Tracleer (Actelion)
62.5 mg and 125 mg film-coated tablets
Approved indication: pulmonary hypertension
Australian Medicines Handbook section 6.7.2

Primary pulmonary hypertension is a rare disease of unknown aetiology. Secondary causes of pulmonary hypertension include systemic sclerosis. Patients become dyspnoeic on exertion and the high pulmonary arterial pressure eventually leads to right ventricular failure. Most patients die within a few years of diagnosis.

Research into the cause of primary pulmonary hypertension has found that patients have increased amounts of endothelin-1. This is a peptide which causes vasodilatation or vasoconstriction depending on which receptors it activates.

Bosentan acts as an antagonist at the endothelin receptors. This reduces the pulmonary artery pressure in rats, so bosentan has been studied as an oral treatment for patients with pulmonary hypertension.

A double-blind study randomised 32 patients to take bosentan or a placebo for 12 weeks in addition to their usual therapy.

Bosentan reduced dyspnoea and patients were able to walk further.1 Similar improvements were seen in a larger study which randomised 213 patients.2

Patients take 62.5 mg twice daily for four weeks then increase to a maintenance dose of 125 mg twice daily. The bioavailability of the tablets is 50% and this is not changed by food. Plasma concentrations decrease during treatment probably because bosentan induces its own metabolism. This metabolism involves cytochromeP450 2C9 and 3A4 so bosentan will alter the plasma concentrations of drugs such as warfarin, glibenclamide and simvastatin. Bosentan also interacts with digoxin and ketoconazole.

Moderate to severe liver disease is a contraindication to bosentan and it can have serious adverse effects on the liver. Patients must therefore have regular tests of liver function during treatment. In clinical trials, 11% of patients had a more than three-fold increase in liver enzymes.

Adverse events that occur more frequently in patients taking bosentan, than in those taking placebo, include headache, flushing, palpitations and hypotension. Nearly 6% of patients will develop anaemia. Bosentan is teratogenic.

While bosentan has statistically significant effects, their clinical importance can be questioned. In the large trial, the mean treatment effect on dyspnoea, using a scale of 1-10, was 0.6.2 After16 weeks of treatment the patients could walk an extra 36 metres in six minutes. It is not clear how long these effects will last or if they make any difference to survival. If a patient's condition deteriorates consideration should be given to withdrawing bosentan as its efficacy in severe pulmonary hypertension is unknown. Its approval is limited to primary pulmonary hypertension and pulmonary hypertension associated with scleroderma.

Bosentan is an adjunctive treatment, but the best combination of therapies is yet to be defined.


Some of the views expressed in the following notes on newly approved products should be regarded as preliminary, as there may have been limited published data at the time of publication, and little experience in Australia of their safety or efficacy. However, the Editorial Executive Committee believes that comments made in good faith at an early stage may still be of value. Before new drugs are prescribed, the Committee believes it is important that more detailed information is obtained from the manufacturer's approved product information, a drug information centre or some other appropriate source.