英文药名：XALKORI(crizotinib capsule） 中文药名：克里唑蒂尼胶囊 生产厂家：Pfizer Inc. 药品介绍 XALKORI®获批—6年来美国首批的治疗肺癌新药 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，用于治疗通过FDA批准的检测方法诊断为ALK阳性的局部晚期或转移的非小细胞肺癌 (NSCLC) FDA药物评价和研究中心肿瘤药品办公室主任Richard Pazdur, M.D.说：“Xalkori与一种特异性检验的批准允许选择更可能对药物反应的患者”“靶向治疗例如Xalkori是为正在治疗这种疾病患者的重要选择和可能最终导致较少副作用。” FDA的设备和放射学健康中心体外诊断设备评价和安全性办公室主任Alberto Gutierrez, Ph.D.,说：“肿瘤研究的趋势继续向靶向治疗，”“这个检验是伴诊断在决定最安全和最有效治疗及时输送给有严重和危及生命疾病患者生命起重要作用的一个实例。” 在2011年7月，FDA发出工业指导原则草案关于监督管理局对于评审伴随诊断和相应药物治疗的政策 。为公众评议可得到这个指导原则。 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。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）250mg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200mg口服每天2次，然后如需要进一步减低至250mg口服每天1次。 剂型和规格 （1）XALKORI胶囊: 250mg和200mg. 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。 （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。 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。 Xalkori 200mg and 250mg hard capsule IMPORTANT SAFETY INFORMATION Hepatotoxicity: Drug-induced hepatotoxicity with fatal outcome occurred in 0.2% of patients treated with XALKORI across clinical trials (n=1225). Transaminase elevations generally occurred within the first 2 months of treatment. Monitor with liver function tests including ALT and total bilirubin every 2 weeks during the first 2 months of treatment, then once a month and as clinically indicated, with more frequent repeat testing for increased liver transaminases, alkaline phosphatase, or total bilirubin in patients who develop transaminase elevations. Permanently discontinue for ALT or AST elevation >3 times ULN with concurrent total bilirubin elevation >1.5 times ULN (in the absence of cholestasis or hemolysis); otherwise, temporarily suspend and dose-reduce XALKORI as indicated. Interstitial Lung Disease (Pneumonitis): Severe, life-threatening, or fatal interstitial lung disease (ILD)/pneumonitis can occur in patients treated with XALKORI. Across clinical trials (n=1225), 2.5% of XALKORI-treated patients had any grade ILD, 0.9% had Grade 3/4, and 0.5% had fatal cases. These cases generally occurred within 2 months after initiation of treatment. Monitor for pulmonary symptoms indicative of ILD/pneumonitis. Exclude other potential causes and permanently discontinue XALKORI in patients with drug-related ILD/pneumonitis. QT Interval Prolongation: QTc prolongation can occur in patients treated with XALKORI. Across clinical trials (n=1225), QTc prolongation (all grades) was observed in 2.7% of patients and QTc >500 ms on at least 2 separate electrocardiograms (ECGs) occurred in 1.4% of patients. Avoid use of XALKORI in patients with congenital long QT syndrome. Consider periodic monitoring with ECGs and electrolytes in patients with congestive heart failure, bradyarrhythmias, electrolyte abnormalities, or who are taking medications that prolong the QT interval. Permanently discontinue XALKORI in patients who develop QTc >500 ms or ≥60 ms change from baseline with Torsade de pointes, polymorphic ventricular tachycardia, or signs/symptoms of serious arrhythmia. Withhold XALKORI in patients who develop QTc >500 ms on at least 2 separate ECGs until recovery to a QTc ≤480 ms, then resume at a reduced dose. Bradycardia: Symptomatic bradycardia can occur in patients receiving XALKORI. Across clinical trials, bradycardia with a heart rate <50 beats per minute (bpm) occurred in 11% of patients treated with XALKORI (n=1174). Avoid using XALKORI in combination with other agents known to cause bradycardia to the extent possible. Monitor heart rate and blood pressure regularly. In cases of symptomatic bradycardia that is not life-threatening, hold XALKORI until recovery to asymptomatic bradycardia or to a heart rate of ≥60 bpm, re-evaluate the use of concomitant medications, and adjust the dose of XALKORI. Permanently discontinue for life-threatening bradycardia due to XALKORI; however, if associated with concomitant medications known to cause bradycardia or hypotension, hold XALKORI until recovery to asymptomatic bradycardia or to a heart rate of ≥60 bpm. If concomitant medications can be adjusted or discontinued, restart XALKORI at 250 mg once daily with frequent monitoring. Otherwise, temporarily suspend and resume or dose-reduce XALKORI as indicated. Embryofetal Toxicity: XALKORI can cause fetal harm when administered to a pregnant woman. Women of childbearing potential should be advised to avoid pregnancy while receiving XALKORI. If the patient or patient's partner becomes pregnant while taking this drug, apprise the patient of potential hazard to the fetus. Adverse Reactions: Safety was evaluated in a phase 3 study in patients with ALK-positive metastatic NSCLC randomized to XALKORI (n=172) or chemotherapy (n=171). Serious adverse reactions were reported in 37.2% patients treated with XALKORI and 23.4% in the chemotherapy arm. The most frequent serious adverse reactions reported in patients treated with XALKORI were pneumonia (4.1%), pulmonary embolism (3.5%), dyspnea (2.3%), and ILD (2.9%). Fatal adverse reactions in XALKORI-treated patients occurred in 9 (5%) patients, consisting of acute respiratory distress syndrome, arrhythmia, dyspnea, ILD, pneumonia, pneumonitis, pulmonary embolism, respiratory failure, and sepsis. Common adverse reactions (all grades) occurring in ≥25% and more commonly (≥5%) in patients treated with XALKORI vs chemotherapy were vision disorder (60% vs 9%), diarrhea (60% vs 19%), nausea (55% vs 37%), vomiting (47% vs 18%), constipation (42% vs 23%), edema (31% vs 16%), upper respiratory infection (26% vs 13%), and dysgeusia (26% vs 9%). Grade 3/4 events occurring at a higher incidence with XALKORI vs chemotherapy and at >2% incidence were syncope (3% vs 0%), QT prolongation (3% vs 0%), and pulmonary embolism (5% vs 2%). In patients treated with XALKORI vs chemotherapy, the following occurred: elevation of ALT (any grade [76% vs 38%] or Grade 3/4 [17% vs 4%]); elevation of AST (any grade [61% vs 33%] or Grade 3/4 [9% vs 0%]); neutropenia (any grade [49% vs 28%] or Grade 3/4 [12% vs 12%]); lymphopenia (any grade [51% vs 60%] or Grade 3/4 [9% vs 25%]). In patients treated with XALKORI vs chemotherapy, renal cysts occurred (4% vs 1%). Decreased appetite (27%), fatigue (27%), and neuropathy (19%) also occurred in patients taking XALKORI. Drug Interactions: Exercise caution with concomitant use of moderate CYP3A inhibitors. Avoid grapefruit or grapefruit juice which may increase plasma concentrations of crizotinib. Avoid concomitant use of strong CYP3A inducers and inhibitors. Avoid concomitant use of CYP3A substrates with narrow therapeutic range in patients taking XALKORI. If concomitant use of CYP3A substrates with narrow therapeutic range is required in patients taking XALKORI, dose reductions of the CYP3A substrates may be required due to adverse reactions. Nursing Mothers: Given the potential for serious adverse reactions in nursing infants, consider whether to discontinue nursing or discontinue XALKORI. Hepatic Impairment: XALKORI has not been studied in patients with hepatic impairment. As crizotinib is extensively metabolized in the liver, hepatic impairment is likely to increase plasma crizotinib concentrations. Use caution in patients with hepatic impairment. Renal Impairment: Administer XALKORI at a starting dose of 250 mg taken orally once daily in patients with severe renal impairment (CLcr<30 mL/min) not requiring dialysis. No starting dose adjustment is needed for patients with mild and moderate renal impairment. INDICATION XALKORI is indicated for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors are anaplastic lymphoma kinase (ALK)-positive as detected by an FDA-approved test.1 FDA批准Xalkori和伴随诊断试验用于晚期肺癌 2011年8月26日，辉瑞和美国食品药品管理局(FDA)宣布，Xalkori(crizotinib)已获准用于治疗特定的晚期(局部进展性或转移性)、表达间变性淋巴瘤激酶(ALK)基因的非小细胞肺癌(NSCLC)患者。罹患这种肺癌的患者通常不吸烟。 Xalkori被批准与雅培的一种伴随诊断基因检测——Vysis ALK Break Apart FISH Probe Kit——共同使用。该检测用于确定患者的癌症是否表达异常的ALK基因。 Xalkori是一种激酶抑制剂，其治疗肺癌的适应证是以应答率为基础的。尚无数据证实该药可改善患者报告的预后或生存率。 Xalkori被认为通过阻断多种细胞通路的信号传导而发挥疗效，据称这些细胞通路对于肿瘤细胞的生长和生存至关重要，该药可使肿瘤趋于稳定和退化。ALK基因的改变被认为是NSCLC之类肿瘤进展的关键驱动因素。 Xalkori的安全性和有效性已在2项多中心、单组研究中获得证实，这2项研究共纳入了255例晚期ALK阳性NSCLC患者。研究者在招募患者前采集其肺癌组织样本，进行ALK基因检测。多数入组患者曾接受过化疗。在其中一项研究中，客观应答率为50%、中位应答时间为42周，而在另一项研究中分别为61%和48周。 两项研究中最常报告的不良反应均为视力障碍、恶心、腹泻、呕吐、浮肿和便秘。两项研究中均有至少4%的患者发生3或4级不良反应，包括谷丙转氨酶水平升高和中性粒细胞减少。 使用Xalkori还与肺炎相关，甚至可危及生命。发生治疗相关性肺炎的患者必须永久停用Xalkori。 Xalkori为胶囊制剂，每日服药2次，单药治疗。 关于非小细胞肺癌 在全球范围内，肺癌是死亡率最高的癌症。其中，非小细胞肺癌（NSCLC）占全部肺癌的85%。这种癌症难以治疗，转移的肺癌更是如此。,  大约有75% 的 非小细胞肺癌（NSCLC） 患者在确诊时已经为转移或晚期，其5年生存率仅为6%. 关于 XALKORI(Crizotinib) XALKORI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。