Bosentan is indicated for the treatment of pulmonary arterial hypertension (PAH) to improve exercise capacity and reduce symptoms in patients with WHO functional class III. Clinical benefits have also been observed in some patients with WHO functional class II.

Bosentan is a dual endothelin receptor antagonist (ERA) that blocks both endothelin A (ETA) and endothelin B (ETB) receptors. By inhibiting these receptors, Bosentan reduces pulmonary and systemic vascular resistance, leading to improved cardiac output without significantly affecting heart rate. Endothelin-1 (ET-1) is a potent vasoconstrictor that also promotes fibrosis, cell proliferation, cardiac hypertrophy, and inflammatory processes. These effects occur through activation of ETA and ETB receptors located in vascular endothelium and smooth muscle. Elevated ET-1 levels are observed in various cardiovascular and connective tissue disorders, including pulmonary arterial hypertension, scleroderma, heart failure, myocardial ischemia, systemic hypertension, and atherosclerosis, indicating its role in disease progression. In pulmonary arterial hypertension and heart failure, increased ET-1 levels are associated with disease severity and prognosis when not counteracted by receptor blockade.

Absorption: Bosentan has an absolute bioavailability of approximately 50% in healthy individuals and is not significantly affected by food. Peak plasma concentrations are reached within 3–5 hours.

Distribution: Bosentan is highly protein-bound (>98%), mainly to albumin.

Elimination: Bosentan is primarily eliminated via biliary excretion after hepatic metabolism by cytochrome P450 enzymes, mainly CYP2C9 and CYP3A4. Less than 3% of the administered dose is excreted in urine.

Tablets are to be taken orally morning and evening, with or without food.

Pulmonary arterial hypertension: In adult patients, Bosentan treatment should be initiated at a dose of 62.5 mg twice daily for 4 weeks and then increased to the maintenance dose of 125 mg twice daily.

For paediatric patients aged 2 years or older, the optimal maintenance dose has not been defined in well-controlled studies. However, paediatric pharmacokinetic data have shown that Bosentan plasma concentrations in children were on average lower than in adult patients and were not increased by increasing the dose of Bosentan above 2 mg/kg body weight twice daily.

Discontinuation of treatment: If the decision to withdraw Bosentan is taken, it should be done gradually while an alternative therapy is introduced.

Increased bosentan levels with CYP3A4 inhibitors (e.g. ketoconazole, ritonavir, diltiazem), CYP2C9 inhibitors (e.g. amiodarone, fluconazole), tacrolimus. Rifampicin initially increases but subsequently decreases bosentan concentration. May decrease plasma levels of warfarin, statins (e.g. simvastatin, lovastatin), hormonal contraceptives, sildenafil, tadalafil.

• Hypersensitivity to the active substance or to any of the excipients
• Moderate to severe hepatic impairment, i.e., Child-Pugh class B or C.
• Baseline values of liver aminotransferases, i.e., aspartate aminotransferases (AST) and/or alanine aminotransferases (ALT), greater than 3 times the upper limit of normal
• Concomitant use of cyclosporine A.
• Pregnancy

Special warnings and precautions for use Liver aminotransferase levels must be measured prior to initiation of treatment and subsequently at monthly intervals for the duration of treatment with Bosentan. In addition, liver aminotransferase levels must be measured 2 weeks after any dose increase.

Treatment with bosentan has been associated with dose dependent elevations in liver aminotransferases and decreases in haemoglobin concentration. Other side effects include Anaemia, haemoglobin decrease, Thrombocytopenia, Neutropenia, leucopenia, Hypersensitivity reactions, Headache, Syncope, Palpitations, Flushing, Hypotension, Gastroesophageal reflux disease, Aminotransferase elevations associated with hepatitis and/or jaundice, Liver cirrhosis, liver failure (rarely), Erythema, Diarrhoea, Oedema, fluid retention.

Bosentan is contraindicated in pregnancy. It is not known whether bosentan is excreted into human breast milk. Breast-feeding is not recommended during treatment with Bosentan.

Consider discontinuation of therapy if pulmonary oedema occurs. Avoid abrupt withdrawal and consider dose reduction (e.g. half the dose for 3-7 days) to minimise risk of clinical deterioration. Lactation. Bosentan may cause dizziness, which could affect the ability to drive or use machines.

Dosage in hepatic impairment: No dose adjustment is needed in patients with mild hepatic impairment. Bosentan is contraindicated in patients with moderate to severe liver dysfunction.

Dosage in renal impairment: No dose adjustment is required in patients with renal impairment. No dose adjustment is required in patients undergoing dialysis.

Dosage in elderly patients: No dose adjustment is required in patients over the age of 65 years.

Hepatic impairment: In patients with mildly impaired liver function (Child-Pugh class A) no relevant changes in the pharmacokinetics have been observed. The pharmacokinetics of Bosentan have not been studied in patients with Child-Pugh class B or C hepatic impairment and Pulmoten is contra-indicated in this patient population.

Renal impairment: No dose adjustment is required in patients with renal impairment. There is no specific clinical experience in patients undergoing dialysis. 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.

Anti-hypertensive, Endothelin receptor antagonist

Store below 30°C. Store in a cool and dry place, protected from light. Keep out of children’s reach.