qanastek/EMEA-V3 huggingface dataset:
It is known that medications with immunosuppressive properties - like leflunomide - may cause patients to be more susceptible to infections, including opportunistic infections.
Huwa magħruf li mediċini bħal leflunomide, li għandhom effetti immunosoppressivi, jagħmlu l - pazjent aktar soxxettibbli għall- infezzjonijiet, iklużi dawk opportunisti.
Infections may be more severe in nature and may, therefore, require early and vigorous treatment.
L- infezzjonijiet jistgħu jkunu aktar severi u, għalhekk, għandu mnejn li jeħtieġu kura minn kmieni u rigoruża.
In the event that severe, uncontrolled infections occur, it may be necessary to interrupt leflunomide treatment and administer a washout procedure as described below.
Jekk fl- eventwalità li l- infezjonijiet ikunu severi u inkontrollabbli, jista ’ jkun meħtieġ li l- kura b’ leflunomide titwaqqaf u ssir il- proċedura tat- tneħħija tiegħu mill- ġisem, kif inhu deskritt hawn taħt.
Patients with tuberculin reactivity must be carefully monitored because of the risk of tuberculosis reactivation.
Pazjenti li juru reattività għat- tuberkulin għandhom ikunu immoniterjati bir- reqqa, imħabba l - possibbiltà ta ’ reattivazzjoni tat- tuberkulosi.
Respiratory reactions
Reazzjonijiet respiratorji
Interstitial Lung disease has been reported during treatment with leflunomide (see section 4.8).
Disturbi ta ’ l- Interstitium tal- Pulmun kien ġie irrapportat waqt it- trattament b’ leflunomide (ara sezzjoni 4. 8).
Interstitial lung disease is a potentially fatal disorder, which may occur acutely during therapy.
Disturbi ta ’ l- interstitium tal- pulmun huwa potenzjalment fatali, li jista ’ jiġri b’ mod akut waqt it- terapija.
Pulmonary symptoms, such as cough and dyspnoea, may be a reason for discontinuation of the therapy and for further investigation, as appropriate.
Is- sintomi pulmonari, bħas- sogħla u l- qtugħ ta ’ nifs, jistgħu jiġġustifikaw il- waqfien tat- terapija u jirrikjedu investigazzjoni ulterjuri, kif inhu xieraq.
Blood pressure
Pressjoni tad- demm
Blood pressure must be checked before the start of leflunomide treatment and periodically thereafter.
Il- pressjoni tad- demm trid tkun iċċekkjata qabel ma tinbeda l- kura b’ leflunomide u perjodikament wara.
Procreation (recommendations for men)
Prokreazzjoni (rakkomandazzjonijiet għall- irġiel)
Male patients should be aware of the possible male-mediated foetal toxicity.
Il- pazjenti maskili għandhom ikunu konxji tal- possibbiltà ta ’ tossiċità fuq il- fetu, ikkawżata mill - missier.
Reliable contraception during treatment with leflunomide should also be guaranteed.
Miżuri kontraċettivi ta ’ min jorbot fuqhom waqt it- trattament b’ leflunomide għandhom ukoll ikunu garantiti.
There are no specific data on the risk of male-mediated foetal toxicity.
5 M’ hemmx tagħrif speċifiku fuq ir- riskju tat- tossiċità għall- fetu li tkun ġejja mill- missier.
However, animal studies to evaluate this specific risk have not been conducted.
Madankollu, studji fl- annimali biex jevalwaw dan ir- riskju speċifiku ma sarux.
To minimise any possible risk, men wishing to father a child should consider discontinuing use of leflunomide and taking colestyramine 8 g 3 times daily for 11 days or 50 g of activated powdered charcoal 4 times daily for 11 days.
Biex jitnaqqas kull riskju possibbli, l- irġiel li jixtiequ jsiru missirijiet għandhom iqisu jekk għandhomx iwaqqfu l- użu ta ’ leflunomide, u jieħdu 8 g colestyramine 3 darbiet kuljum għal 11- il jum, jew 50 g ta ’ trab ta` charcoal mediċinali attivat 4 darbiet kuljum għal 11- il jum.
5 In either case the A771726 plasma concentration is then measured for the first time.
Fiż- żewġ każijiet, il- livelli ta ’ A771726 fil- plażma jridu jitkejjlu fil- bidu.
Thereafter, the A771726 plasma concentration must be determined again after an interval of at least 14 days.
Aktar tard, il- livell ta ’ A771726 fil- plażma jrid jerġa ’ jitkejjel wara perijodu ta ’ mhux anqas minn 14- il jum.
If both plasma concentrations are below 0.02 mg/ l, and after a waiting period of at least 3 months, the risk of foetal toxicity is very low.
Jekk il- livelli fil- plażma jkunu inqas minn 0. 02 mg/ l, u wara stennija ta ’ mhux anqas minn 3 xhur, ir- riskju ta ’ tossiċità għall- fetu huwa żgħir ħafna.
Washout procedure
Il- proċedura biex jitneħħa leflunomide mill- ġisem
Colestyramine 8 g is administered 3 times daily.
Għandu jingħata 8 g colestyramine 3 darbiet kuljum.
Alternatively, 50 g of activated powdered charcoal is administered 4 times daily.
Minnflok, jista ’ jingħata 50 g ta ’ charcoal mediċinali attivat 4 darbiet kuljum.
Duration of a complete washout is usually 11 days.
Il- proċedura tat- tneħħija sħiħa hija normalment ta ’ 11- il jum.
The duration may be modified depending on clinical or laboratory variables.
It- tul ta ’ żmien jista ’ jkun modifikat skond ir- reperti kliniċi u dawk tal- laboratorju.
Arava contains lactose.
Arava fih il lactose.
Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.
Pazjenti bi problemi rari u ereditarji t’ intolleranza għall- galaktosju, id- defiċjenza ta ’ l- enżima lactase tat- tip Lapp, jew il- malassorbiment tal- glukusju- galaktosju, m’ għandhomx jieħdu dan il- prodott mediċinali.
Interactions studies have only been performed in adults.
Ma sarux studji dwar l- effett ta ’ mediċini jew ta’ affarijiet oħra fuq l- effett farmaċewtiku tal- prodott fl - adulti.
Increased side effects may occur in case of recent or concomitant use of hepatotoxic or haematotoxic drugs or when leflunomide treatment is followed by such drugs without a washout period (see also guidance concerning combination with other treatments, section 4.4).
Żieda fl- effetti mhux mixtieqa jistgħu jokkorru f`każ ta ’ użu reċenti jew konkomittanti ta ’ mediċini tossiċi għall- fwied u għad- demm, jew meta l- kura b’ leflunomide tkun segwita bl- użu ta ’ sustanzi simili, mingħajr perijodu tat- tneħħija (ara wkoll il- gwida li tikkonċerna l- użu ta ’ trattamenti b’ sustanzi konkomittanti, sezzjoni 4. 4).
Therefore, closer monitoring of liver enzymes and haematological parameters is recommended in the initial phase after switching.
Għalhekk, l- osservazzjoni mill- qrib tal- parametri ta ’ l- enżimi tal- fwied u dawk tad- demm hija irrakkomandata li ssir fil- fażi tal- bidu wara l- bidla.
In a small (n=30) study with co-administration of leflunomide (10 to 20 mg per day) with methotrexate (10 to 25 mg per week) a 2- to 3-fold elevation in liver enzymes was seen on 5 of 30 patients.
Fi studju żgħir (n = 30) fejn leflunomide (10 sa 20 mg kuljum) ingħata ma ’ methotrexate (10 sa 25 mg fil- ġimgħa), il- livelli ta ’ l- enżimi tal- fwied żdiedu minn darbtejn sa 3 darbiet aktar f’ 5 minn 30 pazjent.
All elevations resolved, 2 with continuation of both drugs and 3 after discontinuation of leflunomide.
Dawn il- livelli għoljin niżlu kollha, 2 minnhom meta tkomplew jingħataw iż- żewġ sustanzi, fil- waqt li fit- 3 l- oħra wara li twaqqaf leflunomide.
A more than 3-fold increase was seen in another 5 patients.
Kien hemm żieda ta ’ aktar minn 3 darbiet f ’ 5 pazjenti oħra.
All of these also resolved,2 with continuation of both drugs and 3 after discontinuation of leflunomide.
Anke dawn kienu riżolti, 2 bit- tkomplija tal- kura biż- żewġ sustanzi, waqt li fi 3 wara li twaqqaf leflunomide.
In patients with rheumatoid arthritis, no pharmacokinetic interaction between the leflunomide (10 to 20 mg per day) and methotrexate (10 to 25 mg per week) was demonstrated.
F’ pazjenti b’ artrite tat- tip rewmatojde, ma kienx hemm interazzjoni farmakokinetika bejn leflunomide (10 sa 20 mg kuljum) u methotrexate (10 sa 25 mg fil- ġimgħa).
It is recommended that patients receiving leflunomide are not treated with colestyramine or activated powdered charcoal because this leads to a rapid and significant decrease in plasma A771726 (the active metabolite of leflunomide; see also section 5) concentration.
Huwa irrakkomandat li l- pazjenti li qed jirċievu leflunomide m’ għandhomx ikunu ikkurati b ’ colestyramine jew bit- trab ta ’ charcoal mediċinali attivat, għax dan iwassal għal tnaqqis mgħaġġel u sinifikanti fil- livell ta ’ l- A771726 fil- plażma (il- prodott attiv tal- metaboliżmu ta` leflunomide; ara wkoll sezzjoni 5).
The mechanism is thought to be by interruption of enterohepatic recycling and/ or gastrointestinal dialysis of A771726.
Il- mekkaniżmu nvolut huwa maħsub li jinterrompi ir- reċiklaġġ enteroepatiku u/ jew id- dijaliżi gastro- intestinali ta ’ A771726.
If the patient is already receiving nonsteroidal anti-inflammatory drugs (NSAIDs) and/ or corticosteroids, these may be continued after starting leflunomide.
Jekk il- pazjent diġà qiegħed fuq is- sustanzi mhux sterojdi kontra l- infjammazzjoni (NSAIDs), u/ jew l - kortikosterojdi, dawn jistgħu jitkomplew wara li jinbeda leflunomide.
The enzymes involved in the metabolism of leflunomide and its metabolites are not exactly known.
L- enżimi nvoluti fil- metaboliżmu ta ’ leflunomide u l- prodotti metaboliċi tiegħu mhux magħrufa b’ eżattezza.
An in vivo interaction study with cimetidine (non-specific cytochrome P450 inhibitor) has demonstrated a lack of a significant interaction.
Studju in vivo dwar l- interazzjoni ma ’ cimetidine (inibitur mhux speċifiku taċ- ċitokromju P450) wera li ma kienx hemm interazzjoni sinifikanti.
Following concomitant administration of a single dose of leflunomide to subjects receiving multiple doses of rifampicin (non-specific cytochrome P450 inducer) A771726 peak levels were increased by approximately 40%, whereas the AUC was not significantly changed.
6 leflunomide, f’ pazjenti li kienu qed jieħdu dożi multipli ta` rifampicin (induttur mhux speċifiku taċ - ċitokromju P450), il- livelli l- aktar għoljin ta ’ A771726 żdiedu b’ madwar 40%, fil- waqt li l- AUC ma nbidlitx b’ mod sinifikanti.
The mechanism of this effect is unclear.
Il- mekkaniżmu ta ’ dan l- effett mhux ċar.
In vitro studies indicate that A771726 inhibits cytochrome P4502C9 (CYP2C9) activity.
Studji in vitro indikaw li l- A771726 jinibixxi l- attività taċ- ċitokromju P4502C9 (CYP2C9).
In clinical trials no safety problems were observed when leflunomide and NSAIDs metabolised by CYP2C9 were co-administered.
Fi provi kliniċi ma kienx hemm problemi dwar is- sigurtà meta leflunomide u l- NSAIDs, metaboliżżati minn CYP2C9, ingħataw flimkien.
Caution is advised when leflunomide is given together with drugs, other than NSAIDs, metabolised by CYP2C9 such as phenytoin, warfarin, phenprocoumon and tolbutamide.
Il- kawtela hija irrakkomandata meta leflunomide jingħata flimkien ma ’ sustanzi oħra, għajr l- NSAIDs, li huma metabolizzati minn CYP2C9 bħal phenytoin, warfarin, phenprocoumon u tolbutamide.
6 In a study in which leflunomide was given concomitantly with a triphasic oral contraceptive pill containing 30 µg ethinyloestradiol to healthy female volunteers, there was no reduction in contraceptive activity of the pill, and A771726 pharmacokinetics were within predicted ranges.
Fi studju fejn leflunomide ngħata flimkien mal- pillola kontraċettiva orali tat- tip ta ’ tlett fażijiet, li kellha 30 μg ethinyloestradiol, lill- voluntiera nisa b’ saħħithom, ma kienx hemm tnaqqis ta ’ l- effett kontraċettiv tal- pillola, u l- komportament farmakokinetiku ta ’ l- A771726 kien fil- limitu previst.
No clinical data are available on the efficacy and safety of vaccinations under leflunomide treatment.
M’ hemmx data klinika fuq l- effikaċja u s- sigurtà tat- tilqim waqt il- kura b’ leflunomide.
Vaccination with live attenuated vaccines is, however, not recommended.
It- tilqim b’ vaċċini ħajjin u attenwati, madanakollu, mhux irrakkomandat.
The long half-life of leflunomide should be considered when contemplating administration of a live attenuated vaccine after stopping Arava.
Wieħed għandu jżomm f’ moħħu l - half- life twila ta`leflunomide, meta jkun qed jikkunsidra li jingħata vaċċin ħaj u attenwat wara li jkun twaqqaf it- teħid ta’ Arava.
The active metabolite of leflunomide, A771726 is suspected to cause serious birth defects when administered during pregnancy.
Il- prodott metaboliku attiv ta ’ leflunomide A771726 kien huwa maħsub li jista ’ jagħmel difetti serji tat- twelid meta jingħata waqt it- tqala.
Arava is contraindicated in pregnancy (see section 4.3).
Arava m’ għandux jingħata waqt it- tqala (ara sezzjoni 4. 3).
Women of childbearing potential have to use effective contraception during and up to 2 years after treatment (see “ waiting period” below) or up to 11 days after treatment (see abbreviated “ washout period” below).
Nisa li jistgħu joħorġu tqal għandhom jużaw kontraċettiv effettiv waqt u sa sentejn wara it- trattament (ara “ perijodu ta ’ stennija ” hawn isfel), jew sa 11- il jum wara it- trattament (ara “ ż- żmien imqassar biex jitneħħa leflunomide ”, hawn isfel).
The patient must be advised that if there is any delay in onset of menses or any other reason to suspect pregnancy, they must notify the physician immediately for pregnancy testing, and if positive, the physician and patient must discuss the risk to the pregnancy.
Il- pazjenta għandha tingħata l- parir li jekk jittardjalha l- pirjid, jew għal xi raġuni oħra tissusspetta li hija tqila, għandha tavża lit- tabib immedjatament biex isirilha test tat- tqala, u jekk dan ikun pożittiv, it - tabib u l- pazjent għandhom jiddiskutu r- riskju għat- tqala.
It is possible that rapidly lowering the blood level of the active metabolite, by instituting the drug elimination procedure described below, at the first delay of menses may decrease the risk to the foetus from leflunomide.
Huwa possibbli li meta jitniżżel malajr il - livell tal- prodott metaboliku attiv, billi tintuża l- proċedura tat- tneħħija deskritta hawn taħt, hekk kif mill- ewwel jittardja l- pirjid, jista ’ jitnaqqas ir- riskju għall- fetu b’ leflunomide.
For women receiving leflunomide treatment and who wish to become pregnant, one of the following procedures is recommended in order to ascertain that the foetus is not exposed to toxic concentrations of A771726 (target concentration below 0.02 mg/ l):
Għan- nisa li qed jieħdu l- kura b’ leflunomide u li jixtiequ joħorġu tqal, waħda minn dawn il- proċeduri hija irrakkomandata biex jiżguraw li l- fetu ma jkunx espost għal livelli tossiċi ta ’ l- A771726 (il- mira tal- livell huwa inqas minn 0. 02 mg/ l):
Waiting period
Żmien ta ’ stennija
A771726 plasma levels can be expected to be above 0.02 mg/ l for a prolonged period.
Il- livelli fil- plażma ta ’ A771726 huma mistennija li jkunu ’ l fuq minn 0. 02 mg/ l għal żmien twil.
The concentration may be expected to decrease below 0.02 mg/ l about 2 years after stopping the treatment with leflunomide.
Il - livell mistenni jonqos taħt dak ta ’ 0. 02 mg/ l wara madwar sentejn li titwaqqaf il- kura b’ leflunomide.
After a 2-year waiting period, the A771726 plasma concentration is measured for the first time.
Wara perijodu ta ’ stennija ta ’ sentejn, il- livell ta ’ A771726 fil- plażma għandu jitkejjel għall- ewwel darba.
Thereafter, the A771726 plasma concentration must be determined again after an interval of at least 14 days.
Wara, il- livell ta ’ A771726 fil- plażma għandu jerġa ’ jkun iċċekkjat mhux inqas minn 14- il jum wara.
If both plasma concentrations are below 0.02 mg/ l no teratogenic risk is to be expected.
Jekk il- livelli fil- plażma taż- żewġ kampjuni huma inqas minn 0. 02 mg/ l, mhux mistenni li jkun hemm riskju teratoġeniku.
For further information on the sample testing please contact the Marketing Authorisation Holder or its local representative (see section 7).
Għal aktar informazzjoni fuq l- ittestjar tal- kampjuni, jekk jogħġbok ikkuntattja lid- Detentur ta ’ l - Awtorizzazzjonigħat- Tqegħid fis- Suq, jew ir- rappreżentant lokali tiegħu (ara sezzjoni 7).
Washout procedure
7 Il- proċedura biex jitneħħa leflunomide mill- ġisem
After stopping treatment with leflunomide:
Wara li jitwaqqaf it- trattament ta ’ leflunomide
• colestyramine 8 g is administered 3 times daily for a period of 11 days,
• jingħata 8 g colestyramine 3 darbiet kuljum għall- perijodu ta ’ 11- il jum
• alternatively, 50 g of activated powdered charcoal is administered 4 times daily for a period of 11 days.
• inkella, 50 g ta ’ trab ta ’ charcoal mediċinali attivat li jittieħed 4 darbiet kuljum għall- perijodu ta ’ 11- il jum.
7 However, also following either of the washout procedures, verification by 2 separate tests at an interval of at least 14 days and a waiting period of one-and-a-half months between the first occurrence of a plasma concentration below 0.02 mg/ l and fertilisation is required.
Madankollu, anke wara li tintuża waħda minn dawn il- proċeduri ta ’ tneħħija, il- verifika b’ żewġ testijiet separati, magħmulin b’ intervall ta ’ mhux inqas minn 14- il jum, u perijodu ta ’ stennija ta ’ xahar u nofs mit- test li juri livell ta ’ inqas minn 0. 02 mg/ l, huwa meħtieġ qabel il- fertilizzazzjoni.
Women of childbearing potential should be told that a waiting period of 2 years after treatment discontinuation is required before they may become pregnant.
Nisa li jistgħu jkollhom it- tfal, għandhom ikunu avżati li ż- żmien ta ’ stennija huwa ta ’ sentejn wara li l- kura titwaqqaf u qabel ma jistgħu joħorġu tqal.
If a waiting period of up to approximately 2 years under reliable contraception is considered unpractical, prophylactic institution of a washout procedure may be advisable.
Jekk il- perijodu ta ’ stennija ta - ’ madwar sentejn, b’ metodu kontraċettiv ta ’ min jorbot fuqu, mhux prattikabbli, il- profilassi bil- proċedura tat- tneħħija tista ’ tkun irrakkomandata.
Both colestyramine and activated powdered charcoal may influence the absorption of oestrogens and progestogens such that reliable contraception with oral contraceptives may not be guaranteed during the washout procedure with colestyramine or activated powdered charcoal.
Dan jista ’ ma jiżgurax kontraċezzjoni ta ’ min jorbot fuqha, bil - kontraċettivi orali, waqt il- proċedura tat- tneħħija bil- colestyramine u trab ta ’ charcoal mediċinali attivat.
Use of alternative contraceptive methods is recommended.
L- użu ta ’ metodi oħra ta ’ kontraċezzjoni huwa irrakkomandat.
Animal studies indicate that leflunomide or its metabolites pass into breast milk.
Treddigħ Studji fl- annimali wrew li leflunomide, jew il- prodotti metaboliċi tiegħu, jgħaddu fil- ħalib tas- sider.
Breast-feeding women must, therefore, not receive leflunomide.
Għalhekk, nisa li qegħdin ireddgħu m’ għandhomx jieħdu leflunomide.
In the case of side effects such as dizziness the patient's ability to concentrate and to react properly may be impaired.
F’ każ ta ’ effetti mhux mixtieqa, bħal sturdament, il- ħila tal- pazjent biex jikkonċentra u jirreaġixxi kif xieraq, tista ’ tonqos.
In such cases patients should refrain from driving cars and using machines.
F’ każijiet bħal dawn il- pazjenti għandhom jieqfu milli jsuqu vetturi u jużaw il - magni.
The most frequently adverse effects reported commonly (≥ 1/ 100 to < 1/ 10) with leflunomide are: mild increase in blood pressure, leucopenia, paraesthesia, headache, dizziness, diarrhoea, nausea, vomiting, oral mucosal disorders (e. g. aphthous stomatitis, mouth ulceration), abdominal pain, increased hair loss, eczema, rash (including maculo-papular rash), pruritus, dry skin, tenosynovitis, CPK increased, anorexia, weight loss (usually insignificant), asthenia, mild allergic reactions and elevation of liver parameters (transaminases (especially ALT), less often gamma-GT, alkaline phosphatise, bilirubin))
Ir- reazzjonijiet avversi l- aktar komunement (≥1/ 100 sa < 1/ 10) irrapportati bi leflunomide huma: żieda ħafifa fil- pressjoni tad- demm, lewkopenja, parasteżija, uġigħ ta ’ ras, sturdament, dijarrea, tqalligħ, rimettar, disturbi tal- mukuża fil- ħalq (e. g. stomatite bl- afte, ulċeri tal- ħalq), uġigħ addominali, twaqqigħ tax- xagħar aktar minn normal, ekżema, raxx (jinkludi raxx ikkaratteriżżat minn titbigħ u ponot), ħakk, ġilda xotta, tenosynovitis, żieda fi CPK, anoreksja, telf fil- piż (normalment mhux sinifikanti), astenja, reazzjonijiet allerġiċi ħfief u livelli għoljin tal- parametri tal- fwied (l- enżimi transaminases [speċjalment ALT], anqas spiss gamma- GT, alkaline phosphatase, bilirubin)
Classification of expected frequencies:
Klassifika tal- frekwenzi mistennija:
Very common (≥ 1/ 10); common (≥ 1/ 100 to < 1/ 10); uncommon (≥ 1/ 1,000 to < 1/ 100); rare (≥ 1/ 10,000 to < 1/ 1,000); very rare (< 1/ 10,000), not known (cannot be estimated from the available data).
Komuni ħafna (≥1/ 10); komuni (≥1/ 100 sa < 1/ 10); mhux komuni (≥1/ 1, 000 sa < 1/ 100); rari (≥1/ 10, 000 sa < 1/ 1, 000); rari ħafna (< 1/ 10, 000); mhux magħruf (ma tistax tittieħed stima mid- data disponibbli).
mild increase in blood pressure
żieda ħafifa fil- pressjoni tad- demm
severe increase in blood pressure
żieda qawwija fil- pressjoni tad- demm
Blood and lymphatic system disorders
8 Disturbi tad demm u tas- sistema limfatika
leucopenia (leucocytes > 2 G/ l)
lewkopenja (lewkoċiti > 2 G/ l)
anaemia, mild thrombocytopenia (platelets < 100 G/ l)
anemija, tromboċitopenja ħafifa (plejtlets < 100 G/ l)
Rare: pancytopenia (probably by antiproliferative mechanism), leucopenia (leucocytes < 2 G/ l), eosinophilia
Rari: panċitopenja (probabilment minn mekkaniżmu anti- proliferattiv), lewkopenja (lewkoċiti < 2 G/ l), eosinofilja,
agranulocytosis
għadd baxx ħafna tal- granuloċiti
Recent, concomitant or consecutive use of potentially myelotoxic agents may be associated with a higher risk of haematological effects.
L- użu reċenti, konkomittanti jew konsekuttiv, ta ’ sustanzi potentjalment tossiċi għall- mudullun, jistgħu jkunu assoċjati ma ’ riskju akbar ta ’ effetti avversi ematoloġiċi.
paraesthesia, headache, dizziness
parasteżija, uġigħ ta ’ ras, sturdament
peripheral neuropathy
newropatija periferali
Rare: interstitial lung disease (including interstitial pneumonitis), which may be fatal
Rari: disturbi ta ’ l- interstitium tal- pulmun (inkluża l- pulmonite interztizjali), li tista ’ tkun fatali
diarrhoea, nausea, vomiting, oral mucosal disorders (e. g., aphthous stomatitis, mouth ulceration), abdominal pain
dijarrea, tqalligħ, rimettar, disturbi tal- mukuża fil- ħalq (e. g. stomatite bl- afte, ulċeri tal- ħalq), uġigħ addominali
taste disturbances
disturbi tat- tegħim
pancreatitis
pankrejatite
Renal and urinary disorders
Distrubi fil- kliewi u fis- sistema urinarja
Skin and subcutaneous tissue disorders
Disturbi fil- ġilda u fil- tessuti ta ’ taħt il- ġilda
increased hair loss, eczema, rash (including maculopapular rash), pruritus, dry skin
twaqqigħ tax- xagħar aktar minn normal, ekżema, raxx (jinkludi raxx ikkaratteriżżat minn titbigħ u ponot), ħakk, ġilda xotta,
urticaria
urtikarja
toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme
in- nekrosi tossika u esfoljattiva tal- ġilda, is- sindrome ta ’ Stevens- Johnson, eritema multiforme
tenosynovitis
tenosynovitis
tendon rupture
qtugħ ta ’ l- għerq tal- muskolu
Metabolism and nutrition disorders
Disturbi fil - metaboliżmu u n- nutrizzjoni
CPK increased
żieda fi CPK
hypokalaemia, hyperlipidemia, hypophosphataemia
livell baxx ta ’ potassju fid- demm, iperlipidemja, ipofosfatimja
LDH increased
Rari: żieda fi LDH
hypouricemia
ipojuriċimja
Rare: severe infections, including sepsis which may be fatal
Rari: infezzjonijiet severi, inkluż sepsis li tista ’ tkun fatali
9 Like other agents with immunosuppressive potential, leflunomide may increase susceptibility to infections, including opportunistic infections (see also section 4.4).
Bħal sustanzi oħra li għandhom potenzjal immunosoppressiv, leflunomide jista ’ jżid is- suxxettibbiltà għall- infezzjonijiet, inklużi dawk opportunistiċi (ara wkoll sezzjoni 4. 4).
Thus, the overall incidence of infections can increase (in particular of rhinitis, bronchitis and pneumonia).
Għalhekk, l- inċidenza totali ta ’ infezzjonijiet tista ’ tiżdied (partikolarment ir- rinite, il- bronkite u l- pulmonite).
The risk of malignancy, particularly lymphoproliferative disorders, is increased with use of some immunosuppressive agents.
Ir- riskju ta ’ tumuri malinni, partikolarment il- mard limfoproliferattiv, jiżdied bl- użu ta ’ xi uħud mis - sustanzi li jrażżnu s- sistema immuni.
anorexia, weight loss (usually insignificant), asthenia
anoreksja, telf fil- piż (normalment mhux sinifikanti), astenja
mild allergic reactions
reazzjonijiet allerġiċi ħfief
severe anaphylactic/ anaphylactoid reactions, vasculitis, including cutaneous necrotizing vasculitis
reazzjonijiet severi anafilattiċi jew reazzjonijiet jixxibħu, vaskulite, li tinkludi l - vaskulite nekrotika tal- ġilda
elevation of liver parameters (transaminases [especially ALT], less often gamma-GT, alkaline phosphatase, bilirubin)
livelli għoljin tal- parametri tal- fwied (l- enżimi transaminases [speċjalment ALT], anqas spiss gamma- GT, alkaline phosphatase, bilirubin
hepatitis, jaundice/ cholestasis
epatite, suffejra/ cholestasis
Very rare:
Rari ħafna
severe liver injury such as hepatic failure and acute hepatic necrosis that may be fatal
ħsara severa tal- fwied bħal insuffiċjenza tal- fwied u nekrosi akuta tal- fwied, li jistgħu jkunu fatali.
Reproductive system and breast disorders
Disturbi fis- sistema reproduttiva u fis- sider
Not known:
Mhux magħruf
marginal (reversible) decreases in sperm concentration, total sperm count and rapid progressive motility
tnaqqis marġinali (u riversibbli) fil- konċentrazzjoni ta ’ l- isperma, l- għadd sħiħ ta ’ l- ispermi, u ċ- ċaqlieq mgħaġġel u progressiv
anxiety
anzjetà
4.9 Overdose
10 4. 9 Doża eċċessiva
There have been reports of chronic overdose in patients taking Arava at daily doses up to five times the recommended daily dose, and reports of acute overdose in adults and children.
Kien hemm rapporti ta ’ pazjenti li kienu qegħdin jieħdu dożi eċċessivi u fit- tul ta ’ Arava, b’ dożaġġ sa ħames darbiet akbar kuljum minn dak irrakkomandat, kif ukoll rapporti ta ’ dożi eċċessivi u akuti, fl - adulti u fit- tfal.
There were no adverse events reported in the majority of case reports of overdose.
Fil- maġġoranza tal- każjiet fejn kienu qegħdin jittieħdu dożi eċċessivi, ma kienx hemm rapporti ta ’ effetti avversi.
Adverse events consistent with the safety profile for leflunomide were: abdominal pain, nausea, diarrhoea, elevated liver enzymes, anaemia, leucopenia, pruritus and rash.
L- effetti avversi konsistenti mal- profil ta ’ sigurtà ta ’ leflunomide kienu: uġigħ addominali, dardir, dijarrea, livelli għoljin ta ’ l- enżimi tal- fwied, anemija, lewkopenja, ħakk u raxx.
In the event of an overdose or toxicity, colestyramine or charcoal is recommended to accelerate elimination.
F’ każ ta’ dożi eċċessivi jew tossiċi, l- użu ta ’ colestyramine jew ta ’ charcoal huwa irrakkomandat biex iħaffef it- tneħħija.
Colestyramine given orally at a dose of 8 g three times a day for 24 hours to three healthy volunteers decreased plasma levels of A771726 by approximately 40% in 24 hours and by 49% to 65% in 48 hours.
Meta colestyramine ingħata mill- ħalq f’ doża ta ’ 8 g tliet darbiet kuljum għal 24 siegħa lil tliet voluntieri b’ saħħithom, il- livelli ta ’ A771726 fil- plażma tnaqqsu b’ madwar 40% f’ 24 siegħa, u b’ 49% sa 65% f’ 48 siegħa.
10 Administration of activated charcoal (powder made into a suspension) orally or via nasogastric tube (50 g every 6 hours for 24 hours) has been shown to reduce plasma concentrations of the active metabolite A771726 by 37% in 24 hours and by 48% in 48 hours.
Intwera li t- teħid ta ’ charcoal attivat (trab f’ suspensjoni) mill- ħalq jew permezz ta ’ tubu li jgħaddi mill- imnieħer u jidħol fl- istonku (50 g kull 6 sigħat għal 24 siegħa), jnaqqas il- livelli fil- plażma tal - prodott metaboliku attiv, A771726, b ’ 37% f’ 24 siegħa u b’ 48% f’ 48 siegħa.
These washout procedures may be repeated if clinically necessary.
Dawn il- proċeduri ta ’ tneħħija jistgħu jkunu repetuti jekk huwa klinikament indikat.
Studies with both hemodialysis and CAPD (chronic ambulatory peritoneal dialysis) indicate that A771726, the primary metabolite of leflunomide, is not dialysable.
Studji fuq id- dijaliżi tad- demm u pazjenti CAPD (dawk fuq saqajhom li qegħdin jagħmlu dijaliżi kronika mill- peritonew) juru li l- A771726, il- prodott metaboliku ewlieni ta ’ leflunomide, mhux dijaliżżabbli.
Pharmacotherapeutic group: selective immunosuppressive agents, ATC code:
Kategorija farmakoterapewtika: sustanzi selettivi immunosoppressivi, kodiċi ATC:
Human pharmacology
Farmakoloġija fil- bniedem
Leflunomide is a disease-modifying anti-rheumatic agent with antiproliferative properties.
Leflunomide huwa sustanza b’ karatteristiċi anti- proliferattivi li taġixxi bħala prodott anti - rewmatoloġiku.
Animal pharmacology
Farmakoloġija fl- annimali
Leflunomide is effective in animal models of arthritis and of other autoimmune diseases and transplantation, mainly if administered during the sensitisation phase.
Leflunomide huwa effettiv f’ mudelli ibbażati fuq annimali bl- artrite, u mard ieħor awto- immunoloġiku u t- trapjanti, l- aktar meta jingħata waqt il- fażi ta ’ sensitiżazzjoni.
It has immunomodulating/ immunosuppressive characteristics, acts as an antiproliferative agent, and displays anti-inflammatory properties.
Għandu karatteristiċi immunosuppressivi u li jikkontrollaw r- reazzjonijiet immunoloġiċi, jaġixxi bħala sustanza anti- proliferattiva, u juri karatteristiċi anti- infjammatorji.
Leflunomide exhibits the best protective effects on animal models of autoimmune diseases when administered in the early phase of the disease progression.
Leflunomide użat f’ mudell ta’ annimali b’ mard awto- immunoloġiku, juri l- aħjar effett protettiv meta jingħata fil- fażi bikrija ta ’ mard progressiv.
In vivo, it is rapidly and almost completely metabolised to A771726 which is active in vitro, and is presumed to be responsible for the therapeutic effect.
In vivo, huwa metaboliżżat malajr u kważi kompletament għal A771726, li huwa attiv in vitro u li huwa preżunt li jikkawża l- effett terapewtiku.
A771726, the active metabolite of leflunomide, inhibits the human enzyme dihydroorotate dehydrogenase (DHODH) and exhibits antiproliferative activity.
A771726, li huwa il- prodott metaboliku attiv ta ’ leflunomide, jinibixxi l- enżima dihydroorotate dehydrogenase (DHODH) fil- bniedem, u juri attività anti- proliferattiva.
Rheumatoid arthritis
11 Artrite rewmatika
The efficacy of Arava in the treatment of rheumatoid arthritis was demonstrated in 4 controlled trials (1 in phase II and 3 in phase III).
L- effikaċja ta ’ Arava fil- kura ta ’ l- artrite rewmatika ntweriet f ’ 4 provi ikkontrollati (1 fil- fażi II u 3 fil- fażi III).
The phase II trial, study YU203, randomised 402 subjects with active rheumatoid arthritis to placebo (n=102), leflunomide 5 mg (n=95), 10 mg (n=101) or 25 mg/ day (n=104).
Fl- istudju tal- fażi II, YU203, 402 pazjenti li kellhom l- artrite rewmatikaattiva kienu mqassmin, mingħajr għażla, f’ erba ’ gruppi: dawk bil- plaċebo (n = 102) u dawk b’ 5 mg (n = 95), 10 mg (n = 101) jew 25 mg (n = 104) leflunomide kuljum.
The treatment duration was 6 months.
It- tul tal- kura kien ta ’ 6 xhur.
All leflunomide patients in the phase III trials used an initial dose of 100 mg for 3 days.
Il- pazjenti kollha fuq leflunomide fil- provi tal- fażi III inbdew fuq doża inizjali ta ’ 100 mg għal tlett ijiem.
Study MN301 randomised 358 subjects with active rheumatoid arthritis to leflunomide 20 mg/ day (n=133), sulphasalazine 2 g/ day (n=133), or placebo (n=92).
Dawn kienu mqassmin, mingħajr għazla, fi tlett gruppi: dawk li ngħataw 20 mg leflunomide kuljum (n = 133), dawk li ngħataw 2 g sulphasalazine kuljum (n = 133) jew il- plaċebo (n = 92).
Treatment duration was 6 months.
It- tul tal- kura kien ta ’ 6 xhur.
Study MN303 was an optional 6-month blinded continuation of MN301 without the placebo arm, resulting in a 12-month comparison of leflunomide and sulphasalazine.
L- istudju MN303, li kien blinded ma kienx obbligatorju u kien twil 6 xhur; u sar bħala kontinwazzjoni tal- MN301, mingħar ma kien ikkontrollat bil- plaċebo.
Study MN302 randomised 999 subjects with active rheumatoid arthritis to leflunomide 20 mg/ day (n=501) or methotrexate at 7.5 mg/ week increasing to 15 mg/ week (n=498).
Fl- istudju MN302 999 pazjent bl- artrite rewmatika attiva tqassmu f’ żewġ gruppi, wieħed fejn ingħataw 20 mg leflunomide kuljum (n = 501), u l- ieħor fejn ingħataw 7. 5 mg methotrexate fil - ġimgħa, b’ żieda għall- 15 mg fil- ġimgħa (n = 498).
Folate supplementation was optional and only used in 10% of patients.
It- teħid addizzjonali ta ’ folate ma kienx obbligatorju u ntuża biss minn 10% tal- pazjenti.
Treatment duration was 12-months.
Il- kura damet 12- il xahar.
Study US301 randomised 482 subjects with active rheumatoid arthritis to leflunomide 20 mg/ day (n=182), methotrexate 7.5 mg/ week increasing to 15 mg/ week (n=182), or placebo (n=118).
Fl- istudju US301, tqassmu, mingħajr għażla, 482 pazjent bl- artrite rewmatika attiva fi tliet gruppi: dawk li ngħataw 20 mg leflunomide kuljum (n = 182), dawk li ingħataw 7. 5 mg methotrexate fil - ġimgħa b’ żieda għall- 15 mg fil- ġimgħa (n = 182) u dawk bil- plaċebo (n = 118).
All patients received folate 1 mg bid.
Il- pazjenti kollha ngħataw 1 mg folate bid.
Treatment duration was 12 months.
Il- kura damet 12- il xahar.
Leflunomide at a daily dose of at least 10 mg (10 to 25 mg in study YU203, 20 mg in studies MN301 and US301) was statistically significantly superior to placebo in reducing the signs and symptoms of rheumatoid arthritis in all 3 placebo-controlled trials.
Leflunomide, f’ doża ta ’ mhux inqas minn 10 mg kuljum (minn 10 sa 25 mg fl- istudju YU203, 20 mg fl- istudji MN301 u US301), kien superjuri għall- plaċebo, u statistikament sinifikanti, fit- tnaqqis tas - sinjali u s- sintomi ta ’ l- artrite rewmatika fit- 3 provi kollha ikkontrollati bil- plaċebo.
The ACR (American College of Rheumatology) response rates in study YU203 were 27.7% for placebo, 31.9% for 5 mg, 50.5% for 10 mg and 54.5% 11 for 25 mg/ day.
Ir- rati ta ’ rispons skond l- ACR (il- Kulleġġ Amerikan tar- Rewmatoloġija) fl- istudju YU203 kienu 27. 7% bil- plaċebo u 31. 9% b’ 5 mg, 50. 5% b’ 10 mg u 54. 5% b’ 25 mg, kuljum.
28.6% (study MN301), and 49.4% vs.
Fil- provi tal- fażi III, ir- rati ta ’ rispons skond l- ACR għal 20 mg leflunomide kuljum versu il- plaċebo, kienu ta ’ 54. 6% versu 28. 6% (studju MN301), u 49. 4% versu 26. 3% (studju US301).
26.3% (study US301). After 12 months with active treatment, the ACR response rates in leflunomide patients were 52.3% (studies MN301/ 303), 50.5% (study MN302) and 49.4% (study US301), compared to 53.8% (studies MN301/ 303) in sulphasalazine patients, 64.8% (study MN302), and 43.9% (study US301) in methotrexate patients.
Wara 12- il xahar ta ’ kura attiva, ir- rati ta ’ rispons skond l- ACR fil- pazjenti fuq leflunomide kienu 52. 3% (studji MN301/ 303), 50. 5% (studju MN302) u 49. 4% (studju US301), ikkomparati ma ’ 53. 8% (studji MN301/ 303) tal- pazjenti fuq sulphasalzine, 64. 8% (studju MN302), u 43. 9% (studju US301) tal- pazjenti fuq methotrexate.
In study MN302 leflunomide was significantly less effective than methotrexate.
Fl- istudju MN302 leflunomide kien anqas effettiv minn methotrexate b’ mod sinifikanti.
However, in study US301 no significant differences were observed between leflunomide and methotrexate in the primary efficacy parameters.
Madankollu, fl- istudju US301 ma kienx hemm differenzi sinifikanti bejn leflunomide u methotrexate fil- parametri t’ effikaċja primarja.
No difference was observed between leflunomide and sulphasalazine (study MN301).
Ma ntwerietx differenza bejn leflunomide u sulphasalazine (studju MN301).
The leflunomide treatment effect was evident by 1 month, stabilised by 3 to 6 months and continued throughout the course of treatment.
L- effett tal- kura b’ leflunomide deher għeluq ix- xahar, stabiliżża f’ perijodu ta ’ bejn 3 u 6 xhur u nżamm tul il- kors tal - kura.
A randomised, double-blind, parallel-group non-inferiority study compared the relative efficacy of two different daily maintenance doses of leflunomide, 10 mg and 20 mg.
Studju randomised u double blind fejn il- pazjenti nqassmu f’ żewġ gruppi paralleli, u li kellhom mard ta ’ l- istess grad ta ’ severità, qabbel l- effikaċja relattiva ta ’ dożi regolari u mantnuti ta ’ wara, b’ 10 mg u 20 mg ta ’ leflunomide.
From the results it can be concluded that efficacy results of the 20 mg maintenance dose were more favourable, on the other hand, the safety results favoured the 10 mg daily maintenance dose.
Mir- riżultati li ħarġu, wieħed jista ’ jikkonkludi li l- effikaċja kienet aħjar fil - grupp li ħa d- doża regolari u mantnuta ta ’ wara, ta ’ 20 mg, fil- waqt li r- riżultati tas- sigurtà jiffavorixxu d- doża regolari, mantnuta u ta ’ wara, ta ’ 10 mg.
Paediatrics
Pedjatrija
Leflunomide was studied in a single multicenter, randomized, double-blind, active-controlled trial in 94 patients (47 per arm) with polyarticular course juvenile rheumatoid arthritis.
Leflunomide kien studjat f’ diversi ċentri fi prova waħda, tat- tip randomised, double blind u active - controlled, f’ 94 pazjent (47 f’ kull grupp) li kellhom l- artrite rewmatika taż- żgħażagħ u li nvolviet diversi ġogi tul il- kors tagħha.
Patients were 3– 17 years of age with active polyarticular course JRA regardless of onset type and naive to methotrexate or leflunomide.
Il- pazjenti kienu minn 3 snin sa 17- il sena fl- età b’ JRA attiva u li involviet diversi ġogi, irrespettivament ta ’ kif bdiet, u fejn il- pazjenti qatt ma ’ kienu ngħataw methotrexate jew leflunomide.
In this trial, the loading dose and maintenance dose of leflunomide was based on three weight categories :< 20kg, 20-40 kg, and > 40kg.
F’ din il- prova, d- doża tal- bidu u d- doża regolari u mantnuta ta ’ wara, ta ’ leflunomide, kienu mfassla għal tliet kategoriji, skond il- piż: < 20 kg, 20- 40 kg, u > 40 kg.
After 16 weeks treatment, the difference in response rates was statistically significant in favour of methotrexate for the JRA Definition of Improvement (DOI) ≥ 30% (p=0.02).
Wara 16 - il ġimgha trattament, id- differenzi fir- rati tar- rispons kienu statistikament sinifikanti favur methotrexate għall- JRA Definition of Improvement (DOI) > 30% (p = 0. 02).
In responders, this response was maintained during 48 weeks.
F’ dawk li rrispondew, l - effett pożittiv kien mantnut għal 48 ġimgħa.
The pattern of adverse events of leflunomide and methotrexate seems to be similar, but the dose used in lighter subjects resulted in a relatively low exposure (see section 5.2).
12 Il- firxa tal- ġrajjiet avversi ta ’ leflunomide u methotrexate kienu l- istess, iżda d- doża użata fis- suġġetti ħfief fil- piż wasslet għall- espożizzjoni aktar baxxa (ara sezzjoni 5. 2).
These data do not allow an effective and safe dose recommendation.
Din id- data ma tippermettix li ssir rakkomandazzjoni ta ’ doża simultanjament effettiva u mhux perikoluża.
The efficacy of Arava was demonstrated in one controlled, randomised, double blind study 3L01 in 188 patients with psoriatic arthritis, treated at 20mg/ day.
L- effikaċja ta ’ Arava intwera fi studju wieħed 3L01, li kien ikkontrollat, randomised u double blind u li sar fuq 188 pazjent bl- artrite psorjatika, ittrattati b’ 20 mg/ jum.
Treatment duration was 6 months.
It- tul ta ’ żmien tat- trattament kien ta ’ 6 xhur.
Leflunomide 20mg/ day was significantly superior to placebo in reducing the symptoms of arthritis in patients with psoriatic arthritis: the PsARC (Psoriatic Arthritis treatment Response Criteria) responders were 59% in the leflunomide group and 29.7% in the placebo group by 6 months (p < 0.0001).
Leflunomide f’ doża ta ’ 20 mg/ jum kien superjuri b’ mod sinifikanti meta mqabbel mal- plaċebo fit - tnaqqis tas- sintomi ta ’ l- artrite f’ pazjenti bl- artrite psorjatika: il- pazjenti li kienu jissodisfaw il- PsARC (Psoriatic Arthritis treatment Response Criteria) kienu 59% għall- grupp ta ’ leflunomide u 29. 7% għall- grupp tal- plaċebo, fi żmien 6 xhur (p < 0. 0001).
The effect of leflunomide on improvement of function and on reduction of skin lesions was modest.
L- effett ta ’ leflunomide fuq it- titjib tal- funzjoni u t- tnaqqis tal- leżjonijiet tal- ġilda kien modest.
Leflunomide is rapidly converted to the active metabolite, A771726, by first-pass metabolism (ring opening) in gut wall and liver.
Leflunomide jiġi mibdul malajr fil- prodott metaboliku attiv, A771726, permezz tal- first pass metabolism (ftuħ taċ- ċirku) fit- tessut tal- musrana u l- fwied.
In a study with radiolabelled 14C-leflunomide in three healthy volunteers, no unchanged leflunomide was detected in plasma, urine or faeces.
Fi studju fejn intuża leflunomide, immarkat bl- użu ta ’ 14C radjuattiv fil- molekula, fi tliet voluntiera b’ saħħithom, ma nstabx leflunomide mhux mibdul fil- plażma, fl- awrina u fl- ippurgar.
In other studies, unchanged leflunomide levels in plasma have rarely been detected, however, at ng/ ml plasma levels.
Fi studji oħrajn, il- livelli ta ’ leflunomide mhux mibdul fil- plażma, kienu osservati f’ każijiet rari, madankollu, f’ livelli ta ’ ng/ ml tal- plażma.
The only plasma-radiolabelled metabolite detected was A771726.
L- uniku prodott metaboliku radjuattiv li deher fil- plażma kien A771726.
This metabolite is responsible for essentially all the in-vivo activity of Arava.
Dan il- prodott metaboliku huwa essenzjalment responsabbli għall- attivita kollha in- vivo ta ’ Arava.
Excretion data from the 14C study indicated that at least about 82 to 95% of the dose is absorbed.
Tagħrif dwar it- tneħħija, fl- istudju tal- 14C uriet li mhux inqas minn 82 sa 95% tad- doża kienet assorbita.
The time to peak plasma concentrations of A771726 is very variable; peak plasma levels can occur between 1 hour and 24 hours after single administration.
Iż- żmien biex jintlaħaq l- ogħla livelli ta ’ A771726 fil- plażma jvarja ħafna; l- ogħla livelli fil - plażma jistgħu jintlaħqu bejn siegħa u 24 siegħa wara t- teħid ta ’ darba.
Due to the very long half-life
Leflunomide jista ’ jingħata ma ’ l- ikel, għaliex l- ammont li ġie assorbit f’ dawk li kielu u f’ dawk li kienu sajmin kien komparabbli.
12 of A771726 (approximately 2 weeks), a loading dose of 100 mg for 3 days was used in clinical studies to facilitate the rapid attainment of steady-state levels of A771726.
Minħabba li A771726 għandu half- life twila ħafna (madwar ġimgħatejn), fi studji kliniċi, kienet mgħotija doża għolja tal- bidu ta ’ 100 mg, għal 3 ijiem, biex tiffaċilita l- kisba mgħaġġla ta ’ livelli, fi stat stabbli, ta ’ A771726.
Without a loading dose, it is estimated that attainment of steady-state plasma concentrations would require nearly two months of dosing.
Mingħajr id- doża għolja tal- bidu huwa stmat li ż- żmien biex jintlaħaq l- istat stabbli tal- livelli fil- plażma kien idum kważi xaharejn bid- doża normali.
In multiple dose studies in patients with rheumatoid arthritis, the pharmacokinetic parameters of A771726 were linear over the dose range of 5 to 25 mg.
Fi studji b’ dożi multipli, f’ pazjenti li kellhom l- artrite rewmatika, il- parametri farmakokinetiċi ta ’ A771726 kienu linejari, f’ firxa ta ’ dożaġġ ta ’ minn 5 sa 25 mg.
In these studies, the clinical effect was closely related to the plasma concentration of A771726 and to the daily dose of leflunomide.
F’ dawn l- istudji, l- effett kliniku kien relatat sew mal- livell ta ’ A771726 fil- plażma u mad- doża ta ’ kuljum ta ’ leflunomide.
At a dose level of 20 mg/ day, average plasma concentration of A771726 at steady state is approximately 35 µg/ ml.
F’ doża ta ’ 20 mg kuljum, il- livell medju fil- plażma ta ’ A771726 fi stat stabbli kien ta ’ madwar 35 μg/ ml.
At steady state plasma levels accumulate about 33- to 35-fold compared with single dose.
Fi stat stabbli, il- livelli fil- plażma ta ’ A771726 akkumulaw u żdiedu għal 33 sa 35 darba meta mqabbla ma ’ doża waħda.
In human plasma, A771726 is extensively bound to protein (albumin).
Fil- plażma tal- bniedem, A771726 kien marbut sew mal- proteina (l- albumina).
The unbound fraction of A771726 is about 0.62%.
Il- parti ta ’ A771726 mhux marbuta hija ta ’ madwar 0. 62%.
Binding of A771726 is linear in the therapeutic concentration range.
Ir- rabta ta ’ A771726 hija linejari fil- firxa tal- livelli terapewtiċi.
Binding of A771726 appeared slightly reduced and more variable in plasma from patients with rheumatoid arthritis or chronic renal insufficiency.
Ir- rabta ta ’ A771726 deheret li kienet daqxejn imnaqqsa u aktar varjabbli fil- plażma ta ’ pazjenti bl - artrite rewmatika jew b’ dawk b’ insuffiċjenza kronika tal- kliewi.
The extensive protein binding of A771726 could lead to displacement of other highly-bound drugs.
Ir- rabta estensiva ta ’ A771726 mal - proteina tista ’ twassal għall- ispustjar ta ’ mediċini oħra li ukoll jintrabtu sew mal- proteina.
In vitro plasma protein binding interaction studies with warfarin at clinically relevant concentrations, however, showed no interaction.
Madankollu, studji in vitro t’ interazzjoni ma ’ warfarin, rigward ir- rabta mal- proteina, f’ livelli klinikament rilevanti, m’ urewx interazzjoni.
Similar studies showed that ibuprofen and diclofenac did not displace A771726, whereas the unbound fraction of A771726 is increased 2- to 3-fold in the presence of tolbutamide.
Studji simili li saru b’ ibuprofen u diclofenac, urew li dawn ma spustjawx lil A771726, fil- waqt li l- parti mhux marbuta ta ’ A771726 żdiedet minn darbtejn sa 3 darbiet fil- preżenza ta ’ tolbutamide.
A771726 displaced ibuprofen, diclofenac and tolbutamide but the unbound fraction of these drugs is only increased by 10% to 50%.
A771726 jisposta lil ibuprofen, lil diclofenac u lil tolbutamide, iżda l- parti mhux marbuta ta ’ dawn il- mediċini tiżdied biss b’ 10% sa 50%.
There is no indication that these effects are of clinical relevance.
M’ hemm l - ebda indikazzjoni li dawn l- effetti għandhom rilevanza klinika.
Consistent with extensive protein binding A771726 has a low apparent volume of distribution (approximately 11 litres).
A771726 għandu volum apparenti ta ’ distribuzzjoni baxxa (madwar 11- il litru) u dan huwa konsistenti mar- rabta estensiva tiegħu mal - proteina.
There is no preferential uptake in erythrocytes.
Iċ- ċelluli ħomor tad- demm ma jtellgħux is- sustanza fihom b’ mod preferenzjali.
Metabolism
13 Metaboliżmu
Leflunomide is metabolised to one primary (A771726) and many minor metabolites including TFMA (4-trifluoromethylaniline).
Leflunomide huwa metaboliżżat għal sustanza waħda ewlenija (A771726) u ħafna oħrajn minuri inkluż TFMA (4- trifluoromethylaniline).
The metabolic biotransformation of leflunomide to A771726 and subsequent metabolism of A771726 is not controlled by a single enzyme and has been shown to occur in microsomal and cytosolic cellular fractions.
Il- bijotrasformazzjoni metabolika ta ’ leflunomide għall - A771726, u l- metaboliżmu sussegwenti ta ’ A771726, mhumiex ikkontrollat b’ enżima waħda, u ntwera li dan jiġri fil- mikrożomi u l- likwidu taċ- ċitoplażma fil- frazzjonijiet ċellulari.
Interaction studies with cimetidine (non-specific cytochrome P450 inhibitor) and rifampicin (non-specific cytochrome P450 inducer), indicate that in vivo CYP enzymes are involved in the metabolism of leflunomide only to a small extent.
Studji fuq l- interazzjoni ta ’ cimetidine (inibitur mhux speċifiku ta ’ ċitokromju P450) u rifampicin (induttur mhux speċifiku ta ċitokromju P450) juru li l- involviment ta ’ l- enżimi CYP in vivo fil- metaboliżmu ta ’ leflunomide huwa zgħir ħafna.
Elimination of A771726 is slow and characterised by an apparent clearance of about 31 ml/ hr.
L- eliminazzjoni ta ’ A771726 issir bil- mod u hija ikkaratterizzata bit- tneħħija apparenti ta ’ madwar 31 ml fis- siegħa.
The elimination half-life in patients is approximately 2 weeks.
Il- half- life t’ eliminazzjoni fil- pazjenti hija ta ’ madwar ġimgħatejn.
After administration of a radiolabelled dose of leflunomide, radioactivity was equally excreted in faeces, probably by biliary elimination, and in urine.
Wara li ngħatat doża ta ’ leflunomide radjuattiv, ir- radjuattività kienet imneħħija ugwalment fl- ipurgar, probabbilment minn eliminazzjoni biljari, u fl- awrina.
A771726 was still detectable in urine and faeces 36 days after a single administration.
A771726 kien għadu jiġi osservat fl- awrina u fl- ippurgar 36 jum wara t- teħid ta ’ doża waħda.
The principal urinary metabolites were glucuronide products derived from leflunomide (mainly in 0 to 24 hour samples) and an oxanilic acid derivative of A771726.
Il- prodotti metaboliċi prinċipali li dehru fl- awrina kienu sustanzi glukoronidi derivati minn leflunomide (prinċiplament f’ kampjuni meħudin f’ 0 sa 24 siegħa) u xi derivattiv ta ’ A771726 tat- tip oxalinic acid.