英文药名：OFEV(nintedanib capsules) 中文药名：尼达尼布胶囊 生产厂家：勃林格殷格翰公 药品介绍 OFEV®(nintedanib)胶囊为新一代治疗特发性肺纤维化口服新药 美国初次批准：2014 作用机制 Nintedanib是一种小分子抑制多种受体酪氨酸激酶(RTKs)和非-受体酪氨酸激酶(nRTKs). Nintedanib抑制以下RTKs：血小板衍生生长因子受体(PDGFR)α和β，成纤维细胞生长因子受体(FGFR)1-3，血管内皮生长因子受体(VEGFR)1-3，和Fms-样酪氨酸激酶-3(FLT3)。它们之中，FGFR，PDGFR，和VEGFR与特发性肺纤维化[IPF]发病机制有牵连。Nintedanib与这些受体的腺苷三磷酸(ATP)结合囊竞争性结合和阻断代表IPF病理机制至关重要成纤维细胞增殖，迁移和转化的细胞内信号。此外，nintedanib抑制以下nRTKs：Lck，Lyn和Src激酶。不知道FLT3和nRTK抑制作用对IPF疗效的贡献。 适应证和用途 OFEV是一种激酶抑制剂适用为特发性肺纤维化(IPF)的治疗。 剂量和给药方法 ⑴ 推荐剂量：150mg每天2次间隔约12小时与食物服用。 ⑵ 考虑暂时剂量减低至100mg，治疗中断，或终止为处理不良反应。 ⑶ 治疗前，进行肝功能检验。 剂型和规格 胶囊：150mg和100mg 禁忌证 无 警告和注意事项 ⑴ 肝酶升高：用OFEV曾发生ALT，AST，和胆红素升高。治疗前和期间监视ALT，AST，和胆红素。可能需要暂时减低剂量或终止。 ⑵ 胃肠道疾病：用OFEV曾发生腹泻，恶心，和呕吐。第一个征象用充分水化和止泻药(如，洛哌丁胺[loperamide])或抗吐药治疗患者。如尽管对症治疗严重腹泻，恶心，或呕吐持续终止OFEV。 ⑶ 胚胎胎儿毒性：应劝告育龄妇女对胎儿潜在危害和避免成为妊娠。 ⑷ 曾报道动脉血栓栓塞事件。当治疗患者处于较高心血管风险包括已知冠状动脉疾病谨慎使用。 ⑸ 曾报道出血事件。只有已知出血风险患者期望获益胜过潜在风险时使用FEV。 ⑹ 曾报道胃肠道穿孔。最近腹部手术治疗患者谨慎使用OFEV。发生胃肠道穿孔患者终止OFEV。只有有已知胃肠道穿孔风险如期望获益胜过潜在风险才使用OFEV。 不良反应 最常见不良反应(≥5%)是：腹泻，恶心，腹痛，呕吐，肝酶升高，食欲减退，头痛，体重减轻，和高血压。 药物相互作用 P-gp和CYP3A4抑制剂共同给药可能增加nintedanib暴露。密切监视患者对OFEV耐受性。 特殊人群中使用 ⑴ 哺乳母亲：终止哺乳或终止药物，考虑药物对母亲重要性。 ⑵ 肝受损：对有轻度肝受损患者监视不良反应和需要时考虑调整剂量或终止OFEV。有中度或严重肝受损患者中不建议使用OFEV。 ⑶ 肾受损：未曾在有严重肾受损和肾病终末期患者研究OFEV的安全性和疗效。 ⑷ 吸烟者：曾注意到吸烟者减低暴露可能改变OFEV疗效图形。 如何供应/贮存和处置 150 mg：棕色，不透明，椭圆形，软胶囊印有黑色勃林格殷格翰公司标志l和"150"。被包装在HDPE瓶有防儿童密封，可得到如下： 60粒瓶 NDC：0597-0145-60 100 mg：桃色，不透明，椭圆形，软胶囊印有黑色勃林格殷格翰公司标志l和"100"。被包装在HDPE有防儿童密封，可得到如下： 60粒瓶 NDC：0597-0143-60 贮存 贮存杂25°C(77°F);外出允许至15°至30°C(59°至86°F)[见USP控制室温]。保护暴露至高湿度和避免过热。如重新包装，使用USP密封容器。保存防止儿童得到。 2014 Boehringer Ingelheim Pharmaceuticals, Inc. has announced that OFEV® (nintedanib) capsules are now commercially available in the United States. OFEV was approved by the U.S. Food and Drug Administration (FDA) on October 15, 2014 for the treatment of idiopathic pulmonary fibrosis (IPF). It is the only kinase inhibitor approved to treat IPF. IPF is a rare and fatal lung disease that affects as many as 132,000 Americans. Most people with IPF only live three to five years after diagnosis. IPF typically affects men over the age of 65. About OFEV® (nintedanib) capsules Indication and Usage OFEV is indicated for the treatment of idiopathic pulmonary fibrosis (IPF). IMPORTANT SAFETY INFORMATION WARNINGS AND PRECAUTIONS Elevated Liver Enzymes The safety and efficacy of OFEV has not been studied in patients with moderate (Child Pugh B) or severe(Child Pugh C) hepatic impairment. Treatment with OFEV is not recommended in patients with moderate or severe hepatic impairment. In clinical trials, administration of OFEV was associated with elevations of liver enzymes (ALT, AST, ALKP, GGT) and bilirubin. Liver enzyme increases were reversible with dose modification or interruption and not associated with clinical signs or symptoms of liver injury. Conduct liver function tests (ALT, AST, and bilirubin) prior to treatment with OFEV, monthly for 3 months, and every 3 months thereafter, and as clinically indicated. Dosage modifications, interruption, or discontinuation may be necessary for liver enzyme elevations.  Gastrointestinal Disorders Diarrhea Diarrhea was the most frequent gastrointestinal event reported in 62% versus 18% of patients treated with OFEV and placebo, respectively. In most patients, the event was of mild to moderate intensity and occurred within the first 3 months of treatment. Diarrhea led to permanent dose reduction in 11% of patients treated with OFEV compared to 0 placebo-treated patients. Diarrhea led to discontinuation of OFEV in 5% of the patients compared to <1% of placebo-treated patients. Dosage modifications or treatment interruptions may be necessary in patients with adverse reactions of diarrhea. Treat diarrhea at first signs with adequate hydration and antidiarrheal medication (e.g., loperamide), and consider treatment interruption if diarrhea continues. OFEV treatment may be resumed at the full dosage (150 mg twice daily), or at the reduced dosage (100 mg twice daily), which subsequently may be increased to the full dosage. If severe diarrhea persists despite symptomatic treatment, discontinue treatment with OFEV. Nausea and Vomiting Nausea was reported in 24% versus 7% and vomiting was reported in 12% versus 3% of patients treated with OFEV and placebo, respectively. In most patients, these events were of mild to moderate intensity. Nausea led to discontinuation of OFEV in 2% of patients. Vomiting led to discontinuation of OFEV in 1% of the patients. For nausea or vomiting that persists despite appropriate supportive care including anti-emetic therapy, dose reduction or treatment interruption may be required. OFEV treatment may be resumed at the full dosage (150 mg twice daily), or at the reduced dosage (100 mg twice daily), which subsequently may be increased to the full dosage. If severe nausea or vomiting does not resolve, discontinue treatment with OFEV. Embryofetal Toxicity OFEV is Pregnancy category D. It can cause fetal harm when administered to a pregnant woman. If OFEV is used during pregnancy, or if the patient becomes pregnant while taking OFEV, the patient should be advised of the potential hazard to a fetus. Women of childbearing potential should be advised to avoid becoming pregnant while receiving treatment with OFEV and to use adequate contraception during treatment and at least 3 months after the last dose of OFEV. Arterial Thromboembolic Events Arterial thromboembolic events have been reported in patients taking OFEV. In clinical trials, arterial thromboembolic events were reported in 2.5% of patients treated with OFEV and 0.8% of placebo-treated patients. Myocardial infarction was the most common adverse reaction under arterial thromboembolic events, occurring in 1.5% of OFEV-treated patients compared to 0.4% of placebo-treated patients. Use caution when treating patients at higher cardiovascular risk including known coronary artery disease. Consider treatment interruption in patients who develop signs or symptoms of acute myocardial ischemia. Risk of Bleeding Based on the mechanism of action (VEGFR inhibition), OFEV may increase the risk of bleeding. In clinical trials, bleeding events were reported in 10% of patients treated with OFEV and in 7% of patients treated with placebo. Use OFEV in patients with known risk of bleeding only if the anticipated benefit outweighs the potential risk. Gastrointestinal Perforation Based on the mechanism of action, OFEV may increase the risk of gastrointestinal perforation. In clinical trials, gastrointestinal perforation was reported in 0.3% of patients treated with OFEV, compared to 0 cases in the placebo-treated patients. Use caution when treating patients who have had recent abdominal surgery. Discontinue therapy with OFEV in patients who develop gastrointestinal perforation. Only use OFEV in patients with known risk of gastrointestinal perforation if the anticipated benefit outweighs the potential risk. ADVERSE REACTIONS •Adverse reactions reported in 5% of patients treated with OFEV and more commonly than in patients treated with placebo included diarrhea (62% vs. 18%), nausea (24% vs.7%), abdominal pain (15% vs 6%), liver enzyme elevation (14% vs 3%), vomiting (12% vs 3%), decreased appetite (11% vs 5%), weight decreased (10% vs 3%), headache (8% vs 5%), and hypertension (5% vs 4%). •The most frequent serious adverse reactions reported in patients treated with OFEV, more than placebo, were bronchitis (1.2% vs. 0.8%) and myocardial infarction (1.5% vs. 0.4%). The most common adverse events leading to death in patients treated with OFEV, more than placebo, were pneumonia (0.7% vs. 0.6%), lung neoplasm malignant (0.3% vs. 0%), and myocardial infarction (0.3% vs. 0.2%). In the predefined category of major adverse cardiovascular events (MACE) including MI, fatal events were reported in 0.6% of OFEV-treated patients and 1.8% of placebo-treated patients. DRUG INTERACTIONS P-glycoprotein (P-gp) and CYP3A4 Inhibitors and Inducers Coadministration with oral doses of a P-gp and CYP3A4 inhibitor, ketoconazole, increased exposure to nintedanib by 60%. Concomitant use of potent P-gp and CYP3A4 inhibitors (e.g., erythromycin) with OFEV may increase exposure to nintedanib. In such cases, patients should be monitored closely for tolerability of OFEV. Management of adverse reactions may require interruption, dose reduction, or discontinuation of therapy with OFEV. Coadministration with oral doses of a P-gp and CYP3A4 inducer, rifampicin, decreased exposure to nintedanib by 50%. Concomitant use of P-gp and CYP3A4 inducers (e.g., carbamazepine, phenytoin, and St. John's wort) with OFEV should be avoided as these drugs may decrease exposure to nintedanib. Anticoagulants Nintedanib is a VEGFR inhibitor, and may increase the risk of bleeding. Monitor patients on full anticoagulation therapy closely for bleeding and adjust anticoagulation treatment as necessary. USE IN SPECIFIC POPULATIONS Nursing Mothers •Excretion of nintedanib and/or its metabolites into human milk is probable. Because of the potential for serious adverse reactions in nursing infants from OFEV, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Hepatic Impairment •Monitor for adverse reactions and consider dose modification or discontinuation of OFEV as needed for patients with mild hepatic impairment (Child Pugh A). Treatment of patients with moderate (Child Pugh B) and severe (Child Pugh C) hepatic impairment with OFEV is not recommended. Smokers •Smoking was associated with decreased exposure to OFEV, which may alter the efficacy profile of OFEV. Encourage patients to stop smoking prior to treatment with OFEV and to avoid smoking when using OFEV. Please click here for full Prescribing Information, including Patient Information. Leading Respiratory Forward Through research, treatments and patient-centric support services, the Boehringer Ingelheim (BI) lung health portfolio is designed to help address the challenges people living with a lung disease face every day. Leveraging the company's cutting edge science and leadership in chronic obstructive pulmonary disease (COPD), BI is researching new treatment approaches where needs persist. It is the company's goal to make a difference in the lives of patients with COPD, asthma, lung cancer, idiopathic pulmonary fibrosis and other respiratory diseases. About Boehringer Ingelheim Pharmaceuticals, Inc. Boehringer Ingelheim Pharmaceuticals, Inc., based in Ridgefield, CT, is the largest U.S. subsidiary of Boehringer Ingelheim Corporation (Ridgefield, CT) and a member of the Boehringer Ingelheim group of companies. The Boehringer Ingelheim group is one of the world's 20 leading pharmaceutical companies. Headquartered in Ingelheim, Germany, it operates globally with 142 affiliates and more than 47,400 employees. Since it was founded in 1885, the family-owned company has been committed to researching, developing, manufacturing and marketing novel medications of high therapeutic value for human and veterinary medicine. Social responsibility is a central element of Boehringer Ingelheim's culture. Involvement in social projects, caring for employees and their families, and providing equal opportunities for all employees form the foundation of the global operations. Mutual cooperation and respect, as well as environmental protection and sustainability are intrinsic factors in all of Boehringer Ingelheim's endeavors. In 2013, Boehringer Ingelheim achieved net sales of about $18.7 billion (14.1 billion euro). R&D expenditure in the Prescription Medicines business corresponds to 19.5% of its net sales. 尼达尼布被FDA批准为美国首个特发性肺纤维化治疗 -- 继尼达尼布*被FDA授予突破性治疗药物的地位之后，该药获得了FDA的上市批准 -- 此次批准基于III期临床试验的结果，试验显示尼达尼布可降低肺功能年下降率，降幅约为50%，而肺功能年下降率是评估疾病进展的指标 -- 尼达尼布目前正在接受欧洲药品管理局（EMA）的注册审核，并已被加入加速审批名单 德国殷格翰2014年10月16日电 /美通社/ -- 勃林格殷格翰公司于今日宣布，美国食品和药品监督管理局（FDA）已经批准 OFEV® (尼达尼布*) 用于治疗特发性肺纤维化 (IPF)，IPF是一种对人类危害严重的致命性肺部疾病，患者在诊断之后的中位生存期仅为2至3年。在今天之前，尚无一种IPF治疗药物获得FDA批准。尼达尼布此前已被FDA授予突破性治疗药物的地位，此次批准也使尼达尼布*成为首个、也是唯一一个获准用于治疗IPF的酪氨酸激酶抑制剂 (TKI) 。尼达尼布* 每日给药两次，每次一粒胶囊，可确保便捷用药。 “作为一名肺科专家，在我的日常工作中，最令我心痛的时刻，就是告诉患者他们被诊断为IPF，因为以往还没有任何一种药物获得批准可被提供用于治疗IPF患者，”来自华盛顿大学的间质性肺病/结节病/肺纤维化科主任、呼吸内科及重症监护科的内科学教授 Ganesh Raghu博士如此说道。“此次批准对于深受这种危害严重的疾病所累的患者及其护理者而言，是一个具有决定性意义的事件。因为 OFEV® 已被证实可有效减缓肺功能的下降，该项指标也是三项临床试验中疾病进展的评估指标。” “作为一名肺科专家，在我的日常工作中，最令我心痛的时刻就是告诉患者他们被诊断为IPF，因为以往还没有任何一种药物获得批准可被用于治疗IPF患者，”来自华盛顿大学的间质性肺病/结节病/肺纤维化科主任、呼吸内科及重症监护科的内科学教授 Ganesh Raghu博士如此说道。“此次批准对于深受这种危害严重的疾病所累的患者及其护理者而言，是一个具有决定性意义的事件，因为 我们现在拥有了首个获得FDA批准的IPF治疗药物。” 临床试验证实尼达尼布*可使绝大多数IPF患者人群获益于疾病进展的减缓，表现为患者的肺功能降幅减少50%，其中也包括处于疾病早期阶段的患者（用力肺活量 [FVC]占预计值百分比>90%）、高分辨率计算机体层扫描（HRCT）未检出蜂窝肺病变和/或合并肺气肿的患者。尼达尼布* 是首个在两项具有相同研究设计的III期临床试验中均达到主要终点的IPF靶向治疗药物。 尼达尼布*还可显著降低经过仲裁判定的IPF急性加重的发生风险。IFP急性加重可显著影响疾病进程，导致肺部疾病恶化的一系列事件。在因IPF急性加重而住院的患者中，有半数的人会在住院期间死亡。 尼达尼布*治疗IPF的作用机制已经明确。作为酪氨酸激酶抑制剂类药物中的一种，尼达尼布*可针对参与肺纤维化病理机制的生长因子受体发挥靶向作用，最重要的生长因子受体包括血小板源性生长因子受体 (PDGFR)、成纤维细胞生长因子受体 (FGFR)以及血管内皮生长因子受体 (VEGFR)。在大多数患者中，尼达尼布*的副反应可被有效控制。 “尼达尼布在美国获得批准是IPF医疗史上的一个具有真正划时代意义的事件，我们非常高兴能有这种新药提供给那些具有迫切需求的患者及其护理者和医生们。我们在勃林格殷格翰公司所做的每一件事都以患者为中心，我们会继续与各国药监当局保持合作，从而确保患者能够尽早获得这一创新药物的治疗，”勃林格殷格翰公司首席医学官 Klaus Dugi 教授如此说道。 勃林格殷格翰公司于2014年6月宣布，尼达尼布*治疗特发性肺纤维化（IPF）的上市许可申请获得欧洲药品管理局（EMA）的确认、并被EMA纳入加速审批名单。 供编辑参考信息 FDA批准尼达尼布*基于来自一项II期临床试验 （TOMORROW研究）以及两项III期临床试验 (INPULSIS™-1研究和 INPULSIS™-2研究的结果)。 关于TOMORROW研究 II期临床试验 TOMORROW 研究是一项为期12个月的随机、双盲、安慰剂对照研究，共在25个国家和地区纳入92家研究中心。5此项研究旨在评估四种口服剂量方案的尼达尼布*应用于432名IPF患者的安全性和疗效，IPF的诊断遵循美国胸科学会（ATS）以及欧洲呼吸学会（ERS）所发布的标准。 TOMORROW 研究的主要终点是用力肺活量（FVC）的年下降率。次要终点包括急性加重、通过圣乔治呼吸问卷（SGRQ）进行评估的生活质量、以及肺总量。研究结果显示，尼达尼布* 150 mg 每日给药两次治疗组患者每年的FVC下降幅度为 0.06L，而安慰剂治疗组则为每年0.19L。与安慰剂相比，上述剂量方案还可降低急性加重的发生率 （两组分别为2.4/100患者年和 15.7/100患者年；p=0.02）。与安慰剂相比，尼达尼布治疗与通过SGRQ评估的患者生活质量得以维持具有相关性。 胃肠道副反应在尼达尼布 150mg bid治疗组中较为常见，但大多数副反应的严重程度为轻度或中度。安慰剂治疗组与活性药物治疗组的重度不良事件发生率是相似的，但尼达尼布150mg每日给药两次治疗组的重度不良事件在数值上较低。 关于尼达尼布*III期临床试验 INPULSIS™ 研究 这两项双盲、随机、安慰剂对照研究共在24个国家纳入1066名患者，旨在评估口服尼达尼布* 150mg每日给药两次治疗方案应用于IPF患者52周对于用力肺活量（FVC）年下降率的影响。这两项研究拥有相同的试验设计、剂量配比、入选标准和研究终点。主要终点是FVC的年下降率 (单位为 mL，评估时间是52周)。关键性的次要终点是：通过圣乔治呼吸问卷（SGRQ）评估的健康相关性生活质量相较于基线期的改变、以及至首次发生急性加重的时间。 关键性结果显示： •尼达尼布*可减缓IPF疾病进展，表现为相较于安慰剂治疗组患者的肺功能降幅减少达到50% •尼达尼布*显著降低经过仲裁的急性加重发生风险达68% •在INPULSIS™-2研究中，尼达尼布*治疗组相较于安慰剂治疗组在SGRQ总分方面出现了小幅、但具有统计学显著性的获益，但在 INPULSIS™-1研究中，则未出现具有统计学显著性的组间差异。 在两项 INPULSIS™ 研究中，最常见的不良事件是胃肠道反应，严重程度为轻度或中度，通常可被控制，极少导致停药。 所有治疗组中发生严重不良事件的患者比例是相似的。 关于尼达尼布* 尼达尼布*是勃林格殷格翰公司针对特发性肺纤维化（IPF）开发的在研小分子酪氨酸激酶抑制剂（TKI）。尼达尼布*胶囊每次一粒每日两次治疗方案可减缓疾病进展，表现为肺功能年下降率减少50%，这一结果在广泛的IPF患者人群中均有体现，包括处于疾病早期阶段 (FVC占预计值百分比>90%)、HRCT未检出蜂窝肺和/或合并肺气肿的患者。仅有尼达尼布*可降低经过仲裁的急性加重□ 发生风险达68%之多。考虑到约有50%的因IPF急性加重入院的患者在住院期间死亡，这一结果具有非常重要的意义。大多数患者的尼达尼布*副反应可被有效控制。 尼达尼布*可靶向针对已被证实在肺纤维化病理机制中具有潜在影响的生长因子受体发挥作用，其中最为重要的就是血小板源性生长因子受体（PDGFR）、成纤维细胞生长因子受体（FGFR）和血管内皮生长因子受体（VEGFR）。通过阻断这些参与纤维化进程的信号转导通路，尼达尼布*被认为有望能够通过减少肺功能下降速度、从而减缓IPF疾病进展。公司目前还在针对尼达尼布*作为癌症治疗选择开展临床研发工作。欧洲药品管理局（EMA）的人用药品委员会（CHMP）最近发布了推荐批准尼达尼布与多西他赛联合方案用于治疗一线化疗之后的、组织学诊断为腺癌的、局部晚期、转移性或局部复发性非小细胞肺癌（NSCLC）的有利意见。 关于特发性肺纤维化 特发性肺纤维化(IPF)是一种慢性、进行性、具有严重致残性、最终可致命的肺部疾病，迄今为止针对这种疾病的治疗选择非常有限。在全球范围内，每十万人中，就有14至43人罹患IPF。IPF的特征性病变是肺组织的进行性瘢痕形成和肺功能的进行性下降 。瘢痕组织的形成被称为纤维化1。随着时间的进展，肺组织由于瘢痕形成而不断增厚和变硬，肺脏摄取氧气并将其传输到血液中的能力不断丧失，从而导致机体的重要脏器无法获得充足的氧气。最终，IPF患者会出现气促和咳嗽，并经常难以从事日常体力活动。