部分中文Xalkori(crizotinib)口服胶囊处方资料（仅供参考）

美国FDA2011年8月26日为一种类型的晚期肺癌批准Xalkori(crizotinib)与伴诊断药盒

批准日期：2011年8月26日；公司：辉瑞Pfizer Inc.

适应证和用途

XALKORI是一种激酶抑制剂适用于有局部晚期或转移非小细胞肺癌(NSCLC)患者的治疗是当用一种FDA批准的检验变性淋巴瘤激酶(ALK)-阳性。(1) 这个适应症是基于反应率。没有可以得到的资料显示用XALKORI报道患者的结局或生存改善。

剂量和给药方法
（1）250 mg口服每天2次有或无食物。
（2）根据个体安全性和耐受性可能需要给药中断和/或剂量减低至200 mg口服每天2次，然后如需要进一步减低至250 mg口服每天1次。

剂型和规格
（1）XALKORI胶囊: 250 mg和200 mg.

禁忌证
无

警告和注意事项
（1）肺炎：严重，包括致命性，治疗-相关肺炎曾观察到。为指示性肺炎肺部症状监视患者。有治疗-相关肺炎诊断患者中永远终止。(5.1)
（2）肝实验室异常：曾发生ALT和总胆红素同时升高。每月监视和当临床指示有2-4级升高患者用更频繁检验。当指示，暂时停止，减低剂量，或永远终止XALKORI。
（3）QT间隔延长：有病史或QTc延长倾向患者，或服用已知延长QT间隔药物, 应考虑监视心电图定期和电解质。
（4）ALK检验：为选择用ALKORI治疗患者需要用一种FDA批准的检验检测ALK-阳性NSCLC，适用于这个用途。
（5） 妊娠：当给予妊娠妇女时XALKOR可能致胎儿危害。

不良反应
最常见不良反应(≥25%)是视力障碍，恶心，腹泻，呕吐，水肿，和便秘。
为报告怀疑不良反应联系Pfizer Inc.电话1-800-438-1985或FDA电话1-800-FDA-1088或www.fda.gov/medwatch.

药物相互作用
（1）CYP3A抑制剂：避免XALKORI与强CYP3A抑制剂同时使用。
（2）CYP3A诱导剂：避免XALKORI与强CYP3A诱导剂同时使用。
（3）CYP3A底物：对共同给药药物主要被CYP3A代谢可能需要减低剂量。避免XALKORI与有狭窄治疗指数CYP3A底物同时使用。

一般描述
XALKORI(crizotinib)是一种口服酪氨酸激酶受体抑制剂。Crizotinib的分子式是C21H22Cl2FN5O。分子量是450.34道尔顿。Crizotinib化学上称为 (R)-3-[1-(2,6-Dichloro-3-fluorophenyl)ethoxy]-5-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]pyridin-2-amine.
其化学结构式为

作用机制
Crizotinib是酪氨酸激酶受体包括ALK，肝细胞生长因子受体(HGFR, c-Met)，和Recepteur d’Origine Nantais(RON)的一种抑制剂。易位[Translocations]可影响ALK基因导致致癌融合蛋白[oncogenic fusion proteins]的表达。ALK融合蛋白的形成导致激活和基因表达和增加细胞增殖有贡献信号的调节异常而生存肿瘤表达这些蛋白。用肿瘤细胞株在基于细胞分析中证实Crizotinib浓度-依赖性抑制ALK和c-Me磷酸化和在负荷表达EML4-或NPM-ALK融合蛋白或c-Met肿瘤小鼠中显示抗肿瘤活性。

临床研究
在2项多中心，单组研究(研究A和B)研究使用单药XALKORI局部晚期或转移ALK-阳性NSCLC。纳入这些研究治疗患者曾接受既往全身治疗，除了在研究B中15例患者对局部晚期或转移疾病无既往全身治疗。在研究A中，用Vysis ALK Break-Apart FISH Probe药盒鉴定ALK-阳性NSCLC。在研究B中，用一些当地临床试验分析鉴定ALK-阳性NSCLC。在两项研究中主要疗效终点都是按照实体肿瘤反应评价标准(RECIST)的客观反应率(ORR)。由研究者和由独立放射评议委员会。还评价反应时间(DR)。患者接受250 mg XALKORI 口服每天2次。表4提供研究A和B人口统计指标和疾病特征。

136例来自研究A局部晚期或转移ALK-阳性NSCLC患者在数据截止时间分析。治疗中位时间是22周。根据研究中评估，有1例完全和67例部分反应对ORR50%(95% CI：42%，59%)。治疗头8周79%达到客观肿瘤反应。中位反应时间为41.9 周。.
在数据截止时间，纳入研究B 190例局部晚期或转移ALK-阳性NSCLC患者。中位治疗时间为32周。根据研究中评估，有2完全和69例部分反应，对ORR61%(95% CI：52%，70%)。在治疗头8周55%达到客观肿瘤反应。中位反应时间为48.1周。.
在表5中提供研究A和B疗效结果。.

如何供应/贮存和处置
250 mg胶囊
硬明胶胶囊有粉色不透明帽和体，帽上用黑墨汁印有“Pfizer”，体上“CRZ 250”；可得到：
60粒胶囊瓶： NDC 0069-8140-20
200 mg胶囊
硬明胶胶囊有粉色不透明帽和白色不透明体，帽上用黑墨汁印有“Pfizer”，体上“CRZ 200“可得到：
60粒胶囊瓶：NDC 0069-8141-20
贮存在室温20至25°C (68至77°F)；外出允许15°至30°C (59°至86°F)[见USP控制室温]。

Xalkori-Treatment for Non-Small Cell Lung Cancer

Xalkori (Crizotinib) is a oral drug indicated for the treatment of non-small cell lung cancer. The drug is developed and manufactured by Pfizer.

Crizotinib obtained orphan drug designation from the US FDA in September 2010. It was granted fast track designation in December 2010. Pfizer filed a new drug application in May 2011.

The FDA approved the drug for the treatment of metastatic anaplastic lymphoma kinase (ALK) positive non-small cell lung cancer in August 2011. The approval was based on trial data of 255 patients enrolled in two clinical trials namely Phase II-Profile 1005 and Phase I-Study 1001.

Pfizer submitted a marketing authorisation application to the European Medicines Agency (EMA) in August 2011. The drug is currently under review by the EMA.

The drug also obtained orphan drug designation in Japan in January 2011. New drug application was submitted to the Japanese Ministry of Health, Labour and Welfare in May 2011.

Crizotinib – mechanism of action
Crizotinib is an oral medication having the ability to inhibit ALK and c-MET.

ALK is an enzyme encoded by ALK gene. It can be carcinogenic due to mutation or due to formation of a fusion with another gene thereby leading to ALCL (anaplastic large-cell lymphomas), NSCLC or neuroblastoma.

After ALK inhibition, the cell signalling necessary for the growth of tumour and survival in various cell pathways is blocked.

Clinical trials
Study 1006, a Phase I study, is being conducted to evaluate safety, efficacy, pharmacokinetics and pharmacodynamics of Crizotinib in 70 NSCLC patients. The trial, which began in April 2010, is expected to be complete by May 2012.

Around 175 patients will be enrolled in another Phase I trial being conducted to evaluate the safety of the drug and determine the maximum tolerable dose.

A Phase II study named PROFILE 1005 was initiated in 400 NSCLC patients in January 2010. The trial is being conducted to evaluate the safety and efficacy of the drug in ALK positive NSCLC patients. The trial is expected to be complete by September 2013.

Phase I/II study 1002 was initiated in January 2010 in 175 patients having NSCLC. It will evaluate the safety and efficacy of Erlotinib alone in comparison with Erlotinib in combination with Crizotinib. The enrolled patients are being administered either 150mg of erlotinib alone or 150mg of erlotinib in combination with 200-250mg of crazotinib. The primary end point is to determine the maximum tolerable dose and the progression free survival. The trial is expected to be complete by July 2014.

The FDA approval of Xalkori was based on the trial data of 255 patients from PROFILE 1005 and Study 1002.

The objective response rate (ORR) of PROFILE 1005 was 50%. The patients were treated for an average period of 22 weeks. Around 79% of tumour responses were observed during the first eight weeks.

In Study 1001, patients were treated for an average period of 32 weeks. The ORR was 61% and around 55% of this was observed during the first eight weeks.

Phase III development
Two Phase III trials PROFILE 1007 and PROFILE 1014 are currently being conducted in patients with NSCLC.

PROFILE 1007 is being conducted to determine the progression free survival of patients treated with Crizotinib in comparison with those treated with Docetaxel or Premetrexed. The trial with and estimated enrolment of 318 patients was initiated in September 2009 and is expected to be completed by September 2012. Patients from the chemotherapy arm of Phase III 1007 trial also have an option to be administered with crizotinib in the Phase II PROFILE 1005 study.

Around 334 NSCLC patients have been enrolled in Phase III PROFILE 1014 trial. The trial, which began in January 2011 will determine the anti-cancer effects of the drug and will compare them to those of the chemotherapy in ALK positive patients. The study has a scheduled primary completion date of October 2013. The entire trial is expected to be complete by December 2013.

Non-small cell lung cancer
Non-small cell lung cancer (NSCLC) is the most common kind of lung cancer. The growth and progression of NSCLC is slower than that of small cell lung cancer. Adenocarcinomas, squamous cell carcinomas and large cell carcinomas are the different types of NSCLC.

NSCLC is usually caused by smoking. It also occurs in people who work near asbestos, products using chloride and formaldehyde, certain alloys, paints, pigments and preservatives.

Symptoms of NSCLC include coughing up blood, shortness of breath, wheezing, chest pain, loss of appetite, losing weight without trying and fatigue.

Around 45,000 patients worldwide are diagnosed with ALK positive NSCLC every year.

治疗肺癌的新药XALKORI(crizotinib)胶囊获批

美国辉瑞公司研发的新药XALKORI(crizotinib)胶囊是第一个对间变性淋巴瘤激酶(ALK)进行靶向治疗的药品，可用于治疗ALK阳性的局部晚期或转移的非小细胞肺癌，近日获得美国食品药品管理局(FDA)批准。

据介绍，新药XALKORI(crizotinib)胶囊是第一个也是目前唯一一个用于治疗局部晚期或转移的ALK阳性非小细胞肺癌的新药，也是近6年来美国FDA批准的第一个治疗肺癌的新药。XALKORI证明了分子标志物检测在非小细胞肺癌中的重要性，成为个体化治疗药物研发的新里程碑，在特定的非小细胞肺癌人群中有显著的客观缓解率。
关于XALKORI(crizotinib)胶囊

XALKORI(crizotinib)胶囊是一种用于治疗通过FDA批准的检测确认为间变性淋巴瘤激酶(ALK)阳性的晚期或转移的非小细胞肺癌(NSCLC)患者的激酶抑制剂。获批适应症基于客观缓解率。目前尚无数据表明XALKORI可以改善患者报告结果（patient reported outcome）或生存。XALKORI通过阻断对肿瘤细胞生长与存活起关键作用的多种细胞通路，导致肿瘤的稳定或消退。ALK基因变异被认为是非小细胞肺癌（NSCLC）等癌症发生的关键驱动因素。尽管ALK在非鳞状细胞癌、无吸烟史或轻度吸烟史患者中较为常见，但也在吸烟和鳞状细胞癌组织患者中也有发现。ALK基因变异的出现与年龄、性别、种族和是否吸烟等无关。试验同时证明，XALKORI可以抑制c-MET受体酪氨酸激酶，目前正在进行试验之中。

在临床研究中与XALKORI治疗相关的严重的、危及生命或致死的局限性肺炎发生率为4/255(1.6%)。应该排除其他因素引起的局限性肺炎。如果患者出现治疗相关的局限性肺炎，应永久停止XALKORI治疗。

患者在试验A和试验B中，分别有7%和4%的患者出现3级或4级ALT升高。在试验A和试验B中，分别有3名(2%)患者和1名(<1%)患者需要永久停止治疗。应该每月和出现临床症状时监测包括ALT与总胆红素指标在内的肝功能变化，如果出现2-4级转氨酶升高时，应增加肝功能监测频度，并根据情况采取临时中断、减少剂量或永久性停用XALKORI等措施。

试验曾发现QT延长。XALKORI应避免用于先天性长QT综合症的患者。充血性心力衰竭、缓慢性心律失常、电解质异常或服用可延长QT间期药品的患者，应对心电图与电解质进行定期监测。如出现4级QTc延长，则应永久停止XALKORI。如果出现3级QTc延长，则应暂停XALKORI，直至恢复到≤1级。如果再次出现3级QTc，则应永久停用XALKORI。

在选择使用XALKORI治疗的患者时，必须使用经过FDA批准的检测方法来诊断ALK阳性非小细胞肺癌（NSCLC）。

根据其作用机制，孕妇服用XALKORI可导致胎儿受损。可能怀孕的妇女应避免在服用XALKORI期间受孕，如果患者或其伙伴在服药时怀孕，则患者应对胎儿的危险进行评估。

在两项单臂临床试验(试验A与试验B)中，对255名局部晚期或转移的ALK-阳性非小细胞肺癌（NSCLC）患者进行了XALKORI安全性的分析。在两项临床试验中，最常见的副作用(≥25%)为视力障碍、恶心、腹泻、呕吐、水肿与便秘。在两项临床试验中，≥4%的患者出现的3/4级副作用包括ALT升高与嗜中性白血球减少症。

视力障碍包括视力受损、闪光感(感受到光线闪耀)、视力模糊、玻璃体漂浮物、畏光(对亮光敏感)以及复视(重影)，在临床试验中，有159(62%)名患者出现过上述问题。

如果患者出现闪光感或出现新的玻璃体漂浮物（vitreousfloaters）或玻璃体漂浮物增多，应予以眼科检查评估。玻璃体漂浮物及/或闪光感（photopsia）的加重或恶化，也可能是提示有视网膜裂孔（retinalhole）或即将发生视网膜脱离（retinaldetachment）的信号。对于出现视力障碍的患者，在驾车或者操作机器时应谨慎对待。
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原产地英文商品名:
XALKORI 250MG/CAP 60CAPS/BOTTLE
原产地英文药品名:
CRIZOTINIB
中文参考商品译名:
XALKORI 250毫克/胶囊 60胶囊/瓶
中文参考药品译名:
克卓替尼   克里唑蒂尼胶囊
生产厂家中文参考译名:
辉瑞
生产厂家英文名:
PFIZER

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原产地英文商品名:
XALKORI 200MG/CAP 60CAPS/BOTTLE
原产地英文药品名:
CRIZOTINIB
中文参考商品译名:
XALKORI 200毫克/胶囊 60胶囊/瓶
中文参考药品译名:
克卓替尼  克里唑蒂尼胶囊
生产厂家中文参考译名:
辉瑞
生产厂家英文名:
PFIZER

Xalkori is available in 250mg oral capsules.