natgillin/translations-raw huggingface dataset:
I et prospektivt multicenter, randomiseret, dobbelblindt, placebokontrolleret studie (BREATHE- 5) fik patienter med pulmonal areteriel hypertension WHO klasse III og Eisenmenger fysiologi associeret med kongenit hjertesygdom Tracleer 62, 5 mg to gange daglig i 4 uger, herefter 125 mg to gang daglig i yderligere 12 uger (n = 37) eller placebo (n = 17).
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).
Det primære formål var at vise, at Tracleer ikke forværrede hypoxæmi.
The primary objective was to show that Tracleer did not worsen hypoxaemia.
Efter 16 uger var den gennemsnitlige iltmætning øget i bosentan gruppen med 1, 0% (95% CI - 0, 7; 2, 8%) sammenlignet med placebo gruppen, hvilke viste, at bosentan ikke forværrer hypoxæmi.
After 16 weeks, the mean oxygen saturation was increased in the bosentan group by 1.0% (95% CI –0.7; 2.8%) as compared to the placebo group, showing that
Efter 16 uger var den gennemsnitlige placebokorrigerede øgning af afstanden ved 6 minutters gang, 53 meter (p = 0, 0079), hvilket afspejler forbedring af arbejdskapaciteten.
After 16 weeks, the mean placebo-corrected increase in 6-minute walk distance was 53 meters (p = 0.0079) reflecting improvement of exercise capacity.
Et åbent, non- komparativt studie (AC- 052- 362; BREATHE- 4) blev udført med 16 patienter med WHO klasse III PAH associeret med HIV- infektion.
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.
Patienterne blev behandlet med Tracleer 62, 5 mg to gange daglig i 4 uger efterfulgt af 125 mg to gange daglig i yderligere 12 uger.
Patients were treated with Tracleer 62.5 mg bid for 4 weeks followed by 125 mg bid for a further 12 weeks.
Gennemsnitlig øgning ved 6 minutters gangtest: +91, 4 m fra 332, 6 m i gennemsnit ved udgangsværdier (p < 0, 001).
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).
Som en del af sikkerhedsvurderingen blev virkningen af bosentan på den antiretrovirale behandling (d. v. s. reducerede systemiske koncentrationer af de samtidigt administrerede antiretrovirale midler med en potentiel negativ indflydelse på virkningen af den antiretrovirale behandling) målt ved CD4 celletælling og HIV- 1 RNA - titere.
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.
En
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.
4. 4).
An increase in HIV viral load was observed in 5 patients (see also Section 4.4).
Der foreligger ingen kliniske data efter 16 uger fra dette studie.
No clinical data are available after 16 weeks from this study.
Der foreligger ingen studier med formålet at vise fordelagtige virkninger af behandling med Tracleer på overlevelse.
There are no studies to demonstrate beneficial effects on survival of treatment with Tracleer.
Vitalstatus over længere tid for alle 235 patienter, som blev behandlet med bosentan, blev imidlertid noteret, i de to pivotale placebo- kontrollerede studier (AC- 052- 351 og AC- 052- 352) og/ eller deres to ukontrollerede, open- label forlængelser.
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.
Den gennemsnitlige varighed for eksponering for bosentan var 1, 9 år ± 0, 7 år; [min:
The mean duration of exposure to bosentan was 1.9 years ± 0.7 years; [min:
0. 1; max:
0.1; max:
3. 3 år] og patienterne blev observeret i gennemsnitligt 2, 0 ± 0, 6 år.
3.3 years] and patients were observed for a mean of 2.0 ± 0.6 years.
Størstedelen af patienterne blev diagnosticeret som PPH (72%) og var i WHO funktionsklasse III (84%).
The majority of patients were diagnosed as PPH (72%) and were in WHO functional class III (84%).
I denne samlede population var Kaplan- Meier estimater vedrørende overlevelse henholdsvis 93% og 84% efter henholdsvis 1 og 2 år efter behandlingsstart med Tracleer.
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.
Estimaterne kan have været påvirket af initieringen af epoprostenol behandling hos 43/ 235 patienter.
The estimates may have been influenced by the initiation of epoprostenol treatment in 43/235 patients.
Undersøgelse med børn med pulmonal arteriel hypertension Der er udført et studie med børn med pulmonal arteriel hypertension.
Study performed in children with pulmonary arterial hypertension One study has been conducted in children with pulmonary hypertension.
10 patienter med primær pulmonal hypertension og 9 patienter med pulmonal arteriel hypertension relateret til kongenit hjertesygdom).
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).
Denne undersøgelse var primært designet som en farmakokinetisk undersøgelse (se pkt.
This study was primarily designed as a pharmacokinetic study (see section 5.2).
Patienterne blev delt i tre grupper afhængig af legemsvægt og modtog doser svarende hertil i 12 uger (se pkt.
Patients were divided into and dosed according to three body- weight groups (see section 4.2) for 12 weeks.
Halvdelen af patienterne i hver gruppe var allerede i behandling med intravenøs epoprostenol og epoprostenoldosis var uændret i hele undersøgelsens forløb.
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.
Aldersmæssigt spændte patienterne fra 3- 15 år.
The age range was 3–15 years.
Alle patienterne var enten i WHO funktionsklasse II (N = 15 patienter, 79%) eller III (N = 4 patienter, 21%) ved basalnieau.
Patients were in WHO functional class II (N = 15 patients, 79%) or class III (N = 4 patients, 21%) at baseline.
Middelstigningen fra basalniveau ved hjerteindeks var 0, 5 l/ min/ m2, gennemsnitligt fald i gennemsnitligt pulmonalt arterielt tryk var 8 mmHg, og gennemsnitligt fald i pulmonal karmodstand var 389 dyn· sec· cm- 5.
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.
Kombination med epoprostenol Kombinationen af Tracleer og epoprostenol er undersøgt i to undersøgelser:
Combination with epoprostenol The combination of Tracleer and epoprostenol has been investigated in two studies:
AC- 052- 355 (BREATHE- 2) og AC- 052- 356 (BREATHE- 3).
AC-052-355 (BREATHE-2) and AC-052-356 (BREATHE-3).
AC- 052- 355 var en multicenter, randomiseret dobbeltblind parallelgruppeundersøgelse af Tracleer sammenlignet med placebo hos 33 patienter med alvorlig pulmonal arteriel hypertension, som var i samtidig behandling med epoprostenol.
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.
10 ud af de 19 pædiatriske patienter fik samtidig behandling med Tracleer og epoprostenol i de 12 uger, undersøgelsen varede.
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.
Systemisk sklerose med fingersårssygdom Der er udført to randomiserede, dobbeltblinde, multicenter, placebokontrollerede studier med henholdsvis 122 (studie AC- 052- 401, RAPIDS- 1) og 190 (studie AC- 052- 331, RAPIDS- 2) voksne paitenter med systemisk sklerose og fingersårssygdom (enten akutte fingersår eller fingersår i anamnesen inden for det seneste år).
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).
I studie AC- 052- 331 skulle patienter have haft mindst et fingersår i nyligt udbrud, og i begge studier havde 85% af patienterne akutte fingersår ved basalniveau.
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.
Efter 4 ugers behandling med Tracleer 62, 5 mg to gange dagligt var vedligeholdelsesdosis i begge studier 125 mg to gange dagligt.
After 4 weeks of Tracleer 62.5 mg twice daily, the maintenance doses studied in both these trials were 125 mg twice daily.
Varigheden af den dobbeltblinde behandling var 16 uger i studie AC- 052- 401 og 24 uger i studie AC- 052- 331.
The duration of double-blind therapy was 16 weeks in study AC-052-401, and 24 weeks in study AC-052-331.
Behandling med Tracleer resulterede i færre nye fingersår i behandlingens varighed sammenlignet med
Treatment with Tracleer resulted in fewer new digital ulcers for the duration of therapy, compared with placebo.
I studie AC- 052- 401udviklede patienter i bosentan- gruppen i løbet af de 16 uger dobbeltblind behandling gennemsnitligt 1, 4 nye fingersår vs.
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.
2, 7 nye fingersår i placebogruppen (p= 0, 0042).
2.7 new digital ulcers in the placebo group (p = 0.0042).
I studie AC - 052- 331 var de tilsvarende tal i løbet af 24 ugers dobbeltblind behandling henholdsvis 1, 9 vs.
In study AC-052-331, during 24 weeks of double-blind therapy, the corresponding figures were 1.9 vs.
2, 7 nye fingersår (p= 0, 0351).
2.7 new digital ulcers, respectively (p = 0.0351).
Virkningen af bosentan på reduktion af antallet af nye fingersår vare mere udtalt hos patienter med mange fingersår.
The effect of bosentan on reduction of the number of new digital ulcers was more pronounced in patients with multiple digital ulcers.
2 gange højere end hos voksne, raske individer.
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.
Hos raske individer udviser bosentan dosis - og tidsafhængig farmakokinetik.
In healthy subjects, bosentan displays dose- and time-dependent pharmacokinetics.
Ved højere perorale doser forøges Cmax og AUC mindre end proportionalt med dosis.
At higher oral doses Cmax and AUC increase less than proportionally to the dose.
Hos raske individer er bosentans absolutte biotilgængelighed omkring 50% og påvirkes ikke af føde.
In healthy subjects the absolute bioavailability of bosentan is approximately 50% and is not affected by food.
Den maksimale plasmakoncentration opnås inden for 3– 5 timer.
The maximum plasma concentrations are attained within 3–5 hours.
18 liter blev konstateret efter en intravenøs dosis på 250 mg.
A volume of distribution (Vss) of about 18 litres was determined after an intravenous dose of 250 mg.
Efter en enkelt intravenøs dosis på 250 mg var clearance 8, 2 l/ t.
After a single intravenous dose of 250 mg, the clearance was 8.2 l/h.
Den terminale eliminationshalveringstid (t½) er 5, 4 timer.
The terminal elimination half-life (t1/2) is 5.4 hours.
Efter gentagne doser falder plasmakoncentrationerne af bosentan gradvist til 50% – 65% af de koncentrationer, som observeres efter administration af en enkeltdosis.
16 Upon multiple dosing, plasma concentrations of bosentan decrease gradually to 50%–65% of those seen after single dose administration.
Steady- state tilstande opnås inden for 3– 5 dage.
Steady-state conditions are reached within 3–5 days.
Bosentan elimineres gennem galden efter metabolisering i leveren via cytochrom P450- isoenzymer CYP2C9 og CYP3A4.
Bosentan is eliminated by biliary excretion following metabolism in the liver by the cytochrome P450 isoenzymes, CYP2C9 and CYP3A4.
Bosentan har en fremmende effekt på CYP2C9 og CYP3A4 og muligvis også på CYP2C19 og P- glycoprotein.
Bosentan is an inducer of CYP2C9 and CYP3A4 and possibly also of CYP2C19 and the P-glycoprotein.
In vitro inhiberer bosentan galdesalt- eksportpumpen i hepatocytkulturer.
In vitro, bosentan inhibits the bile salt export pump in hepatocyte cultures.
17 In vitro data påviste, at bosentan ikke havde nogen relevant inhiberende virkning på de CYP- isoenzymer, som blev testet (CYP1A2, 2A6, 2B6, 2C8, 2C9, 2D6, 2E1 og 3A4).
In vitro data demonstrated that bosentan had no relevant inhibitory effect on the CYP isoenzymes tested (CYP1A2, 2A6, 2B6, 2C8, 2C9, 2D6, 2E1, 3A4).
Der foreligger ingen kinetiske data for børn under 3 år.
No kinetic data are available in children under 3 years.
Børn Farmakokinetikken af enkelte og gentagne perorale doser blev undersøgt hos pædiatriske patienter med pulmonal arteriel hypertension, som modtog en dosis afhængig af legemsvægten (se pkt.
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).
Eksponering for bosentan aftog over tid på en måde, der svarede til bosentans kendte autoinduktionsegenskaber.
The exposure to bosentan decreased with time in a manner consistent with the known auto- induction properties of bosentan.
Middel AUC (CV%) værdier for bosentan hos pædiatriske patienter behandlet med 31, 25, 62, 5 eller 125 mg 2 gange daglig var henholdsvis 3496 (49), 5428 (79) og 6124 (27) ng· h/ ml, og var lavere end værdien 8149 (47) ng· h/ ml, der blev set hos voksne patienter med pulmonal arteriel hypertension, som blev behandlet med 125 mg 2 gange daglig.
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.
Ved steady state er den systemiske eksponering hos pædiatriske patienter med en legemsvægt på 10– 20 kg, 20– 40 kg og > 40 kg henholdsvis 43%, 67% og 75% af den systemiske eksponering hos voksne.
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.
Årsagen til denne forskel er uklar og muligvis relateret til en forøget hepatisk metabolisme og udskillelse.
The reason for this difference is unclear and possibly related to an increased hepatic metabolism and excretion.
Følgerne af disse resultater med hensyn til hepatotoksicitet er ukendte.
The consequences of these findings regarding hepatotoxicity are unknown.
Køn og samtidig anvendelse af intravenøs epoprostenol havde ingen signifikant indflydelse på bosentans farmakokinetik.
Gender and the concomitant use of intravenous epoprostenol had no significant effect on the pharmacokinetics of bosentan.
Nedsat leverfunktion Hos patienter med let nedsat leverfunktion (Child- Pugh klasse A) er der ikke blevet observeret nogen relevante farmakokinetiske ændringer.
Hepatic impairment In patients with mildly impaired liver function (Child-Pugh class A) no relevant changes in the pharmacokinetics have been observed.
Steady state- AUC for bosentan var 9% højere, og AUC for den aktive metabolit, Ro 48- 5033, var 33% højere hos patienter med let nedsat leverfunktion end hos raske voluntører.
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.
4. 3).
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).
Nedsat nyrefunktion Hos patienter med alvorligt nedsat nyrefunktion (kreatininclearance 15– 30 ml/ min) faldt plasmakoncentrationer af bosentan med omkring 10%.
Renal impairment In patients with severe renal impairment (creatinine clearance 15–30 ml/min), plasma concentrations of bosentan decreased by approximately 10%.
4. 2).
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).
5. 3 Prækliniske sikkerhedsdata
17 5.3 Preclinical safety data
2 til 4 gange de plasmakoncentrationer, der blev opnået ved den terapeutiske dosis hos mennesker.
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.
9 til 14 gange de plasmakoncentrationer, der blev opnået ved terapeutiske doser hos mennesker.
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.
Der fandtes bevis for en mild thyroid hormonel ubalance, som blev fremkaldt af bosentan hos rotter.
There was evidence for a mild thyroid hormonal imbalance induced by bosentan in rats.
18 Bosentan har vist sig at være teratogent hos rotter ved plasmakoncentrationer, der er mere end 1, 5 gange højere end de plasmakoncentrationer, der blev opnået ved terapeutiske doser hos mennesker.
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.
Ligheden mellem det mønster for misdannelser, der er iagttaget i forbindelse med andre ET- receptorantagonister og hos ET - knockoutmus, indikerer, at der er tale om en klasseeffekt.
The similarities of the pattern of malformations observed with other ET receptor antagonists and in ET knock-out mice indicate a class effect.
4. 3, 4. 4 og 4. 6).
Appropriate precautions must be taken for women of child-bearing potential (see sections 4.3, 4.4, 4.6).
Der observeredes heller ingen negative virkninger på udviklingen af præimplantationsembryoet eller på implantationen.
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.
Majsstivelse Prægelatineret stivelse Natriumstivelsesglycolat Povidon Glyceroldibehenat Magnesiumstearat
Maize starch Pregelatinised starch Sodium starch glycollate Povidone Glycerol dibehenate Magnesium stearate
Hypromellose Glyceroltriacetat Talcum Titandioxid (E171) Jernoxid, gult (E172) Jernoxid, rødt (E172) Ethylcellulose
Hypromellose Glycerol triacetate Talc Titanium dioxide (E171) Iron oxide yellow (E172) Iron oxide red (E172) Ethylcellulose
Må ikke opbevares over 30°C.
18 Do not store above 30°C.
PVC/ PE/ PVDC/ aluminium- blisterpakninger, der indeholder 14 filmovertrukne tabletter.
PVC/PE/PVDC/aluminium-blisters containing 14 film-coated tablets.
19 6. 6 Regler for destruktion og anden håndtering
6.6 Special precautions for disposal and other handling
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Date of renewal:
Orange- hvide, ovale, bikonvekse, filmovertrukne tabletter, med “ 125 ” præget på den ene side.
Orange-white, oval, biconvex, film-coated tablets, embossed with “125” on one side.
Effektivitet er blevet påvist ved: • Primær (idiopatisk og familiær) PAH • PAH sekundært til sklerodermi uden signifikant interstitiel pulmonalsygdom • PAH associeret med kongenit systemisk til pulmonal shunt og Eisenmengers fysiologi
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
Pulmonal arteriel hypertension.
Pulmonary arterial hypertension.
I tilfælde af klinisk forværring (f. eks. mindst 10% reduktion i 6- minutters gangtest i sammenligning med målinger inden behandlingens start) på trods af Tracleer behandling i mindst 8 uger (måldosis i mindst 4 uger), bør alternativ behandling overvejes.
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.
4. 4 og 5. 1).
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 Behandlingsophør
20 Discontinuation of treatment
4. 4 og 4. 8).
A careful risk/benefit assessment should be made, taking into consideration the liver toxicity of bosentan (see sections 4.4 and 4.8).
Child- Pugh klasse A) (se pkt.
No dose adjustment is needed in patients with mild hepatic impairment (i.e., Child-Pugh class A) (see section 5.2).
Sikkerhed og virkning hos børn under 12 år er ikke tilstrækkeligt dokumenteret.
The following dosing regimen was used in study AC-052-356 (BREATHE-3):
≤ × ≤ 20 < × ≤ 40 > 40
< × ≤ 40 > 40
5. 2), som kan give en suboptimal virkning på det pulmonale karsystem.
21 sub-optimal effect on pulmonary vasculature.
- Systemisk sklerose med eksisterende fingersår:
- Systemic sclerosis with ongoing digital ulcer disease:
4. 4, 4. 5 og 4. 6)
• 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)
4. 2).
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).
Balancen mellem fordele/ risici for bosentan er ikke undersøgt hos patienter med WHO klasse I funktionsstatus ved pulmonal arteriel hypertension.
The benefit/risk balance of bosentan has not been established in patients with WHO class I functional status of pulmonary arterial hypertension.
Forøgelser af leveraminotransferaser, dvs. aspartat - og alaninaminotransferaser (ASAT og/ eller ALAT) i forbindelse med bosentan er dosisafhængige.
Elevations in liver aminotransferases, i.e., aspartate and alanine aminotransferases (AST and/or ALT), associated with bosentan are dose dependent.