近日，美国食品药品管理局（FDA）批准Adempas(Riociguat)用于治疗成人两种形式的肺动脉高压。肺动脉高压由肺部动脉异常高血压引起。该病症使右侧心脏工作起来比正常情况更艰难。在其各种疾病形式中，肺动脉高压是一种慢性、进展性并使人衰弱的疾病，常常会导致死亡或需要肺移植。
Adempas属于一类叫做可溶性鸟苷酸环化酶激活剂的药物，这类药物有助于动脉松弛，从而使血流增加，血压降低。这款药物旨在治疗术后慢性血栓栓塞性肺动脉高压(CTEPH)患者或无法接受手术的患者，以改善他们的运动能力。Adempas也用于治疗不明原因引起的、遗传性的或与结缔组织病有关的肺动脉高压(PAH)患者，以改善患者的运动能力并推迟他们疾病的临床恶化进度。
“Adempas是可溶性鸟苷酸环化酶激活剂中首款获批用于治疗肺动脉高压的药物，也是首款证明对CTEPH患者有效的药物。”FDA药物评价与研究中心心血管与肾病药物产品部门主任、医学博士与理学博士Norman Stockbridge说。FDA是在优先审评计划下完成Adempas审评的，优先审评可以为治疗上能提供重要进展的药物提供一个加快的6个月的审评。
批准日期：2013年10月8日；公司：Bayer HealthCare Pharmaceuticals Inc.
Adempas(利奥西呱[riociguat]) 片，为口服使用
美国初次批准：2013
作用机制
Riociguat是一种可溶性鸟苷酸环化酶(sGC)的刺激剂，心肺系统中的酶和对一氧化氮(NO)受体。
当NO结合至sGC，酶催化信号分子环磷酸鸟苷(cGMP)的合成。在影响血管张力，增殖，纤维化和炎症调节过程中细胞内cGMP起重要作用。
肺动脉高压伴随内皮功能障碍，一氧化氮的合成受损和NO-sGC-cGMP通路的刺激不足.
Riociguat有双重作用模式。它合成GC至内源性NO通过稳定化NO-sGC结合。Riociguat还通过独立于NO的不同结合位点直接刺激。
Riociguat刺激NO-sGC-cGMP通路和导致cGMP生成增加与随后血管扩张。
Riociguat的活性代谢物(M1)的效力为riociguat的1/3至1/10。
适应证和用途
Adempas是一种可溶性鸟苷酸环化酶(sGC)刺激剂适用为有以下情况成年的治疗：
（1）手术治疗后或不手术的慢性血栓栓塞性肺高血压(CTEPH)(WHO组4)持久性/复发性CTEPH提高运动能力和WHO功能性类别。
（2）肺动脉高压(PAH)(WHO组1)提高运动能力，改善WHO功能性类别和延缓临床恶化。
剂量和给药方法
（1）开始治疗服用在1 mg 1天3次。
（2）对可能不能耐受Adempas的降血压作用患者，考虑开始剂量0.5mg，1天3次。
（3）通过间隔不短于2周增加剂量0.5 mg当耐受最大2.5mg 1天3次。
剂型和规格
片：0.5mg，1mg，1.5mg，2mg和2.5mg
禁忌证
（1）妊娠。
（2）与任何形式的硝酸盐或一氧化氮供体使用。
（3）与磷酸二酯酶(PDE)抑制剂使用。
警告和注意事项
（1）症状性低血压。
（2）出血。
（3）在有肺静脉闭塞病患者中如被确证肺水肿，终止治疗。
不良反应
用Adempas比安慰剂更频(≥3%)发生的不良反应是头痛，眩晕，消化不良/胃炎，恶心，腹泻，低血压，呕吐，贫血，胃食道反流，和便秘。
药物相互作用
（1）强CYP和P-gp/BCRP抑制剂：对接受强CYP和P-gp/BCRP抑制剂患者，考虑开始剂量0.5mg 1天3次。监视低血压。
（2）抗酸药：分开给药间隔至少1小时。
特殊人群中使用
（1）哺乳母亲：终止药物或哺乳。
（2）肾受损：肌酐清除率<15 mL/min或用透析患者建议不要使用。
（3）肝受损：有严重(Child Pugh C)肝受损患者建议不要使用。
（4）吸烟：如耐受可能需要剂量高于2.5 mg 1天3次。停止吸烟患者可能需要减低剂量。
IMPORTANT SAFETY INFORMATION
WARNING: EMBRYO-FETAL TOXICITY
Do not administer Adempas (riociguat) tablets to a pregnant female because it may cause fetal harm.
Females of reproductive potential: Exclude pregnancy before the start of treatment, monthly during treatment, and 1 month after stopping treatment. Prevent pregnancy during treatment and for one month after stopping treatment by using acceptable methods of contraception.
For all female patients, Adempas is available only through a restricted program called the Adempas Risk eva luation and Mitigation Strategy (REMS) Program.
Contraindications
Adempas is contraindicated in:
•Pregnancy. Adempas may cause fetal harm when administered to a pregnant woman. Adempas was consistently shown to have teratogenic effects when administered to animals. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus
•Co-administration with nitrates or nitric oxide donors (such as amyl nitrite) in any form.•Concomitant administration with phosphodiesterase (PDE) inhibitors, including specific PDE-5 inhibitors (such as sildenafil, tadalafil, or vardenafil) or nonspecific PDE inhibitors (such as dipyridamole or theophylline).
Warnings and Precautions
Embryo-Fetal Toxicity. Adempas may cause fetal harm when administered during pregnancy and is contraindicated for use in women who are pregnant. In females of reproductive potential, exclude pregnancy prior to initiation of therapy, advise use of acceptable contraception and obtain monthly pregnancy tests. For females, Adempas is only available through a restricted program under the Adempas REMS Program.
Adempas REMS Program.  Females can only receive Adempas through the Adempas REMS Program, a restricted distribution program.
Important requirements of the Adempas REMS program include the following:
•Prescribers must be certified with the program by enrolling and completing training.
•All females, regardless of reproductive potential, must enroll in the Adempas REMS Program prior to initiating Adempas. Male patients are not enrolled in the Adempas REMS Program.
•Female patients of reproductive potential must comply with the pregnancy testing and contraception requirements.
•Pharmacies must be certified with the program and must only dispense to patients who are authorized to receive Adempas.
Further information, including a list of certified pharmacies, is available at www.AdempasREMS.com or 1-855-4ADEMPAS.
Hypotension. Adempas reduces blood pressure. Consider the potential for symptomatic hypotension or ischemia in patients with hypovolemia, severe left ventricular outflow obstruction, resting hypotension, autonomic dysfunction, or concomitant treatment with antihypertensives or strong CYP and P-gp/BCRP inhibitors. Consider a dose reduction if patient develops signs or symptoms of hypotension.
Bleeding.  In the placebo-controlled clinical trials program, serious bleeding occurred in 2.4% of patients taking Adempas compared to 0% of placebo patients. Serious hemoptysis occurred in 5 (1%) patients taking Adempas compared to 0 placebo patients, including one event with fatal outcome. Serious hemorrhagic events also included 2 patients with vaginal hemorrhage, 2 with catheter site hemorrhage, and 1 each with subdural hematoma, hematemesis, and intra-abdominal hemorrhage.
Pulmonary Veno-Occlusive Disease. Pulmonary vasodilators may significantly worsen the cardiovascular status of patients with pulmonary veno-occlusive disease (PVOD). Therefore, administration of Adempas to such patients is not recommended. Should signs of pulmonary edema occur, the possibility of associated PVOD should be considered and if confirmed, discontinue treatment with Adempas.
Most Common Adverse Reactions
The most common adverse reactions occurring more frequently (≥3%) on Adempas than placebo were headache (27% vs. 18%), dyspepsia/gastritis (21% vs. 8%), dizziness (20% vs. 13%), nausea (14% vs. 11%), diarrhea (12% vs. 8%), hypotension (10% vs. 4%), vomiting (10% vs. 7%), anemia (7% vs. 2%), gastroesophageal reflux disease (5% vs. 2%), and constipation (5% vs. 1%).
Other events that were seen more frequently in Adempas compared to placebo and potentially related to treatment were: palpitations, nasal congestion, epistaxis, dysphagia, abdominal distension and peripheral edema.
For important risk and use information, please see the full Prescribing Information, including Boxed Warning, at www.adempas-us.com.
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