2013年10月8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。
Adempas治疗CTEPH的安全性和有效性基于一项由261名受试者参与的临床试验，试验中受试者被随机配给Adempas，用药剂量逐渐增加到2.5mg，每天用药三次，或配给安慰剂每天使用三次。这项研究的目的是检测受试者6分钟之内所能行走距离的变化。经过16周的治疗后，Adempas用药患者6分钟行走距离平均增加46米，远超过安慰剂治疗患者。
用来评价Adempas治疗PAH安全性和有效性的临床试验由443名受试者参与，患者被随机配给1.5mg或2.5mg剂量的Adempas或者安慰剂，每天用药三次。经过16周治疗后，Adempas用药患者6分钟行走距离平均提高36米，远超过安慰剂治疗患者。
Adempas药品标签中带有一项黑框警告，提示患者与卫生保健专业人员这款药物不能用于孕妇，因为它会伤害胎儿的发育。女性患者只能通过Adempas风险评估与降低（REMS）计划来获取这款药物。所有女性患者必须加入这个计划，遵守怀孕测试要求，并得到需要进行避孕的劝告。限制药品分销的REMS计划要求开处方者加入该项计划并获得认证。同时，药店必须通过认证并只能将这款药物分发给按REMS要求有资格使用的患者。
Adempas治疗患者常见的副作用包括头痛、头晕、消化不良、组织肿胀(外围性水肿)、恶心、腹泻和呕吐。Adempas由位于新泽西州韦恩的拜耳医药保健制药公司上市销售。
Adempas(riociguat) 片，为口服使用
美国初次批准：2013
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动脉高压(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1mg 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0.5mg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。
报告怀疑不良反应，联系Bayer HealthCare Pharmaceuticals Inc公司电话1-888-842-2937或FDA电话1-800-FDA-1088或www.fda.gov/medwatch。
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2.5mg 1天3次。停止吸烟患者可能需要减低剂量。

 
FDA Approves Bayer’s New Class of Drug Adempas® (riociguat) tablets to Treat Adults with PAH and Persistent, Recurrent or Inoperable CTEPH

First and only drug approved in U.S. to Treat Two Forms of Pulmonary Hypertension (WHO Group 1 and 4)
WHIPPANY, N.J., Oct. 9, 2013 /PRNewswire/ — Bayer HealthCare announced today that the United States Food and Drug Administration (FDA) has approved Adempas® (riociguat) tablets for: (i) the treatment of adults with persistent/recurrent chronic thromboembolic pulmonary hypertension (CTEPH) (WHO* Group 4) after surgical treatment or inoperable CTEPH to improve exercise capacity and WHO functional class; and (ii) the treatment of adults with pulmonary arterial hypertension (PAH) (WHO Group 1) to improve exercise capacity, improve WHO functional class and delay clinical worsening.
In PAH, efficacy was shown in patients on Adempas monotherapy or in combination with endothelin receptor antagonists (ERAs) or prostanoids (inhaled, oral or subcutaneous). Studies establishing effectiveness included predominately patients with WHO functional class II-III and etiologies of idiopathic or heritable PAH (61%) or PAH associated with connective tissue diseases (25%).
Adempas is the only treatment approved in the U.S. for use in two types of pulmonary hypertension (WHO Group 1 and 4). It is the first and only FDA-approved drug therapy for persistent/recurrent CTEPH after surgical treatment or inoperable CTEPH. It is also the only approved oral therapy in PAH with efficacy shown in monotherapy or in combination with ERAs or prostanoids.
For all female patients, Adempas is available only through a restricted program called the Adempas Risk Evaluation and Mitigation Strategy (REMS) Program.
“CTEPH and PAH are serious and life-threatening diseases,” said Nick H. Kim, Associate Clinical Professor of Medicine, Division of Pulmonary and Critical Care Medicine; Director, Pulmonary Vascular Medicine; Director, Fellowship Program; University of California San Diego.  “The approval of Adempas equips physicians with a new approach to treating PAH patients, and it gives us the first approved drug treatment for patients with inoperable CTEPH or with persistent/recurrent CTEPH after surgery.  While surgery should always be considered as the first treatment option for CTEPH, the fact remains that up to forty percent of CTEPH patients are not eligible for surgery, and ten to thirty-five percent of CTEPH patients have disease that persists after surgery.”
PAH is a disease characterized by elevated pressure in the pulmonary arteries. CTEPH is a form of pulmonary hypertension in which blood clots and thromboembolic occlusion of the pulmonary vessels leads to increased pressure in the pulmonary arteries. The standard treatment for CTEPH is pulmonary endarterectomy, a potentially curative surgery that clears clots and scar material from the blood vessels of the lung.
“Bayer is deeply committed to bringing new treatment options to patients with life-threatening diseases. Adempas is an excellent example of this commitment, because it is the result of years of dedicated research in our Bayer laboratories into a new way of treating two forms of pulmonary hypertension,” said Pamela A. Cyrus, MD, Vice President and Head, U.S. Medical, Bayer HealthCare Pharmaceuticals. “We are pleased to bring this new class of treatment to patients with PAH or with inoperable CTEPH or persistent/recurrent CTEPH after surgical treatment.”
Rino Aldrighetti, President and CEO, Pulmonary Hypertension Association added, “From a patient’s perspective, living with pulmonary hypertension remains difficult. We know that not all treatments work for all people. We get excited when there is a new treatment option for PAH patients, and we are thrilled there is finally an approved drug treatment for people living with persistent/recurrent CTEPH after surgical treatment or inoperable CTEPH.”
Adempas, a stimulator of soluable guanylate cyclase (sGC), represents a new class of drug now available in the U.S. Pulmonary hypertension is associated with endothelial dysfunction, impaired synthesis of nitric oxide (NO) and insufficient stimulation of the NO-sGC-cGMP pathway. Adempas sensitizes sGC to endogenous NO by stabilizing the NO-sGC binding. Adempas also directly stimulates sGC via a different binding site independently of NO. Adempas restores the NO-sGC-cGMP pathway and leads to increased generation of cGMP with subsequent vasodialation.
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.
About Patient Assistance Program
Bayer offers patient assistance through the Adempas Aim Support Center program, which will assist with obtaining coverage and patient support of Adempas. Patients and providers may contact the program at 1-855-4ADEMPAS for additional information.
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 Evaluation 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.