5 mg and 10 mg film-coated tablets
Approved indication: pulmonary arterial hypertension
Australian Medicines Handbook section 6.7
Pulmonary arterial hypertension may be idiopathic or be associated with other conditions such as connective tissue disease. The severity of pulmonary arterial hypertension is classified (I-IV) according to its effect on the patient's physical activity. Conventional treatment includes diuretics and warfarin, but more severe cases may need treatment with prostacyclins, such as epoprostenol, or endothelin receptor antagonists, such as bosentan and sitaxentan.
Ambrisentan is a selective antagonist of the endothelin type A receptor. This action blocks the vasoconstrictive effect of endothelin, a peptide produced by endothelial cells.
Like bosentan and sitaxentan, ambrisentan is taken orally. The tablets should not be chewed or crushed, but food does not affect bioavailability. Most of the dose is metabolised and excreted from the gut. The effective half-life is approximately nine hours. As the enzymes involved in the metabolism include cytochrome P450 3A4 and 2C19 there is a potential for drug interactions, but their clinical significance is currently unclear. Ambrisentan is not recommended for patients with liver disease, or if the patient has transaminase concentrations more than three times the upper limit of normal.
A dose-ranging study enrolled 64 patients with symptomatic pulmonary arterial hypertension despite conventional therapy. They could only walk an average of 343 metres in six minutes at the start of the study. After 12 weeks this had increased by approximately 36 metres irrespective of the dose. Pulmonary artery pressure decreased and there was less dyspnoea.1
Ambrisentan was then compared with placebo in two trials which randomised 394 patients. At the start of the study these patients could only walk an average of 340-355 metres in six minutes. One study used 5 mg or 10 mg doses. After 12 weeks these doses had increased the distance the patients could walk by 31-51 metres more than placebo. The other trial tested 2.5 mg and 5 mg. These doses increased the distance covered in six minutes by 32-59 metres more than placebo. A group of 280 patients completed an extension of the studies. After 48 weeks of taking ambrisentan they were able to walk 39 metres further than they were able to at the start of the studies.2
Ambrisentan's adverse effects and interactions will become clearer with more widespread use. The most frequent adverse effects in the trials, occurring more often than with placebo, were peripheral oedema, nasal congestion, sinusitis, flushing and palpitations.2Fluid retention may present as decompensated heart failure. Hepatic function must be monitored at least once a month because of the risk of liver damage. Haemoglobin should also be measured regularly as anaemia can occur in 7% of patients. Ambrisentan is contraindicated in pregnancy.
Although ambrisentan is the seventh drug to be approved for pulmonary arterial hypertension in recent years, the clinical benefit of these drugs is unclear. While they improve the six-minute walk test, this is a surrogate outcome. Their effect on survival is uncertain. There is also a need to compare the effectiveness of these drugs in longer-term studies.
The Transparency Score ( ) is explained in New drugs: transparency', Vol 37 No 1, Aust Prescr 2014;37:27.
Note 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).
- Galie N, Badesch D, Oudiz R, Simonneau G, McGoon MD, Keogh AM, et al. Ambrisentan therapy for pulmonary arterial hypertension. J Am Coll Cardiol 2005;46:529-35.
- Galie N, Olschewski H, Oudiz RJ, Torres F, Frost A, Ghofrani HA, et al. Ambrisentan for the treatment of pulmonary arterial hypertension. Results of the ambrisentan in pulmonary arterial hypertension, randomized, double-blind, placebo-controlled, multi center, efficacy (ARIES) Study 1 and 2. Circulation 2008;117:3010-19.