部份中文瑞戈非尼处方资料（仅供参考）
药品名称：Regorafenib
商品名称：Stivarga
中文药名：瑞戈非尼
原研厂家：拜耳
剂    型：片剂
批准日期：2017年4月28日
药品介绍
STIVARGA®（瑞戈非尼[regorafenib]）片剂，用于口服使用
美国初步批准：2012年
警告：
致命毒性请参阅完整的BOXED警告的完整说明信息。
•临床试验中发生严重有时致命的肝毒性。
•在治疗前和治疗期间监测肝功能。
•根据严重程度和持续性，中毒，然后减少或停止STIVARGA的肝毒性，表现为肝功能检查升高或肝细胞坏死。
最近的主要变化
适应症和用法，结直肠癌：6/2016
适应症和用法，肝细胞癌：4/2017
剂量和给药，剂量修改：4/2017
警告和注意事项：4/2017
作用机制
Regorafenib是一种涉及正常细胞功能和肿瘤发生，肿瘤血管生成，转移和肿瘤免疫等病理过程的多种膜结合和细胞内激酶的小分子抑制剂。在体外生物化学或细胞测定中，regorafenib或其主要人类活性代谢物M-2和M-5抑制RET，VEGFR1，VEGFR2，VEGFR3，KIT，PDGFR-α，PDGFR-β，FGFR1，FGFR2，TIE2， DDR2，TrkA，Eph2A，RAF-1，BRAF，BRAF V600E，SAPK2，PTK5，Abl和CSF1R在临床上达到的regorafenib浓度。在体内模型中，regorafenib在大鼠肿瘤模型中表现出抗血管生成活性，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，胃肠道基质和肝细胞癌的肿瘤生长。雷卡非尼也显示了在小鼠异种移植模型和人结肠直肠癌的两个小鼠原位模型中的抗转移活性。
适用范围及用途
STIVARGA是用于治疗患者的激酶抑制剂：
•以前用氟嘧啶，奥沙利铂和伊立替康为基础的化学疗法治疗转移性结直肠癌（CRC），抗VEGF治疗，以及RAS野生型抗EGFR治疗。
•以前曾接受甲磺酸伊马替尼和苹果酸苹果酸盐治疗的局部晚期，不可切除或转移性胃肠道间质瘤（GIST）。
•以前用索拉非尼治疗的肝细胞癌（HCC）
剂量和管理
•推荐剂量：口服160 mg，每28天一次的头21天每日一次。
•吃低脂饭后服用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，减少或停止STIVARGA。
•感染：在恶化或严重感染的患者中禁止STIVARGA。
•出血：永久性停止STIVARGA，用于严重或危及生命的出血。
•胃肠穿孔或瘘管：停止STIVARGA。
•皮肤毒性：根据皮肤毒性的严重性和持续性，禁止并减少或停止STIVARGA。
•高血压：暂时或永久性地阻止STIVARGA严重或不受控制的高血压。
•心脏缺血和梗塞：阻止STIVARGA用于新的或急性心肌缺血/梗死，并且仅在解决急性缺血事件后恢复。
•可逆性后脑白质病综合征（RPLS）：停止STIVARGA。
•创伤愈合并发症：手术前停止STIVARGA。伤口开裂患者停药。
•胚胎 - 胎儿毒性：可引起胎儿的危害。建议对胎儿有潜在危险的妇女，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药。
不良反应
最常见的不良反应（≥20％）是疼痛（包括胃肠和腹痛），HFSR，乏力/疲劳，腹泻，食欲降低/食物摄取，高血压，感染，发音障碍，高胆红素血症，发热，粘膜炎，体重减轻，皮疹和恶心。
药物相互作用
•强CYP3A4诱导物：避免强CYP3A4诱导物。
•强CYP3A4抑制剂：避免强烈的CYP3A4抑制剂。
•BCRP底物：密切观察患者暴露于BCRP底物的症状。
在特定人口中使用
护理母亲：停止药物或哺乳，考虑到药物对母亲的重要性。
如何提供/存储和处理
提供
片剂以包装三瓶的包装的形式提供，每瓶含28片，每片包装共84片（NDC 50419-171-03）。
储存和处理
将STIVARGA储存在25°C（77°F）; 允许偏离15至30°C（59至86°F）[见USP受控室温]。
将片剂储存在原始瓶子中，不要取出干燥剂。 首先打开瓶子后，保持瓶子的密封。
打开瓶子7周后丢弃任何未使用的药片。 按照当地要求处理未使用的药片。 
Bayer’s Stivarga® (regorafenib) Tablets Approved by U.S. FDA for Treatment of Metastatic Colorectal Cancer
U.S. Food and Drug Administration (FDA) approved Bayer’s Stivarga® (regorafenib) tablets for the treatment of patients with metastatic colorectal cancer (mCRC) who have been previously treated with currently available therapies (including fluoropyrimidine–, oxaliplatin– and irinotecan–based chemotherapy, an anti-VEGF therapy, and, if KRAS wild type, an anti-EGFR therapy).
The approval of Stivarga is based on results from the pivotal Phase III study (CORRECT) that demonstrated improvement in overall survival (OS) and progression-free survival (PFS) compared to placebo in patients with mCRC whose disease had progressed after approved standard therapies.
Stivarga is a Bayer compound developed by Bayer. In 2011, Bayer entered into an agreement with Onyx Pharmaceuticals, Inc. under which Onyx will receive a royalty on any future global net sales of Stivarga in oncology.
Bayer and Onyx will jointly promote Stivarga in the United States.
“The approval of regorafenib adds to the treatments we have for metastatic colorectal cancer, which is important for those patients who have no further options,” said Heinz-Josef Lenz, MD, FACP, CORRECT investigator and associate director for clinical research and co-leader of the Gastrointestinal Cancers Program at the USC Norris Comprehensive Cancer Center.
“The drug has been shown to prolong survival and slow the progression of cancer in patients whose disease has progressed after treatment with currently available therapies. It provides patients another avenue to fight this cancer.”
In the CORRECT (Colorectal cancer treated with regorafenib or placebo after failure of standard therapy) trial, Stivarga plus best supportive care (BSC) significantly improved OS [HR=0.77 (95% CI, 0.64-0.94), two-sided p=0.0102] and PFS [HR=0.49 (95% CI, 0.42-0.58), two-sided p<0.0001] compared to placebo plus BSC. Median OS was 6.4 months with Stivarga versus 5.0 months with placebo; median PFS was 2.0 months with Stivarga versus 1.7months with placebo. No difference in overall response rate was observed.
Five patients (1%) in the regorafenib arm and one patient (0.4%) in the placebo armexperienced partial responses.
The most frequently observed adverse drug reactions (≥30%) in patients receiving Stivarga were asthenia/fatigue, decreased appetite and food intake, hand-foot-skin reaction (HFSR)/palmar-plantar erythrodysesthesia (PPE), diarrhea, mucositis, weight loss, infection, hypertension and dysphonia. The most serious adverse drug reactions in patients receiving Stivarga included hepatotoxicity, hemorrhage, and gastrointestinal perforation. Full results from the study were presented at the 2012 Gastrointestinal Cancers Symposium of the American Society of Clinical Oncology (ASCO) (January 2012), and updated results at the 48th ASCO Annual Meeting (June 2012).
“The approval of Stivarga reflects Bayer’s commitment to confronting the challenges of difficult-to-treat cancers,” said Pamela A. Cyrus, MD, Vice President and Head of U.S. Medical Affairs, Bayer HealthCare Pharmaceuticals. “Patients with metastatic colorectal cancer whose disease has returned after treatment will now have a new option that has been shown to prolong survival and keep the cancer from progressing.”
About Colorectal Cancer
Colorectal cancer is the third most commonly diagnosed cancer and the third leading cause of cancer death in the United States, in both men and women. It is estimated that more than 143,000 people will be diagnosed with CRC in 2012, and nearly 52,000 people will die from the disease.4 Approximately 50% of colon cancer patients will be diagnosed with metastases (most commonly to the liver) either at the time of diagnosis or due to recurrent disease.
In mCRC, KRAS status is an important biomarker and can be a predictor of treatment response.6 Approximately 40% of colorectal cancers are characterized by mutations in the KRAS gene.
About the CORRECT Study
CORRECT was an international, multicenter, randomized, double-blind, placebo-controlled Phase III study that enrolled 760 patients with mCRC whose disease had progressed during or within three months following last administration of approved standard therapies. Patients were randomized to receive regorafenib plus BSC or placebo plus BSC. Treatment cycles consisted of 160 mg of regorafenib (or matching placebo) once daily for three weeks on/one week off plus BSC.
About Stivarga (regorafenib)
Stivarga is indicated for the treatment of patients with mCRC who have been previously treated with fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapy, an anti-VEGF therapy, and, if KRAS wild type, an anti-EGFR therapy.
Stivarga is an oral multi-kinase inhibitor that inhibits various kinases within the mechanisms involved in tumor growth and progression – angiogenesis, oncogenesis and the tumor microenvironment. In preclinical studies, Stivarga inhibits several angiogenic VEGF receptor tyrosine kinases that play a role in tumor neoangiogenesis (the growth of new blood vessels). It also inhibits various oncogenic and tumor microenvironment kinases including KIT, RET, PDGFR, and FGFR, which individually and collectively impact upon tumor growth, formation of a stromal microenvironment and disease progression.1
Stivarga was developed and reviewed under the fast track program and received priority review designation from the FDA. These designations are granted by the FDA to expedite the development and review of drugs to treat serious diseases and fill an unmet medical need (fast track), and given to drugs that provide a treatment where no adequate therapy exists (priority review).
For full prescribing information, including BOXED WARNINGS, visit www.Stivarga-us.com. Bayer offers patient assistance through the Bayer REACH® (Resources for Expert Assistance and Care Helpline) program.
Important Safety Information for Stivarga (regorafenib)
WARNING: HEPATOTOXICITY: Severe and sometimes fatal hepatotoxicity has been observed 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.
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.
In clinical trials, Stivarga was associated with an increased incidence of hemorrhage, including fatal hemorrhage. Permanently discontinue Stivarga in patients with severe or life-threatening hemorrhage and monitor INR levels more frequently in patients receiving warfarin.
Hand-foot skin reaction (HFSR) (also known as palmar-plantar erythrodysesthesia [PPE]) and rash are the most frequently observed dermatological reactions with Stivarga. Temporarily hold and then reduce or permanently discontinue Stivarga depending on the severity and persistence of dermatologic toxicity.
An increased incidence of hypertension has been observed with Stivarga. 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.
Stivarga has been associated with an increased incidence of myocardial ischemia and infarction. Withhold Stivarga in patients who develop new or acute cardiac ischemia or infarction, and resume only after resolution of acute cardiac ischemic events.
Reversible posterior leukoencephalopathy syndrome (RPLS) has been reported with Stivarga. Confirm the diagnosis of RPLS with MRI and discontinue Stivarga in patients who develop RPLS.
Gastrointestinal perforation and fistula have been reported in patients treated with Stivarga. Permanently discontinue Stivarga in patients who develop gastrointestinal perforation or fistula.
Treatment with Stivarga should be stopped at least 2 weeks prior to scheduled surgery. The decision to resume regorafenib after surgery should be based on clinical judgment of adequate wound healing. Stivarga should be discontinued in patients with wound dehiscence.
Stivarga can cause fetal harm when administered to a pregnant woman. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.
The most frequently observed adverse drug reactions (≥30%) in Stivarga-treated patients vs placebo-treated patients, respectively, were: asthenia/fatigue (64% vs 46%), 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%).
About Oncology at Bayer
Bayer is committed to delivering science for a better life by advancing a portfolio of innovative treatments. Bayer’s oncology franchise now includes two oncology products and several other compounds in various stages of clinical development. Together, these products reflect the company’s approach to research, which prioritizes novel targets and pathways with the potential to transform the way that cancer is treated across tumor types and stages of disease.
About Bayer HealthCare Pharmaceuticals Inc.
Bayer HealthCare Pharmaceuticals Inc. is the U.S.-based pharmaceuticals business of Bayer HealthCare LLC, a subsidiary of Bayer AG. Bayer HealthCare is one of the world’s leading, innovative companies in the healthcare and medical products industry, and combines the activities of the Animal Health, Consumer Care, Medical Care, and Pharmaceuticals divisions. As a specialty pharmaceutical company, Bayer HealthCare provides products for General Medicine, Hematology, Neurology, Oncology and Women’s Healthcare. The company’s aim is to discover and manufacture products that will improve human health worldwide by diagnosing, preventing and treating diseases. 。 
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