波生坦片是一种双重内皮素受体拮抗剂，具有对ETA 和ETB 受体的亲和作用。波生坦可降低肺和全身血管阻力，从而在不增加心率的情况下增加心脏输出量。 神经激素内皮素是一种有力的血管收缩素，能够促进纤维化、细胞增生和组织重构。波生坦片用于治疗WHO III 期和IV 期原发性肺高压病人的肺动脉高压，或者硬皮病引起的肺高压。 【通用名】 波生坦片 　　 【商品名】 全可利 　　 【英文名】 Bosentan Tablets 　　 【汉语拼音】Tracleer 　　 【批准文号】 H20070091 　　 【生产企业】 Allpack Group AG 　　 【规格】 0.125gx56片/盒 　　 【性状】 　　 本品为橙白色薄膜衣片。 　　 【药理毒理】 在许多心血管失调疾病，包括肺动脉高压，血浆和组织的内皮素浓度增加，表明内皮素在这些疾病中起病理作用。在肺动脉高压，血浆内皮素浓度与预后不良紧密相关。 波生坦是特异性内皮素受体。波生坦与ETA 和ETB 受体竞争结合，与ETA 受体的亲和力比与ETB 受体的亲和力稍高。在动物肺动脉高压模型中，长期口服波生坦能减少肺血管阻力、逆转肺血管和右心室肥大。在动物肺纤维化模型中，波生坦能减少胶原沉积。 　　 【药代动力学】 波生坦的绝对生物利用度大约为50％，而且不受食物影响。最大血浆浓度在口服给药后3-5 小时后达到。分布体积大约为18L，清除率大约为8L/h。表面消除半衰期（t1/2）为5.4 小时。波生坦与血浆蛋白高度结合（>98%），主要是白蛋白。波生坦不会渗透到红细胞。 波生坦在肝脏中被细胞色素P450 同工酶CYP3A4 和CYP2C9 代谢。在人血浆中有三种波生坦代谢物。只有一种代谢物Ro 48-5033 具有药学活性，占化合物活性的10-20%。波生坦代谢通过胆汁清除。 在严重肾功能受损的病人（肌酐清除率为15-30mL/min），波生坦血浆浓度减少大约10％，与肾功能正常的志愿者相比，三种代谢物的血浆浓度增加约2 倍。因为低于3％的剂量通过尿排出，对于肾功能受损的病人不需调整剂量。 未在肝脏损伤的病人中进行波生坦药代动力学影响的评估。由于波生坦被肝脏广泛代谢并通过胆汁排出，肝脏受损预计影响其药代动力学和代谢。因此，有轻度肝脏损伤病人应慎用波生坦。仅仅当潜在益处高于风险时才在这些病人中使用波生坦。严重肝损伤的病人禁忌用波生坦（见禁忌和警告）。 　　 【用法用量】 本品初始剂量为一天2 次、每次62.5mg，持续4 周，随后增加至维持剂量 125mg，一天2 次。高于一天2 次、一次125mg 的剂量不会带来足以抵消肝脏损伤风险的益处。可在进食前或后，早、晚服用本品。 肾功能受损病人： 肾功能受损对本品药代动力学的影响很小。不需作剂量调整。 老年人： 本品的临床研究没有包括足够的年龄在65 岁及大于65 岁的病人并测定他们的反应是否与年轻病人相同。 通常来说，因为肾和/或心脏功能下降、有伴随疾病、其它药物治疗，尤其有肝功能降低，所以老年病人的剂量应该慎重选择。 肝脏损害病人： 肝脏轻度损害病人应慎用本品。中度和重度肝脏损害病人严禁使用。 治疗中止： 没有在推荐剂量下肺动脉高压病人突然中止使用本品的经验。为了避免临床突然恶化，应紧密监视病人，在停药前的3-7 天应将剂量减至一半。 【不良反应】 在安慰剂对照研究中，165 名肺动脉高压病人每日接受本品 250mg（n＝95）以及500mg（n＝70）。对667 名肺动脉高压或者其它症状病人进行安慰剂对照和开放研究中，获得本品的安全性数据。剂量高达给予肺动脉高压推荐剂量的8 倍。治疗期为1 天到4.1 年。在推荐的维持剂量125mg、b.i.d.，本品治疗的肺动脉高压病人中发生率超过1％的不良事件见下表： 肺动脉高压安慰剂对照研究中，本品（125mg b.i.d.）治疗病人中发生率超过1％的不良事件，不考虑药物因果 在肺动脉高压和其它疾病的本品安慰剂对照研究中，共677 名病人接受本品治疗，288 名病人接受安慰剂治疗，剂量范围为每天100～2000mg。治疗期为4周至6个月。 本品治疗病人中发生率高于1％的不良事件见下表：   安慰剂对照研究中，本品治疗病人中发生率超过1％的不良事件，不考虑药物因果 注意：病人数量包括肺动脉高压病人和其它症状病人。在某些安慰剂对照研究中，使用高于推荐治疗肺动脉高压的剂量。本品治疗的病人比安慰剂组病人发生率高的不良事件为头疼、潮红、肝功能异常、贫血和腿水肿。 本品治疗病人中发生率低于1％的不良事件为：碱性磷酸酶增加、过敏性休克、厌食、腹水、吸引、哮喘、房室完全阻滞、血尿素增加、支气管痉挛、心跳停止、中枢神经系统阻抑、脑血管病、胸痛（非心脏）、凝血时间延长、凝血时间缩短、结膜炎、膀胱炎、脱水、皮炎、注意力失调、皮肤干燥、十二指肠溃疡、排尿困难、淤斑、湿疹、嗜酸性细胞计数增加、鼻出血、红斑、眼炎、情绪激动、气胀、胃肠炎、糖耐量受损、痛风、血尿、咯血、轻偏瘫、脑积水、高血糖、感染、失眠、肠梗阻、过敏、乳酸脱氢酶增加、疲劳、性欲增加、易排便、情绪不宁、嘴溃疡、肌肉痉挛、颤搐、肌肉骨骼疼痛、心肌梗塞、鼻充血、梦魇、疼痛、恐慌、感觉异常、外周局部出血、畏光、肺炎、肾衰、肾功能不全、呼吸抑制、呼吸衰竭、不宁腿综合征、负重感、颤抖、皮肤变色、瞌睡、痰液增加、Stevens-Johnson 综合症、蛛网膜下腔出血、出汗增加、心动过速、口渴、血小板减少、耳鸣、震颤、尿频、尿深、荨麻疹、迷走发射、心室心率失常、心动过速、眩晕、虚弱、体重降低以及眼球干燥。 实验室异常： 安慰剂对照研究中，丙氨酸转氨酶（ALT）和天冬氨酸转氨酶（AST）高于正常上限值3 倍的发生率，在本品治疗病人中为11％（n＝658），在安慰剂治疗组中为2％（n＝280）。95 名肺动脉高压病人接受本品125mg、b.i.d.治疗，12％病人ALT 和AST 增加3 倍；70 名肺动脉高压病人接受本品 250mg、b.i.d.治疗，14％病人ALT 和AST 增加3 倍。在接受125mg、b.i.d 治疗的病人中，2％病人ALT 和AST 增加8 倍；接受250mg、b.i.d.治疗的病人中，7％病人ALT 和AST 增加8 倍。 胆红素升高至超过正常值上限的3 倍，与本品治疗的658 名病人中的2名（0.3%）转氨酶升高有关。 本品引起的ALT 和AST 升高是剂量相关的，发生于治疗的早期，偶尔晚期发生。 通常进展缓慢，无典型症状，当治疗中断或者停止后是可逆的。持续用本品治疗，转氨酶升高也可能自然逆转。在所有使用本品的安慰剂对照试验中，治疗组6.2%的病人和安慰剂组2.9%病人出现显著血红蛋白降低（比基线值降低超过15％，且 <11 g/dL）。 在125 和250 mg b.i.d.剂量治疗的肺动脉高压病人中，3％的病人血红蛋白显著减少，安慰剂对照组为1％。 观察到治疗组57％的病人和安慰剂组29％病人血红蛋白浓度至少下降1g/dL。血红蛋白降低至少1g/dL 的病人中，80％的病人血红蛋白减少出现在本品治疗的前6周。 治疗组68％病人和安慰剂组76％病人的血红蛋白浓度在治疗期间保持在正常范围。还不清楚血红蛋白变化的原因，但并没有出血、溶血或者骨髓毒性。   建议在治疗后的第一和第三个月以及随后每隔3 个月检查血红蛋白浓度。 体液潴留: 在安慰剂对照研究中，1611 名严重慢性心衰病人接受本品治疗，治疗期平均1.5 年。 在研究中，发现以前肺动脉高压研究中没有观察到的新的安全性结果。由于慢性心衰恶化而导致早期入院率增加，本品和安慰剂组间的死亡率没有差异。在研究末期，本品和安慰剂组病人间的总体入院人数或者死亡率均没有差异。本品治疗的前4-8 周中观察到的入院率增加可能是由于体液潴留的结果。在试验中，下面这些症状表明体液潴留：早期体重增加、血红蛋白浓度降低和腿水肿发生率增加。 在肺动脉高压病人的安慰剂对照试验中，外周水肿和血红蛋白浓度降低，没有因临床恶化而很早入院的证据。 建议监测病人的体液潴留症状（例如体重增加）。 建议在出现体液潴留时采用利尿剂治疗，或者增加正在使用的利尿剂剂量。 建议在本品治疗前，对有体液潴留症状的病人用利尿剂治疗。 　　 【禁忌症】 以下病人禁用本品：  对于本品任何组分过敏者；  怀孕或者可能怀孕者，除非采取了充分的避孕措施。在动物中报道有胎儿畸形；  中度或严重肝功能损害和/或肝脏转氨酶即天冬氨酸转氨酶（AST）和/或丙氨酸转氨酶的基线值高于正常值上限的3倍（ULN），尤其是总胆红素增加超过正常值上限的2倍；  伴随使用环孢素A 者； 伴随使用格列本脲者。 　　 【注意事项】 如果病人系统收缩压低于85mm Hg，须慎用本品。 血液学变化: 用本品治疗伴随剂量相关的血红蛋白浓度降低（平均0.9 g/dL），可能是由于血液的稀释。多数在本品治疗开始的数周内观察到，治疗4-12 周后稳定，一般不需要输血。 建议在开始治疗前、治疗后第1 个月和第3 个月检测血红蛋白浓度，随后每3 个月检查一次。如果出现血红蛋白显著降低，须进一步评估来决定原因以及是否需要特殊治疗。 体液潴留: 严重慢性心脏衰竭的病人用本品治疗伴随住院率升高，因为在本品治疗的前4-8 周慢性心脏衰竭恶化，可能是体液潴留的结果。建议监测病人体液潴留的症状（例如体重增加）。 出现症状后，建议开始用利尿剂或者增加正在使用利尿剂的剂量。建议在开始本品治疗前，对体液潴留症状的病人用利尿剂治疗。   警告 肝功能：波生坦伴随可逆性、剂量相关的天冬氨酸转氨酶（AST）和丙氨酸转氨酶（ALT）增加，在某些病例中还伴随有胆红素升高。肝酶升高通常在开始治疗前16 周内出现，然后在数天至9 周内恢复到治疗前水平，或者减少剂量或者停药后自动恢复。 在治疗前需检测肝脏转氨酶水平，随后最初12 个月内每个月检测一次，以后4个月一次。 先前存在肝脏损伤:在以下病人中，中度或严重肝损伤和/或肝脏转氨酶即天冬氨酸转氨酶（AST）和/或丙氨酸转氨酶的基线值高于正常值上限的3 倍（ULN），尤其当总胆红素增加超过正常值上限2 倍，禁用本品。（见警告） 肝脏转氨酶升高病人的处理： ALT/AST 水平> 3 及≤5 ULN，治疗和监测的建议如下： 再做一次肝功能检验证实，如果证实，减少每日剂量或者停止治疗，至少每 2 周监测一次转氨酶水平。如果转氨酶恢复到治疗前水平，考虑继续或者再次使用波生坦（见再次治疗）。 ALT/AST 水平> 5 及≤8 ULN，治疗和监测的建议如下： 再做一次肝功能检验证实；如果证实，减少每日剂量或者停止治疗，至少每 2 周监测一次转氨酶水平。一旦转氨酶恢复到治疗前水平，考虑继续或者再次使用波生坦（见再次治疗）。 ALT/AST 水平> 8 × ULN，治疗和监测的建议如下：   必需停止治疗，不考虑再使用波生坦。 在转氨酶升高，伴随有肝脏损伤的临床症状（例如恶心、呕吐、发热、腹痛、黄疸或者罕见嗜睡或疲劳）或者胆红素升高超过正常值上限水平2 倍时，治疗必需停止，不考虑使用波生坦。 再次治疗 仅当本品治疗的潜在益处高于风险，而且转氨酶位于正常值内，才考虑再次使用波生坦。本品以开始的剂量再次使用，转氨酶必须在再次使用后3 天内进行检测，过2 周后再检测，随后根据以上建议进行。 　　 【孕妇及哺乳期妇女用药】   波生坦被认为对人具有潜在致畸性。当给予大鼠≥60 mg/kg/day（人口服治疗剂量的2 倍，每次125mg，每日2 次，基于mg/m2）时， 波生坦显示有致畸性。在大鼠的胚胎毒性研究中，波生坦表现出剂量相关的致畸性作用，包括头部、脸部和主要血管畸形。剂量高达1500 mg/kg/day 时，在家兔中没有观察到出生缺陷；但其血浆浓度低于大鼠的血浆浓度。波生坦诱导的畸形和内皮素-1 基因剔除小鼠和以其它内皮素受体拮抗剂治疗的动物中所观察到的畸形相似，表明这些药物有类致畸性效应。没有对孕妇进行研究。在本品治疗前必须排除妊娠，之后必须采用充分的避孕措施防止妊娠。（见药物相互作用：激素避孕药）。 尚不清楚本品是否分泌进入人乳汁。因为大多数药物都分泌到乳汁中，应建议服用波生坦的哺乳妇女停止哺乳。 　 【儿童用药】 还没有建立波生坦在儿童中的安全性和有效性，不建议用于儿童。 　　 【老年患者用药】 年龄65岁或以上病人有限的临床经验表明，老年人和年轻人对药物的反应没有差异，但应考虑老年人肝功能低下的可能性（见用法用量）。 　　 【药物相互作用】 细胞色素P450 系统: 波生坦对细胞色素P450 同工酶CYP1A2、CYP3A4、 CYP2C9、CYP2C19 和CYP2D6 没有相关的抑制作用。本品不会增加这些酶所代谢药物的血浆浓度。 波生坦是CYP3A4 和CYP2C9 的轻微至中度的诱导剂。伴随使用本品时，被这2种酶代谢的药物血浆浓度可能降低。 华法令: 伴随使用本品，500mg 每日2 次，可使S-华法令和R-华法令的血浆浓度降低大约30％。长期接受华法令治疗的肺动脉高压病人服用本品 125mg， b.i.d.，对凝血时间/INR 没有临床显著的影响。对华法令无须另外调整剂量，但建议进行常规INR 监测。 辛伐他汀和其它他汀：伴随使用本品时会降低辛伐他汀和它的主要活性β- 氢氧基酸代谢物的血浆浓度，大约50％。 本品的血浆浓度不受影响。 本品也降低其它主要受CYP3A4 代谢的他汀类的血浆浓度。对于这些他汀类，须考虑他汀功效下降。 格列本脲：在接受格列本脲伴随治疗的病人中观察到转氨酶升高的风险。因此，禁止本品和格列本脲联合使用，应考虑用其它替代的降血糖药物（见禁忌）。联用本品可使格列本脲的血浆浓度降低约40％。本品的血浆浓度也降低30％。本品也可能降低其它主要由CYP2C9 和CYP3A4 代谢的降血糖药物的血浆浓度。使用这些药物病人，须考虑血糖失控的可能性。 酮康唑：本品和酮康唑伴随使用可使本品的血浆浓度增加大约2 倍。无需剂量调整，但应考虑本品作用增加。 尼莫地平、地高辛、洛沙坦： 本品与地高辛和尼莫地平之间没有药代动力学的相互作用。洛沙坦对本品血浆水平没有影响。 环孢素A：伴随使用本品可使血液中环孢素A 的浓度降低大约50％。联用本品的初始谷浓度比单独使用时高大约30 倍。但在稳态时，本品的血浆浓度仅仅高出3-4 倍。 禁止本品和环孢素A 联用。 没有进行他克莫司的药物相互作用的研究，但可预计有相似的相互作用。建议避免将本品和他克莫司伴随使用。 激素避孕药: 没有进行与口服、注射或者植入避孕药的特殊相互作用研究。许多这类药物被CYP3A4 代谢，当与本品联用时有避孕失败的可能性。因此应采用另外或者替代的避孕方法。 　　 【药物过量】 本品在健康志愿者中单次给药2400mg，病人持续2 个月给予剂量2000mg/天，没有任何主要临床症状。 最主要的副作用是轻度到中度的头疼。在环孢素A 药物相互作用研究中，剂量500 和1000mg 的本品与环孢素A 共同使用时，初始血浆谷浓度增加30 倍，结果导致严重头疼、恶心和呕吐，但没有出现严重不良事件。观察到轻微的血压降低和心率增加。 没有超过上述剂量的药物过量研究。严重过量可能导致低血压，需要给予积极的心血管支持治疗。 　　 【贮藏】 室温保存，15-30℃。 ----------------------------------------------------------------- 原产地英文商品名: TRACLEER 62.5mg/tablet 60tablets/bottle 原产地英文药品名: BOSENTAN 中文参考商品译名: TRACLEER 62.5毫克/片 60片/瓶 中文参考药品译名: 波生坦 生产厂家中文参考译名: ACTELION 生产厂家英文名: ACTELION ------------------------------------------------------------------- 原产地英文商品名: TRACLEER 125mg/tablet 60tablets/bottle 原产地英文药品名: BOSENTAN 中文参考商品译名: TRACLEER 125毫克/片 60片/瓶 中文参考药品译名: 波生坦 生产厂家中文参考译名: ACTELION 生产厂家英文名: ACTELION ---------------------------------------------------------------TRACLEER (bosentan) Tablets DRUG DESCRIPTION Bosentan is an endothelin receptor antagonist, belonging to a class of highly substituted pyrimidine derivatives, with no chiral centers. It is designated chemically as 4-tert-butyl-N-[6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-[2,2´]-bipyrimidin-4-yl]-benzenesulfonamide monohydrate. Bosentan has a molecular weight of 569.64 and a molecular formula of C27H29N5O6S•H2O. Bosentan is a white to yellowish powder. It is poorly soluble in water (1.0 mg/100 mL) and in aqueous solutions at low pH (0.1 mg/100 mL at pH 1.1 and 4.0; 0.2 mg/100 mL at pH 5.0). Solubility increases at higher pH values (43 mg/100 mL at pH 7.5). In the solid state, bosentan is very stable, is not hygroscopic and is not light sensitive. Tracleer is available as 62.5 mg and 125 mg film-coated tablets for oral administration, and contains the following excipients: corn starch, pregelatinized starch, sodium starch glycolate, povidone, glyceryl behenate, magnesium stearate, hydroxypropylmethylcellulose, triacetin, talc, titanium dioxide, iron oxide yellow, iron oxide red, and ethylcellulose. Each Tracleer 62.5 mg tablet contains 64.541 mg of bosentan, equivalent to 62.5 mg of anhydrous bosentan. Each Tracleer 125 mg tablet contains 129.082 mg of bosentan, equivalent to 125 mg of anhydrous bosentan. INDICATIONS Pulmonary Arterial Hypertension Tracleer® is indicated for the treatment of pulmonary arterial hypertension (WHO Group I) in patients with WHO Class II - IV symptoms, to improve exercise ability and decrease the rate of clinical worsening [see Clinical Studies]. 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. DOSAGE AND ADMINISTRATION Recommended Dosing Tracleer treatment should be initiated at a dose of 62.5 mg twice daily for 4 weeks and then increased to the maintenance dose of 125 mg twice daily. Doses above 125 mg twice daily did not appear to confer additional benefit sufficient to offset the increased risk of liver injury. Tablets should be administered morning and evening with or without food. Required Monitoring Liver aminotransferase levels must be measured prior to initiation of treatment and then monthly. If elevated aminotransferase levels are seen, changes in monitoring and treatment must be initiated. Dosage Adjustments for Patients Developing Aminotransferase Elevations The table below summarizes the dosage adjustment and monitoring recommendations for patients who develop aminotransferase elevations > 3 X ULN during therapy with Tracleer. If liver aminotransferase elevations are accompanied by clinical symptoms of liver injury (such as nausea, vomiting, fever, abdominal pain, jaundice, or unusual lethargy or fatigue) or increases in bilirubin ≥ 2 x ULN, treatment with Tracleer should be stopped. There is no experience with the re-introduction of Tracleer in these circumstances. Use in Females of Childbearing Potential Initiate treatment in females of child-bearing potential only after a negative pregnancy test and only in females who are using two reliable methods of contraception. Females who have had a tubal sterilization or a Copper T 380A IUD or LNg 20 IUS inserted do not require other forms of contraception. Effective contraception must be practiced throughout treatment and for one month after stopping Tracleer. Females should seek contraceptive advice as needed from a gynecologist or similar expert. Urine or serum pregnancy tests should be obtained monthly in females of childbearing potential taking Tracleer [see Boxed Warning, CONTRAINDICATIONS, DRUG INTERACTIONS]. Use in Patients with Pre-existing Hepatic Impairment Tracleer should generally be avoided in patients with moderate or severe liver impairment. There are no specific data to guide dosing in hepatically impaired patients; caution should be exercised in patients with mildly impaired liver function [see WARNINGS AND PRECAUTIONS]. Patients with Low Body Weight In patients with a body weight below 40 kg but who are over 12 years of age the recommended initial and maintenance dose is 62.5 mg twice daily. There is limited information about the safety and efficacy of Tracleer in children between the ages of 12 and 18 years. Use with Ritonavir Co-administration of Tracleer in Patients on Ritonavir In patients who have been receiving ritonavir for at least 10 days, start Tracleer at 62.5 mg once daily or every other day based upon individual tolerability [see DRUG INTERACTIONS]. Co-administration of Ritonavir in Patients on Tracleer Discontinue use of Tracleer at least 36 hours prior to initiation of ritonavir. After at least 10 days following the initiation of ritonavir, resume Tracleer at 62.5 mg once daily or every other day based upon individual tolerability [see DOSAGE AND ADMINISTRATION and DRUG INTERACTIONS]. Treatment Discontinuation There is limited experience with abrupt discontinuation of Tracleer. No evidence for acute rebound has been observed. Nevertheless, to avoid the potential for clinical deterioration, gradual dose reduction (62.5 mg twice daily for 3 to 7 days) should be considered. HOW SUPPLIED Dosage Forms And Strengths Tracleer is available as 62.5 mg and 125 mg film-coated, unscored tablets for oral administration.62.5 mg tablets: film-coated, round, biconvex, orange-white tablets, embossed with identification marking “62,5”125 mg tablets: film-coated, oval, biconvex, orange-white tablets, embossed with identification marking “125”62.5 mg film-coated, round, biconvex, orange-white tablets, embossed with identification marking “62,5”, packaged in a white high-density polyethylene bottle and a white polypropylene child-resistant cap.NDC 66215-101-06: Bottle containing 60 tablets.125 mg film-coated, oval, biconvex, orange-white tablets, embossed with identification marking “125”, packaged in a white high-density polyethylene bottle and a white polypropylene child-resistant cap. NDC 66215-102-06: Bottle containing 60 tablets. Store at 20ºC – 25ºC (68ºF – 77ºF). Excursions are permitted between 15°C and 30°C (59°F and 86°F). [See USP Controlled Room Temperature]. SIDE EFFECTS The following important adverse reactions are described elsewhere in the labeling: •Potential liver injury [see Boxed Warning, WARNINGS AND PRECAUTIONS] •Fluid retention [see WARNINGS AND PRECAUTIONS] Clinical Studies Experience Safety data on bosentan were obtained from 13 clinical studies (9 placebo-controlled and 4 open-label) in 870 patients with pulmonary arterial hypertension and other diseases. Doses up to 8 times the currently recommended clinical dose (125 mg twice daily) were administered for a variety of durations. The exposure to bosentan in these trials ranged from 1 day to 4.1 years (N=94 for 1 year; N=61 for 1.5 years and N=39 for more than 2 years). Exposure of pulmonary arterial hypertension patients (N=328) to bosentan ranged from 1 day to 1.7 years (N=174 more than 6 months and N=28 more than 12 months). Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Treatment discontinuations due to adverse events other than those related to pulmonary hypertension during the clinical trials in patients with pulmonary arterial hypertension were more frequent on bosentan (6%; 15/258 patients) than on placebo (3%; 5/172 patients). In this database the only cause of discontinuations > 1% and occurring more often on bosentan was abnormal liver function. DRUG INTERACTIONS Cytochrome P450 Summary Bosentan is metabolized by CYP2C9 and CYP3A. Inhibition of these enzymes may increase the plasma concentration of bosentan (see ketoconazole). Concomitant administration of both a CYP2C9 inhibitor (such as fluconazole or amiodarone) and a strong CYP3A inhibitor (e.g., ketoconazole, itraconazole) or a moderate CYP3A inhibitor (e.g., amprenavir, erythromycin, fluconazole, diltiazem) with bosentan will likely lead to large increases in plasma concentrations of bosentan. Co-administration of such combinations of a CYP2C9 inhibitor plus a strong or moderate CYP3A inhibitor with Tracleer is not recommended. Bosentan is an inducer of CYP3A and CYP2C9. Consequently plasma concentrations of drugs metabolized by these two isozymes will be decreased when Tracleer is co-administered. Bosentan had no relevant inhibitory effect on any CYP isozyme in vitro (CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A). Consequently, Tracleer is not expected to increase the plasma concentrations of drugs metabolized by these enzymes. Hormonal Contraceptives Hormonal contraceptives, including oral, injectable, transdermal, and implantable forms, may not be reliable when Tracleer is co-administered. Females should practice additional methods of contraception and not rely on hormonal contraception alone when taking Tracleer [see Boxed Warning, CONTRAINDICATIONS]. An interaction study demonstrated that co-administration of bosentan and a combination oral hormonal contraceptive produced average decreases of norethindrone and ethinyl estradiol levels of 14% and 31%, respectively. However, decreases in exposure were as much as 56% and 66%, respectively, in individual subjects. Cyclosporine A The concomitant administration of bosentan and cyclosporine A is contraindicated [see CONTRAINDICATIONS]. During the first day of concomitant administration, trough concentrations of bosentan were increased by about 30-fold. The mechanism of this interaction is most likely inhibition of transport protein-mediated uptake of bosentan into hepatocytes by cyclosporine. Steady-state bosentan plasma concentrations were 3- to 4-fold higher than in the absence of cyclosporine A. Co-administration of bosentan decreased the plasma concentrations of cyclosporine A (a CYP3A substrate) by approximately 50%. Glyburide An increased risk of elevated liver aminotransferases was observed in patients receiving concomitant therapy with glyburide. Therefore, the concomitant administration of Tracleer and glyburide is contraindicated, and alternative hypoglycemic agents should be considered [seeCONTRAINDICATIONS]. Co-administration of bosentan decreased the plasma concentrations of glyburide by approximately 40%. The plasma concentrations of bosentan were also decreased by approximately 30%. Bosentan is also expected to reduce plasma concentrations of other oral hypoglycemic agents that are predominantly metabolized by CYP2C9 or CYP3A. The possibility of worsened glucose control in patients using these agents should be considered. Lopinavir/Ritonavir or Other Ritonavir-containing HIV Regimens In vitro data indicate that bosentan is a substrate of the Organic Anion Transport Protein (OATP), CYP3A and CYP2C9. Ritonavir inhibits OATP and inhibits and induces CYP3A. However, the impact of ritonavir on the pharmacokinetics of bosentan may largely result from its effect on OATP. In normal volunteers, co-administration of Tracleer 125 mg twice daily and lopinavir/ritonavir 400/100 mg twice daily increased the trough concentrations of bosentan on Days 4 and 10 approximately 48-fold and 5-fold, respectively, compared with those measured after Tracleer administered alone. Therefore, adjust the dose of Tracleer when initiating lopinavir/ritonavir [see DOSAGE AND ADMINISTRATION]. Co-administration of Tracleer 125 mg twice daily had no substantial impact on the pharmacokinetics of lopinavir/ritonavir 400/100 mg twice daily. Simvastatin and Other Statins Co-administration of bosentan decreased the plasma concentrations of simvastatin (a CYP3A substrate), and its active P-hydroxy acid metabolite, by approximately 50%. The plasma concentrations of bosentan were not affected. Bosentan is also expected to reduce plasma concentrations of other statins that are significantly metabolized by CYP3A, such as lovastatin and atorvastatin. The possibility of reduced statin efficacy should be considered. Patients using CYP3A-metabolized statins should have cholesterol levels monitored after Tracleer is initiated to see whether the statin dose needs adjustment. Rifampin Co-administration of bosentan and rifampin in normal volunteers resulted in a mean 6-fold increase in bosentan trough levels after the first concomitant dose (likely due to inhibition of OATP by rifampin), but about a 60% decrease in bosentan levels at steady-state. The effect of bosentan on rifampin levels has not been assessed. When consideration of the potential benefits and known and unknown risks leads to concomitant use, measure liver function weekly for the first 4 weeks before reverting to normal monitoring. Tacrolimus Co-administration of tacrolimus and bosentan has not been studied in humans. Coadministration of tacrolimus and bosentan resulted in markedly increased plasma concentrations of bosentan in animals. Caution should be exercised if tacrolimus and bosentan are used together. Ketoconazole Co-administration of bosentan 125 mg twice daily and ketoconazole, a potent CYP3A inhibitor, increased the plasma concentrations of bosentan by approximately 2-fold in normal volunteers. No dose adjustment of bosentan is necessary, but increased effects of bosentan should be considered. Warfarin Co-administration of bosentan 500 mg twice daily for 6 days in normal volunteers, decreased the plasma concentrations of both S-warfarin (a CYP2C9 substrate) and R-warfarin (a CYP3A substrate) by 29 and 38%, respectively. Clinical experience with concomitant administration of bosentan and warfarin in patients with pulmonary arterial hypertension did not show clinically relevant changes in INR or warfarin dose (baseline vs. end of the clinical studies), and the need to change the warfarin dose during the trials due to changes in INR or due to adverse events was similar among bosentan- and placebo-treated patients. Digoxin, Nimodipine, and Losartan Bosentan has no significant pharmacokinetic interactions with digoxin and nimodipine, and losartan has no significant effect on plasma levels of bosentan. Sildenafil In normal volunteers, co-administration of multiple doses of 125 mg twice daily bosentan and 80 mg three times daily sildenafil resulted in a reduction of sildenafil plasma concentrations by 63% and increased bosentan plasma concentrations by 50%. The changes in plasma concentrations were not considered clinically relevant and dose adjustments are not necessary. This recommendation holds true when sildenafil is used for the treatment of pulmonary arterial hypertension or erectile dysfunction. Iloprost In a small, randomized, double-blind, placebo-controlled study, 34 patients treated with bosentan 125 mg twice daily for at least 16 weeks tolerated the addition of inhaled iloprost (up to 5 mcg 6 to 9 times per day during waking hours). The mean daily inhaled dose was 27 mcg and the mean number of inhalations per day was 5.6. OVERDOSE Bosentan has been given as a single dose of up to 2400 mg in normal volunteers, or up to 2000 mg/day for 2 months in patients, without any major clinical consequences. The most common side effect was headache of mild to moderate intensity. In the cyclosporine A interaction study, in which doses of 500 and 1000 mg twice daily of bosentan were given concomitantly with cyclosporine A, trough plasma concentrations of bosentan increased 30-fold, resulting in severe headache, nausea, and vomiting, but no serious adverse events. Mild decreases in blood pressure and increases in heart rate were observed.In the postmarketing period, there was one reported overdose of 10,000 mg of bosentan taken by an adolescent male patient. He had symptoms of nausea, vomiting, hypotension, dizziness, sweating, and blurred vision. He recovered within 24 hours with blood pressure support. Bosentan is unlikely to be effectively removed by dialysis due to the high molecular weight and extensive plasma protein binding. CONTRAINDICATIONS Pregnancy Category X [see Boxed Warning] Use of Tracleer is contraindicated in females who are or may become pregnant. While there are no adequate and well controlled studies in pregnant females, animal studies show that Tracleer is likely to cause major birth defects when administered during pregnancy. In animal studies, bosentan caused teratogenic effects including malformations of the head, mouth, face, and large blood vessels. Therefore, pregnancy must be excluded before the start of treatment with Tracleer. Throughout treatment and for one month after stopping Tracleer, females of child bearing potential must use two reliable methods of contraception unless the patient has a tubal sterilization or Copper T 380A IUD or LNg 20 IUS inserted, in which case no other contraception is needed. Monthly pregnancy tests should also be obtained. If this drug is used during pregnancy or if a patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. [see Use in Specific Populations]. Use with Cyclosporine A Co-administration of cyclosporine A and bosentan resulted in markedly increased plasma concentrations of bosentan. Therefore, concomitant use of Tracleer and cyclosporine A is contraindicated [see DRUG INTERACTIONS]. Use with Glyburide An increased risk of liver enzyme elevations was observed in patients receiving glyburide concomitantly with bosentan. Therefore co-administration of glyburide and Tracleer is contraindicated [see DRUG INTERACTIONS]. Hypersensitivity Tracleer is contraindicated in patients who are hypersensitive to bosentan or any component of the product. Observed reactions include rash and angioedema [see ADVERSE REACTIONS].