英文药名：ENTRESTO(sacubitril and valsartan)tablets 中文药名：复方奥帕曲拉/缬沙坦片 生产厂家：诺华制药 药品介绍 ENTRESTO™(sacubitril和缬沙坦[valsartan])片，为口服使用 批准日期：2015年7月7日；公司：Novartis Pharmaceuticals Corporation 美国初次批准：2015 中文名：奥帕曲拉/缬沙坦 通用名：Entresto(LCZ696) 英文名：Sacubitril+Valsartan trisodium hemipentahydrate 作用机制 ENTRESTO含一种脑啡肽酶抑制剂，sacubitril，和一种血管紧张素受体阻断剂，缬沙坦。ENTRESTO抑制脑啡肽酶(中性内肽酶；NEP)通过LBQ657，前药sacubitril的活性代谢物，和通过缬沙坦阻断血管紧张素II类型-1(AT1)受体。ENTRESTO在心力衰竭患者中心血管和肾效应是归咎于被脑啡肽酶降解多肽水平的增加，例如利钠肽被LBQ657，和同时被缬沙坦的血管紧张素II抑制作用。缬沙坦抑制通过血管紧张素II选择性阻断AT1受体效应，和还抑制血管紧张素II-依赖的醛固酮释放。 适应证和用途 ENTRESTO是sacubitril，一种脑啡肽酶[neprilysin]抑制剂，和缬沙坦，一种血管紧张素II受体阻断剂组合复方，适用于在有慢性心力衰竭(NYHA类别II-IV)患者中减低对心力衰竭心血管死亡和住院的风险和减少射血分数。 ENTRESTO是通常与其他心力衰竭治疗结合，代替一种ACE抑制剂或其他血管紧张素II受体阻断剂[ARB]。 剂量和给药方法 ⑴ ENTRESTO的推荐起始剂量是49/51 mg(sacubitril/缬沙坦)每天2次。当患者耐受，2至4周后加倍ENTRESTO剂量至目标维持剂量97/103 mg(sacubitril/缬沙坦)每天2次。 ⑵ 对以下患者减低起始剂量至24/26 mg(sacubitril/缬沙坦)每天2次： ①患者当前未服用一种血管紧张素-转化酶抑制剂(ACEi)或一种血管紧张素II受体阻断剂(ARB)或以前用低剂量这些药物 ②有严重肾受损患者 ③有中度肝受损患者 当被患者耐受时，每2至4周加倍ENTRESTO的剂量至目标维持剂量97/103 mg(sacubitril/缬沙坦)每天2次。 剂型和规格 膜-包衣片(sacubitril/缬沙坦)：24/26mg; 49/51mg; 97/103mg 禁忌证 ⑴对任何组分超敏性。 ⑵与以前ACE抑制剂或血管紧张素II受体阻断剂[ARB]治疗相关的血管水肿病史。 ⑶与ACE抑制剂同时使用。 ⑷在有糖尿病患者中同时使用与阿利吉仑[aliskiren]。 警告和注意事项 ⑴ 观察对血管水肿和低血压的体征和症状。 ⑵在易感患者中监视肾功能和钾。 不良反应 发生 ≥5%不良反应是低血压，高钾血症，咳嗽，眩晕，和肾衰竭。 药物相互作用 ⑴肾素-血管紧张素系统的双重阻断：不要与一种ACEi使用，在患者有糖尿病不要与阿利吉仑使用，和避免与一种血管紧张素II受体阻断剂[ARB]使用。 ⑵ 保钾利尿剂：可能导致血清钾增加。 ⑶ NSAIDs：可能导致肾受损的风险增加。 ⑷锂：增加锂毒性的风险。 在特殊人群中使用 ⑴ 哺乳：应终止哺乳喂养或药物。 ⑵ 严重肝受损：建议不使用。 包装规格 24mg/26mg  Violet white  L Z 0659-20 0659-67 0659-35   瓶：60  180  吸塑的包装100 49mg/51mg  Pale yellow   L 1 0777-20 0777-67 0777-35   瓶：60  180  吸塑的包装100 97mg/103mg Light pink    L 11 0696-20 0696-67 0696-35  瓶：60  180  吸塑的包装100 Novartis new heart failure medicine LCZ696 approved by FDA to reduce risk of cardiovascular death and heart failure hospitalization; now called Entresto™ (sacubitril/valsartan) •First in the world approval brings hope of longer life and fewer HF hospitalizations by reducing the devastating impact of heart failure with reduced ejection fraction for millions of patients in the US1-3 •Entresto is the first and only treatment to show a significant mortality benefit in a head-to-head trial against ACE-inhibitor enalapril4 •Heart failure is a life-threatening condition affecting nearly 6 million Americans; about half have the reduced ejection fraction form •Approval comes six weeks ahead of FDA’s priority review action date; Novartis is working to make Entresto available to patients as quickly as possible US Food and Drug Administration (FDA) has approved Entresto™ (sacubitril/valsartan) tablets, previously known as LCZ696, to reduce the risk of cardiovascular death and hospitalization for heart failure in patients with chronic heart failure (NYHA Class II-IV) and reduced ejection fraction (HFrEF). It is usually administered in conjunction with other heart failure therapies, in place of an ACE inhibitor or other angiotensin receptor blocker (ARB).1 Reduced ejection fraction means the heart doesn't contract with enough force, so less blood is pumped out. Read More Related ResourcesEntresto Fact Sheet Download VideosAdvocacy Video Entresto B-Roll Entresto MOA Physician Video Heart Failure Disease ResourcesHeart Failure Media Backgrounder Heart Failure Infographic The information provided in this section is intended to be used for educational purposes only to better understand the heart failure disease state. Related LinksNovartis Follow us on TwitterTweets by @Novartis “The approval of Entresto marks a new era in the treatment of heart failure made possible by the collective efforts of our Novartis associates, the hundreds of cardiologists and nurses, and thousands of patients who participated in the research,” said Christi Shaw, US Country Head, President of Novartis Corporation and Novartis Pharmaceuticals Corporation. “We have so many people in the heart failure community to thank for helping bring this exciting new treatment to patients and are working hard to make it available at pharmacies as quickly as possible.” The FDA’s decision is based on results from the 8,442-patient PARADIGM-HF study, the largest clinical trial ever conducted in heart failure.1,7 In the study, Entresto demonstrated clinically relevant and statistically significant superiority to ACE-inhibitor enalapril, reducing the risk of cardiovascular death or heart failure hospitalization by 20% (the primary endpoint) at a median follow-up of 27 months. Entresto also improved overall survival by 16% versus enalapril, driven by the lower incidence of cardiovascular death.1,4 The study was stopped early after the Data Monitoring Committee overseeing the study found that Entresto significantly reduced the risk of cardiovascular death and that the primary endpoint had been met. “The vey meaningful survival advantage of Entresto seen in the PARADIGM-HF trial should persuade physicians to consider Entresto for all appropriate patients, in place of traditional ACE inhibitors or angiotensin receptor blockers,” said Dr. Milton Packer, Professor and Chair for the Department of Clinical Sciences at University of Texas Southwestern Medical Center, Texas, USA. “Entresto is expected to change the management of patients with HFrEF for years to come.” Nearly 6 million people in the United States suffer from heart failure and about half have the reduced ejection fraction form.2,3 Up to 2.2 million of these patients have heart failure classified as NYHA II-IV, based on how much their symptoms limit physical activity.9,10 Heart failure is a debilitating and life-threatening condition in which the heart cannot pump enough blood around the body.5 Patients face a high risk of death, repeated hospitalizations and symptoms such as breathlessness, fatigue and fluid retention that significantly impact quality of life. “Heart failure places a tremendous physical, emotional and financial burden on patients, their caregivers and society,” said Michele Blair, Chief Executive Officer at the Heart Failure Society of America. “There is a great need in the heart failure community for therapies that improve patient outcomes. Today’s approval is a victory for patients, and we welcome the addition of a new treatment option to help manage this very serious condition.” About Heart Failure Heart failure represents a major and growing health-economic toll that currently exceeds $30 billion in the United States, accounting for both direct and indirect costs. Hospitalizations account for 80% of the $21 billion spent on the direct costs of heart failure.15 Some 870,000 new heart failure patients are diagnosed annually.2 With the aging population, it is estimated over 8 million Americans will have heart failure by 2030.15 It is the most common reason people over 65 go into the hospital, and overall it accounts for more than 1 million hospitalizations each year.2,16 Despite available therapies, nearly half of heart failure patients die within 5 years of diagnosis. About Entresto Entresto is a twice-a-day medicine that reduces the strain on the failing heart. It does this by enhancing the protective neurohormonal systems of the heart (NP system) while simultaneously suppressing the harmful effects of the overactive renin-angiotensin-aldosterone system (RAAS).1 Other heart failure medicines only block the harmful effects of the overactive RAAS.10 Entresto contains the neprilysin inhibitor sacubitril, which is a new molecular entity, and the angiotensin receptor blocker (ARB) valsartan. Entresto film-coated tablets are available in three dosage strengths: 24/26 mg, 49/51 mg, and 97/103 mg (sacubitril/valsartan). These doses are referred to as 50 mg, 100 mg, and 200 mg in the clinical trial literature including the New England Journal of Medicine publication of the results of PARADIGM-HF. The target dose of Entresto is 97/103 mg twice daily. Generic Name and Formulations: Sacubitril, valsartan; 24mg/26mg, 49mg/51mg, 97mg/103mg; tabs. Company: Novartis Pharmaceuticals Corp Indications for ENTRESTO: To reduce risk of cardiovascular death and hospitalization for heart failure in patients with chronic heart failure (NYHA Class II–IV) and reduced ejection fraction; usually given with other therapies, in place of an ACEI or other ARB. Adult: Initially 49mg/51mg twice daily; double the dose after 2–4 weeks to target maintenance dose of 97mg/103mg twice daily as tolerated. Not currently on ACEI/ARB, previously on low doses of ACEI/ARB, severe renal impairment (eGFR <30mL/min/1.73m2), or moderate hepatic impairment (Child-Pugh B): initially 24mg/26mg twice daily; double the dose every 2–4 weeks to target maintenance dose of 97mg/103mg twice daily as tolerated. If switching from or to an ACEI: allow 36 hour wash-out period between taking the two drugs. Children: Not established. Contraindications: History of angioedema related to previous ACE inhibitor or ARB therapy. Concomitant ACE inhibitors. Concomitant aliskiren in patients with diabetes. Warnings/Precautions: Fetal toxicity may develop; discontinue if pregnancy is detected. Discontinue if angioedema occurs; do not re-administer. Give SC epinephrine for airway obstruction if indicated. Black patients may have higher risk of angioedema than non-Black patients. May cause symptomatic hypotension. Correct salt/volume depletion prior to initiation or start at a lower dose. Adjust concomitant diuretic or antihypertensive doses if hypotension occurs. Reduce dose or temporarily discontinue if hypotension persists. Monitor renal function in renal artery stenosis, severe CHF. Monitor serum creatinine and down-titrate or interrupt dose if significant renal dysfunction develops. Monitor for hyperkalemia esp. in severe renal impairment, diabetes, hypoaldosteronism, or high K+ diet. Severe hepatic impairment: not recommended. Neonates. Pregnancy (2nd & 3rd trimesters); consider alternative therapy. Nursing mothers: not recommended. Interactions: See Contraindications. Dual inhibition of the renin-angiotensin system: avoid concomitant with an ARB. Concomitant aliskiren in renal impairment (eGFR <60mL/min/1.73m2); avoid. Concomitant K+ supplements, K+ -sparing diuretics, K+ -containing salt substitutes may cause hyperkalemia. Worsening renal function and possible acute renal failure with NSAIDs, including selective COX-2 inhibitors (monitor renal function periodically in elderly and/or volume depleted). May increase lithium levels; monitor. May inhibit OATP1B1 and OATP1B3 transporters. Pharmacological Class: Neprilysin inhibitor + angiotensin II receptor blocker. Adverse Reactions: Hypotension, hyperkalemia, cough, dizziness, renal failure, increased serum creatinine, decreased hemoglobin/hematocrit. Generic Availability: NO How Supplied: Tabs—60, 180 http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=000dc81d-ab91-450c-8eae-8eb74e72296f Entresto (LCZ696，sacubitril/缬沙坦)获FDA批准治疗心衰的新药 2015年7月7日，美国食品和药物管理局今天批准Entresto（sacubitril/缬沙坦）片剂用于心脏衰竭的治疗。该药物已被证实可以降低心血管死亡和住院相关的心脏衰竭的速率。 心脏衰竭是一种常见的情况影响到约510万人在美国。 它是在心脏不能泵出足够的血液来满足身体的需要的条件。 心脏衰竭恶化，通常随着时间的推移心脏的抽吸作用变得越来越虚弱。心脏衰竭的主要原因是损害心脏，如心脏发作和高血压病。 “心力衰竭是死亡和残疾的成年人的主要原因，”诺曼·斯托克布里奇，医学博士，心血管和肾脏产品司在FDA的药品评价中心和研究总监。 “治疗可以帮助人们与心脏衰竭寿命更长，享受更多的积极的生活。” Entresto是根据FDA的优先审查程序，它提供的药物被用来治疗严重的疾病或状况，并且可以提供显著改进现有的治疗加急审查审查。 它也获得快速轨道指定，它支持FDA的努力，以促进发展和加快药物来治疗严重或危及生命的条件和填补未满足的医疗需求进行审查。 Entresto，研究了8000余成年人的临床试验，并显示出降低心血管死亡和相关的心脏衰竭住院率相比另一种药物，依那普利。 大多数患者还接受目前批准的心脏衰竭的治疗，包括β-阻滞剂，利尿剂，和盐皮质激素受体拮抗剂。 与Entresto治疗在临床试验参与者中最常见的副作用是低血压（低血压），高血钾水平（高血钾症），以及肾脏功能不佳（肾功能损害）。 血管性水肿（过敏反应通常显示为嘴唇或面部肿胀）也报道了Entresto; 黑色患者和患者的血管性水肿的病史有更高的风险。 应建议患者得到紧急医疗帮助，马上，如果他们有血管神经性水肿或呼吸Entresto而烦恼的症状。 医护人员应建议患者不要与血管紧张素转换酶（ACE）抑制剂类使用Entresto用任何药物，因为血管神经性水肿的危险性增加。 当Entresto和ACE抑制剂之间的切换，使用两种药物的应通过36小时来分离。 医护人员应告知患者有关的伤害未出生的胎儿的风险。 如果在怀孕检测，使用Entresto应尽快停止。 关于 Entresto Entresto是首个血管紧张素受体脑啡肽酶抑制剂（ARNI）类药物，来降低衰竭心脏的压力。这是一种每天服用2次的片剂，其通过增强心脏的保护性神经内分泌系统（NP系统）并同时抑制有害系统（RAAS）来发挥作用5。 PARADIGM-HF研究在8,442例患者中得出的结果显示，与依那普利相比，Entresto1： 使心血管死亡风险降低20% 使心衰住院风险降低21% 使全因死亡风险降低16% 总体而言，主要终点（心血管死亡或至首次心衰住院时间的复合终点）的风险降低20%。 Entresto 组因不良事件停用研究药物的患者数量少于依那普利组。与依那普利组相比，Entresto 组低血压和非严重血管性水肿的发生率略高，但肾损害、高钾血症和咳嗽发生率更低。 Entresto由诺华公司制造。