Tracleer（bosentan）是Actelion公司在欧洲的主要罕用药物，目前已经被批准用于肺动脉高压。这一产品同时也在参与另一个罕见病系统性硬化病的治疗研究。      瑞士Actelion公司的Tracleer(bosentan，波生坦)(I)可与ETa和ETb受体结合，是一种内皮素双受体拮抗剂，是唯一被批准用于治疗肺动脉高压的口服药物。已经有证据表明，它可改善患者的症状及临床进程，同时提高患者的长期生存率。      Tracleer是Actelion公司在全球最先开发并成功推向市场的内皮素受体拮抗剂（ERA），可口服给药。　　 Tracleer目前已在美国，加拿大及欧盟诸国等一些全球重要的医药市场上被上市销售。在对日本患者进行的临床试验中,关于Tracleer的安全性及疗效数据与在英国《新英格兰医学杂志》及《柳叶刀》上刊载的相关数据类似.Tracleer在今年1月,被厚生省指定为罕见病用药,可得到厚生省的快速审批。在欧美,约有10万人患有没有特定原因的原发性肺高血压,或是硬皮病,爱滋,先天性心脏病及食疗引起的二次性肺高血压。在出现呼吸不畅，疲劳感及运动困难这些初期症状时，常被误诊为其他病症，或者是在病情进一步恶化时才被诊断出来，未接受治疗的肺高血压患者生存率自症状出现后能存活两年的只有40-55%。如果患者已达到WHO分类标准的III级或四级，除了应用依前列醇治疗外，常常没有其他可选的治疗方案。最终这些患者通常要接受肺移植。在欧美的临床试验中，给予Tracleer治疗的肺高血压患者，约有11%的人出现肝酶水平异常。这种异常是可逆的，因此可以控制。建议应用此药的患者，每月要进行肝功能检查。另外因怀疑此药有致畸性，怀孕或打算怀孕的妇女要禁忌给药. 【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】 注：以下产品是不同的规格和价格，购买时请以电话咨询为准！ ·TRACLEER 125毫克/片 60片/瓶 ·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 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].