关于Enbrel（恩利）

由美国惠氏专有，英文原名Entanercept（依那西普），商品名为恩利（Enbrel），是一种治疗类风湿关节炎的可溶性TNFa受体融合蛋白。它是由TNFa受体蛋白的膜外区与人IgG1的Fc段融合蛋白构成的二聚体。Enbrel可结合血清中的可溶性TNFa及TNFb，并由此阻断二者与细胞表面TNF受体的结合，抑制由TNF受体介导的异常免疫反应及炎症过程。Enbrel含934个氨基酸，分子量为150kd，其半衰期为115小时。

国外已完成的几个多中心随机双盲对照研究证明，慢作用抗风湿药治疗无效的类风湿关节炎患者经Enbrel治疗后有肯定的效果。临床观察发现，类风湿关节炎患者的美国风湿病学会（ACR）20%有效率在50-75%，关节肿痛的缓解率达52-61%（5-7）。Enbrel的副作用仅见轻度注射部位反应。 

FDA批准Immunex公司Enbrel的新适应症
美国食品和药物管理局（FDA）在今年1月18日批准Immunex公司的药物Enbrel用于治疗银屑病关节炎新适应症，这是FDA第一次批准银屑病关节炎治疗药物。FDA曾在2001年9月就批准对Enbrel新适应症作快速审查处理。

Enbrel是一种批准用于治疗中度到重度类风湿性关节炎的药物，预计全美有150万人患有这种由于免疫系统紊乱造成的关节和软骨疼痛及膨胀的疾病。

银屑病关节炎是一种严重的慢性炎症疾病，可引起关节疼痛、肿胀，很容易导致失能。传统的治疗包括非甾体抗炎药，皮质内固醇和改善用抗风湿药，如氨甲蝶呤和环孢菌素。以前的统计资料表明全美大约有30万银屑病关节炎患者，但是Immunex在本周三宣称由国家银屑病基金会进行的最新统计表明当前美国有100万银屑病患者。

银屑病基金会的主管Gail Zimmerman介绍说，“银屑病关节炎与其他类型的关节炎不同，患者除皮肤表面有带磷红色斑块外，还伴有关节疼痛和膨胀症状。目前对银屑病关节炎的治疗仅仅是借鉴了其他治疗方法，并不是对每位患者都有效。”

该药物通过结合到特定蛋白使之失去活性而起到治疗作用，后者在正常的免疫功能和类风湿性关节炎及银屑病关节炎引起的反馈反应中都起关键性作用。Enbrel的副作用除注射部位皮肤有反馈作用外，对呼吸系统和其他部位也有潜在的感染性。

注射性药物Enbrel由位于西雅图的Immunex公司和位于新泽西州Madison的一家制药公司——美国家庭用品公司(American Home Products，NYSE:AHP)负责销售。

Immunex公司已在上个月已同意被其竞争对手Amgen公司(NasdaqNM:AMGN)用价值160亿美元的现金及股票收购，包括Enbrel。

2001年Enbrel销售额达7.5亿美元，Amgen公司称到2005年其销售额将增加到30亿美元。

UBS Warburg分析家Geoffrey Harris在一份报道中指出，“在今年第一季度获得的批准进一步巩固了对Enbrel销售额今年达到9.5亿美元，2005年将增加到27亿美元的估算。”他预计银屑病关节炎治疗申请的批准将为今年Enbrel销售额带来5600万美元，到2005年将每年达到4亿美元或者更多。

Immunex公司希望建一个新的药物生产工厂，将于10月份获得批准。此外，还将对Enbrel对包括鳞癣在内其他疾病的治疗作用进行研究。

关节炎基金会的医学理事John Klippel博士称，我们已进入关节炎有效治疗的新时期，将完全改变和改善关节炎的治疗方法。相信生物应答调节器将带来关节炎治疗模式的革命。

除了银屑病关节炎，FDA还批准Enbrel用于改善成年人类风湿性关节炎的征候及症状，以延缓其关节损害，以及儿童的多关节性幼态类风湿性关节炎。预计今后10年，扩充Enbrel的适应症使其能治疗银屑病关节炎可能是关节炎治疗医学进展的第一步。

Enbrel现可用于改善中重度RA病人的身体功能 
 
阿目金公司和惠氏制药公司宣布：ＦＤＡ批准Enbrel（etanercept）还可用于改善中、重度活性类风湿性关节炎（RA）病人的身体功能。

3个安慰剂对照试验评估了Enbrel改善身体功能和失能的能力，病人总有955人，患中或晚期RA。在这些开放性研究中，身体功能和失能的改善维持了4年。用来评估改善的主要工具是健康评估调查问卷（HAQ：0分表明没有失能）。“中、重度RA可能对病人的生活有破坏性影响，限制他们一些甚至最简单的日常生活能力，如系扣子、端茶杯等”，阿目金公司副总裁杨（Kevin Young）说，“这次批准证实Enbrel有能力帮助病人恢复正常生活，这可能是病人治疗的最终目标”。

“近几年来，改善病人的日常生活能力，包括身体功能和失能，已成为评估成功治疗RA的重要测量措施”，惠氏公司北美医学执行官兼副总裁库西亚科（Victoria Kusiak）说，“通过评估身体功能的改善，我们进一步理解了Enbrel对RA病人生活的影响”。

早期RA病人单用Enbrel治疗，6个月后平均HAQ改善0.7，而改善0.22就有临床意义。一年时22%的病人HAQ为0分。许多用Enbrel治疗（单用或与氨甲喋呤联用）的晚期病人（至少一种缓解疾病的抗类风湿性疾病药失败）HAQ与用安慰剂或只用氨甲喋呤的病人HAQ分改善，治疗头一个月就出现的改善维持了整个研究期，，6个月时Enbrel组平均改善0.6，而安慰剂组0、0.2，15%单用Enbrel和15%联用Enbrel与氨甲喋呤的病人HAQ到0分，而安慰剂组分别只有0%和3%。

在安慰剂对照的试验(n=349)中，最常见的副作用是注射部位反应（ISR）（37%）、感染（35%）和头痛（17%），只有ISR率高于安慰剂组；在氨甲喋呤对照的试验(n=415)中，最常见的副作用是感染（64%）、ISR (34%)和头痛（24%），只有ISR率高于氨甲喋呤组。

Enbrel是唯一一种完全的抗TNF受体，批准用于减少中、重度活性RA病人的症状和体征、改善身体功能、抑制结构损害及减少银屑病关节炎病人活性关节炎的症状和体征。它是唯一被批准用作RA病人一线治疗的生物学制剂，可联合或单独使用。它还被批准用来减少中、重度活性多关节青少年类风湿性关节炎病人（JRA）的症状和体征，也是第一种被准许用于治疗活性强直性脊柱炎病人症状和体征的生物学制剂。全世界18万名病人的治疗确定了它的好处和长期安全性，自使用以来有以下报告：

－重度感染：多见于易于感染者，如晚期或控制不良的糖尿病人；有些重度感染可致命；极少见结核菌感染。

－注意：如果你正感染或对Enbrel及其成份过敏不要开始用它；如果你容易感染要告诉医生，如果有重度感染要停掉Enbrel；若有问题或出现感染要与医生联系。

－严重的神经系统病症，如多发性硬化症、癫痫或眼部神经的炎症。如有以上病症之一要告诉医生。

－极少数时候致血液病症（有些可致命）：如果持续发烧、瘀伤、出血或苍白要立即联系医生。

－对有JRA史的病人，头痛、腹痛、呕吐和恶心多于成人，但多较轻。其它很少报告的副作用包括重度感染（2%）和抑郁/人格障碍（1%）。  
【医业网据Docguide.com2003年6月25日讯】阿目金和惠氏制药公司宣布，Enbrel(etanercept)是FDA关节炎专家顾问小组委员会推荐治疗强直性脊柱炎(AS)的第一种生物学制剂。

“我们很高兴委员会全体投票通过，并将同FDA密切合作尽快把Enbrel提供给强直性脊柱炎病人，目前他们的治疗选择很有限”，阿目金发展部副总裁塞登贝格(BethSeidenberg)说，“Enbrel能显著改善疼痛、脊柱的可动性和身体功能”。当前FDA除了批准非甾体抗炎药和类固醇治疗AS外几乎没有什么其它药，本病在美国约有35万名患者。
“专家小组的这个提议让医生和病人离一种新药又更近了”，惠氏公司全球医务副总裁、北美医学主任库西亚科(VictoriaKusiak)说，“我们期待这个增加Enbrel治疗类风湿关节炎、幼年型类风湿关节炎、银屑病关节炎以外利益和影响的机会，让长期以来没什么好办法的病人明显减少疼痛症状”。

在重要的3期研究中，用Enbrel治疗的病人关节疼痛和早晨强直明显减少，脊柱活动性和身体功能改善。“这些研究结果非常鼓舞人，有些病人早到治疗两周时就有反应了，头两个月内就达到最大缓解”，主要研究人员、加州大学的副教授、临床试验中心医药部副主任戴维斯(JohnDavis)说。“委员会对批准Enbrel的提议强调了帮助强直性脊柱炎病人寻找新药的重要性”，美国脊椎炎学会执行主任布鲁科尔(JaneBrucke)说，“我们支持研制本病疗法的工作，因为脊椎炎可能显著影响病人的生活”。

Enbrel是唯一批准来减少中重度活性RA症状体征、抑制结构性损害进展和减少银屑病关节炎患者活性关节炎症状体征的全人抗TNF受体，也是唯一批准治疗新诊断RA病人的生物制剂，可以单独使用。对缓解疾病的抗风湿性药无效的青少年类风湿性关节炎，其中重度活性多关节炎症状也可用Enbrel来减少。医生已开始熟悉Enbrel的优点，且证实它可长期耐受。5年前自从上市来全世界已有18万病人用过它。它的作用机理是吸附TNF，使炎症明显减少。每个人的效果差异很大，医学研究中对2/3的RA病人、3/4的JRA病人和1/2的银屑病关节炎病人有效。该药从使用以来在病人中有下列报告：

严重感染：多在易感染者中出现，如晚期或控制不良的糖尿病患者；有些重度感染是致命的；罕见结核病人。

注意：如果有感染或对Enbrel及其成份过敏，不要使用；如果你容易感染的话要告诉医生；如果出现重度感染，停用Enbrel；如对Enbrel有什么疑问或出现感染与医生联系。

严重的神经系统病症，如多发性硬化症、癫痫或眼神经炎：如果你曾有这些疾病或如果用Enbrel后出现这些疾病要告诉医生。

很少的血液疾病(有些是致命的)报告：如果出现持续性发烧、瘀伤、出血或苍白要立即与医生联系。

也可能引起注射局部反应
一个对JRA病人的研究发现，感染、头痛、异常腹痛、呕吐和恶心比成人更多；患儿的感染通常较轻，且与其它儿童相似；偶然可见一些不良副反应，包括严重感染(2%)和抑郁/人格障碍(1%)。

日本批准依那西普用于类风湿治疗

2008年06月14日

惠氏日本公司和Takeda Pharmaceutical公司于2005年1月25日宣布，日本厚生省批准依那西普（etanercept，Enbrel）用于治疗对现有药物应答不足的类风湿性关节炎（RA）患者。 至此，本品已在全球70多个国家上市。

惠氏日本公司和Takeda Pharmaceutical公司于2005年1月25日宣布，日本厚生省批准依那西普（etanercept，Enbrel）用于治疗对现有药物应答不足的类风湿性关节炎（RA）患者。 至此，本品已在全球70多个国家上市。

依那西普为一靶向肿瘤坏死因子（TNF）的完全人源化单克隆抗体药物，可缓解对传统抗关节炎药物应答不足的RA患者的体征和症状。其于1998年首次获得FDA批准用于治疗疼痛性关节疾病，长期安全性和疗效已在临床上得到了证明。依那西普可以单用治疗RA，以每周皮下注射2次的方式给药，在日本由惠氏公司和Takeda Pharmaceutical公司共同销售。本品最常见不良反应有注射部位反应、感染和头痛。 

RA为一种可致残的慢性疾病。在日本大约有70万RA患者。严重的RA会引起机体免疫系统攻击关节内衬和结缔组织，致使关节疼痛和肿胀。如果不进行及时有效的治疗，还可能导致疲乏、残疾、畸形、器官损伤，甚至早死。在日本，畿患RA的女性患者人数是男性患者的4倍之多。RA可以在所有的年龄段包括儿童时期发病，其高发年龄段为25～50岁。 

依那西普说明书

药品名:依那西普(Etanercept)

英文名:Infliximab、Enbrel@(Amgen Inc 生产)、Remicade@(Centacor.Inc生产).

来源: 英利昔是利用重组DNA和单克隆抗体技术制备的人源化的人鼠嵌合搞TNFα受体单抗.

依那西普是完全由人Ig生产的抗TNFα受体单抗.

作用机制: 本品为二聚体融合蛋白,由人类75kD肿瘤坏死因子(tumor necrosis factor, TNF)受体的细胞外配体结合部分和人类IgG1Fc段连接而成.本品Fc段含有GH2区、CH3区铰链区,但是不含有CH1区.
   
近年来研究发现骨髓异常增生综合征(myelo-dysplastic syndrome, MDS)伴有程序化细胞死亡(凋亡)加速,并且这种细胞凋亡与过度表达TNFα有关.本品特异性地与TNFα受体结合,阻断TNFa与细胞表面TNFα受体的相互作用;此外,本品还可以调节TNFα诱导或者介导的生物学作用.

药代动力学:
 
1.吸收:单药25mg皮下注射.吸收较慢,平均69±34小时,达到血药峰浓度.每周两次,每次25mg皮下注射用药6个月后,平均血药浓度2.4±1.0 μg/ml.
2.分布:无资料.
3.半衰期:单药25mg皮下注射,清除率160±80ml/h.平均半衰期102±20小时.
4.清除:经体内蛋白质降解途径清除.
 
药物相互作用: 尚无相关资料.

适应证: 治疗低危/中危MDS、难治性贫血(RA)期伴有TNFa升高的病例.

单药有效率: 治疗MDS,有效率12.5%～30%.

剂型: 无菌白色不含防腐剂的冻干粉,每支含有Enbrel25mg,D-甘露醇40mg,蔗糖10mg,氨丁三醇1.2mg.依那西普为无菌冻干粉,每支含Remicade100mg.

剂量: 试验治疗MDS剂量(Remicade):3mg/kg静脉用药6次(第0、2、6、14、22、30周).Embrel,25mg皮下注射,每周2次,3个月为一疗程.

给药途径: 皮下注射或者静脉点滴.

配伍:
本品不宜与其他药品混合使用并且不应使用注射用水以外的溶媒溶药.

禁忌证:
败血症患者、已知对Embrel和Remicade或者制剂中其他成分过敏的患者禁用.心衰患者、老年患者、孕妇、哺乳期妇女慎用.

不良反应:
1.注射部位局灶反应:红斑、痛痒、疼痛、肿胀、出血、瘀伤。平均持续3~5天,一般不需停药.
2.感染:最常见下呼吸道感染,其他感染有:鼻炎、咽炎、肾盂肾炎、支气管炎、脓毒性关节炎、腹腔脓肿、蜂窝织炎、骨髓炎、伤口感染、肺炎、足部脓肿、腿部溃疡、腹泻、鼻窦炎、败血症。并有可能增加原有感染患者的死亡率.
3.心血管系统:心力衰竭、心肌梗死、心肌缺血、高血压、低血压、深静脉血栓、血栓性静脉炎。
4.消化系统：胆囊炎、胰腺炎、胃肠道出血、腹痛、消化不良、呕吐、食欲不振、口干、口腔溃疡。
5.肌肉骨骼系统:滑囊炎、多发性肌炎、关节痛、狼疮样综合征。
6.神经系统:头痛、眩晕、脑缺血、抑郁、多发性硬化、血管神精性水肿、偏瘫、脑卒中、癫痫、孤立性脱髓鞘病、横断性脊髓炎、视神精炎。
7.呼吸系统：咳嗽、呼吸困难、肺栓塞、间质性肺炎。
8.泌尿生死系统:膜性肾小球肾炎.
9.血液系统:淋巴结肿大、贫血、再生障碍性贫血、白细胞减少症、粒细胞减少症、全血减少、血小板减少症。
10.皮肤病变:脉管炎、皮下结节、风疹、皮疹、脱发。

临床应用规程：
1.用药前做血常规、心电图、超声心动图等检查，评定左室功能。
2.用药前准备好抢救过敏反应药物和简易呼吸器.
3.用英利昔前可预防性应用抗组胺药和解热镇痛药物.用依那西普前可仅用抗组胺类药.
4.监测血压、呼吸、心率等生命体征。
5.用药期间均需监测血象,进行左室功能评定.出现下述情况应考虑停药:确定相关的明显的血液学异常、严重过敏反应、狼疮样综合征。监测病情直至症状和体征恢复正常。
6.使用时以1ml无菌注射用水溶解.稀释剂应缓慢注入药瓶中,尽量避免摇动或剧烈震动.严禁将两支药品溶液混用,或者将一支中的药液倒入另一支中.如果药液出现褪色、絮状物、颗粒状物质，应废弃不用。

贮存：
原药避光贮于2～8℃。溶解后最多只能保存14天。

About Enbrel® (etanercept)

How does ENBREL work?

ENBREL is a type of protein called a tumor necrosis factor (TNF) blocker that blocks the action of a substance your body makes called TNF. Tumor necrosis factor is made by your body's immune system. People with immune diseases such as RA, JRA, AS, psoriatic arthritis, and plaque psoriasis have too much TNF in their bodies.

About moderate to severe rheumatoid arthritis
About moderate to severe juvenile rheumatoid arthritis
About ankylosing spondylitis
About psoriatic arthritis
About chronic moderate to severe plaque psoriasis
 
Important information about taking prescription ENBREL 

ENBREL can reduce the amount of TNF in the body. And while ENBREL can block the damage that too much TNF can cause, it can also lower the ability of your immune system to fight infections. So, taking ENBREL can make you more prone to getting infections or make any infection that you may have worse. To find out more about prescription ENBREL, talk with your doctor. Your doctor is the best source of information. You can also view the Important Safety Information. If you have additional questions, call 1-888-4ENBREL (1-888-436-2735). This line is open Monday through Friday, 8:00 am to 11:00 pm, Eastern Time.
 
How ENBREL is taken 

Administering ENBREL can be convenient. ENBREL is a protein and is injected (by you or someone else) just under the skin. Once you've filled your prescription, schedule a training session with your doctor's office to learn the proper techniques for self-injection. During this session, you may administer your first dose of ENBREL. You'll learn what you need to know at the doctor's office to inject ENBREL at home.
 
Proven experience 

ENBREL has more than 14 years of collective clinical experience.

The first ENBREL clinical trials began in 1992. Since its approval for moderate to severe rheumatoid arthritis in 1998, ENBREL has also been approved for use in treating moderate to severe juvenile rheumatoid arthritis (JRA), psoriatic arthritis, ankylosing spondylitis (AS), and moderate to severe plaque psoriasis.
 
Established safety profile 

The safety profile for ENBREL during clinical trials showed:

Rates of serious adverse events were comparable to control patients in rheumatoid arthritis, psoriatic arthritis, and plaque psoriasis clinical trials.

The most common adverse events reported were injection site reactions, infections, and headache.

Routine laboratory monitoring specific for ENBREL therapy is not required; however, careful medical management and supervision of patients are recommended. Tell your doctor if you are prone to infection or have had hepatitis B.
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Learn More: 

rheumatoid arthritis  

juvenile rheumatoid arthritis  

psoriatic arthritis  

ankylosing spondylitis  

plaque psoriasis
 
What important safety information do I need to know about taking prescription ENBREL?

ENBREL is a type of protein called a tumor necrosis factor (TNF) blocker that blocks the action of a substance your body's immune system makes called TNF. People with an immune disease, such as rheumatoid arthritis, juvenile idiopathic arthritis, ankylosing spondylitis, psoriatic arthritis, or psoriasis, have too much TNF in their bodies. ENBREL can reduce the amount of active TNF in the body to normal levels, helping to treat your disease. But, in doing so, ENBREL can also lower the ability of your immune system to fight infections.

Serious infections, including tuberculosis (TB), have happened in patients taking ENBREL. Some of these serious infections have been fatal. Many serious infections occurred in people prone to infection. Serious infections have also occurred in patients with advanced or poorly controlled diabetes. Do not start ENBREL if you have an infection or are allergic to ENBREL or its components. Once on ENBREL, if you get an infection or have any sign of an infection, including fever, cough, or flu-like symptoms, or have open sores, tell your doctor. Your doctor should test you for TB before starting ENBREL and should monitor you closely for signs and symptoms of TB.

Serious nervous system disorders, such as multiple sclerosis, seizures, or inflammation of the nerves of the eyes have been reported. There have been rare reports of serious blood disorders (some fatal).

In medical studies, more cases of lymphoma (a type of cancer) were seen in patients taking TNF blockers compared to similar patients who were not taking TNF blockers. The risk of lymphoma may be several-fold higher in people with rheumatoid arthritis and psoriasis; the role of TNF blockers in the development of malignancies is unknown.

Tell your doctor if you:

Think you have, are being treated for, have signs of, or are prone to infection
Have any open sores
Have or have had TB or hepatitis B
Have ever been treated for heart failure
Have ever had or develop a serious nervous system disorder
Develop symptoms such as persistent fever, bruising, bleeding, or paleness while taking ENBREL
Common side effects in adult clinical trials were injection site reaction, infection and headache.

In a medical study of patients with JIA, infection, headache, abdominal pain, vomiting, and nausea occurred more frequently than in adults. The kinds of infections reported were generally mild and similar to those usually seen in children. Other serious adverse reactions were reported, including serious infection and depression/personality disorder.

If you have any questions about this information, be sure to discuss them with your doctor. You are encouraged to report negative side effects of prescription drugs to the FDA. Visit www.fda.gov/medwatch, or call 1-800-FDA-1088.

If you have any questions about this information, be sure to discuss them with your doctor. Please see full Prescribing Information.

INDICATIONS

Moderate to Severe Rheumatoid Arthritis (RA)

ENBREL is indicated for reducing signs and symptoms, keeping joint damage from getting worse, and improving physical function in patients with moderate to severe rheumatoid arthritis. ENBREL can be taken with methotrexate or used alone.

In medical studies, ENBREL was shown to be effective in about 2 out of 3 adults with RA who used it, and has been shown to begin working in as few as 2 weeks, with most patients receiving benefit within 3 months. In an RA medical study, 55% of patients had no progression of joint damage.
 
Moderate to Severe Polyarticular Juvenile Idiopathic Arthritis (JIA)

ENBREL is indicated for reducing signs and symptoms of moderately to severely active polyarticular juvenile idiopathic arthritis (JIA) in children ages 2 years and older.

In medical studies, ENBREL was shown to be effective in about 3 out of 4 children with JIA who used it. For these JIA patients, ENBREL has been shown to begin working in approximately 2 to 4 weeks.

Psoriatic Arthritis

ENBREL is indicated for reducing signs and symptoms, keeping joint damage from getting worse, and improving physical function in patients with psoriatic arthritis. ENBREL can be used in combination with methotrexate in patients who do not respond adequately to methotrexate alone.

In medical studies, ENBREL was shown to be effective in about 50% of psoriatic arthritis patients who used it. Clinical responses were apparent at the time of the first visit (4 weeks) and were maintained through 6 months of therapy.
 
Ankylosing Spondylitis (AS)

ENBREL is indicated for reducing signs and symptoms in patients with active ankylosing spondylitis.

In a medical study, ENBREL was shown to be effective in about 3 out of 5 adults with AS who used it. Clinical responses were seen at 2 weeks in 46% of patients, with 59% of patients receiving benefit within 8 weeks.
 
Moderate to Severe Plaque Psoriasis

ENBREL is indicated for the treatment of adult patients (18 years or older) with chronic moderate to severe plaque psoriasis who are candidates for systemic therapy or phototherapy.

In medical studies, nearly half of patients saw a significant improvement in their plaque psoriasis within 3 months of using ENBREL. Overall, 3 out of 4 patients saw improvement. ENBREL can work fast; many patients saw improvement within 2 months. ENBREL has been shown to be effective through 12 months of therapy.