Treatment of pulmonary arterial hypertension (PAH) to improve exercise capacity and symptoms in patients with WHO functional class III
Anti-hypertensive, Endothelin receptor antagonist
Bosentan is a dual endothelin receptor antagonist (ERA) with affinity for both endothelin A and B (ETA and ETB) receptors. Bosentan decreases both pulmonary and systemic vascular resistance resulting in increased cardiac output without increasing heart rate. The neurohormone endothelin-1 (ET-1) is one of the most potent vasoconstrictors known and can also promote fibrosis, cell proliferation, cardiac hypertrophy and remodelling, and is pro-inflammatory. These effects are mediated by endothelin binding to ETA and ETB receptors located in the endothelium and vascular smooth muscle cells. ET-1 concentrations in tissues and plasma are increased in several cardiovascular disorders and connective tissue diseases, including pulmonary arterial hypertension, scleroderma, acute and chronic heart failure, myocardial ischaemia, systemic hypertension and atherosclerosis, suggesting a pathogenic role of ET-1 in these diseases. In pulmonary arterial hypertension and heart failure, in the absence of endothelin receptor antagonism, elevated ET-1 concentrations are strongly correlated with the severity and prognosis of these diseases.
Absorption: In healthy subjects, the absolute bioavailability of bosentan is approximately 50% and is not affected by food. The maximum plasma concentrations are attained within 3-5 hours.
Distribution: Bosentan is highly bound (>98%) to plasma proteins, mainly albumin.
Elimination: Bosentan is eliminated by biliary excretion following metabolism in the liver by the cytochrome P450 isoenzymes, CYP2C9 and CYP3A4. Less than 3% of an administered oral dose is recovered in urine.
Adult/Geriatric: <40 kg: Initial and maintenance: 62.5 mg twice daily ?40 kg: Initial: 62.5 mg twice daily for 4 weeks; increase to maintenance dose of 125 mg twice daily. Doses more than 125 mg twice daily do not appear to confer additional clinical benefit but may increase risk of liver toxicity. Pediatric: Infants ?7 months and Children: Limited data available (Barst 2003; Ivy 2004; Maiya 2006; Rosenzweig 2005): 5 to <10 kg: Initial: 15.6 mg daily for 4 weeks; increase to maintenance dose of 15.6 mg twice daily. 10 to 20 kg: Initial: 31.25 mg daily for 4 weeks; increase to maintenance dose of 31.25 mg twice daily. >20 to 40 kg: Initial: 31.25 mg twice daily for 4 weeks; increase to maintenance dose of 62.5 mg twice daily. >40 kg: Initial: 62.5 mg twice daily for 4 weeks; increase to maintenance dose of 125 mg twice daily. Children >12 years and Adolescents: Refer to adult dosing.
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.
Acute porphyria; moderate and severe hepatic impairment. Coadministration with ciclosporin or glibenclamide. Pregnancy (use 2 forms of contraception during treatment and 1 mth after stopping). 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.
Headache, nasopharyngitis, flushing, fluid retention (e.g. peripheral oedema), hypotension, palpitations, dyspepsia, fatigue, pruritus, rash, anaemia (dose-related), reduced sperm count (reversible).
Pregnancy Category X. Studies in animals or human beings have demonstrated foetal abnormalities or there is evidence of foetal risk based on human experience or both, and the risk of the use of the drug in pregnant women clearly outweighs any possible benefit. The drug is contraindicated in women who are or may become pregnant.
Store below 30°C. Store in a cool and dry place, protected from light. Keep out of children’s reach.
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