色瑞替尼， 色瑞替尼胶囊ceritinib/LDK378（Zykadia Kaps 150mg 3x50Stk）

药店国别：无 产地国家：瑞士 处方药：是 所属类别： 150毫克/胶囊 150胶囊/盒（3x50粒） 包装规格： 150毫克/胶囊 150胶囊/盒（3x50粒） 计价单位：盒 生产厂家中文参考译名：无 生产厂家英文名：Novartis Pharma Schweiz AG 原产地英文商品名：Zykadia Kaps 150mg 3x50Stk 原产地英文药品名：ceritinib/LDK378 中文参考商品译名：Zykadia胶囊 150毫克/粒 3板x50粒 中文参考药品译名：色瑞替尼 曾用名：无

简介

近日，诺华研发的新药针对间变性淋巴瘤激酶阳性（ALK+）转移性非小细胞肺癌（NSCLC）患者的治疗药物Zykadia被欧洲药品管理局的批准上市，本品获前获美国就已经批准了该药物。 商品名:Zykadia® 英文名:Ceritinib Capsules 中文名:色瑞替尼 作用机制 Ceritinib是一种激酶抑制剂。在临床相关浓度的生物化学或细胞测定中鉴定的ceritinib抑制的靶标包括ALK，胰岛素样生长因子1受体（IGF-1R），胰岛素受体（InsR）和ROS1。其中，ceritinib对ALK的活性最高。在体外和体内测定中，Ceritinib抑制ALK的自身磷酸化，ALK介导的下游信号蛋白STAT3的磷酸化和ALK依赖性癌细胞的增殖。Ceritinib抑制表达EML4-ALK和NPM-ALK融合蛋白的细胞系的体外增殖，并证实在小鼠和大鼠中EML4-ALK阳性NSCLC异种移植物生长的剂量依赖性抑制。 Ceritinib在携带EML4-ALK阳性NSCLC异种移植物的小鼠中表现出剂量依赖性抗肿瘤活性，其在临床相关范围内的浓度下显示出对克唑替尼的抗性。 适应证和用途 色瑞替尼是一种激酶抑制剂适用为对克唑替尼[crizotinib]治疗后已进展或不能耐受的间变性淋巴瘤激酶(ALK)-阳性转移非小细胞肺癌(NSCLC)患者的治疗。这个是一种是在根据肿瘤反应率和反应时间在加速批准下被批准的。尚未确定生存或疾病-相关症状改善。可能依验证性试验临床获益证实和描述情况而确定继续批准这个适应证。 剂量和给药方法：每天1次口服750mg。空腹给予ZYKADIA(即，不要餐后2小时内给予)。 剂型和规格胶囊：150mg 禁忌证：无 警告和注意事项 ⑴ 严重和持续胃肠道毒性：在38%患者由于发生腹泻，恶心，呕吐或腹痛调整剂量。如止抗吐药或止泻药无反应不给药，然后减低ZYKADIA剂量。 ⑵ 肝毒性：ZYKADIA可能致肝毒性。至少每月监查肝实验室检验。不给药然后减低剂量，或永久终止ZYKADIA。 ⑶ 间质性肺疾病(ILD)/肺炎：在4%患者中发生。在被诊断有治疗相关ILD/肺炎患者中永久终止ZYKADIA。 ⑷QT间期延长：ZYKADIA可能致QTc间期延长。监视心电图和电解质in患者有充血性心脏衰竭，缓慢性心律失常，电解质异常，或患者正在用药物已知延长QTc间期。不给药然后减低剂量，或永久终止ZYKADIA。 ⑸ 高血糖：ZYKADIA可能致高血糖。监视葡萄糖和如指示开始或优化抗高血糖药物。不给药然后减低剂量，或永久终止ZYKADIA。 ⑹ 心动过缓：ZYKADIA可能致心动过缓。定期监视心率和血压。不给药然后减低剂量，或永久终止ZYKADIA。 ⑺ 胚胎胎儿毒性：ZYKADIA可能致胎儿危害。忠告有生殖潜能女性对胎儿潜在风险。 不良反应 最常见不良反应(发生率至少25%)为腹泻，恶心，转氨酶升高，呕吐，腹痛，疲乏，食欲减退，和便秘。 药物相互作用 ⑴ CYP3A抑制剂和诱导剂：避免ZYKADIA与强CYP3A抑制剂或诱导剂的同时使用。如不可避免同时使用某种强CYP3A抑制剂，减低ZYKADIA的剂量。 ⑵ CYP3A和CYP2C9底物：避免ZYKADIA 与有狭窄治疗指数的CYP3A或CYP2C9底物同时使用。

英文版说明

IMPORTANT SAFETY INFORMATION AND INDICATIONSevere or Persistent Gastrointestinal ToxicityDiarrhea, nausea, vomiting, or abdominal pain occurred in 96% of patients, including severe cases in 14% of patients treated with ZYKADIA in the registration trial. Dose modification due to diarrhea, nausea, vomiting, or abdominal pain occurred in 38% of patientsMonitor and manage patients using standards of care, including antidiarrheals, antiemetics, or fluid replacement as indicatedBased on the severity of the event, withhold ZYKADIA, with resumption at a reduced doseHepatotoxicityDrug-induced hepatotoxicity occurs in patients treated with ZYKADIA. Elevations in alanine aminotransferase (ALT) >5 times the upper limit of normal (ULN) occurred in 27% of 255 patients in the registration trial. One patient (0.4%) required permanent discontinuation due to elevated transaminases and jaundiceMonitor with liver laboratory tests including ALT, aspartate aminotransferase (AST), and total bilirubin once a month and as clinically indicated, with more frequent testing in patients who develop transaminase elevationsBased on the severity of the event, withhold ZYKADIA with resumption at a reduced dose, or permanently discontinue ZYKADIAInterstitial Lung Disease (ILD)/PneumonitisSevere, life-threatening, or fatal ILD/pneumonitis can occur in patients treated with ZYKADIAIn the registration trial, pneumonitis was reported in 4% of 255 patients treated with ZYKADIA. Grade 3/4 ILD/pneumonitis was reported in 3% of patients and fatal ILD/pneumonitis in 1 patient. One percent of patients discontinued ZYKADIA due to ILD/pneumonitisMonitor patients for pulmonary symptoms indicative of ILD/pneumonitis. Exclude other potential causes, and permanently discontinue ZYKADIA in patients diagnosed with treatment-related ILD/pneumonitisQT Interval ProlongationQTc interval prolongation occurs in patients treated with ZYKADIAThree percent of 255 patients experienced a QTc interval increase over baseline > 60 msec in the registration study. A pharmacokinetic analysis suggested that ZYKADIA causes concentration-dependent increases in the QTc intervalWhen possible, avoid use of ZYKADIA in patients with congenital long QT syndromeConduct periodic monitoring with electrocardiograms (ECGs) and electrolytes in patients with congestive heart failure, bradyarrhythmias, electrolyte abnormalities, or those who are taking medications that are known to prolong the QTc intervalWithhold ZYKADIA in patients who develop a QTc interval >500 msec on at least 2 separate ECGs until the QTc interval <481 msec or recovery to baseline if the baseline QTc interval is ≥481 msec, then resume ZYKADIA at a reduced dosePermanently discontinue ZYKADIA in patients who develop QTc interval prolongation in combination with torsades de pointes or polymorphic ventricular tachycardia or signs/symptoms of serious arrhythmiaHyperglycemiaHyperglycemia can occur in patients receiving ZYKADIAIn the registration trial, grade 3/4 hyperglycemia occurred in 13% of 255 patients. There was a 6-fold increase in the risk of grade 3/4 hyperglycemia in patients with diabetes or glucose intolerance and a 2-fold increase in patients taking corticosteroidsMonitor serum glucose levels as clinically indicated. Initiate or optimize antihyperglycemic medications as indicatedBased on the severity of the event, withhold ZYKADIA until hyperglycemia is adequately controlled, then resume ZYKADIA at a reduced doseIf adequate hyperglycemic control cannot be achieved with optimal medical management, permanently discontinue ZYKADIABradycardiaBradycardia can occur in patients receiving ZYKADIAIn the registration trial, sinus bradycardia (heart rate of <50 beats per minute [bpm]) was a new finding in 1% of 255 patients. Bradycardia was reported as an adverse reaction in 3% of patientsAvoid using ZYKADIA in combination with other agents known to cause bradycardia (eg, beta-blockers, non-dihydropyridine calcium channel blockers, clonidine, and digoxin), when possibleMonitor heart rate and blood pressure regularlyIn cases of symptomatic bradycardia that is not life-threatening, withhold ZYKADIA until recovery to asymptomatic bradycardia or to a heart rate ≥60 bpm, eva luate the use of concomitant medications, and adjust the dose of ZYKADIAPermanently discontinue ZYKADIA for life-threatening bradycardia if no contributing concomitant medication is identifiedIf associated with a concomitant medication that causes bradycardia or hypotension, withhold ZYKADIA until recovery to asymptomatic bradycardia or a heart rate ≥60 bpmIf the concomitant medication can be adjusted or discontinued, resume ZYKADIA at a reduced dose upon recovery to asymptomatic bradycardia or to a heart rate ≥60 bpm, with frequent monitoringEmbryofetal ToxicityBased on its mechanism of action, ZYKADIA causes fetal harm when administered to a pregnant womanInform patients of childbearing potential to use an effective method of contraception while receiving ZYKADIA and for at least 2 weeks after ending treatmentIf ZYKADIA is used during pregnancy, or if the patient becomes pregnant, the patient should be apprised of the potential hazard to the fetusNursing MothersBecause many drugs are present in human milk and because of the potential for serious adverse reactions in nursing infants from ceritinib, advise mothers to discontinue nursingAdverse ReactionsThe most common adverse reactions (incidence ≥25% all grades) were diarrhea (86%), nausea (80%), increased AST/ALT (75%/80%), vomiting (60%), abdominal pain (54%), fatigue (52%), decreased appetite (34%), and constipation (29%)Grade 3-4 adverse reactions (incidence ≥2%) were increased AST/ALT (13%/27%), diarrhea (6%), fatigue (5%), nausea (4%), vomiting (4%), ILD/pneumonitis (3%), and abdominal pain (2%)Serious adverse drug reactions reported (incidence >2%) were convulsion, pneumonia, ILD/pneumonitis, dyspnea, dehydration, hyperglycemia, and nausea. Fatal adverse reactions occurred in 5% of patients, consisting of: pneumonia (4 patients), respiratory failure, ILD/pneumonitis, pneumothorax, gastric hemorrhage, general physical health deterioration, pulmonary tuberculosis, cardiac tamponade, and sepsis (1 patient each)Drug InteractionsEffect of Other Drugs on CeritinibCYP3A inhibitors increase ceritinib plasma concentrations: Avoid concurrent use of ZYKADIA with strong CYP3A inhibitors. If concomitant use of strong CYP3A inhibitors is unavoidable, reduce the ZYKADIA dose by approximately one-third, rounded to the nearest 150-mg dosage strength. After discontinuation of a strong CYP3A inhibitor, resume the ZYKADIA dose that was taken prior to initiating the strong CYP3A4 inhibitorCYP3A inducers decrease ceritinib plasma concentrations: Avoid concurrent use of ZYKADIA with strong CYP3A inducersEffect of Ceritinib on Other DrugsCeritinib may inhibit CYP3A and CYP2C9 at clinical concentrations. Avoid concurrent use of CYP3A and CYP2C9 substrates known to have narrow therapeutic indices or substrates primarily metabolized by CYP3A and CYP2C9 during treatment with ZYKADIAIf use of these medications is unavoidable, consider dose reduction of CYP3A substrates with narrow therapeutic indices and CYP2C9 substrates with narrow therapeutic indicesDrug-Food/Drink InteractionsThe bioavailability of ceritinib is increased in the presence of food, depending on the fat contentAdvise patients to take ZYKADIA 2 hours before or 2 hours after a mealDo not consume grapefruit and grapefruit juice as they may inhibit CYP3A in the gut wall and increase the bioavailability of ceritinibINDICATIONZYKADIATM (ceritinib) capsules is indicated for the treatment of patients with anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer (NSCLC), who have progressed on or who are intolerant to crizotinib.This indication is approved under accelerated approval, based on tumor response rate and duration of responseAn improvement in survival or disease-related symptoms has not been establishedContinued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials