Pharmacological Class:
Soluble guanylate cyclase (sGC) stimulator.
Active Ingredient(s):
Riociguat 0.5mg, 1mg, 1.5mg, 2mg, 2.5mg; tabs.
Company
Bayer Healthcare Pharmaceuticals Inc.
Indication(s):
Treatment of persistent/recurrent chronic thromboembolic pulmonary hypertension (CTEPH), (Who Group 4) after surgical treatment, or inoperable CTEPH, to improve exercise capacity and WHO functional class. Pulmonary arterial hypertension (PAH), (Who Group 1) to improve exercise capacity, WHO functional class, and to delay clinical worsening.
Pharmacology:
Riociguat has a dual mode of action: it sensitizes sGC to endogenous nitric oxide (NO) by stabilizing the NO-sGC binding. Also, riociguat directly stimulates sGC via a different binding site, independently of NO. Riociguat stimulates the NO-sGC-cGMP pathway and leads to increased cGMP generation with subsequent vasodilation.
Clinical Trials:
CHEST-1, a double-blind, multi-national, multi-center study was conducted in 261 patients with CTEPH. Patients were randomized to Adempas titrated up to 2.5mg three daily (n=173) or placebo (n=88).
The primary endpoint was change from baseline in six minute walking distance (6MWD) after 16 weeks based on imputed values. Improvements in walking distance were apparent from Week 2 onward. At Week 16, the placebo adjusted mean increase in 6MWD within the Adempas group was 46m (95% CI: 25m–67m; P<0.0001). The median difference in 6MWD was 39m (95% CI: 25m–54m). Patients treated with Adempas (83%) experienced an improvement in 6MWD vs. placebo (57%).
An open-label extension study, CHEST-2, included 237 patients who had completed CHEST-1. The mean treatment duration for the total population was 582 days (+/− 317 days). The probabilities of survival at 1 and 2 years were 97% and 94%, respectively.
For more clinical trial data, see full labeling.
Legal Classification:
Rx
Adults:
Initially 1mg three times daily; if intolerant, consider starting at 0.5mg three times daily. Increase dose by 0.5mg (three times daily) at intervals of ≥2 weeks as tolerated (SBP >95mmHg and no hypotension); max 2.5mg three times daily. If intolerant at any time, decrease dose by 0.5mg three times daily. Smokers: consider titrating to doses >2.5mg three times daily; may require dose reduction after smoking cessation. Concomitant strong CYP450 and P-gp/BCRP inhibitors: initiate at 0.5mg three times daily.
Children:
Not established.
Contraindication(s):
Pregnancy (Category X). Concomitant nitrates or nitric oxide donors in any form, specific or non-specific phosphodiesterase (PDE) inhibitors (eg, sildenafil, tadalafil, vardenafil, dipyridamole, theophylline).
Warnings/Precautions:
In females of reproductive potential, exclude pregnancy prior to starting, monthly during, and for 1 month after treatment discontinuation; must use acceptable methods of contraception. Risk of hypotension or ischemia in hypovolemia, severe left ventricular outflow obstruction, resting hypotension, autonomic dysfunction; consider dose reduction if signs/symptoms occur. Bleeding risk. Pulmonary veno-occlusive disease: not recommended; discontinue if confirmed. Severe hepatic (Child Pugh C) or renal impairment (CrCl<15mL/min), or on dialysis: not recommended. Nursing mothers: not recommended.
Interaction(s)
See Contraindications. Potentiated by strong CYP450 and P-gp/BCRP inhibitors (eg, ketoconazole, itraconazole, ritonavir); monitor for hypotension. Antagonized by smoking. May be antagonized by strong CYP3A inducers (eg, rifampin, phenytoin, carbamazepine, phenobarbital, St. John’s Wort). Separate dosing of antacids by ≥1 hour of riociguat.
Adverse Reaction(s)
Headache, dizziness, dyspepsia/gastritis, nausea, diarrhea, vomiting, anemia, gastroesophageal reflux, constipation.
Notes:
For all female patients: available only through the Adempas REMS program. To enroll call (855) 4ADEMPAS or www.AdempasREMS.com.
How Supplied:
Tabs—42, 90
LAST UPDATED:
12/13/2013
新型口服血管舒张药riociguat获准用于肺动脉高压
2013年10月9日，FDA已批准Adempas（riociguat）用于2种类型的肺动脉高压：
a）用于肺动脉高压（PAH）成人患者（WHO分级I）的治疗，以提高运动能力、WHO功能分级、推迟临床恶化；
b）用于不能手术或手术后持续性、复发性慢性阻塞性肺动脉高压（CTEPH）成人患者（WHO分级IV）的治疗CETPH的治疗，以提高运动能力和WHO功能分级。
Adempas是唯一一种获FDA批准可用于治疗2种类型肺动脉高压的药物，同时也是唯一一种获FDA批准用于不能手术或手术治疗后持续性/复发性CTEPH的治疗药物。上个月，加拿大卫生部批准Adempas用于CTEPH的治疗。
Adempas的获批，是基于2项随机、双盲、安慰剂对照、全球性III期研究CHEST-1和PATENT-1、以及CHEST-2和PATENT-2目前获得的的长期数据。这些研究分别调查了口服riociguat治疗CTEPH和PAH的有效性和安全性。2项III期研究CHEST-1和PATENT-1均达到了研究的主要终点，此外riociguat在横跨多个相关次要终点均表现出持续改善，同时耐受性良好。
PAH和CTEPH是2种罕见的、危及生命的肺动脉高压，其特点是肺动脉压力明显增加。
Riociguat是拜耳开发的首个新一类可溶性鸟苷酸环化酶(sGC)激动剂，能够直接刺激sGC，增强其对低水平一氧化氮（NO）的敏感度，该药开发用于治疗2种肺动脉高压——慢性血栓栓塞性肺动脉高压(CTEPH)和肺动脉高压(PAH)，改善患者的运动能力，riociguat将以品牌名Adempas销售。
拜耳去年称，预计该药的销售峰值将超过5亿欧元（约合6.46亿美元）。汤姆森路透发布分析报告称，预计该药在2017年的销售将达到6.79亿美元，同时将对市面上来自Actelion和吉利德（Gilead）的药物构成潜在的威胁。
拜耳于2013年2月提交了riociguat的新药申请（NDA），并于2013年8月6日获得了FDA心血管和肾脏药物顾问委员会（CRDAC）建议批准的积极意见，同时FDA于2013年9月授予riociguat治疗PAH和CTEPH的2个孤儿药地位认定。此前，FDA也已授予riociguat新药申请（NDA）优先审查资格。