【药品名称】

通用名称：波生坦片
英文名称：Bosentan Tablets

【 适应症 】

用于治疗WHOIII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。

【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。

【不良反应】

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、

【禁忌】

 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85mmHg，须慎用本品。血液学变化：用本品治疗伴随剂量相关的

【特殊人群用药】

妊娠与哺乳期注意事项：

　　怀孕或者可能怀孕者禁用。

【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。

【药理作用】

本品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。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。

【贮藏】

 室温保存，15-30℃。

Bosentan

Medically reviewed on Sep 10, 2018

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Tablet, Oral:

Tracleer: 62.5 mg, 125 mg

Tablet Soluble, Oral:

Tracleer: 32 mg [scored; contains aspartame]

Brand Names: U.S.

· Tracleer

Pharmacologic Category

· Endothelin Receptor Antagonist

· Vasodilator

Pharmacology

Endothelian receptor antagonist that blocks endothelin receptors on endothelium and vascular smooth muscle (stimulation of these receptors is associated with vasoconstriction). Bosentan blocks both ETA and ETB receptors, with a slightly higher affinity for the A subtype.

Distribution

Vd: ~18 L (does not distribute into RBCs)

Metabolism

Hepatic via CYP2C9 and 3A4 to three metabolites (one active, contributing ~10% to 20% pharmacologic activity); steady-state plasma concentrations are 50% to 65% of those attained after single dose (most likely due to autoinduction of liver enzymes); steady-state is attained within 3 to 5 days

Excretion

Feces (as metabolites); urine (<3% as unchanged drug)

Time to Peak

Plasma: 3 to 5 hours

Half-Life Elimination

~5 hours; prolonged with heart failure, possibly with PAH

Protein Binding

Plasma: >98%, primarily to albumin

Special Populations: Renal Function Impairment

In patients with severe renal impairment (CrCl 15 to 30 mL/minute), concentrations of the 3 metabolites may increase 2-fold, although it is not clinically significant.

Special Populations: Hepatic Function Impairment

Exposure to bosentan may be significantly increased in hepatic impairment.

Special Populations: Children

Exposure to bosentan reaches a plateau at lower doses in pediatric patients than in adults, and doses >2 mg/kg twice daily do not increase the exposure to bosentan in pediatric patients.

Use: Labeled Indications

Pulmonary arterial hypertension: Treatment of pulmonary artery hypertension (PAH) (WHO Group I) in adults with WHO-FC II, III, or IV symptoms to improve exercise ability and to decrease clinical deterioration; treatment of PAH (WHO Group 1) in pediatric patients ≥3 years with idiopathic or congenital PAH to improve pulmonary vascular resistance (PVR), resulting in an improvement in exercise ability.

Note: According to treatment guidelines from the Fifth World Symposium on Pulmonary Hypertension (WSPH), only a small number of PAH patients with WHO-FC IV symptoms (ie, severely ill patients) were included in clinical trials, therefore, most experts consider bosentan second-line therapy in these patients (WSPH [Gailè 2013]).

Off Label Uses

Prevention of digital ulcers in systemic sclerosis

Based on the limited patient population for which data are available, bosentan may be effective for patients with digital ulcers caused by systemic sclerosis. Bosentan has been found to decrease the number of new ulcers, but has not been found to improve healing of existing ulcers.

Raynaud phenomenon in systemic sclerosis

Data from controlled and noncontrolled trials evaluating bosentan in the management of secondary Raynaud phenomenon demonstrate conflicting results in clinical and microvascular assessments. According to evidence-based international consensus-derived recommendations, bosentan has no confirmed efficacy in the treatment of active digital ulcers in systemic sclerosis patients but is effective in the prevention of digital ulcers, particularly multiple ulcers, and should be considered after other therapies have failed.

Contraindications

Hypersensitivity to bosentan or any component of the formulation; concurrent use of cyclosporine or glyburide; use in women who are or may become pregnant.

Canadian labeling: Additional contraindications (not in US labeling): Moderate to severe hepatic impairment (eg, ALT or AST >3 times ULN, particularly when total bilirubin >2 times ULN).

Dosing: Adult

Pulmonary artery hypertension: Oral:

<40 kg: Initial and maintenance: 62.5 mg twice daily

≥40 kg: Initial: 62.5 mg twice daily for 4 weeks; increase to maintenance dose of 125 mg twice daily. Doses >125 mg twice daily do not appear to confer additional clinical benefit but may increase risk of hepatotoxicity.

Note: When discontinuing treatment, consider a reduction in dosage to 62.5 mg twice daily for 3 to 7 days (to avoid clinical deterioration).

Coadministration with ritonavir: Oral:

Dosage adjustment for concurrent use with ritonavir:

Coadministration of bosentan in patients currently receiving ritonavir for at least 10 days: Begin with bosentan 62.5 mg once daily or every other day based on tolerability.

Coadministration of ritonavir in patients currently receiving bosentan: Discontinue bosentan 36 hours prior to the initiation of ritonavir. After at least 10 days following the initiation of ritonavir, resume bosentan 62.5 mg once daily or every other day based on tolerability.

Prevention of digital ulcers in systemic sclerosis (off-label use): Oral: 62.5 mg twice daily for 4 weeks followed by an increase to a maintenance dose of 125 mg twice daily; has been studied in clinical trials for up to 12 weeks (Korn 2004)

Raynaud phenomenon in systemic sclerosis (off-label use): Oral: 62.5 mg twice daily for 4 weeks followed by an increase to a maintenance dose of 125 mg twice daily (Giordano 2010; Hettema 2007).

Dosing: Geriatric

Refer to adult dosing.

Dosing: Pediatric

Pulmonary artery hypertension: Oral:

Manufacturer’s labeling: Children 3 to ≤ 12 years:

≥4 to 8 kg: Initial and maintenance: 16 mg twice daily.

>8 to 16 kg: Initial and maintenance: 32 mg twice daily.

>16 to 24 kg: Initial and maintenance: 48 mg twice daily.

>24 to 40 kg: Initial and maintenance: 64 mg twice daily.

Alternate recommendations: Infants ≥7 months and Children ≤12 years: Limited data available (Barst 2003; Ivy 2004; Maiya 2006; Rosenzweig 2005):

5 to <10 kg: Initial: 15.6 mg daily for 4 weeks; increase to maintenance dose of 15.6 mg twice daily.

10 to 20 kg: Initial: 31.25 mg daily for 4 weeks; increase to maintenance dose of 31.25 mg twice daily.

>20 to 40 kg: Initial: 31.25 mg twice daily for 4 weeks; increase to maintenance dose of 62.5 mg twice daily.

>40 kg: Initial: 62.5 mg twice daily for 4 weeks; increase to maintenance dose of 125 mg twice daily.

Children >12 years and Adolescents (>40 kg): Refer to adult dosing.

Dosing: Renal Impairment

No dosage adjustment necessary. Bosentan is unlikely to be removed by dialysis (due to high molecular weight and extensive plasma protein binding).

Dosing: Hepatic Impairment

Hepatic impairment at treatment initiation:

Mild impairment (Child-Pugh class A): No dosage adjustment necessary.

Moderate to severe impairment (Child-Pugh class B and C) and/or baseline transaminase >3 times ULN: Avoid use; systemic exposure is significantly increased in patients with moderate impairment (has not been studied in severe impairment).

Hepatotoxicity during treatment: Modification based on transaminase elevation:

Transaminase elevations accompanied by clinical symptoms of hepatotoxicity (unusual fatigue, nausea, vomiting, abdominal pain, fever, or jaundice) or a serum bilirubin ≥2 times ULN: Discontinue treatment.

AST/ALT >3 times but ≤5 times ULN:

Children 3 to ≤12 years: Confirm with additional test; if confirmed, interrupt treatment with no prior dose reduction. If transaminase levels return to pretreatment values, may reintroduce treatment at the dose used prior to treatment interruption. When reintroducing treatment, recheck transaminases within 3 days and at least every 2 weeks thereafter.

Adolescents >12 years and Adults (>40 kg): Confirm with additional test; if confirmed, reduce dose to 62.5 mg twice daily or interrupt treatment and monitor at least every 2 weeks. If transaminase levels return to pretreatment values, may continue or reintroduce treatment (at the starting dose), as appropriate. When reintroducing treatment, recheck transaminases within 3 days and at least every 2 weeks thereafter.

AST/ALT >5 times but ≤8 times ULN:

Children 3 to ≤12 years: Confirm with additional test; if confirmed, stop treatment. Monitor transaminase levels at least every 2 weeks. If transaminase levels return to pretreatment values, consider reintroduction at the dose used prior to treatment interruption. When reintroducing treatment, recheck transaminases within 3 days and at least every 2 weeks thereafter.

Adolescents >12 years and Adults (>40 kg): Confirm with additional test; if confirmed, stop treatment. Monitor transaminase levels at least every 2 weeks. If transaminase levels return to pretreatment values, may reintroduce treatment (at the starting dose) as appropriate. When reintroducing treatment, recheck transaminases within 3 days and at least every 2 weeks thereafter.

AST/ALT >8 times ULN: Stop treatment and do not reintroduce.

Extemporaneously Prepared

Note: Tablets for oral suspension (32 mg dispersible tablets) are commercially available.

6.25 mg/mL Oral Suspension

Note: The following personal protective equipment should be used when preparing bosentan oral suspension: Double gloving, protective gown and a respiratory mask if preparation does not occur in a fume hood.

A 6.25 mg/mL oral suspension may be made from nondispersable tablets and a 1:1 mixture of FlavorPlus and FlavorSweet. Crush three 62.5 mg tablets in a ceramic mortar. Add a small amount of glycerin and reduce to a fine powder. Add ~10 mL of the vehicle and titurate; add an additional 10 mL of vehicle and transfer to a calibrated amber bottle. Rinse the mortar and pestle with 10 mL vehicle and add to bottle to bring the final volume to 30 mL. Stable for 30 days when stored in a amber bottle at room temperature or under refrigeration.