qanastek/EMEA-V3 huggingface dataset:
Tracleer was added to patients' current therapy, which could include a combination of anticoagulants, vasodilators (e.g., calcium channel blockers), diuretics, oxygen, and digoxin, but not epoprostenol.
Tracleer żdied mat- terapija kurrenti tal- pazjenti, li setgħet tinkludi kumbinazzjoni ta ’ sustanzi kontra l - koagulazzjoni, sustanzi li jwessgħu l- vini u l- arterji (eż. calcium channel blockers), dijuretiċi, ossiġnu, u digoxin, immispa mhux epoprostenol.
Control was placebo plus current therapy.
Il- kontroll kien il- plaċebo flimkien mat- terapija kurrenti.
The primary endpoint for each study was change in 6-minute walk distance at 12 weeks for the first study and 16 weeks for the second study.
L- endpoint primarju għal kull studju kien it- tibdil fid- distanza tal- mixja ta ’ 6 minuti, wara 12- il ġimgħa għall- ewwel studju, u wara 16- il ġimgħa għat- tieni studju.
In both trials, treatment with Tracleer resulted in significant increases in exercise capacity.
Fiż- żewg provi, il- kura bi Tracleer irriżultat f’ żieda sinifikanti fil- kapaċità ta ’ l- eżerċizzju fiżiku.
The placebo-corrected increases in walk distance compared to baseline were 76 metres (p = 0.02; t-test) and 44 metres (p = 0.0002; Mann-Whitney U test) at the primary endpoint of each trial, respectively.
Iż- żidiet fid- distanza tal- mixja korretti għal plaċebo, meta mqabbla mal- linja bażi kienu 76 metru (p = 0. 02; t- test) u 44 metru (p = 0. 0002; U test ta ’ Mann- Whitney) fl- endpoint primarju ta ’ kull prova, rispettivament.
The differences between the two groups 125 mg twice daily and
Id- differenzi bejn iż- żewġ gruppi, fejn grupp ingħata 125 mg darbtejn kuljum u grupp ieħor ingħata 250 mg darbtejn kuljum, ma
13 250 mg twice daily were not statistically significant but there was a trend towards improved exercise capacity in the group treated with 250 mg twice daily.
14 kienux statistikament sinifikanti imma kien hemm tendenza lejn titjib fil- kapaċità ta ’ l- eżerċizzju fiżiku fil- grupp ikkurat bil- 250 mg darbtejn kuljum.
The improvement in walk distance was apparent after 4 weeks of treatment, was clearly evident after 8 weeks of treatment and was maintained for up to 28 weeks of double-blind treatment in a subset of the patient population.
It- titjib fid- distanza tal- mixja dehret wara 4 ġimgħat ta ’ kura, u kienet evidenti 8 ġimgħat ta ’ kura u nżammet sa 28 ġimgħa ta ’ kura double- blind f’ subset tal- populazzjoni tal- pazjenti.
In a retrospective responder analysis based on change in walking distance, WHO functional class and dyspnoea of the 95 patients randomised to Tracleer 125 mg twice daily in the placebo-controlled trials, it was found that at week 8, 66 patients had improved, 22 were stable and 7 had deteriorated.
F’ analiżi tar- rispons retrospettiv (retrospective responder analysis) ibbażata fuq bidla fid- distanza tal - mixja, il- Klassi Funzjunali tal- WHO u dispnea tal- 95 pazjent randomised għal Tracleer 125 mg darbtejn kuljum fil- provi kkontrollati mill- plaċebo, instab li wara 8 ġimgħat, 66 pazjent marru għall - aħjar, 22 kienu stabbli u 7 marru għall- agħar.
Of the 22 patients stable at week 8, 6 improved at week 12/16 and 4 deteriorated compared with baseline.
Mit- 22 pazjent li kienu stabbli wara 8 ġimgħat, 6 marru għall- aħjar wara 12/ 16- il ġimgħa u 4 marru għall- agħar meta mqabbla mal- linja bażi.
Of the 7 patients that deteriorated at week 8, 3 improved at week 12/16 and 4 deteriorated compared with baseline.
Mis- 7 pazjenti li marru għall- agħar wara 8 ġimgħat, 3 marru għall- aħjar wara 12/ 16- il ġimgħa u 4 marru għall- agħar meta mqabbla mal- linja bażi.
Invasive haemodynamic parameters were assessed in the first study only.
Il- parametri emodinamiċi invażivi kienu evalwati fl- ewwel studju biss.
Treatment with Tracleer led to a significant increase in cardiac index associated with a significant reduction in pulmonary artery pressure, pulmonary vascular resistance and mean right atrial pressure.
Il- kura bi Tracleer wasslet f’ żieda fl- indiċi tal- qalb assoċjat ma ’ tnaqqis sinifikanti fil- pressjoni ta ’ l- arterja pulmonari, fir - reżistenza vaskulari pulmonari u fil- pressjoni medja ta ’ l- atriju tal- lemin.
A reduction in symptoms of pulmonary arterial hypertension was observed with Tracleer treatment.
Kien osservat tnaqqis fis- sintomi tal- pressjoni għolja arterjali pulmonari bil- kura bi Tracleer.
Dyspnoea measurement during walk tests showed an improvement in Tracleer-treated patients.
Il- kejl tad- dispnea matul it- testijiet tal- mixi wera titjib fil- pazjenti kkurati bi Tracleer.
In the AC-052-352 trial, 92% of the 213 patients were classified at baseline as WHO functional class III and 8% as class IV.
Fil- prova AC- 052- 352, 92% mill- 213- il pazjent kienu kklassifikati fil- linja bażi bħala Klassi Funzjonali III tal- WHO u 8% bħala Klassi IV.
Treatment with Tracleer led to a WHO functional class improvement in 42.4% of patients (placebo 30.4%).
Kura bi Tracleer wasslet f’ titjib fil- Klassi Funzjonali tal- WHO fi 42. 4% tal- pazjenti (plaċebo 30. 4%).
The overall change in WHO functional class during both trials was significantly better among Tracleer-treated patients as compared with placebo-treated patients.
Il- bidla totali fil- Klassi Funzjonali tal- WHO matul iż- żewg provi kienet aħjar b’ mod sinifikanti fil- pazjenti li ngħataw Tracleer meta mqabbla mal- pazjenti kkurati bil- plaċebo.
Treatment with Tracleer was associated with a significant reduction in the rate of clinical worsening compared with placebo at 28 weeks (10.7% vs 37.1%, respectively; p = 0.0015).
Il- kura bi Tracleer kienet assoċjata ma ’ tnaqqis sinifikanti fir- rata tas- sitwazzjoni klinika li tmur għall- agħar meta mqabbla mal- kura bil- plaċebo wara 28 ġimgħa (10. 7% vs 37. 1%, rispettivament; p = 0. 0015).
In a randomised, double-blind, multi-centre, placebo-controlled trial (AC-052-364; EARLY),185 PAH patie nts in WHO functional class II (mean baseline 6-minute walk distance of 435 metres) received bosentan 62.5 mg b.i.d. for 4 weeks followed by 125 mg b.i.d.
Fi prova randomised, double- blind, multi- centre u kkontrollata bil- plaċebo (AC- 052- 364; EARLY), 185 pazjent b’ PAH fi klassi II ta ’ l- istat funzjonali tal- WHO (medja fil- linja bażi tad- distanza ta ’ mixja f’ 6 minuti ta ’ 435 metru) irċevew bosentan 62. 5 mg b. i. d. għal 4 ġimgħat segwit minn 125 mg b. i. d.
(n = 93), or placebo (n = 92) for 6 months.
(n = 93), jew plaċebo (n = 92) għal 6 xhur.
Enrolled patients were PAH-treatment-naïve (n = 156) or on a stable dose of sildenafil (n = 29).
Pazjenti li daħlu fl- istudju jew qatt ma kienu ħadu kura qabel għal PAH (n = 156) jew kienu fuq doża stabbli ta ’ sildenafil (n = 29).
The co-primary endpoints were percentage change from baseline in PVR and change from baseline in 6-minute walk distance to Month 6 versus placebo.
L- endpoints ko- primarji kienu l - persentaġġ ta ’ bidla mil- linja bażi f’ PVR u bidla mil- linja bażi fid- distanza ta ’ mixja f’ 6 minuti sa Xahar 6 kontra l- plaċebo.
The table below illustrates the pre- specified protocol analyses.
It- tabella isfel turi l- analiżi tal- protokol speċifikat minn qabel.
6-Minute Walk Distance (m)
Distanza ta ’ Mixja f’ 6 Minuti (m)
Placebo (n =88) Bosentan (n=80) Placebo (n=91) Bosentan (n=86) Baseline (BL); mean (SD) Change from BL; mean (SD) Treatment effect
Plaċebo (n =88) Bosentan (n=80) Plaċebo (n=91) Bosentan (n=86) Linja bażi (BL); medja (SD) Bidla minn BL; medja (SD) Effett tal- kura
802 (365) 128 (465)
802 (365) 128 (465)
-22.6%
- 22. 6%
851 (535) -69 (475)
851 (535) - 69 (475)
431 (92) -8 (79)
431 (92) - 8 (79)
P-value
Valur- p
0.0758
0. 0758
Treatment with bosentan was associated with a reduction in the rate of clinical worsening, defined as a composite of symptomatic progression, hospitalisation for PAH and death, compared with placebo (proportional risk reduction 77%, 95% CI 20%–94%, p = 0.0114).
Kura b' bosentan kienet assoċjata ma 'tnaqqis fir- rata ta' rkadar kliniku, definita bħala taħlita ta ’ progressjoni sintomatika, żamma l- isptar minħabba PAH u mewt, meta mqabbla mal- plaċebo (tnaqqis proporzjonali fir- riskju ta ’ 77%, 95% CI 20% – 94%, p = 0. 0114).
The treatment effect was driven by improvement in the component symptomatic progression.
L- effett tal- kura kien immexxi minn titjib fil- komponent ta ’ progressjoni sintomatika.
There was one hospitalisation related to PAH worsening in the bosentan group and 3 hospitalisations in the placebo group.
Kien hemm każ wieħed ta ’ żamma l- isptar relatat ma ’ rkadar ta ’ PAH fil- grupp ta ’ bosentan u 3 każijiet ta ’ żamma l- isptar fil- grupp bil- plaċebo.
Only one death occurred in each treatment group during the 6-month double-blind study period, therefore no conclusion can be drawn on survival.
F’ kull grupp ta ’ kura seħħet biss mewt waħda waqt il- perijodu ta ’ studju double- blind ta ’ 6 xhur, għalhekk ma tista 'tittieħed l- ebda konklużjoni dwar is- sopravivenza.
In a prospective, multi-centre, randomized, double-blind, placebo-controlled study (BREATHE-5), patients with pulmonary arterial hypertension WHO functional Class III and Eisenmenger physiology associated with congenital heart disease received Tracleer 62.5 mg bid for 4 weeks, then 125 mg b.i.d. for a further 12 weeks (n = 37), or placebo (n = 17).
Fi studju prospettiv, multi- ċentriku, randomised, double- blind u kkontrollat bil- plaċebo (BREATHE - 5), pazjenti bi pressjoni għolja arterjali pulmonari ta ’ Klassi Funzjonali III tal- WHO u fiżjoloġija ta ’ Eisenmenger marbuta ma ’ mard tal- qalb konġenitali, irċivew Tracleer 62. 5 mg mogħti darbtejn kuljum għal 4 ġimgħat, imbagħad 125 mg mogħti darbtejn kuljum għal 12- il ġimgħa addizzjonali (n = 37), jew plaċebo (n = 17).
The primary objective was to show that Tracleer did not worsen hypoxaemia.
L- għan prinċipali kien li jintwera li Tracleer ma jiggravax il- livell baxx ta ’
14 bosentan did not worsen hypoxemia.
15 ossiġnu fid- demm.
The mean pulmonary vascular resistance was significantly reduced in the bosentan group (with a predominant effect observed in the subgroup of patients with bidirectional intracardiac shunt).
Wara 16- il ġimgħa, il- medja tas- saturazzjoni ta ’ l- ossiġnu żdiedet fil- grupp ta ’ bosentan minn 1. 0% (95% CI – 0. 7; 2. 8%) meta mqabbla mal- grupp tal- plaċebo, li turi li bosentan ma ’ kompliex jiggrava l- livell baxx ta ’ ossiġnu fid- demm.
After 16 weeks, the mean placebo-corrected increase in 6-minute walk distance was 53 meters (p = 0.0079) reflecting improvement of exercise capacity.
Wara 16- il ġimgħa, il- medja taż- żieda fid- distanza tal- mixja ta ’ 6 minuti, ikkoreġuta għall- plaċebo, kienet ta ’ 53 metru (p = 0. 0079), li tirrifletti t- tijib fil- kapaċità ta ’ l- eżerċizzju.
An open label, non-comparative study (AC-052-362; BREATHE-4) was performed in 16 patients with WHO Class III PAH associated with HIV infection.
Studu open label, mhux komparattiv (AC- 052- 362; BREATHE- 4) twettaq fuq 16- il pazjent bil- PAH ta ’ Klassi Funzjonali III tal- WHO marbuta ma ’ infezzjoni bl- HIV.
Patients were treated with Tracleer 62.5 mg bid for 4 weeks followed by 125 mg bid for a further 12 weeks.
Il- pazjenti kienu kkurati bi 62. 5 mg ta ’ Tracleer mogħtija darbtejn kuljum għal 4 ġimgħat, segwiti minn 125 mg mogħtija darbtejn kuljum għal 12- il ġimgħa addizzjonali.
After 16 weeks treatment, there were significant improvements from baseline in exercise capacity: mean increase in 6-minute walk test: +91.4 meters from 332.6 meters on average at baseline (p < 0.001).
Wara 16- il ġimgħa ta ’ kura, kien hemm titjib sinifikanti mil- linja bażi fil- kapaċità ta ’ l- eżerċizzju: żieda medja fit- test tal- mixja ta ’ 6 minuti: +91. 4 metri minn 332. 6 metri bħala medja fil- linja bażi (p < 0. 001).
As part of the safety assessment, the effect of bosentan on the antiretroviral therapy (i.e. reduced systemic concentrations of the co- administered antiretroviral agents with a potential negative impact on the efficacy of the antiretroviral therapy) was assessed through CD4 cell counts and HIV-1 RNA titers.
Bħala parti mill- evalwazzjoni tas- sigurtà, l- effett ta ’ bosentan fuq it- terapija antiretrovirali (i. e. konċentrazzjonijiet sistemiċi mnaqqsa tal- mediċini antiretrovirali mogħtija flimkien li għandhom impatt potenzjalment negattiv fuq l- effikaċja tat- terapija antiretrovirali) kien evalwat permezz ta ’ l- għadd taċ- ċelluli CD4 u l- għadd taċ- ċelluli u titers ta ’ l - RNA ta ’ l- HIV- 1.
Given the limitations of the study (small number of patients, non-standardized pharmacokinetic investigation of antiretroviral drugs, heterogeneity of drug regimens), no formal conclusion can be drawn regarding the effects of bosentan on antiretroviral drug efficacy.
Minħabba l- limitazzjonijiet ta ’ l- istudju (numru żgħir ta ’ pazjenti, investigazzjoni farmakokinetika mhux standardizzata tal- mediċini antiretrovirali, eteroġeneità tal- korsijiet tal - mediċina), ma nistgħu naslu għall- ebda konklużjoni formali dwar l- effetti ta ’ bosentan fuq l- effikaċja tal- mediċina antiretrovirali.
An increase in HIV viral load was observed in 5 patients (see also Section 4.4).
Żieda fit- tagħbija virali ta ’ l- HIV kienet osservata f’ 5 pazjenti (ara wkoll sezzjoni 4. 4).
No clinical data are available after 16 weeks from this study.
L- ebda tagħrif kliniku mhu disponibbli wara 16- il ġimgħa minn dan l- istudju.
There are no studies to demonstrate beneficial effects on survival of treatment with Tracleer.
M’ hemm l- ebda studji li juru effetti ta ’ beneficcju fuq is- sopravivenza tal- kura bi Tracleer.
However, long-term vital status was recorded for all 235 patients who were treated with bosentan in the two pivotal placebo-controlled trials (AC-052-351 and AC-052-352) and/or their two uncontrolled, open- label extensions.
Madankollu, l- istatus vitali għal tul ta ’ żmien kien irrekordjat għall- 235 pazjent kollha li kienu kkurati b’ bosentan f’ żewġ studji importanti ħafna kkontrollati bil- plaċebo (AC- 052- 351 u AC- 052- 352) u/ jew iż- żewġ estensjonijiet open- label tagħhom.
The mean duration of exposure to bosentan was 1.9 years ± 0.7 years; [min:
Il- medja tat- tul ta ’ żmien ta ’ l- espożizzjoni għal bosentan kienet ta ’ 1. 9 snin ± 0. 7 snin; [minimu:
0.1; max:
0. 1; massimu:
3.3 years] and patients were observed for a mean of 2.0 ± 0.6 years.
3. 3 snin] u l- pazjenti kienu osservati għal medja ta ’ 2. 0 ± 0. 6 snin.
The majority of patients were diagnosed as PPH (72%) and were in WHO functional class III (84%).
Il- maġġoranza tal- pazjenti kienu dijanjostikati bħala PPH (72%) u kienu fil- Klassi Funzjonali III tal- WHO (84%).
In this total population, Kaplan-Meier estimates of survival were 93% and 84% after 1 and 2 years after the start of treatment with Tracleer, respectively.
F’ din il- popolazzjoni totali, l- istimi ta ’ Kaplan- Meier tas- sopravivenza kienu ta ’ 93% u 84% wara sena u sentejn wara l- bidu tal- kura bi Tracleer, rispettivament.
Survival estimates were lower in the subgroup of patients with PAH secondary to systemic sclerosis.
L- istimi tas - sopravivenza kienu iktar baxxi fis- sottogrupp ta ’ pazjenti b’ PAH sekondarja għal sklerożi sistemika.
The estimates may have been influenced by the initiation of epoprostenol treatment in 43/235 patients.
L- istimi setgħu kienu influwenzati mill- bidu tal- kura b’ epoprostenol fi 43/ 235 pazjenti.
Study performed in children with pulmonary arterial hypertension One study has been conducted in children with pulmonary hypertension.
Studji fit- tfal bi pressjoni għolja arterjali pulmonari Sar studju wieħed fuq tfal bi pressjoni għolja arterjali pulmonari.
Tracleer has been evaluated in an open-label non-controlled study in 19 paediatric patients with pulmonary arterial hypertension (AC-052-356, BREATHE-3: primary pulmonary hypertension 10 patients, and pulmonary arterial hypertension related to congenital heart diseases 9 patients).
Tracleer ġie evalwat fi studju open - label, mhux ikkontrollat f’ 19- il pazjent pedjatriku bi pressjoni għolja arterjali pulmonari (AC- 052- 356, BREATHE- 3: pressjoni għolja pulmonari primarja f’ 10 pazjenti, u pressjoni għolja pulmonari marbuta ma ’ mard konġenitali tal- qalb f’ 9 pazjenti).
This study was primarily designed as a pharmacokinetic study (see section 5.2).
Dan l- istudju kien primarjament maħsub bħala studju farmakokinetiku (ara sezzjoni 5. 2).
Patients were divided into and dosed according to three body- weight groups (see section 4.2) for 12 weeks.
Il- pazjenti nqasmu fi 3 gruppi skond il- piż korporju tagħhom u ngħataw doża skond il- grupp (ara sezzjoni 4. 2) għal 12- il ġimgħa.
Half of the patients in each group were already being treated with intravenous epoprostenol and the dose of epoprostenol remained constant for the duration of the trial.
Nofs il- pazjenti f’ kull grupp kienu diġà qed jiġu kkurati b’ epoprostenol minn ġol- vini u d- doża ta ’ epoprostenol baqgħet l- istess matul l - istudju.
The age range was 3–15 years.
Il- medda ta ’ età tal- pazjenti kienet bejn 3– 15- il sena.
Patients were in WHO functional class II (N = 15 patients, 79%) or class III (N = 4 patients, 21%) at baseline.
Il- pazjenti kienu fi Klassi Funzjonali II tal- WHO (N = 15 pazjenti, 79%) jew Klassi III (N = 4 pazjenti, 21%) fil- linja bażi.
Haemodynamics were measured in 17 patients.
L- emodinamiċi kienu mkejla fi 17- il pazjent.
The mean increase from baseline in cardiac index was 0.5 l/min/m2, the mean decrease in mean pulmonary arterial pressure was 8 mmHg, and the mean decrease in pulmonary vascular resistance was 389 dyn·sec·cm-5.
Iż- żieda medja fl- indiċi tal- qalb mil- linja bażi kienet ta ’ 0. 5 l/ min/ m2, it- tnaqqis medju fil- pressjoni arterjali pulmonari kienet ta ’ 8 mmHg, u t- tnaqqis medju fir- reżistenza vaskulari pulmonari kienet ta ’ 389 dyn· sek· ċm- 5.
These haemodynamic improvements from baseline were similar with or without co-administration of epoprostenol.
Dan it- titjib emodinamiku fil- parametri dinamiċi mil- linja bażi kien l- istess bl- għoti flimkien ta ’ epoprotestenol jew mingħajru.
Changes in exercise test parameters at week 12 from baseline were highly variable and none were significant.
Il- bidliet fil - parametri tat- test ta ’ l- eżerċizzju wara 12- il ġimgħa mil- linja bażi varjaw ħafna u l- ebda wieħed minnhom ma kien sinifikanti.
Combination with epoprostenol The combination of Tracleer and epoprostenol has been investigated in two studies:
L- użu ta ’ Tracleer flimkien ma ’ epoprostenol Il- kumbinazzjoni ta ’ Tracleer u epoprostenol kienet eżaminata f’ żewg studji AC- 052- 355 (BREATHE- 2) u AC- 052- 356 (BREATHE- 3).
AC-052-355 was a multi-centre, randomised, double-blind, parallel-group trial of Tracleer versus placebo in 33 patients with severe pulmonary arterial hypertension who were receiving concomitant epoprostenol therapy.
AC- 052- 355 kienen prova multi- ċentrika, randomised, double- blind, parallel- group ta ’ Tracleer kontra l- plaċebo fi 33 pazjent bi pressjoni għolja arterjali 16 pulmonari serja li kienu qed jirċievu terapija b’ epoprostenol konkomitanti.
AC-052-356 was an open-label, non-controlled trial; 10 of the 19 paediatric patients were on concomitant Tracleer and epoprostenol therapy during the 12-week trial.
AC- 052- 356 kienet prova open- label, non- controlled; 10 mid- 19- il pazjent pedjatriku kienu qed jieħdu Tracleer u terapija b’ epoprostenol fl- istess ħin matul it- 12- il ġimgħa tal- prova.
The safety profile of the combination was not different from the one expected with each component and the combination therapy was well tolerated in children and adults.
Il- profil tas- sigurtà tal- kumbinazzjoni ma kienx differenti minn dak mistenni b’ kull komponent, u t- terapija mħallta kienet ittollerata sew fit- tfal u fl- adulti.
The clinical benefit of the combination has not been demonstrated.
Il- benefiċċju kliniku ta ’ din il- kumbinazzjoni ma ntwerix.
15 Systemic sclerosis with digital ulcer disease Two randomised, double-blind, multi-centre, placebo-controlled trials have been conducted in 122 (Study AC-052-401, RAPIDS-1) and 190 (Study AC-052-331, RAPIDS-2) adult patients with systemic sclerosis and digital ulcer disease (either ongoing digital ulcers or a history of digital ulcers within the last year).
Sklerosi sistemika bil- marda tal- ulċeri fis- swaba Saru żewġ provi kkontrollati bil- plaċebo, randomised, double- blind u multi- centre, f’ 122 (Studju AC - 052- 401, RAPIDS- 1) u 190 (Studju AC- 052- 331, RAPIDS- 2) pazjent adult bi sklerosi sistemika u l - marda tal- ulċeri fis- swaba (preżenza ta ’ ulċeri fis- swaba jew passat ta ’ ulċeri fis- swaba fl- aħħar sena).
In study AC-052-331, patients had to have at least one digital ulcer of recent onset, and across the two studies 85% of patients had ongoing digital ulcer disease at baseline.
Fl- istudju AC- 052- 331, il- pazjenti ried ikkollhom mill- anqas ulċera waħda fis- swaba b’ bidu reċenti, u tul iż- żewġ studji 85% tal- pazjenti kellhom il- preżenza tal- marda tal- ulċeri fis- swaba fil- linja bażi.
After 4 weeks of Tracleer 62.5 mg twice daily, the maintenance doses studied in both these trials were 125 mg twice daily.
Wara 4 ġimgħat b’ Tracleer 62. 5 mg darbtejn kuljum, id- dożi ta ’ manteniment studjati fiż- żewġ studji kienu ta ’ 125 mg darbtejn kuljum.
The duration of double-blind therapy was 16 weeks in study AC-052-401, and 24 weeks in study AC-052-331.
It- terapija double- blind damet 16- il ġimgħa fl- istudju AC- 052- 401, u 24 ġimgħa fl- istudju AC- 052- 331.
Background treatments for systemic sclerosis and digital ulcers were permitted if they remained constant for at least 1 month prior to the start of treatment and during the double-blind study period.
Kura oħra li kienet qed titieħed għal sklerosi sistemika u l- ulċeri fis- swaba kienet permessa jekk baqgħet konstanti mill- anqas xahar qabel il- bidu tal- kura u waqt il- perjodu tal- istudju double- blind.
The number of new digital ulcers from baseline to study endpoint was a primary endpoint in both studies.
In- numru ta ’ ulċeri fis- swaba ġodda mill- linja bażi sa l- aħħar ta ’ l- istudju kien il- mira prinċipali taż - żewġ studji.
Treatment with Tracleer resulted in fewer new digital ulcers for the duration of therapy, compared with placebo.
Meta mqabbla ma ’ plaċebo, kura b’ Tracleer irriżultat f’ anqas ulċeri ġodda waqt it - terapija.
In study AC-052-401, during 16 weeks of double-blind therapy, patients in the bosentan group developed a mean of 1.4 new digital ulcers vs.
Fl- istudju AC- 052- 401, waqt 16- il ġimgħa ta ’ terapija double- blind, il- pazjenti fil- grupp b’ bosentan żviluppaw medja ta ’ 1. 4 ulċeri fis- swaba ġodda vs.
2.7 new digital ulcers in the placebo group (p = 0.0042).
2. 7 ulċeri fis- swaba ġodda fil- grupp bil - plaċebo (p = 0. 0042).
In study AC-052-331, during 24 weeks of double-blind therapy, the corresponding figures were 1.9 vs.
Fl- istudju AC- 052- 331, waqt 24 ġimgħa ta ’ terapija double- blind, il- figuri korrispondenti kienu ta ’ 1. 9 vs.
2.7 new digital ulcers, respectively (p = 0.0351).
2. 7 ulċeri fis- swaba ġodda, rispettivament (p = 0. 0351).
In both studies, patients on bosentan were less likely to develop multiple new digital ulcers during the study and took longer to develop each successive new digital ulcer than did those on placebo.
Fiż- żewġ studji, pazjenti fuq bosentan kienu anqas probabbli li jiżviluppaw ulċeri fis- swaba ġodda waqt l - istudju u damu iżjed biex jiżviluppaw ulċera fis- swaba ġdida ta ’ wara, meta mqabbla ma ’ dawk fuq il - plaċebo.
The effect of bosentan on reduction of the number of new digital ulcers was more pronounced in patients with multiple digital ulcers.
L- effett ta ’ bosentan li jnaqqas in- numru ta ’ ulċeri fis- swaba ġodda deher aktar f’ pazjenti b’ ulċeri fis- swaba multipli.
No effect of bosentan on time to healing of digital ulcers was observed in either study.
Fiż- żewġ studji ma kien osservat l- ebda effett ta ’ bosentan fuq iż- żmien sal- fejqan ta ’ l- ulċeri fis - swaba.
The pharmacokinetics of bosentan have mainly been documented in healthy subjects.
Il- farmakokinetiċi ta ’ bosentan kienu ddokumentati l- aktar f’ pazjenti f’ saħħithom.
Limited data in patients show that the exposure to bosentan in adult pulmonary arterial hypertension patients is approximately 2-fold greater than in healthy adult subjects.
Informazzjoni limitata dwar il- pazjenti turi li l- espożizzjoni ta ’ bosentan fl- adulti bi pressjoni għolja arterjali pulmonari hi madwar id- doppju ta ’ dik f’ pazjenti f’ saħħithom.
In healthy subjects, bosentan displays dose- and time-dependent pharmacokinetics.
F’ pazjenti f’ saħħithom, bosentan juri farmakokinetiċi li jiddependu mid- doża u mill- ħin.
Clearance and volume of distribution decrease with increased intravenous doses and increase with time.
Ir- rata ta ’ tneħħija u l- volum tad- distribuzzjoni jonqsu meta jiżdiedu d- dożi mogħtija ġol- vini u jiżdiedu maż - żmien.
After oral administration, the systemic exposure is proportional to dose up to 500 mg.
Wara l- għoti mill- ħalq, l- espożizzjoni sistemika hi proporzjonali mad- doża sa 500 mg.
At higher oral doses Cmax and AUC increase less than proportionally to the dose.
B’ dożi orali ogħla, is- Cmax u l- AUC jiżdiedu inqas minn proporzjonalment mad- doża.
In healthy subjects the absolute bioavailability of bosentan is approximately 50% and is not affected by food.
F’ pazjenti f’ saħħithom il- bijodisponibilità assoluta ta ’ bosentan hi ta ’ madwar 50%, u mhix affettwata mill- ikel.
The maximum plasma concentrations are attained within 3–5 hours.
Il- konċentrazzjonijiet massimi fil- plażma jintlaħqu fi żmien 3– 5 sigħat.
Bosentan is highly bound (> 98%) to plasma proteins, mainly albumin.
Bosentan jeħel sew (> 98%) mal- proteini tal- plażma, l- aktar ma ’ l- albumina.
Bosentan does not penetrate into erythrocytes.
Bosentan ma jippenetrax fiċ- ċelluli tad- demm ħomor.
A volume of distribution (Vss) of about 18 litres was determined after an intravenous dose of 250 mg.
Il- volum tad- distribuzzjoni (Vss) ta ’ madwar 18- il litru kien determinat wara doża ġol- vini ta ’ 250 mg.
Biotransformation and elimination
17 Bijotransformazzjoni u eliminazzjoni
After a single intravenous dose of 250 mg, the clearance was 8.2 l/h.
Wara doża waħda ġol- vini ta ’ 250 mg, ir- rata li biha jitneħħa bosentan kienet ta ’ 8. 2 l/ siegħa.
The terminal elimination half-life (t1/2) is 5.4 hours.
Hemm bżonn ta ’ 5. 4 sigħat (t1/ 2) biex il- konċentrazzjonijiet ta ’ bosentan tonqos bin- nofs.
16 Upon multiple dosing, plasma concentrations of bosentan decrease gradually to 50%–65% of those seen after single dose administration.
Wara ħafna dozi, il- konċentrazzjonijiet ta ’ bosentan fil- plażma jonqsu gradwalment għal 50% – 65% ta ’ dawk li jidhru wara doża waħda.
This decrease is probably due to auto-induction of metabolising liver enzymes.
Dan it- tnaqqis probabbilment iseħħ minħabba l- awto- induzzjoni ta ’ l - enzimi li jimmetabolaw tal- fwied.
Steady-state conditions are reached within 3–5 days.
Il- kundizzjonijiet ta ’ l- istat fiss jintlaħqu fi żmien 3– 5 ijiem.
Bosentan is eliminated by biliary excretion following metabolism in the liver by the cytochrome P450 isoenzymes, CYP2C9 and CYP3A4.
Bosentan jiġi eliminat mis- sistema tal- marrara wara metaboliżmu fil- fwied mill- isoenzimi taċ - ċitokromju P450, CYP2C9 u CYP3A4.
Less than 3% of an administered oral dose is recovered in urine.
Inqas minn 3% tad- doża meħuda mill- ħalq tiġi rkuprata fl - arwrina.
Bosentan forms three metabolites and only one of these is pharmacologically active.
Bosentan jifforma tliet metaboliti u wieħed biss minn dawn hu attiv farmakoloġikament.
This metabolite is mainly excreted unchanged via the bile.
Dan jitneħħa fil- biċċa l- kbira tiegħu mhux mibdul permezz tal- bila.
In adult patients, the exposure to the active metabolite is greater than in healthy subjects.
F’ pazjenti adulti, l- espożizzjoni għal metabolit attiv hi akbar milli fil- pazjenti f’ saħħithom.
In patients with evidence of the presence of cholestasis, the exposure to the active metabolite may be increased.
F’ pazjenti li għandhom evidenza ta ’ kolestażi, l - espożizzjoni għall- metabolit attiv tista ’ tiżdied.
Bosentan is an inducer of CYP2C9 and CYP3A4 and possibly also of CYP2C19 and the P-glycoprotein.
Bosentan jinduċi CYP2C9 u CYP3A4 u possibbilment CYP2C19 ukoll u P- glycoprotein.
In vitro, bosentan inhibits the bile salt export pump in hepatocyte cultures.
In vitro, bosentan jimpedixxi l- bile salt export pump f’ kultivazzjoni taċ- ċelluli tal- fwied.
In vitro data demonstrated that bosentan had no relevant inhibitory effect on the CYP isoenzymes tested (CYP1A2, 2A6, 2B6, 2C8, 2C9, 2D6, 2E1, 3A4).
Tagħrif minn studji in vitro juri li bosentan ma kellu l- ebda effett rilevanti ta ’ inibizzjoni fuq l - isoenzimi CYP li ġew ittestjati (CYP1A2, 2A6, 2B6, 2C8, 2C9, 2D6, 2E1, 3A4).
Consequently, bosentan is not expected to increase the plasma concentrations of medicinal products metabolised by these isoenzymes.
Għalhekk, bosentan mhux mistenni li jżid il- konċentrazzjonijiet fil- plażma ta ’ prodotti mediċinali li jiġu metabolati minn dawn l- isoenzimi.
Pharmacokinetics in special populations
Tagħrif farmakokinetiku f’ popolazzjonijiet speċjali.
Based on the investigated range of each variable, it is not expected that the pharmacokinetics of bosentan will be influenced by gender, body weight, race, or age in the adult population to any relevant extent.
Ibbażat fuq il- medda investigata ta ’ kull varjant, mhux mistenni li l- farmakokinetiċi ta ’ bosentan ser jiġu influwenzati mis- sess, il- piż korporju, ir- razza, jew l- età fil- popolazzjoni adulta sa punt li hu rilevanti.
No kinetic data are available in children under 3 years.
Ma teżisti l- ebda informazzjoni kinetika fi tfal taħt it- 3 snin.
Children The pharmacokinetics of single and multiple oral doses were studied in paediatric patients with pulmonary arterial hypertension who were dosed on the basis of body weight (see sections 4.2 and 5.1).
Tfal Il- farmakokinetiċi ta ’ dożi singoli jew ripetuti ġew studjati fit- tfal bi pressjoni għolja arterjali pulmonari li ngħataw doża skond il- piż korporju tagħhom (ara sezzjoni 4. 2 u 5. 1).
The exposure to bosentan decreased with time in a manner consistent with the known auto- induction properties of bosentan.
L- espożizzjoni għal bosentan naqset maż- żmien b’ mod konsistenti mal- proprjetajiet magħrufa ta ’ l- awto- induzzjoni ta ’ bosentan.
The mean AUC (CV%) values of bosentan in paediatric patients treated with 31.25, 62.5 or 125 mg b.i.d. were 3496 (49), 5428 (79), and 6124 (27) ng·h/ml, respectively, and were lower than the value of 8149 (47) ng·h/ml observed in adult patients with pulmonary arterial hypertension receiving 125 mg b.i.d.
Il- valuri medji ta ‘ l- AUC (CV%) ta ’ bosentan f’ pazjenti pedjatriċi kkurati b’ doża ta ’ 31. 25, 62. 5 jew 125 mg darbtejn kuljum kienu 3496 (49), 5428 (79), u 6124 (27) ng· h/ ml, rispettivament, u kienu inqas mill- valur ta ’ 8149 (47) ng· h/ ml osservat f’ pazjenti adulti bi pressjoni għolja arterjali pulmonari li kienu qed jirċievu doża ta ‘ 125 mg darbtejn kuljum.
At steady state the systemic exposure in paediatric patients weighing 10–20 kg, 20–40 kg and > 40kg were 43%, 67% and 75%, respectively, of the adult systemic exposure.
Fl- istat fiss, l- espożizzjoni sistemika fit- tfal li jiżnu 10– 20 kg, 20– 40 kg u > 40kg kienet 43%, 67% u 75%, rispettivament, ta ’ l - espożizzjoni sistemika fl- adulti.
The reason for this difference is unclear and possibly related to an increased hepatic metabolism and excretion.
Ir- raġuni għal din id- differenza mhijiex magħrufa u huwa possibbli li din hi marbuta ma ’ żieda fil- metaboliżmu u l- eliminazzjoni mill- fwied.
The consequences of these findings regarding hepatotoxicity are unknown.
Il- konsegwenzi ta ’ dawn is - sejbiet dwar l- epatotossiċità mhumiex magħrufa.
Gender and the concomitant use of intravenous epoprostenol had no significant effect on the pharmacokinetics of bosentan.
Is- sess tal- persuna u l- użu ta ’ epoprostenol flimkien ma ’ bosentan ġol- vini ma kellhom l- ebda effett sinifikanti fuq il- farmakokinetiċi ta ’ bosentan.
Hepatic impairment In patients with mildly impaired liver function (Child-Pugh class A) no relevant changes in the pharmacokinetics have been observed.
Indeboliment tal- fwied F’ pazjenti b’ indeboliment ħafif tal- fwied (Child- Pugh Klassi A) ma ġew osservati l- ebda bidliet farmakokinetiċi sinifikanti.
The steady state AUC of bosentan was 9% higher and the AUC of the active metabolite, Ro 48-5033, was 33% higher in patients with mild hepatic impairment than in healthy volunteers.
L- AUC fl- istat fiss ta ’ bosentan kien 9% ogħla u l- AUC tal- metabolit attiv, Ro 48- 5033, kien 33% ogħla f’ pazjenti b’ indeboliment ħafif tal- fwied milli f’ voluntiera f’ saħħithom.
The pharmacokinetics of bosentan have not been studied in patients with Child- Pugh class B or C hepatic impairment and Tracleer is contra-indicated in this patient population (see section 4.3).
Il- farmakokinetiċi ta ’ bosentan ma kienux studjati f’ pazjenti b’ indeboliment tal- fwied (Child- Pugh Klassi B jew Ċ), u Tracleer hu kontra- indikat f’ din il- popolazzjoni ta ’ pazjenti (ara sezzjoni 4. 3).
Renal impairment In patients with severe renal impairment (creatinine clearance 15–30 ml/min), plasma concentrations of bosentan decreased by approximately 10%.
18 Indeboliment tal- kliewi F’ pazjenti b’ indeboliment serju tal- kliewi (tneħħija tal- krejatinina 15– 30 ml/ min), il - konċentrazzjonijiet ta ’ bosentan fil- plażma naqsu b’ madwar 10%.
Plasma concentrations of bosentan metabolites increased about 2-fold in these patients as compared to subjects with normal renal function.
Il- konċentrazzjonijiet tal- metaboliti ta ’ bosentan fil- plażma rduppjaw f’ dawn il- pazjenti meta mqabbla ma ’ suggetti mingħajr b’ funzjoni normali tal- kliewi.
No dose adjustment is required in patients with renal impairment.
M’ hemm bżonn l- ebda aġġustament f’ pazjenti b’ indeboliment tal- kliewi.
There is no specific clinical experience in patients undergoing dialysis.
M’ hemm l- ebda esperjenza klinika speċifika f’ pazjenti li qed issirilhom id- dijaliżi.
Based on physicochemical properties and the high degree of protein binding, bosentan is not expected to be removed from the circulation by dialysis to any significant extent (see section 4.2).
Ibbażat fuq proprjetajiet fiżiċi u kimiċi u l- ammont qawwi ta ’ bosentan li jeħel mal- proteini, mhux mistenni li d- dijaliżi tnaqqas l- ammont ta ’ bosentan fiċ- ċirkolazzjoni b’ mod sinifikanti (ara sezzjoni 4. 2).
17 5.3 Preclinical safety data
5. 3 Tagħrif ta ’ qabel l- użu kliniku dwar is- sigurtà tal- mediċina
A 2-year carcinogenicity study in mice showed an increased combined incidence of hepatocellular adenomas and carcinomas in males, but not in females, at plasma concentrations about 2 to 4 times the plasma concentrations achieved at the therapeutic dose in humans.
Studju fil- ġrieden dwar il- karċinoġeniċità li dam sentejn, wera żieda fl- inċidenża kombinata ta ’ adenomi fiċ- ċelluli tal- fwied flimkien ma ’ karċinomi fil- ġrieden irġiel, imma mhux fil- ġrieden nisa, f’ konċentrazzjonijiet fil- plażma madwar darbtejn sa erba ’ darbiet aktar mill- konċentrazzjonijiet fil - plażma li ntlaħqu fid- doża terapewtika fil- bniedem.
In rats, oral administration of bosentan for 2 years produced a small, significant increase in the combined incidence of thyroid follicular cell adenomas and carcinomas in males, but not in females, at plasma concentrations about 9 to 14 times the plasma concentrations achieved at the therapeutic dose in humans.
Fil- firien, l- għoti mill- ħalq ta ’ bosetan għal sentejn ipproduċa żieda żgħira imma sinifikanti fl- inċidenza ta ’ adenomi taċ- ċelluli follikulari tat- tirojde u karċinomi fil- firien irġiel, imma mhux fil- firien nisa, f’ konċentrazzjonijiet fil- plażma ta ’ madwar 9 sa 14- il darba iktar mill- konċentrazzjonijiet fil- plażma li ntlaħqu fid- doża terapewtika fil- bniedem.
Bosentan was negative in tests for genotoxicity.
Bosentan kien negattiv fit- testijiet għal ġenotossiċità.
There was evidence for a mild thyroid hormonal imbalance induced by bosentan in rats.
Kien hemm evidenza ta ’ żbilanċ żgħir fl- ormoni tat- tirojde ikkawżat minn bosentan fil- firien.
However, there was no evidence of bosentan affecting thyroid function (thyroxine, TSH) in humans.
Madankollu, m’ hemm l- ebda evidenza li bosentan jaffettwa l- funzjoni tat- tirojde (thyroxine, TSH) fil- bnedmin.
The effect of bosentan on mitochondrial function is unknown.
L- effett ta ’ bosentan fuq il- funzjoni tal- mitokondrija mhuwiex magħruf.
Bosentan has been shown to be teratogenic in rats at plasma levels higher than 1.5 times the plasma concentrations achieved at the therapeutic dose in humans.
Bosentan wera effetti teratoġeniċi fil- firien fejn intlaħqu livelli fil- plażma ogħla minn 1. 5 darbiet iktar mill- konċentrazzjonijiet fil- plażma li ntlaħqu fid- doża terapewtika fil- bniedem.
Teratogenic effects, including malformations of the head and face and of the major vessels, were dose dependent.
L- effetti teratoġeniċi, li jinkludu malformazzjonijiet tar- ras u tal- wiċċ u tal- vini u arterji prinċipali, kienu jiddependu mid - doża.
The similarities of the pattern of malformations observed with other ET receptor antagonists and in ET knock-out mice indicate a class effect.
Ix- xebh ta ’ kif kienu l- malformazzjonijiet li kienu osservati b’ antagonisti oħra tar- riċetturi ta ’ ET u fi ġrieden ET knock- out jindikaw effett tal- klassi.
Appropriate precautions must be taken for women of child-bearing potential (see sections 4.3, 4.4, 4.6).
Għandhom jittieħdu prekawzjonijiet adattati f’ nisa li jistgħu joħorġu tqal (ara sezzjoni 4. 3, 4. 4, 4. 6).
In fertility studies in male and female rats at plasma concentrations 21 and 43 times, respectively, the expected therapeutic level in humans, no effects on sperm count, motility and viability, or on mating performance or fertility were observed, nor was there any adverse effect on the development of the pre-implantation embryo or on implantation.
Meta sarux studji dwar il- fertilità fil- firien irġiel u nisa, f’ konċentrazzjonijiet fil- plażma li kienu 21 u 43 darba, rispettivament, tal- livell terapewtiku mistenni fil- bniedem, ma ġew osservati l- ebda effetti fuq l- għadd ta ’ l- isperma, fuq il- motilità u l- vijabilità, fuq il- prestazzjoni ta ’ l- att sesswali jew fuq il - fertilità, u l- anqas ma kien hemm l- ebda effetti avvers fuq l- iżvilupp ta ’ l- embriju qabel jew waqt l - impjantazzjoni.
Maize starch Pregelatinised starch Sodium starch glycollate Povidone Glycerol dibehenate Magnesium stearate
Maize starch Pregelatinised starch Sodium starch glycollate Povidone Glycerol dibehenate Magnesium stearate
Film coat:
Kisja tar- rita:
Hypromellose Glycerol triacetate Talc Titanium dioxide (E171) Iron oxide yellow (E172) Iron oxide red (E172) Ethylcellulose
Hypromellose Glycerol triacetate Talc Titanium dioxide (E171) Iron oxide yellow (E172) 19 Iron oxide red (E172) Ethylcellulose
18 Do not store above 30°C.
Taħżinx f’ temperatura ’ l fuq minn 30°C
PVC/PE/PVDC/aluminium-blisters containing 14 film-coated tablets.
Folji magħmula minn PVC/ PE/ PVDC/ aluminju li fihom 14- il pillola miksija b’ rita.
62.5 mg:
62. 5 mg:
Cartons contain 14, 56 or 112 film-coated tablets.
Il- kartun fihom 14, 56 jew 112- il pillola miksija b’ rita.
Not all pack sizes may be marketed.
Jista ’ jkun li mhux il- pakketti tad- daqsijiet kollha jkunu għal bejgħ.
Actelion Registration Ltd BSI Building 13th Floor 389 Chiswick High Road London W4 4AL United Kingdom
Actelion Registration Ltd BSI Building 13th Floor 389 Chiswick High Road London W4 4AL Ir- Renju Unit
Date of first authorisation:15 May 2002
Data ta ’ l- ewwel awtorizzazzjoni:
Date of renewal:
15 ta ’ Mejju, 2002 Data ta ’ tiġdid:
15 May 2007
15 ta ’ Mejju 2007
Detailed information on this medicinal product is available on the website of the European Medicines Agency (EMEA) http://www.emea.europa.eu/.
Informazzjoni dettaljata dwar dan il- prodott tinsab fuq il- website ta ’ l- Aġenzija Ewropeja dwar il- Mediċini (EMEA) http: // www. emea. europa. eu /.
Tracleer 125 mg film-coated tablets
Tracleer 125 mg, pillola miksija b’ rita
Each film-coated tablet contains 125 mg bosentan (as monohydrate).
Kull pillola fiha 125 mg ta ’ bosentan (bħala monohydrate)
Orange-white, oval, biconvex, film-coated tablets, embossed with “125” on one side.
Pillola miksija b’ rita, oranġjo- bojod, ovali, bil- kitba “ 125 ” imnaqqxa fuq naħa waħda.
Efficacy has been shown in: • Primary (idiopathic and familial) PAH • PAH secondary to scleroderma without significant interstitial pulmonary disease • PAH associated with congenital systemic-to-pulmonary shunts and Eisenmenger’s physiology
L- effikaċja ntweriet fi: • PAH primarja (idjopatika u familjali) • PAH bħala konsegwenza ta ’ l- iskleroderma (meta l- ġilda teħxien) mingħajr mard pulmonari interstizjali sinifikanti • PAH marbuta ma 'shunts sistemiċi- pulmonari konġenitali u fiżjoloġija ta ’ Eisenmenger
Pulmonary arterial hypertension.
Ipertensjoni arterjali pulmonari.
In the case of clinical deterioration (e.g., decrease in 6-minute walk test distance by at least 10% compared with pre-treatment measurement) despite Tracleer treatment for at least 8 weeks (target dose for at least 4 weeks), alternative therapies should be considered.
F’ każ li s- sitwazzjoni klinika tmur għall- agħar (eż. tnaqqis fid- distanza tat- test tal- mixja ta ’ 6 minuti ta ’ mill- inqas 10% meta mqabbel mal- kejl ta ’ qabel il- kura) minkejja li l- kura b’ Tracleer għal mill - inqas 8 ġimgħat (bid- doża fil- mira mogħtija għal mill- inqas 4 ġimgħat), terapiji alternattivi għandhom jiġu kkunsidrati.
In the case of late clinical deterioration despite treatment with Tracleer (i.e., after several months of treatment), the treatment should be re-assessed.
F’ każ li l- istat kliniku jmur għall- agħar wara ħafna żmien li jkun ilu jittieħed Tracleer (i. e. wara ħafna xhur ta ’ kura), il- kura għandha terġa ’ tkun evalwata mill- ġdid.
A careful risk/benefit assessment should be made, taking into consideration that the liver toxicity is dose dependent (see sections 4.4 and 5.1).
21 tar- riskju/ benefiċċju, u jiġi kkunsidrat il- fatt li t- tossiċità tal- fwied tiddependi mid- doża (ara sezzjonijiet 4. 4 u 5. 1).
20 Discontinuation of treatment
Twaqqif tal- kura
The patient’s response to treatment and need for continued therapy should be re-evaluated on a regular basis.
Ir- respons tal- pazjent għall- kura u l- bżonn ta ’ aktar terapija għandu jiġi evalwat mill- ġdid fuq bażi regolari.
A careful risk/benefit assessment should be made, taking into consideration the liver toxicity of bosentan (see sections 4.4 and 4.8).
Għandha ssir stima b’ attenzjoni tar- riskju/ benefiċċju b’ konsiderazzjoni tat- tossiċità għall - fwied ta ’ bosentan (ara sezzjonijiet 4. 4 u 4. 8).
No dose adjustment is needed in patients with mild hepatic impairment (i.e., Child-Pugh class A) (see section 5.2).
F’ każ ta ’ indeboliment ħafif tal- fwied, m’ hemmx bżonn ta ’ aġġustament fid- doża li tingħata (i. e.
This study was primarily designed to assess pharmacokinetics in children.
22 Dan l- istudju kien maħsub primarjament biex jevalwa l- farmakokinetiċi fit- tfal.
- Systemic sclerosis with ongoing digital ulcer disease:
Sklerosi sistemika bil- preżenza tal- marda ta ’ ulċeri fis- swaba:
• Hypersensitivity to the active substance or to any of the excipients • Child-Pugh Class B or C, i.e., moderate to severe hepatic impairment (see section 5.2) • Baseline values of liver aminotransferases, i.e., aspartate aminotransferases (AST) and/or alanine aminotransferases (ALT), greater than 3 times the upper limit of normal (see section 4.4) • Concomitant use of cyclosporine A (see section 4.5) • Pregnancy • Women of childbearing potential who are not using reliable methods of contraception (see sections 4.4, 4.5 and 4.6)
• Sensittività eċċessiva għas- sustanza attiva jew għal xi sustanzi mhux attivi. • Il- marda Child- Pugh Klassi B jew Ċ, i. e. ħsara epatika minn moderata sa serja (ara sezzjoni 5. 2) • Valuri tal- linja bażi ta ’ l- aminotransferases fil- fwied, i. e. aspartate aminotransferases (AST) u/ jew alanin aminotransferases (ALT), ta ’ aktar minn tliet darbiet il- limitu ta ’ fuq tan- normal (Upper Limit of Normal) • Użu konkomitanti ta ’ cyclosporine A (ara sezzjoni 4. 5) • Tqala • Nisa li għandhom il- potenzjali li joħorġu tqal u li mhumiex qed jużaw metodu affidabbli ta ’ kontraċezzjoni (ara sezzjonijiet 4. 4, 4. 5 u 4. 6)
Transfer to a therapy that is recommended at the severe stage of the disease (e.g., epoprostenol) should be considered if the clinical condition deteriorates (see section 4.2).
Jekk il- kundizzjoni klinika tal- pazjent tmur għall- agħar, għandu jiġi kkunsidrat jekk il- kura għandhiex tinbidel għal dik li hi rakkomandata fil- fażi severa tal- marda (eż. epoprostenol) (ara sezzjoni 4. 2).
The benefit/risk balance of bosentan has not been established in patients with WHO class I functional status of pulmonary arterial hypertension.
Il- bilanċ bejn il- benefiċċju u r- riskju ta ’ bosentan ma ġiex stabbilit f’ pazjenti bi Klassi I ta ’ l- istat funzjonali tal- WHO tal- pressjoni għolja arterjali pulmonari.
Elevations in liver aminotransferases, i.e., aspartate and alanine aminotransferases (AST and/or ALT), associated with bosentan are dose dependent.
Żieda ta ’ aminotransferases fil- fwied, i. e. ta ’ aspartate u ta ’ alanin (AST u/ jew ALT), assoċjata ma ’ bosentan tiddependi mid- doża.
The se increases may be partly due to competitive inhibition of the elimination of bile salts from hepatocytes but other mechanisms, which have not been clearly established, are probably also involved in the occurrence of liver dysfunction.
Parti minn din iż- żieda tista ’ tkun parzjalment minħabba l- inibizzjoni kompetittiva ta ’ l- eliminazzjoni tal- bile salts mill- hepatocytes, iżda mekkaniżmi oħrajn, li ma kienux stabbiliti b’ mod ċar, huma wkoll involuti ma ’ funzjoni ħażina tal- fwied.
Liver dysfunction risk may also be increased when medicinal products that are inhibitors of the bile salt export pump (BSEP), e.g., rifampicin, glibenclamide and cyclosporine A (see sections 4.3 and 4.5), are co- administered with bosentan, but limited data are available.
Madankollu, m’ hemmx biżżejjed informazzjoni dwar dan.
Liver aminotransferase levels must be measured prior to initiation of treatment and subsequently at monthly intervals for the duration of treatment with Tracleer.
23 Il- livelli ta ’ aminotransferase fil- fwied għandhom jiġu eżaminati qabel ma tinbeda l- kura u wara dan, kull xahar għal kemm iddum il- kura bi Tracleer.
Recommendations in case of ALT/AST elevations
Rakkomandazzjonijiet f’ każ ta ’ żidiet fl- ALT/ AST
22 ALT/AST levels > 3 and ≤ 5 × ULN
Livell ta ‘ l- ALT/ AST Rakkomandazzjonijiet dwar il- kura u l- monitoraġġ. > 3 u ≤ 5 × ULN
In case of associated clinical symptoms of liver injury, i.e., nausea, vomiting, fever, abdominal pain, jaundice, unusual lethargy or fatigue, flu-like syndrome (arthralgia, myalgia, fever), treatment must be stopped and re-introduction of Tracleer is not to be considered.
F’ każ ta ’ sintomi kliniċi assoċjati ma ’ ħsara tal- fwied, i. e. dardir, rimettar, deni, uġigħ addominali, suffejra, telqa u għeja mhux tas- soltu, sindrome bħall- influwenza (uġigħ fil- ġogi, uġigħ fil- muskoli, deni), il- kura għandha titwaqqaf u m’ għandux jiġi kkunsidrat li l- kura bi Tracleer terġa ’ tinbeda.
In placebo-controlled studies, bosentan-related decreases in haemoglobin concentration were not progressive, and stabilised after the first 4–12 weeks of treatment.
Fi studji kkontrollati bil- plaċebo, tnaqqis fil- konċentrazzjoni ta ’ l- emoglobina marbuta ma ’ l- użu ta ’ bosentan ma kienx progressiv u stabbilizza wara l- ewwel 4- 12- il ġimgħa tal - kura.
23 Pulmonary veno-occlusive disease
Mard veno- okklussiv pulmonari
However, 1,611 patients (804 Tracleer- and 807 placebo-treated patients) with severe chronic heart failure (CHF) were treated for a mean duration of 1.5 years in a placebo- controlled study (study AC-052-301/302 [ENABLE 1 & 2]).
Madankollu, 1, 611- il pazjent (804 li kienu qed jieħdu Tracleer u 807 li kienu qed jieħdu l- plaċebo) b’ kollass kroniku tal- qalb (chronic heart failure - CHF) kienu kkurati għal tul ta ’ żmien medju ta ’ sena u nofs fl- istudju kkontrollat bil- plaċebo (studju numru AC- 052- 301/ 302 [ENABLE 1 & 2]).