qanastek/EMEA-V3 huggingface dataset:
Toxicity studies in cynomolgus monkeys have shown no other effect than the expected pharmacological depletion of B cells in peripheral blood and in lymphoid tissue.
Studji dwar it- tossiċità f’ xadini ċinomolgus ma urew l- ebda effett ieħor barra t- telf farmakoloġiku mistenni ta ’ ċelluli B fid - demm periferali u fit- tessut limfojdi.
Developmental toxicity studies have been performed in cynomolgus monkeys at dosages up to 100 mg/ kg (treatment on gestation days 20-50) and have revealed no evidence of toxicity to the foetus due to rituximab.
Studji dwar l- effett tossiku fuq l- iżvilupp ġew imwettqa fuq xadini cynomolgus b’ dożi sa 100 mg/ kg (kura f’ jum 20- 50 tat- tqala) u ma wrew l- ebda evidenza ta ’ tossiċità għall- fetu minħabba rituximab.
However, dose-dependent pharmacologic depletion of B cells in the lymphoid organs of the foetuses was observed, which persisted post natally and was accompanied by a decrease in IgG level in the newborn animals affected.
Madankollu, kien osservat tnaqqis farmakoloġiku dipendenti fuq id- doża taċ- ċelluli B fl- organi limfojdi tal- feti, li ppersista wara t- twelid u kien akkumpanjat bi tnaqqis fil- livell ta ’ IgG fl- annimali mwielda ġodda affettwati.
B cell counts returned to normal in these animals within 6 months of birth and did not compromise the reaction to immunization.
L- għadd ta ’ ċelluli B reġa ’ lura għan- normal f’ dawn l- annimali sa 6 xhur mit- twelid u ma kkompromettiex ir- reazzjoni għat- tilqim.
No long-term animal studies have been performed to establish the carcinogenic potential of rituximab, or to determine its effects on fertility in males or females.
Ma twettqux studji fuq perijodu ta ’ żmien fit- tul fuq l- annimali sabiex jistabbilixxu l- potenzjal karċinoġeniku ta ’ rituximab, jew sabiex jiddeterminaw l- effetti tiegħu fuq il- fertilità fl- irġiel u fin- nisa.
Standard tests to investigate mutagenicity have not been carried out, since such tests are not relevant for this molecule.
Lanqas ma twettqu testijiet standard sabiex jinvestigaw il- mutaġeniċità, minħabba li dawn it- testijiet mhumiex rilevanti għal din il- molekula.
However, due to its character it is unlikely that rituximab has any mutagenic potential.
Madankollu, minħabba n- natura tiegħu, mhux probabbli li rituxmab jkollu potenzjal mutaġeniku.
Sodium citrate Polysorbate 80 Sodium chloride Sodium hydroxide Hydrochloric acid Water for injections
Ċitrat tas- sodju Polisorbat 80 Kloro tas- sodju Idrossidju tas- sodju Aċidu idrokloriku Ilma għall- injezzjonijiet
26 6.2 Incompatibilities
6. 2 Inkompatibilitajiet
No incompatibilities between MabThera and polyvinyl chloride or polyethylene bags or infusion sets have been observed.
Ma ġiex osservat li MabThera ma jaqbilx mal- kloro tal- polivinil jew mal- boroż tal- politin jew mas - settijiet ta ’ l- infużjoni.
The prepared infusion solution of MabThera is physically and chemically stable for 24 hours at 2 °C - 8 °C and subsequently 12 hours at room temperature.
Is- soluzzjoni għal infużjoni mħejjija ta ’ MabThera hija fiżikament u kimikament stabbli għal 24 siegħa f’ temperatura ta ’ 2°C - 8°C u sussegwentement għal 12- il siegħa f’ temperatura tal- kamra.
From a microbiological point of view, the prepared infusion solution should be used immediately.
Minn aspett mikrobijoloġiku, is- soluzzjoni ppreparata għal infużjoni għandha tintuża mill- ewwel.
If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2 °C – 8 °C, unless dilution has taken place in controlled and validated aseptic conditions.
Jekk ma tintużax mill- ewwel, iż- żminijiet ta ’ ħażna waqt l- użu u l- kundizzjonijiet ta ’ qabel l- użu huma fir - responsabilità ta ’ min jużaha u ġeneralment ma jkunux ta ’ aktar minn 24 siegħa f’ temperatura ta ’ 2 °C – 8 °C, sakemm id- dilwizzjoni ma tkunx saret f’ kundizzjonijiet asettiċi kkontrollati u validati.
Store in a refrigerator (2 °C – 8 °C).
Aħżen fi friġġ (2°C - 8°C).
Keep the container in the outer carton in order to protect from light.
Żomm il- kontenitur fil- kartuna ta ’ barra sabiex tilqa ’ mid- dawl.
Clear Type I glass vials with butyl rubber stopper containing 100 mg of rituximab in 10 ml.
Kunjetti tal- ħġieġ ta ’ Tip I ċar b’ tapp tal- lastku butyl li jesgħu 100 mg ta ’ rituximab f’ 10 ml.
Packs of 2 vials.
Pakketti ta ’ 2 kunjetti.
MabThera is provided in sterile, preservative-free, non-pyrogenic, single use vials.
MabThera jiġi fornut f’ kunjetti sterili, mingħajr preservattivi, mhux piroġeniċi, li jintużaw darba biss.
Aseptically withdraw the necessary amount of MabThera, and dilute to a calculated concentration of 1 to 4 mg/ ml rituximab into an infusion bag containing sterile, pyrogen-free sodium chloride 9 mg/ ml (0.9%) solution for injection or 5% D-Glucose in water.
Neħħi b’ mod assetiku l- ammont neċessarju ta ’ MabThera, u ħallat ma ’ l- ilma għal konċentrazzjoni kkalkulata ta ’ minn 1 sa 4 mg/ ml ta ’ rituximab f’ borża ta ’ l- infużjoni li jkun fiha, soluzzjoni għall - injezzjoni ta ’ sodium chloride 9 mg/ ml (0. 9%), sterili u mingħajr piroġeni jew 5% D- Glucose fl- ilma.
For mixing the solution, gently invert the bag in order to avoid foaming.
Sabiex tħawwad is- soluzzjoni, aqleb il- borża bil- galbu sabiex tevita li tifforma r- ragħwa.
Care must be taken to ensure the sterility of prepared solutions.
Għandha tingħata attenzjoni sabiex tiġi żgurata l- isterilità tas- soluzzjonijiet ippreparati.
Since the medicinal product does not contain any anti-microbial preservative or bacteriostatic agents, aseptic technique must be observed.
Minħabba li l- prodott mediċinali ma jinkludix xi preservattiv għal kontra l- mikrobi jew aġenti batterjostatiċi, għandha tiġi osservata teknika aseptika.
Parenteral medicinal products should be inspected visually for particulate matter and discoloration prior to administration.
Prodotti mediċinali parenterali għandhom ikunu spezzjonati viżwalment għal elementi partikulati u għat- telf tal- kulur waqt l- amministrazzjoni.
2 June 1998 Date of last renewal:
2 ta ’ Ġunju 1998 Data ta ’ l- aħħar tiġdid:
20 MAY 2008
20 ta ’ Mejju 2008
Detailed information on this medicinal product is available on the website of the European Medicines Agency (EMEA) http: / /www. emea. europa. eu/
Informazzjoni dettaljata dwar dan il- prodott tinsab fuq il- website ta ’ l- Aġenzija Ewropeja dwar il - Mediċini (EMEA) http: // www. emea. europa. eu /.
MabThera 500 mg (10 mg/ ml) concentrate for solution for infusion
MabThera 500 mg (10 mg/ ml) konċentrat għal soluzzjoni għal infużjoni
Each single-use vial containing 500 mg of Rituximab.
Kull kunjett għall- użu ta ’ darba fih 500 mg ta ’ Rituximab.
For a full list of excipients, see section 6.1.
Għal- lista kompleta ta ’ sustanzi mhux attivi, ara sezjoni 6. 1.
MabThera in combination with methotrexate is indicated for the treatment of adult patients with severe active rheumatoid arthritis who have had an inadequate response or intolerance to other disease-
MabThera flimkien ma ’ methotrexate huwa indikat għall- kura ta ’ pazjenti adulti b’ artrite rewmatika attiva severa li kellhom rispons inadegwat jew intolleranza għal mediċini anti- rewmatiċi oħra li
29 modifying anti-rheumatic drugs (DMARD) including one or more tumour necrosis factor (TNF) inhibitor therapies.
30 jimmodifikaw il- marda (DMARD) fosthom terapija ta ’ inibizzjoni waħda jew aktar tal- fattur tan - nekrosi tat- tumuri (TMF).
4.2 Posology and method of administration
4. 2 Posoloġija u metodu ta ’ kif għandu jingħata
Monotherapy/ maintenance The recommended dose of MabThera used as a maintenance treatment for patients with relapsed/ refractory follicular NHL who have responded to induction treatment with chemotherapy, with or without MabThera is:
Monoterapija/ manteniment Id- doża rrakkomandata ta ’ MabThera użata bħala kura ta ’ manteniment għal pazjenti b’ NHL li reġgħet tfaċċat/ reżistenti li rrispondew għall- kura ta ’ induzzjoni b’ kimoterapija, bi jew bla MabThera hija:
For retreatment with MabThera monotherapy for patients who have responded to previous treatment with MabThera monotherapy for relapsed/ refractory follicular NHL, the recommended dose is:
Għal kura mill- ġdid b’ monoterapija b’ MabThera għall- pazjenti li jkunu rrispondew għal kura minn qabel b’ monoterapija b’ MabThera għal NHL follikulari li reġgħet tfaċċat/ reżistenti, id- doża rakkomandata hija:
The recommended dosage is 375 mg/ m2 body surface area, administered on day 1 of each chemotherapy cycle for 8 cycles after intravenous infusion of the glucocorticoid component of CHOP.
Id- doża rakkomandata hija ta ’ 375 mg/ m2 ta ’ arja tas- superfiċje tal- ġisem, amministrata fl- ewwel ġurnata ta ’ kull ċiklu ta 'kimoterapija għal 8 ċikli wara l - infużjoni fil- vini tal- komponent glukokortikojdi ta ’ CHOP.
For CLL patients whose lymphocyte counts are > 25 x 109/ L it is recommended to administer prednisone/ prednisolone 100 mg intravenous shortly before infusion with MabThera to decrease the rate and severity of acute infusion reactions and/ or cytokine release syndrome.
Għall - pazjenti b’ CLL li għandhom għadd ta ’ limfoċiti ta ’ > 25 x 109/ L huwa rrakkomandat li tingħata 100 mg prednisone/ prednisolone fil- vini eżatt qabel infużjoni b’ MabThera biex titnaqqas ir- rata u s - severità ta ’ reazzjonijiet akuti għall- infużjoni u/ jew is- sindrome tar- reħa taċ- ċitokina.
30 The recommended dosage of MabThera in combination with chemotherapy is 375 mg/ m2 body surface area administered on day 1 of the first treatment cycle followed by 500 mg/ m2 body surface area administered on day 1 of each subsequent cycle for 6 cycles in total.
31 Id- dożaġġ irrakkomandata ta ’ MabThera flimkien ma ’ kimoterapija huwa 375 mg/ m2 ta ’ erja tas - superfiċje tal- ġisem mogħti fl- ewwel ġurnata ta ’ l- ewwel ċiklu ta ’ kura segwit minn 500 mg/ m2 ta ’ erja tas- superfiċje tal- ġisem mogħti fl- ewwel ġurnata ta ’ kull ċiklu sussegwenti għal total ta ’ 6 ċikli.
Special populations Paediatric use MabThera is not recommended for use in children and adolescents due to a lack of data on safety and efficacy.
Popolazzjonijiet speċjali Użu fit- tfal MabThera mhux irrakkomandat għall- użu fit- tfal u l- adoloxxenti peress li m’ hemmx biżżejjed informazzjoni dwar is- sigurtà u l- effikaċja.
Premedication with glucocorticoids should be considered if MabThera is not given in combination with glucocorticoid-containing chemotherapy for treatment of non-Hodgkin’ s lymphoma and chronic lymphocytic leukaemia.
Metodu ta ’ l- Għoti Jekk MabThera ma jingħatax flimkien ma ’ kimoterapija li fiha l- glukokortikojdi għandha tiġi kkunsidrata medikazzjoni minn qabel bil- glukokortikojdi għall- kura ta ’ limfoma mhux ta ’ Hodgkin u ta ’ lewkimja limfoċitika kronika.
First infusion The recommended initial rate for infusion is 50 mg/ hr; after the first 30 minutes, it can be escalated in 50 mg/ hr increments every 30 minutes, to a maximum of 400 mg/ hr.
L- ewwel infużjoni Ir- rata inizjali rrakkomandata għall- infużjoni hija ta ’ 50 mg/ siegħa; wara l- ewwel 30 minuta, din tista ’ tiżdied f’ żjidiet ta ’ 50 mg/ siegħa kull 30 minuta, sa massimu ta ’ 400 mg/ siegħa.
31 Subsequent infusions Subsequent doses of MabThera can be infused at an initial rate of 100 mg/ hr, and increased by 100 mg/ hr increments at 30 minutes intervals, to a maximum of 400 mg/ hr.
32 Infużjonijiet sussegwenti Dożi sussegwenti ta ’ MabThera jistgħu jiġu infużi b’ rata inizjali ta ’ 100 mg/ siegħa, u miżjuda b’ żjidiet ta ’ 100 mg/ siegħa f’ intervalli ta ’ 30 minuta, sa massimu ta ’ 400 mg/ siegħa.
The physician should be particularly alert to symptoms suggestive of PML that the patient may not notice (e. g. cognitive, neurological or psychiatric symptoms).
33 It- tabib għandu joqgħod attent b’ mod partikolari għal sintomi li jissuġġerixxu PML li l- pazjent jista ’ ma jinnutax (e. ż. sintomi konoxxittivi, newroloġiċi jew psikjatriċi).
32 Following reconstitution of the immune system in immunocompromised patients with PML, stabilisation or improved outcome has been seen.
Wara r- rikostituzzjoni tas- sistema immuni f’ pazjenti immunokompromessi b’ PML, kien osservat stabilizzazzjoni jew titjib fir- riżultat.
This syndrome may be associated with some features of tumour lysis syndrome such as hyperuricaemia, hyperkalaemia, hypocalcaemia, hyperphosphaetemia, acute renal failure, elevated Lactate dehydrogenase (LDH) and may be associated with acute respiratory failure and death.
Din is- sindrome tista ’ tiġi assoċjata ma ’ xi karatteristiċi tas- sindrome tal- lisi tat- tumur bħall- iperuriċemija, iperkalemja, ipokalċemja, iperfosfatimja, insuffiċjenza akuta tal- kliewi, Lactate dehydrogenase (LDH) elevat u jista ’ jkun assoċjat mal- kollass respiratorju akut u l- mewt.
Further treatment of patients after complete resolution of signs and symptoms has rarely resulted in repeated severe cytokine release syndrome.
Aktar kura wara li s- sinjali u s- sintomi tal- pazjenti ma jibqgħux evidenti rari rriżultat f’ sindrome tar- reħa taċ- ċitokina gravi.
Infusion related adverse reactions including cytokine release syndrome (see section 4.8) accompanied by hypotension and bronchospasm have been observed in 10% of patients treated with MabThera.
Reazzjonijiet avversi li għandhom x’ jaqsmu ma ’ l- infużjoni, inkluż is- sindrome tar- reħa taċ- ċitokina (ara sezzjoni 4. 8) flimkien ma ’ pressjoni baxxa u bronkospażmi ġew osservati f’ 10% tal- pazjenti trattati b’ MabThera.
These symptoms are usually reversible with interruption of MabThera infusion and administration of an anti-pyretic, an antihistaminic, and, occasionally, oxygen, intravenous saline or bronchodilators, and glucocorticoids if required.
Dawn is- sintomi huma ġeneralment riversibbli bl- interruzzjoni ta ’ l- infużjoni ta ’ MabThera u l- amministrazzjoni ta ’ mediċina kontra d- deni, antistamina, u, xi kultant, ossiġnu, soluzzjoni ta ’ melħ fil- vini jew bronkodilaturi, u glukokortikojdi jekk meħtieġ.
Please see cytokine release syndrome above for severe reactions.
Jekk jogħġbok ara s - sindrome tar- reħa taċ- ċitokina hawn fuq għal reazzjonijiet severi.
Angina pectoris, or cardiac arrhythmias such as atrial flutter and fibrillation heart failure or myocardial infarction have occurred in patients treated with MabThera.
34 Anġina pektoris, jew arritmija kardijaka bħal kollass tal- qalb minħabba taħbit u fibrillazzjoni atrijali jew infart mijokardijaku dehru f’ pazjenti trattati b’ MabThera.
33 Consideration should be given to the need for regular full blood counts, including platelet counts, during monotherapy with MabThera.
Għandha tingħata attenzjoni għall- bżonn tat- teħid regolari tad- demm, inkluż l- għadd platelet, waqt il - monoterapija b’ MabThera.
The reactions reported were usually reversible with a reduction in rate, or interruption, of MabThera infusion and administration of an anti-pyretic, an antihistamine, and, occasionally, oxygen, intravenous saline or bronchodilators, and glucocorticoids if required.
Ir- reazzjonijiet irrapportati kienu ġeneralment riversibbli bi tnaqqis fir- rata, jew l- interruzzjoni, ta ’ l- infużjoni ta ’ MabThera u l - amministrazzjoni ta ’ mediċina kontra d- deni, antiħistamina, u kultant, ossiġnu, soluzzjoni ta ’ melħ fil -
34 In clinical studies 10/ 990 (1%) patients with rheumatoid arthritis who received a first infusion of MabThera at any dose experienced a serious reaction during the infusion (see section 4.8).
Fi studji kliniċi 10/ 990 (1%) pazjent b’ artrite rewmatika li rċevew l- ewwel infużjoni ta ’ MabThera fi kwalunkwe doża esperjenzaw reazzjoni serja matul l- infużjoni (ara sezzjoni 4. 8).
42%), reduced rates to pneumococcal polysaccharide vaccine (43% vs.
42%), u rati mnaqqsa għall- vaċċin ta ’ polysaccharide pnewmokokkali (43% vs 82% għal ta ’ l- inqas żewġ serotipi
82% to at least 2 pneumococcal antibody serotypes), and KLH neoantigen (47% vs.
36 ta ’ antikorpi pnewmokokkali), u KLH neoantigen (47% vs.
Should non-live vaccinations be required whilst receiving MabThera therapy, these should be completed at least 4 weeks prior to commencing the next course of MabThera
Jekk waqt terapija b’ MabThera hemm il- ħtieġa ta ’ tilqim mhux ħaj, dawn għandhom jitkomplew ta ’ l- inqas 4 ġimgħat qabel il- bidu tal- kors li jmiss ta ’ MabThera.
35 Concomitant/ Sequential use of other DMARDs The concomitant use of MabThera and antirheumatic therapies other than those specified under the rheumatoid arthritis indication and posology is not recommended.
Użu konkomitanti/ sekwenzjali ta ’ DMARDs oħra L- użu konkomitanti ta ’ MabThera u terapiji anti- rewmatiċi għajr dawk speċifikati taħt l- indikazzjoni u l- pożoloġija għall- artrite rewmatika mhux rakkomandat.
Currently, there are limited data on possible drug interactions with MabThera.
Attwalment teżisti informazzjoni limitata dwar l- interazzjonijiet possibbli ta ’ mediċini oħra ma ’ MabThera.
Patients with human anti-mouse antibody or human anti-chimeric antibody (HAMA/ HACA) titres may have allergic or hypersensitivity reactions when treated with other diagnostic or therapeutic monoclonal antibodies.
Pazjenti b’ titres ta ’ antikorpi umani ta ’ kontra l- ġrieden jew antikorpi anti- kimeriċi umani (HAMA/ HACA) titres jista ’ jkollhom reazzjonijiet allerġiċi jew ta ’ sensittività eċċessiva meta trattati flimkien ma ’ antikorpi monoklonali dijanjostiċi jew terapewtiċi oħrajn.
B cell levels in human neonates following maternal exposure to MabThera have not been studied in clinical trials.
Immunoglobulini IgG huma magħrufa li jgħaddu mill- barriera tal- plaċenta. Il- livelli taċ- ċellula B fi trabi umani tat- twelid wara l- esponiment ta ’ l- omm għal MabThera ma ġewx studjati fi provi kliniċi.
Due to the long retention time of rituximab in B cell depleted patients, women of childbearing potential should use effective contraceptive methods during treatment and for 12 months following MabThera therapy.
Minħabba t- tul ta ’ żmien li fih jinżamm ir- rituximab f’ pazjenti li jbatu minn telf taċ- ċellula B, nisa li potenzjalment jista ’ jkollhom it- tfal waqt il- kura u għal 12- il xahar wara t- terapija b’ MabThera għandhom jużaw metodi kontraċettivi effettivi.
Developmental toxicity studies performed in cynomolgus monkeys revealed no evidence of embryotoxicity in utero.
37 Studji dwar l- effett tossiku fuq l- iżvilupp li twettqu fuq xadini cynomolgus ma żvelaw l- ebda evidenza ta ’ effett tossiku fuq l- embriju in utero.
Whether rituximab is excreted in human milk is not known.
Mhux magħruf jekk rituximab jitneħħiex fil- ħalib uman.
36 4.7 Effects on ability to drive and use machines
4. 7 Effetti fuq il- ħila biex issuq u tħaddem magni
Infectious events (predominantly bacterial and viral) occurred in approximately 30-55% of patients during clinical trials in patients with NHL and in 30-50% of patients during clinical trial in patients with CLL.
Avvenimenti infettivi (fil- biċċa l- kbira kkawżati minn batterja jew virusis) seħħew f’ madwar 30- 55% tal- pazjenti waqt provi kliniċi f’ pazjenti b’ NHL u f’ 30- 50% tal- pazjenti waqt prova klinika f’ pazjenti b’ CLL.
Frequencies are defined as very common (≥ 1/ 10), common (≥ 1/ 100 to < 1/ 10) and uncommon (≥ 1/ 1,000 to < 1/ 100) and rare (≥ 1/ 10,000 to < 1/ 1000).
F’ kull sezzjoni ta ’ frekwenza, l- effetti mhux mixtieqa huma mniżżla skond is- serjetà tagħhom, bl- aktar serji jitniżżlu l- ewwel. Il- frekwenzi huma definiti bħala komuni ħafna (≥ 1/ 10), komuni (≥ 1/ 100 sa < 1/ 10) u mhux komuni (≥ 1/ 1, 000 sa < 1/ 100) u rari (≥ 1/ 10, 000 sa < 1/ 1000).
Table 1
38 Tabella 1
infusion related reactions, angioedema
reazzjonijiet relatati ma ’ l -
hypersensitivity
sensittività eċċessiva
hyperglycaemia, weight decrease, peripheral oedema, face oedema, increased LDH, hypocalcaemia
ipergliċemija, tnaqqis fil- piż, edima periferali, edima fil- wiċċ, żjieda fl- LDH, ipokalċimja
Psychiatric disorders
depressjoni, nervi
depression, nervousness,
sindrome tar- reħa ta ’ ċitokina3, marda tas- serum, anafilassi
dysgeusia
Disġewsja
severe vision loss4
39 Sistema tal - Klassifika tal - Organi
arrhythmia, + atrial fibrillation,
ventrikulari tax - xellug, +takikardja
tachycardia, + ventricular tachycardia, +
arritmija, +
tachycardia, +
fibrillazjoni atrijali, takikardja, +
angina, +myocardial
supraventrikulari, + takikardja
cardiac disorder
disturb fil- qalb
ischaemia, bradycardia,
ventrikulari, + anġina, + iskemija mijokardijaka, bradikardja
bronchospasm3, respiratory disease, chest pain, dyspnoea, increased cough, rhinitis
pressjoni ortostatika baxxa, pressjoni baxxa bronkospażmu3, marda
38
toraċiċi u
39 events (heart failure, myocardial infarction, atrial fibrillation), pulmonary oedema, multi-organ failure, tumour lysis syndrome, cytokine release syndrome, renal failure, and respiratory failure were reported at lower or unknown frequencies.
Rkadar ta ’ kundizzjonijiet kardijaċi eżistenti minn qabel bħal anġina pectoris jew insuffiċjenza tal- qalb konġestiva jew avvenimenti kardijaċi severi (insuffiċjenza tal- qalb, infart mijokardijaku, fibrillazzjoni atrijali), edima pulmonari, insuffiċjenza ta ’ ħafna organi, sindrome tal- lisi tat- tumur, sindrome tar- reħa ta ’ cytokine, insuffiċjenza tal- kliewi, u insuffiċjenza respiratorja kienu rrapportati bi frekwenza aktar baxxa jew bi frekwenza mhux magħrufa.
Haematologic Adverse Reactions In clinical trials with MabThera monotherapy given for 4 weeks, haematological abnormalities occurred in a minority of patients and were usually mild and reversible.
41 Reazzjonijiet Ematoloġiċi Avversi Fi provi kliniċi b’ monoterapija b’ MabThera mogħtija għal 4 ġimgħat, anormalitajiet ematoloġiċi seħħew f’ minoranza ta ’ pazjenti u normalment kienu ħfief u riversibbli.
40 grade 3 and 4 cardiac arrhythmias, predominantly supraventricular arrhythmias such as tachycardia and atrial flutter/ fibrillation, was higher in the R-CHOP group (14 patients, 6.9%) as compared to the CHOP group (3 patients, 1.5%).
Fi studji li vvalutaw MabThera flimkien ma ’ kimoterapija, l- inċidenza ta ’ arritmija kardijaka ta ’ grad 3 u 4, l- aktar arritmija supraventrikolari bħal takikardija u taħbit irregolari/ fibrillazzjoni atrijali, kienet ogħla fil- grupp ta ’ R - CHOP (14- il pazjent, 6. 9%) meta mqabbel mal- grupp ta ’ CHOP (3 pazjenti, 1. 5%).
In the CLL first-line study, the overall incidence of grade 3 or 4 nervous system disorders was low (4% R-FC, 4% FC).
FL- istudju primarju dwar CCL, l- inċidenza globali ta ’ disturbi fis- sitema nervuża ta ’ grad 3 jew 4 kien baxx (4% R- FC, 4% FC).
IgG levels In the clinical trial evaluating MabThera maintenance treatment, median IgG levels were below the lower limit of normal (LLN) (< 7 g/ L) after induction treatment in both the observation and the MabThera groups.
42 Livelli ta ’ IgG Fil- prova klinika li vvalutat kura ta ’ manteniment b’ MabThera, livelli medjana ta ’ IgG kienu taħt il - limitu l- baxx tan- normal (LLN) (< 7 g/ L) wara l- kura ta ’ induzzjoni kemm fil- grupp ta ’ osservazzjoni kif ukoll f’ dak ta ’ MabThera.
Patient subpopulations (MabThera monotherapy) Elderly patients(≥ 65 years):
Pazjenti anzjani (≥ 65 sena):
More than 1000 patients received at least one treatment course and were followed for periods ranging from 6 months to over 3 years; nearly 600 patients received two or more courses of treatment during the follow up period.
Aktar minn 1000 pazjent irċevew mill- anqas kors wieħed ta ’ kura u kienu segwiti għal perjodi li varjaw minn 6 xhur għal aktar minn 3 snin; kważi 600 pazjent irċevew żewġ korsijiet jew aktar ta ’ kura matul il- perijodu ta ’ wara.
41 Patients received 2 x 1000 mg of MabThera separated by an interval of two weeks; in addition to methotrexate (10-25 mg/ week).
Il- pazjenti rċevew 2 x 1000 mg ta ’ MabThera separati b’ intervall ta ’ ġimagħtejn; flimkien ma ’ methotrexate (10- 25 mg/ ġimgħa).
Table 2
43 Tabella 2
42 Infusion-related reactions Symptoms suggesting an acute infusion reaction (e. g. pruritis, fever, urticaria/ rash, chills, pyrexia, rigors, sneezing, angioneurotic edema, throat irritation, cough and bronchospasm, with or without associated hypotension or hypertension) were observed in 79/ 540 (15%) patients following their first exposure to MabThera; In a study comparing the effect of glucocorticoid regimen, these events were observed in 5/ 149 (3%) of patients following their first rituximab placebo infusion and 42/ 192 (22%) of patients receiving their first infusion of 1000 mg rituximab.
Reazzjonijiet relatati ma ’ l- infużjoni Sintomi li jissuġġerixxu reazzjoni akuta għall- infużjoni (eż. ħakk, deni, urtikarja/ raxx, kesħa, deni, tregħid, għatis, edima anġjonewrotika, irritazzjoni fil- griżmejn, sogħla u bronkospażmi, bi jew mingħajr pressjoni baxxa jew pressjoni għolja assoċjata) kienu osservati f’ 79/ 540 (15%) pazjent wara l- ewwel esponiment tagħhom għal MabThera; Fi studju li qabbel l- effett ta ’ reġim bil- glukokortikojd, dawn l- episodji kienu osservati f’ 5/ 149 (3%) pazjent wara l- ewwel infużjoni tagħhom ta ’ rituximab plaċebo u fi 42/ 192 (22%) pazjent li rċevew l- ewwel infużjoni tagħhom ta ’ 1000 mg rituximab.
Of the patients who received 1000 mg rituximab without premedication with glucocorticoids, 18/ 65 (28%) experienced an acute infusion reaction, compared with 24/ 127 (19%) in patients given intravenous glucocorticoid premedication, respectively.
Mill- pazjenti li rċevew 100 mg rituximab mingħajr premedikazzjoni bi glukokortikojdi, 18/ 65 (28%) esperjenzaw reazzjoni akuta għall- infużjoni, meta mqabbel ma ’ 24/ 127 (19%) f’ pazjenti mogħtija premedikazzjoni bi glukokortikojdi fil- vini, rispettivament.
Infections The rate of infection was approximately 0.9 per patient year in MabThera treated patients.
44 Infezzjonijiet Ir- rata ta ’ infezzjoni kienet bejn wieħed u ieħor 0. 9 għal kull sena ta ’ pazjent fil- pazjenti ttrattati b’ MabThera.
However, single doses higher than 1000 mg have not been tested in controlled clinical trials.
Madanakollu, dożi waħdiena ta ’ aktar minn 1000 mg ma ġewx ippruvati fi provi kliniċi kkontrollati.
43 The Fab domain of rituximab binds to the CD20 antigen on B lymphocytes and the Fc domain can recruit immune effector functions to mediate B cell lysis.
L- arja Fab tar- rituximab torbot ma ’ l- antiġen CD20 fuq limfositi B u l- arja Fc tkun tista ’ tqabbad funzjonijiet li jaffetwaw l- immunità sabiex iservu ta ’ medjaturi fil- lisi taċ- ċellula B.
Possible mechanisms of effector-mediated cell lysis include complement-dependent cytotoxicity (CDC) resulting from C1q binding, and antibody-dependent cellular cytotoxicity (ADCC) mediated by one or more of the Fcγ receptors on the surface of granulocytes, macrophages and NK cells.
Il- mekkaniżmi possibli tal- lisi taċ- ċellula effector- mediated jinkludu ċitotossiċità komplimentari- dipendenti (ĊKD) li tirriżulta minn irbit C1q, u ċitotossiċità ċellulari dipendenti fuq l- antikorp (ĊĊDA) medjata bir - reċetturi Fcγ, wieħed jew aktar, fuq il- wiċċ tal- granuloċiti, makrofaġi u ċelluli NK.
Peripheral B cell counts declined below normal following completion of the first dose of MabThera.
L- għadd ta ’ ċelluli B periferali waqa ’ taħt in- normal wara t- teħid ta ’ l- ewwel doża ta ’ MabThera.
In rheumatoid arthritis patients, immediate depletion of B cells in the peripheral blood was observed following two infusions of 1000 mg MabThera separated by a 14 day interval.
45 infużjonijiet ta ’ 1000 mg MabThera separati b’ intervall ta ’ 14- il jum.
Clinical Experience in Non-Hodgkin’ s lymphoma and chronic lymphocytic leukaemia
L- Esperjenza Klinika f’ limfoma Mhux ta ’ Hodgkin u f’ lewkimja limfoċitika kronika
Initial treatment, weekly for 8 doses In a multi-centre, single-arm study, 37 patients with relapsed or chemoresistant, low grade or follicular B cell NHL received 375 mg/ m2 of MabThera as intravenous infusion weekly for eight doses.
Trattament inizjali, darba fil- ġimgħa għal 8 dożi Fi studju speċifiku b’ aktar minn ċentru wieħed, 37 pazjent b’ NHL taċ- ċellula B follikulari jew ta ’ grad baxx kemoreżistenti jew li reġgħet tfaċċat ingħataw 375 mg/ m2 ta ’ MabThera bħala infużjoni fil- vini kull ġimgħa għal tmien dożi.
For the 60 re-treatments on study, the ORR was 38% (CI95% 26% – 51%; 10% CR, 28% PR) with a projected median TTP for responding patients of 17.8 months (range 5.4 – 26.6).
Għas- 60 kura mill- ġdid fl- istudju, ir- RRĠ kienet ta ’ 38% (CI95% 26% – 51%; 10% RK, 28% RP) b’ medja ta ’ ŻPP għal pazjenti li rrispondew ta ’ 17. 8 xhur (firxa minn 5. 4 sa 26. 6 xhur).
Initial treatment, in combination with chemotherapy In an open-label randomised trial, a total of 322 previously untreated patients with follicular lymphoma were randomised to receive either CVP chemotherapy (cyclophosphamide 750 mg/ m2, vincristine 1.4 mg/ m2 up to a maximum of 2 mg on day 1, and prednisolone 40 mg/ m2/ day on days 1 -5) every 3 weeks for 8 cycles or MabThera 375 mg/ m2 in combination with CVP (R-CVP).
46 Fi prova klinika tat- tip open- label u randomised, total ta ’ 322 pazjent b’ limfoma follikulari li ma kinux irċevew kura qabel ġew randomised biex jirċievu kimoterapija (cyclophosphamide 750 mg/ m2, vincristine 1. 4 mg/ m2 sa massimu ta ’ 2 mg fl- ewwel jum, u prednisolone 40 mg/ m2/ kuljum mill- ewwel sal- ħames jum) kull 3 ġimgħat għal 8 ċikli jew MabThera 375 mg/ m2 flimkien ma ’ CVP (R- CVP).
Key results from all four studies are summarized in table 3.
Riżultati minn tliet provi randomised oħra bl- użu ta ’ MabThera flimkien ma ’ kors ta ’ kimoterapija barra minn CVP (CHOP, MCP, CHVP/ Interferon- α) ukoll urew titjib sinifikanti fir- rati ta ’ rispons, fil - parametri li huma dipendenti mill- ħin kif ukoll fis- sopravivenza globali.
Table 3
Riżultati kruċjali mill- erba ’ studji kollha huma mqassra f’ tabella 3.
Median Median OS Treatment, CR,
TTF/ PFS/ EFS FU Rati ta ’ Kura, CR, Medju Medju,
FU, ORR,% TTF/ PFS/ EFS rates, n% months mo% Median TTP:
ORR,% OS, n% xhur% mo TTP Medju:
53-months CVP, 159 57 10 14.7 71.1
53- xahar CVP, 159 57 10 14. 7 71. 1 53
53 33.6 80.9 R-CVP, 162 81 41 P < 0.0001 p=0.029
33. 6 80. 9 R- CVP, 162 81 41 P < 0. 0001 p=0. 029
p = 0.029
p = 0. 029 IFN, 175
45 TTP – Time to progression or death PFS – Progression-Free Survival TTF – Time to Treatment Failure OS rates – survival rates at the time of the analyses
EFS – Sopravivenza Mingħajr Avveniment TTP – Żmien sal- progressjoni jew sal- mewt PFS – Sopravivenza Mingħajr Progressjoni TTF – Żmien sal- Falliment tal- Kura Rati ta ’ OS – rati ta ’ sopravivenza fi żmien l- analiżi
Maintenance therapy In a prospective, open label, international, multi-centre, phase III trial, 465 patients with relapsed/ refractory follicular NHL were randomised in a first step to induction therapy with either CHOP (cyclophosphamide, doxorubicin, vincristine, prednisolone; n=231) or MabThera plus CHOP (R-CHOP, n=234).
Terapija ta ’ manteniment Fi prova prospettiva, internazzjonali, tat- tip open label, multi- ċentri, ta ’ fażi III, 465 pazjent b’ NHL follikulari li reġgħet tfaċċat/ refrattarja ntgħażlu b’ mod każwali fl- ewwel pass għal terapija ta ’ induzzjoni b’ CHOP (cyclophosphamide, doxorubicin, vincristine, prednisolone; n=231) jew MabThera flimkien ma ’ CHOP (R- CHOP, n=234).
A total of 334 patients achieving a complete or partial remission following induction therapy were randomised in a second step to MabThera maintenance therapy (n=167) or observation (n=167).
Total ta ’ 334 pazjent li kisbu remissjoni kompleta jew parzjali wara terapija ta ’ induzzjoni ġew magħżula b’ mod każwali fi stadju ieħor għal terapija ta ’ manteniment b’ MabThera (n=167) jew osservazzjoni (n=167).
MabThera maintenance treatment consisted of a single infusion of MabThera at 375 mg/ m2 body surface area given every 3 months until disease progression or for a maximum period of two years.
Il- kura ta ’ manteniment b’ MabThera kienet tikkonsisti minn infużjoni waħda ta ’ MabThera f’ doża ta ’ 375 mg/ m2 ta ’ arja tas- superfiċje tal - ġisem sakemm damet tavanza l- marda jew għal perijodu massimu ta ’ sentejn.
The final efficacy analysis included all patients randomized to both parts of the study.
L- analiżi finali ta ’ l- effikaċja kienet tinkludi l- pazjenti kollha magħżula b’ mod każwali għaż- żewġ partijiet ta ’ l- istudju.
After a median observation time of 31 months for patients randomised to the induction phase, R-CHOP significantly improved the outcome of patients with relapsed/ refractory follicular NHL when compared to CHOP (see Table 4).
Wara perijodu medju ta ’ osservazzjoni ta ’ 31 xahar għall- pazjenti magħżula b’ mod każwali għall- fażi ta ’ induzzjoni, R- CHOP tejbet b’ mod sinifikanti r- riżultat tal- pazjenti b’ NHL li reġgħet tfaċċat/ refrattarja meta mqabbel ma ’ CHOP (ara Tabella 4).
Table 4
48 Tabella 4
R-CHOP (31 months median observation time)
Fażi ta ’ induzzjoni: ħarsa ġenerali tar- riżultati ta ’ l- effikaċja għal CHOP vs R - CHOP (perijodu medjan ta ’ osservazzjoni ta ’ 31 xahar)
Primary Efficacy 1)
Effikaċja Primarja 1)
87% 29% 58%
CHOP R- CHOP Valur p Tnaqqis tar - riskju1) ORR2) 74% 87% 0. 0003 na CR2) 16% 29% 0. 0005 na PR2) 58% 58% 0. 9449 na
46 Table 5
49 Tabella 5
Efficacy Parameter
Tnaqqis tar -
Risk
Riskju
Median Time to Event (Months)
Osservazzjo
Reduction
(N=167)
Progression-free survival (PFS)
Sopravivenza mingħajr - progressjoni (PFS)
14.3
22. 1
37.8
51. 9
< 0.0001
0. 0008
OS
< 0. 0001
NR NR
14. 3
0.0348
37. 8
55%
OS 55% 0. 0348
NR: not reached; a: only applicable to patients achieving a CR
NR: mhux milħuq; a: tapplika biss għall- pazjenti li kisbu CR
In a randomised, open-label trial, a total of 399 previously untreated elderly patients (age 60 to 80 years) with diffuse large B cell lymphoma received standard CHOP chemotherapy (cyclophosphamide 750 mg/ m2, doxorubicin 50 mg/ m2, vincristine 1.4 mg/ m2 up to a maximum of 2 mg on day 1, and prednisolone 40 mg/ m2/ day on days 1-5) every 3 weeks for eight cycles, or MabThera 375 mg/ m2 plus CHOP (R-CHOP).
Fi prova tat- tip open- label magħmula b’ għażla każwali, total ta ’ 399 pazjenti anzjani mhux trattati preċedentement (età bejn is- 60 u t- 80 sena) b’ limfoma taċ- ċellula B kbira mxerrda ngħataw kimoterapija CHOP standard (cyclophosphamide 750 mg/ m2, doxorubicin 50 mg/ m2, vincristine 1. 4 mg/ m2 sa massimu ta ’ 2 mg fl- ewwel ġurnata, u prednisolone 40 mg/ m2/ ġurnata fil- ġranet 1- 5) kull 3 ġimgħat għal tmien ċikli, jew MabThera 375 mg/ m2 kif ukoll CHOP (R- CHOP).
The final analysis confirmed that R-CHOP treatment was associated with a clinically relevant and statistically significant improvement in the duration of event-free survival (the primary efficacy parameter; where events were death, relapse or progression of lymphoma, or institution of a new anti-lymphoma treatment) (p = 0.0001).
L - analiżi finali kkonfermat li l- kura R- CHOP kienet assoċjata ma ’ titjib kliniku relevanti u statistikament sinifikanti fit- tul ta ’ żmien ta ’ sopravivenza mingħajr episodji (il- parametru ta ’ effikaċja primarju; fejn
47 A subsequent analysis of the duration of overall survival, carried out with a median follow-up duration of 60 months, confirmed the benefit of R-CHOP over CHOP treatment (p=0.0071), representing a risk reduction of 32%.
Analiżi sussegwenti tat- tul tas- sopravivenza globali, imwettqa b’ tul ta ’ żmien medju ta ’ wara l- kura ta ’ 60 xahar, ikkonfermat il- benefiċċju tal- kura R- CHOP fuq dik CHOP (p=0. 0071), li tirrappreżenta tnaqqis ta ’ 32%.
The primary endpoint of progression-free survival was 40 months in median in the R-FC group and 32 months in the FC group (p < 0.0001, log-rank test).
Il- mira primarja ta ’ sopravivenza mingħajr progressjoni kienet ta ’ medjan ta ’ 40 xahar fil- grupp ta ’ R - FC u 32 xahar fil- grupp ta ’ FC (p < 0. 0001, test log- rank).
The analysis of overall survival showed an improved survival in favour of the R-FC arm (p=0.0427, log-rank test), however longer follow-up is needed to confirm this observation.
L- analiżi tas- sopravivenza globali wriet sopravivenza mtejba favur il- grupp ta ’ R- FC (p=0. 0427, test log- rank), iżda huma meħtieġa visti ta ’ wara aktar fit- tul biex din l- osservazzjoni tkun ikkonfermata.
Table 6
51 Tabella 6
Overview of observation
Kura preferita ta ’ lewkimja limfoċitika kronika
efficacy results for MabThera plus FC vs.
Sommarju tar- riżultati ta ’ l- effikaċja għal MabThera flimkien ma ’ FC vs.
FC alone (20.7 months median time)
FC waħdu (perijodu medjan ta ’ osservazzjoni ta ’ 20. 7 xahar)
Response rate (CR, nPR,
Rata ta ’ Rispons (CR, nPR, jew PR)
Duration of response*
Tul tar- rispons * Sopravivenza ħielsa mill- marda (DFS) **
34.7
34. 7 NR.
40.2
40. 2 NR
0.0040
0. 0040 0. 7882
Disease free survival (DFS)**
Żmien sa kura ġdida
only applicable to patients achieving a CR, nPR, PR; applicable
Rata ta ’ rispons u rati ta ’ CR analizzati bl- użu tat- Test Chi- squared. *: jgħodd biss għall- pazjenti li laħqu CR, nPR, PR; **: jgħodd biss għall- pazjenti li laħqu CR;
Clinical experience in rheumatoid arthritis
Esperjenza Klinika fl- Artrite Rewmatika
Study 1 was a double blind comparative study which included 517 patients that had experienced an inadequate response or intolerance to one or more TNF inhibitor therapies.
Studju 1 kien studju komparattiv tat- tip double- blind li kien jinkludi 517- il pazjent li kienu esperjenzaw rispons inadegwat jew intolleranza għal terapija waħda jew aktar ta ’ inibizzjoni tat- TNF.
Eligible patients had active rheumatoid arthritis for at least 6 months, diagnosed according to the criteria of the American College of Rheumatology (ACR), with swollen joint count (SJC) (8 (66 joint count), and tender joint count (TJC) (8 (68 joint count) and elevated CRP or ESR.
52 kriterji tal- Kulleġġ Amerikan tar- Rewmatoloġija (ACR), bl- għadd ta ’ ġogi minfuħa (SJC – swollen joint count) (8 (għadd tal- ġogi 66) u l- għadd ta ’ ġogi sensittivi (TJC – tender joint count) (8 (għadd tal- ġogi 68) u CRP jew ESR għoli.
Study 2 was a randomized, double-blind, double-dummy, controlled, 3 x 3 multifactorial study which compared two different dose levels of rituximab given with or without one of two peri infusional corticosteroid regimens in combination with weekly methotrexate in patients with active rheumatoid arthritis which had not responded to treatment with 1 to 5 other DMARDs.
Studju 2 kien studju double- blind, double- dummy, ikkontrollat, 3 x 3 multifattorjali, magħmul b’ għażla każwali, li qabbel żewġ livelli ta ’ dożi differenti mogħtija bi jew mingħajr wieħed minn żewġ reġimi ta ’ kortikosterojdi peri- infużjonali flimkien ma ’ methotrexate darba fil- ġimgħa f’ pazjenti b’ artrite rewmatika attiva li ma kinux irrispondew għal għall- kura b’ 1 sa 5 DMARDs oħra.
Disease activity outcomes In all three studies, rituximab 2 x 1000 mg significantly increased the proportion of patients achieving at least a 20% improvement in ACR score compared with patients treated with methotrexate alone
Riżultati ta ’ l- attività tal- marda Fit- tliet studji kollha, rituximab 2 x 1000 mg żied b’ mod sinifikanti l- proporzjon ta ’ pazjenti li kisbu mill- anqas 20% titjib fil- punteġġ ACR meta mqabbel mal- pazjenti kkurati b’ methotrexate waħdu (Tabella 7).
Cross-Study Comparison of
Paragun
ACR Responses at Week 24 (ITT Population)
Cross- Study tar- Risponsi ACR fil- Ġimgħa 24 (Popolazzjoni ITT)
Study 1
Rispons Plaċebo+MTX Rituximab+MTX ACR
ACR Response
Studju 1
96 (52%)2 61 (33%)2 28 (15%)2 N= 40 28 (70%)3 17 (43%)3 9 (23%)3
p ≤ 0. 0001; p ≤ 0. 001; 3 p < 0. 05 2
p ≤ 0.0001; 2 p ≤ 0.001; 3 p < 0.05 MTX – Methotrexate
MTX – Methotrexate
Rituximab treated patients had a significantly greater reduction in disease activity score (DAS28) than patients treated with methotrexate alone (Mean change in DAS28 from baseline -1.9 vs. -0.4, p < 0.0001, respectively).
53 Il- pazjenti kkurati b’ rituximab kellhom tnaqqis sinifikanti akbar fil- punteġġ ta ’ l- attività tal- marda (DAS28) mill- pazjenti kkurati b’ methotrexate waħdu (Bidla medja fid- DAS28 mil- linja bażika - 1. 9 vs - 0. 4, p < 0. 0001, rispettivament).
Radiographic mean changes over 56 weeks in Study 1
Bidliet radjografiċi medji fuq 56 ġimgħa fi Studju 1
p=0.0046 Erosion Score
Punteġġ tat- tgħawwir
p=0.0114 Joint Space narrowing score
Punteġġ tat- tidjiq ta ’ l- Ispazju bejn il -
p=0.0006 Proportion of patients with no erosive
Ġogi Proporzjon ta ’ pazjenti mingħajr ebda progressjoni tat- tgħawwir fuq 56 ġimgħa
61%
p=0. 0006 61% p=0. 0494
FACIT-F 1 ,2
FACIT- F
Laboratory evaluations A total of 96/ 1039 (9.2%) patients with rheumatoid arthritis tested positive for HACA in clinical studies following therapy with MabThera.
54 Evalwazzjonijiet tal- laboratorju Total ta ’ 96/ 1039 (9. 2%) pazjent b’ artrite rewmatika kienu ttestjati pożittivi għal HACA fi studji kliniċi wara terapija b’ MabThera.
The presence of HACA may be associated with worsening of infusion or allergic reactions after the second infusion of subsequent courses.
Il - preżenza ta ’ HACA tista ’ tkun assoċjata mat- taħżin ta ’ reazzjonijiet għall- infużjoni jew allerġiċi wara t- tieni infużjoni ta ’ korsijiet suċċessivi.
51 Plasma total immunoglobulin concentrations, total lymphocytes counts, and white cells generally remained within normal limits following MabThera treatment, with the exception of a transient drop in white cells counts over the first four weeks following therapy.
Il- konċentrazzjonijiet globali ta ’ immunoglobulina fil- plasma, l- għadd totali ta ’ limfoċiti, u ċ- ċelluli bojod ġeneralment baqgħu fil- limiti normali wara kura b’ MabThera, bl- eċċezzjoni ta ’ tnaqqis temporanju fl- għadd ta ’ ċelluli bojod matul l- ewwel erba ’ ġimgħat wara t- terapija.
This analysis suggests that dose adjustment of rituximab with any of the tested covariates is not expected to result in a meaningful reduction in its pharmacokinetic variability.
55 rituximab ma ’ kull ko- varjabbli ttestjat mhux mistenni li jirriżulta fi tnaqqis sinifikanti fil- varjabilità tal- farmakokinetika tiegħu.
Upon administration of rituximab at a dose of 375 mg/ m2 as an intravenous infusion at weekly intervals for 8 doses to 37 patients with NHL, the mean Cmax increased with each successive infusion, spanning from a mean of 243 µg/ mL (range, 16 – 582 µg/ mL) after the first infusion to 550 µg/ mL (range, 171 – 1177 µg/ mL) after the eighth infusion.
Ma l- għoti ta ’ Rituximab f’ doża ta ’ 375 mg/ m2 bħala infużjoni fil- vini f’ intervalli ta ’ kull ġimgħa għal 8 dożi lil 37 pazjent b’ NHL, Cmax medja żdiedet ma ’ kull infużjoni ta ’ wara, varjat minn medja ta ’ 243 µg/ mL (firxa, 16 – 582 µg/ mL) wara l- ewwel infużjoni għal 550 µg/ mL (firxa, 171 – 1177 µg/ mL) wara t- tmin infużjoni.
Population pharmacokinetic analysis
L- analiżi farmakokinetika fuq il - popolazzjoni ta ’ l- istess informazzjoni tat valuri medji simili għat- tneħħija sistemika u l- half- life, 0. 26 L/ kuljum u 20. 4 ġurnata, rispettivament.
52 revealed that BSA and gender were the most significant covariates to explain inter-individual variability in pharmacokinetic parameters.
L- analiżi farmakokinetika fuq il- popolazzjoni wriet li l- BSA u s- sess tal- persuna kienu l- aktar covariates sinifikanti biex tiġi spjegata l- varjabilità fil- parametri farmakokinetiċi bejn l- individwi.
No long-term animal studies have been performed to establish the carcinogenic potential of rituximab, or to determine its effects on fertility in males or females.
Ma twettqux studji fuq perijodu fit- tul fuq l- annimali sabiex jistabbilixxu l- potenzjal karċinoġeniku ta ’ rituximab, jew sabiex jiddeterminaw l- effetti tiegħu fuq il- fertilità fl- irġiel u fin- nisa.
53 6.4 Special precautions for storage
6. 4 Prekawzjonijiet speċjali għall- ħażna
Clear Type I glass vials with butyl rubber stopper containing 500 mg of rituximab in 50 ml.
Kunjetti tal- ħġieġ ta ’ Tip I ċar b’ tapp tal- lastku butyl li jesgħu 500 mg ta ’ rituximab f’ 50 ml.
Packs of 1 vials.
Pakketti ta ’ kunjett wieħed.
Aseptically withdraw the necessary amount of MabThera, and dilute to a calculated concentration of 1 to 4 mg/ ml rituximab into an infusion bag containing sterile, pyrogen-free sodium chloride 9 mg/ ml (0.9%) solution for injection or 5% D-Glucose in water.
Neħħi b’ mod aseptiku l- ammont neċessarju ta ’ MabThera, u ħallat ma ’ l- ilma għal konċentrazzjoni kkalkulata ta ’ minn 1 sa 4 mg/ ml ta ’ rituximab f’ borża ta ’ l- infużjoni li jkun fiha, soluzzjoni għall - injezzjoni ta ’ sodium chloride 9 mg/ ml (0. 9%), sterili u mingħajr piroġeni, jew 5% D- Glucose fl- ilma.
Since the medicinal product does not contain any anti-microbial preservative or bacteriostatic agents, aseptic technique must be observed.
Minħabba li l- prodott mediċinali ma jinkludix xi prrservattiv għal kontra l- mikrobi jew aġenti batterjostatiċi, għandha tiġi osservata teknika aseptika.
DATE OF REVISION OF THE TEXT Detailed information on this medicinal product is available on the website of the European Medicines Agency (EMEA) http: / /www. emea. europa. eu/
Informazzjoni dettaljata dwar dan il- prodott tinsab fuq il- website ta ’ l- Aġenzija Ewropeja dwar il - Mediċini (EMEA) http: // www. emea. europa. eu /.
54 ANNEX II
58 ANNESS II
MANUFACTURERS OF THE BIOLOGICAL ACTIVE SUBSTANCE AND MANUFACTURING AUTHORISATION HOLDER RESPONSIBLE FOR BATCH RELEASE
MANIFATTURI TAS- SUSTANZA BIJOLOĠIKA ATTIVA U D - DETENTUR TA ’ L- AWTORIZZAZZJONI TAL- MANIFATTURI RESPONSABBLI GĦALL- ĦRUĠ TAL- LOTT
55 A MANUFACTURERS OF THE BIOLOGICAL ACTIVE SUBSTANCE AND MANUFACTURING AUTHORISATION HOLDER RESPONSIBLE FOR BATCH RELEASE
59 A MANIFATTURI TAS- SUSTANZA BIJOLOĠIKA ATTIVA U D- DETENTUR TA ’ L - AWTORIZZAZZJONI TAL- MANIFATTURA RESPONSABBLI GĦALL- ĦRUĠ TAL - LOTT
1 DNA Way South San Francisco, CA 94080-4990 USA
1 DNA Way South San Francisco, CA 94080- 4990 L- ISTATI UNITI
1000 New Horizons Way Vacaville, CA 95688 USA
1000 New Horizons Way Vacaville, CA 95688 L- ISTATI UNITI
Lonza Biologics, PLC Pease International Tradeport 101 International Drive Portsmouth, NH 03801 USA
Lonza Biologics, PLC Pease International Tradeport 101 International Drive Portsmouth, NH 03801 L- Istati Uniti
1 D-79639 Grenzach-Wyhlen Germany
1 D- 79639 Grenzach- Wyhlen Il- Ġermanja
The MAH will continue to submit yearly PSURs, unless otherwise specified by the CHMP.
Id- Detentur ta ’ l- Awtorizzazzjoni għat- tqegħid fis- Suq se jkompli jissottometti PSURs ta ’ kull sena sakemm mhux speċifikat mod ieħor mis- CHMP.
The MAH commits to performing the studies and additional pharmacovigilance activities detailed in the Pharmacovigilance Plan, as agreed in version 2.0 of the Risk Management Plan (RMP) presented in Module 1.8.2. of the Marketing Authorisation Application and any subsequent updates of the RMP agreed by the CHMP.
Id- Detentur ta ’ l- Awtorizzazzjoni għat- Tqegħid fis- Suq iwiegħed li jwettaq l- istudji u l- attivitajiet ta ’ farmakoviġilanza oħrajn dettaljati fil- Pjan ta ’ Farmakoviġilanza kif miftiehem f’ verżjoni 2. 0 tal- Pjan għall- Immaniġġjar ta ’ Riskji (RMP) ippreżentat f’ Modulu 1. 8. 2 ta ’ l- Applikazzjoni għal - Awtorizzazzjoni għat- Tqegħid fis- Suq u kull aġġornament sussegwenti tal- RMP miftiehem mis - CHMP.
As per the CHMP Guideline on Risk Management Systems for medicinal products for human use, the updated RMP should be submitted at the same time as the next Periodic Safety Update Report (PSUR).
60 Skond il- Linji Gwida tas- CHMP dwar Sistemi ta ’ Mmaniġġjar ta ’ Riskji għall- prodotti mediċinali għall- użu fil- bniedem, l- RMP aġġornat għandu jiġi sottomess fl- istess waqt mar- Rapport Perjodiku Aġġornat dwar is- Sigurtà (PSUR) ta ’ wara.
56 In addition, an updated RMP should be submitted: • When new information is received that may impact on the current Safety Specification, Pharmacovigilance Plan or risk minimisation activities • Within 60 days of an important (pharmacovigilance or risk minimisation) milestone being reached • At the request of the EMEA.
Meta tinkiseb informazzjoni ġdida li jista ’ jkollha effett fuq l- Ispeċifikazzjonijiet ta ’ Sigurtà kurrenti, Pjan ta ’ Farmakoviġilanza jew attivitajiet li jnaqqsu r- riskju
59 PARTICULARS TO APPEAR ON THE OUTER PACKAGING
63 TAGĦRIF LI GĦANDU JIDHER FUQ IL- PAKKETT TA ’ BARRA
MabThera 100 mg concentrate for solution for infusion
MabThera 100 mg konċentrat għal soluzzjoni għal infużjoni
1 vial contains 10 mg/ ml rituximab.
Kunjett wieħed fih 10 mg/ ml rituximab.
Sodium citrate, polysorbate 80, sodium chloride, sodium hydroxide, hydrochloric acid, water for injections.
Ċitrat tas- sodju, polisorbat 80, kloro tas- sodju, idrossidju tas- sodju, aċidu idrokloriku, ilma għall - injezzjonijiet.
Concentrate for solution for infusion 2 vials of 10 ml
Konċentrat għal soluzzjoni għal infużjoni 2 kunjetti ta ’ 10 ml
For intravenous use after dilution Read the package leaflet before use
Għal użu ġol- vina wara dilwizzjoni Aqra l- fuljett ta ’ tagħrif qabel l- użu