英文药名：Stivarga (regorafenib tablets) 中文药名：瑞格非尼片 生产厂家：拜耳制药 药品介绍 靶向抗癌药Stivarga（regorafenib）再次获FDA批准 成为近10年来首个肝癌新药 近日,美国食品和药物管理局（FDA）已批准Stivarga用于既往接受拜耳自身已上市靶向抗癌药多吉美、治疗期间病情进展的不可切除性肝细胞癌（HCC）患者的二线治疗。   Stivarga是一种口服多激酶抑制剂，能够阻断数个促血管生成VEGF受体酪氨酸激酶，这些激酶在肿瘤的血管生成中发挥着重要作用。除了VEGFR 1-3之外，该药还可以抑制各种癌和肿瘤微环境中的多种激酶，包括TIE-2，RAF-1，BRAF V600，KIT, RET, PDGFR及FGFR，每种激酶单独和联合调控肿瘤的生长、基质微环境的形成及疾病的进展。   此次批准，使Stivarga成为美国FDA在近10年来批准的首个肝癌新药。此前，FDA已授予Stivarga二线治疗肝细胞癌（HCC）的孤儿药地位和优先审查资格。据美国国家癌症研究所（NCI）数据，在2017年，美国将确诊大约40710例肝癌，死亡大约28920例。肝细胞癌（HCC）源于肝脏，是最常见的肝癌类型。 批准日期：2017年4月28日 公司：拜耳医药保健制药 STIVARGA®（瑞格非尼[regorafenib]）片剂，口服使用 美国最初批准：2012年 警告： HEPATOTOXICITY请参阅完整的BOXED警告的完整预定信息。 •临床试验中发生严重且有时致命的肝毒性。 •在治疗前和治疗期间监测肝功能。 •根据严重程度和持续性，中断并随后减少或停止STIVARGA的肝毒性，表现为肝功能检查升高或肝细胞坏死。 作用机制 瑞格非尼是多种膜结合和细胞内激酶的小分子抑制剂，参与正常细胞功能和病理过程，如肿瘤发生，肿瘤血管生成，转移和肿瘤免疫。在体外生化或细胞试验中，瑞格非尼或其主要人活性代谢物M-2和M-5抑制RET，VEGFR1，VEGFR2，VEGFR3，KIT，PDGFR-α，PDGFR-β，FGFR1，FGFR2，TIE2的活性，在临床上已达到的瑞格非尼浓度的DDR2，TrkA，Eph2A，RAF-1，BRAF，BRAF V600E，SAPK2，PTK5，Abl和CSF1R。在体内模型中，瑞格非尼在大鼠肿瘤模型中显示出抗血管生成活性，并且在几种小鼠异种移植模型中抑制肿瘤生长，包括一些用于人结肠直肠癌，胃肠道间质和肝细胞癌。Regorafenib还在小鼠异种移植模型和两种人结肠直肠癌小鼠原位模型中显示出抗转移活性。 适应症和用法 STIVARGA是一种激酶抑制剂，适用于治疗患者： •先前曾接受氟嘧啶，奥沙利铂和伊立替康化疗，抗VEGF治疗，以及RAS野生型抗EGFR治疗的转移性结直肠癌（CRC）。 •先前用甲磺酸伊马替尼和苹果酸舒尼替尼治疗的局部晚期，不可切除或转移性胃肠道间质瘤（GIST）。 •曾接受过索拉非尼治疗的肝细胞癌（HCC） 剂量和给药 •推荐剂量：口服160毫克，每28天周期的前21天每天一次。 •在低脂肪餐后服用STIVARGA。 剂量形式和强度 片剂：40毫克 禁忌症 没有。 警告和注意事项 •肝毒性：监测肝功能检查。根据严重程度和持续时间扣留然后减少或停止STIVARGA。 •感染：在患有恶化或严重感染的患者中扣留STIVARGA。 •出血：永久性地停止STIVARGA治疗严重或危及生命的出血。 •胃肠穿孔或瘘管：停止STIVARGA。 •皮肤病毒性：根据皮肤病毒性的严重程度和持续性，扣留然后减少或停用STIVARGA。 •高血压：暂时或永久性地扣留STIVARGA治疗严重或不受控制的高血压。 •心肌缺血和梗塞：扣留STIVARGA治疗新的或急性心肌缺血/梗死，并在解决急性缺血事件后才恢复。 •可逆性后部白质脑病综合征（RPLS）：停用STIVARGA。 •伤口愈合并发症：手术前停用STIVARGA。伤口裂开患者停止使用。 •胚胎-胎儿毒性：可能导致胎儿伤害。建议女性对胎儿有潜在风险，并在治疗期间和最终剂量后2个月内使用有效的避孕措施。建议男性在最终剂量后2个月内使用有效的避孕措施。 不良反应 最常见的不良反应（≥20％）是疼痛（包括胃肠和腹痛），HFSR，虚弱/疲劳，腹泻，食欲减退/食物摄入，高血压，感染，发音困难，高胆红素血症，发热，粘膜炎，体重减轻，皮疹，恶心。 药物相互作用 •强CYP3A4诱导剂：避免使用强CYP3A4诱导剂。 •强CYP3A4抑制剂：避免使用强CYP3A4抑制剂。 •BCRP底物：密切监测患者BCRP底物暴露的症状。 用于特定人群 护理母亲：考虑到药物对母亲的重要性，停止使用药物或护理。 包装提供/存储和处理 提供 片剂以包含三个瓶子的包装提供，每个瓶子包含28个片剂，每个包装总共84个片剂（NDC 50419-171-03）。 存储和处理 将STIVARGA储存在25°C（77°F）; 允许偏差在15至30°C（59至86°F）之间[参见USP受控室温]。 将药片存放在原瓶中，不要除去干燥剂。 首次打开后保持瓶子紧闭。 打开瓶子7周后丢弃任何未使用的药片。 根据当地要求处理未使用的药片。 完整说明书附件： https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=824f19c9-0546-4a8a-8d8f-c4055c04f7c7 Stivarga (regorafenib) tablets STIVARGA is indicated for the treatment of patients with metastatic colorectal cancer (CRC) who have been previously treated with fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapy, an anti-VEGF therapy, and, if RAS wild-type, an anti-EGFR therapy. STIVARGA is indicated for the treatment of patients with locally advanced, unresectable or metastatic gastrointestinal stromal tumor (GIST) who have been previously treated with imatinib mesylate and sunitinib malate. STIVARGA is indicated for the treatment of patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib. MPORTANT SAFETY INFORMATION WARNING: HEPATOTOXICITY Severe and sometimes fatal hepatotoxicity has occurred in clinical trials. Monitor hepatic function prior to and during treatment. Interrupt and then reduce or discontinue STIVARGA for hepatotoxicity as manifested by elevated liver function tests or hepatocellular necrosis, depending upon severity and persistence. Hepatotoxicity: Severe drug-induced liver injury with fatal outcome occurred in STIVARGA-treated patients across all clinical trials. In most cases, liver dysfunction occurred within the first 2 months of therapy and was characterized by a hepatocellular pattern of injury. In metastatic colorectal cancer (mCRC), fatal hepatic failure occurred in 1.6% of patients in the STIVARGA arm and in 0.4% of patients in the placebo arm. In gastrointestinal stromal tumor (GIST), fatal hepatic failure occurred in 0.8% of patients in the STIVARGA arm. In hepatocellular carcinoma (HCC), there was no increase in the incidence of fatal hepatic failure as compared to placebo. Liver Function Monitoring: Obtain liver function tests (ALT, AST, and bilirubin) before initiation of STIVARGA and monitor at least every 2 weeks during the first 2 months of treatment. Thereafter, monitor monthly or more frequently as clinically indicated. Monitor liver function tests weekly in patients experiencing elevated liver function tests until improvement to less than 3 times the upper limit of normal (ULN) or baseline values. Temporarily hold and then reduce or permanently discontinue STIVARGA, depending on the severity and persistence of hepatotoxicity as manifested by elevated liver function tests or hepatocellular necrosis. Infections: STIVARGA caused an increased risk of infections. The overall incidence of infection (Grades 1-5) was higher (32% vs 17%) in 1142 STIVARGA-treated patients as compared to the control arm in randomized placebo-controlled trials. The incidence of grade 3 or greater infections in STIVARGA-treated patients was 9%. The most common infections were urinary tract infections (5.7%), nasopharyngitis (4.0%), mucocutaneous and systemic fungal infections (3.3%) and pneumonia (2.6%). Fatal outcomes caused by infection occurred more often in patients treated with STIVARGA (1.0%) as compared to patients receiving placebo (0.3%); the most common fatal infections were respiratory (0.6% vs 0.2%). Withhold STIVARGA for Grade 3 or 4 infections, or worsening infection of any grade. Resume STIVARGA at the same dose following resolution of infection. Hemorrhage: STIVARGA caused an increased incidence of hemorrhage. The overall incidence (Grades 1-5) was 18.2% in 1142 patients treated with STIVARGA vs 9.5% with placebo in randomized, placebo-controlled trials. The incidence of grade 3 or greater hemorrhage in patients treated with STIVARGA was 3.0%. The incidence of fatal hemorrhagic events was 0.7%, involving the central nervous system or the respiratory, gastrointestinal, or genitourinary tracts. Permanently discontinue STIVARGA in patients with severe or life-threatening hemorrhage and monitor INR levels more frequently in patients receiving warfarin. Gastrointestinal Perforation or Fistula: Gastrointestinal perforation occurred in 0.6% of 4518 patients treated with STIVARGA across all clinical trials of STIVARGA administered as a single agent; this included eight fatal events. Gastrointestinal fistula occurred in 0.8% of patients treated with STIVARGA and in 0.2% of patients in the placebo arm across randomized, placebo-controlled trials. Permanently discontinue STIVARGA in patients who develop gastrointestinal perforation or fistula. Dermatological Toxicity: In randomized, placebo-controlled trials, adverse skin reactions occurred in 71.9% of patients with STIVARGA arm and 25.5% of patients in the placebo arm including hand-foot skin reaction (HFSR) also known as palmar-plantar erythrodysesthesia syndrome (PPES) and severe rash, requiring dose modification. In the randomized, placebo-controlled trials, the overall incidence of HFSR was higher in 1142 STIVARGA-treated patients (53% vs 8%) than in the placebo-treated patients. Most cases of HFSR in STIVARGA-treated patients appeared during the first cycle of treatment. The incidences of Grade 3 HFSR (16% vs <1%), Grade 3 rash (3% vs <1%), serious adverse reactions of erythema multiforme (<0.1% vs 0%), and Stevens-Johnson syndrome (<0.1% vs 0%) were higher in STIVARGA-treated patients. Across all trials, a higher incidence of HFSR was observed in Asian patients treated with STIVARGA (all grades: 72%; Grade 3: 18%). Toxic epidermal necrolysis occurred in 0.02% of 4518 STIVARGA-treated patients across all clinical trials of STIVARGA administered as a single agent. Withhold STIVARGA, reduce the dose, or permanently discontinue depending on the severity and persistence of dermatologic toxicity. Hypertension: Hypertensive crisis occurred in 0.2% in STIVARGA-treated patients and in none of the patients in placebo arm across all randomized, placebo-controlled trials. STIVARGA caused an increased incidence of hypertension (30% vs 8% in mCRC, 59% vs 27% in GIST, and 31% vs 6% in HCC). The onset of hypertension occurred during the first cycle of treatment in most patients who developed hypertension (67% in randomized, placebo controlled trials). Do not initiate STIVARGA until blood pressure is adequately controlled. Monitor blood pressure weekly for the first 6 weeks of treatment and then every cycle, or more frequently, as clinically indicated. Temporarily or permanently withhold STIVARGA for severe or uncontrolled hypertension. Cardiac Ischemia and Infarction: STIVARGA increased the incidence of myocardial ischemia and infarction (0.9% with STIVARGA vs 0.2% with placebo) in randomized placebo-controlled trials. Withhold STIVARGA in patients who develop new or acute cardiac ischemia or infarction, and resume only after resolution of acute cardiac ischemic events if the potential benefits outweigh the risks of further cardiac ischemia. Reversible Posterior Leukoencephalopathy Syndrome (RPLS): Reversible posterior leukoencephalopathy syndrome (RPLS), a syndrome of subcortical vasogenic edema diagnosed by characteristics finding on MRI, occurred in one of 4800 STIVARGA-treated patients across all clinical trials. Perform an evaluation for RPLS in any patient presenting with seizures, severe headache, visual disturbances, confusion, or altered mental function. Discontinue STIVARGA in patients who develop RPLS. Wound Healing Complications: Treatment with STIVARGA should be stopped at least 2 weeks prior to scheduled surgery. Resuming treatment after surgery should be based on clinical judgment of adequate wound healing. STIVARGA should be discontinued in patients with wound dehiscence. Embryo-Fetal Toxicity: STIVARGA can cause fetal harm when administered to a pregnant woman. There are no available data on STIVARGA use in pregnant women. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential and males with female partners of reproductive potential to use effective contraception during treatment with STIVARGA and for 2 months after the final dose. Nursing Mothers: Because of the potential for serious adverse reactions in breastfed infants from STIVARGA, do not breastfeed during treatment with STIVARGA and for 2 weeks after the final dose. Most Frequently Observed Adverse Drug Reactions in mCRC (≥30%): The most frequently observed adverse drug reactions (≥30%) in STIVARGA-treated patients vs placebo-treated patients in mCRC, respectively, were: asthenia/fatigue (64% vs 46%), pain (59% vs 48%), decreased appetite and food intake (47% vs 28%), HFSR/PPE (45% vs 7%), diarrhea (43% vs 17%), mucositis (33% vs 5%), weight loss (32% vs 10%), infection (31% vs 17%), hypertension (30% vs 8%), and dysphonia (30% vs 6%). Most Frequently Observed Adverse Drug Reactions in GIST (≥30%): The most frequently observed adverse drug reactions (≥30%) in STIVARGA-treated patients vs placebo-treated patients in GIST, respectively, were: HFSR/PPE (67% vs 12%), pain (60% vs 55%), hypertension (59% vs 27%), asthenia/fatigue (52% vs 39%), diarrhea (47% vs 9%), mucositis (40% vs 8%), dysphonia (39% vs 9%), infection (32% vs 5%), decreased appetite and food intake (31% vs 21%), and rash (30% vs 3%). Most Frequently Observed Adverse Drug Reactions in HCC (≥30%): The most frequently observed adverse drug reactions (≥30%) in STIVARGA-treated patients vs placebo-treated patients in HCC, respectively, were: pain (55% vs 44%), HFSR/PPE (51% vs 7%), asthenia/fatigue (42% vs 33%), diarrhea (41% vs 15%), hypertension (31% vs 6%), infection (31% vs 18%), decreased appetite and food intake (31% vs 15%). 拜耳Stivarga（瑞戈非尼 regorafenib）获欧盟批准用于肝癌二线系统治疗 2017年8月10日，欧盟委员会（EC）已经批准其Stivarga®（regorafenib，瑞戈非尼）上市许可，用于治疗既往接受Nexavar®（索拉非尼）治疗的HCC成人患者。Stivarga是首个也是唯一的对二线HCC总体生存（OS）有显著改善的药物。这标志着Stivarga在五个月内获得第三个批准，同时该产品也分别在四月和六月于美国和日本获批，用于肝癌二线治疗。 “到目前为止，没有有效的二线治疗方案可供肝癌患者及欧洲的治疗医师使用。随着欧盟批准Stivarga用于HCC，HCC患者的前景可能会显著改善，因为他们可以在Nexavar之后直接使用Stivarga治疗，“RESORCE试验的主要研究者、西班牙巴塞罗那大学医院肝脏科Jordi Bruix博士表示。   该批准是基于国际多中心安慰剂对照的III期RESORCE（NCT 01774344）试验数据。该试验研究了在Nexavar治疗期间疾病进展的HCC患者。 在试验中使用regorafenib加最佳支持治疗（BSC），结果显示，与安慰剂加BSC相比，OS数据存在统计学显著性和临床意义上的改善（10.6个月与7.8个月）（HR 0.63; 95％CI 0.50-0.79; p <0.0001），这意味着在试验期内死亡风险降低了37％。RESORCE试验中观察到的不良事件与已知的regorafenib安全性一致。 最常见的治疗不良事件是手足皮肤反应，腹泻，疲劳和高血压。   “肝癌经常被诊断迟发，难以治疗，但欧盟批准Stivarga用于HCC标志着近十年来HCC患者的首例治疗进展。拜耳继续支持肝癌群体，致力于在该领域持续进行研究，并继续为全球推广Stivarga追加法规备案，“拜耳执行副总裁兼肿瘤战略业务部门负责人Robert LaCaze说。 肝癌往往比其他癌症更难治疗，欧盟的年死亡人数达48,000。在全球范围内，这是与癌症相关的第二大死因。   世界其他国家，包括中国，正在对Stivarga用于HCC进行额外的监管文件审查。Stivarga已经在全球90多个国家（包括美国、日本、中国和欧盟国家）获批用于治疗转移性结直肠癌。Stivarga也在全球80多个国家（包括美国、日本、中国和欧盟国家）被批准用于治疗转移性胃肠道间质瘤。