qanastek/EMEA-V3 huggingface dataset:
There is limited clinical trial experience with the use of Tracleer in patients with PAH associated with HIV infection, treated with antiretroviral medicinal products (see section 5.1).
Hemm esperjenza limitata mill- provi kliniċi bl- użu ta ’ Tracler f' pazjenti b’ PAH marbuta ma ’ infezzjoni bl- HIV, ikkurati bi prodotti mediċinali antiretrovirali (ara sezzjoni 5. 1).
No specific interaction studies between bosentan and antiretroviral medicinal products have been performed.
Ma saru l- ebda studji speċifiċi dwar l- interazzjoni bejn bosentan u prodotti mediċinali antiretrovirali.
Due to the potential for such interactions especially related to the inducing effect of bosentan on CYP450 (see section 4.5), which could affect the efficacy of antiretroviral therapy, these patients should be monitored carefully regarding control of their HIV infection.
Minħabba l - potenzjal ta ’ interazzjonijiet bħal dawn li huma marbuta b’ mod speċjali ma ’ l- effett inducing ta ’ bosentan fuq CYP450 (ara sezzjoni 4. 5), li jista ’ jaffettwa l- effikaċja tat- terapija antiretrovirali, dawn il- pazjenti għandhom jiġu mmonitorjati bl- attenzjoni dwar il- kontroll ta ’ l- infezzjoni tagħhom bl- HIV.
An increased risk of hepatic toxicity and haematological adverse events cannot be excluded when bosentan is used in combination with antiretroviral medicinal products.
Riskju miżjud ta ’ tossiċità epatika u ta ’ avvenimenti avversi ematoloġiċi ma jistgħux jiġu esklużi meta bosentan jintuża flimkien ma ’ prodotti mediċinali antiretrovirali.
Concomitant use with other medicinal products
L- użu flimkien ma ’ prodotti mediċinali oħra
Tracleer should not be used concomitantly with glibenclamide, due to an increased risk of elevated liver aminotransferases (see section 4.5).
Dawk il- pazjenti li
An alternative antidiabetic medicinal product should be used in patients in whom an antidiabetic treatment is indicated.
6 għandhom bżonn ta ’ mediċina antidijabetika għandhom jużaw prodott mediċinali alternattiv kontra d - dijabete.
Fluconazole: concomitant use of Tracleer with fluconazole is not recommended (see section 4.5).
Fluconazole: l- użu ta ’ Tracleer flimkien ma ’ fluconazole mhux rakkomandat (ara sezzjoni 4. 5).
Although not studied, this combination may lead to large increases in plasma concentrations of bosentan.
Għalkemm ma sarx studju dwar dan, din il- kumbinazzjoni tista ’ tirriżulta f’ żidiet kbar fil - konċentrazzjonijiet ta ’ bosentan fil- plażma.
Rifampicin: co-administration of Tracleer with rifampicin is not recommended (see section 4.5).
Rifampicin: l- għoti ta ’ Tracleer flimkien ma ’ rifampicin mhuwiex rakkomandat (ara sezzjoni 4. 5).
Concomitant administration of both a CYP3A4 inhibitor and a CYP2C9 inhibitor should be avoided (see section 4.5).
L- għoti flimkien kemm ta ’ impeditur ta ’ CYP3A4 u impeditur ta ’ CYP2C9 għandu jiġi evitat (ara sezzjoni 4. 5).
Bosentan is an inducer of the cytochrome P450 (CYP) isoenzymes CYP2C9 and CYP3A4.
Bosentan hu inducer taċ- ċitokromju P450 (CYP) isoenzimi CYP2C9 u CYP3A4.
In vitro data also suggest an induction of CYP2C19.
L- informazzjoni minn studji in vitro tindika li bosentan jinduċi wkoll CYP2C19.
Consequently, plasma concentrations of substances metabolised by these isoenzymes will be decreased when Tracleer is co-administered.
Bħala konsegwenza, il - konċentrazzjonijiet fil- plażma ta ’ sustanzi li jiġu metabolati minn dawn l- isoenzimi tonqos meta Tracleer jingħata magħhom.
The possibility 6 of altered efficacy of medicinal products metabolised by these isoenzymes should be considered.
Għandha tkun ikkunsidrata l- possibbiltà li l- effikaċja ta ’ prodotti mediċinali metabolati minn dawn l- isoenzimi tinbidel.
The dosage of these products may need to be adjusted after initiation, dose change or discontinuation of concomitant Tracleer treatment.
Jista ’ jkun li d- dożaġġ ta ’ dawn il- prodotti mediċinali jkollu bżonn li jiġi aġġustat wara l- bidu tal- kura, tibdil fid- doża, jew f’ każ li l- kura flimkien ma ’ Tracleer titwaqqaf.
Bosentan is metabolised by CYP2C9 and CYP3A4.
Bosentan huwa metabolat minn CYP2C9 u CYP3A4.
Inhibition of these isoenzymes may increase the plasma concentration of bosentan (see ketoconazole).
Inibizzjoni ta ’ dawn l- isoenzimi tista ’ żżid il - konċentrazzjoni ta ’ bosentan fil- plażma (ara ketoconazole).
The influence of CYP2C9 inhibitors on bosentan concentration has not been studied.
L- influwenza ta ’ l- impedituri CYP2C9 fuq il- konċentrazzjoni ta ’ bosentan ma kinitx studjata.
The combination should be used with caution.
Din il- kumbinazzjoni għandha tintuża bl- attenzjoni.
Concomitant administration with fluconazole, which inhibits mainly CYP2C9, but to some extent also CYP3A4, could lead to large increases in plasma concentrations of bosentan.
L- għoti flimkien ma ’ fluconazole, li prinċipalment jimpedixxi CYP2C9, iżda anki xi ftit lil CYP3A4, jista ’ jwassal għal żidiet kbar fil- konċentrazzjoni ta ’ bosentan fil- plażma.
The combination is not recommended (see section 4.4).
Din il- kumbinazzjoni mhix rakkomandata (ara sezzjoni 4. 4).
For the same reason, concomitant administration of both a potent CYP3A4 inhibitor (such as ketoconazole, itraconazole and ritonavir) and a CYP2C9 inhibitor (such as voriconazole) with Tracleer is not recommended (see section 4.4).
Għall- istess raġuni, l- għoti flimkien kemm ta ’ impeditur qawwi ta ’ CYP3A4 (bħal ketoconazole, itraconazole u ritonavir) u ta ’ impeditur ta ’ CYP2C9 (bħal voriconazole) flimkien ma ’ Tracleer mhuwiex rakkomandat (ara sezzjoni 4. 4).
Specific interaction studies have demonstrated the following:
Studji speċifiċi dwar l- interazzjoni wrew dan li ġej:
Co-administration of Tracleer 125 mg twice daily for 7 days with a single dose of oral contraceptive containing norethisterone 1 mg + ethinyl estradiol 35 mcg decreased the AUC of norethisterone and ethinyl estradiol by 14% and 31%, respectively.
L- għoti flimkien ta ’ Tracleer 125 mg darbtejn kuljum għal 7 ijiem ma ’ doża waħda ta ’ kontraċettiv orali li fih norethisterone 1 mg + ethinyl estradiol 35 mcg naqqas l- AUC ta ’ norethisterone u ethinyl estradiol b’ 14% u 31%, rispettivament.
However, decreases in exposure were as much as 56% and 66%, respectively, in individual subjects.
Madankollu, tnaqqis fl- espożizzjoni kien sa 56% u 66%, rispettivament, f’ pazjenti individwali.
Therefore, hormone- based contraceptives alone, regardless of the route of administration (i. e. oral, injectable, transdermal, and implantable forms), are not considered as reliable methods of contraception (see sections 4.4, 4.6).
Cyclosporine A:
Cyclosporine A: co-administration of Tracleer and cyclosporine A (a calcineurin inhibitor) is contraindicated (see section 4.3).
L- għoti flimkien ta ’ Tracleer u cyclosporine A (impeditur calcineurin) hu kontra - indikat (ara sezzjoni 4. 3).
Indeed, when co-administered, initial trough concentrations of bosentan were approximately 30-fold higher than those measured after bosentan alone.
Fil- fatt, meta dawn iż- żewg mediċini jintużaw flimkien, l- inqas konċentrazzjonijiet inizjali (initial trough concentrations) ta ’ bosentan kienu madwar 30 darba ogħla minn dawk imkejla wara li bosentan intuża waħdu.
At steady state, bosentan plasma concentrations were 3- to 4-fold higher than with bosentan alone.
Fl- istat fiss, il- konċentrazzjonijiet ta ’ bosentan fil - plażma kienu minn 3 sa 4 darbiet aktar milli b’ bosentan waħdu.
The blood concentrations of cyclosporine A (a CYP3A4 substrate) decreased by approximately 50%.
Il- konċentrazzjonijiet ta ’ cyclosporine A (sottostrat ta ‘ CYP3A4) fid- demm naqset b’ madwar 50%.
Tacrolimus, sirolimus: co-administration of tacrolimus or sirolimus and Tracleer has not been studied in man but co-administration of tacrolimus or sirolimus and Tracleer may result in increased plasma concentrations of bosentan in analogy to co-administration with cyclosporine A.
Tacrolimus, sirolimus: l- għoti flimkien ta ’ tacrolimus jew sirolimus u Tracleer ma kienx studjat fil - bniedem, imma l- għoti flimkien ta ’ tacrolimus jew sirolimus u Tracleer jista ’ jirriżulta f’ konċentrazzjonijiet miżjuda ta ’ bosentan fil- plażma, bħal fil- każ ta ’ l- għoti flimkien ma ’ cyclosporine A.
Concomitant Tracleer may reduce the plasma concentrations of tacrolimus and sirolimus.
It- teħid flimkien ma ’ Tracleer jista ’ jnaqqas il- konċentrazzjonijiet tal- plażma ta ’ tacrolimus u sirolimus.
Therefore, concomitant use of Tracleer and tacrolimus or sirolimus is not advisable.
Għalhekk, l- għoti flimkien ta ’ Tracleer u tacrolimus jew sirolimus mhuwiex rakkomandat.
Patients in need of the combination should be closely monitored for adverse events related to Tracleer and for tacrolimus and sirolimus blood concentrations.
7 ssorveljati mill- qrib għal avvenimenti avversi marbuta ma ’ Tracleer u għall- konċentrazzjonijiet ta ’ tacrolimus u sirolimus fid- demm.
Glibenclamide: co-administration of Tracleer 125 mg twice daily for 5 days decreased the plasma concentrations of glibenclamide (a CYP3A4 substrate) by 40%, with potential significant decrease of the hypoglycaemic effect.
Glibenclamide: l- għoti flimkien ta ’ 125 mg ta ’ Tracleer darbtejn kuljum għal 5 ijiem naqqas il - konċentrazzjonijiet ta ’ glibenclamide fil- plażma (sottostrat ta ‘ CYP3A4) b’ 40%, bi tnaqqis sinifikanti potenzjali ta ’ l- effett ipoglikemiku.
The plasma concentrations of bosentan were also decreased by 29%.
Il- konċentrazzjoni ta ’ bosentan fil- plażma tnaqqset ukoll b’ 29%.
In addition, an increased incidence of elevated aminotransferases was observed in patients receiving concomitant therapy.
Flimkien ma ’ dan, inċidenza miżjuda ta ’ żieda fil- livell ta ’ aminotransferases kienet osservata f’ pazjenti li kienu qed jirċievu terapija konkomitanti.
Both glibenclamide and bosentan inhibit the bile salt export pump, which could explain the elevated aminotransferases.
Kemm glibenclamide kif ukoll bosentan jimpedixxu l- bile salt export pump, u dan jista ’ jispjega għaliex il- livell ta ’ aminotranferases jiżdied.
In this context, this combination should not be used (see section 4.4).
F’ dan il- kuntest, din il- kumbinazzjoni m’ għandhiex tintuża (ara sezzjoni 4. 4).
No drug-drug interaction data are available with the other sulfonylureas.
M’ hemm l- ebda tagħrif dwar l- interazzjoni bejn il- mediċini ma ’ sulfonylureas oħrajn.
Warfarin: co-administration of bosentan 500 mg twice daily for 6 days decreased the plasma concentrations of both S-warfarin (a CYP2C9 substrate) and R-warfarin (a CYP3A4 substrate) by 29% and 38%, respectively.
Warfarin: l- għoti flimkien ta ’ 500 mg ta ’ bosentan darbtejn kuljum għal 6 ijiem naqqas il - konċentrazzjonijiet fil- plażma kemm ta ’ S- warfarin (sottostrat ta ‘ CYP2C9) kif ukoll ta ’ R- warfarin (sottostrat ta ‘ CYP3A4) b’ 29% u 38%, rispettivament.
Clinical experience of concomitant administration of bosentan with warfarin in patients with pulmonary arterial hypertension did not result in clinically relevant changes in International Normalized Ratio (INR) or warfarin dose (baseline versus end of the clinical studies).
L- esperjenza klinika ta ’ l- għoti ta ’ bosentan flimkien ma ’ warfarin f’ pazjenti bi pressjoni għolja arterjali pulmonari ma rriżultatx f’ bidliet kliniċi rilevanti ta ’ l- International Normalized Ratio (INR) jew tad- doża ta ’ warfarin (linja bażi meta mqabbla mal- livelli li ntlaħqu fit- tmiem ta ’ l- istudji kliniċi).
In addition, the frequency of changes in warfarin dose during the trials due to changes in INR or due to adverse events was similar among bosentan- and placebo-treated patients.
Flimkien ma ’ dan, il- frekwenza tat- tibdil fid- doża ta ’ warfarin matul il- provi minħabba bidliet fl- INR jew minħabba avvenimenti avversi kienu simili fil - pazjenti kkurati b’ bosentan u f’ dawk ikkurati bil- plaċebo.
No dose adjustment is needed for warfarin and similar oral anticoagulant agents when bosentan is initiated but intensified monitoring of INR is recommended, especially during bosentan initiation and the up-titration period.
L- ebda aġġustament fid- doża mhu meħtieġ għal warfarin jew għal mediċini oħra kontra l- koagulazzjoni tad- demm li jittieħdu mill- ħalq meta tinbeda l- kura b’ bosentan, imma monitoraġġ intensifikat ta ’ l- INR hu rakkomandat, speċjalment waqt il- bidu tal- kura b’ bosentan u matul il- perjodu taż- żieda fid- doża.
Simvastatin: co-administration of Tracleer 125 mg twice daily for 5 days decreased the plasma concentrations of simvastatin (a CYP3A4 substrate), and its active β -hydroxy acid metabolite by 34% 7 and 46%, respectively.
Simvastatin: l- għoti flimkien ta ‘ 125 mg ta ’ Tracleer darbtejn kuljum għal 5 ijiem naqqas il - konċentrazzjonijiet ta ‘ simvastatin fil- plażma (sottostrat ta ‘ CYP3A4), u l- metabolit attiv tiegħu β - hydroxy acid b’ 34% u 46% rispettivament.
The plasma concentrations of bosentan were not affected by concomitant simvastatin.
L- għoti flimkien ta ’ simvastatin flimkien ma ’ bosentan ma kellux effett fuq il- konċentrazzjonijiet ta ’ bosentan fil- plażma.
Monitoring of cholesterol levels and subsequent dosage adjustment should be considered.
Il- monitoraġġ tal- livelli tal- kolesterol u aġġustament sussegwenti tad- dożaġġ għandhom ikunu kkunsidrati.
Ketoconazole: co-administration of Tracleer 62.5 mg twice daily for 6 days and ketoconazole, a potent CYP3A4 inhibitor, increased the plasma concentrations of bosentan approximately 2-fold.
Ketoconazole: l- għoti flimkien ta ’ 62. 5 mg ta ’ Tracleer darbtejn kuljum għal 6 ijiem flimkien ma ’ ketoconazole, impeditur qawwi ta ’ CYP3A4, żied il- konċentrazzjonijiet ta ’ bosentan fil- plażma b’ madwar id- doppju.
No dose adjustment of Tracleer is considered necessary.
L- ebda aġġustament fid- doża ta ’ Tracleer mhu meħtieġ.
Although not demonstrated through in vivo studies, similar increases in bosentan plasma concentrations are expected with the other potent CYP3A4 inhibitors (such as itraconazole and ritonavir).
Għalkemm ma ntweriex permezz ta ’ studji in vivo, żidiet simili fil- konċentrazzjonijiet ta ’ bosentan fil- plażma huma mistennija bl- użu ta ’ impedituri qawwija oħra ta ’ CYP3A4 (bħal itraconazole u ritonavir).
However, when combined with a CYP3A4 inhibitor, patients who are poor metabolisers of CYP2C9 are at risk of increases in bosentan plasma concentrations that may be of higher magnitude, thus leading to potential harmful adverse events.
Madankollu, meta bosentan jintuża ma ’ impeditur ta ’ CYP3A4, hemm ir- riskju li l- konċentrazzjonijiet ta ’ bosentan fil - plażma tal- pazjenti li ma jimmetabolawx sewwa CYP2C9 jiżdiedu, u għalhekk dan jista ’ jwassal għal avvenimenti avversi li potenzjalment jistgħu jkunu ta ’ ħsara.
Digoxin: co-administration of bosentan 500 mg twice daily for 7 days decreased the AUC, Cmax and Cmin of digoxin by 12%, 9% and 23%, respectively.
Digoxin: l- għoti flimkien ta ’ 500 mg ta ’ bosentan darbtejn kuljum għal 7 ijiem naqqas l- erja ta ’ taħt il - kurva (AUC), il- konċentrazzjonijiet massimi (Cmax) u l- konċentrazzjonijiet minimi (Cmin) ta ’ digoxin bi 12%, 9% u 23%, rispettivament.
The mechanism for this interaction may be induction of P-glycoprotein.
Jista ’ jkun li l- mekkaniżmu għal din l- interazzjoni tista ’ tkun l - induzzjoni ta ’ P- glycoprotein.
This interaction is unlikely to be of clinical relevance.
Din l- interazzjoni mhix mistennija li jkollha rilevanza klinika.
Epoprostenol: limited data obtained from a study (AC-052-356, BREATHE-3) in which 10 paediatric patients received the combination of Tracleer and epoprostenol indicate that after both single- and multiple-dose administration, the Cmax and AUC values of bosentan were similar in patients with or without continuous infusion of epoprostenol (see section 5.1).
Epoprostenol: tagħrif limitat miksub minn studju (AC- 052- 356, BREATHE- 3) fejn 10 pazjenti tfal ingħataw il- kumbinazzjoni ta ’ Tracleer u epoprostenol jindika li wara l- għoti kemm ta ’ doża waħda u kemm ta ’ dożi multipli, il- valuri tas- Cmax kif ukoll ta ‘ l- AUC ta ’ bosentan kienu simili kemm fil - pazjenti li ngħataw infużjoni kontinwa ta ’ epoprostenol kif ukoll f’ dawk li ma ngħatawx infużjoni (ara sezzjoni 5. 1).
Rifampicin: co-administration in 9 healthy subjects of Tracleer 125 mg twice daily for 7 days and rifampicin, a potent inducer of CYP2C9 and CYP3A4, decreased the plasma concentrations of bosentan by 58%, and this decrease could achieve almost 90% in an individual case.
Rifampicin: l- għoti flimkien f’ 9 pazjenti f' saħħithom ta ’ 125 mg ta ’ Tracleer darbtejn kuljum għal 7 ijiem u rifampicin, inducer potenti ta ’ CYP2C9 u CYP3A4, naqqas il- konċentrazzjonijiet ta ’ bosentan fil- plażma bi 58%, u dan it- tnaqqis laħaq kważi 90% f’ każ individwali.
A subsequent significantly reduced effect of bosentan is expected when it is co-administered with rifampicin.
Effett sussegwenti ta ’ bosetan li jkun imnaqqas b’ mod sinifikanti hu mistenni meta dan jingħata flimkien ma ’ rifampicin.
Data on other CYP3A4 inducers, e. g. carbamazepine, phenobarbital, phenytoin and St John's wort are lacking, but their concomitant administration is expected to lead to reduced systemic exposure to bosentan.
M’ hemmx informazzjoni fuq inducers oħrajn ta ’ CYP3A4, eż. carbamazepine, phenobarbital, phenytoin u St
A clinically significant reduction of efficacy cannot be excluded.
Tnaqqis klinikament sinifikanti ta ’ l- effikaċja ma jistax jiġi eskluż.
Sildenafil: co-administration of Tracleer 125 mg twice daily (steady state) with sildenafil 80 mg three times a day (at steady state) concomitantly administered during 6 days in healthy volunteers resulted in a 63% decrease of the sildenafil AUC and a 50% increase of the bosentan AUC.
Sildenafil: l- għoti flimkien ta ’ 125 mg ta ’ Tracleer darbtejn kuljum (stat fiss) ma ’ 80 mg ta ’ sildenafil tliet darbiet kuljum (fl- istat fiss) mogħtija flimkien fuq medda ta ’ 6 ijiem f' voluntiera f’ saħħithom, irriżulta fi tnaqqis ta ’ 63% fl- AUC ta ’ sildenafil u żieda ta ’ 50% fl- AUC ta ’ bosentan.
Caution is recommended in case of co-administration.
L- attenzjoni hi rakkomandata fil- każ ta ’ għoti flimkien.
Studies in animals have shown reproductive toxicity (teratogenicity, embryotoxicity, see section 5.3).
Studji fl- annimali juru tossiċità fis- sistema riproduttiva (teratoġeniċità, embrijotossiċità, ara sezzjoni 5. 3).
There are minimal data on the use of Tracleer in pregnant women.
Hemm informazzjoni minimali fuq l- użu ta ’ Tracleer f’ nisa tqal.
The potential risk for humans is still unknown.
Ir- riskju potenzjali fil- bniedem għadu mhux magħruf.
Tracleer is contraindicated in pregnancy (see section 4.3).
Tracleer hu kontra- indikat waqt it- tqala (ara sezzjoni 4. 3).
Before the initiation of Tracleer treatment in women of child-bearing potential, the absence of pregnancy should be checked, appropriate advice on reliable methods of contraception provided, and reliable contraception initiated.
Qabel tinbeda kura b’ Tracleer f’ nisa li jistgħu joħorġu tqal, in- nuqqas tat- tqala għandha tiġi ċċekkjata, għandu jingħata parir xieraq dwar metodi ta ’ kontraċezzjoni affidabbli u għandha tinbeda kontraċezzjoni affidabbli.
Patients and prescribers must be aware that due to potential pharmacokinetic interactions, Tracleer may render hormonal contraceptives ineffective (see section 4.5).
Pazjenti u tobba għandhom ikunu jafu li, minħabba interazzjonijiet farmakokinetiċi potenzjali, hemm il- possibbiltà li Tracleer ineħħi l- effetti tal- kontraċettivi ormonali (ara sezzjoni 4. 5).
Therefore, women of childbearing potential must not use hormonal contraceptives (including oral, injectable, transdermal, and implantable forms) as the sole method of contraception but must use an additional or an alternative reliable method of contraception.
Għalhekk nisa li jistgħu joħorgu tqal m’ għandhomx jużaw kontraċettivi ormonali (li jinkludu forom ta ’ kontraċettivi orali, li jistgħu jiġi injettati, transdermali, u dawk li jistgħu jiġi impjantati) bħala l- uniku metodu ta ’ kontraċezzjoni, iżda għandhom jużaw metodu addizzjonali jew metodu affidabbli ta ’ kontraċezzjoni alternattiva.
If there is any doubt on what contraceptive advice should be given to the individual patient, consultation with a gynaecologist is recommended.
Jekk għandek xi dubju dwar liema parir ta ’ kontraċezzjoni għandu jingħata lill- pazjent individwali, konsultazzjoni ma ’ ġinekologu hija rakkomandata.
Because of possible hormonal contraception failure during Tracleer treatment, and also bearing in mind the risk that pulmonary hypertension severely deteriorates with pregnancy, monthly pregnancy tests during treatment with Tracleer are recommended to allow early detection of pregnancy.
Minħabba l- possibbiltà ta ’ falliment ta ’ kontraċezzjoni ormonali waqt kura b’ Tracleer, kif ukoll b’ konsiderazzjoni tar- riskju li pressjoni pulmonari għolja tista ’ tiddeterjora b’ mod sever bit - tqala, hu rakkomandat li jsiru testijiet tat- tqala matul il- kura bi Tracleer biex tkun possibbli s- sejba bikrija tat- tqala.
8 Use during lactation
L- użu waqt it- treddigħ
It is not known whether bosentan is excreted into human milk.
Mhuwiex magħruf jekk bosentan joħroġx mal- ħalib tas- sider uman.
Breast-feeding is not recommended during treatment with Tracleer.
It- treddigħ mhux rakkomandat waqt kura b’ Tracleer.
No studies on the effect of Tracleer on the ability to drive and use machines have been performed.
Ma sarux studji dwar l- effetti ta ‘ Tracleer fuq il- ħila biex issuq jew tħaddem il- magni.
Tracleer may cause dizziness, which could influence the ability to drive or use machines.
Tracleer jista ’ jikkawża sturdament, li jista ’ jinfluwenza l- ħila biex issuq jew tħaddem il- magni.
Integrated findings from placebo-controlled trials
Sejbiet integrati minn provi kkontrollati bil- plaċebo
In eight placebo-controlled studies, six of which were for indications other than pulmonary arterial hypertension, a total of 677 patients were treated with bosentan at daily doses ranging from 100 mg to 2000 mg and 288 patients were treated with placebo.
Fi tmien studji kkontrollati bil- plaċebo, li sitta minnhom kienu għal indikazzjonijiet li ma jinkludux il - pressjoni għolja arterjali pulmonari, total ta ’ 677 pazjent kienu kkurati b’ bosentan b’ dożi ta ’ bejn 100 mg sa 2000 mg kuljum u 288 pazjent ingħataw il- plaċebo.
The foreseen duration of treatment ranged from 2 weeks to 6 months.
It- tul tal- kura kien ta ’ bejn ħmistax sa 6 xhur.
The adverse drug reactions that occurred more frequently on bosentan than on placebo (≥ 3% of bosentan-treated patients, with ≥ 2% difference) were headache (15.8% vs 12.8%), flushing (6.6% vs 1.7%), abnormal hepatic function (5.9% vs 2.1%), leg oedema (4.7% vs 1.4%), and anaemia (3.4% vs 1.0%), all of which were dose related.
Dawn l- effetti kollha keinu jiddependu mid- doża.
Placebo-controlled trials in primary (idiopathic/ familial) PAH and PAH associated with connective tissue diseases
9 Provi kkontrollati bil- plaċebo f’ PAH primarja (idjopatika/ familjali) u PAH marbuta ma ’ mard tat - tessut konnettiv
The table below shows the adverse drug reactions that occurred in ≥ 3% of patients treated with Tracleer (125 and 250 mg twice daily) in the phase 3 placebo-controlled trials in pulmonary arterial hypertension, and which were more frequent in these patients:
It- tabella taħt turi reazzjonijiet avversi tal- mediċina li seħħew f’ ≥ 3% tal- pazjenti kkurati b’ Tracleer (125 u 250 mg darbtejn kuljum) fil- provi ta ’ fażi 3 ikkontrollati bil- plaċebo b’ ipertensjoni arterjali pulmonari, li kienu aktar frekwenti f’ dawn il- pazjenti:
Adverse drug reactions occurring in ≥ 3% of patients, and more frequently in patients on Tracleer (125 and 250 mg twice daily), in placebo-controlled trials in pulmonary arterial hypertension
Reazzjonijiet avversi tal- mediċina li seħħew f’ ≥ 3% tal- pazjenti, u aktar ta ’ spiss f’ pazjenti kkurati bi Tracleer (125 mg u 250 mg darbtejn kuljum), fi provi kkontrollati bil- plaċebo f’ pazjenti bi pressjoni għolja fl- arterja tal- pulmun
Body system / Adverse event
Sistema tal- ġisem / Avveniment avvers
Placebo N = 172
Plaċebo N = 172
Tracleer (all) N = 258
Tracleer (kollha) N = 258
Upper respiratory tract infection Nasopharyngitis Respiratory tract infection
Infezzjoni fl- apparat respiratorju ta ’ fuq Nażofarinġite Infezzjoni fl- apparat respiratorju Sinożite Disturbi tad- demm u tas- sistema limfatika
6.4% 8.1% 2.9%
6. 4% 8. 1% 2. 9% 2. 3%
24 9.3% 24 9.3% 9 3.5%
24 9. 3% 24 9. 3% 9 3. 5% 9 3. 5%
Anaemia Nervous system disorders
Anemija Disturbi fis- sistema nervuża
8
8 3. 1%
Headache Syncope Cardiac disorders
Uġigħ ta ’ ras Sinkope Disturbi fil- qalb
14.5% 4.1%
14. 5% 4. 1%
39 12
39 15. 1% 12 4. 7%
Palpitations Vascular disorders
Palpitazzjonijiet Disturbi vaskulari
9
9 3. 5%
Flushing Hypotension Musculoskeletal and connective tissue disorders
Fwawar Pressjoni baxxa Disturbi muskolu- skeltrali u tal- connective tissue
2.9% 1.7%
2. 9% 1. 7%
10 10
10 3. 9% 10 3. 9%
Arthralgia General disorders and administration site conditions
Artralġja Disturbi ġenerali u kondizzjonijiet ta 'mnejn jingħata
Oedema peripheral Chest pain Oedema Investigations
Edima periferali Uġigħ fis- sider Edima Investigazzjonijiet
7.6% 4.7% 2.3%
7. 6% 4. 7% 2. 3%
20 13 8
20 7. 8% 13 5. 0% 8 3. 1%
Liver function test abnormal
Test tal- funzjoni tal- fwied mhux normali
Note: only AEs with onset from start of treatment to 1 calendar day after end of treatment are included.
Nota: huma inklużi biss AEs li bdew mill- bidu tal- kura sa ġurnata wara t- tmiem tal- kura.
One patient could have had more than one AE.
Pazjent wieħed seta ’ kellu aktar minn AE wieħed.
At the recommended maintenance dose or double the dose (i.e., 125 or 250 mg twice daily) the adverse drug reactions that occurred more frequently with Tracleer than with placebo (in ≥ 3% of Tracleer-treated patients, with ≥ 2% difference) were upper respiratory tract infection, hypotension, and anaemia.
125 jew 250 mg darbtejn kuljum), ir- reazzjonijiet avversi tal- mediċina li seħħew aktar ta ’ spiss bl- użu ta ’ Tracleer milli bl- użu tal- plaċebo (fi ≥3% tal- pazjenti kkurati bi Tracleer, b’ differenza ta ’ ≥2%) kienu infezzjoni fl - apparat respiratorju ta ’ fuq, pressjoni baxxa, u anemija.
Adverse drug reactions that occurred in ≥ 1% and < 3% of these patients and more frequently on Tracleer than on placebo (≥ 2% difference) were hepatic enzyme increased (2.7% on Tracleer versus 0% on placebo) and flushing (2.7% on Tracleer versus 0.6% on placebo).
Reazzjonijiet avversi tal- mediċina li seħħew f’ ≥ 1% u < 3% ta ’ dawn il- pazjenti u b’ mod aktar frekwenti b’ Tracleer milli bil- plaċebo (≥ 2% differenza) kienu żjieda fl- enzimi tal- fwied (2. 7% b’ Tracleer kontra 0% bil- plaċebo) u fwawar (2. 7% b’ Tracleer kontra 0. 6% bil- plaċebo).
Treatment discontinuations due to adverse events, during the clinical trials in patients with pulmonary arterial hypertension, at doses of 125 and 250 mg twice daily, occurred with the same frequency (5.8%) in bosentan and placebo-treated patients.
It- twaqqif tal- kura minħabba l- effetti avversi, matul il- provi kliniċi fuq pazjenti bi pressjoni għolja arterjali pulmonari, b’ dozi ta ’ 125 u 250 mg darbtejn kuljum, seħħew bl- istess frekwenza (5. 8%) fil - pazjenti li ħadu bosentan u fil- pazjenti li ħadu l- plaċebo.
Placebo-controlled trial in PAH associated with congenital heart disease (BREATHE-5)
10 Prova kkontrollata bil- plaċebo f' PAH marbuta ma ’ mard konġenitali tal- qalb (BREATHE- 5)
The safety profile of Tracleer in this population was similar to that observed in the pivotal trials in patients with PAH.
Il- profil tas- sigurtà ta ’ Tracleer f’ din il- popolazzjoni kien simili għal dak li kien osservat fil- provi ta ’ importanza kbira f’ pazjenti bil- PAH.
Adverse events that occurred in a greater proportion of patients on Tracleer 62.5 mg twice daily for four weeks, followed by 125 mg twice daily (n = 37) than on placebo (n = 17) included peripheral oedema (18.9% vs.
11. 8%), palpitazzjonijiet (10. 8% vs.
5.9%), headache (13.5% vs.
0%), sturdament (8. 1% vs.
Four patients discontinued due to adverse events, two (5.4%) in the bosentan group and two (11.8%) in the placebo group.
Erba ’ pazjenti ma komplewx minħabba avvenimenti avversi, tnejn (5. 4%) fil- grupp ta ’ bosentan u tnejn (11. 8%) fil- grupp tal- plaċebo.
Uncontrolled trial in patients with PAH associated with HIV infection (BREATHE-4)
Prova mhux ikkontrollata f’ pazjenti bil- PAH marbuta ma ’ infezzjoni bl- HIV (BREATHE- 4)
The safety profile in this population (n = 16) when treated with Tracleer 62.5 mg twice daily for four weeks, followed by 125 mg twice daily was similar to that observed in the pivotal trials in patients with PAH.
Il- profil tas- sigurtà f’ din il- popolazzjoni (n = 16) meta l- pazjenti kienu kkurati bi Tracleer 62. 5 mg darbtejn kuljum għal erba ’ ġimgħat, segwiti minn 125 mg darbtejn kuljum, kien simili għal dak osservat fi provi ta ’ importanza kbira f’ pazjenti bil- PAH.
The most frequent adverse events were peripheral oedema (31%), headache (19%), abnormal liver function (13%), muscle cramps (13%), fluid retention (13%) and vomiting (13%).
L- avvenimenti avversi l- iktar frekwenti kienu edema periferali (31%), uġigħ ta ’ ras (19%), funzjoni anormali tal- fwied (13%), bugħawwieġ fil- muskoli (13%), żamma ta ’ fluwidu (13%) u rimettar (13%).
Haematological abnormalities (anaemia and decrease in neutrophil count) were observed in some patients (see section 4.4).
Anormalitajiet ematoloġiċi (anemija u tnaqqis fl- għadd tan- newtrofili) kienu osservati f’ xi pazjenti (ara sezzjoni 4. 4).
Placebo-controlled trials in digital ulcers
Provi kkontrollati bil- plaċebo f’ ulċeri fis- swaba
The table below shows the adverse drug reactions that occurred in ≥ 3% of patients treated with Tracleer (125 mg twice daily) in the two pivotal placebo-controlled trials in digital ulcers, and which were more frequent in Tracleer-treated patients:
It- tabella taħt turi r- reazzjonijiet avversi tal- mediċina li seħħew f ’ ≥ 3% tal- pazjenti kkurati b’ Tracleer (125 mg darbtejn kuljum), u li kienu aktar frekwenti f’ pazjenti kkurati b’ Tracleer, fiż- żewġ provi kliniċi pivitali kkontrollati bil- plaċebo b’ ulċeri fis- swaba:
Adverse drug reactions occurring in ≥ 3% of patients, and more frequently in patients on Tracleer (125 mg twice daily), in the placebo-controlled trials in digital ulcers
Reazzjonijiet avversi tal- mediċina li seħħew f ’ ≥ 3% tal- pazjenti, u bi frekwenza akbar f’ pazjenti fuq Tracleer (125 mg darbtejn kuljum), fil- provi kkontrollati bil- plaċebo b’ ulċeri fis- swaba
Body system / Adverse event
Sistema tal- ġisem / Episodju avvers
Placebo N = 133
Plaċebo N = 133
Tracleer (all) N = 175
Tracleer (kollha) N = 175
Infected skin ulcer Urinary tract infection Vascular disorders
Ulċera fil- ġilda nfettata Infezzjoni fis- sistema urinarja Disturbi vaskulari
Flushing Respiratory, thoracic and mediastinal disorders
Fwawar Disturbi respiratorji, toraċiċi u medjastinali
Dyspnoea
Qtugħ ta ’ nifs Disturbi gastro- intestinali
Diarrhoea Gastrointestinal reflux disease Abdominal pain Constipation Skin and subcutaneous tissue disorders
Dijarea Marda ta ’ rifluss gastro- intestinali Uġigħ addominali Stitikezza Disturbi fil- ġilda u fit- tessuti ta ’ taħt il- ġilda
Erythema Dermatitis Musculoskeletal system disorders
Eritema Dermatite Disturbi muskolu- skeletrali
Pain in extremity Back pain General disorders and administration site conditions
Uġigħ fl- estremitajiet Uġigħ ta ’ dahar Disturbi ġenerali u kondizzjonijiet ta ’ mnejn jingħata
Peripheral oedema Peripheral oedema-worsening Fatigue Investigations
Edima periferali Edima periferali- tmur għal agħar Għejja Investigazzjonijiet
Aspartate aminotransferase increased Alanine aminotransferase increased Liver function test abnormal
11 Żieda fl- aspartate aminotransferase Żieda fl- alalanine aminotransferase Test tal- funzjoni tal- fwied mhux normali
Note: only AEs with onset from start of treatment to 1 calendar day after end of treatment are included.
AEs li seħħew mil- bidu tal- kura sa ġurnata wara li spiċċat il- kura biss huma nklużi.
One patient could have had more than one AE.
Pazjent seta ’ kellu aktar minn AE wieħed.
Laboratory abnormalities
Anormalitajiet fil- laboratorju
Liver test abnormalities
Anormalitajiet fit- testijiet tal- fwied
Bosentan has been associated with dose-related elevations in liver aminotransferases, i.e., aspartate and alanine aminotransferases.
Bosentan kien assoċjat ma ’ żieda fl- aminotransferases, i. e. aspartate u alanin aminotransferases, tal - fwied, li kienet marbuta mad- doża.
In the clinical programme, liver enzyme changes generally occurred within the first 26 weeks of treatment, usually developed gradually, and were mainly asymptomatic.
Fil- programm kliniku, bidliet fl- enzimi tal- fwied ġeneralment seħħew matul l- ewwel 26 ġimgħa tal- kura, u normalment, żviluppaw gradwalment, u kienu ġeneralment asintomatiċi.
They returned, in all cases during the clinical programme, to pre-treatment levels, without sequelae, within a few days to 9 weeks either spontaneously or after dose reduction or discontinuation.
Il- livelli ta ’ aminotransferases f’ kull pazjent fl- istudju kliniku, reġgħu lura għal- livelli ta ’ qabel bdiet il- kura, mingħajr konsegwenzi, fi ftit jiem sa 9 ġimgħat, jew b’ mod spontanju jew wara li tnaqqset jew twaqqfet id- doża.
In the post-marketing period rare cases of liver cirrhosis and liver failure have been reported (see end of section 4.8).
Fil- perjodu wara li l- mediċina bdiet tinbiegħ, każijiet rari ta ’ ċirrożi tal- fwied u kollass tal- fwied kienu rrappurtati (ara l- aħħar ta ’ sezzjoni 4. 8).
The mechanism of this adverse effect is unclear.
Il- mekkaniżmu ta ’ dawn l- effetti avversi mhuwiex magħruf.
These elevations in aminotransferases may reverse spontaneously while continuing treatment with the maintenance dose of Tracleer or after dose reduction, but interruption or cessation may be necessary (see section 4.4).
Iż- żieda fl- aminotransferases tista ’ terġa ’ lura għan- normal b’ mod spontanju waqt it- tkomplija tal- kura bid- doża tal- manteniment ta ’ Tracleer jew wara li titnaqqas id- doża, imma l- interruzzjoni jew it- twaqqif tal- kura jistgħu jkunu meħtieġa (ara sezzjoni 4. 4).
In the eight integrated placebo-controlled studies, six of which were for indications other than pulmonary arterial hypertension, elevations in liver aminotransferases by greater than 3 times the upper limit of normal (ULN) were observed in 11.2% of the bosentan-treated patients as compared to 1.8% of the placebo-treated patients.
Fit- tmien studji integrati kkontrollati bil- plaċebo, li sitta minnhom kienu għal indikazzjonijiet li ma kienux pressjoni għolja arterjali pulmonari, żieda fl- aminotransferases tal- fwied ta ’ iktar minn tliet darbiet il- limitu ta ’ fuq tan- normal (ULN) kienu osservati fi 11. 2% ta ’ pazjenti kkurati b’ bosentan meta mqabbla ma ’ 1. 8% tal- pazjenti kkurati bil- plaċebo.
Bilirubin increases to > 3 × ULN were associated with aminotransferase increases (> 3 × ULN) in 2 of 658 (0.3%) of patients treated with bosentan.
Żieda fil- bilirubin għal > 3 × ULN kienet assoċjata ma ’ żidiet fl- aminotransferases (> 3 × ULN) fi 2 minn 658 (0. 3%) tal- pazjenti kkurati b’ bosentan.
Nine of the 74 bosentan-treated patients who had elevated liver aminotransferases (> 3 × ULN) also had symptoms such as abdominal pain, nausea/vomiting, and fever.
Disgħa mill- 74 pazjent ikkurati b’ bosentan li kellhom żieda fl- aminotransferases tal- fwied (> 3 × ULN) kellhom ukoll sintomi bħal ugigħ ta ’ żaqq, dardir/ rimettar, u deni.
In studies in patients with pulmonary arterial hypertension, the incidence of elevated liver aminotransferases (> 3 × ULN) was 12.8% in bosentan-treated patients (N = 257), 12.3% in patients treated with 125 mg twice daily and 14.3% in patients treated with 250 mg twice daily.
Fi studji fuq pazjenti bi pressjoni għolja arterjali pulmonari, l- inċidenza taż- żieda fl- aminotransferases tal- fwied (> 3 × LFN) kienet 12. 8% f’ pazjenti kkurati b’ bosentan (N = 257), 12. 3% f’ pazjenti kkurati b’ 125 mg darbtejn kuljum u 14. 3% f’ pazjenti kkurati b’ 250 mg darbtejn kuljum.
Eight-fold increases were seen in 3.7% of pulmonary arterial hypertension patients on 125 mg twice daily and 7.1% of pulmonary arterial hypertension patients on 250 mg twice daily.
Żieda ta ’ tmien darbiet iktar dehret fi 3. 7% tal- pazjenti bi pressjoni għolja pulmonari fuq 125 mg darbtejn kuljum u 7. 1% tal- pazjenti bi pressjoni għolja pulmonari fuq 250 mg darbtejn kuljum.
In the two studies in patients with digital ulcers the incidence of elevated liver aminotransferases (> 3 × ULN) was 11.3% in bosentan-treated patients (N = 168) compared with 0.8% in placebo-treated patients (N = 129).
Fiż- żewġ studji f’ pazjenti b’ ulċeri fis- swaba l- inċidenza ta ’ żieda fl- aminotransferases tal- fwied (> 3 × ULN) kienet ta ’ 11. 3% f’ pazjenti kkurati b’ bosentan (N = 168) meta mqabbla ma ’ 0. 8% f’ pazjenti kkurati bil- plaċebo (N = 129).
Elevations to > 8 × ULN were seen in 2.4% of bosentan-treated patients with digital ulcers.
Żiediet sa > 8 × ULN kienu osservati f’ 2. 4% tal- pazjenti b’ ulċeri fis- swaba kkurati b’ bosentan.
The mean decrease in haemoglobin concentration from baseline to trial completion for the bosentan- treated patients was 0.9 g/dl and for the placebo-treated patients was 0.1 g/dl.
Il- medja tat- tnaqqis fil- konċentrazzjoni ta ’ l- emoglobina mil- linja bażi sat- tmiem tal- prova għal pazjenti kkurati b’ bosentan kienet 0. 9 g/ dl u fil- pazjenti kkurati bil- plaċebo kienet 0. 1 g/ dl.
In eight placebo-controlled studies, clinically relevant decreases in haemoglobin (> 15% decrease from baseline resulting in values < 11 g/dl) were observed in 5.6% of bosentan-treated patients as compared with 2.6% of placebo-treated patients.
Fi tmien studji kkontrollatti bil- plaċebo, tnaqqis klinikament rilevanti fl- emoglobina (tnaqqis ta ’ > 15% mil- livell ta ’ qabel il- kura, biex laħaq il- livell ta ‘ < 11g/ dl) kien osservat f’ 5. 6% tal- pazjenti kkurati b’ bosentan meta pparagunat mal- pazjenti kkurati bil- plaċebo.
In patients with pulmonary arterial hypertension treated with doses of 125 and 250 mg twice daily, clinically relevant decreases in haemoglobin occurred in 3.0% and 1.3% of the bosentan- and placebo-treated patients, respectively.
Fil- pazjenti bi pressjoni għolja pulmonari kkurati b’ dożi ta ’ 125 u 250 mg darbtejn kuljum, tnaqqis klinikament rilevanti fil - emoglobina deher f’ 3. 0% u f’ 1. 3% tal- pazjenti kkurati b’ bosentan u dawk ikkurati bil- plaċebo, rispettivament.
In the two studies in patients with digital ulcers, clinically relevant decreases in haemoglobin (decrease from baseline resulting in haemoglobin values < 10 g/dL) were observed in 4.2% of bosentan-treated patients (N = 167), compared with 3.1% of placebo-treated patients (N = 129).
12 Fiż- żewġ studji f’ pazjenti b’ ulċeri fis- swaba, tnaqqis fl- emoglobina (tnaqqis mill- linja bażi li rriżultaw f’ valuri ta ’ l- emoglobina ta ’ < 10 g/ dL) ta ’ sinifikanza klinika kienu osservati f’ 4. 2% tal- pazjenti kkurati b’ bosentan (N = 167), meta mqabbla ma ’ 3. 1% tal- pazjenti kkurati bil- plaċebo (N = 129).
In the post-marketing period cases of anaemia requiring red blood cell transfusion have been reported (see end of section 4.8).
Fil- perjodu ta ’ wara t- tqegħid fis- suq, ġew irrapportati każijiet ta ’ anemija li kienu jinħtieġu trasfużjoni ta ’ ċelluli ħomor tad- demm (ara t- tmiem ta ’ sezzjoni 4. 8).
Post-Marketing Experience
Esperjenza ta ’ Wara l- Bejgħ
The majority of adverse events reported during the post-marketing period have been similar to those reported in clinical trials.
Il- maġġoranza ta ’ l- avvenimenti avversi rrapportati waqt il- perjodi ta ’ wara t- tqegħid fis- suq kienu simili għal dawk li kienu rrappurtati fi provi kliniċi.
Undesirable effects are ranked under headings of frequency using the following convention;very common (≥ 1/10); common (> 1/100, < 1/10); uncommon (> 1/1,000, ≤ 1/100); rare (> 1/10,000, ≤ 1/1,000); very rare (≤ 1/10,000).
Ir- reazzjonijiet avversi tal- mediċina huma kklassifikati taħt kategoriji ta ’ frekwenza billi tintuża l - konvenzjoni li ġejja: komuni ħafna (≥ 1/ 10); komuni (> 1/ 100, < 1/ 10); mhux komuni (> 1/ 1, 000, ≤ 1/ 100); rari (> 1/ 10, 000, ≤ 1/ 1, 000); rari ħafna (≤ 1/ 10, 000).
Common: nausea.
Komuni: dardir.
Hepato-biliary disorders:
Mhux komuni: rimettar, uġigħ ta ’ żaqq, dijarea Mard tal- fwied u tal- marrara:
Uncommon: aminotransferase elevations associated with hepatitis and/or jaundice.
Mhux komuni: żidiet fl- aminotransferase marbuta ma ’ epatite u/ jew suffejra.
Rare: liver cirrhosis, liver failure Skin and subcutaneous tissue disorders:
Rari: ċirrożi tal- fwied, kollass tal- fwied Mard tal- ġilda u tat- tessuti ta ’ taħt il- ġilda:
Uncommon: hypersensitivity reactions including dermatitis, pruritus and rash.
Mhux komuni: reazzjonijiet minħabba sensittività eċċessiva li jinkludu dermatite, ħakk u raxx.
Immune system:
Sistema immuni:
Rare: anaphylaxis and/or angioedema Blood and lymphatic system disorders:
Rari: anafilassi u/ jew anġjodema Disturbi tad- demm u tas- sistema limfatika:
Common: anaemia or haemoglobin decreases, sometimes requiring red blood cell transfusion (see section 4.4) Uncommon: thrombocytopenia
Komuni: anemija jew tnaqqis fl- emoglobina, xi kultant jinħtieġu trasfużjoni ta ’ ċelluli ħomor tad- demm (ara sezzjoni 4. 4) Mhux komuni: tromboċitopenja
In the post-marketing period rare cases of unexplained hepatic cirrhosis were reported after prolonged therapy with Tracleer in patients with multiple co-morbidities and drug therapies.
Fil- perjodu wara li l- mediċina bdiet tinbiegħ, każijiet rari ta ’ ċirrożi tal- fwied li ma setgħux ikunu spjegati, kienu rrappurtati wara terapija fit- tul bi Tracleer f’ pazjenti b’ ko- morbożitajiet multipli u terapiji tal- mediċina.
There have also been rare reports of liver failure.
Kien hemm rapporti rari ta ’ kollass tal- fwied.
These cases reinforce the importance of strict adherence to the monthly schedule for monitoring of liver function for the duration of treatment with Tracleer (see section 4.4).
Dawn il- każijiet isaħħu l - importanza li wieħed isegwi b’ mod strett l- iskeda ta ’ kull xahar għal monitoraġġ tal- funzjoni tal- fwied għal kemm iddum il- kura bi Tracleer (ara sezzjoni 4. 4).
Bosentan has been administered as a single dose of up to 2400 mg to healthy subjects and up to 2000 mg/day for 2 months in patients with a disease other than pulmonary hypertension.
Bosentan intuża bħala doża waħda sa 2400 mg f’ pazjenti f’ saħħithom u sa 2000 mg kuljum għal xahrejn f’ pazjenti b’ mard ieħor barra pressjoni għolja pulmonari.
The most common adverse event was headache of mild to moderate intensity.
L- effett avvers l- iktar komuni kien uġigħ ta ’ ras ħafif sa moderat.
Massive overdose may result in pronounced hypotension requiring active cardiovascular support.
Doża eċċessiva massiva tista ’ tirriżulta fi pressjoni baxxa ħafna fejn ikun hemm bżonn ta ’ appoġġ kardjovaskulari attiv.
In the post-marketing period there was one reported overdose of 10,000 mg of bosentan taken by an
Fil- perjodu ta ’ wara t- tqegħid fis- suq, kienet irrapportata doża eċċessiva waħda ta ’ 10, 000 mg ta ’ bosentan li ttieħdet minn pazjent maskili adoloxxenti.
He had symptoms of nausea, vomiting, hypotension, dizziness, sweating, blurred vision.
Huwa kellu sintomi ta ’ tqalligħ, rimettar, pressjoni baxxa, sturdament, għaraq, vista mċajpra.
He recovered completely within 24 hours with blood pressure support.
Huwa rkupra kompletament fi żmien 24 siegħa b’ appoġġ għall- pressjoni tad- demm.
Note: bosentan is not removed through dialysis.
Nota: bosentan ma jitneħħiex permezz ta ’ dijalisi.
Pharmacotherapeutic group: other antihypertensives, ATC code:
Kategorija farmakoterapewtika: sustanzi oħra kontra l- pressjoni għolja, Kodiċi ATC:
Mechanism of action
Mod kif jaħdem
Bosentan is a dual endothelin receptor antagonist (ERA) with affinity for both endothelin A and B (ETA and ETB) receptors.
Bosentan huwa antagonist doppju tar- riċetturi ta ’ endothelin (ERA) b’ affinità għar- riċetturi ta ’ endothelin A u B (ETA u ETB).
Bosentan decreases both pulmonary and systemic vascular resistance B
Bosentan inaqqas ir- reżistenza vaskulari pulmonari kif ukoll dik sistemika u dan jirriżulta f’ żieda fl- awtput kardijaku mingħajr ma tiżdied ir- rata li biha tħabbat il- qalb.
The neurohormone endothelin-1 (ET-1) is one of the most potent vasoconstrictors known and can also promote fibrosis, cell proliferation, cardiac hypertrophy, and remodeling and is pro-inflammatory.
In- newro- ormon endothelin- 1 (ET- 1) huwa wieħed mis- sustanzi magħrufa l- iktar qawwija li jdejjaq il - vini u l- arterji u li jista ’ jikkawża wkoll il- fibrożi, il- proliferazzjoni taċ- ċelluli, it- tkabbir tal- qalb, u jista ’ jerġa ’ jimmudella l- qalb u jippromwovi l- infjammazzjoni.
These effects are mediated by endothelin binding to ETA and ETB receptors located in the endothelium B
Dawn l- effetti jseħħu billi endothelin jeħel mar- riċetturi ETA u ETB li qegħdin fl- endotilju u fiċ- ċelluli tal- muskoli l- lixxi vaskulari.
ET-1 concentrations in tissues and plasma are increased in several cardiovascular disorders and connective tissue diseases, including pulmonary arterial hypertension, 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 fit- tessuti u fil- plażma jiżdiedu f’ ħafna mard kardjovaskulari u mard tat - tessut konnettiv, li jinkludu pressjoni għolja arterjali pulmonari, skleroderma, kollass akut jew kroniku tal- qalb, iskemija mijokardjali, pressjoni għolja sistemika u aterosklerożi, li 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- każ ta ’ pressjoni għolja arterjali pulmonari u kollass tal- qalb, u fl- assenza ta ’ l- antagoniżmu tar- riċettur ta ’ endothelin, konċentrazzjonijiet għolja ta ’ ET- 1 huma kkorrelati mas- severità u mal- pronjosi ta ’ dan il- mard.
with a slightly higher affinity for ETA receptors (Ki = 4.1–43 nM) than for ETB receptors B
Bosentan jikkompeti mat- twaħħil ta ’ ET- 1 u peptidi ET oħrajn mar- riċetturi kemm ta ’ ETA u ETB, b’ affinità kemmxejn ogħla għar- riċetturi ta ’ ETA (Ki = 4. 1– 43 nM) milli għar- riċetturi ta ’ ETB (Ki = 38- 730 nM).
Bosentan specifically antagonises ET receptors and does not bind to other receptors.
Bosentan jantagonizza speċifikament ir- riċetturi ta ’ ET u ma jeħilx ma ’ riċetturi oħrajn.
Animal models In animal models of pulmonary hypertension, chronic oral administration of bosentan reduced pulmonary vascular resistance and reversed pulmonary vascular and right ventricular hypertrophy.
Mudelli ta ’ l- annimali F’ mudelli ta ’ l- annimali bi pressjoni għolja arterjali pulmonari, l- użu kroniku mill- ħalq ta ’ bosentan naqqas ir- reżistenza vaskulari pulmonari u reġġa ’ lura l- ipertrofija vaskulari pulmonari u dik tal - ventrikolu tal- lemin.
In an animal model of pulmonary fibrosis, bosentan reduced collagen deposition in the lungs.
F’ mudell ta ’ annimali b’ fibrożi pulmonari, bosentan naqqas id- depożitu tal - kollaġen fil- pulmuni.
Efficacy in adult patients with pulmonary arterial hypertension Two randomised, double-blind, multi-centre, placebo-controlled trials have been conducted in 32 (Study AC-052-351) and 213 (Study AC-052-352, BREATHE-1) adult patients with WHO functional class III–IV pulmonary arterial hypertension (primary pulmonary hypertension or pulmonary hypertension secondary mainly to scleroderma).
Effikaċja f’ pazjenti adulti bi pressjoni għolja arterjali pulmonari Żewġ studji randomised, double- blind, multi- ċentriċi, ikkontrollati bil- plaċebo, saru fi 32 (Studju AC - 052- 351) u 213 (Studju AC- 052- 352, BREATHE- 1) pazjent adult bi pressjoni għolja arterjali pulmonari tal- Klassi Funzjonali III– IV tal- WHO (pressjoni għolja pulmonari primarja jew pressjoni għolja pulmonari bħala konsegwenza ta ’ l- iskleroderma).
After 4 weeks of Tracleer 62.5 mg twice daily, the maintenance doses studied in these trials were 125 mg twice daily in AC-052-351 and 125 mg twice daily and 250 mg twice daily in AC-052-352.
Wara 4 ġimgħat ta ’ kura bi Tracleer b’ doża ta ’ 62. 5 mg darbtejn kuljum, id- dożi tal- manteniment studjati f’ dawn l- esperimenti kienu ta ’ 125 mg darbtejn kuljum f’ AC- 052- 351 u 125 mg darbtejn kuljum u 250 mg darbtejn kuljum f’ AC- 052- 352.