Bosentan

(BAN, USAN, rINN)
Bosentan Chemical formula
Synonyms: Bosentaani; Bosentán; Bosentano; Bosentanum; Ro-470203/029. ptert-ButylN-[6-(2-hydroxyethoxy)-5-(o-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]benzenesulfonamide.
Cyrillic synonym: Бозентан.

💊 Chemical information

Chemical formula: C27H29N5O6S = 551.6.
CAS — 147536-97-8 (anhydrous bosentan); 157212-550 (bosentan monohydrate).
ATC — C02KX01.
ATC Vet — QC02KX01.

💊 Adverse Effects

Adverse effects reported with bosentan include headache, nasopharyngitis, flushing, oedema, hypotension, dizziness, palpitations, gastrointestinal disturbances, pruritus, skin rashes, fatigue, muscle cramps, and anaemia. Anaphylaxis and angioedema have been reported rarely. Dose-related increases in liver aminotransferases may also occur, and hepatic cirrhosis and liver failure have been reported.
Bosentan is teratogenic in animals.

Effects on the liver.

In a postmarketing study,1 increases in liver aminotransferases to more than 3 times the upper limit of normal occurred in 352 (7.6%) of 4623 patients started on bosentan for pulmonary hypertension; treatment was continued or successfully reintroduced after temporary withdrawal in 165 (47%) of these patients.
1. Humbert M, et al. Results of European post-marketing surveillance of bosentan in pulmonary hypertension. Eur Respir J 2007; 30: 338–44.

Effects on the skin.

Vasculitis was reported1 in a patient receiving bosentan shortly after the dose was increased to 125 mg twice daily. She was also taking metolazone and acenocoumarol long term, and spironolactone had recently been added. The skin lesions improved slowly over a period of weeks after bosentan was stopped. All other treatment was continued and it was concluded that the lesions were attributable to bosentan alone or to a previously unknown interaction.
1. Gasser S, et al. Severe necrotising leucocytoclastic vasculitis in a patient taking bosentan. BMJ 2004; 329: 430.

💊 Precautions

Bosentan is contra-indicated in patients with moderate to severe hepatic impairment (Child-Pugh Class B or C). Liver-aminotransferase concentrations should be measured before starting therapy, at monthly intervals during therapy, and 2 weeks after any increase in dose:
bosentan therapy should not be started in patients with concentrations more than 3 times the upper limit of normal
if concentrations increase to between 3 and 5 times the upper limit of normal during treatment, bosentan should be stopped or the dose reduced and concentrations should be monitored every 2 weeks until they are below the pretreatment value; therapy may then be continued or reintroduced, but aminotransferase concentrations should be checked after 3 days, after a further 2 weeks, and then monthly
if concentrations increase to more than 5 times the upper limit of normal bosentan should be stopped; reintroduction may be considered when concentrations return to below the pretreatment value
if concentrations increase above 8 times the upper limit of normal or there are symptoms of hepatotoxicity or increases in total bilirubin levels greater than twice the upper limit of normal, treatment should be stopped and not reintroduced
Haemoglobin concentrations should be monitored every 3 months during therapy, more frequently at the start. Bosentan should not be given to patients with hypotension. Although there is no evidence of rebound effects after stopping bosentan, it is recommended that therapy should be withdrawn gradually. Bosentan and related endothelin receptor antagonists are teratogenic in rats and should not be used in pregnancy or in women of child-bearing potential who are not using a reliable method of contraception; hormonal contraceptives alone may not be adequate and additional measures may be required (see Interactions, below).

💊 Interactions

Bosentan is metabolised by the cytochrome P450 isoenzymes CYP2C9 and CYP3A4 and is also an inducer of the same isoenzymes. It may also possibly induce CYP2C19. Interactions may therefore occur with other drugs that are either metabolised by, or inhibit, these isoenzymes. Use with ciclosporin is contra-indicated since plasma concentrations of bosentan are significantly increased (see below). There is an increased risk of hepatotoxicity if bosentan is given with glibenclamide and such use should be avoided; the hypoglycaemic effect of glibenclamide may also be reduced. Bosentan has reduced the plasma concentrations of some hormonal contraceptives and additional contraceptive measures are advised.

Anticoagulants.

For reports of bosentan decreasing the anticoagulant effect of warfarin, see Endothelin Receptor Antagonists.

Ciclosporin.

There appears to be a complex interaction between bosentan and ciclosporin. In a pharmacokinetic study1 in healthy subjects given both drugs, doses of ciclosporin needed increasing to achieve target trough ciclosporin concentrations; it was calculated that plasma concentrations of ciclosporin would otherwise have been reduced by about half in the presence of bosentan. In addition, plasma concentrations of bosentan were almost doubled by ciclosporin. Licensed product information for bosentan states that plasma concentrations at steady state are 3 to 4 times higher in the presence of ciclosporin and contra-indicates the combination.
1. Binet I, et al. Renal hemodynamics and pharmacokinetics of bosentan with and without cyclosporine A. Kidney Int 2000; 57: 224–31.

💊 Pharmacokinetics

Bosentan is absorbed from the gastrointestinal tract with an absolute bioavailability of about 50%. Peak plasma concentrations occur about 3 to 5 hours after an oral dose. It is more than 98% bound to plasma proteins, mainly to albumin. Bosentan is metabolised in the liver by the cytochrome P450 isoenzymes CYP2C9 and CYP3A4 and is an inducer of these enzymes and possibly also of CYP2C19; after multiple dosing, plasma concentrations of bosentan decrease gradually to 50 to 65% of those seen after a single dose. Bosentan has three metabolites, one of which is active. Bosentan is excreted almost entirely as metabolites in the bile; less than 3% of an oral dose is excreted in the urine. The terminal elimination half-life is about 5 hours.
1. Weber C, et al. Multiple-dose pharmacokinetics, safety, and tolerability of bosentan, an endothelin receptor antagonist, in healthy male volunteers. J Clin Pharmacol 1999; 39: 703–14
2. van Giersbergen PLM, et al. Influence of mild liver impairment on the pharmacokinetics and metabolism of bosentan, a dual endothelin receptor antagonist. J Clin Pharmacol 2003; 43: 15–22.

💊 Uses and Administration

Bosentan is an endothelin receptor antagonist used in the management of pulmonary hypertension (below) and systemic sclerosis (see Scleroderma, below). It has also been investigated in heart failure and in hypertension. In pulmonary hypertension, patients over 12 years of age may be given bosentan orally in an initial dose of 62.5 mg twice daily, increased after 4 weeks to a maintenance dose of 125 mg twice daily. In those with low body weight (below 40 kg) both the initial and maintenance doses are 62.5 mg twice daily. For the use of bosentan in children, see below. In systemic sclerosis with ongoing digital ulcer disease, bosentan is given in the same doses as for pulmonary hypertension; there are no data on safety or efficacy in patients under 18 years of age.
1. Krum H, et al. The effect of an endothelin-receptor antagonist, bosentan, on blood pressure in patients with essential hypertension. N Engl J Med 1998; 338: 784–90
2. Sutsch G, et al. Short-term oral endothelin-receptor antagonist therapy in conventionally treated patients with symptomatic severe chronic heart failure. Circulation 1998; 98: 2262–8
3. Kenyon KW, Nappi JM. Bosentan for the treatment of pulmonary arterial hypertension. Ann Pharmacother 2003; 37: 1055–62
4. Cohen H, et al. Bosentan therapy for pulmonary arterial hypertension. Am J Health-Syst Pharm 2004; 61: 1107–19
5. Dingemanse J, van Giersbergen PLM. Clinical pharmacology of bosentan, a dual endothelin receptor antagonist. Clin Pharmacokinet 2004; 43: 1089–1115.

Administration in children.

A short-term study1 in 19 children with pulmonary hypertension aged 3 to 15 years found that treatment with bosentan resulted in haemodynamic improvement and was well tolerated, and another small study2 suggested that addition of bosentan allowed epoprostenol dosage to be reduced or stopped. Longer-term studies3,4 have reported that benefit is maintained and that bosentan may have a role in children with both idiopathic pulmonary hypertension and pulmonary hypertension secondary to heart or lung disease. Licensed product information in the UK states that the safety and efficacy of bosentan has not been substantially documented in children under the age of 12 years (some postmarketing data has subsequently been published5) but notes that the studies cited above used the following doses; these doses are also recommended in the BNFC, but for children aged 3 to 18 years:
body-weight 10 to 20 kg: initial dose 31.25 mg once daily, increased to 31.25 mg twice daily after 4 weeks
body-weight 20 to 40 kg: initial dose 31.25 mg twice daily, increased to 62.5 mg twice daily after 4 weeks
body-weight over 40 kg and age 12 to 18 years: as for adults (see above)
1. Barst RJ, et al. Pharmacokinetics, safety, and efficacy of bosentan in pediatric patients with pulmonary arterial hypertension. Clin Pharmacol Ther 2003; 73: 372–82
2. Ivy DD, et al. Weaning and discontinuation of epoprostenol in children with idiopathic pulmonary arterial hypertension receiving concomitant bosentan. Am J Cardiol 2004; 93: 943–6
3. Maiya S, et al. Response to bosentan in children with pulmonary hypertension. Heart 2006; 92: 664–70
4. Rosenzweig EB, et al. Effects of long-term bosentan in children with pulmonary arterial hypertension. J Am Coll Cardiol 2005; 46: 697–704
5. Beghetti M, et al. Safety experience with bosentan in 146 children 2-11 years old with pulmonary arterial hypertension: results from the European Postmarketing Surveillance program. Pediatr Res 2008; 64: 200–4.

Pulmonary hypertension.

Pulmonary hypertension is a progressive and incurable disease associated with an increase in pulmonary arterial pressure. Treatment usually involves the use of vasodilators such as calcium-channel blockers or intravenous epoprostenol, but systemic effects limit their use. Patients with pulmonary hypertension have raised plasma concentrations of the potent vasoconstrictor endothelin I, and endothelin antagonists such as bosentan have therefore been tried. Studies1,2 with oral bosentan have shown improvement in exercise tolerance and in time to clinical progression; an open study3 showed sustained benefit with treatment for 1 year or more. However, no effect on mortality has yet been found in randomised studies, although there is some evidence4,5 that survival may be improved. Bosentan has also been tried with epoprostenol.6 There was a non-significant trend towards greater improvement in the group receiving both drugs compared with epoprostenol alone. There is some evidence that bosentan may be of benefit in pulmonary hypertension associated with congenital heart disease,7,8including Eisenmenger syndrome,8-10 and in pulmonary hypertension associated with HIV infection.11 Positive results have also been reported12-14 in chronic thromboembolic pulmonary hypertension.
1. Channick RN, et al. Effects of the dual endothelin-receptor antagonist bosentan in patients with pulmonary hypertension: a randomised placebo-controlled study. Lancet 2001; 358: 1119–23
2. Rubin LJ, et al. Bosentan therapy for pulmonary arterial hypertension. N Engl J Med 2002; 346: 896–903. Correction. ibid.; 1258
3. Sitbon O, et al. Effects of the dual endothelin receptor antagonist bosentan in patients with pulmonary arterial hypertension: a 1-year follow-up study. Chest 2003; 124: 247–54
4. McLaughlin VV, et al. Survival with first-line bosentan in patients with primary pulmonary hypertension. Eur Respir J 2005; 25: 244–9
5. Sitbon O, et al. Survival in patients with class III idiopathic pulmonary arterial hypertension treated with first line oral bosentan compared with an historical cohort of patients started on intravenous epoprostenol. Thorax 2005; 60: 1025–30
6. Humbert M, et al. Combination of bosentan with epoprostenol in pulmonary arterial hypertension: BREATHE-2. Eur Respir J 2004; 24: 353–9
7. Apostolopoulou SC, et al. Long-term oral bosentan treatment in patients with pulmonary arterial hypertension related to congenital heart disease: a 2-year study. Heart 2007; 93: 350–4
8. Diller G-P, et al. Long-term safety, tolerability and efficacy of bosentan in adults with pulmonary arterial hypertension associated with congenital heart disease. Heart 2007; 93: 974–6
9. Galiè N, et al. for the Bosentan Randomized Trial of Endothelin Antagonist Therapy-5 (BREATHE-5) Investigators. Bosentan therapy in patients with Eisenmenger syndrome: a multicenter, double-blind, randomized, placebo-controlled study. Circulation 2006; 114: 48–54
10. D’Alto M, et al. Long term effects of bosentan treatment in adult patients with pulmonary arterial hypertension related to congenital heart disease (Eisenmenger physiology): safety, tolerability, clinical, and haemodynamic effect. Heart 2007; 93: 621–5
11. Barbaro G, et al. Highly active antiretroviral therapy compared with HAART and bosentan in combination in patients with HIVassociated pulmonary hypertension. Heart 2006; 92: 1164–6
12. Hughes R, et al. Bosentan in inoperable chronic thromboembolic pulmonary hypertension. Thorax 2005; 60: 707
13. Hoeper MM, et al. Bosentan therapy for inoperable chronic thromboembolic pulmonary hypertension. Chest 2005; 128: 2363–7
14. Bonderman D, et al. Bosentan therapy for inoperable chronic thromboembolic pulmonary hypertension. Chest 2005; 128: 2599–2603.

Scleroderma.

Bosentan has an established role in pulmonary hypertension secondary to scleroderma or other connective tissue disorders, but may also have additional benefits. Several case reports1-3 have suggested that treatment with bosentan may be associated with healing of refractory digital ulcers in patients with scleroderma, and a controlled study4 found that bosentan reduced the incidence of new digital ulcers, although there was no improvement in the healing of existing ulcers. Relatively long-term treatment may need to be given.5
1. Humbert M, Cabane J. Successful treatment of systemic sclerosis digital ulcers and pulmonary arterial hypertension with endothelin receptor antagonist bosentan. Rheumatology (Oxford) 2003; 42: 191–3
2. Snyder MJ, et al. Resolution of severe digital ulceration during a course of bosentan therapy. Ann Intern Med 2005; 142: 802–3
3. Tillon J, et al. Successful treatment of systemic sclerosis-related digital ulcers and sarcoidosis with endothelin receptor antagonist (bosentan) therapy. Br J Dermatol 2006; 154: 1000–1002
4. Korn JH, et al. Digital ulcers in systemic sclerosis: prevention by treatment with bosentan, an oral endothelin receptor antagonist. Arthritis Rheum 2004; 50: 3985–93
5. García de la Peña-Lefebvre P, et al. Long-term experience of bosentan for treating ulcers and healed ulcers in systemic sclerosis patients. Rheumatology (Oxford) 2008; 47: 464–6.

💊 Preparations

Proprietary Preparations

Austral.: Tracleer; Belg.: Tracleer; Canad.: Tracleer; Cz.: Tracleer; Denm.: Tracleer; Fin.: Tracleer; Fr.: Tracleer; Ger.: Tracleer; Gr.: Tracleer; Hung.: Tracleer; Irl.: Tracleer; Israel: Tracleer; Ital.: Tracleer; Malaysia: Tracleer; Neth.: Tracleer; Norw.: Tracleer; NZ: Tracleer; Port.: Tracleer; Singapore: Tracleer; Spain: Tracleer; Swed.: Tracleer; Switz.: Tracleer; Thai.: Tracleer; UK: Tracleer; USA: Tracleer.
Published December 27, 2018.