaqqis fl - emoglobina
26.2 4.2
26. 2
10.4 0.0
0. 0
Platelets decreased
Tnaqqis fil - plejtlits
23.2 5.4
23. 2
8.6 0.0
0. 0
5.4 0.0
0. 0
0.6 0.0
0. 0
Gastrointestinal Disorders
Disturbi Gastro- intestinali
Diarrhoea Vomiting Stomatitis/ Pharyngitis
Dijarrea Rimettar Stomatite / Farinġite
16.7 3.6 56.5 10.7 23.2 3.0
16. 7 56. 5 23. 2
8.0 0.0 49.7 4.3 6.1 0.0
8. 0 49. 7 6. 1
Nausea Anorexia Constipation
Tqallih Anoressija Stitikezza
82.1 11.9 20.2 1.2 11.9 0.6
11. 9 1. 2 0. 6
76.7 5.5 14.1 0.6 7.4 0.6
0. 6
5.4 0.6
0. 6
General Disorders
Disturbi Ġenerali
47.6
47. 6
42.3
42. 3
Dehydration
Diżidratazzjoni
Neuropathy- Sensory
Newropatija sensittiva
9.8
9. 8
Taste disturbance
Tibdil fit - togħma
0.0***
0. 0 ***
Renal and Urinary Disorders
Disturbi fil - Kliewi u fis - Sistema Awrinarja
Creatinine elevation
Żieda fil - krejatinina
10.7
10. 7
Creatinine clearance decreased**
Tnaqqis fit - tneħħija tal - krejatinina **
17.8
17. 8
Skin and Subcutaneous
Disturbi fil- Ġilda u fit- Tessuti ta ’
Tissue Disorders
Taħt il- Ġilda *
Alopecia
Alopeċja
*Refer to National Cancer Institute CTC version 2 for each grade of toxicity except the term “ creatinine clearance decreased” ** which is derived from the term “ renal/ genitourinary other”. *** According to National Cancer Institute CTC (v2.0; NCI 1998), taste disturbance and alopecia should only be reported as Grade 1 or 2.
Irreferi għal verżjoni 2 tas - CTC ta 'l- Istitut Nazzjonali tal- Kanċer għal kull grad ta ’ tossiċità ħlief għat- terminu “ tnaqqis fit- tneħħija tal- krejatinina ” ** li ġejja mit- terminu “ renali/ ġenito- awrinarji oħrajn ”. *** Skont is- CTC (v2. 0; NCI 1998) ta ’ l- Istitut Nazzjonali tal- Kanċer, it- tibdil fit- togħma u l - alopeċja għandhom jiġu rrapportati biss bħala Grad 1 jew 2.
8 Very common - ≥ 10%; Common is normally defined as - ≥ 1% and < 10%.
8 Komuni ħafna - > 10%; Komuni huwa normalment definit bħala > 1% u < 10%.
For the purpose of this table a cut off of 5% was used for inclusion of all events where the reporter considered a possible relationship to pemetrexed and cisplatin.
Għall- iskopijiet ta ’ din it- tabella ntuża limitu ta ’ 5% sabiex jiġi nklużi kull avveniment li min kien qed jirrapporta ikkonsidra li kien hemm xi konnessjoni possibbli ma ’ pemetrexed u cisplatin.
Clinically relevant CTC toxicities that were reported in - ≥ 1% and < 5% (common) of the patients that were randomly assigned to receive cisplatin and pemetrexed include: renal failure, infection, pyrexia, febrile neutropenia, increased AST, ALT, and GGT, urticaria and chest pain.
Tossiċitajiet CTC klinikament rilevanti li ġew irrapportati f ’ > 1% u < 5% (komuni) tal- pazjenti li ntgħażlu bl- addoċċ biex jirċievu cisplatin u pemetrexed jinkludu: insuffiċjenza renali, infezzjoni, deni, newtropenja bid- deni, żieda fl- AST, ALT u GGT, urtikarja, u uġigħ fis- sider.
Clinically relevant CTC toxicities that were reported in < 1% (uncommon) of the patients that were randomly assigned to receive cisplatin and pemetrexed include arrhythmia and motor neuropathy.
Tossiċitajiet CTC klinikament rilevanti li ġew irrapportati f ’ < 1% (mhux komuni) tal- pazjenti li ntgħażlu bl- addoċċ biex jirċievu cisplatin u pemetrexed jinkludu arritmja u newropatija motorja.
The table below provides the frequency and severity of undesirable effects that have been reported in > 5% of 265 patients randomly assigned to receive single agent pemetrexed with folic acid and vitamin B12 supplementation and 276 patients randomly assigned to receive single agent docetaxel.
It- tabella hawn taħt tati l- frekwenza u s- severità ta ’ l- effetti mhux mixtieqa li ġew irrapportati f ’ > 5% tal- 265 pazjent li ntgħażlu bl- addoċċ biex jirċievu pemetrexed waħdu b’ supplimentazzjoni ta ’ folic acid u vitamina B12 u 276 pazjent li ntgħażlu bl- addoċċ biex jirċievu docetaxel waħdu.
All patients were diagnosed with locally advanced or metastatic non-small cell lung cancer and received prior chemotherapy.
Il- pazjenti kollha kellhom dijanjosi ta ’ kanċer tal- pulmun mhux b’ ċelluli żgħar lokalment avvanzat jew metastatiku u qabel kienu diġà rċevew il- kimoterapija.
System Organ Class
Sistema tal - klassifika ta ’ l -
All Grades Grade 3 – Toxicity 4 Toxicity (%) (%)
Grad ta ’ Kull Grad Tossiċità Ta ’ 3– 4 Tossiċità (%) (%)
All Grades Grade 3 – Toxicity 4 Toxicity (%) (%)
Grad ta ’ Tossiċità 3– 4 (%)
10.9 5.3
10. 9
45.3 40.2
5. 3 45. 3
12.1 4.2
27. 2
19.2 4.2
19. 2
22.1 4.3
4. 2 22. 1
8.3 1.9
1. 9 1. 1
1.1 0.4
0. 4
12.8 0.4 16.2 1.5 14.7 1.1
12. 8 16. 2 14. 7
24.3 2.5 12.0 1.1 17.4 1.1
0. 4 24. 3 1. 5 12. 0 1. 1 17. 4
Nausea Anorexia
2. 5 1. 1 1. 1
30.9 2.6 21.9 1.9
Tqallih Anoressija
16.7 1.8 23.9 2.5
2. 6 16. 7 1. 9 23. 9
5.7 0.0
0. 0 4. 0
4.0 0.0
0. 0
34.0 5.3
34. 0
35.9 5.4
5. 3 35. 9
8.3 0.0
0. 0 7. 6
7.6 0.0
0. 0
Hepatobilliary Disorders
Disturbi fil - Fwied u fil -
SGPT (ALT) elevation
Żieda fl- SGPT (ALT)
7.9 1.9
1. 9 1. 4
1.4 0.0
0. 0
SGOT (AST) elevation
Żieda fl- SGOT (AST)
6.8 1.1
1. 1 0. 7
0.7 0.0
0. 0
Skin and Sub- cutaneous
Disturbi fil - Ġilda u fit -
Rash/ desquamation
Raxx / twaqqigħ ta 'qxur
14.0 0.0
0. 0 6. 2
6.2 0.0
0. 0
Tissue Disorders Common
Tessuti ta ’ Taħt Komuni
0.4**
0. 4 **
37.7
37. 7
2.2**
2. 2 **
*Refer to National Cancer Institute CTC version 2 for each grade of toxicity. **According to National Cancer Institute CTC (v2.0; NCI 1998), alopecia should only be reported as Grade 1 or 2.
* Irreferi għal verżjoni 2 tas- CTC ta 'l- Istitut Nazzjonali tal- Kanċer għal kull grad ta ’ tossiċità. ** Skont is- CTC (v 2. 0; NCI 1998) ta ’ l- Istitut Nazzjonali tal- Kanċer, l- alopeċja għandha tiġi rrapportata biss bħala Grad 1 jew 2.
Very common ≥ 10%; Common is normally defined as ≥ 1% and < 10%.
9 Komuni ħafna > 10%; Komuni huwa normalment definit bħala > 1% u < 10%.
For the purpose of this table a cut off of 5% was used for inclusion of all events where the reporter considered a possible relationship to pemetrexed.
Għall- iskopijiet ta ’ din it- tabella ntuża limitu ta ’ 5% sabiex jiġi inkluż kull avveniment li min kien qed jirrapporta ikkunsidra li kien hemm xi konnessjoni possibbli ma ’ pemetrexed.
9 Clinically relevant CTC toxicities that were reported in ≥ 1% and < 5% (common) of the patients that were randomly assigned to pemetrexed include: infection without neutropenia, febrile neutropenia, allergic reaction/ hypersensitivity, increased creatinine, motor neuropathy, sensory neuropathy, erythema multiforme, and abdominal pain.
Tossiċitajiet CTC klinikament rilevanti li ġew irrapportati f ’ > 1% u < 5% (komuni) tal- pazjenti li ntgħażlu bl- addoċċ biex jirċievu pemetrexed jinkludu: infezzjoni mingħajr newtropenja newtropenja bid- deni, reazzjoni allerġika/ sensittivita aċċessiva, żieda fil- krejatinina, newropatija motorja, newropatija sensittiva, eritema multiforme u wġigħ addominali.
Clinically relevant CTC toxicities that were reported in < 1% (uncommon) of the patients that were randomly assigned to pemetrexed include supraventricular arrhythmias.
Tossiċitajiet CTC klinikament rilevanti li ġew irrapportati f ’ < 1% (mhux komuni) tal- pazjenti li ntgħażlu bl- addoċċ biex jirċievu pemetrexed jinkludu arritmji supraventrikulari.
Clinically relevant Grade 3 and Grade 4 laboratory toxicities were similar between integrated Phase 2 results from three single agent pemetrexed studies (n = 164) and the Phase 3 single agent pemetrexed study described above, with the exception of neutropenia (12.8% versus 5.3%, respectively) and alanine transaminase elevation (15.2% versus 1.9%, respectively).
Tossiċitajiet ta ’ laboratorju klinikament rilevanti ta ’ Grad 3 u Grad 4 kienu simili bejn ir- riżultati integrati ta ’ Fażi 2 minn tliet studji ta ’ pemetrexed bħala mediċina weħidha (n = 164) u l- istudju ta ’ Fażi 3 ta ’ pemetrexed bħala mediċina weħidha deskritta hawn fuq bl- eċċezzjoni ta ’ newtropenja (12. 8% kontra 5. 3%, rispettivament) u ż- żieda fl- alanine transaminase (15. 2% konta 1. 9%, rispettivament).
These differences were likely due to differences in the patient population, since the Phase 2 studies included both chemonaive and heavily pre-treated breast cancer patients with pre-existing liver metastases and/ or abnormal baseline liver function tests.
Wisq probabbli dawn id- differenzi kienu minħabba d- differenzi fil- popolazzjoni tal - pazjenti, peress li l- istudji ta ’ Fażi 2 kienu jinkludu kemm pazjenti li qatt ma kienu rċevew xi kimoterapija kif ukoll pazjenti b’ kanċer tas- sider li kienu digà rċevew ħafna kimoterapija u li diġà kellhom metastasi tal- fwied u/ jew testijiet tal- funzjoni tal- fwied b’ livelli tal- linja bażi anormali.
The table below provides the frequency and severity of undesirable effects considered possibly related to study drug that have been reported in > 5% of 839 patients with NSCLC who were randomized to receive cisplatin and pemetrexed and 830 patients with NSCLC who were randomized to receive cisplatin and gemcitabine.
It- tabella hawn taħt tati l- frekwenza u s- severità ta ’ l- effetti mhux mixtieqa li huma kkunsidrati possibbilment relatati ma 'l- mediċina taħt studju u li ġew irrapportati f ’ > 5% ta' 839 pazjent b' NSCLC li b’ mod arbitrarju ntgħażlu biex jirċievu cisplatin u pemetrexed u 830 pazjent b' NSCLC li b’ mod arbitrarju ntgħażlu biex jirċievu cisplatin u gemcitabine.
All patients received study therapy as initial treatment for locally advanced or metastatic NSCLC and patients in both treatment groups were fully supplemented with folic acid and vitamin B12.
Il- pazjenti kollha rċevew it- terapija taħt studju bħala kura inizjali għal kanċer tal- pulmun mhux b’ ċelluli żgħar (NSCLC) lokalment avanzat jew metastatiku u l- pazjenti fiż- żewġ gruppi ta 'kura kellhom supplimentazzjoni sħiħa ta ’ folic acid u vitamina B12.
10 System Organ Class
Sistema tal - klassifika ta ’ l - organi
Event**
Avveniment **
Pemetrexed/ cisplatin (N = 839)
Pemetrexed / cisplatin (N = 839)
Gemcitabine/ cisplatin (N = 830)
Gemcitabine / cisplatin (N = 830)
Blood and Lymphatic
Disturbi fid -
Very Common
Komuni
Hemoglobin decreased
Emoglobina
33.0* 5.6*
33. 0 *
45.7* 9.9*
5. 6 * 45. 7 *
System Disorders
Demm u fis - Sistema
Neutrophils/ Granulocytes decreased
Newtrofili / Granuloċiti
29.0* 15.1*
29. 0 *
38.4* 26.7*
15. 1 *
Leukocytes decreased
38. 4 *
17.8 4.8*
26. 7 *
20.6 7.6*
Limfatika
Platelets decreased
Lewkoċiti Plejtlits
10.1* 4.1*
20. 6 26. 6 *
26.6* 12.7*
7. 6 * 12. 7 *
Nausea Vomiting Anorexia Constipation Stomatitis/ pharyngitis
Tqalligħ Rimettar Anoressija Stitikezza Stomatite / Farinġite
56.1 39.7 26.6 21.0 13.5
56. 1 39. 7 26. 6 21. 0 13. 5
7.2* 6.1 2.4* 0.8 0.8
7. 2 * 6. 1 2. 4 * 0. 8 0. 8
53.4 35.5 24.2 19.5 12.4
53. 4 35. 5 24. 2 19. 5 12. 4
3.9* 6.1 0.7* 0.4 0.1
3. 9 * 6. 1 0. 7 * 0. 4 0. 1
Diarrhoea without colostomy
Dijarrea mingħajr kolostomija
12.4
12. 4
12.8
12. 8
Dyspepsia/ heartburn
Dispepsja/ qrusa ta 'l- istonku
General Disorders and Administration Site Conditions
Disturbi Ġenerali u Kondizzjonijiet ta 'Mnejn Jingħata
42.7
42. 7
44.9
44. 9
Nervous System
Disturbi fis - Sistema Nervuża
Neuropathy- sensory
Newropatija sensittiva
8.5*
8. 5 *
0.0*
0. 0 *
12.4*
12. 4 *
Creatinine elevation
Krejatinina
10.1*
10. 1 *
6.9*
6. 9 *
Skin and Subcutaneous
Disturbi fil- Ġilda u fit- Tessuti ta ’ Taħt il- Ġilda
11.9*
11. 9 *
21.4*
21. 4 *
0.5***
0. 5 ***
Rash/ desquamation
Raxx/ twaqqigħ ta 'qxur
*P-values < 0.05 comparing pemetrexed/ cisplatin to gemcitabine/ cisplatin, using Fisher Exact test. **Refer to National Cancer Institute CTC (v2.0; NCI 1998) for each Grade of Toxicity. ***According to National Cancer Institute CTC (v2.0; NCI 1998), taste disturbance and alopecia should only be reported as Grade 1 or 2.
* Valuri P < 0. 05 meta tqabbel pemetrexed/ cisplatin ma 'gemcitabine/ cisplatin, permezz tal- Fisher Exact test. ** Irreferi għas- CTC (v 2. 0; NCI 1998) ta ’ l- Istitut Nazzjonali tal- Kanċer għal kull Grad ta ’ Tossiċità. *** Skont is- CTC (v 2. 0; NCI 1998) ta ’ l- Istitut Nazzjonali tal- Kanċer, it- tibdil fit- togħma u l - alopeċja għandhom jiġu rrapportati bħala Grad 1 jew 2 biss.
Very common ≥ 10%; common is normally defined as ≥ 1% and < 10%.
Komuni ħafna ≥10%; Komuni huwa normalment definit bħala ≥1% u < 10%.
For the purpose of this table, a cut-off of 5% was used for inclusion of all events where the reporter considered a possible relationship to pemetrexed and cisplatin).
Għall- iskopijiet ta ’ din it- tabella ntuża limitu ta ’ 5% sabiex jiġu nklużi kull avveniment li min kien qed jirrapporta kkonsidra li kien hemm xi konnessjoni possibbli ma ’ pemetrexed u cisplatin.
AST increase, ALT increase, infection, febrile neutropenia, renal failure, pyrexia, dehydration, conjunctivitis, and creatinine clearance decrease.
Tossiċitajiet klinikament rilevanti li ġew irrapportati f ’ ≥ 1% u ≤5% (komuni) tal- pazjenti li ntgħażlu bl- addoċċ biex jirċievu cisplatin u pemetrexed jinkludu: żieda fl- AST, żieda fl- ALT, infezzjoni, newtropenja bid- deni, insuffiċjenza renali, deni, diżidratazzjoni, konġuntivite u tnaqqis fit- tneħħija ta 'krejatinina.
11 Clinically relevant toxicity that was reported in < 1% (uncommon) of the patients that were randomly assigned to receive cisplatin and pemetrexed include:
Tossiċitajiet klinikament rilevanti li ġew irrapportati f ’ < 1% (mhux komuni) tal- pazjenti li b’ mod arbitrarju ntgħażlu biex jirċievu cisplatin u pemetrexed jinkludu: żieda fil- GGT, uġigħ fis- sider, arritmja, u newropatija motorja.
Clinically relevant toxicities with respect to gender were similar to the overall population in patients receiving pemetrexed plus cisplatin.
Tossiċitajiet klinikament rilevanti skond is- sess, kienu simili għall- popolazzjoni totali f’ pazjenti li rċevew pemetrexed flimkien ma ’ cisplatin.
Serious cardiovascular and cerebrovascular events, including myocardial infarction, angina pectoris, cerebrovascular accident and transient ischaemic attack have been uncommonly reported during clinical studies with pemetrexed, usually when given in combination with another cytotoxic agent.
Avvenimenti serji ċerebrovaskulari u kardjovaskulari, li jinkludu infart mijokardijaku angina pectoris, inċident ċerebrovaskulari u attakk iskemiku tranżitorju ġew irrapportati mhux frekwentement matul l - istudji kliniċi b’ pemetrexed, ħafna drabi meta ngħata ma ’ sustanza ċitotossika oħra.
Most of the patients in whom these events have been observed had pre-existing cardiovascular risk factors.
Ħafna mill - pazjenti li fuqhom ġew osservati dawn l- avvenimenti diġà kellhom fatturi ta ’ riskju kardjovaskulari.
Rare cases of hepatitis, potentially serious, have been reported during clinical studies with pemetrexed.
Każijiet rari ta ’ epatite, potenzjalment serji, ġew irrapportati matul l- istudji kliniċi b’ pemetrexed.
Pancytopenia has been uncommonly reported during clinical trials with pemetrexed.
Panċitopenja ġiet irrapportata mhux frekwentement matul l- istudji kliniċi b’ pemetrexed.
In clinical trials, cases of colitis (including intestinal and rectal bleeding, sometimes fatal, intestinal perforation, intestinal necrosis and typhlitis) have been reported uncommonly in patients treated with pemetrexed.
Fi studji kliniċi, b’ mod mhux komuni, ġew irrapportati każijiet ta ’ kolite (li jinkludu fsada intestinali u rettali, xi kultant fatali, perforazzjoni intestinali, nekrożi intestinali u tiflite), f’ pazjenti kkurati b’ pemetrexed.
In clinical trials, cases of interstitial pneumonitis with respiratory insufficiency, sometimes fatal, have been reported uncommonly in patients treated with pemetrexed.
Fi studji kliniċi, b’ mod mhux komuni, ġew irrapportati każijiet ta ’ pulmonite interstizjali b’ insuffiċjenza respiratorja, xi kultant fatali, f’ pazjenti kkurati b’ pemetrexed.
Uncommon cases of oedema have been reported in patients treated with pemetrexed.
Każijiet mhux komuni ta ’ edima ġew irraportati f’ pazjenti kkurati b’ pemetrexed.
During post marketing surveillance, the following adverse reactions have been reported in patients treated with pemetrexed:
Waqt sorveljanza ta ’ wara t- tqegħid fis- suq, ġew irrapportati dawn ir- reazzjonijiet avversi f’ pazjenti kkurati b’ pemetrexed:
Cases of acute renal failure have been reported with pemetrexed alone or in association with other chemotherapeutic agents (see section 4.4).
11 Każijiet ta ’ insuffiċjenza renali akuta ġew irrapportati meta ntuża pemetrexed waħdu jew flimkien ma ’ sustanzi kimoterapewtiċi oħra (ara sezzjoni 4. 4).
Cases of radiation pneumonitis have been reported in patients treated with radiation either prior, during or subsequent to their pemetrexed therapy (see section 4.4).
Każijiet ta ’ pulmonite kawża ta ’ radjazzjoni ġew irrapportati f’ pazjenti li ġew mogħtija r- radjazzjoni qabel, waqt jew wara l- kura b’ pemetrexed (ara sezzjoni 4. 4).
Cases of radiation recall have been reported in patients who have received radiotherapy previously (see section 4.4) Cases of peripheral ischemia leading sometimes to extremity necrosis have been reported.
Ġew irrapportati każijiet ta ’ iskemija periferali li xi kultant waslu għal nekrożi fl- estremitajiet.
Reported symptoms of overdose include neutropenia, anaemia, thrombocytopenia, mucositis, sensory polyneuropathy and rash.
Sintomi ta ’ doża eċċessiva li ġew irrapportati jinkludu: newtropenja, anemija, tromboċitopenja, mukożite, polinewropatija sensittiva, u raxx.
Anticipated complications of overdose include bone marrow suppression as manifested by neutropenia, thrombocytopenia and anaemia.
Komplikazzjonijiet mistennija ta ’ doża eċċessiva jinkludu: soppressjoni tal- mudullun kif jixhdu n- newtropenja, t- tromboċitopenja u l- anemija.
In addition, infection with or without fever, diarrhoea, and/ or mucositis may be seen.
Barra minn hekk, jista ’ jkun hemm, infezzjoni kemm bid- deni jew mingħajr deni, dijarrea, u/ jew mukożite.
In the event of suspected overdose, patients should be monitored with blood counts and should receive supportive therapy as necessary.
Fl- eventwalità ta ’ suspett ta ’ xi doza eċċessiva, il- pazjenti jridu jinżammu taħt osservazzjoni u jittieħdilhom l- għadd tad- demm u għandhom jirċievu terapija ta ’ support kif xieraq.
The use of calcium folinate / folinic acid in the management of pemetrexed overdose should be considered.
Fit- trattament ta ’ doża eċċessiva ta ’ pemetrexed għandu jiġi kkunsidrat l- użu ta ’ calcium folinate / folinic acid.
Folic acid analogues, ATC code:
Kategorija farmakoterapewtika: analogi ta ’ folic acid, Kodiċi ATC:
ALIMTA (pemetrexed) is a multi-targeted anti-cancer antifolate agent that exerts its action by disrupting crucial folate-dependent metabolic processes essential for cell replication.
Taħdem billi tfixkel proċessi metaboliċi kruċjali li jiddipendu mill- folat u li huma essenzjali għar- replikazzjoni taċ- ċelluli.
Pemetrexed is transported into cells by both the reduced folate carrier and membrane folate binding protein transport systems.
Studji in vitro wrew li pemetrexed jaġġixxi bħala antifolat b’ iżjed minn objettiv wieħed billi jinibbixxi thymidylate synthase (TS), dihydrofolate reductase (DHFR), u glycinamide ribonucleotide formyltransferase (GARFT), li huma enzimi dipendenti fuq il- folat u huma kruċjali għall- bijosintesi de novo tan- nukleotidi thymidine u purine. Pemetrexed jittieħed ġewwa ċ- ċelluli permezz taż- zewġ sistemi tat- trasport, it- trasportatur ta ’ folat ridott u proteina fil- membrana li jeħel magħha l- folat.
Once in the cell, pemetrexed is rapidly and efficiently converted to polyglutamate forms by the enzyme folylpolyglutamate synthetase.
La darba jkun fiċ- ċellula, pemetrexed jiġi konvertit malajr u b’ mod effiċjenti f’ forom ta ’ poliglutamati permezz ta ’ l- enzima folylpolyglutamate synthetase.
The polyglutamate forms are retained in cells and are even more potent inhibitors of TS and GARFT.
Il- forom poliglutamati jinżammu fiċ- ċelluli u fil - fatt huma inibituri aktar potenti ta ’ TS u GARFT.
Polyglutamation is a time- and concentration-dependent process that occurs in tumour cells and, to a lesser extent, in normal tissues.
Il- poliglutamazzjoni hija proċess dipendenti fuq iż - żmien u l- konċentrazzjoni u sseħħ f’ ċelluli tat- tumur u fuq skala iżgħar f’ tessuti normali.
Polyglutamated metabolites have an increased intracellular half-life resulting in prolonged drug action in malignant cells.
Ġewwa ċ - ċelluli, il- metaboliti poliglutamati għandhom half- life itwal li jwassal biex l- azzjoni tal- mediċina fiċ - ċelluli malinni ddum aktar.
Clinical Efficacy:
Effikaċja klinika:
EMPHACIS, a multicentre, randomised, single-blind phase 3 study of ALIMTA plus cisplatin versus cisplatin in chemonaive patients with malignant pleural mesothelioma, has shown that patients treated with ALIMTA and cisplatin had a clinically meaningful 2.8-month median survival advantage over patients receiving cisplatin alone.
EMPHACIS, studju ta ’ fażi 3, single- blind, magħmul f’ ħafna ċentri, randomised, b’ ALIMTA flimkien ma ’ cisplatin kontra cisplatin, f’ pazjenti b’ mesoteljoma plewrali malinna u li ma kienu ħadu ebda kimoterapija oħra, wera li pazjenti kkurati b’ ALIMTA u cisplatin kellhom medjan ta ’ vantaġġ ta ’ sopravivenza klinikament sinifikanti ta ’ 2. 8 xhur fuq pazjenti li rċevew cisplatin waħdu.
During the study, low-dose folic acid and vitamin B12 supplementation was introduced to patients’ therapy to reduce toxicity.
Matul l- istudju, sabiex titnaqqas it- tossiċità, ġew introdotti mat- terapija tal- pazjenti, folic acid f’ doża baxxa u l- vitamina B12 bħala supplimentazzjoni.
A subgroup analysis was performed on patients who received folic acid and vitamin B12 supplementation during the entire course of study therapy (fully supplemented).
L- analiżi primarja ta ’ dan l- istudju saret fuq il - popolazzjoni kollha ta ’ pazjenti li ntgħażlu bl- addoċċ għal fergħa ta ’ kura fejn ingħatat il- mediċina taħt studju (mgħażula bl- addoċċ u kkurati). Analiżi ta ’ sottogrupp saret fuq pazjenti li rċevew folic acid u l- vitamina B12 bħala supplimentazzjoni matul il- kors kollu tat- terapija taħt studju (mgħotija suppliment tul it- terapija kollha).
The results of these analyses of efficacy are summarised in the table below:
Sommarju tar- riżultati ta ’ dawn l- analiżi ta ’ effikaċja jidher fit- tabella hawn taħt:
Efficacy of ALIMTA plus Cisplatin vs.
12 Effikaċja ta ’ ALIMTA ma ’ Cisplatin vs.
Cisplatin in Malignant Pleural Mesothelioma
Cisplatin f’ Mesoteljoma Plewrali Malinna
Randomized and Treated Patients
Pazjenti mgħotija suppliment
Fully Supplemented Patients
mgħażula bl- addoċċ u kkurati
Efficacy Parameter
Parametru ta ’ Effikaċja
Median Overall Survival (months)
Sopravivenza globali medjana (xhur)
= 226) 12.1
= 226) 12. 1
= 222) 9.3
= 222) 9. 3
= 168) 13.3
= 168) 13. 3
= 163) 10.0
= 163) 10. 0
(95% CI) Log Rank p-value*
(95% CI) Log Rank p- value *
(10.0 - 14.4) 0.020
(10. 0 - 14. 4) 0. 020
(7.8 - 10.7)
(7. 8 - 10. 7) (11. 4 - 14. 9) 0. 051
- 11.9)
(8. 4 - 11. 9)
Median Time to tumour progression (months)
Żmien Medjan fil- progress tat- tumur (xhur)
3.9
5. 7
6.1
3. 9 6. 1
(2.8 - 4.4)
(4. 9 - 6. 5) 0. 001
(5.3 - 7.0)
(2. 8 - 4. 4) (5. 3 - 7. 0) 0. 008
(2.8 - 4.5)
(2. 8 - 4. 5)
Time to Treatment Failure (months) (95% CI) Log Rank p-value*
Żmien sal- falliment fil- kura (xhur) (95% CI) Log Rank p- value *
4.5 (3.9 - 4.9)
4. 5 (3. 9 - 4. 9) 0. 001
4.7 (4.3 - 5.6)
2. 7 4. 7 (2. 1 - 2. 9) (4. 3 - 5. 6) 0. 001
2.7 (2.2 - 3.1)
2. 7 (2. 2 - 3. 1)
Overall response rate**
Ir- rata ta ’ respons globali **
41.3%
41. 3%
16.7%
16. 7% 45. 5%
19.6%
19. 6%
(12.0 - 22.2)
(34. 8 - 48. 1)
(37.8 - 53.4)
(12. 0 - 22. 2) (37. 8 - 53. 4)
(13.8 - 26.6)
(13. 8 - 26. 6)
Fisher’ s exact p-value*
Fisher’ s exact p- value *
Abbreviation: * p-value refers to comparison between arms.
Abbrevjazzjoni:
CI = confidence interval
CI = Intervall ta ’ Kunfidenza
13 ** In the ALIMTA/ cisplatin arm, randomized and treated (N = 225) and fully supplemented (N = 167)
* p- value jirreferi għat- tqabbil ta ’ bejn iż- żewġ fergħat ** Fil- fergħa ta ’ ALIMTA/ cisplatin, ntgħażlu bl- addoċċ u kkurati (N = 225) u mgħotija suppliment tul it- terapija kollha (N = 167)
Statistically significant differences in pulmonary function tests were also observed.
Titjib statistikament sinifikanti fis- sintomi klinikament rilevanti (uġigħ u qtugħ ta ’ nifs) assoċjati ma ’ mesoteljoma plewrali malinna kien dimonstrat fil- fergħa ta ’ ALIMTA/ cisplatin (212- il pazjent) meta kkomparat mal- fergħa ta ’ cisplatin waħdu (218- il pazjent) meta ġie użat il- Lung Cancer Symptom Scale. Differenzi statistikament sinifikanti kienu osservati wkoll fit- testijiet tal- funzjoni tal - pulmun.
The separation between the treatment arms was achieved by improvement in lung function in the ALIMTA/ cisplatin arm and deterioration of lung function over time in the control arm.
Is- separazzjoni bejn iż- żewġ fergħat ta ’ kura seħħet minħabba titjib fil- funzjoni tal- pulmun fil- fergħa ta ’ ALIMTA/ cisplatin u deterjorazzjoni fuq medda ta ’ żmien fil- funzjoni tal- pulmun fil - fergħa ta ’ kontroll.
There are limited data in patients with malignant pleural mesothelioma treated with ALIMTA alone.
L- informazzjoni hija limitata f’ pazjenti b’ mesoteljoma plewrali malinna ikkurati b’ ALIMTA waħdu.
ALIMTA at a dose of 500 mg/ m2 was studied as a single-agent in 64 chemonaive patients with malignant pleural mesothelioma.
Bħala mediċina weħidha ALIMTA kienet studjata, f’ 64 pazjent b’ mesoteljoma plewrali malinna u li ma kienu ħadu ebda kimoterapija oħra, f’ doża ta ’ 500mg/ m2.
The overall response rate was 14.1%.
Il- rata ta ’ respons globali kienet ta ’ 14. 1%.
A multicentre, randomised, open label phase 3 study of ALIMTA versus docetaxel in patients with locally advanced or metastatic NSCLC after prior chemotherapy has shown median survival times of 8.3 months for patients treated with ALIMTA (Intent To Treat population n = 283) and 7.9 months for patients treated with docetaxel (ITT n = 288).
Studju ta ’ Fażi 3, open- label, randomised, magħmul f’ ħafna ċentri b’ ALIMTA kontra docetaxel f’ pazjenti b’ NSCLC lokalment avvanzat jew metastatiku wara kimoterapija preċedenti, wera żminijiet medjani ta ’ sopravivenza ta ’ 8. 3 xhur f’ pazjenti kkurati b’ ALIMTA (Popolazzjoni bl- Intenzjoni Li Jiġu Kkurati( ITT), n = 283) u 7. 9 xhur f’ pazjenti kkurati b’ docetaxel (ITT n = 288).
An analysis of the impact of NSCLC histology on the treatment effect on overall survival was in favour of ALIMTA versus docetaxel for other than predominantly squamous histologies (n=399, 9.3 versus 8.0 months, adjusted HR = 0.78; 95% CI =0 .61-1.00, p =0.047) and was in favour of docetaxel for squamous cell carcinoma histology (n=172, 6.2 versus 7.4 months, adjusted HR = 1.56; 95% CI =1.08-2.26, p =0.018).
Analiżi ta ’ l - impatt ta 'l- istoloġija ta' NSCLC fuq is- sopravivenza totali wriet id- differenzi ta ’ ALIMTA kontra docetaxel għal kull tip ta ’ istoloġija minbarra l- istoloġiji li fil- biċċa l- kbira tagħhom kienu tat- tip squamous (n=399, 9. 3 kontra 8. 0 xhur, HR aġġustat = 0. 78; 95% CI =0. 61- 1. 00, p =0. 047) u istoloġija ta ’ karċinoma b’ tip ta ’ ċellula squamous (n=172, 6. 2 kontra 7. 4 xhur, HR aġġustat = 1. 56; 95% CI =1. 08- 2. 26, p =0. 018).