qanastek/EMEA-V3 huggingface dataset:
Bleeding There is an increased risk of bleeding with Thelin, mainly in the form of epistaxis and gingival bleeding.
Ħruġ ta ’ demm Hemm żieda fir- riskju ta ’ ħruġ ta ’ demm b’ Thelin, primarjament fis- sura ta ’ friġ u ħruġ ta ’ demm ġinġivali.
Vitamin K antagonists Thelin increases the plasma levels of Vitamin K antagonists such as warfarin, acenocoumarol and fenprocoumon (see section 4.5).
Antagonisti tal- Vitamina K Thelin iżid il- livelli tal- plażma ta ’ l- antagonisti tal- Vitamina K bħal warfarin, acenocoumarol u fenprocoumon (ara taqsima 4. 5).
Drugs which inhibit Organic Anion Transporting Polypeptides (OATP) The extent of interaction with potent OATP inhibitors (e. g. some statins, proteinase inhibitors, tuberculostatics) is unknown.
Mediċini li jimpedixxu Organic Anion Transporting Polypeptides (OATP) Il- firxa ta ’ l- interazzjoni ma ’ inibituri qawwija ta ’ OATP (eż. xi statins, inibituri tal- protinase, tuberculostatics) mhijiex magħrufa.
As this could result in raised plasma levels of sitaxentan sodium, patients in need of the combination should be closely monitored for adverse events related to sitaxentan sodium (see section 4.5).
Peress li din tista ’ tirriżulta f’ livelli għoljin ta ’ sitaxentan sodium fil- plażma, il- pazjenti li għandhom bżonn ta ’ din il- kumbinazzjoni għandhom ikunu ssorveljati mill - qrib għall- reazzjonijiet avversi marbuta ma ’ sitaxentan sodium (ara sezzjoni 4. 5).
Oral contraceptive agents Thelin increases oestrogen exposure when given concomitantly with oral contraceptive agents (see Section 4.5).
Sustanzi kontraċettivi orali Thelin iżid l- espożizzjoni għall- estroġeni meta jingħata flimkien ma ’ sustanzi kontraċettivi orali (ara Taqsima 4. 5).
Therefore, especially in women who smoke, there is an increased risk for thromboembolism.
Għalhekk, speċjalment fin- nisa li jpejpu, hemm riskju akbar għal tromboemboliżmu.
Given a theoretical higher risk for thromboembolism, traditional concomitant use of vitamin K antagonists should be considered.
Minħabba r- riskju teoretiku ogħla għat- tromboemboliżmu, l- użu tradizzjonali konkomitanti ta ’ antagonisti tal- vitamina K għandu jkun ikkunsidrat.
If necessary, pregnancy testing should be undertaken (see Section 4.6).
Tqala Minħabba l- possibbiltà ta ’ teratoġeniċità, Thelin m’ għandux jinbeda f’ nisa li jista ’ jkollhom it- tfal, ħlief jekk ma jużawx kontraċezzjoni affidabbli Jekk ikun meħtieġ, għandu jsir test tat- tqala (ara Sezzjoni 4. 6).
4 Pulmonary veno-occlusive disease (PVOD) No data are available with Thelin in patients with pulmonary hypertension associated with pulmonary veno-occlusive disease.
4 Mard okklużiv tal- vini pulmonari (PVOD) M’ hemm l- ebda informazzjoni disponibbli dwar Thelin f’ pazjenti bi pressjoni għolja pulmonari assoċjata ma ’ mard veno- okklusiv pulmonari.
However, cases of life threatening pulmonary oedema have been reported with vasodilators (mainly prostacyclin) when used in those patients.
Madankollu, ġew rrappurtati każijiet ta ’ edema pulmonari li tipperikola l- ħajja meta dawn il- pazjenti użaw vasodilaturi (prinċipalment prostcyclin).
Consequently, should signs of pulmonary oedema occur when Thelin is administered in patients with pulmonary hypertension, the possibility of associated veno-occlusive disease should be considered.
Konsegwentement, jekk jidhru sinjali ta ’ edema pulmonari meta Thelin jkun qed jingħata lill- pazjenti bi pressjoni għolja pulmonari, il- possibbiltà ta ’ mard veno- okklusiv assoċjat għandha tiġi kkunsidrata.
Haemoglobin concentration Treatment with Thelin was associated with a dose-related decrease in haemoglobin (see section 4.8).
Konċentrazzjoni ta ’ l- emoglobina Il- kura b’ Thelin kienet assoċjata ma ’ tnaqqis fl- emoglobina marbuta mad- doża (ara taqsima 4. 8).
Most of this decrease of haemoglobin concentration was detected during the first few weeks of treatment and haemoglobin levels stabilized by 4 weeks of Thelin treatment.
Il - biċċa l- kbira ta ’ dan it- tnaqqis fil- konċentrazzjoni ta ’ l- emoglobina kien osservat waqt l- ewwel ftit ġimgħat tal- kura u l- livelli ta ’ l- emoglobina stabbilizzaw ruħhom sar- raba ’ ġimgħa tal- kura b’ Thelin.
It is recommended that haemoglobin concentrations be checked prior to treatment, after 1 and 3 months, and every 3 months thereafter.
Huwa rrakkomandat li l- konċentrazzjonijiet ta ’ l- emoglobina jiġu ċċekkjati qabel il- bidu tal- kura, wara xahar u 3 xhur, u minn hemm ’ il quddiem kull 3 xhur.
If a marked decrease in haemoglobin concentration occurs, further evaluation should be undertaken to determine the cause and need for specific treatment.
Jekk il- konċentrazzjoni ta ’ l- emoglobina tinżel ħafna, evalwazzjoni addizzjonali għandha ssir biex tistabbilixxi l- kawża u l- bżonn ta ’ kura speċifika.
Excipients Thelin tablets contain lactose monohydrate.
Sustanzi mhux attivi Il- pilloli Thelin fihom lattosju monohydrate.
Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency, or glucose-galactose malabsorption should not take this medicine.
Pazjenti bi problemi ereditarji rari ta ’ intolleranza għal galattosju, id- defiċjenza ta ’ Lapp lactase, jew assorbiment difettuż ta ’ glukosju- galattosju m’ għandomx jieħdu din il- mediċina.
Sitaxentan sodium is metabolised in the liver by cytochrome P450 CYP2C9 and CYP3A4/ 5 isoenzymes.
Sitaxentan sodium huwa metabolizzat fil- fwied miċ- ċitokromu P450 u isoenżimi CYP2C9 u CYP3A4/ 5.
Sitaxentan sodium is an inhibitor of CYP2C9 and, to a lesser extent, CYP2C19, CYP3A4/ 5 and CYP2C8.
Sitaxentan sodium huwa inibitur ta ’ CYP2C9 u, sa ċertu punt, inibitur iktar dgħajjef ta ’ CYP2C19, CYP3A4/ 5 u CYP2C8.
Plasma concentrations of drugs principally metabolized by CYP2C9 may be increased during sitaxentan sodium co-administration.
Konċentrazzjonijiet fil- plażma ta ’ mediċini li huma metabolizzati prinċipalment minn CYP2C9, jistgħu jiżdiedu meta jingħataw flimkien ma ’ sitaxentan sodium.
Co-administration with drugs metabolized by CYP2C19 or CYP3A4/ 5 is not expected to result in clinically significant drug interactions.
Meta jingħata ma ’ mediċini metabolizzati minn CYP2C19 jew CYP3A4/ 5 mhix mistennija li tirriżulta f’ interazzjonijiet mediċinali klinikament sinifikanti.
Sitaxentan sodium does not affect the p-glycoprotein transporter, but it is postulated to be a substrate of OATP transporter proteins.
Sitaxentan sodium ma jaffettwax it- trasportatur p - glycoprotein, imma kien issoponut li huwa sottostrat tal- proteini tat- trasportaturi ta ’ OATP.
Effects of other medicinal products on Thelin
Effetti ta ’ prodotti mediċinali oħrajn fuq Thelin
Organic Anion Transporting Polypeptides (OATP) Inhibitors:
Inibituri ta ’ Organic Anion Transporting Polypeptides (OATP):
Co-administration with ciclosporin A, a potent OATP inhibitor, resulted in a 6-fold increase in Cmin and a 67% increase in AUC of sitaxentan therefore the use of Thelin in patients receiving systemic ciclosporin A is contraindicated (see section 4.3).
L- għoti flimkien ma ’ ciclosporin A, inibitur qawwi ta ’ OATP irriżulta f’ żieda ta ’ 6 darbiet iktar fil - Cmin u żieda ta ’ 67% fl- AUC ta ’ sitaxentan, u għalhekk l- użu ta ’ Thelin f’ pazjenti li qegħdin jieħdu ciclosporin A huwa kontra- indikat (ara taqsima 4. 3).
Clearance of ciclosporin A was unchanged.
Ir- rata ta ’ l- eliminazzjoni ta ’ ciclosporin A ma nbidlitx.
The extent of interaction with other OATP inhibitors (some HMG CoA reductase inhibitors eg, atorvastatin, protease inhibitors eg, ritonavir, tuberculostatics eg, rifamycin) is unknown but could result in raised plasma levels of sitaxentan.
Il- firxa ta ’ l- interazzjoni ma ’ inibituri oħra ta ’ OATP (xi inibituri tal- HMG CoA reductase eż. atorvastatin, inibituri tal- protinase eż. ritonavir, tuberculostatics eż. rifamycin) mhijiex magħrufa, imma din tista ’ tirriżulta f’ livelli għoljin ta ’ sitaxentan sodium fil- plażma.
The clinical significance of this is unknown.
Mhux magħruf kemm din il - possibilta hija klinikament sinifikanti.
Patients in need of the combination should be closely monitored.
Pazjenti li għandhom bżonn ta ’ din il- kumbinazzjoni għandhom ikunu ssorveljati mill- qrib.
Moreover, Clinical interaction studies with nelfinavir, a moderately potent OATP inhibitor, and pravastatin, a low affinity OATP inhibitor, did not result in clinically significant changes in sitaxentan plasma levels.
Barra minn hekk, studji ta ’ interazzjonijiet kliniċi b’ nelfinavir, inibitur moderat ta ’ l- OATP, u bi pravastatin, inibitur ta ’ l- OATP b’ affinita baxxa, ma rriżultatx fi bdil klinikament sinifikanti fil - livelli ta ’ sitaxentan sodium fil- plażma.
Fluconazole (inhibitor of CYP2C19, CYP2C9 and CYP3A4/ 5):
Fluconazole (inibitur ta ’ CYP2C19 u CYP2C9, u CYP3A4/ 5):
Co-administration of Thelin and fluconazole had no effect on the clearance of sitaxentan sodium.
Meta Thelin ingħata ma ’ fluconazole ma kien hemm l- ebda effett fuq l- eliminazzjoni ta ’ sitaxentan sodium.
Ketoconazole (substrate and inhibitor of CYP3A4/ 5):
Ketoconazole (sottostrat u inibitur ta ’ CYP3A4/ 5):
Co-administration with Thelin did not cause a clinically significant change in the clearance of either sitaxentan sodium or ketoconazole.
L- għoti ta ’ Thelin flimkien ma ’ ketoconazole ma bidilx b’ mod klinikament sinifikanti l- eliminazzjoni ta ’ sitaxentan sodium jew ta ’ ketoconazole.
Nelfinavir (substrate of CYP3A4/ 5, CYP2C19):
Nelfinavir (sottostrat ta ’ CYP3A4/ 5 u CYP2C19):
Co-administration with Thelin did not cause a clinically significant change in the clearance of either sitaxentan sodium or nelfinavir.
L- għoti ta ’ Thelin flimkien ma ’ nelfinavir ma bidilx b’ mod klinikament sinifikanti l- eliminazzjini ta ’ sitaxentan sodium jew ta ’ nelfinavir.
The clearance of nelfinavir was not clinically significantly changed in one subject that was classified as a CYP2C19 poor metaboliser.
L - eliminazzjoni ta ’ nelfinavir ma kellix bdil klinikament sinifikanti f’ suġġett wieħed partikulari li kien klassifikat bħala metabolizzatur batut ta ’ CYP2C19.
5 Effects of Thelin on other medicinal products
5 Effetti ta ’ Thelin fuq prodotti mediċinali oħrajn
Warfarin (vitamin K antagonist, substrate of CYP2C9):
Warfarin (antagonista tal- vitamina K, sottostrat ta ’ CYP2C9):
Concomitant treatment with sitaxentan sodium resulted in a 2.4 fold increase in S-warfarin exposure.
Kura konkomitanti ma sitaxentan sodium irriżultat f’ żieda ta ’ 2. 4 darbiet fl- espożizzjoni ta ’ S- Warfarin.
Subjects receiving warfarin achieve therapeutic anticoagulation (International Normalised Ratio [INR] target) with lower doses of the anticoagulant in the presence of sitaxentan sodium.
Individwi li jieħdu warfarin jilħqu livelli terapewtiċi ta ’ antikoagulazzjoni (International Normalised Ratio (INR) target) b’ dożi aktar baxxi ta ’ antikoagulant fil- preżenza ta ’ sitaxentan sodium.
It is expected that a similar increase in anticoagulant effect will be seen with warfarin analogues, including acenocoumarol, fenprocoumon and fluindione.
Huwa mistenni li żieda simili fl- effett antikoagulanti tidher meta jittieħdu analogi ta ’ warfarin, inklużi acenocoumarol, fenprocoumon u fluindione.
When initiating vitamin K antagonist therapy in a patient taking sitaxenten sodium, it is recommended to start at the lowest available dose.
Meta tinbeda terapija bl- antagonisti tal- vitamina K f’ pazjent li qed jieħu sitaxenten sodium, huwa rrakkomandat li tibda bl- aktar doża baxxa disponibbli.
In patients already taking a vitamin K antagonist, it is recommended that the dose of the vitamin K antagonist be reduced when starting sitaxentan sodium.
F’ pazjenti li diġà qed jieħdu antagonista tal- vitamina K, huwa rrakkomandat li id- doża tal- antagonista tal- vitamina K jitnaqqas meta jinbeda sitaxentan sodium.
In all cases, INR should be monitored on a regular schedule.
Fil- każijiet kollha, l- INR għandu jiġi sorveljat skond skeda regolari.
Increases in the vitamin K antagonist dose should be done in small increments to reach an appropriate target INR.
Żidiet fl - antagonista tal- vitamina K għandhom isiru b’ inkrimenti żgħar biex jilħqu l- mira adattata ta ’ l- INR.
If INR is not properly monitored and increased exposure to vitamin K antagonists remains undetected, severe or life-threatening bleeding episodes may occur.
Jekk l- INR ma jkunx segwit kif suppost u tibqa ma tkunx magħrufa li jkun hemm żieda fl- espożizzjoni għall- antagonisti tal- vitamina K, jista jkun hemm episodji ta ’ fsad sever jew saħansitra li jista jipperikola il- ħajja.
Oral contraceptives (substrate of CYP3A4/ 5):
Kontraċettivi orali (sottostrat ta ’ CYP3A4/ 5):
Concomitant administration of Thelin and Ortho- Novum 1/ 35 (1 mg norethindrone/ 0.035 mg ethinyl estradiol) resulted in increases in exposure to ethinyl estradiol (substrate of CYP3A4/ 5) and norethindrone (CYP3A4/ 5) of 59% and 47%, respectively.
Meta Thelin ingħata flimkien ma ’ Ortho- Novum 1/ 35 (1 mg norethindrone / 0. 035 mg ethinyl estradiol) irriżulta f’ żidiet fl- espożizzjoni għal ethinyl estradiol (sottostrat ta ’ CYP3A4/ 5) u għal norethindrone (CYP3A4/ 5) ta ’ 59% u 47%, rispettivament.
However, sitaxentan sodium did not affect the anti-ovulatory activity of the oral contraceptive as assessed by the plasma concentrations of follicle stimulating hormone (FSH), luteinising hormone (LH), and progesterone (see section 4.4).
Madanakollu, sitaxentan sodium ma affettwax l- attività anti- ovulatorja tal- kontraċettiv orali kif assessjat mill- konċentrazzjonijiet tal- follicle stimulating hormone (FSH), lutenising hormone (LH), u progesterone fil- plażma (ara sezzjoni 4. 4).
Sildenafil (substrate of CYP3A4):
Sildenafil (sottostrat ta ’ CYP3A4):
A single dose of sildenafil 100 mg coadministered with Thelin increased Cmax and AUC∞ of sildenafil by 18% and 28%, respectively.
Doża waħda ta ’ sildenafil 100 mg mogħtija ma ’ Thelin żiedet Cmax and AUC∞ ta ’ sildenafil bi 18% u 28% rispettivament.
There was no change in Cmax or AUC for the active metabolite, n-desmethylsildenafil.
Ma kien hemm l- ebda bidla f’ Cmax jew f’ AUC għall- metabolit attiv, n- desmethylsildenafil.
These changes in sildenafil plasma concentrations were not considered clinically significant.
Dawn il- bidliet fil- konċentrazzjonijiet ta ’ sildenafil fil - plażma ma ġewx ikkunsidrati klinikament sinifikanti.
Interaction with sildenafil may be serious if hypotension occurs beyond a safe level.
Interazzjoni ma ’ sildenafil tista ’ tkun serja jekk ikun hemm pressjoni baxxa ħafna li tkun lil hinn mill- livell sikur.
Study results suggest that the dose of sildenafil does not need to be adjusted during concomitant administration with sitaxentan sodium.
Riżultati ta ’ l- istudju jissuġġerixxu li d- doża ta ’ sildenafil m’ hemmx għalfejn tiġi aġġustata waqt l- għoti flimkien ma ’ sitaxentan sodium.
Nifedipine (substrate of CYP3A4/ 5):
Nifedipine (sottostrat ta ’ CYP3A4/ 5):
The clearance of nifedipine was not clinically significantly changed when given concomitantly with Thelin.
L- eliminazzjoni ta ’ nifedipine ma nbidlitx b’ mod klinikament sinifikanti meta ngħata flimkien ma ’ Thelin.
This was tested for low-dose nifedipine only.
Dan kien ittestjat biss għal dożi baxxi ta ’ nifedipine.
Therefore, at higher doses of nifedipine, an increase in exposure cannot be excluded.
Għalhekk, f’ dożaġġi ogħla ta ’ nifedipine, żieda fl- espożizzjoni ma tistax tiġi eskluża.
Omeprazole (substrate of CYP2C19):
Omeprazole (sottostrat ta ’ CYP2C19):
Concomitant administration of Thelin with omeprazole increased the omeprazole AUC0-24 by 30%; Cmax was unchanged.
Meta Thelin ingħata flimkien ma ’ omeprazole kien hemm żiedet fl- AUC0- 24 ta ’ omeprazole bi 30%; Cmax ma nbidilx.
The change in AUC was not considered clinically significant.
Il- bidla fl- AUC ma kenitx ikkunsidrata li hi klinikament sinifikanti.
Digoxin (substrate of p-Glycoprotein):
Digoxin (Sottostrat ta ’ p- Glycoprotein):
Concomitant administration of Thelin did not alter the pharmacokinetics of digoxin indicating no effect on the p-glycoprotein transporter
L- għoti flimkien ma ’ Thelin ma bidilx il- farmokokinetiċi ta ’ digoxin, li jindika li ma kien hemm l- ebda effett fuq it- trasportatur ta ’ p- glycoprotein.
No clinical interaction study was performed with a substrate of CYP 2C8.
Ma sar l- ebda studju dwar interazzjonijiet kliniċi ma ’ s- sottostrat ta ’ CYP 2C8.
Therefore an interaction with such a drug cannot be excluded.
Għalhekk, interazzjoni ma ’ mediċina ta ’ dan it- tip ma tistax tiġi eskluża.
Pregnancy There are no human data regarding the use of sitaxentan sodium during pregnancy.
Tqala M’ hemmx tagħrif fuq il- bnedmin dwar l- użu ta ’ sitaxentan sodium waqt it- tqala.
Sitaxentan sodium caused teratogenicity in rats (see section 5.3).
Sitaxentan sodium ikkawża teratoġeniċità fil- firien (ara taqsima 5. 3).
Potential effects in humans are unknown.
Effetti li jistgħu jseħħu fil- bniedem mhumiex magħrufa.
Thelin should not be used during pregnancy unless clearly necessary ie, in case no alternative treatment options are available.
Thelin m’ għandux jintuża waqt it- tqala ħlief jekk ikun meħtieġ b’ mod ċar, ie, f’ każ li ebda għażliet ta ’ kura alternattiva ma jkunu disponibbli.
Lactation Sitaxentan sodium was detected in the plasma of breast fed pups from female rats treated with sitaxentan sodium, indicating that sitaxentan sodium was present in the breast milk.
6 Treddigħ Sitaxentan sodium instab fil- plażma ta ’ frieħ imredda ’ minn firien nisa kkurati b’ sitaxentan sodium, li jindika li sitaxentan sodium kien preżenti fil- ħalib ta ’ l- omm.
It is unknown whether or not sitaxentan sodium is excreted into human milk.
Mhux magħruf jekk sitaxentan sodium jiġix eliminat jew le fil- ħalib ta ’ l- omm.
Women should not breastfeed while using Thelin.
In- nisa m’ għandhomx ireddgħu meta jkunu qed jieħdu Thelin.
6 Women of child-bearing potential Treatment must not be initiated in women of child-bearing potential unless they practice reliable contraception, due to possible teratogenicity.
Nisa li jista ’ jkollhom it- tfal Il- kura m’ għandhiex tinbeda f’ nisa li għandhom potenzjal li jista ’ jkollhom it- tfal, sakemm ma jkunux qed jużaw kontraċezzjoni affidabbli, minħabba l- possibbiltà ta ’ teratoġeniċità.
If necessary, pregnancy testing should be undertaken.
Jekk ikun meħtieġ, għandu jsir test tat- tqala.
A known undesirable effect is dizziness, which could influence the ability to drive or use machines.
Effett mhux mixtieq magħruf huwa l- isturdament, li jista ’ jinfluwenza l- ħila li ssuq jew tħaddem il- magni.
General description Safety of Thelin has been evaluated in clinical trials of more than 1200 patients with PAH, as well as post-marketing safety data.
Deskrizzjoni ġenerali Is- sigurta ’ ta ’ Thelin ġiet evalwata fi studji kliniċi ta ’ iktar minn 1200 pazjent bi PAH, kif ukoll b’ informazzjoni dwar is- sigurta ’ wara t- tqegħid fis- suq.
At the recommended dose during placebo-controlled trials in pulmonary arterial hypertension PAH, the most common adverse drug reactions considered to be at least possibly related to Thelin treatment were headache in 15% of patients, and peripheral oedema and nasal congestion, each in 9% of patients.
Fid- doża rakkomandata waqt provi kkontrollati bil- plaċebo għal pressjoni għolja fl- arterji pulmonari PAH, l- aktar reazzjonijiet avversi komuni li huma kkunsidrati li jistgħu ta ’ mill- inqas ikunu marbuta mal- kura b’ Thelin kienu l- uġigħ ta ’ ras fi 15% tal- pazjenti, u edema periferali u l- imnieħer misdud, kull wieħed minn dawn seħħ f’ 9% tal - pazjenti.
Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
F’ kull grupp ta ’ frekwenza, l- effetti mhux mixtieqa huma ikklassifikati skond il- gravità tagħhom.
Frequencies are reported as very common (≥ 1/ 10), common (> 1/ 100 ,< 1/10), uncommon (> 1/ 1,000, ≤ 1/ 100), rare (> 1/ 10,000, ≤ 1/ 1,000), and very rare (≤ 1/ 10,000).
Il- frekwenzi huma rrappurtati bħala komuni ħafna (≥1/ 10), komuni (> 1/ 100, < 1/ 10), mhux komuni (> 1/ 1, 000, ≤1/ 100), rari (> 1/ 10, 000, ≤1/ 1, 000), u rari ħafna (≤1/ 10, 000).
System Organ Class / Adverse reaction Blood and lymphatic system disorders
Sistema tal- klassifika tal- organi / Reazzjoni avversa Disturbi tad- demm u tas- sistema limfatika
Haemoglobin decrease (rarely resulting in anaemia), haematocrit decrease
Tnaqqis fl- emoglobina (li rarament tirriżulta f’ anemija), tnaqqis fl - ematokrita
Nervous system disorders Headache Insomnia, dizziness
Disturbi tas- sistema nervuża Uġiegħ ta ’ ras Nuqqas ta ’ rqad, sturdament
Vascular disorders Gingival bleeding, flushing
Disturbi vaskulari ħruġ ta ’ demm ġinġivali, fwawar
Respiratory, thoracic, and mediastinal disorders Nasal congestion, epistaxis
Disturbi respiratorji, toraċiċi u medjastinali Imnieħer misdud, friġ mill- imnieħer
Gastrointestinal disorders Nausea, constipation, upper abdominal pain, vomiting, dyspepsia and diarrhoea
Disturbi gastro- intestinali Dardir, stitikezza, uġigħ addominali fil- parti ta ’ fuq, rimettar, dispepsja u dijarea.
Hepatobiliary disorders Liver aminotransferases increase, bilirubin increase (associated with liver aminotransferase increase)
Żieda fl- aminotransferases tal- fwied, żieda fil- bilirubin (assoċċjata ma ’ żieda tal- aminotransferase tal- fwied)
Symptomatic hepatitis
Epatite sintomatika
7 Skin and subcutaneous tissue Rash (various types and presentations)
Disturbi fil- ġilda u fit- tessuti ta ’ taħt il- ġilda Raxx (tipi u preżentazzjonijiet varji)
Musculoskeletal and connective tissue disorders Muscle cramp
Disturbi muskolu- skeltrali u tal- connective tissue Bugħawwieġ fil- muskoli
General disorders and administration site conditions Fatigue, oedema (most commonly peripheral)
Disturbi ġenerali u kondizzjonijiet ta 'mnejn jingħata Għejja, edema (l- aktar komuni dik periferali)
Investigations INR increase (with concomitant vitamin K antagonist therapy).
Investigazzjonijiet Zieda fl- INR (b’ terapija konkomittanti ta ’ antagonisti ta ’ vitamina K).
Prothrombin time (PT) increase (with concomitant vitamin K antagonist therapy).
Prothrombin (PT) imtawwal (b’ terapija konkomittanti ta ’ antagonisti ta ’ vitamina K)
Increased Liver Aminotransferases (see section 4.4) Elevations of AST and/ or ALT are associated with sitaxentan sodium.
Żidiet ta ’ l- AST u/ jew ALT huma assoċjati ma ’ sitaxentan sodium.
In phase 2 and 3 oral studies in patients with PAH, elevations in ALT and/ or AST > 3 ULN were observed in 5% of placebo-treated patients (N = 155) and 7% of Thelin 100 mg-treated patients (N = 887).
F’ fażi 2 u 3 ta ’ studji orali f’ pazjenti bil- PAH, livelli ogħla fl- ALT u/ jew AST > 3 ULN kienu osservati f’ 5% ta ’ pazjenti ttrattati bil- plaċebo (N = 155) u f’ 7% tal- pazjenti ttrattati b ’ Thelin 100 mg.
Elevations in ALT values > 5 ULN were 4% (36/ 887) for sitaxentan 100 mg QD and 0.6% in the placebo group (1/ 155).
Żidiet fil- valuri ta ’ l- ALT ta ’ > 5 ULN kienu 4% (36/ 887) għal sitaxentan 100 mg QD u 0. 6% fil- grupp plaċebo (1/ 155).
The Sitaxentan population also included patients (N = 53) who had discontinued another endothelin receptor antagonist due to liver function abnormalities.
Il- popolazzjoni ta ’ Sitaxentan kienet tinkludi wkoll pazjenti (N = 53) li minħabba anormalitajiet fil - funzjoni tal- fwied, kienu waqqfu antagonist tar- riċetturi endothelin ieħor.
This specific group had a higher risk (19%; N = 10/ 53) of developing elevations in ALT and/ or AST > 3 x ULN indicating that appropriate care should be exercised when initiating sitaxentan in this patient population.
Dan il- grupp speċifiku kellu riskju ogħla (19%; N = 10/ 53) li jiżviluppa żidiet f’ ALT u/ jew AST > 3 x ULN, u dan jindika li trid tingħata attenzjoni meta jinbeda sitaxentan f’ din il popolazzjoni ta ’ pazjenti.
Decreased Haemoglobin (see section 4.4) The overall mean decrease in haemoglobin concentration for Thelin -treated patients was 0.5 g/ dl (change to end of treatment).
Tnaqqis fl- Emoglobina (ara taqsima 4. 4) It- tnaqqis totali medju fil- konċentrazzjoni ta ’ l- emoglobina f’ pazjenti ttrattati b’ Thelin kien ta ’ 0. 5 g/ dl (g/ dl (bidla sa tmiem il- kura).
In placebo-controlled studies, marked decreases in haemoglobin (> 15% decrease from baseline with value < lower limit of normal) were observed in 7% of patients treated with Thelin (N = 149) and 3% of placebo-treated patients (N = 155).
Fi studji kkontrollati bil- plaċebo, tnaqqis sostanzjali fl- emoglobina (tnaqqis ta ’ > 15% mill- linja bażi b’ valur < limitu t’ isfel tan- normal) kien osservat f’ 7% tal- pazjenti ttrattati b’ Thelin (N = 149) u fi 3% ta ’ pazjenti ttrattati bil- plaċebo (N = 155).
A decrease in haemoglobin concentration by at least 1 g/ dl was observed in 60% of patients treated with Thelin as compared to 32% of placebo-treated patients.
Tnaqqis fil - konċentrazzjoni ta ’ l- emoglobina b’ ta ’ mill- inqas 1 g/ dl kien osservat f’ 60% tal- pazjenti ttrattati b’ Thelin meta mqabbel ma ’ 32% ta ’ pazjenti ttrattati bil- plaċebo.
Post marketing experience Adverse events reported during the post-marketing period to date have been similar to those reported in clinical trials.
Reazzjonijiet avversi li ġew irrappurtati fil- perijodu ta ’ wara t- tqegħid tal- mediċina fis- suq kienu simili għall- dawk irrappurtati waqt l- istudji kliniċi.
There is no specific experience with the management of Thelin overdose.
M’ hemmx esperjenza speċifika dwar l- immaniġġjar ta ’ doża eċċessiva b’ Thelin.
In the event of overdose, symptomatic and supportive measures should be employed.
F’ każ ta ’ doża eċċessiva, għandhom jittieħdu miżuri sintomatiċi u ta ’ appoġġ.
During clinical trials, Thelin was given as a daily oral dose of 1000 mg/ day for 7 days to healthy volunteers.
8 Waqt provi kliniċi, Thelin kien qed jingħata bħala doża orali ta ’ 1000 mg/ kuljum għal 7 ijiem lil voluntieri b’ saħħithom.
The most common adverse effects at this dose were headache, nausea, and vomiting.
L- aktar effetti avversi komuni b’ din id- doża kienu l- uġigħ ta ’ ras, id- dardir u r- rimettar.
In an open-label hypertension study, 10 patients received 480 mg twice daily (approximately a 10-fold increase in daily dose compared to the MRHD) for up to 2 weeks.
Fi studju open- label dwar il- pressjoni għolja, 10 pazjenti ngħataw 480 mg darbtejn kuljum (żieda ta ’ madwar 10 darbiet fid- doża ta ’ kuljum meta mqabbla mal- MRHD) għal mhux aktar minn ġimgħatejn.
Headaches (some severe), peripheral oedema, and anaemias were the most common adverse events reported in these patients, none of which were considered serious.
L- uġigħ ta ’ ras (kultant qawwi), edema periferali, u anemiji kienu l- aktar effetti avversi komuni rrappurtati minn dawn il- pazjenti, iżda l- ebda wieħed minnhom ma kien ikkunsidrat bħala serju.
8 In an open-label PAH study, one fatal case of hepatic failure has been reported after chronic dosing of sitaxentan at 600 mg/ day administered as 300 mg bid.
Fi studju open- label dwar PAH, kien hemm każ waħdieni ta ’ falliment tal- fwied fatali, li kien irrappurtat wara dużaġġ kroniku ta ’ sitaxentan 600mg/ kuljum, mogħti f’ żewġ dożi ta ’ 300mg darbtejn kuljum.
Other antihypertensives, ATC code:
Prodotti oħrajn għal pressjoni għolja, Kodiċi ATC:
Mechanism of action Endothelin-1 (ET-1) is a potent vascular paracrine and autocrine peptide in the lung, and can also promote fibrosis, cell proliferation, cardiac hypertrophy, and remodelling and is pro-inflammatory.
Mekkaniżmu ta ’ kif jaħdem Endothelin- 1 (ET- 1) huwa paracrine vaskulari u autocrine peptide qawwi fil- pulmun, u jista ’ jikkaġuna l- fibrożi, il- proliferazzjoni taċ- ċelluli, tkabbir fid- daqs u tibdil fil- forma u fil- funzjoni tal - qalb u jiffavorixxi l- infjammazzjoni.
ET-1 concentrations are elevated in plasma and lung tissue of patients with pulmonary arterial hypertension, as well as other cardiovascular disorders and connective tissue diseases, including scleroderma, acute and chronic heart failure, myocardial ischaemia, systemic hypertension, and atherosclerosis, suggesting a pathogenic role of ET-1 in these diseases.
Il- konċentrazzjonijiet ta ’ ET- 1 huma għoljin fil- plażma u fit - tessut tal- pulmun ta ’ pazjenti bi pressjoni għolja fl- arterji pulmonari, kif ukoll f’ każijiet ta ’ mard kardjovaskulari u mard tat- tessut konnettiv, inkluża l- iskleroderma, insuffiċjenza tal- qalb akuta u kronika, iskemija mijokardijaka, pressjoni għolja sistemika, u aterosklerożi; dan jissuġġerixxi rwol patoġeniku ta ’ ET- 1 f’ dan il- mard.
In pulmonary arterial hypertension and heart failure, in the absence of endothelin receptor antagonism, elevated ET-1 concentrations are strongly correlated with the severity and prognosis of these diseases.
Fil- pressjoni għolja fl- arterji pulmonari u fl- insuffiċjenza tal- qalb, fin- nuqqas ta ’ antagoniżmu tar- riċettur ta’ endothelin, konċentrazzjonijiet għoljin ta ’ ET- 1 jikkorrispondu b’ mod qawwi mal- gravità u mal- pronjosi ta ’ dan il- mard.
Additionally, pulmonary arterial hypertension also is characterized by reduced nitric oxide activity.
Barra minn hekk, pressjoni għolja fl- arterji pulmonari hi ukoll ikkaratterizzata minn tnaqqis fl- attività tan- nitric oxide.
ET-1 actions are mediated through endothelin A receptors (ETA), present on smooth muscle cells, and endothelin B receptors (ETB), present on endothelial cells.
L- effetti ta ’ ET- 1 isiru permezz ta ’ riċetturi ta ’ endothelin A (ETA), li jinsabu fuq iċ- ċelluli tal - muskoli lixxi, u riċetturi ta ’ endothelin B (ETB) li jinsabu fuq iċ- ċelluli endoteljali.
Predominant actions of ET-1 binding to ETA are vasoconstriction and vascular remodelling, while binding to ETB results in ET-1 clearance, and vasodilatory/ antiproliferative effects due in part to nitric oxide and prostacyclin release.
L- effetti predominanti tat- twaħħil ta ’ ET- 1 ma ’ ETA huma, vasorestrizzjoni u mmudellar vaskulari mill- ġdid, filwaqt li t- twaħħil ma ’ ETB jirriżulta fl- eliminazzjoni ta ’ ET- 1, u f’ effetti vasodilatorji/ antiproliferattivi li parti minnhom huma effetti tal- liberazzjoni ta ’ nitric oxide u prostacyclin.
Thelin is a potent (Ki 0.35 nM) and highly selective ETA antagonist (approximately 6,500-fold more selective for ETA as compared to ETB).
Thelin huwa antagonist qawwi ta ’ l- ETA (Ki 0. 35 nM) u selettiv ħafna (bejn wieħed u ieħor 6, 500 aktar selettiv għall- ETA meta mqabbel ma ’ ETB).
Efficacy Two randomized, double-blind, multi-centre, placebo-controlled trials were conducted to demonstrate efficacy.
Effikaċja Żewġ provi randomized, double- blind, multi- centre, ikkontrollati bil- plaċebo twettqu biex juru l - effikaċja.
STRIDE-1, which included 178 patients, compared 2 oral doses of Thelin (100 mg once daily and 300 mg once daily) with placebo during 12 weeks of treatment.
STRIDE- 1, li kien jinkludi 178 pazjent, qabbel 2 dożi orali ta ’ Thelin (100 mg darba kuljum u 300 mg darba kuljum) mal- plaċebo waqt 12- il ġimgħa ta ’ kura.
The 18 week STRIDE-2 trial, conducted in 246 patients, included 4 treatment arms: placebo once daily, Thelin 50 mg once daily, Thelin 100 mg once daily, and open-label bosentan twice daily (efficacy-rater blinded, administered according to the approved package insert).
Il- prova STRIDE- 2 li damet 18- il ġimgħa, saret fuq 246 pazjent, inkludiet 4 oqsma ta ’ kura: plaċebo darba kuljum, Thelin 50 mg darba kuljum, Thelin 100 mg darba kuljum, u open- label bosentan darbtejn kuljum (efficacy- rater blinded, mogħti skond il- fuljett ta ’ tagħrif approvat).
Patients had moderate to severe (NYHA/ WHO functional class II-IV) pulmonary arterial hypertension resulting from idiopathic pulmonary arterial hypertension (IPAH, also known as primary pulmonary hypertension), connective tissue disease (CTD), or congenital heart disease (CHD).
Il- pazjenti kellhom pressjoni għolja fl- arterji pulmonari li kienet minn moderata sa severa (klassi funzjonali II- IV NYHA/ WHO) li tirriżulta minn pressjoni għolja idjopatika fl- arterji tal- pulmun (IPAH, magħrufa ukoll bħala pressjoni pulmonari għolja primarja), mard tat- tessut konnettiv (CTD), jew mard tal- qalb konġenitali (CHD).
In these studies, the study medicine was added to patients’ current therapy, which could have included a combination of digoxin, anticoagulants, diuretics, oxygen, and vasodilators (eg, calcium channel blockers, ACE inhibitors).
F’ dawn l- istudji, il- mediċina li kienet qed tiġi studjata żdiedet mal- kura attwali tal- pazjenti, li setgħet kienet tinkludi kumbinazzjoni ta ’ digoxin, antikoagulanti, dijuretiċi, ossiġnu u vasodilaturi (eż.
Patients with pre-existent hepatic disease and patients using non- conventional PAH treatments (eg, iloprost) were excluded.
Pazjenti li kienu diġà jbatu b’ mard tal- fwied u pazjenti li kienu qegħdin jużaw xi PAH mhux konvenzjonali (eż. iloprost) ġew esklużi.
Sub-maximal exercise capacity was assessed by measuring distance walked in 6 minutes (6-minute walk test) at 12 weeks for STRIDE-1 and 18 weeks for STRIDE-2.
Il- kapaċità għall- eżerċizzju taħt il- massimu kienet assessjata billi tkejlet id- distanza li l- pazjent mexa f’ 6 minuti (test ta ’ mixja ta ’ 6 minuti) wara 12- il ġimgħa għal STRIDE- 1 u wara 18- il ġimgħa għal STRIDE- 2.
In both trials, treatment with Thelin resulted in a significant increase in exercise capacity.
Fiż- żewġ provi, il- kura b’ Thelin irriżultat f’ żieda sinifikanti fil- kapaċità għall- eżerċizzju.
The placebo-corrected increases in walk distance compared to baseline were 35 metres (p = 0.006; ANCOVA) and 31 metres (p < 0.05; ANCOVA), respectively.
Iż- żidiet fid- distanza li l- pazjent mexa (ikkoreġuta għall- plaċebo) meta mqabbla mal- linja bażi kienet ta ’ 35 metru (p=0. 006, ANCOVA) u 31 metru (p < 0. 05, ANCOVA), rispettivament.
Among patients with CTD, a statistically significant difference versus placebo was observed (37.73 metres, p < 0.05).
Fost il- pazjenti b’ CTD, kienet osservata differenza statistikament sinifikanti meta mqabbla mal - plaċebo (37. 73 metri, p < 0. 05).
A reduction in symptoms of pulmonary arterial hypertension was observed with Thelin treatment.
Tnaqqis fis- sintomi ta ’ pressjoni għolja fl- arterji pulmonari kienet osservata bil- kura b’ Thelin.
9 II (mean baseline 6 minute walk distance 451 meters) and 117 (66%) as functional class III (mean baseline 6 minute walk distance 372 meters).
Fil - prova STRIDE- 1, 59 (33%) mill- 178 pazjent kienu kklassifikati li qegħdin fil- linja bażi bħala klassi funzjonali II NYHA (medja tal- linja bażi ta ’ mixja ta ’ 6 minuti għal distanza ta ’ 451 metru) u 117 (66%) bħala klassi funzjonali III (medja tal- linja bażi ta ’ mixja ta ’ 6 minuti għal distanza ta ’ 372 metru).
Treatment with Thelin led to net improvement in NYHA functional class in 25% of patients (placebo 8%, p < 0.05).
Il- kura b’ Thelin wasslet għal titjib nett fil- klassi funzjonali NYHA f’ 25% tal- pazjenti (plaċebo 8%, p < 0. 05).
In the STRIDE-2 trial 93 (38%) of the 246 patients were classified at baseline as NYHA functional class II (mean baseline 6 minute walk distance 370 meters) and 144 (59%) as functional class III (mean baseline 6 minute walk distance 322 meters).
Fil- prova STRIDE- 2, 93 (38%) tal- 246 pazjent kienu kklassifikati li qegħdin fil- linja bażi bħala klassi funzjonali II NYHA (medja tal- linja bażi ta ’ mixja ta ’ 6 minuti għal distanza ta ’ 370 metru) u 144 (59%) bħala klassi funzjonali III (medja tal- linja bażi ta ’ mixja ta ’ 6 minuti għal distanza ta ’ 322 metru).
Treatment with Thelin led to net improvement in WHO functional class in 12% of patients (placebo -3%, p < 0.05).
Il- kura b’ Thelin wasslet għal titjib nett fil- klassi funzjonali WHO fi 12% tal- pazjenti (plaċebo - 3%, p < 0. 05).
Haemodynamic parameters were assessed in STRIDE-1.
Parametri emodinamiċi kienu assessjati fi STRIDE- 1.
Compared with placebo treatment, Thelin resulted in improvement (p < 0.05) in cardiac index of +0.3 L/ min/ m2 (13%), in pulmonary vascular resistance of-221 dynes*sec/ cm5 (22%), and in systemic vascular resistance of -276 dynes*sec/ cm5 (16%) after 12 weeks of treatment.
Meta mqabbel mal- kura bil- plaċebo, Thelin irriżulta f’ titjib (p < 0. 05) fl- indiċi tal- qalb ta ’ +0. 3 L/ min/ m2 (13%), f’ reżistenza vaskulari pulmonari ta ’ - 221 dynes* sek/ ċm5 (22%), u f’ reżistenza vaskulari sistematika ta ’ - 276 dynes* sek/ ċm5 (16%) wara 12- il ġimgħa ta ’ kura.
The reduction in mean pulmonary artery pressure of 3 mmHg (6%) was not statistically significant.
It- tnaqqis ta ’ 3mmHg (6%) fil- medja tal- pressjoni arterjali pulmonari ma kenitx statistikament sinifikanti.
The effect of Thelin on the outcome of the disease is unknown.
L- effett ta ’ Thelin fuq ir- riżultat aħħari tal- marda mhuwiex magħruf.
However, patients completing STRIDE-2 were eligible to enrol in STRIDE-2X, a 1-year open-label study of Thelin 100 mg.
Informazzjoni fuq perijodu twil ta ’ żmien M’ hemm l- ebda studju li juri li l- kura b’ sitaxentan sodium għandha effetti ta ’ benefiċċju għas - sopravivenza Madankollu, pazjenti li temmew STRIDE- 2 kienu eliġibbli biex jirreġistraw fi STRIDE - 2X, studju open- label ta ’ sena b’ 100 mg ta ’ Thelin.
A total of 145 patients were treated with Thelin 100 mg.
Total ta ’ 145 pazjent ġew ikkurati b’ 100 mg ta ’ Thelin.
In this total population, Kaplan-Meier estimates of survival were 96% for patients after 1 year of therapy with sitaxentan sodium.
F’ din il- popolazzjoni totali, stimi ta ’ sopravivenza Kaplan- Meier kienu ta ’ 96% għall- pazjenti wara terapija ta ’ sena b’ sitaxentan sodium.
One-year survival estimates were similar in the subgroup of patients with PAH secondary to connective tissue disease for the Thelin treated group (98%).
Stimi ta ’ sopravivenza fuq sena waħda kienu simili fis - sottogrupp ta ’ pazjenti b’ PAH ikkawżata minħabba mard tat- tessut konnettiv għall- grupp ikkurat b’ Thelin (98%).
The estimates may have been influenced by the initiation of new or additional PAH therapies, which occurred in 24% of patients.
L- istimi setgħu ġew influwenzati mill- introduzzjoni ġdida jew addizzjonali ta ’ terapiji għal PAH, li seħħew f’ 24% tal- pazjenti.
Absorption Sitaxentan sodium is rapidly absorbed following oral administration.
Assorbiment Sitaxentan sodium huwa assorbit malajr wara li jittieħed mill- ħalq.
In PAH patients, peak plasma concentrations are generally achieved within 1-4 hours.
F’ pazjenti bil- PAH, konċentrazzjonijiet massimi fil- plażma jintlaħqu fi żmien 1- 4 sigħat.
The absolute bioavailability of Thelin is between 70 and 100%.
Il- biodisponibilità assoluta ta ’ Thelin hi ta ’ bejn 70% u 100%.
When administered with a high fat meal, the rate of absorption (Cmax) of Thelin was decreased by 43% and the Tmax delayed (2-fold increase) compared to fasted conditions, but the extent of absorption was the same.
Meta ngħata ma ’ ikel b’ ħafna grass, ir- rata ta ’ l- assorbiment (Cmax) tnaqqset b’ 43% u t- Tmax ittardjat (żieda ta ’ darbtejn iżjed), meta mqabbla ma ’ kundizzjonijiet fl- istat sajjem, iżda l- ammont ta ’ assorbiment kien l- istess.
Distribution Sitaxentan sodium is more than 99% protein bound to plasma proteins, predominantly albumin.
Distribuzzjoni Sitaxentan sodium huwa aktar minn 99% mwaħħal mal- proteini tal- plażma, l- biċċa l- kbira albumina.
The degree of binding is independent of concentration in the clinically relevant range.
Il- grad ta ’ twaħħil huwa independenti mill- konċentrazzjoni fil- medda klinikament rilevanti.
Sitaxentan sodium does not penetrate into erythrocytes and does not appear to cross the blood-brain barrier.
Sitaxentan sodium ma jippenetrax fiċ- ċelluli tad- demm il- ħomor u ma jidhirx li jaqsam il- blood brain barrier.
Metabolism and Elimination Following oral administration to healthy volunteers, sitaxentan sodium is highly metabolised.
10 Metaboliżmu u Eliminazzjoni Wara l- għoti mill- ħalq lil voluntiera b’ saħħithom, sitaxentan sodium huwa mmetabolizzat b’ mod qawwi.
The most common metabolic products are at least 10 times less potent as ETA antagonists than sitaxentan sodium in a standard in vitro test of activity.
L- aktar prodotti metaboliċi komuni huma mill- inqas 10 darbiet inqas qawwija minn sitaxentan sodium bħala antagonisti ta ’ ET A f’ test ta ’ attività in vitro standard.
In vitro, sitaxentan sodium is metabolized by CYP2C9 and CYP3A4/ 5.
In vitro, sitaxentan sodium huwa metabolizzat minn CYP2C9 u CYP3A4.
In vitro studies using human liver microsomes or primary hepatocytes show that sitaxentan sodium inhibits CYP2C9, and, to a lesser extent, CYP 2C8, CYP2C19 and CYP3A4/ 5.
Studji in vitro bl- użu ta ’ mikrosomi tal- fwied tal- bniedem jew epatoċiti primarji juru li sitaxentan sodium jimpedixxi CYP2C9, u, bi ftit inqas, lil CYP 2C8, CYP2C19 u CYP3A4/ 5.
Approximately 50-60% of an oral dose is excreted in the urine with the remainder eliminated in the faeces.
Madwar 50- 60% tad- doża orali hi eliminata fl- awrina bil- bqija tiġi eliminata ma ’ l- ippurgar.
Less than 1% of the dose is excreted as unchanged active ingredient.
Inqas minn 1% tad- doża hi eliminata bħala ingredjent attiv mhux mibdul.
The terminal elimination half-life (t½) is 10 hours.
Il- half- life ta ’ l- eliminazzjoni terminali (t½) hi ta ’ 10 sigħat.
Steady state in volunteers is reached within about 6 days.
L- istat fiss fil- voluntieri jintlaħaq bejn wieħed u ieħor fi żmien 6 ijiem.
No unexpected accumulation in the plasma was observed after multiple dosing at the recommended dose of 100 mg once daily.
L- ebda akkummulazzjoni mhux mistennija fil- plażma ma ġiet osservata wara dożaġġ ripetut bid- doża rrakkomandata ta ’ 100 mg kuljum.
However, at doses of 300 mg or higher, non-linear pharmacokinetics result in disproportionately higher plasma concentrations of sitaxentan sodium.
Madankollu, f’ dożi ta ’ 300 mg jew ogħla, farmakokinetiċi mhux lineari rriżultaw f’ konċentrazzjonijiet sproporzjonalment ogħla ta ’ sitaxentan sodium fil- plażma.
10 Special Populations Based on results of the population pharmacokinetic analysis and pooled pharmacokinetic data over several studies, it was found that gender, race, and age do not clinically significantly affect the pharmacokinetics of sitaxentan sodium.
Popolazzjonijiet Speċjali Ibbażat fuq riżultati ta ’ analiżi farmakokinetika tal- popolazzjoni u informazzjoni farmakokinetika miġbura minn bosta studji, instab li s- sess, ir- razza, u l- età ma jaffettwawx, b’ mod klinikament sinifikanti, il- farmakokinetiċi ta ’ sitaxentan sodium.
Liver Function Impairment The influence of liver impairment on the pharmacokinetics of sitaxentan sodium has not been evaluated.
L- influwenza ta ’ indeboliment tal- fwied fuq il- farmakokinetiċi ta ’ sitaxentan sodium ma ġietx evalwata.
Refer to section 4.3.
Irreferi għal taqsima 4. 3.
In repeated-dose toxicity studies, dose-related liver changes (weight, centrilobular hypertrophy, occasionally necrosis), induction of hepatic drug metabolising enzymes and slightly decreased erythron parameters were seen in mice, rats and dogs.
Fi studji dwar it- tossiċità b’ doża ripetuta, bidliet fil- fwied marbuta mad- doża (piż, ipertrofija ċentrilobulari, kultant nekrosi), induzzjoni ta ’ enzimi tal- fwied li jimmetabolizzaw il- mediċini u parametri erythron ftit imnaqqsa ntwerew fil- ġrieden, firien u klieb.
At high doses, dose-related increases in prothrombin time (PT) and activated partial thromboplastin time (APTT) were also seen, most prominently in rats, and coagulopathy (bleedings) in rats and dogs, but not mice.
F’ dożi għoljin, żidiet marbuta mad- doża fil- prothrombin time (PT) u fl- activated partial thromboplastin time (APTT), intwerew ukoll, bl- iktar mod prominenti fil- firien, u koagulopatija (ħruġ ta ’ demm) fil- firien u fil- klieb, imma mhux fil- ġrieden.
The significance of these findings for humans is unknown.
Is- sinifikat ta ’ dawn ir- riżultati għall- bniedem mhuwiex magħruf.
Testicular tubular atrophy was observed in rats, but not in mice or dogs.
Atropija tubulari testikulari kienet osservata fil- firien, imma mhux fil- ġrieden jew fil- klieb.
In the 26-week study, moderate to marked diffuse seminiferous tubular atrophy was present at a very low incidence, whereas in the 99-week study there was a dose-related, slightly increased incidence of minimal to mild focal atrophy at doses providing 29 to 94 times the human exposure.
Fl- istudju ta ’ 26 ġimgħa, atropija tubulari seminiferuża mifruxa minn moderata sa severa kienet preżenti f’ inċidenza baxxa ħafna, filwaqt li fl- istudju ta ’ 99 ġimgħa kien hemm inċidenza kemmxejn ogħla ta ’ atropija fokali minn minima sa ħafifa f’ dożi li jipprovdu minn 29 sa 94 darba aktar mill- espożizzjoni fil- bniedem.
Reproduction toxicity has been evaluated in rats only.
It- tossiċità riproduttiva kienet evalwata fil- firien biss.
Thelin did not affect fertility in males and females.
Thelin ma affettwax il- fertilità fl- irġiel u fin- nisa.
Thelin was teratogenic at the lowest tested dose in rats, corresponding to exposures more than 30 times the human exposure.
Thelin kien teratoġeniku fl- inqas doża ttestjata fil- firien, li tikkorrispondi għal espożizzjonijiet ta ’ aktar minn 30 darba dawk fil- bniedem.
Dose-dependent malformations of the head, mouth, face and large blood vessels occurred.
Kien hemm malformazzjonijiet tar- ras, tal- ħalq, tal- wiċċ u ta ’ l- arterji u l- vini l- kbar, li kienu dipendenti fuq id- doża.
A NOAEL has not been established.
NOAEL ma ġiex stabbilit.
Administration of Thelin to female rats from late-pregnancy through lactation reduced pup survival, and caused testis tubular aplasia and delayed vaginal opening at the lowest exposure tested (17-45 times the human exposure).
L- għoti ta ’ Thelin lil firien nisa bejn l- aħħar żmien tat- tqala saż- żmien tat- treddigħ, naqqas is- sopravivenza tal- frieħ, u kkawża aplasija tubulari tat- testikoli u l- ittardjar tal- ftuħ tal- bokka tal- vaġina fl- inqas espożizzjoni ttestjata (17 – 45 darba l- espożizzjoni fil- bniedem).
Large / abnormally shaped livers, a delay in auditory function development, a delay in preputial separation and a reduction in the number of embryonic implants occurred at higher maternal doses.
Fwied kbir / ta ’ għamla anormali, dewmien fl - iżvilupp tal- funzjoni tas- smigħ, dewmien fis- separazzjoni tal- prepuzju u tnaqqis fin- numru ta ’ impjantazzjonijiet embrijoniċi seħħew f’ dożi materni ogħla.
In vitro and in vivo tests on genetic toxicology did not provide any evidence for a clinically relevant genotoxic potential.
Testijiet in vitro u in vivo fuq it- tossikoloġija ġenetika ma pprovdew ebda evidenza għal potenzjal ġenotossiku klinikament rilevanti.
Thelin was not carcinogenic when administered to rats for 97-99 weeks or when administered to p53(+/ -) transgenic mice for 6 months.
Thelin ma kienx karċinoġeniku meta ngħata lil firien għal 97- 99 ġimgħa jew meta ngħata lil ġrieden transġeniċi p53( + / -) għal 6 xhur.
PHARMACEUTICAL PARTICULARS
11 6 TAGĦRIF FARMAĊEWTIKU
Cellulose, microcrystalline (E460) Lactose monohydrate Hypromellose (E464) Sodium starch glycolate Magnesium stearate (E470b) Disodium phosphate, anhydrous (E339) Ascorbyl palmitate (E304) Disodium edetate Monobasic sodium phosphate (E339)
Cellulose, microcrystalline (E460) Lactose monohydrate Hypromellose (E464) Sodium starch glycolate Magnesium stearate (E470b) Disodium phosphate, anhydrous (E339) Ascorbyl palmitate (E304) Disodium edetate Monobasic sodium phosphate (E339)
11 Film coat:
Il- kisi tar- rita:
Stearic acid (E570b) Hypromellose (E464) Cellulose, microcrystalline (E460) Titanium dioxide (E171) Yellow iron oxide dehydrate (E172) Red iron oxide dehydrate (E172) Talc (E553b)
Stearic acid (E570b) Hypromellose (E464) Cellulose, microcrystalline (E460) Titanium dioxide (E171) Yellow iron oxide dihydrate (E172) Red iron oxide dihydrate (E172) Talc (E553b)
24 months
24- il xahar
Store below 25°C.
Aħżen f’ temperatura taħt il- 25°C.
PVC/ ACLAR/ paper-backed aluminium blisters containing 14 tablets.
PVC/ ACLAR/ folji ta ’ l- aluminju b’ dahar tal- karta li fihom 14- il pillola.
Cartons contain 14, 28, 56, or 84 tablets.
Il- pakketti fihom 14, 28, 56, jew 84 pillola.
High-density polyethylene (HDPE) bottles containing 28 tablets.
Fliexken tal- polyethylene ta ’ densità għolja (HDPE) li fihom 28 pillola.
6.6 Special precautions for disposal
6. 6 Prekawzjonijiet speċjali għar- rimi
10 August 2006
10 t’ Awwissu, 2006
Encysive (UK) Limited Regus House Highbridge Industrial Estate Oxford Road Uxbridge UB8 1HR United Kingdom
Encysive (UK) Limited Regus House Highbridge Industrial Estate Oxford Road Uxbridge UB8 1HR Ir- Renju Unit
Patheon UK Limited Kingfisher Drive Covingham Swindon, Wilts SN3 5BZ United Kingdom
Patheon UK Limited Kingfisher Drive Covingham Swindon, Wilts SN3 5BZ Ir- Renju Unit
Polar Speed Distribution Ltd Unit 8 Chartmoor Road Leighton Buzzard Bedfordshire LU7 4WG United Kingdom
Polar Speed Distribution Ltd Unit 8 Chartmoor Road Leighton Buzzard Bedfordshire LU7 4WG Ir- Renju Unit