ST LOUIS (MD Consult) - On August 10, 2009, Actelion announced that the US Food and Drug Administration (FDA) has approved Tracleer (bosentan) for the treatment of patients with mildly symptomatic pulmonary arterial hypertension (PAH). (For this approval, patients are considered "mildly symptomatic" if their disease is classified as functional class II [FC II] in terms of the World Health Organization's [WHO's] diagnostic classification for pulmonary hypertension.) Tracleer is an oral dual endothelin receptor antagonist that was previously approved for the treatment of more advanced PAH (FC III and IV).

This FDA approval was granted on the basis of data from a multicenter, randomized, double-blind, placebo-controlled study conducted in a mildly symptomatic population of patients with PAH. According to Actelion, the results of the study (published in The Lancet [abstract]) underscore the relentlessly progressive nature of PAH even in its early stages, as evidenced by the clinical worsening that occurred in members of the placebo group.

The primary end points of the study were changes in pulmonary vascular resistance (PVR) and exercise capacity as measured by a 6-minute walk test (6-MWD). Disease progression was assessed by the secondary end points, which included time to clinical worsening and assignment to WHO functional class.

A highly significant reduction of 22.6% in PVR (P < .0001) and a significant 77% risk reduction in clinical worsening (P = .011) were seen after 24 weeks of bosentan treatment compared with placebo. (For purposes of the study, clinical worsening occurred if a patient died, was hospitalized for PAH, or demonstrated symptomatic progression of PAH.) Study results showed that more patients remained stable without signs of deterioration in the bosentan-treated group compared with patients in the placebo group (3.4% vs 13.2%, P = .029). In addition, a significant delay in WHO functional class deterioration was observed in the bosentan group compared with the placebo group.

Because of the potential for serious liver injury (including rare cases of liver failure and unexplained hepatic cirrhosis in a setting of close monitoring) in patients receiving bosentan, the monitoring of hepatic status is essential before treatment initiation and monthly thereafter. In addition, a high potential for major birth defects exists if the medication is taken during pregnancy. As a result, patients with childbearing potential must undergo pretreatment pregnancy testing and must be using 2 forms of birth control during bosentan therapy. Monthly pregnancy tests should be obtained in these patients.

Tracleer is contraindicated for use with cyclosporine A and glyburide.

 

圣路易斯(MD Consult)——2009年8月10日，瑞士爱泰隆制药公司宣布，美国食品药品管理局(FDA)已批准Tracleer(波生坦)用于治疗症状较轻的肺动脉高压患者(PAH)。(在此条批准令中，“症状较轻”的患者是指按照世界卫生组织肺动脉高压诊断分级标准属肺功能II级的PAH患者。)Tracleer是一种口服双重内皮素受体拮抗剂，先前获准用于治疗较晚期的PAH(肺功能III级和IV级)。

FDA批准这一新适应证是基于对症状较轻的PAH患者进行的一项多中心、随机、双盲、安慰剂对照研究的数据。据爱泰隆制药公司称，这项研究的结果(以摘要形式发表于《柳叶刀》)强调了PAH即使处于早期亦不断进展这一特点，在研究中表现为安慰剂对照组成员临床症状发生恶化。

该研究的主要终点为肺血管阻力(PVR)变化及运动能力的变化，后者通过6分钟步行运动实验(6-MWD)测量。次要终点包括临床恶化时间以及所属的WHO功能分级，以此评价病情进展程度。

与安慰剂对照组相比，波生坦治疗组患者在24w治疗后PVR减少22.6%(P < 0.0001)，临床恶化风险下降77% (P = 0.011)，差异均具统计学意义。(考虑到研究目的，将“临床恶化”定义为患者死亡、因PAH住院，或证实PAH症状有进展。)研究结果显示，波生坦治疗组病情稳定、无恶化征象的患者多于安慰剂对照组(3.4% 比 13.2%，P = 0.029)。此外，与安慰剂对照组相比，波生坦治疗组WHO功能分级恶化显著延迟。

由于患者接受波生坦治疗有发生严重肝损伤的可能(包括密切监测时观察到的极少数肝衰竭病例及未明原因的肝硬化病例)，因此一定要在治疗开始前以及开始后每月进行一次肝功能检查。此外，在妊娠期间服用此药发生严重出生缺陷的可能性较高，所以育龄妇女必须在治疗前进行妊娠检测，在接受波生坦治疗期间也必须使用两种节育措施，而且还应每月进行一次妊娠检测。

Tracleer不得与环孢素A和格列本脲一同应用。