100 mg tablets
Approved indication: pulmonary hypertension
Australian Medicines Handbook section 6.7.2
Pulmonary hypertension results from intimal hypertrophy narrowing small pulmonary arteries. The increase in pulmonary vascular resistance leads to right ventricular failure. Primary pulmonary hypertension is less common than the pulmonary hypertension associated with other conditions such as connective tissue diseases. The choice of treatment has expanded over recent years 1with the approval of drugs such as bosentan, epoprostenol and treprostinil.
Patients with pulmonary arterial hypertension have increased concentrations of endothelin 1. This peptide acts on the endothelin A receptor to cause vasoconstriction and on the endothelin B receptor to cause vasodilation. Sitaxentan antagonises the endothelin A receptor, so the arterial pressure should reduce.
The daily dose of sitaxentan is well absorbed. The molecule is metabolised by cytochrome P450 2C9 and 3A4. As warfarin is also metabolised by P450 2C9, sitaxentan can increase the anticoagulant effect. Sitaxentan's metabolites are excreted in the urine and faeces, with an elimination half-life of eight hours.
There have been three placebo-controlled trials of sitaxentan involving a total of 516 patients. One trial lasted for 12 weeks and the others for 18 weeks. All three trials used changes in the distance patients could walk in six minutes as an outcome measure. At the start of the 12-week study, the patients could walk approximately 400 metres in six minutes. By the end of the study, patients given sitaxentan 100 mg could walk 35 metres further than the placebo group in six minutes. At the start of the 18-week studies, the patients could walk 322–361 metres. After treatment, those given sitaxentan 100 mg could walk 25–31 metres further than those in the placebo group. There was an improvement in the severity of the condition in 12–25% of the patients. Although patients with less severe disease were included in the trials, the approval of sitaxentan is limited to patients with class III disease, according to the World Health Organization's classification. The approval also specifies primary pulmonary hypertension and pulmonary hypertension associated with connective tissue disease.
Peripheral oedema, headache, insomnia, nasal congestion and epistaxis were common adverse events which occurred more frequently with sitaxentan than with placebo. Liver function must be checked before and during treatment with sitaxentan as hepatitis can develop. A rise in liver enzymes may require treatment to be stopped. Sitaxentan may also cause a decline in haemoglobin.
It is not clear if sitaxentan has any advantage over bosentan, another endothelin antagonist. Patients who do not respond to bosentan are unlikely to respond to sitaxentan.
The Transparency Score ( ) is explained in New drugs: transparency', Vol 37 No 1, Aust Prescr 2014;37:27.
Notes on references
At the time the comment was prepared, information about this drug was available on the web site of the Food and Drug Administration in the USA (www.fda.gov).
At the time the comment was prepared, a scientific discussion about this drug was available on the website of the European Medicines Agency (www.emea.europa.eu).
- 1. Keogh AM, McNeil KD, Williams T, Gabbay E, Cleland LG. Pulmonary arterial hypertension: a new era in management. Med J Aust 2003;178:564-7.