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瑞戈非尼(Stivarga)说明书

瑞戈非尼（Stivarga）
【规格】
40mg/片
【适应症】
用于不能通过手术切除以及使用其它已上市药物治疗无效的晚期胃肠道间质瘤(GIST)患者治疗。

【禁忌症】
对本品有严重超敏反应者禁用。

【用法用量】
160mg口服。

每天1次每28天疗程，与食物服用。

【不良反应】
最常见不良反应(≥30%)是乏力/疲乏、减低食欲和食物摄入量、手足皮肤反应(HFSR)、腹泻、口腔粘膜炎、体重减轻、感染、高血压和发音困难。

【注意事项】
1.出血：对严重或威胁生命出血永久终止用药。

2.皮肤学毒性：减低或终止Stivarga取决于皮肤学毒性的严重程度和持久性。

3.高血压：对严重或不能控制的高血压暂时或永久终止Stivarga。

4.心脏缺血和梗死：拒给Stivarga对新或急性心脏缺血/梗死和只有急性缺血事件解决后恢复。

5.可逆性后部白质脑病综合征(RPLS)：终止Stivarga。

6.胃肠道穿孔或瘘管：终止Stivarga。

7.伤口愈合并发症：术前停止Stivarga，在伤口裂开患者中终止。

8.胚胎胎儿毒性：可能致胎儿危害，劝告妇女对胎儿潜在风险。

瑞戈非尼片说明书

核准日期：2017年3月22日修改日期：2017年12月5日瑞戈非尼片说明书请仔细阅读说明书并在医师指导下使用。

【药品名称】通用名称：瑞戈非尼片商品名称：Stivarga® 拜万戈® 英文名称：Regorafenib Tablets 汉语拼音：Ruigefeini Pian【成份】主要成份：瑞戈非尼化学名称：4-[4-({[4-氯-3-(三氟甲基)苯基]氨基甲酰}氨基)-3-氟苯氧基]-N-甲基吡啶-2-甲酰胺一水合物化学结构式：分子式：C 21H 15ClF 4N 4O 3•H 2O 分子量：500.83 【性状】本品为浅粉色椭圆形薄膜衣片。

【适应症】1. 适用于治疗既往接受过以氟尿嘧啶、奥沙利铂和伊立替康为基础的化疗, 以及既往接受过或不适合接受抗VEGF 治疗、抗EGFR 治疗（RAS 野生型）的转移性结直肠癌（mCRC ）患者。

2. 既往接受过甲磺酸伊马替尼及苹果酸舒尼替尼治疗的局部晚期的、无法手术切除的或转移性的胃肠道间质瘤（GIST ）患者。

3. 既往接受过索拉非尼治疗的肝细胞癌（HCC ）患者。

【规格】警告：肝脏毒性•在临床研究中发生了严重的、有时是致命性的肝脏毒性; •在治疗前及治疗中进行肝功能监测；•在使用瑞戈非尼片治疗中，可根据肝功检测或肝细胞坏死所表现出来的肝脏毒性的严重程度和持续性，暂停后降低剂量或停药。

40mg【用法用量】瑞戈非尼应由在抗癌治疗给药方面有经验的医生开具。

推荐剂量推荐剂量为160mg（4片，每片含40mg 瑞戈非尼），每日一次，于每一疗程的前21天口服，28天为一疗程。

服用方法瑞戈非尼片应在每天同一时间，在低脂早餐（脂肪含量30%）后随水整片吞服。

患者不得在同一天服用两剂药物以弥补（前一天）漏服的剂量。

如果服用瑞戈非尼后出现呕吐，同一天内患者不得再次服药。

治疗时间应持续治疗直至患者不能临床受益或出现不可耐受的毒性反应。

剂量调整及特殊使用说明基于个人的安全性及耐受性考虑，可能需要中断给药或降低剂量。

瑞戈非尼说明书

瑞戈非尼说明书关键信息项：1、药品名称：瑞戈非尼2、适应症：＿___________________________3、用法用量：＿___________________________4、不良反应：＿___________________________5、禁忌：＿___________________________6、注意事项：＿___________________________11 药品介绍瑞戈非尼是一种口服的多靶点激酶抑制剂，属于抗肿瘤药物。

111 作用机制其主要通过抑制多种与肿瘤血管生成、肿瘤细胞增殖和肿瘤微环境相关的激酶，发挥抗肿瘤作用。

12 适应症适用于治疗既往接受过以氟尿嘧啶、奥沙利铂和伊立替康为基础的化疗，以及既往接受过或不适合接受抗 VEGF 治疗、抗 EGFR 治疗（RAS 野生型）的转移性结直肠癌（mCRC）患者。

还适用于既往接受过索拉非尼治疗的肝细胞癌（HCC）患者。

121 特定疾病的应用限制在某些特定情况下，可能需要根据患者的具体病情、合并疾病等因素来评估是否适合使用瑞戈非尼进行治疗。

13 用法用量131 剂量推荐剂量为每次 160mg，每日一次，口服，连续服用 3 周，停药 1 周，每 4 周为一个治疗周期。

132 服用方法应在每天相同的时间服用，整片吞服，不得咀嚼或压碎。

133 剂量调整根据患者的个体耐受性和安全性，可能需要对剂量进行调整。

14 不良反应141 常见不良反应包括手足皮肤反应、疲劳、腹泻、食欲下降、高血压、发声困难等。

142 严重不良反应可能出现肝功能异常、出血、心肌缺血和梗死等严重不良反应。

143 不良反应的处理对于轻度至中度的不良反应，可通过对症治疗、剂量调整等方式处理。

对于严重不良反应，可能需要停药并进行相应的治疗。

15 禁忌对瑞戈非尼成分过敏者禁用。

151 特殊人群禁忌孕妇、哺乳期妇女禁用。

16 注意事项161 肝功能监测在治疗开始前、治疗期间定期监测肝功能。

瑞戈非尼说明书

HIGHLIGHTS OF PRESCRIBING INFORMATIONThese highlights do not include all the information needed to use STIVARGA safely and effectively. See full prescribing information for STIVARGA.STIVARGA® (regorafenib) tablets, for oral useInitial U.S. Approval: 2012WARNING: HEPATOTOXICITYSee full prescribing information for complete boxed warning.∙Severe and sometimes fatal hepatotoxicity has been observed inclinical trials. (5.1)∙Monitor hepatic function prior to and during treatment. (5.1)∙Interrupt and then reduce or discontinue Stivarga for hepatotoxicity as manifested by elevated liver function tests or hepatocellularnecrosis, depending upon severity and persistence. (2.2)-------------------------- RECENT MAJOR CHANGES --------------------------Dosage and Administration (2.1) 4/2015 --------------------------- INDICATIONS AND USAGE --------------------------Stivarga is a kinase inhibitor 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 KRAS wild type, an anti-EGFR therapy. (1.1)∙Locally advanced, unresectable or metastatic gastrointestinal stromal tumor (GIST) who have been previously treated with imatinib mesylate and sunitinib malate. (1.2)----------------------DOSAGE AND ADMINISTRATION ---------------------- ∙Recommended Dose: 160 mg orally, once daily for the first 21 days of each 28-day cycle. (2.1)∙Take Stivarga with a low-fat meal. (2.1, 12.3)--------------------- DOSAGE FORMS AND STRENGTHS --------------------40 mg film-coated tablets (3)------------------------------ CONTRAINDICATIONS -----------------------------None.----------------------- WARNINGS AND PRECAUTIONS ----------------------∙Hemorrhage: Permanently discontinue Stivarga for severe or life-threatening hemorrhage. (5.2) ∙Dermatological toxicity: Interrupt and then reduce or discontinue Stivarga depending on severity and persistence of dermatologic toxicity. (5.3)∙Hypertension: Temporarily or permanently discontinue Stivarga for severe or uncontrolled hypertension. (5.4)∙Cardiac ischemia and infarction: Withhold Stivarga for new or acute cardiac ischemia/infarction and resume only after resolution of acute ischemic events. (5.5)∙Reversible Posterior Leukoencephalopathy Syndrome (RPLS): Discontinue Stivarga. (5.6)∙Gastrointestinal perforation or fistulae: Discontinue Stivarga. (5.7)∙Wound healing complications: Stop Stivarga before surgery. Discontinue in patients with wound dehiscence. (5.8)∙Embryofetal toxicity: Can cause fetal harm. Advise women of potential risk to a fetus. (5.9, 8.1)------------------------------ ADVERSE REACTIONS -----------------------------The most common adverse reactions (≥20%) are asthenia/fatigue, HFSR, diarrhea, decreased appetite/food intake, hypertension, mucositis, dysphonia, infection, pain (not otherwise specified), decreased weight, gastrointestinal and abdominal pain, rash, fever, and nausea. (6)To report SUSPECTED ADVERSE REACTIONS, contact Bayer HealthCare Pharmaceuticals Inc. at 1-888-842-2937 or FDA at 1-800FDA-1088 or /medwatch------------------------------ DRUG INTERACTIONS -----------------------------∙Strong CYP3A4 inducers: Avoid strong CYP3A4 inducers. (7.1)∙Strong CYP3A4 inhibitors: Avoid strong CYP3A4 inhibitors. (7.2)----------------------- USE IN SPECIFIC POPULATIONS ----------------------Nursing Mothers: Discontinue drug or nursing, taking into consideration the importance of the drug to the mother. (8.3)See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling.Revised: 4/2015FULL PRESCRIBING INFORMATION: CONTENTS* WARNING: HEPATOTOXICITY1 INDICATIONS AND USAGE1.1 Colorectal Cancer1.2 Gastrointestinal Stromal Tumors2 DOSAGE AND ADMINISTRATION2.1 Recommended Dose2.2 Dose Modifications3 DOSAGE FORMS AND STRENGTHS4 CONTRAINDICATIONS5 WARNINGS AND PRECAUTIONS5.1 Hepatotoxicity5.2 Hemorrhage5.3 Dermatological Toxicity5.4 Hypertension5.5 Cardiac Ischemia and Infarction5.6 Reversible Posterior Leukoencephalopathy Syndrome (RPLS)5.7 Gastrointestinal Perforation or Fistula5.8 Wound Healing Complications5.9 Embryo-Fetal Toxicity6 ADVERSE REACTIONS6.1 Clinical Trials Experience6.2 Postmarketing Experience7 DRUG INTERACTIONS7.1 Effect of Strong CYP3A4 Inducers on Regorafenib7.2 Effect of Strong CYP3A4 Inhibitors on Regorafenib8 USE IN SPECIFIC POPULATIONS8.1 Pregnancy8.3 Nursing Mothers8.4 Pediatric Use8.5 Geriatric Use8.6 Hepatic Impairment8.7 Renal Impairment8.8 Females and Males of Reproductive Potential10 OVERDOSAGE11 DESCRIPTION12 CLINICAL PHARMACOLOGY12.1 Mechanism of Action12.3 Pharmacokinetics12.6 Cardiac Electrophysiology13 NONCLINICAL TOXICOLOGY13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility13.2 Animal Toxicology and/or Pharmacology14 CLINICAL STUDIES14.1 Colorectal Cancer14.2 Gastrointestinal Stromal Tumors16 HOW SUPPLIED/STORAGE AND HANDLING16.1 How Supplied16.2 Storage and Handling17 PATIENT COUNSELING INFORMATION*Sections or subsections omitted from the full prescribing information are not listed.FULL PRESCRIBING INFORMATIONWARNING: HEPATOTOXICITY∙Severe and sometimes fatal hepatotoxicity has been observed in clinical trials [see Warnings and Precautions(5.1)].∙ Monitor hepatic function prior to and during treatment [see Warnings and Precautions (5.1)].∙ Interrupt and then reduce or discontinue Stivarga for hepatotoxicity as manifested by elevated liver function tests or hepatocellular necrosis, depending upon severity and persistence [see Dosage and Administration (2.2)].1 INDICATIONS AND USAGE1.1 Colorectal CancerStivarga® 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 KRAS wild type, an anti-EGFR therapy.1.2 Gastrointestinal Stromal TumorsStivarga 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.2 DOSAGE AND ADMINISTRATION2.1 Recommended DoseThe recommended dose is 160 mg regorafenib (four 40 mg tablets) taken orally once daily for the first 21 days of each 28day cycle. Continue treatment until disease progression or unacceptable toxicity.Take Stivarga at the same time each day. Swallow tablet whole with water after a low-fat meal that contains less than 600 calories and less than 30% fat [see Clinical Pharmacology (12.3)]. Do not take two doses of Stivarga on the same day to make up for a missed dose from the previous day.2.2 Dose ModificationsInterrupt Stivarga for the following:∙ NCI CTCAE Grade 2 hand-foot skin reaction (HFSR) [palmar-plantar erythrodysesthesia (PPE)] that is recurrent or does not improve within 7 days despite dose reduction; interrupt therapy for a minimum of 7 days for Grade 3 HFSR ∙ Symptomatic Grade 2 hypertension∙ Any NCI CTCAE Grade 3 or 4 adverse reactionReduce the dose of Stivarga to 120 mg:∙ For the first occurrence of Grade 2 HFSR of any duration∙ After recovery of any Grade 3 or 4 adverse reaction∙ For Grade 3 aspartate aminotransferase (AST)/alanine aminotransferase (ALT) elevation; only resume if the potential benefit outweighs the risk of hepatotoxicityReduce the dose of Stivarga to 80 mg:∙For re-occurrence of Grade 2 HFSR at the 120 mg dose∙After recovery of any Grade 3 or 4 adverse reaction at the 120 mg dose (except hepatotoxicity)Discontinue Stivarga permanently for the following:∙Failure to tolerate 80 mg dose∙Any occurrence of AST or ALT more than 20 times the upper limit of normal (ULN)∙Any occurrence of AST or ALT more than 3 times ULN with concurrent bilirubin more than 2 times ULN∙Re-occurrence of AST or ALT more than 5 times ULN despite dose reduction to 120 mg∙For any Grade 4 adverse reaction; only resume if the potential benefit outweighs the risks3 DOSAGE FORMS AND STRENGTHSStivarga is a 40 mg, light pink, oval shaped, film-coated tablet, debossed with ‘BAYER’ on one side and ‘40’ on the other side.4 CONTRAINDICATIONSNone5 WARNINGS AND PRECAUTIONS5.1 HepatotoxicitySevere drug induced liver injury with fatal outcome occurred in 0.3% of 1200 Stivarga-treated patients across all clinical trials. Liver biopsy results, when available, showed hepatocyte necrosis with lymphocyte infiltration. In Study 1, fatal hepatic failure occurred in 1.6% of patients in the regorafenib arm and in 0.4% of patients in the placebo arm; all the patients with hepatic failure had metastatic disease in the liver. In Study 2, fatal hepatic failure occurred in 0.8% of patients in the regorafenib arm [see Adverse Reactions (6.1)].Obtain liver function tests (ALT, AST and bilirubin) before initiation of Stivarga and monitor at least every two 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 ULN or baseline.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 [see Dosage and Administration (2.2)].5.2 HemorrhageStivarga caused an increased incidence of hemorrhage. The overall incidence (Grades 1-5) was 21% and 11% in Stivargatreated patients compared to 8% and 3% in placebo-treated patients in Studies 1 and 2. Fatal hemorrhage occurred in 4 of 632 (0.6%) of Stivarga-treated patients in Studies 1 and 2 and involved the respiratory, gastrointestinal, or genitourinary tracts.Permanently discontinue Stivarga in patients with severe or life-threatening hemorrhage. Monitor INR levels more frequently in patients receiving warfarin [see Clinical Pharmacology (12.3)].5.3 Dermatological ToxicityStivarga caused increased incidences of adverse reactions involving the skin and subcutaneous tissues (72% versus 24% in Study 1 and 78% versus 24% in Study 2), including hand-foot skin reaction (HFSR) also known as palmar-plantar erythrodysesthesia (PPE), and severe rash requiring dose modification.The overall incidence of HFSR was higher in Stivarga-treated patients, (45% versus 7% in Study 1 and 67% versus 12% in Study 2), than in the placebo-treated patients. Most cases of HFSR in Stivarga-treated patients appeared during the first cycle of treatment (69% and 71% of patients who developed HFSR in Study 1 and Study 2, respectively). The incidence of Grade 3 HFSR (17% versus 0% in Study 1 and 22% versus 0% in Study 2), Grade 3 rash (6% versus <1% in Study 1 and 7% versus 0% in Study 2), serious adverse reactions of erythema multiforme (0.2% vs. 0% in Study 1) and Stevens Johnson Syndrome (0.2% vs. 0% in Study 1) was higher in Stivarga-treated patients [see Adverse Reactions (6.1)].Toxic epidermal necrolysis occurred in 0.17% of 1200 Stivarga-treated patients across all clinical trials.Withhold Stivarga, reduce the dose, or permanently discontinue Stivarga depending on the severity and persistence of dermatologic toxicity [see Dosage and Administration (2.2)]. Institute supportive measures for symptomatic relief.5.4 HypertensionStivarga caused an increased incidence of hypertension (30% versus 8% in Study 1 and 59% versus 27% in Study 2) [see Adverse Reactions (6.1)]. Hypertensive crisis occurred in 0.25% of 1200 Stivarga-treated patients across all clinical trials. The onset of hypertension occurred during the first cycle of treatment in most patients who developed hypertension (72% in Study 1 and Study 2).Do not initiate Stivarga unless 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 [see Dosage and Administration (2.2)].5.5 Cardiac Ischemia and InfarctionStivarga increased the incidence of myocardial ischemia and infarction in Study 1 (1.2% versus 0.4%) [see Adverse Reactions (6.1)]. Withhold Stivarga in patients who develop new or acute onset cardiac ischemia or infarction. Resume Stivarga only after resolution of acute cardiac ischemic events, if the potential benefits outweigh the risks of further cardiac ischemia.5.6 Reversible Posterior Leukoencephalopathy Syndrome (RPLS)Reversible Posterior Leukoencephalopathy Syndrome (RPLS), a syndrome of subcortical vasogenic edema diagnosed by characteristic finding on MRI, occurred in one of 1200 Stivarga-treated patients across all clinical trials. Perform an evaluation for RPLS in any patient presenting with seizures, headache, visual disturbances, confusion or altered mental function. Discontinue Stivarga in patients who develop RPLS.5.7 Gastrointestinal Perforation or FistulaGastrointestinal perforation or fistula occurred in 0.6% of 1200 patients treated with Stivarga across all clinical trials; this included four fatal events. In Study 2, 2.1% (4/188) of Stivarga-treated patients who were treated during the blinded or open-label portion of the study developed gastrointestinal fistula or perforation; of these, two cases of gastrointestinal perforation were fatal. Permanently discontinue Stivarga in patients who develop gastrointestinal perforation or fistula.5.8 Wound Healing ComplicationsNo formal studies of the effect of regorafenib on wound healing have been conducted. Since vascular endothelial growth factor receptor (VEGFR) inhibitors such as regorafenib can impair wound healing, treatment with regorafenib 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. Regorafenib should be discontinued in patients with wound dehiscence. 5.9 Embryo-Fetal ToxicityStivarga can cause fetal harm when administered to a pregnant woman. Regorafenib was embryolethal and teratogenic in rats and rabbits at exposures lower than human exposures at the recommended dose, with increased incidences of cardiovascular, genitourinary, and skeletal malformations. 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 a fetus [see Use in Specific Populations (8.1)].6 ADVERSE REACTIONSThe following serious adverse reactions are discussed elsewhere in the labeling:∙Hepatotoxicity [See Warnings and Precautions (5.1)]∙Hemorrhage [See Warnings and Precautions (5.2)]∙Dermatological Toxicity [See Warnings and Precautions (5.3)]∙Hypertension [See Warnings and Precautions (5.4)]∙Cardiac Ischemia and Infarction [See Warnings and Precautions (5.5)]∙Reversible Posterior Leukoencephalopathy Syndrome (RPLS) [See Warnings and Precautions (5.6)]∙Gastrointestinal Perforation or Fistula [See Warnings and Precautions (5.7)]Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rate observed in practice.The most frequently observed adverse drug reactions (≥20%) in patients receiving Stivarga are asthenia/fatigue, HFSR, diarrhea, decreased appetite/food intake, hypertension, mucositis, dysphonia, infection, pain (not otherwise specified), decreased weight, gastrointestinal and abdominal pain, rash, fever, and nausea.The most serious adverse drug reactions in patients receiving Stivarga are hepatotoxicity, hemorrhage, and gastrointestinal perforation.6.1 Clinical Trials ExperienceColorectal CancerThe safety data described below, except where noted, are derived from a randomized (2:1), double-blind, placebo-controlled trial (Study 1) in which 500 patients (median age 61 years; 61% men) with previously-treated metastatic colorectal cancer received Stivarga as a single agent at the dose of 160 mg daily for the first 3 weeks of each 4 week treatment cycle and 253 patients (median age 61 years; 60% men) received placebo. The median duration of therapy was 7.3 (range 0.3, 47.0) weeks for patients receiving Stivarga. Due to adverse reactions, 61% of the patients receiving Stivarga required a dose interruption and 38% of the patients had their dose reduced. Drug-related adverse reactions that resulted in treatment discontinuation were reported in 8.2% of Stivarga-treated patients compared to 1.2% of patients whoreceived placebo. Hand-foot skin reaction (HFSR) and rash were the most common reasons for permanent discontinuation of Stivarga.Table 1 compares the incidence of adverse reactions (≥10%) in patients receiving Stivarga and reported more commonly than in patients receiving placebo (Study 1).Table 1 Adverse drug reactions (≥10%) reported in patients treated with Stivarga in Study 1 and reported more commonly than in patients receiving placeboAdverse ReactionsStivarga(N=500)Placebo(N=253) Grade GradeAll%≥ 3%All%≥ 3%General disorders and administration site conditionsAsthenia/fatigue PainFever 642928153246211592Metabolism and nutrition disordersDecreased appetite and food intake 47 5 28 4Skin and subcutaneous tissue disorders HFSR/PPERash a 452617674<1Gastrointestinal disorders DiarrheaMucositis 4333841752InvestigationsWeight loss 32 <1 10 0 Infections and infestationsInfection 31 9 17 6 Vascular disordersHypertension Hemorrhage b 30218288<1<1Respiratory, thoracic and mediastinaldisordersDysphonia 30 0 6 0Nervous system disordersHeadache 10<170 amaculo-papular rash, papular rash, and pruritic rash.b Fatal outcomes observed.Laboratory AbnormalitiesLaboratory abnormalities observed in Study 1 are shown in Table 2. Table 2 Laboratory test abnormalities reported in Study 1 Laboratory Parameter Stivarga (N=500 a) Placebo(N=253 a )Grade b Grade b All %3 %4 %All %3 %4 %Blood and lymphatic systemdisordersAnemia 79 5 1 66 3 0Thrombocytopenia 41 2 <1 17 <1 0 Neutropenia 3 1 0 0 0 0 Lymphopenia 54 9 0 34 3 0 Metabolism and nutrition disorders Hypocalcemia 59 1 <1 18 1 0 Hypokalemia 26 4 0 8 <1 0 Hyponatremia30 7 1 22 4 0 Hypophosphatemia 57 31 1 11 4 0 Hepatobiliary disordersHyperbilirubinemia 45 10 3 17 5 3 Increased AST 65 5 1 46 4 1 Increased ALT 45 5 1 30 3 <1 Renal and urinary disordersProteinuria 60 <1 0 34 <1 0 InvestigationsIncreased INR c24 4 N/A 17 2 N/AIncreased Lipase 46 9 2 19 3 2Increased Amylase 26 2 <1 17 2 <1 a% based on number of patients with post-baseline samples which may be less than 500 (regorafenib) or 253 (placebo). bCommon Terminology Criteria for Adverse Events (CTCAE), v3.0. cInternational normalized ratio: No Grade 4 denoted in CTCAE, v3.0. Gastrointestinal Stromal TumorsThe safety data described below are derived from a randomized (2:1), double-blind, placebo-controlled trial (Study 2) in which 132 patients (median age 60 years; 64% men) with previously-treated GIST received Stivarga as a single agent at a dose of 160 mg daily for the first 3 weeks of each 4 week treatment cycle and 66 patients (median age 61 years; 64% men) received placebo. The median duration of therapy was 22.9 (range 0.1, 50.9) weeks for patients receiving Stivarga. Dose interruptions for adverse events were required in 58% of patients receiving Stivarga and 50% of patients had their dose reduced. Drug-related adverse reactions that resulted in treatment discontinuation were reported in 2.3% of Stivargatreated patients compared to 1.5% of patients who received placebo.Table 3 compares the incidence of adverse reactions (≥10%) in GIST patients receiving Stivarga and reported more commonly than in patients receiving placebo (Study 2).Table 3 Adverse reactions (≥10%) reported in patients treated with Stivarga in Study 2 and reported more commonly than in patients receiving placeboAdverse ReactionsStivarga(N=132)Placebo(N=66)Grade Grade All%≥ 3%All%≥ 3%Skin and subcutaneous tissue disordersHFSR/PPE Rash a Alopecia 673024227212322General disorders and administration site conditionsAsthenia/Fatigue Fever 52214391122Vascular disordersHypertension Hemorrhage 59112842735Gastrointestinal disordersDiarrhea Mucositis Nausea Vomiting 47402017822<19812822Respiratory, thoracic and mediastinaldisordersDysphonia 3990 Infections and infestationsInfection 32550 Metabolism and nutrition disordersDecreased appetite and food intake Hypothyroidism b 3118<12163Nervous system disordersHeadache 1690 InvestigationsWeight loss 14 0 8 0Musculoskeletal and connective tissuedisordersMusculoskeletal stiffness 14 0 3 0a The term rash represents reports of events of rash, erythematous rash, macular rash, maculo-papular rash, papular rashand pruritic rash.b Hypothyroidism incidence based on subset of patients with normal TSH and no thyroid supplementation at baseline.Laboratory AbnormalitiesLaboratory abnormalities observed in Study 2 are shown in Table 4. Table 4 Laboratory test abnormalities reported in Study 2Laboratory ParameterStivarga(N=132 a)Placebo(N=66 a)Grade b Grade bAll%3%4%All%3%4%Blood and lymphaticsystem disordersThrombocytopenia 13 1 0 2 0 2 Neutropenia 16 2 0 12 3 0 Lymphopenia 30 8 0 24 3 0 Metabolism and nutritiondisordersHypocalcemia 17 2 0 5 0 0 Hypokalemia 21 3 0 3 0 0 Hypophosphatemia 55 20 2 3 2 0 Hepatobiliary disordersHyperbilirubinemia 33 3 1 12 2 0Increased AST 58 3 1 47 3 0Increased ALT 39 4 1 39 2 0Renal and urinarydisordersProteinuria 333-c 30 3 -c InvestigationsIncreasedLipase 14 0 1 5 0 0ab CTCAE, v4.0.c No Grade 4 denoted in CTCAE, v4.0.6.2 Postmarketing ExperienceThe following adverse reaction has been identified during postapproval use of Stivarga. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure:hypersensitivity reaction7 DRUG INTERACTIONS7.1 Effect of Strong CYP3A4 Inducers on RegorafenibCo-administration of a strong CYP3A4 inducer (rifampin) with a single 160 mg dose of Stivarga decreased the mean exposure of regorafenib, increased the mean exposure of the active metabolite M-5, and resulted in no change in the mean exposure of the active metabolite M-2. Avoid concomitant use of Stivarga with strong CYP3A4 inducers (e.g. rifampin, phenytoin, carbamazepine, phenobarbital, and St. John’s Wort) [see Clinical Pharmacology (12.3)].7.2 Effect of Strong CYP3A4 Inhibitors on RegorafenibCo-administration of a strong CYP3A4 inhibitor (ketoconazole) with a single 160 mg dose of Stivarga increased the mean exposure of regorafenib and decreased the mean exposure of the active metabolites M-2 and M-5. Avoid concomitant use of Stivarga with strong inhibitors of CYP3A4 activity (e.g. clarithromycin, grapefruit juice, itraconazole, ketoconazole, nefazodone, posaconazole, telithromycin, and voriconazole) [see Clinical Pharmacology (12.3)].8 USE IN SPECIFIC POPULATIONS8.1 PregnancyPregnancy Category D [see Warnings and Precautions (5.9)]Risk SummaryBased on its mechanism of action, Stivarga can cause fetal harm when administered to a pregnant woman. There are no adequate and well-controlled studies with Stivarga in pregnant women. Regorafenib was embryolethal and teratogenic in rats and rabbits at exposures lower than human exposures at the recommended dose, with increased incidences of cardiovascular, genitourinary, and skeletal malformations. 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 a fetus.Animal DataIn embryo-fetal development studies, a total loss of pregnancy (100% resorption of litter) was observed in rats at doses as low as 1 mg/kg (approximately 6% of the recommended human dose, based on body surface area) and in rabbits at doses as low as 1.6 mg/kg (approximately 25% of the human exposure at the clinically recommended dose measured by AUC).In a single dose distribution study in pregnant rats, there was increased penetration of regorafenib across the blood-brain barrier in fetuses compared to dams. In a repeat dose study with daily administration of regorafenib to pregnant rats during organogenesis, findings included delayed ossification in fetuses at doses > 0.8 mg/kg (approximately 5% of the recommended human dose based on body surface area) with dose-dependent increases in skeletal malformations including cleft palate and enlarged fontanelle at doses ≥ 1 mg/kg (approximately 10% of the clinical exposure based on AUC). At doses ≥ 1.6 mg/kg (approximately 11% of the recommended human dose based on body surface area), there were dose-dependent increases in the incidence of cardiovascular malformations, external abnormalities, diaphragmatic hernia, and dilation of the renal pelvis.In pregnant rabbits administered regorafenib daily during organogenesis, there were findings of ventricular septal defects evident at the lowest tested dose of 0.4 mg/kg (approximately 7% of the AUC in patients at the recommended dose). At doses of ≥ 0.8 mg/kg (approximately 15% of the human exposure at the recommended human dose based on AUC), administration of regorafenib resulted in dose-dependent increases in the incidence of additional cardiovascular malformations and skeletal anomalies as well as significant adverse effects on the urinary system including missing kidney/ureter; small, deformed and malpositioned kidney; and hydronephrosis. The proportion of viable fetuses that were male decreased with increasing dose in two rabbit embryo-fetal toxicity studies.8.3 Nursing MothersIt is unknown whether regorafenib or its metabolites are excreted in human milk. In rats, regorafenib and its metabolites are excreted in milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Stivarga, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.8.4 Pediatric UseThe safety and efficacy of Stivarga in pediatric patients less than 18 years of age have not been established.In 28-day repeat dose studies in rats there were dose-dependent findings of dentin alteration and angiectasis. These findings were observed at regorafenib doses as low as 4 mg/kg (approximately 25% of the AUC in humans at the recommended dose). In 13-week repeat dose studies in dogs there were similar findings of dentin alteration at doses as low as 20 mg/kg (approximately 43% of the AUC in humans at the recommended dose). Administration of regorafenib in these animals also led to persistent growth and thickening of the femoral epiphyseal growth plate.8.5 Geriatric UseOf the 632 Stivarga-treated patients enrolled in Studies 1 and 2, 37% were 65 years of age and over, while 8% were 75 and over. No overall differences in safety or efficacy were observed between these patients and younger patients.8.6 Hepatic ImpairmentStivarga is eliminated mainly via the hepatic route. No clinically important differences in the mean exposure of regorafenib or the active metabolites M-2 and M-5 were observed in patients with hepatocellular carcinoma and mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic impairment compared to patients with normal hepatic function [see Clinical Pharmacology (12.3)]. No dose adjustment is recommended in patients with mild or moderate hepatic impairment. Closely monitor patients with hepatic impairment for adverse reactions [see Warnings and Precautions (5.1)].Stivarga is not recommended for use in patients with severe hepatic impairment (Child-Pugh Class C), as it has not been studied in this population.8.7 Renal ImpairmentNo clinically relevant differences in the mean exposure of regorafenib and the active metabolites M-2 and M-5 were observed in patients with mild renal impairment (CLcr 60-89 mL/min) compared to patients with normal renal function following regorafenib 160 mg daily for 21 days [see Clinical Pharmacology (12.3)]. No dose adjustment is recommended for patients with mild renal impairment. Limited pharmacokinetic data are available from patients with moderate renal impairment (CLcr 30-59 mL/min). Stivarga has not been studied in patients with severe renal impairment or end-stage renal disease.8.8 Females and Males of Reproductive PotentialContraceptionUse effective contraception during treatment and up to 2 months after completion of therapy.InfertilityThere are no data on the effect of Stivarga on human fertility. Results from animal studies indicate that regorafenib can impair male and female fertility [see Nonclinical Toxicology (13.1)].10 OVERDOSAGEThe highest dose of Stivarga studied clinically is 220 mg per day. In the event of suspected overdose, interrupt Stivarga, institute supportive care, and observe until clinical stabilization.。

瑞戈非尼中文说明书

瑞戈非尼中文说明书瑞戈非尼中文说明书警告：肝毒性·在既往临床研究中报道有严重甚至致命的肝毒性[见警告和注意事项（5.1）]·治疗前和治疗过程中需要监测肝功能[见警告和注意事项（5.1）] ·当肝功能监测发现肝酶升高或肝细胞坏死时，应中止治疗，根据肝功能损失的严重程度和持续时间评估后续是否需要减量或停止拜万戈治疗[见剂量和用法（2.2）]1 适应症和用法1.1 结直肠癌拜万戈获批用于治疗既往接受过氟尿嘧啶、奥沙利铂和伊立替康为基础的化疗，以及既往接受过或不适合接受抗VEGF治疗、抗EGFR 治疗（RAS野生型）的转移性结直肠癌患者。

1.2 胃肠间质瘤拜万戈获批用于治疗既往接受过甲磺酸伊马替尼及苹果酸舒尼替尼治疗的局部晚期的、无法手术切除的或转移性的胃肠间质瘤患者。

1.3 肝癌拜万戈获批用于治疗既往接受过索拉非尼治疗的肝细胞肝癌。

2 用法和用量2.1 推荐剂量推荐服用拜万戈的剂量为160mg（4x40mg），口服，1日1次，28天为1个周期，每个周期的第1-21天服药。

持续治疗直至患者出现疾病进展或不可耐受的毒性反应。

在每天同一时间段服药拜万戈。

在低脂饮食（热量低于600卡路里，脂肪含量<30%）后服用[见临床药理学（12.3）]，以温开水送服。

若前1天漏服，第2天无需补服前1天的药量。

2.2 剂量调整如果需要调整剂量，每次减量40mg（1片）；推荐的拜万戈每日最低剂量为80mg。

出现以下情况时需中止拜万戈治疗：· 再次出现2度的手足皮肤反应（HFSR）[手足综合症（PPES）]或调整剂量后一周内HFSR无缓解；3度的HFSR需要停药至少7天· 有症状的2度高血压· 3-4度的任意不良反应· 任意级别的感染加重出现以下情况时拜万戈需减量至120mg：· 首次出现2度HRSF，无论时间长短· 除感染以为的其他3-4度不良反应恢复后· 3度的天冬氨酸转氨酶（AST）／丙氨酸转氨酶（ALT）升高，仅当潜在获益超过肝脏毒性的风险时才考虑继续原来的用药剂量出现以下情况时拜万戈需减量至80mg：· 在120mg剂量时，再次出现2度HFSR· 在120mg剂量时，任意3-4度不良反应恢复后（肝脏毒性或感染除外）出现以下情况时需终止拜万戈治疗：· 不能耐受80mg剂量· AST或ALT升高超过正常上限（ULN）的20倍· AST或ALT升高超过ULN的3倍且同时伴有胆红素超过ULN2倍· 在减量至120mg剂量时，再次出现AST或ALT升高超过ULN 的5倍· 任意的4度不良反应；仅当潜在获益超过风险时才考虑继续用药3 剂型和优势瑞戈非尼为40mg，淡红色，椭圆形，薄膜包衣片剂，药片两侧分别印有‘BAYER’和‘40’。

瑞格菲尼中文说明书

【药物名】Regorafenib【商品名】Stivarga【通用名】瑞格非尼【初次获批时间】2012年【类别】小分子抑制剂【靶点】VEGFR【分子结构】分子式：C21H15ClF4N4O3•H2O分子量为：500.83【生产公司】拜耳医疗保健制药有限公司【适应症】 Stivarga 是一种激酶抑制剂适用于既往曾用基于氟嘧啶、奥沙利铂和伊立替康化疗方案(抗VEGF疗法)以及如果是KRAS野生型(抗EGFR 疗法)的转移结肠直肠癌(CRC)患者的治疗。

Stivarga还可以用于治疗曾接受甲磺酸伊马替尼和苹果酸舒尼替治疗的局部晚期、不可移除的或转移性胃肠道间质瘤患者的治疗。

【剂量和药物管理】推荐剂量： 28天为一个周期，每个周期的前21天，每天一次性口服160毫克Regorafenib。

持续治疗直到出现疾病进展或不可耐受的药物毒性。

每天的同一时间服药，用药前用低脂餐（热量少于60卡路里，脂肪少于30%）。

不要再同一天服用两剂Stivarga。

剂量调整：出现以下情况，中断用药：出现2级的手足皮肤反应，且反复发作，即使减少用药量也无法在7天内缓解。

若出现3级的手足皮肤反应，至少停药7天；出现症状的2级高血压；3级或4级副反应。

将剂量减少到120毫克： 2级的手足皮肤反应首次复发；3级或4级副反应缓解后；3级天冬氨酸转氨酶（AST）/丙氨酸转氨酶(ALT)升高，且用药获益大于潜在风险。

将剂量减少到80毫克： 120毫克剂量时，2级的手足皮肤反应复发；120毫克时，3级或4级副反应恢复后；永久停药：无法耐受80毫克剂量；AST或ALT超过20倍的正常上限值；AST或ALT超过3倍的正常上限值，伴随着胆红素超过2倍的正常上限值；剂量减少到120毫克后，AST或ALT超过5倍的正常上限值；任何4级不良反应。

【剂型和规格】40毫克、淡粉色、椭圆形、有薄膜包衣，两边分别写有“BAYER”和‘40’。

【禁忌症】无。

【警告和注意事项】（1）出血：对严重或威胁生命出血永久终止Stivarga。

欧盟委员会批准拜耳Stivarga(瑞戈非尼)用于治疗肝细胞癌

欧盟委员会批准拜耳Stivarga(瑞戈非尼)用于治疗肝细胞癌佚名
【期刊名称】《临床合理用药杂志》
【年(卷),期】2017(10)23
【摘要】拜耳制药表示,欧盟委员会已经批准了Stivarga（regorafenib,瑞戈非尼）用于之前接受了Nexavar（sorafenib-索拉非尼）一线治疗的肝细胞癌成人患者
治疗的上市许可。

Stivarga在欧洲的适应证包括：单药用于既往经当前可用疗法
治疗过或不适用于当前可用疗法（包括基于氟尿嘧啶的化疗,抗VEGF疗法、抗EGFR疗法）的转移性结直肠癌（mC RC）成人患者的治疗,该适应症已在包括中
国在内的90多个国家上市;
【总页数】1页(P132-132)
【正文语种】中文
【中图分类】R737.9
【相关文献】
1.针对“瑞戈非尼用于索拉非尼治疗后进展的肝细胞癌患者（RESORCE）：一项
随机、双盲、安慰剂对照Ⅲ期临床试验”导读2.瑞戈非尼为中国转移性结直肠癌
患者带来了新的希望瑞戈非尼加最佳支持治疗与安慰剂加最佳支持治疗用于亚洲经治转移性结直肠癌患者的对比（CONCUR）：随机、双盲、安慰剂对照、Ⅲ期试
验解读3.针对"瑞戈非尼用于索拉非尼治疗后进展的肝细胞癌患者(RESORCE):一项随机、双盲、安慰剂对照Ⅲ期临床试验"导读4.欧盟批准索拉非尼上市用于治疗肝
细胞癌5.瑞戈非尼(Stivarga)胃肠道间质瘤新药欧盟上市
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瑞戈非尼可用于治疗胃肠间质瘤

瑞戈非尼可用于治疗胃肠间质瘤*导读：胃肠间质瘤是一种具有高度侵袭性的癌症，其可能持续多年不被发现，且在诊断之时，大多数患者已进展至疾病的晚期。

在伊马替尼及舒尼替尼治疗后，生存率较低且治疗方法有限，瑞戈非尼已在包括美国及日本在内的多个国家以Stivarga 的商标名获得批准，用于治疗胃肠道间质瘤。

该产品同时在包括美国、欧洲及日本在内的全球60个国家被批准用于治疗转移性结直肠癌（mCRC）患者。

……记者从拜耳医药获悉，该公司生产的抗肿瘤药物Stivarga （瑞戈非尼）已被欧盟委员会（EC）批准用于治疗患有不可切除或转移性胃肠间质瘤（GIST）且在既往伊马替尼及苏尼替尼治疗后疾病进展或无法耐受的成年患者。

Stivarga被批准用于治疗胃肠间质瘤依据的是关键性III期研究（GRID）的结果，这项研究在既往治疗后疾病进展的胃肠间质瘤患者中证明了在无进展生存期（PFS）方面与安慰剂相比的统计上显著的改善。

“继Stivarga在包括美国和日本在内的全球多个国家获批用于治疗胃肠道间质瘤之后，我们很高兴能为欧洲的患者提供治疗这一罕见而恶性癌症的新选择，”拜耳医药保健执行委员会成员及全球研发总监Joerg Moeller博士如是说，“在拜耳，我们致力于为不同的肿瘤类型探索解决方案，并推动创新以满足医师及患者未满足的需求。

”“胃肠间质瘤是一种具有高度侵袭性的癌症，其可能持续多年不被发现，且在诊断之时，大多数患者已进展至疾病的晚期。

在伊马替尼及舒尼替尼治疗后，生存率较低且治疗方法有限，”GRID研究者、克洛德贝纳尔-里昂第一大学（法国里昂）里昂贝纳尔中心内科肿瘤学医学教授及内科肿瘤系主任JeanYves-Blay如是说，“III期GRID试验证明了使用瑞戈非尼的无进展生存期是使用安慰剂的五倍以上。

”瑞戈非尼已在包括美国及日本在内的多个国家以Stivarga 的商标名获得批准，用于治疗胃肠道间质瘤。

该产品同时在包括美国、欧洲及日本在内的全球60个国家被批准用于治疗转移性结直肠癌（mCRC）患者。

小分子抑制剂瑞戈非尼的药理和临床概述

小分子抑制剂瑞戈非尼的药理和临床概述王明森;刘正平;侯良玉;张菊红;张建强【摘要】Pharmacology,pharmacokinetics,clinical study and safety of regorafenib in the treatment of colorectal cancer and gastrointestinal stromal tumors were reviewed in the paper. The main refeience to foreign - related registration and clini-cal data of regorafenib. Clinical trials showed the Overall Survival(OS)and Progression - Free - Survival(PFS)was sig-nificantly increased in patients treated with regorafenib. The most serious adverse drug reactions in patients receiving Stivar-ga were severe liver injury,haemorrhage and gastrointestinal perforation. The most frequently observed adverse drug reactions (≥30% )in patients receiving Stivarga were asthenia/ fatigue,decreased appetite and food intake,hand foot skin reaction, diarrhoea,weight loss,hypertension and dysphonia.%本文综述了瑞戈非尼治疗结肠直肠癌和胃肠道间质瘤的药理、药动学、临床研究和安全性信息。

瑞戈非尼使用说明书

Stivarga瑞戈非尼使用说明书2013 年 2 月 25日，美国食品药品管理局（FDA ）批准 Stivarga(regorafenib，瑞格菲尼 )新适应症，用于不能通过手术切除以及使用其它已上市药物治疗无效的晚期胃肠道间质瘤 (GIST) 患者治疗。

临床试验数据Stivarga 是一种多激酶抑制剂，可以阻断几种促进肿瘤生长的酶。

Stivarga新适应症的安全性和有效性通过一项199名胃肠道间质瘤患者参与的临床试验得到评价，该199名患者的胃肠道间质瘤不能通过手术切除，并且使用格列卫或索坦治疗后病情仍有进展。

试验中，患者被随机配给Stivarga或安慰剂。

同时所有患者也接受最佳的支持治疗，包括对副作用及癌症症状的管理治疗。

试验研究中，患者要等到癌症进展或者副作用无法接受时开始使用Stivarga或安慰剂。

结果显示，接受Stivarga治疗的患者与接受安慰剂治疗的患者相比，肿瘤增长平均延期 3.9个月。

试验中，使用安慰剂的患者在其癌症进展后获得了转换成Stivarga治疗的机会。

处方重点资料【适应症】Stivarga是一种激酶抑制剂，适用于不能通过手术切除以及使用其它已上市药物治疗无效的晚期胃肠道间质瘤(GIST) 患者治疗。

【规格】40mg，28片/盒。

【用法用量】(1)推荐剂量： 160mg 口服。

每天 1 次每 28 天疗程的头 21 天。

(2)与食物服用 Stivarga( 一种低脂肪早餐 )。

【如何购买】美国是医药分开的国家，销售，必须凭美国医生（电子医疗平台实现远程的病历交互，药房全部实行严格的处方药与非处方药分类管理。

对处方药的/ 纸质）处方。

如今国内患者可以依托科技，通过好医友国际由美国医生根据患者病情开具电子处方，以正规渠道在好医友美国药房购买到处方药。

【不良反应】最常见不良反应( ≥30%)是乏力 / 疲乏、减低食欲和食物摄入量、手足皮肤反应(HFSR)、腹泻、口腔粘膜炎、体重减轻、感染、高血压和发音困难。

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瑞格菲尼说明书
YKK standardization office【 YKK5AB- YKK08- YKK2C- YKK18】
瑞格菲尼说明书
商品名称:Stivarga通用名称:
瑞戈非尼片英文名称:regorafenib汉语拼音:Ruigefeinipian
【产品价格】40mg×28片×3瓶
【适应症】Stivarga是一种激酶抑制剂适用于既往曾用基于氟嘧啶，奥沙利铂-和伊立替康化疗，一种抗-VEGF治疗，和，如KRAS野生型，一种抗-EGFR治疗过的转移结肠直肠癌(CRC)患者的治疗。

【用法用量】（1）推荐剂量：160?mg口服，每天1次每28天疗程的头21天。

（2）与食物服用Stivarga(一种低脂肪早餐)。

【不良反应】最常见不良反应(≥30%)是乏力/疲乏，减低食欲和食物摄入量，手足皮肤反应(HFSR)
[掌足红肿(PPE)]，腹泻，口腔粘膜炎，体重减轻，感染，高血压，和发音困难。

【注意事项】
（1）出血：对严重或威胁生命出血永久终止Stivarga。

（2）皮肤学毒性：瑞格非尼片价格中断和然后减低或终止Stivarga取决于皮肤学毒性的严重程度和持久性。

（3）高血压：对严重或不能控制的高血压暂时或永久终止Stivarga
（4）心脏缺血和梗死：拒给Stivarga对新或急性心脏缺血/梗死和只有急性缺血事件解决后恢复。

（5）可逆性后部白质脑病综合征(RPLS)：终止Stivarga。

（6）胃肠道穿孔或瘘管：终止Stivarga。

（7）伤口愈合并发症：瑞格非尼片哪里卖术前停止Stivarga。

在伤口裂开患者中终止。

（8）胚胎胎儿毒性：可能致胎儿危害。

劝告妇女对胎儿潜在风险。

【规格】40mg，28片/盒。

【贮藏】遮光，密封保存。

【生产企业】德国拜耳医药公司。