Ambrisentan ± tadalafil in WHO functional class II/III pulmonary arterial hypertension: a guide to its use in the EU
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Ambrisentan [Volibris® (EU), Letairis® (USA)], an endothelin-1 receptor antagonist, is effective in treating WHO functional class (FC) II/III pulmonary arterial hypertension (PAH) when used as monotherapy or in combination with tadalafil (a phosphodiesterase type-5 inhibitor). In patients with idiopathic PAH or PAH associated with connective tissue diseases, ambrisentan monotherapy provided sustained clinical benefits, including improvements in exercise capacity. Clinical benefits, including a lower risk of clinical failure, were greater with initial combination treatment with ambrisentan + tadalafil than with initial monotherapy with either ambrisentan or tadalafil in patients with PAH, including those in various patient subgroups. Ambrisentan has an acceptable tolerability and safety profile with or without concomitant tadalafil. Based on the results of clinical trials, current guidelines recommend ambrisentan as initial mono- or combination treatment in patients with non-vasoreactive WHO FC class II/III PAH.
The manuscript was reviewed by: L. Sargento, Heart Failure Unit, Cardiology Department, Pulido Valente Hospital, Lisbon North Hospital Centre, Lisbon, Portugal; D. Skowasch, Department of Internal Medicine II, Division of Cardiology and Pneumology, University of Bonn, Bonn, Germany. During the peer review process, Glaxo Group Ltd, the marketing authorisation holder of ambrisentan, was also offered an opportunity to provide a scientific accuracy review of their data. Changes resulting from comments received were made on the basis of scientific and editorial merit.
Compliance with ethical standards
The preparation of this review was not supported by any external funding.
Conflict of interest
K. A. Lyseng-Williamson is a salaried employee of Adis/Springer and declares no conflict of interest. J. Behr declares having received payments for consulting and lecturing from Actelion, Bayer, Biogen, Boehringer-Ingelheim, Galapagos NV, Novartis and Roche, and having received a grant from Boehringer-Ingelheim.
- 1.Galiè N, Humbert M, Vachiery JL, et al. 2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension: The Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS). Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT). Eur Heart J. 2015;46(4):903–75.Google Scholar
- 4.Volibris (ambrisentan) 5 and 10 mg film-coated tablets: summary of product characteristics. London: European Medicines Agency, 2017.Google Scholar
- 7.Talmaco (tadalafil) 20 mg film-coated tablets: summary of product characteristics. London: European Medicines Agency; 2017.Google Scholar
- 13.Galiè N, Olschewski H, Oudiz RJ, et al. Ambrisentan for the treatment of pulmonary arterial hypertension: results of the ambrisentan in pulmonary arterial hypertension, randomized, double-blind, placebo-controlled, multicenter, efficacy (ARIES) study 1 and 2. Circulation. 2008;117(23):3010–9.CrossRefGoogle Scholar
- 20.Oudiz R, Allard M, Blair C, et al. Ambrisentan therapy in patients with pulmonary arterial hypertension: 3-year outcome [abstract plus poster no. 2622]. In: American College of Chest Physicians International Conference; 2011.Google Scholar
- 21.Pulido T. Long-term ambrisentan therapy for pulmonary arterial hypertension: comparison by etiology [abstract plus poster no. K89]. In: The American Thoracic Society International Conference; 2009.Google Scholar
- 23.Mclaughlin V, Galie N, Barbera JA, et al. A comparison of characteristics and outcomes of patients with atypical and classical pulmonary arterial hypertension from the AMBITION trial [abstract]. Am J Resp Crit Care Med. 2015;191(Abstr Suppl):A2196.Google Scholar
- 24.Hoeper MM, McLaughlin VV, Barberá JA, et al. Initial combination therapy with ambrisentan and tadalafil and mortality in patients with pulmonary arterial hypertension: a secondary analysis of the results from the randomised, controlled AMBITION study. Lancet Respir Med. 2016;4:894–901.CrossRefGoogle Scholar
- 28.Badesch DB, Peschel T, Pizzuti D, et al. Post-marketing hepatic safety profile of ambrisentan in patients with pulmonary arterial hypertension: 4 year update [abstract no. 152]. In: 32nd annual meeting and scientific sessions of the International Society for Heart and Lung Transplantation; 2012.Google Scholar
- 29.Lepist E, Gillies H, Smith W, et al. Evaluation of the endothelin receptor antagonists ambrisentan, bosentan, macitentan, and sitaxsentan as hepatobiliary transporter inhibitors and substrates in sandwich-cultured human hepatocytes. PLoS One. 2014;9(1):e87548. https://doi.org/10.1371/journal.pone.0087548.CrossRefPubMedPubMedCentralGoogle Scholar
- 38.Gillies HC, Wang X, Staehr P, et al. Pah therapy in HIV: lack of drug-drug interactions between ambrisentan and ritonavir [abstract]. Am J Respir Crit Care Med. 2011;183:A5913.Google Scholar
- 39.Spence R, Mandagere A, Walker G, et al. Effect of steady-state ambrisentan on the pharmacokinetics of a single dose of the oral contraceptive norethindrone (norethisterone) 1 mg/ethinylestradiol 35 microg in healthy subjects: an open-label, single-sequence, single-centre study. Clin Drug Investig. 2010;30(5):313–24.CrossRefGoogle Scholar
- 42.Mandagere A, Coar B, Bird SW, et al. Absence of a clinically relevant pharmacokinetic interaction between ambrisentan and mycophenolate mofetil [abstract]. Am J Respir Crit Care Med. 2010;181(Abstr Suppl):A3356.Google Scholar
- 43.Harrison B, Despain D, Mandagere A, et al. Omeprazole has no clinically relevant effect on the pharmacokinetics of ambrisentan [abstract]. Am J Respir Crit Care Med. 2009;179(Abstr Suppl):A3348.Google Scholar
- 44.Mandagere A, Coar B, Bird SW, et al. Steady state tacrolimus has no effect on the steady state pharmacokinetics of ambrisentan in healthy subjects [abstract]. Am J Respir Crit Care Med. 2010;181(Abstr Suppl):A3352.Google Scholar
- 48.Ghofrani H-A, Schermuly R, Weissmann N, et al. Drug interactions in pulmonary arterial hypertension and their implications. US Cardiol. 2009;6(2):101–6.Google Scholar
- 53.Bourge RC, Pamboukian SV, Tallaj JA, et al. The safely change from bosentan to ambrisentan in pulmonary hypertension (SCOBA-PH) study [abstract]. Am J Respir Crit Care Med. 2013;187:A3299.Google Scholar