Tracleer (bosentan), an orally available endothelin receptor antagonist, was the first oral treatment approved for PAH.
In the US, Tracleer is indicated for the treatment of PAH (WHO Group 1) to improve exercise ability and to decrease clinical worsening.
Studies establishing effectiveness included predominantly patients with NYHA Functional Class II-IV symptoms and etiologies of idiopathic or heritable PAH (60%), PAH associated with connective tissue diseases (21%), and PAH associated with congenital systemic-to-pulmonary shunts (18%). Considerations for use: Patients with WHO class II symptoms showed reduction in the rate of clinical deterioration and a trend for improvement in walk distance. Physicians should consider whether these benefits are sufficient to offset the risk of liver injury in WHO class II patients, which may preclude future use as their disease progresses.
In Europe, Tracleer is approved for treatment of PAH Functional Class III to improve exercise capacity and symptoms, as well as PAH Functional Class II, where some improvements have also been shown.
In the EU, Tracleer is also indicated to reduce the number of new digital ulcers in patients with systemic sclerosis and ongoing digital ulcer disease.
A quadrisect, dispersible 32 mg tablet formulation of Tracleer has been approved in the EU for children. In addition, Tracleer is approved for the treatment of PAH in children aged from 1 year old.
Tracleer can cause serious liver damage, including in rare cases liver failure, and is very likely to cause major birth defects. It is contraindicated for use with cyclosporine A, glyburide, and in pregnancy and breast feeding. In the US, Tracleer is distributed under a risk evaluation and mitigation strategy.
Tracleer is commercially available in over 60 markets, including the US (since November 2001), the European Union (since May 2002), and Japan (since April 2005).
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A comprehensive clinical trial program has been conducted to evaluate the efficacy and safety of Tracleer® across a broad range of PAH patient populations.
For a detailed analysis of the study results please refer to the scientific publications - reference information is given on the key scientific literature page.
The results of clinical studies including two pivotal randomized controlled studies, Study 351 and BREATHE-1, demonstrate the efficacy of Tracleer® in the treatment of patients with idiopathic PAH (where no specific cause can be identified), or PAH secondary to connective tissue diseases such as scleroderma.
The combination of Tracleer® with the initiation of intravenous therapy with epoprostenol in adult patients suffering from PAH is well tolerated, as shown in the randomized controlled BREATHE-2 study.
The BREATHE-3 open-label study provided safety and efficacy data in children with PAH treated with Tracleer® with or without concomitant prostanoid therapy. It also provided important information on the dose required in the pediatric formulation.
Results of the open-label BREATHE-4 study in patients whose PAH is related to their infection with the human immuno deficiency virus (HIV) showed improvement in exercise capacity, WHO functional class, and quality of life, as well as cardiopulmonary hemodynamics, compared to baseline after 16 weeks of treatment with Tracleer®.
The first ever randomized placebo-controlled study in patients with Eisenmenger’s syndrome (PAH associated with a congenital heart defect) BREATHE-5 showed that Tracleer® decreases pulmonary vascular resistance and improves exercise capacity in these patients.
The EARLY (Endothelin Antagonist tRial in miLdlY symptomatic PAH patients) study was a randomized, double-blind, placebo-controlled trial, and the only randomized controlled trial to study a dedicated early-stage, or WHO Functional Class II, PAH population. Patients were followed for at least six months, and results showed a significant reduction in pulmonary vascular resistance and a delay in time to clinical worsening. A trend towards improvement in exercise capacity was observed.
FUTURE-1 (Pediatric FormUlation of bosenTan in pUlmonary arterial hypeRtEnsion) an open-label study, evaluated the safety and pharmacokinetics of a new dispersible tablet formulation of Tracleer®. This study provided important pharmacokinetic and dosing information using the new pediatric formulation of Tracleer®. In FUTURE-1, the observed exposure to Tracleer® was similar to that in children who participated in BREATHE-3.
FUTURE-2, an open-label safety and tolerability extension study for subjects that completed FUTURE-1, assessed long-term safety and outcome data in children with PAH.
FUTURE-3, an open label study, further assessed the pharmacokinetics, tolerability, safety, and efficacy of the pediatric formulation of bosentan when administered twice versus three times a day in children from 3 months to less than 12 years of age with PAH.
FUTURE-4, a randomized and placebo-controlled study, investigated the pharmacokinetics, safety and efficacy of bosentan as adjunctive therapy to inhaled nitric oxide (NO) in the management of persistent pulmonary hypertension of the newborn (PPHN).
The RAPIDS (RAndomized Placebo-controlled Investigation of Digital ulcers in Scleroderma) program, consisting of two Phase III clinical trials (RAPIDS-1 and RAPIDS-2), tested the benefits of Tracleer® in ischemic digital ulcers secondary to systemic sclerosis. In both studies, Tracleer® reduced the number of new digital ulcers.
Study 351: Channick RN, Simonneau G, Sitbon O, et al. Study 351: Effects of the dual endothelin-receptor antagonist bosentan in patients with pulmonary hypertension: a randomised placebo-controlled study. Lancet 2001;358:1119-23.
BREATHE-1: Rubin LJ, Badesch DB, Barst RJ, et al. Bosentan therapy for pulmonary arterial hypertension. N Engl J Med 2002;346:896-903.
BREATHE-2: Humbert M, Barst RJ, Robbins IM, et al. Combination of bosentan with epoprostenol in pulmonary arterial hypertension: BREATHE-2. Eur Respir J 2004;24:353-9.
BREATHE-3: Barst RJ, Ivy D, Dingemanse J, et al. Pharmacokinetics, safety, and efficacy of bosentan in pediatric patients with pulmonary arterial hypertension. Clin Pharmacol Ther 2003;73:372-82.
BREATHE-4: Sitbon O, Gressin V, Speich R, et al. Bosentan for the treatment of human immunodeficiency virus-associated pulmonary arterial hypertension. Am J Respir Crit Care Med 2004;170:1212-17.
BREATHE-5: Galiè N, Beghetti M, Gatzoulis MA, et al. Bosentan therapy in patients with Eisenmenger syndrome: a multicenter, double-blind, randomized, placebo-controlled study. Circulation 2006;114:48-54.
EARLY: Galiè N, Rubin LJ, Hoeper MM, et al. Treatment of patients with mildly symptomatic pulmonary arterial hypertension with bosentan (EARLY study): a double-blind, randomised controlled trial. Lancet 2008;371:2093-100.
RAPIDS-1: Korn JH, Mayes M, Matucci Cerinic M, et al. Digital ulcers in systemic sclerosis: prevention by treatment with bosentan, an oral endothelin receptor antagonist. Arthritis Rheum 2004;50:3985-93.
RAPIDS-2: Seibold JR, Denton CP, Furst DE et al. Bosentan Prevents Occurrence But Does Not Speed Healing of Digital Ulcers in Patients with Systemic Sclerosis (SSc) [abstract]. ACR; San Diego, USA; 2005.