qanastek/EMEA-V3 huggingface dataset:
Other opportunistic infections have been reported with use of TYSABRI, primarily in patients with Crohn’ s disease who were immunocompromised or where significant co-morbidity existed, however increased risk of other opportunistic infections with use of TYSABRI in patients without these co- morbidities cannot currently be excluded.
Infezzjonijiet opportunistiċi oħra ġew irrappurtati bl- użu ta ’ TYSABRI, speċjalment f’ pazjenti bil - marda ta ’ Crohn li kellhom immunità mdgħajjfa li kellhom fl- istess waqt marda oħra sinifikanti, iżda żjieda fir- riskju ta ’ infezzjonijiet opportunistiċi oħra bl- użu ta ’ TYSABRI f’ pazjenti li m’ għandhomx mard ieħor fl- istess ħin bħalissa ma tistax tiġi eskluża.
Opportunistic infections were also detected in MS patients treated with TYSABRI as a monotherapy (see section 4.8).
Instabu wkoll infezzjonijiet opportunistiċi f’ pazjenti b’ MS kkurati b’ TYSABRI bħala monoterapija (ara sezzjoni 4. 8).
Prescribers should be aware of the possibility that other opportunistic infections may occur during TYSABRI therapy and should include them in the differential diagnosis of infections that occur in TYSABRI-treated patients.
It- tobba għandhom ikunu konxji mill- possibilità li infezzjonijiet opportunistiċi oħra jistgħu jseħħu waqt terapija b’ TYSABRI u għandhom jinkluduhom fid- dijanjożi divrenzjali ta ’ infezzjonijiet li jseħħu f’ pazjenti kkurati b’ TYSABRI.
If an opportunistic infection is suspected, dosing with TYSABRI is to be suspended until such infections can be excluded through further evaluations.
Jekk ikun hemm suspett ta ’ infezzjoni opportunistika, l- għotja ta ’ TYSABRI għandha titwaqqaf sakemm dawn l- infezzjonijiet jistgħu jiġu esklużi permezz ta ’ aktar eżamijiet.
If a patient receiving TYSABRI develops an opportunistic infection, dosing of TYSABRI must be permanently discontinued.
Jekk pazjent li qed jieħu TYSABRI jiżviluppa infezzjoni opportunistika, l- għotja ta ’ TYSABRI għandha titwaqqaf għal kollox.
Educational guidance
Gwida ta ’ edukazzjoni
All physicians who intend to prescribe TYSABRI must ensure they are familiar with the Physician Information and Management Guidelines.
It- tobba kollha li għandhom il- ħsieb li jippreskrivu TYSABRI għandhom jassiguraw li huma familjari ma ’ l- Informazzjoni għat- Tabib u Linji Gwida għall- Immaniġġjar.
Physicians must discuss the benefits and risks of TYSABRI therapy with the patient and provide them with a Patient Alert Card.
It- tobba għandhom jiddiskutu l- benefiċċji u r- riskji ta ’ terapija b’ TYSABRI mal- pazjent u għandhom jipprovdulu Kartuna ta ’ Allarm.
Patients should be instructed that if they develop any infection then they should inform their physician that they are being treated with TYSABRI.
Il- pazjenti għandhom jiġu nfurmati li jekk jizviluppaw xi infezzjoni għandhom jinfurmaw lit- tabib tagħhom li qed jiġu kkurati b’ TYSABRI.
4 Physicians should counsel patients on the importance of uninterrupted dosing, particularly in the early months of treatment (see hypersensitivity).
4 It- tobbagħandhom jikkonsultaw lil pazjenti dwar l- importanza tad- doża mhux interrota, partikolarment fil- bidu tat- trattament (ara sensitività eċċessiva).
Hypersensitivity reactions have been associated with TYSABRI, including serious systemic reactions (see section 4.8).
Reazzjonijiet ta ’ sensittività eċċessiva kienu assoċjati ma ’ TYSABRI, inkluż reazzjonijiet sistemiċi serji (ara sezzjoni 4. 8).
These reactions usually occurred during the infusion or up to 1 hour after completion of the infusion.
Dawn ir- reazzjonijiet normalment seħħew waqt l- infużjoni jew sa siegħa wara t- tmiem tal- infużjoni.
The risk for hypersensitivity was greatest with early infusions and in patients re-exposed to TYSABRI following an initial short exposure (one or two infusions) and extended period (three months or more) without treatment.
Ir- riskju ta ’ sensittività eċċessiva kienet l- akbar b’ infużjonijiet tal- bidu u f’ pazjenti li huma esposti mill- ġdid għal TYSABRI wara espożizzjoni qasira fil- bidu (wieħed jew tnejn infużjonijiet) u perijou estiż (tlett xhur jew aktar) mingħajr kura.
However, the risk of hypersensitivity reactions should be considered for every infusion administered.
Madankollu, r- riskju ta ’ reazzjonijiet ta ’ sensittività eċċessiva għandhom jiġu kkunsidrati f’ kull infużjoni li tingħata.
Patients are to be observed during the infusion and for 1 hour after the completion of the infusion (see section 4.8).
Il- pazjenti għandhom jiġu sorveljati waqt l- infużjoni u sa siegħa wara t- tmiem tal- infużjoni (ara sezzjoni 4. 8).
Resources for the management of hypersensitivity reactions should be available.
Riżorsi għall- immaniġġjar ta ’ reazzjonijiet ta ’ ipersensitività għandhom ikunu disponibbli.
Discontinue administration of TYSABRI and initiate appropriate therapy at the first symptoms or signs of hypersensitivity.
Ma ’ l- ewwel sintomi jew sinjali ta ’ sensittività eċċessiva, waqqaf l- għotja ta ’ TYSABRI u ibda ’ terapija xierqa.
Patients who have experienced a hypersensitivity reaction must be permanently discontinued from treatment with TYSABRI.
Pazjenti li kellhom esperjenza ta ’ reazzjoni ta ’ sensittività eċċessiva għandhom iwaqqfu għal kollox il - kura b’ TYSABRI.
Concurrent or prior treatment with immunosuppressants
Kura b’ immunosoppressanti fl- istess waqt jew minn qabel
The safety and efficacy of TYSABRI in combination with other immunosuppressive and antineoplastic therapies have not been fully established.
Is- sigurtà u l- effikaċja ta ’ TYSABRI meta jingħata flimkien ma ’ terapiji immunosoppressivi u antinejoplastiċi oħra għadhom ma ġewx stabbiliti għal kollox.
Concurrent use of these agents with TYSABRI may increase the risk of infections, including opportunistic infections, and is contraindicated (see section 4.3).
L- użu ta ’ dawn l- aġenti fl- istess waqt ma ’ TYSABRI jista ’ jżid ir- riskju ta ’ infezzjonijiet, inkluż infezzjonijiet opportunistiċi, u huwa kontra- indikat (ara sezzjoni 4. 3).
Patients with a treatment history of immunosuppressant medications, including cyclophosphamide and mitoxantrone, may experience prolonged immunosuppression and therefore may be at increased risk for PML.
Pazjenti b’ passat ta ’ kura b’ mediċini immunosoppressivi, inkluż cyclophosphamide u mitoxantrone, jista ’ jkollhom immunosoppressjoni mtawwla u b’ hekk ikunu f’ riskju ikbar ta ’ PML.
Care should be taken with patients who have previously received immunosuppressants to allow sufficient time for immune function recovery to occur.
Għandha tittiħed attenzjoni f’ pazjenti li qabel ingħataw immunosoppressanti ħalli jingħata żmien biżżejjed biex tirkupra l- funżjoni immunitarja.
Physicians must evaluate each individual case to determine whether there is evidence of an immunocompromised state prior to commencing treatment with TYSABRI (see section 4.3).
It- tobba għandhom jagħmlu valutazzjoni ta ’ kull każ individwali sabiex jistabilixxu jekk hemmx evidenza ta ’ stat immunokompromess qabel tinbeda kura b’ TYSABRI (ara sezzjoni 4. 3).
In Phase 3 MS clinical trials, concomitant treatment of relapses with a short course of corticosteroids was not associated with an increased rate of infection.
Fi provi kliniċi ta ’ Fażi III b’ MS, kura flimkien tal- irkadar b’ kors qasir ta ’ kortikosterojdi ma kienx assoċjat ma ’ żjieda fir- rata ta ’ infezzjoni.
Short courses of corticosteroids can be used in combination with TYSABRI.
Korsijiet qosra ta ’ kortikosterojdi jistgħu jingħataw flimkien ma ’ TYSABRI.
Disease exacerbations or infusion related events may indicate the development of antibodies against natalizumab.
Żjieda fis- severità tal- marda jew episodji relatati mal- infuzjoni jistgħu jindikaw l- iżvilupp ta ’ antikorpi kontra natalizumab.
In these cases the presence of antibodies should be evaluated and if these remain positive in a confirmatory test after 6 weeks, treatment should be discontinued, as persistent antibodies are associated with a substantial decrease in efficacy of TYSABRI and an increased incidence of hypersensitivity reactions (see section 4.8).
F ’ dawn il- każijiet l- preżenza ta ’ dawn l- antikorpi għandha tiġi evalwata u jekk din tibqa pożittiva f’ test ta ’ konferma wara 6 ġimgħat, il- kura għandha titwaqqaf, la darba anti korpi persistenti huma assoċjati ma tnaqqis sostanzjali f ’ l- effikaċja ta ’ TYSABRI u iżid iċ- ċans ta ’ reazzjonijiet ta ’ sensittività eċċessiva (Ara sezzjoni 4. 8).
Since patients who have received an initial short exposure to TYSABRI and then had an extended period without treatment are more at risk for hypersensitivity upon redosing, the presence of antibodies should be evaluated and if these remain positive in a confirmatory test after 6 weeks treatment should not be resumed.
La darba pazjenti li jrċevew espożizzjoni qasira inizjali ta ’ TYSABRI u wara perijodu twil mingħajr trattament huma aktar fir- riskju ta ’ sensittività eċċessiva meta jerġaw jieħdu id- doża, il- preżenza ta ’ l - antikorpi għandha tkun evalwata u jekk dawn jibqaw pożittivi fit- test konfermatorju wara 6 ġimgħat it - trattament ma għandhux jitkompla.
Hepatic Events
Avvenimenti Epatiċi
Spontaneous serious adverse reactions of liver injury have been reported during the post marketing phase.
5 Reazzjonijiet avversi spontanji serji ta ’ ħsara fil- fwied kienu rrappurtati matul il- fażi ta ’ wara l- bejgħ.
These liver injuries may occur at any time during treatment, even after the first dose.
Dawn il- ħsarat fil- fwied jistgħu jseħħu fi kwalunkwe ħin matul il- kura, anki wara l- ewwel doża.
Some patients with a past
F’ xi każijiet, ir- reazzjoni seħħet mill- ġdid meta TYSABRI kien introdott mill- ġdid.
5 medical history of an abnormal liver test have experienced an exacerbation of abnormal liver test while on TYSABRI.
Xi pazjenti bi storja medika fil- passat ta ’ testijiet tal- fwied b’ riżultat anormali, kellhom aggravament tat- testijiet tal- fwied li jagħtu riżultat anormali waqt li kienu fuq TYSABRI.
Patients should be monitored as appropriate for impaired liver function, and be instructed to contact their physician in case signs and symptoms suggestive of liver injury occur, such as jaundice and vomiting.
Il- pazjenti għandhom ikunu mmonitorjati kif suppost għal indeboliment fil- funzjoni tal- fwied, u jingħataw struzzjonijiet biex jikkuntattjaw lit- tabib tagħhom fil- każ li jseħħu sinjali u s- sintomi li jindikaw li hemm ħsara fil- fwied, bħal suffejra u rimettar.
In cases of significant liver injury TYSABRI should be discontinued.
F’ każijiet ta ’ ħsara sinifikanti fil- fwied, TYSABRI għandu jitwaqqaf.
Stopping TYSABRI therapy
Twaqqif tat- terapija TYSABRI
If a decision is made to stop treatment with natalizumab, the physician needs to be aware that natalizumab remains in the blood, and has pharmacodynamic effects (e. g increased lymphocyte counts) for approximately 12 weeks following the last dose.
Jekk tittieħed deċiżjoni li titwaqqaf il- kura b’ natalizumab, it- tabib għandu jkun konxju li natalizumab jibqa ’ fid- demm, u għandu effetti farmakodinamiċi (e. ż żjieda fl- għadd ta ’ limfoċiti) għal madwar 12 - il ġimgħa wara l- aħhar doża.
Starting other therapies during this interval will result in a concomitant exposure to natalizumab.
Il- bidu ta ’ terapiji oħra waqt dan l- intervall jirriżulta f’ espożizzjoni fl - istess waqt għal natalizumab.
For drugs such as interferon and glatiramer acetate, concomitant exposure of this duration was not associated with safety risks in clinical trials.
Għall- mediċini bħal interferon u glatiramer acetate, espożizzjoni fl- istess waqt ta ’ dan it- tul ma kienetx assoċjata ma ’ riskji ta ’ sikurtà fi provi kliniċi.
No data are available in MS patients regarding concomitant exposure with immunosuppressant medication.
M’ hemmx tagħrif disponibbli f’ pazjenti b’ MS dwar l- espożizzjoni fl- istess ħin ma ’ mediċini immunosoppressivi.
Use of these medicines soon after the discontinuation of natalizumab may lead to an additive immunosuppressive effect.
L- użu ta ’ dawn il- mediċini ftit wara t- twaqqif ta ’ natalizumab jista ’ jwassal għall- effett immunosoppressiv miżjud.
This should be carefully considered on a case-by-case basis, and a wash-out period of natalizumab might be appropriate.
Dan għandu jiġi kkunsidrat b’ attenzjoni fuq bażi ta ’ kull każ b’ mod individwali, u jista ’ jinħtieġ perijodu ta ’ tneħħijja għal kollox ta ’ natalizumab.
Short courses of steroids used to treat relapses were not associated with increased infections in clinical trials.
Korsijiet qosra ta ’ sterojdi wżati għall- kura ta ’ episodji ta ’ rkadar ma kienux assoċjati ma ’ żjieda fl- infezzjonijiet fi provi kliniċi.
See section 4.3.
Ara sezzjoni 4. 3.
There are no adequate data from the use of natalizumab in pregnant women.
M’ hemmx tagħrif biżżejjed dwar l- użu ta ’ natalizumab waqt it- tqala.
Natalizumab should not be used during pregnancy unless clearly necessary.
Natalizumab m’ għandux jintuża waqt it- tqala jekk m’ hemmx bżonn ċar.
If a woman becomes pregnant while taking TYSABRI, discontinuation of TYSABRI should be considered.
Jekk mara toħroġ tqila waqt li qed tieħu TYSABRI, għandu jiġi kkunsidrat it- twaqqif ta ’ TYSABRI.
It is not known whether TYSABRI is excreted in human milk, but it has been observed in animal studies (see section 5.3).
Mhux magħruf jekk TYSABRI jitneħħiex fil- ħalib tal- bniedem, iżda dan kien osservat fi studji fl - annimali (ara sezzjoni 5. 3).
Patients receiving TYSABRI should not breastfeed their infants.
Pazjenti li qed jirċievu TYSABRI m’ għandhomx ireddgħu lit- trabi tagħhom.
Based on the pharmacological mechanism of action of natalizumab, the use of TYSABRI is not expected to affect patient's ability to drive and use machines.
Ibbażat fuq il- mekkaniżmu ta ’ azzjoni farmakoloġika ta ’ natalizumab, l- użu ta ’ TYSABRI mhux mistenni li jaffettwa l- ħila tal - pazjent biex isuq u jħaddem magni.
In placebo-controlled trials in 1,617 MS patients treated with natalizumab for up to 2 years (placebo:
Fi provi kkontrollati bil- plaċebo f’ 1, 617 pazjent b’ MS kkurat b’ natalizumab sa sentejn (plaċebo:
1,135), adverse events leading to discontinuation of therapy occurred in 5.8% of patients treated with natalizumab (placebo:
1, 135), effetti avversi li wasslu għal twaqqif tat- terapija seħħew f’ 5. 8% tal- pazjenti kkurati b’ natalizumab (plaċebo:
4.8%).
4. 8%).
Over the 2-year duration of the studies, 43.5% of patients treated with natalizumab reported adverse drug reactions (placebo:
Tul is- sentejn li damu l- istudji, 43. 5% tal- pazjenti kkurati b’ natalizumab irrappurtawa reazzjonijiet avversi tal- mediċina (plaċebo:
39.6%)1.
39. 6%) 1.
Adverse drug reactions reported with natalizumab with an incidence of 0.5% greater than reported with placebo are shown below.
Reazzjonijiet avversi mill- mediċina rrappurtati b’ natalizumab b’ inċidenza ta ’ 0. 5% akbar minn dik irrappurtat bil- plaċebo huma mniżżla taħt.
The reactions are reported as MedDRA preferred terms under the MedDRA primary system organ class.
Ir- reazzjonijiet huma rrappurtati bħala termini ppreferuti MedDRA taħt is- sitema primarja tal- klassifika tal- organi MedDRA.
Frequencies were defined as follows:
Il- frekwenzi kienu ddefiniti kif ġej:
Common (≥ 1/ 100 to < 1/ 10), uncommon (≥ 1/ 1,000 to < 1/ 100).
Komuni (≥ 1/ 100 sa < 1/ 10), mhux komuni (≥ 1/ 1, 000 sa < 1/ 100).
1 An adverse event judged related to therapy by the investigating physician.
1 Effett avvers maħsub mit- tabib li qed jinvestiga li huwa relatat mat- terapija.
6 Nervous system disorders Common
6 F’ kull sezzjoni ta ’ frekwenza, l- effetti mhux mixtieqa huma mniżżla skond is- serjetà tagħhom, bl - aktar serji jitniżżlu l- ewwel.
Gastrointestinal disorders Common
Disturbi gastro- intestinali Komuni
Vomiting Nausea
Rimettar Tqalligħ
Musculoskeletal and connective tissue disorders Common
Disturbi muskolu- skeltrali u tal- connective tissue Komuni
Arthralgia
Atralġja
Infections and infestations Common
Infezzjonijiet u infestazzjonijiet Komuni
Urinary tract infection Nasopharyngitis
Infezzjoni fil- passaġġ ta ’ l- awrina Nasofarinġite
General disorders
Disturbi ġenerali u kundizzjonijiet ta 'mnejn jingħata Komuni
and administration site conditions
Rogħda ta ’ bard Deni Għeja
Common
Disturbi fis- sistema immuni Komuni
Rigors Pyrexia Fatigue
Urtikarja
Urticaria Hypersensitivity
Mhux komuni Sensitività eċċessiva
Infusion reactions
Reazzjonijiet għall- infużjoni
In 2-year controlled clinical trials in MS patients, an infusion-related event was defined as an adverse event occurring during the infusion or within 1 hour of the completion of the infusion.
Fi provi kliniċi kkontrollati ta ’ sentejn f’ pazjenti b’ MS, episodju relatat ma ’ l- infużjoni kien definit bħala episodju avvers li seħħ waqt l- infużjoni jew sa siegħa mit- tmiem tal- infużjoni.
These occurred in 23.1% of MS patients treated with natalizumab (placebo:
Dawn seħħew f’ 23. 1% tal- pazjenti b’ MS kkurati b’ natalizumab (plaċebo:
18.7%).
18. 7%).
Events reported more commonly with natalizumab than with placebo included dizziness, nausea, urticaria and rigors.
Episodji rrappurtati aktar komuni b’ natalizumab milli bil- plaċebo inkludew sturdament, tqalligħ, urtikarja u rogħda ta ’ bard.
In 2-year controlled clinical trials in MS patients, hypersensitivity reactions occurred in up to 4% of patients.
Fi provi kliniċi kkontrollati ta ’ sentejn f’ pazjenti b’ MS, reazzjonijiet ta ’ sensittività eċċessiva seħħew f’ mhux aktar minn 4% tal- pazjenti.
Anaphylactic/ anaphylactoid reactions occurred in less than 1% of patients receiving TYSABRI.
Reazzjonijiet anafilattiċi/ anafilattojdi seħħew f’ anqas minn 1% tal - pazjenti li rċevew TYSABRI.
Hypersensitivity reactions usually occurred during the infusion or within the 1-hour period after the completion of the infusion (See section 4.4).
Reazzjonijiet ta ’ ipersensittività normalment seħħew waqt l- infużjoni jew sa siegħa wara t- tmiem tal- infużjoni (Ara sezzjoni 4. 4).
In post-marketing experience, there have been reports of hypersensitivity reactions which have occurred with one or more of the following associated symptoms: hypotension, hypertension, chest pain, chest discomfort, dyspnoea, angioedema, in addition to more usual symptoms such as rash and urticaria.
Fl- esperjenza ta ’ wara t- tqegħid fis- suq, kien hemm rapporti ta ’ reazzjonijiet ta ’ sensittività eċċessiva li seħħew flimkien ma ’ wieħed jew aktar mis- sintomi li ġejjin: pressjoni baxxa, pressjoni għolja, uġigħ fis- sider, skomdu fis- sider, qtugħ ta ’ nifs, anġjoedima, flimkien ma ’ sintomi aktar komuni bħal raxx u utikarja.
In 10% of patients antibodies against natalizumab were detected in 2-year controlled clinical trials in MS patients.
F’ 10% tal- pazjenti antikorpi kontra natalizumab ġew osservati fi provi kliniċi kkontrollati li damu sentejn f’ pażjenti b’ MS.
Persistent anti-natalizumab antibodies (one positive test reproducible on retesting at least 6 weeks later) developed in approximately 6% of patients.
Antikorpi persistenti kontra natalizumab (test wieħed possitiv li jerġa jagħti l - istess riżultat meta ttestjati mil- ġdid ta ’ l- anqas 6 ġimgħat wara) żviluppaw f’ madwar 6% tal- pazjenti.
Antibodies were detected on only one occasion in an additional 4% of patients.
Antikorpi ġew osservati f’ okkażjoni waħda biss f’ 4% tal- pazjenti l- oħra.
Persistent antibodies were associated with a substantial decrease in the effectiveness of TYSABRI and an increased incidence of hypersensitivity reactions.
Antikorpi persistenti kienu assoċjati ma tnaqqis sostanzjali fl- effikaċja ta ’ TYSABRI u ma ’ incidenza akbar ta ’ reazzjonijiet ta ’ sensittività eċċessiva.
Additional infusion-related reactions associated with persistent antibodies included rigors, nausea, vomiting and flushing (see section 4.4).
Effetti mhux mixtieqa oħra relatati mal- infużjoni assoċjati ma ’ antikorpi persistenti inkludew rogħda ta ’ bard, tqalliġh, rimettar u fwawar (ara sezzjoni 4. 4).
If, after approximately 6 months of therapy, persistent antibodies are suspected, either due to reduced efficacy or due to occurrence of infusion-related events, they may be detected and confirmed with a subsequent test 6 weeks after the first positive test.
Jekk, wara madwar 6 xhur ta ’ terapija, antikorpi persistenti huma suspettati, minħabba tnaqqis fl - effikaċja jew minħabba d- dehra ta ’ episodji relatati ma ’ l- infużjoni, dawn jistgħu jinstabu u jiġu
Given that efficacy may be reduced or the incidence of hypersensitivity or infusion-related reactions may be increased in a patient with persistent antibodies, treatment should be discontinued in patients who develop persistent antibodies.
Minħabba li l- effikaċja tista ’ tonqos jew l- inċidenza ta ’ sensittività eċċessiva jew reazzjonijiet relatati ma ’ l- infużjoni jistgħu jiżdiedu f’ pazjent b’ antikorpi persistenti, il- kura għandha titwaqqaf f’ pazjenti li jiżviluppaw antikopri persistenti.
7 Infections, including PML and opportunistic infections
Infezzjonijiet, inkluż PML u infezzjonijiet opportunistiċi
In 2-year controlled clinical trials in MS patients, the rate of infection was approximately 1.5 per patient-year in both natalizumab- and placebo-treated patients.
Fi provi kliniċi kkontrollati fuq sentejn f’ pazjenti b’ MS, ir- rata ta ’ infezzjoni kienet ta ’ madwar 1. 5 kull sena tal- pazjent kemm fil- pazjenti kkurati b’ natalizumab kif ukoll f’ dawk ikkurati bil- plaċebo.
The nature of the infections was generally similar in natalizumab- and placebo-treated patients.
In - natura tal- infezzjonijiet kienu ġeneralment simili fil- pażjenti kkurati b’ natalizumab u f’ dawk ikkurati bil- plaċebo.
A case of cryptosporidium diarrhoea was reported in MS clinical trials.
Każ ta ’ dijareja ikkawżata minn cryptosporidium kienet irrappurtata waqt provi kliniċi ta ’ MS.
In other clinical trials, cases of additional opportunistic infections have been reported, some of which were fatal.
Fi provi kliniċi oħra, każijiet ta ’ infezzjonijiet opportunistiċi oħra li wħud minnhom li kienu fatali, kienu rrappurtati.
In clinical trials, herpes infections (Varicella-Zoster virus, Herpes-simplex virus) occurred slightly more frequently in natalizumab-treated patients than in placebo-treated patients.
Fi provi kliniċi, infezzjonijiet ta ’ herpes (Varicella- Zoster virus, Herpes - simplex virus) seħħew ftit aktar frekwenti f’ pazjenti bil- kura natalizumab minn f’ pazjenti bil- kura placebo.
In post marketing experience, there have been reports of serious cases, including one fatal case of herpes encephalitis.
F ’ esperjenza bikrija tas- suq kien hemm rapporti ta ’ każijiet serji, inkluż każ fatali ta ’ enċefalite kkawżata minn herpes.
The majority of patients did not interrupt natalizumab therapy during infections and recovery occurred with appropriate treatment.
Il- maġġoranza tal- pazjenti ma waqqfux it- terapija b’ natalizumab waqt l- infezzjonijiet u l- irpiljar seħħ permezz ta ’ kura xierqa.
In clinical trials, cases of PML have been reported.
Fi provi kliniċi, kienu rrappurtati każijiet ta ’ PML.
PML usually leads to severe disability or death (see section 4.4).
PML ġeneralment twassal għal diżabilità severa jew mewt (ara sezzjoni 4. 4).
In pivotal clinical trials, two cases, including one fatality, occurred in MS patients who were being treated with concomitant interferon beta-1a therapy for more than 2 years.
Fi provi klinċi pivitali, żewġ każijiet, inkluż fatalità, seħħew f’ pazjenti b’ MS li kienu qed jiġu kkurati fl- istess waqt b’ terapija b’ interferon beta- 1a għal aktar minn sentejn.
In another trial, one patient with Crohn’ s disease, who had a long history of treatment with immunosuppressants and associated lymphopenia also developed PML and died.
Fi prova oħra, pazjent bil- marda ta ’ Crohn, li kellu passat twil ta ’ kura b’ immunosoppressanti u limfopenija assoċjata, wkoll żviluppa PML u miet.
PML has been reported in post-marketing experience in patients treated with TYSABRI monotherapy.
Fl- esperjenza ta ’ wara t- tqegħid fis- suq kien hemm rapporti ta ’ PML f’ pazjenti kkurati b’ TYSABRI bħala monoterapija.
Spontaneous cases of serious liver injuries, increased liver enzymes, hyperbilirubinaemia have been reported during the post marketing phase (see section 4.4).
Każijiet spontanji ta ’ ħsarat serji fil- fwied, żjieda fl- enzimi tal- fwied, u iperbilirubinemja kienu rrappurtati matul il- fażi ta ’ wara l- bejgħ (ara sezzjoni 4. 4).
No differences in incidence rates or the nature of malignancies between natalizumab- and placebo-treated patients were observed over 2 years of treatment.
Ma kienitx osservata differenza fir- rata ta ’ l- inċidenza jew fin- natura tat- tumuri malinni bejn pazjenti kkurati b’ natalizumab u dawk kkurati bil- plaċebo tul is- sentejn ta ’ kura.
However, observation over longer treatment periods is required before any effect of natalizumab on malignancies can be excluded.
Iżda, tinħtieġ sorveljanza fuq perijodu ta ’ kura itwal qabel ma jista ’ jiġi eskluż kull effett ta ’ natalizumab fuq tumuri malinni.
Effects on laboratory tests
Effetti fuq it- testijiet tal- laboratorju
TYSABRI treatment was associated with increases in circulating lymphocytes, monocytes, eosinophils, basophils and nucleated red blood cells.
Kura b’ TYSABRI kienet assoċjata ma ’ żjieda fiċ- ċirkolazzjoni ta ’ limfoċiti, monoċiti, eżinofili, bażofili u ċelluli ħomor tad- demm b’ nukleju.
Elevations in neutrophils were not seen.
Ma kienx hemm żjieda fin- newtrofili.
Increases from baseline for lymphocytes, monocytes, eosinophils and basophils ranged from 35% to 140% for individual cell types but mean cell counts remained within normal ranges.
Żjieda mill- linja bażi ta ’ limfoċiti, monoċiti, eżinofili u bażofili varjat minn 35% sa 140% għal kull tip ta ’ ċellula individwali iżda l- għadd medju taċ- ċelluli baqa ’ fil- firxa normali.
During treatment with TYSABRI, small reductions in haemoglobin (mean decrease 0.6 g/ dl), haematocrit (mean decrease 2%) and red blood cell counts (mean decrease 0.1 x 106/ l) were seen.
Waqt kura b’ TYSABRI, kien hemm tnaqqis żgħir fl- emoglobina (tnaqqis medju ta ’ 0. 6 g/ dl), ematokrita (tnaqqis medju ta ’ 2%) u fl- għadd taċ- ċelluli ħomor fid- demm (tnaqqis medju ta ’ 0. 1 x 106/ l).
All changes in haematological variables returned to pre-treatment values, usually within 16 weeks of last dose of TYSABRI and the changes were not associated with clinical symptoms.
Kull tibdil fil- varjabbli ematoloġiċi rritornaw għall- valuri ta ’ qabel il- kura, normalment f’ madwar 16- il ġimgħa mill- aħħar doża ta ’ TYSABRI u t- tibdiliet ma kienux assoċjati ma ’ sintomi kliniċi.
Selective Immunosuppressive Agent, ATC code:
Aġent Immunosoppressiv Selettiv, Kodiċi ATC:
Pharmacodynamic properties
Kwalitajiet farmakodinamiċi
8 Natalizumab is a selective adhesion-molecule inhibitor and binds to the α 4-subunit of human integrins, which is highly expressed on the surface of all leukocytes, with the exception of neutrophils.
Natalizumab huwa inibitur selettiv tal- molekola ta ’ adeżjoni u jeħel mas- sotto- unità α4 tal- integrins umani, li jinstabu fi kwantità għolja fil- wiċċ tal- lewkoċiti kollha, bl- eċċezzjoni tan- newtrofili.
Specifically, natalizumab binds to the α 4β 1 integrin, blocking the interaction with its cognate receptor, vascular cell adhesion molecule-1 (VCAM-1), and ligands osteopontin, and an alternatively spliced domain of fibronectin, connecting segment-1 (CS-1).
Speċifikatament, natalizumab jeħel mal- integrin α4β1, u b’ hekk jimblokka l- interazzjoni mar- riċettur kumplimentari tiegħu, molekola- 1 ta ’ adeżjoni ta ’ ċellula vaskulari (VCAM- 1), u mal- ligandi osteopontin, u segment- 1 ta ’ konnessjoni (CS- 1), dominju ta ’ splicing alternattiv ta ’ fibronectin.
Natalizumab blocks the interaction of α 4β 7 integrin with the mucosal addressin cell adhesion molecule-1 (MadCAM-1).
Natalizumab jimblokka l- interazzjoni ta ’ integrin α4β7 mal- molekola- 1 ta ’ adeżjoni ta ’ addressin ta ’ ċellula mukosali (MadCAM- 1).
Disruption of these molecular interactions prevents transmigration of mononuclear leukocytes across the endothelium into inflamed parenchymal tissue.
L- alterazzjoni ta ’ dawn l- interazzjonijiet molekolari tipprevjeni it - transmigrazzjoni ta ’ lewkoċiti mononuklejari minn ġo l- endotilju għal ġot- tessut parenkemali nfjammat.
A further mechanism of action of natalizumab may be to suppress ongoing inflammatory reactions in diseased tissues by inhibiting the interaction of α 4-expressing leukocytes with their ligands in the extracellular matrix and on parenchymal cells.
Mekkaniżmu ieħor ta ’ azzjoni ta ’ natalizumab jista ’ jkun li jissopprimi r- reazzjonijiet ta ’ infjammazzjoni li jkunu għaddejjin fit- tessut marid billi jinibixxi l- interazzjoni tal- lewkoċiti li għandhom α4 mal- ligandi tagħhom fil- matriċi extraċellulari u fuq iċ- ċelluli parenkemali.
As such, natalizumab may act to suppress inflammatory activity present at the disease site, and inhibit further recruitment of immune cells into inflamed tissues.
B’ hekk, natalizumab jista ’ jaħdem biex jissopprimi l- attività infjammatorja preżenti fil- post tal- marda, u jinibixxi aktar migrazzjoni ta ’ ċelluli immuni ġot- tessuti nfjammati.
In MS, lesions are believed to occur when activated T-lymphocytes cross the blood-brain barrier (BBB).
F’ MS, huwa maħsub li l- leżjonijiet jseħħu meta l- limfoċiti- T attivati jaqsmu l- barriera ta ’ bejn id - demm u l- moħħ (BBB).
Leukocyte migration across the BBB involves interaction between adhesion molecules on inflammatory cells and endothelial cells of the vessel wall.
Il- migrazzjoni tal- lewkoċiti mill- BBB tinvolvi interazzjoni bejn il- molekoli ta ’ adeżjoni fuq iċ- ċelluli infjammati u ċ- ċelluli endotiljali tal- ħajt tal- kanal.
The interaction between α 4β 1 and its targets is an important component of pathological inflammation in the brain and disruption of these interactions leads to reduced inflammation.
L- interazzjoni bejn α4β1 u l- miri tagħha hija parti importanti tal- infjammazzjoni patoloġika fil- moħħ u disintegrazzjoni ta ’ dawn l- interazzjonijiet twassal għal tnaqqis fl- infjmmazzjoni.
Under normal conditions, VCAM-1 is not expressed in the brain parenchyma.
Taħt kundizzjonijiet normali, VCAM- 1 ma jinstabx fil- parenkima tal- moħħ.
However, in the presence of pro-inflammatory cytokines, VCAM-1 is upregulated on endothelial cells and possibly on glial cells near the sites of inflammation.
Iżda fil- preżenza ta ’ ċitokini li jippromwovu l- infjammazjoni, tiġi attivata aktar mis- soltu l- VCAM- 1 fuq iċ- ċelluli endotiljali u possibilment fuq iċ- ċelluli glijali qrib il - postijiet ta ’ infjammazzjoni.
In the setting of central nervous system (CNS) inflammation in MS, it is the interaction of α 4β 1 with VCAM-1, CS-1 and osteopontin that mediates the firm adhesion and transmigration of leukocytes into the brain parenchyma and may perpetuate the inflammatory cascade in CNS tissue.
Fis- sitwazzjoni ta ’ infjammazzjoni tas- sistema nervuża ċentrali (CNS) f’ MS, hija l- interazzjoni ta ’ α4β1 ma ’ VCAM- 1, CS- 1 u osteopontin li timmedja it- twaħħil sod u t - transmigrazzjoni tal- lewkoċiti ġol- parenkima tal- moħħ u tista ’ tipperpetwa l- kaskata infjammatorja fit - tessut CNS.
Blockade of the molecular interactions of α 4β 1 with its targets reduces inflammatory activity present in the brain in MS and inhibits further recruitment of immune cells into inflamed tissue, thus reducing the formation or enlargement of MS lesions.
Imblokk tal- interazzjonijiet molekolari ta ’ α4β1 minn mal- miri tiegħu inaqqas l- attività infjammatorja preżenti fil- moħħ f’ MS u jnibixxi aktar migrazzjoni ta ’ ċelluli mmuni għal ġot- tessut infjammat, u b’ hekk inaqqas il- formazzjoni u t- tkabbir ta ’ leżjonijiet ta ’ MS.
TYSABRI is indicated as a single disease modifying therapy in relapsing remitting multiple sclerosis to prevent relapses and delay progression of disability.
TYSABRI® huwa indikat bħala terapija li timmodifika l- marda u li jintuża waħdu fi sklerożi multipla li tirkada u tbatti sabiex ma jkunx hemm irkadar u jittardja l- progressjoni tad- diżabilità.
Due to safety concerns (see sections 4.4 and 4.8) treatment is restricted to the following patient groups:
Minħabba raġunijiet ta ’ sigurtà (ara sezzjoni 4. 4 u 4. 8) il- kura hija limitata għall- gruppi ta ’ pazjenti li ġejjin:
• Patients who have failed to respond to a full and adequate course of a beta-interferon.
• Pazjenti li ma rrispondewx għal- kors ta ’ kura sħiħa u xierqa b’ beta- interferon.
Patients should have had at least 1 relapse in the previous year while on therapy, and have at least 9 T2-hyperintense lesions in cranial MRI or at least 1 Gadolinium-enhancing lesion.
Il- pazjenti ried ikollhom minn ta ’ l- inqas episodju wieħed ta ’ rkadar fis- sena ta ’ qabel waqt li qed jirċievu t - terapija, u għandhom minn ta ’ l- inqas 9 leżjonijiet- T2 iperintensi f’ MRI tal- kranju jew ta ’ l - inqas leżjoni waħda li tidher aħjar b’ Gadolinium.
• Patients with rapidly evolving severe relapsing remitting multiple sclerosis, defined by 2 or more disabling relapses in one year, and with 1 or more Gadolinium enhancing lesions on brain MRI or a significant increase in T2 lesion load as compared to a previous recent MRI.
• Pazjenti bi sklerozi multipla qawwija li tirkada u tbatti u li qed tiżviluppa malajr, ikkaratterizzata minn żewġ episodji jew aktar ta ’ rkadar li jikkawżaw diżabilità f’ sena, u b’ leżjoni waħda jew aktar li tidher aħjar b’ Gadolinium f’ MRI tal- moħħ jew żjieda sinnifikanti fil- kwantità ta ’ leżjonijiet T2 meta mqabbla ma ’ MRI reċenti ta ’ qabel.
Efficacy as monotherapy has been evaluated in one randomised, double-blind, placebo-controlled study lasting 2 years (AFFIRM study) in relapsing-remitting MS patients who had experienced at least 1 clinical relapse during the year prior to entry and had a Kurtzke Expanded Disability Status Scale (EDSS) score between 0 and 5.
L- effikaċja bħala monoterapija kienet evalwata fi studju randomised, double- blind, kkontrollat bil - plaċebo u li dam sentejn (studju AFFIRM) f’ pazjenti b’ MS li tirkada u tbatti li esperjenzaw minn ta ’ l - inqas episodju wieħed ta ’ rkadar waqt is- sena ta ’ qabel ma daħlu u kellhom punteġġ Kurtzke Expanded Disability Status Scale (EDSS) ta ’ bejn 0 u 5.
Median age was 37 years, with a median disease duration of 5 years.
L- eta ’ medjana kienet ta ’ 37 sena, b’ tul 9 medjan tal- marda ta ’ 5 snin.
The patients were randomised with a 2:1 ratio to receive TYSABRI 300 mg (n = 627) or placebo (n = 315) every 4 weeks for up to 30 infusions.
Il- pazjenti kienu randomised f’ proporzjon ta ’ 2: 1 biex jirċievu TYSABRI 300 mg (n = 627) jew plaċebo (n = 315) kull 4 ġimgħat sa 30 infużjoni.
Neurological evaluations were performed every 12 weeks and at times of suspected relapse.
Valutazzjonijiet newroloġiċi saru kull 12- il ġimgħa u meta kien hemm suspett ta ’ rkadar.
MRI evaluations for T1-weighted gadolinium (Gd)-enhancing lesions and T2-hyperintense lesions were performed annually.
Valutazzjoni b’ MRI għall- leżjonijiet msaħħa f’ T1 u li tidher aħjar b’ Gadolinium (Gd) u leżjonijiet iperintensi f’ T2 saru kull sena.
Study features and results are presented in the table below.
Il- karatteristiċi ta ’ l- istudju u r- riżultati huma ppreżentati fit- tabella taħt.
9 AFFIRM study:
Studju AFFIRM:
Main features and results Monotherapy; randomised double-blind placebo-controlled Design parallel-group trial for 120 weeks Subjects
Karatteristiċi prinċipali u riżultati Monoterpija; prova randomised, double- blind, ikkontrollata bil - Disinn plaċebo, fi gruppi parallel, li dam 120 ġimgħa Soġġetti
RRMS (McDonald criteria)
RRMS (kriterji McDonald)
Placebo / Natalizumab 300 mg i. v. every 4 weeks Relapse rate Progression on EDSS
Kura Plaċebo / Natalizumab 300 mg i. v. kull 4 ġimgħat Mira ta ’ l- ewwel sena
Subjects Randomised
Rata ta ’ rkadar
Secondary endpoints
Mira tat- tieni sena
Relapse rate derived variables / MRI-derived variables Placebo Natalizumab 315 627
Progressjoni fl- EDSS
Completing 1 years Completing 2 years
Varjabbli derivati mir- rata ta ’ rkadar / varjabbli derivati mill - Miri sekondarji MRI Soġġetti Randomised Temmew l- ewwel sena Temmew it- tieni sena
296 285
Plaċebo 315 296 285
Age yrs, median (range) MS-history yrs, median (range) Time since diagnosis, yrs median
Eta ’ snin, medjan (firxa) Passat- MS snin, medjan (firxa) Tul ta ’ żmien mid- dijanjożi, snin
37 (19-50) 6.0 (0-33)
37 (19- 50) 6. 0 (0- 33)
36 (18-50) 5.0 (0-34)
36 (18- 50) 5. 0 (0- 34)
(range) Relapses in previous 12 months,
medjan (firxa) Episodji ta ’ rkadar fit- tnax- il xahar
2.0 (0-23)
2. 0 (0- 23)
2.0 (0-24)
2. 0 (0- 24)
median (range) EDSS-baseline, median (range)
ta ’ qabel, medjan (firxa) Linja bażika- EDSS, medjan (firxa)
1.0 (0-5) 2 (0-6.0)
1. 0 (0- 5) 2 (0- 6. 0)
1.0 (0-12) 2 (0-6.0)
1. 0 (0- 12) 2 (0- 6. 0)
RESULTS Annual relapse rate
RIŻULTATI Rata ta ’ rkadar annwali
After one year (primary endpoint) After two years
Wara l- ewwel sena (mira primarja) Wara sentejn
0.805 0.733
0. 805 0. 733
0.261 0.235
0. 261 0. 235
One year
Sena
Rate ratio 0.33 CI95% 0.26; 0.41
Proporzjon tar- rata 0. 33 CI95% 0. 26; 0. 41
Relapse free
Bla rkadar
Two years
Sentejn
Rate ratio 0.32 CI95% 0.26; 0.40
Proporzjon tar- rata 0. 32 CI95% 0. 26; 0. 40
After one year
Wara sena
After two years
Wara sentejn
Disability
Diżabilità
Proportion progressed1(12-week
Proporzjon li avvanzaw1( 12- il
confirmation; primary outcome)
ġimgħa ta ’ konferma; żvilupp primarju)
Hazard ratio 0.58, CI95% 0.43; 0.73, p < 0.001 Proportion progressed1(24-week
Proporzjon ta ’ riskju 0. 58, CI95% 0. 43; 0. 73, p < 0. 001 1 Proporzjon li avvanzaw (24 ġimgħa
confirmation)
ta ’ konferma)
Hazard ratio 0.46, CI95% 0.33; 0.64, p < 0.001 MRI (0-2 years)
Proporzjon ta ’ riskju 0. 46, CI95% 0. 33; 0. 64, p < 0. 001 MRI (0- sentejn)
Median% change in T2-
Medjan tat- tibdil% fil- volum ta ’
+8.8%
+8. 8%
-9.4%
- 9. 4%
hyperintense lesion volume
leżjonijiet iperintensi f’ T2
(p < 0.001)
(p < 0. 001)
Mean number of new or newly-
Numru medju ta ’ leżjonijiet ġodda 1. 9
11.0
11. 0
1.9
(p < 0. 001)
enlarging T2-hyperintense lesions Mean number of T1-hypointense
Numru medju ta ’ leżjonijiet
4.6
1. 1
(p < 0.001) 1.1
(p < 0. 001)
lesions Mean number of Gd-enhancing
Numru medju ta ’ feriti li tidher aħjar
(p < 0.001) 0.1
0. 1
lesions
b’ Gd
Progression of disability was defined as at least a 1.0 point increase on the EDSS from a baseline EDSS > =1.0 sustained for 12 or 24 weeks or at least a 1.5 point increase on the EDSS from a baseline EDSS =0 sustained for 12 or 24 weeks.
Progressjoni tad- diżabilità kienet definita bħala żjieda ta ’ l- inqas punt fuq l- EDSS mill- linja bażika ta ’ EDSS > =1. 0 miżmum għal 12 jew 24 ġimgħa jew ta ’ l- inqas żjieda ta ’ punt u nofs fuq l- EDSS mill - linja bażika ta ’ EDSS =0 miżmum għal 12 jew 24 ġimgħa.
10 the TYSABRI treated group (n = 148) and 1.455 in the placebo group (n = 61) (p < 0.001).
Fis- sottogrupp ta ’ pazjenti indikati għall- kura ta ’ MS li tirkada u tbatti li qed tevolvi malajr (pazjenti b’ 2 episodji ta ’ rkadar jew aktar u ferita waħda Gd+ jew aktar), ir- rata ta ’ rkadar fis- sena kienet 0. 282 fil- grupp ikkurat b’ TYSABRI (n = 148) u 1. 455 fil- grupp ikkurat bil- plaċebo (n = 61) (p < 0. 001).
Hazard ratio for disability progression was 0.36 (95% CI:
L - indiċi ta ’ riskju għall- progressjoni tad- diżabilità kien 0. 36 (95% CI:
0.17, 0.76) p = 0.008.
0. 17, 0. 76) p = 0. 008.
These results were obtained from a post hoc analysis and should be interpreted cautiously.
Dawn ir - riżultati inkiżbu minn analiżi post hoc u għandhom jiġu nterpretati b’ kawtela.
No information on the severity of the relapses before inclusion of patients in the study is available.
Mhux disponibbli tagħrif dwar is- severità ta ’ rkadar qabel ma ġew inklużi l- pazjenti fl- istudju.
Following the repeat intravenous administration of a 300 mg dose of natalizumab to MS patients, the mean maximum observed serum concentration was 110 ± 52 μ g/ ml.
Wara għotja ripetuta ġol- vini ta ’ doża ta ’ 300 mg ta ’ natalizumab f’ pazjenti b’ MS, il- medja ta’ konċentrazzjoni massima osservata fis- serum kienet ta ’ 110 ± 52 μg/ ml.
Mean average steady-state trough natalizumab concentrations over the dosing period ranged from 23 μ g/ ml to 29 μ g/ ml.
Il- medja ta ’ konċentrazzjonijiet fi stat stabbli ta ’ natalizumab tul il- perijodu ta ’ dożaġġ varjat minn 23 μg/ ml sa 29 μg/ ml.
The predicted time to steady-state was approximately 36 weeks.
It- tul ta ’ żmien mistenni biex jintlaħaq stat stabbli kien ta ’ madwar 36 ġimgħa.
A population pharmacokinetics analysis was conducted on samples from over 1,100 MS patients receiving doses ranging from 3 to 6 mg/ kg natalizumab.
Twettqet analiżi tal- farmakokinetika tal- popolazzjoni fuq kampjuni ta ’’ l fuq minn 1, 100 pazjenti b’ MS li kienu qed jirċievu dożi ta ’ natalizumab li varjaw minn 3 sa 6 mg/ kg.
Of these, 581 patients received a fixed 300 mg dose as monotherapy.
Minn dawn, 581 pazjent rċevew doża fissa ta ’ 300 mg bħala monoterapija.
The mean ± SD steady-state clearance was 13.1 ± 5.0 ml/ h, with a mean ± SD half-life of 16 ± 4 days.
Il- medja ± SD tat- tneħħijja fi stat stabbli kienet ta ’ 13. 1 ± 5. 0 ml/ h, b ’ medja ± SD tal- half- life ta ’ 16 ± 4 ġranet.
The analysis explored the effects of selected covariates including body weight, age, gender, hepatic and renal function, and presence of anti-natalizumab antibodies upon pharmacokinetics.
L- analiżi esplorat l- effetti ta ’ kovarjanti magħżula inkluż piż tal- ġisem, eta ’, sess, funżjoni tal- fwied u tal- kliewi, u l- preżenza ta ’ antikorpi għal natalizumab fuq il- farmakokinetika.
Only body weight and the presence of anti-natalizumab antibodies were found to influence natalizumab disposition.
Il- piż tal - ġisem u l- preżenza ta ’ antikorpi għal natalizumab biss instabu li jinfluwenzaw id- dispożizzjoni ta ’ natalizumab.
Body weight was found to influence clearance in a less-than-proportional manner, such that a 43% change in body weight resulted in a 31% to 34% change in clearance.
Instab li l- piż tal- ġisem influwenza t- tneħħijja f’ mod inqas minn proporzjonali, b’ tali mod li tibdil ta ’ 43% fil - piż tal- ġisem wassal għall- tibdil ta ’ 31% sa 34% fit- tneħħijja.
The change in clearance was not clinically significant.
It- tibdil fit- tneħħijja ma kienetx klinikament sinifikanti.
The presence of persistent anti-natalizumab antibodies increased natalizumab clearance approximately 3-fold, consistent with reduced serum natalizumab concentrations observed in persistently antibody-positive patients, (see section 4.8).
Il- preżenza ta ’ antikorpi persistenti għal natalizumab żiedu t- tneħħijja ta ’ natalizumab b’ madwar 3 - darbiet, konsistenti ma ’ tnaqqis fil- konċentrazzjonijiet fis- serum ta ’ natalizumab osservati f’ pazjenti li kellhom antikorpi persistenti, (ara sezzjoni 4. 8).
The pharmacokinetics of natalizumab in paediatric MS patients or in patients with renal or hepatic insufficiency has not been studied.
Il- farmakokinetika ta ’ natalizumab f’ pazjenti pedjatriċi b’ MS jew f’ pazjenti b’ insuffiċjenza tal- kliewi jew tal- fwied ma ġietx studjata.
The effect of plasma exchange on natalizumab clearance and pharmacodynamics was evaluated in a study of 12 MS patients.
L- effett ta ’ tibdil fil- plażma fuq it- tneħħija u l- farmakodinamika ta ’ natalizumab kien evalwat fi studju ta ’ 12- il pazjent b’ MS.
Estimates of the total drug removal after 3 plasma exchanges (over a 5-8 day interval) was approximately 70-80%.
Estimi tat- tneħħija totali tal- mediċina wara 3 tibdiliet fil- plażma (fuq intervall ta ’ 5- 8 ijiem) kienu madwar 70- 80%.
This compares to approximately 40% seen in earlier studies in which measurements occurred after drug discontinuation over a similar period of observation.
Dawn jaqblu ma ’ madwar 40% osservati fi studji aktar bikrija fejn il- kejl seħħ wara l - waqfien tal- mediċina fuq perijodu simili ta ’ osservazzjoni.
The impact of plasma exchange on the restitution of lymphocyte migration and ultimately its clinical usefulness is unknown.
L- impatt ta ’ tibdil fil- plażma fuq ir- restawr ta ’ migrazzjoni tal- limfoċiti u finalment is- siwi kliniku tiegħu mhux magħruf.
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity and genotoxicity.
Informazzjoni li mhux klinika, magħmula fuq studji konvenzjonali ta ’ sigurtà farmakoloġika, effett tossiku minn dożi ripetuti, u effett tossiku fuq il- ġeni, ma ’ turi l- ebda periklu speċjali.
Consistent with the pharmacological activity of natalizumab, altered trafficking of lymphocytes was seen as white blood cell increases as well as increased spleen weights in most in vivo studies.
Konsistenti ma ’ l- attività farmakoloġika ta ’ natalizumab, l- attività mibdula tal- limfoċiti deheret bħala żjieda fiċ- ċelluli bojod fid- demm kif ukoll żjieda fil- piż tal- milsa fil- maġġoranza tal- istudji in vivo.
These changes were reversible and did not appear to have any adverse toxicological consequences.
Dawn it- tibdiliet kienu riversibbli u ma dehrux li kellhom xi konsegwenzi tossikoloġiċi avversi.
In studies conducted in mice, growth and metastasis of melanoma and lymphoblastic leukaemia tumour cells was not increased by the administration of natalizumab.
Fi studji mwettqa fil- ġrieden, ma kienx hemm żjieda fit- tkabbir u l- metastasi taċ- ċelluli tat- tumur ta ’ melanoma u lewkimja limfoblastika minħabba l- għotja ta ’ natalizumab.
No clastogenic or mutagenic effects of natalizumab were observed in the Ames or human chromosomal aberration assays.
Ma kienu osservati l- ebda effetti klastoġeniċi jew mutaġeniċi fit- testijiet ta ’ Ames jew ta ’ abberazzjoni kromożomali uman.
Natalizumab showed no effects on in vitro assays of α 4-integrin-positive tumour line proliferation or cytotoxicity.
Natalizumab ma wera l- ebda effett ta ’ proliferazzjoni jew ċitotossiċità fuq testijiet in vitro b’ razzez ta ’ ċelluli tat- tumur pożittivi għal α4- integrin.
Reductions in female guinea pig fertility were observed in one study at doses in excess of the human dose; natalizumab did not affect male fertility.
11 Tnaqqis fil- fertilità ta ’ fniek ta ’ l- indi nisa kienet osservata fi studju wieħed b’ dożi aktar mid- doża umana; natalizumab ma affettwax il- fertilità fl- irġiel.
The effect of natalizumab on reproduction was evaluated in 5 studies, 3 in guinea pigs and 2 in cynomolgus monkeys.
L- effett ta ’ natalizumab fuq ir- riproduzzjoni kienet evalwata f’ 5 studji, 3 fil- fniek ta ’ l- indi u 2 f’ xadini cynomolgus.
These studies showed no evidence of teratogenic effects or effects on growth of offspring.
Dawn l- istudji ma wrew l- ebda evidenza ta ’ effetti teratoġeniċi jew effetti fuq it - tkabbir tal- frieħ.
In one study in guinea pigs, a small reduction in pup survival was noted.
Fi studju wieħed fi fniek ta ’ l- indi, kienet innotata tnaqqis żgħir fis- sopravivenza tal - frieħ.
This was the result of a high incidence of abortions in treated groups in the
Fi studji fix- xadini, in- numru ta ’ aborti rduppjaw fil- gruppi kkurati b’ natalizumab 30 mg/ kg meta mqabbla mal- gruppi ta ’ kontroll pariġġ.
11 first cohort that was not observed in the second cohort.
Dan kien ir- riżultat ta ’ inċidenza għolja ta ’ aborti fil - gruppi kkurati fl- ewwel kohort li ma kienx osservaat fit- tieni kohort.
No effects on abortion rates were noted in any other study.
Ma kien hemm l- ebda effett fuq ir- rati ta ’ abort fl- istudji l- oħra.
A study in pregnant cynomolgus monkeys demonstrated natalizumab-related changes in the foetus that included mild anaemia, reduced platelet counts, increased spleen weights and reduced liver and thymus weights.
Studju f’ xadini cynomolgus tqal wera tibdiliet relatati ma ’ natalizumab fil- fetu li nkludew anemija ħafifa, għadd imnaqqas ta ’ plejtlits, żjieda fil- piż tal- milsa u tnaqqis fil- piż tal- fwied u tat- timu.
These changes were associated with increased splenic extramedullary haematopoiesis, thymic atrophy and decreased hepatic haematopoiesis.
Dawn it- tibdiliet kienu assoċjati ma ’ żjieda fl- ematopoesi ekstramedullari tal - milsa, atrofija tat- timu u tnaqqis fl- ematopoesi tal- fwied.
Platelet counts were also reduced in offspring born to mothers treated with natalizumab until parturition, however there was no evidence of anaemia in these offspring.
L- għadd tal- plejtlits naqsu wkoll fil- frieħ li twieldu minn ommijiet kkurati b’ natalizumab sat- twelid, iżda ma kien hemm l- ebda evidenza ta ’ anemija f’ dawn il- frieħ.
All changes were observed at doses in excess of the human dose and were reversed upon clearance of natalizumab.
It- tibdiliet kollha kienu osservati f’ dożi għola mid- doża tal- bniedem u kienu osservati wara t- tneħħijja ta ’ natalizumab.