【药品名称】
商品名称：凡瑞克Endobloc
通用名称：安立生坦片
【成份】安立生坦Ambrisentan
【性状】5mg片为粉红色双凸的方形薄膜衣片，一面刻有"GS"，另一面刻有"K2C"；10mg片为深粉红色双凸的椭圆形薄膜衣片，一面刻有"GS"，另一面刻有"KE3"。
【适应症】适用于治疗有WHOII级或III级症状的肺动脉高压患者（WHO组1），用以改善运动能力和延缓临床恶化。
【规　　格】5mg×30s
【用法用量】
成人：起始剂量为空腹或进餐后口服5mg每日1次；如果耐受则可考虑调整为10mg每日1次。
药片可在空腹或进餐后服用。不能对药片进行掰半、压碎、或咀嚼。没有在肺动脉高压患者中进行过高于10mg每日1次剂量的研究。在开始使用本药治疗前和治疗的过程中要进行肝功能的监测（见
【注意事项】部分）。
育龄期女性：女性只有在妊娠测试阴性、以及使用2种合适的避孕方法进行避孕的情况下才能接受治疗，但如果患者已行输卵管结扎术或选择使用T型铜380AIUD或LNg20IUS进行避孕，则不需要采取另外的避孕措施。接受本药治疗的育龄期女性应该每月进行妊娠测试
【警　　告】已存在肝脏损害：不推荐在中重度肝功能损害的患者中应用本药
【注意事项】目前尚无在轻度肝功能损害患者中的应用信息；但是，此类患者对安立生坦的暴露可能会有所增加。
【服药与进食】服药不受进食影响(整片吞服。
【禁　　忌】妊娠。妊娠妇女使用本药很有可能会导致严重的出生缺陷，在动物中应用此药物时经常会观察到这种作用
【禁　　忌】因此在开始治疗前必须排除妊娠，并且在治疗过程中以及治疗后1个月内都应该使用2种合适的避孕方法进行避孕，但如果患者已行输卵管结扎术或选择使用T型铜380AIUD或LNg20IUS进行避孕，则不需要采取另外的避孕措施。每月都进行妊娠测试。
妊娠分类X。在妊娠妇女中应用本药可能会导致胎儿损害。安立生坦口服剂量分别在大鼠≥15mg/kg/日，以及在兔子≥7mg/kg/日时有致畸作用；目前没有关于更低剂量的研究。在两个种属动物中都可以观察到下颚、硬腭和软腭、以及心脏和大血管的畸形，以及胸腺和甲状腺的形成障碍。致畸性是内皮素受体拮抗剂的一类作用。目前没有关于在妊娠妇女中应用本药的数据。
本药禁用于确实或可能已经怀孕的妇女。如果在妊娠期间应用该药，或在应用该药的过程中怀孕，患者应该被告知可能会对胎儿产生的危害。因此在开始治疗前必须排除妊娠，并且在治疗过程中以及治疗后1个月内都应该使用2种合适的避孕方法进行避孕，但如果患者已行输卵管结扎术或选择使用T型铜380AIUD或LNg20IUS进行避孕，则不需要采取另外的避孕措施
【注意事项】
血液学改变：在应用其它内皮素受体拮抗剂后会出现血红蛋白浓度及红细胞压积的下降，此类现象在本药的临床试验中也有出现。这些指标的下降出现在开始本药治疗后的前几周，之后则保持稳定。在为期12周的安慰剂对照研究中，接受本药治疗的患者在治疗结束时的血红蛋白与基线时相比平均下降0.8g/dL。
有7%接受本药治疗的患者（其中10%的患者每日剂量为10mg）出现血红蛋白明显下降（与基线相比降低幅度>15%，并且绝对值低于正常值低限），而与之相比安慰剂组仅有4%的患者发生此类情况。目前尚不清楚导致血红蛋白下降的原因，但它似乎不是由于出血或溶血所致。
应在开始本药治疗前、开始治疗后第1个月、以及随后定期检测血红蛋白。如果患者伴有临床意义的贫血，则不推荐使用本药治疗。如果患者在治疗过程中出现有临床意义的贫血、并且排除了其它诱因，则应考虑停止本药治疗。
液体潴留：外周性水肿是内皮素受体拮抗剂类药物的一种已知效应，同时它也是肺动脉高压和肺动脉高压恶化的临床结果。在安慰剂对照研究中，与安慰剂组相比，接受5或10mg本药治疗的患者外周性水肿的发生率更高（见
【不良反应】大部分水肿的严重性为轻至中度，且在老年患者中的发生率和严重度更高。
此外，目前已有关于肺动脉高压患者在使用本药治疗后的几周内发生液体潴留的上市后报告。患者需要使用利尿剂、限制液体摄入，或者，在某些情况下还因为心功能衰竭失代偿而需要住院治疗。
如果有临床意义的液体潴留进一步发展（伴或不伴体重增加），应该开展进一步的评估以明确病因（如本药或潜在心衰），在必要的时候进行特殊治疗或中断本药治疗。
精子计数下降：为期5个月的另一种内皮素受体拮抗剂（波生坦）研究评估了药物对睾丸功能的影响，受试者为25名患有WHO功能III级和IV级肺动脉高压并且基线精子计数正常的男性患者。使用波生坦治疗3或6个月后，有25%的患者精子计数下降了至少50%。其中1名患者在3个月时发生了明显的精子减少，并且在随后6周的2次随访中所检测的精子计数仍然很低。停止波生坦治疗后2个月，精子计数恢复到基线水平。在22名完成6个月治疗的患者中，精子计数维持在正常范围内，并且没有观察到精子形态、精子活动力、或者激素水平的变化。根据这些关于内皮素受体拮抗剂的发现和临床前数据（见
【儿童用药】
目前尚无关于本药在儿科患者中应用的安全性和有效性数据。
老年患者用药在两项关于本药的安慰剂对照临床研究中，有21%的患者≥65岁，而有5%的患者≥75岁。老年患者（≥65岁）接受本药治疗后在步行距离方面的改善程度要差于较年轻的患者，但对此类亚组分析的结果必需进行谨慎的解释。与较年轻的患者相比，外周性水肿在老年患者中更为常见。

【孕妇及哺乳期妇女用药】
妊娠患者：妊娠分类X
【禁　　忌】
哺乳母亲：目前还不清楚安立生坦是否会随着乳汁进行分泌。不推荐在服用安立生坦的时候进行母乳喂养。一项在大鼠中开展的临床前期研究显示，从妊娠晚期至断奶给母鼠喂食安立生坦会导致新生小鼠生存率下降（中至高剂量），并且会影响小鼠睾丸的大小和成熟度（高剂量）。所检测出的剂量分别为人类最大口服剂量（10mg）的17、51和170倍（分别为低、中、高剂量），单位为mg/mm2。
【不良反应】临床试验经验：关于潜在性肝脏损害的讨论参见
【警　　告】，而关于血液学变化的讨论参见
【注意事项】
本药的安全性数据来自两项在肺动脉高压患者中开展的为期12周的安慰剂对照研究（ARIES-1和ARIES-2）、以及四项在483名肺动脉高压患者（每日1次服用剂量分别为1、2.5、5、或10mg）中开展的安慰剂对照研究。在这些研究中，受试者与本药接触的时间为1天到4年不等（N=418接触至少6个月，N=343接触至少1年）。
在ARIES-1和ARIES-2中，总共261名患者每日1次服用剂量分别为2.5、5、或10mg的本药，而132名患者服用安慰剂。在接受本药治疗的患者中不良事件发生率>3%，明显高于安慰剂组（见下表）。

点击图标参阅图表
这个表格包括了所有在本药治疗组中发生率>3%并且高于安慰剂组的不良事件，而且这些事件在本药治疗组和安慰剂组中发生率的差别≥1%。
大多数药物不良反应为轻至中度，仅有鼻充血呈剂量依赖性。与安慰剂组相比，本药治疗组中仅有少数患者发生的不良事件与肝功能检测有关。
仅有少数几种药物不良反应的发生率在不同年龄和性别的患者中发生率有显著差异。年轻患者中（<65岁），本药治疗组的外周性水肿发生率（14%；29/205例）和安慰剂组（13%；13/104例）相近；而在老年患者中（>65岁），本药治疗组（29%；16/56例）的外周性水肿发生率高于安慰剂组（4%；1/28例）。此类亚组分析的结果必需进行谨慎的解释。
在肺动脉高压患者参加临床试验的过程中，本药治疗组因为不良事件（与肺动脉高压不相关）而中断治疗的发生率（2%；5/261例）与安慰剂（2%；3/132例）相近。在肺动脉高压患者参加临床试验的过程中，本药治疗组中严重不良事件（与肺动脉高压不相关）的发生率（5%；13/261例）与安慰剂组（7%；9/132例）相近。
上市后经验：下述不良反应是在本药获得批准后的使用过程中被识别的：液体潴留（见
【注意事项】心衰（与液体潴留相关），超敏反应（如血管性水肿、皮疹），以及贫血。
因为这些自发报告的反应来自规模大小不确定的人群，因此不可能估算出非常可靠的发生率、或确定一个与药物接触相关的因果关系。
药物相互作用体外研究：用人类肝脏组织进行的研究表明，安立生坦由CYP3A、CYP2C19、5'-二磷酸葡萄糖基转移酶（UGTs）、1A9S、2B7S以及1A3S进行代谢。体外实验提示，安立生坦是器官阴离子转运蛋白（OATP）的底物，同时也是P-gp的底物（而非抑制剂）。
体内研究：安立生坦与下述药物联合应用不会导致有临床意义的安立生坦暴露量改变：酮康唑、奥美拉唑、昔多芬、他达拉非。
联合应用安立生坦不会导致下述药物暴露量的改变：华法令、地高辛、昔多芬、他达拉非、乙炔雌二醇/炔诺酮。
一项在健康受试者中进行的临床试验显示，10mg安立生坦稳态剂量不会对复合口服避孕药（Ortho-Novum1/35）中乙炔雌二醇或炔诺酮成分的单剂药代动力学产生显著影响。根据此项药代动力学研究，安立生坦预计不会对雌激素或黄体酮类避孕药的暴露产生影响。
未知：安立生坦潜在的药物相互作用尚没有得到充分的认识，因为目前还没有开展过下列药物的体内药物相互作用研究：CYP3A和2C19的强诱导物（利福平），UGTs和P-gp的诱导物（利福平），运载体P-gp（环孢素A）和OATP（环孢素A、利福平、利托那韦）的强抑制剂。因为利托那韦、环孢素A和利福平会对上述包含于安立生坦分布过程中的酶产生影响，因此不排除会对安立生坦的暴露产生有临床意义的影响。
查看凡瑞克[Volibris]详细药物相互作用信息

ambrisentan

Generic Name: ambrisentan (AM bri SEN tan)
Brand Name: Letairis

Pronunciation

(am bri SEN tan)

Index TermsBSF208075Dosage Forms

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

Tablet, Oral:

Letairis: 5 mg, 10 mg [contains fd&c red #40 aluminum lake]

Brand Names: U.S.LetairisPharmacologic CategoryEndothelin Receptor AntagonistVasodilatorPharmacology

Blocks endothelin receptor subtypes ETA and ETB on vascular endothelium and smooth muscle. Stimulation of ETA receptors, located primarily in pulmonary vascular smooth muscle cells is associated with vasoconstriction and cellular proliferation. Stimulation of ETB receptors, located in both pulmonary vascular endothelial cells and smooth muscle cells is associated with vasodilation, antiproliferative effects, and endothelin clearance. Although ambrisentan blocks both ETA and ETB receptors, the affinity is greater for the ETA receptor (>4,000-fold higher affinity).

Metabolism

Hepatic via CYP3A4, CYP2C19, and uridine 5'-diphosphate glucuronosyltransferases (UGTs) 1A9S, 2B7S, and 1A3S; in vitro studies also suggest it is a substrate of organic anion transporting polypeptides (OATP) 1B1 and 1B3 and P-glycoprotein (P-gp)

Excretion

Primarily nonrenal

Time to Peak

~2 hours

Half-Life Elimination

~9 hours

Protein Binding

99%

Use: Labeled Indications

Pulmonary arterial hypertension: Treatment of pulmonary artery hypertension (PAH) (World Health Organization [WHO] Group I) to improve exercise ability and delay clinical worsening; in combination with tadalafil to reduce the risks of disease progression and hospitalization for worsening PAH, and to improve exercise ability. Studies establishing effectiveness included predominantly patients with WHO Functional Class II to III symptoms and etiologies of idiopathic or heritable PAH (60%) or PAH associated with connective tissue diseases (34%).

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 ambrisentan second-line therapy in these patients (WSPH [Gailè 2013]).

Contraindications

Pregnancy; idiopathic pulmonary fibrosis, including idiopathic pulmonary fibrosis with pulmonary hypertension (WHO Group 3)

Canadian labeling: Additional contraindications (not in US labeling): Hypersensitivity to ambrisentan or any component of the formulation; severe hepatic impairment (with or without cirrhosis); ALT or AST >3 times ULN at baseline; breastfeeding

Dosing: Adult

Pulmonary arterial hypertension: Oral: Initial: 5 mg once daily, with or without tadalafil; at 4-week intervals, as tolerated and necessary, may increase either the dose of ambrisentan (maximum dose: 10 mg/day) or tadalafil (if used concomitantly).

Dosage adjustment for concomitant therapy: Coadministration with cyclosporine: Ambrisentan dose should not exceed 5 mg/day

Dosing: Geriatric

Refer to adult dosing.

Dosing: Renal Impairment

US labeling:

Mild-to-moderate impairment: No dosage adjustment necessary.

Severe impairment: There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied).

Canadian labeling: No dosage adjustment necessary.

Dosing: Hepatic Impairment

Preexisting impairment:

US labeling:

Mild impairment: There are no dosage adjustments provided in the manufacturer’s labeling; exposure may be increased.

Moderate or severe impairment: Use not recommended.

Canadian labeling:

Mild or moderate impairment: There are no dosage adjustments provided in the manufacturer’s labeling; use with caution and monitor closely.

Severe impairment: Use is contraindicated.

ALT or AST >3 times ULN at baseline: Use is contraindicated.

Impairment developing during therapy:

US labeling:

ALT or AST >5 times ULN: Discontinue therapy.

ALT or AST increased with signs/symptoms of hepatic injury or with bilirubin >2 times ULN: Discontinue therapy.

Canadian labeling:

ALT or AST >3 times ULN: Discontinue therapy.

ALT or AST increased with signs/symptoms of hepatic injury or with bilirubin >2 times ULN: Discontinue therapy.

May consider reinitiation after ALT or AST levels normalize and if there are no signs/symptoms of hepatic injury or jaundice.

Administration

Oral: Swallow tablet whole. Do not split, crush, or chew tablets. Administer with or without food.

Storage

Store at 25°C (77°F); excursions are permitted between 15°C and 30°C (59°F and 86°F). Store in original packaging.

Drug Interactions

CycloSPORINE (Systemic): May increase the serum concentration of Ambrisentan. Management: Limit ambrisentan dose to 5 mg/day and monitor for ambrisentan adverse reactions in patients receiving systemic cyclosporine. Consider therapy modification

Adverse Reactions

Frequency not always defined.

Cardiovascular: Peripheral edema (14% to 38%), flushing (4%)

Central nervous system: Headache (34%)

Gastrointestinal: Dyspepsia (3%)

Genitourinary: Oligospermia

Hematologic & oncologic: Decreased hemoglobin (7% to 10%; dose-dependent), anemia (7%), decreased hematocrit

Respiratory: Nasal congestion (6% to 16%), cough (13%), bronchitis (4%), sinusitis (3%)

<1% (Limited to important or life-threatening): Cardiac failure, dizziness, hypersensitivity, hypotension, increased liver enzymes, weakness

 ALERT: U.S. Boxed Warning

Pregnancy:

Do not administer ambrisentan to a pregnant woman because it may cause fetal harm. Ambrisentan is very likely to produce serious birth defects if used by pregnant women because this effect has been seen consistently when it is administered to animals. Therefore, pregnancy must be excluded before the initiation of treatment. Females of reproductive potential must use acceptable methods of contraception during treatment and for 1 month after treatment. Obtain monthly pregnancy tests during treatment and 1 month after discontinuation.

Dispensing program:

Because of the risk of embryo-fetal toxicity, females can only receive ambrisentan through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the Letairis REMS program.

Warnings/Precautions

Concerns related to adverse effects:

• Fluid retention/peripheral edema: Development of peripheral edema due to treatment and/or disease state (pulmonary arterial hypertension) may occur; a higher incidence is seen with concomitant use of tadalafil and in elderly patients. There have also been postmarketing reports of fluid retention requiring treatment (eg, diuretics, fluid management, hospitalization). Further evaluation may be necessary to determine cause and appropriate treatment or discontinuation of therapy.

• Hematologic changes: A reduction in hematocrit/hemoglobin may be observed within the first few weeks of therapy with subsequent stabilization of levels. Hemoglobin reductions >15% have been observed in some patients. Measure hemoglobin prior to initiating therapy, at 1 month, and periodically thereafter. Significant decreases in hemoglobin in the absence of other causes may warrant the discontinuation of therapy. Use not recommended in patients with clinically significant anemia.

• Hepatic effects: Increases in serum liver aminotransferases have been reported during postmarketing use; however, in the majority of the cases, alternative causes of hepatotoxicity could be identified. Perform liver enzyme testing when clinically indicated. Discontinue therapy if signs/symptoms of hepatic injury appear, if serum liver aminotransferases >5 times ULN (US labeling) or >3 times ULN (Canadian labeling) are observed, or if aminotransferases are increased in the presence of bilirubin >2 times ULN. Hepatotoxicity has been reported with other endothelin receptor antagonists (eg, bosentan); however, ambrisentan may be tried in patients that have experienced asymptomatic increases in liver enzymes caused by another endothelin receptor antagonist after the liver enzymes have returned to normal.

• Spermatogenesis: Sperm count may be reduced in men during treatment (as observed with bosentan). No changes in sperm function or hormone levels have been noted. Fertility issues may require discussion with patient.

Disease-related concerns:

• Hepatic impairment: Use caution in patients with mild hepatic impairment; ambrisentan exposure may be increased. The US labeling does not recommend use in patients with moderate or severe impairment. The Canadian labeling recommends use with caution in moderate impairment with monthly monitoring of ALT/AST during therapy and contraindicates use in severe hepatic impairment (with or without cirrhosis) and in patients with ALT or AST >3 times ULN at baseline.

• Pulmonary veno-occlusive disease (PVOD): Discontinue in any patient with pulmonary edema suggestive of PVOD.

Special populations:

• Pregnancy: [US Boxed Warning]: May cause birth defects; use in pregnancy is contraindicated. Exclude pregnancy prior to initiation of therapy and obtain pregnancy tests monthly during treatment and for 1 month after therapy is complete. Reliable contraception must be used during therapy and for 1 month after stopping treatment. Two reliable methods of contraception (eg, hormone method with a barrier method or two barrier methods) must be used throughout treatment and for one month after stopping treatment. Patients who have undergone a tubal ligation or the insertion of a contraceptive implant or intrauterine device (Copper T 380A or LNg 20) do not require additional contraceptive measures. A missed menses or suspected pregnancy should be reported to a healthcare provider and prompt immediate pregnancy testing. Women should also be educated on the appropriate use of emergency contraception if failure of contraceptive is known or suspected or in the event of unprotected sex.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Other warnings/precautions:

• Letairis REMS Program: [US Boxed Warning]: Because of the high likelihood of teratogenic effects, ambrisentan is only available through the Letairis REMS restricted distribution program. Female patients (regardless of reproductive potential), prescribers, and pharmacies must be registered with and meet conditions of the program. Call 1-866-664-5327 or visit www.letairisrems.com for more information.

Monitoring Parameters

Monitor for significant peripheral edema and evaluate etiology if it occurs; hepatic enzyme testing when clinically appropriate. The Canadian labeling recommends hepatic function testing at baseline then as clinically indicated (all patients) and monthly during therapy (patients with moderate impairment or other risk factors [eg, significant right heart failure, preexisting hepatic disease or previously elevated transaminases, concurrent medications known to increase transaminases]).

A woman of childbearing potential must have a negative pregnancy test prior to the initiation of therapy, monthly during treatment, and 1 month after stopping treatment. Hemoglobin and hematocrit should be measured at baseline, at 1 month, and periodically thereafter (generally stabilizes after the first few weeks of treatment).

Pregnancy Risk Factor

X

Pregnancy Considerations

[US Boxed Warning]: May cause birth defects; use in pregnancy is contraindicated. Exclude pregnancy prior to initiation of therapy and obtain pregnancy tests monthly during treatment and for 1 month after therapy is complete. Reliable contraception must be used during therapy and for 1 month after stopping treatment. Based on animal studies, ambrisentan is likely to produce major birth defects if used by pregnant women. Two reliable methods of contraception (eg, hormone method with a barrier method or 2 barrier methods) must be used throughout treatment and for 1 month after stopping treatment. Patients who have undergone a tubal ligation or the insertion of a contraceptive implant or intrauterine device (Copper T 380A or LNg 20) do not require additional contraceptive measures. A missed menses or suspected pregnancy should be reported to a healthcare provider and prompt immediate pregnancy testing. Sperm counts may be reduced in men during treatment (as observed with bosentan). Women with pulmonary arterial hypertension are encouraged to avoid pregnancy (McLaughlin 2009; Taichman 2014).

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience headache, flushing, cough, or rhinorrhea. Have patient report immediately to prescriber signs of liver problems (dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or jaundice), shortness of breath, excessive weight gain, swelling of arm or leg, or loss of strength and energy (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.