抗癌口服药STIVARGA(REGORAFENIB)TABLET ORAL获美国及欧盟等全球多个国家批准用于治疗胃肠道间质瘤，结直肠癌 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。 胃肠道间质瘤的癌症细胞在人体消化系统的胃肠道组织内形成。根据美国国家癌症中心的信息，美国每年估计有3300人到6000人的胃肠道间质瘤新病例，且大多数患者为老年人。 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 新适应症的获批，可以使该产品用于胃肠道间质瘤不能通过手术切除或者肿瘤已扩散到身体其它部位的患者，也可用于 FDA 批准的其它两种药物格列卫（伊马替尼）及索坦治疗后不再有效的胃肠道间质瘤患者。 “Stivarga 是 FDA 批准的第三个用于治疗胃肠道间质瘤的药物，” FDA 药物评价和研究中心血液和肿瘤产品办公室主任Richard Pazdur医学博士说。“该产品给其它治疗药物无效的胃肠道间质瘤患者提供了一种新的治疗选择。” Stivarga是通过 FDA 优先审评程序获得批准的，通过优先审评程序，FDA 可以在6个月内完成药物的审评，优先审评程序一般针对那些可能为当下没有令人满意替代疗法的疾病提供安全、有效治疗的药物，或者与已上市药物相比，能使疾病得到明显改进的药物。该药物因用于治疗罕有疾病而同时获得孤儿药资格。 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。 Stivarga治疗患者常见的副作用有虚弱和乏力、手足综合征、腹泻、食欲不振、高血压、口腔溃疡、感染、声音或音调变化、疼痛、体重减轻、胃痛、皮疹、发烧及恶心。严重副作用发生率不到1%，包括肝损伤、严重出血、皮肤起水泡和脱皮、需要紧急处理的严重高血压、心脏病发作及肠道穿孔 (洞)。 Stivarga于2012年9月获得批准用于结直肠癌治疗。Stivarga由新泽西州韦恩的拜耳制药上市销售 HIGHLIGHTS OF PRESCRIBING INFORMATION These 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 use Initial U.S. Approval: 2012 WARNING: HEPATOTOXICITYSee full prescribing information for complete boxed warning. • Severe and sometimes fatal hepatotoxicity has occurred in clinical 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 hepatocellular necrosis, depending upon severity and persistence. (2.2) RECENT MAJOR CHANGES Indications and Usage, Colorectal Cancer ( 1.1) 6/2016 Warnings and Precautions, Hepatotoxicity ( 5.1) 6/2016 Warnings and Precautions, Dermatologic Toxicity ( 5.3) 6/2016 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 RAS-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 Tablets: 40 mg (3) CONTRAINDICATIONS None. (4) WARNINGS AND PRECAUTIONS • Hepatotoxicity: Monitor liver function tests and dose reduce or discontinue based on severity and duration. • Hemorrhage: Permanently discontinue Stivarga for severe or life-threatening hemorrhage. ( 5.2) • Dermatologic 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 fistula: Discontinue Stivarga. ( 5.7) • Wound healing complications: Stop Stivarga before surgery. Discontinue in patients with wound dehiscence. ( 5.8) • Embryo-fetal toxicity: Can cause fetal harm. Advise women of potential risk to a fetus and to use effective contraception during treatment and for 2 months after the final dose. Advise males to use effective contraception for 2 months after the final dose. ( 5.9, 8.1, 8.3) ADVERSE REACTIONS The most common adverse reactions (≥20%) are asthenia/fatigue, hand-foot skin reaction (HFSR), diarrhea, decreased appetite/food intake, hypertension, mucositis, dysphonia, infection, pain, 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 1-800-FDA-1088 or www.fda.gov/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: 6/2016 FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE 1.1 Colorectal Cancer 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. 1.2 Gastrointestinal Stromal Tumors 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. 2 DOSAGE AND ADMINISTRATION 2.1 Recommended Dose The recommended dose is 160 mg Stivarga (four 40 mg tablets) taken orally once daily for the first 21 days of each 28-day 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 Modifications Interrupt Stivarga for the following: • 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 Grade 3 or 4 adverse reaction. Reduce 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 hepatotoxicity Reduce 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 risks 3 DOSAGE FORMS AND STRENGTHS Stivarga is a 40 mg, light pink, oval-shaped, film-coated tablet, debossed with ‘BAYER’ on one side and ‘40’ on the other side. 4 CONTRAINDICATIONS None 5 WARNINGS AND PRECAUTIONS 5.1 Hepatotoxicity Severe drug-induced liver injury with fatal outcome occurred in Stivarga-treated patients in 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 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. 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) and Use in Specific Populations (8.6)]. 5.2 Hemorrhage Stivarga caused an increased incidence of hemorrhage. The overall incidence (Grades 1-5) was 21% and 11% in Stivarga-treated 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 Dermatologic Toxicity Stivarga increased the incidence 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)]. In both studies, a higher incidence of HFSR was observed in Asian patients treated with Stivarga (all grades: 78.4% in Study 1 and 88.2% in Study 2 and Grade 3: 28.4% in Study 1 and 23.5% in Study 2) [see Use in Specific Populations (8.8)]. 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 Hypertension Stivarga 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 Infarction Stivarga 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 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, severe headache, visual disturbances, confusion or altered mental function. Discontinue Stivarga in patients who develop RPLS. 5.7 Gastrointestinal Perforation or Fistula Gastrointestinal 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 Complications No 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, discontinue treatment with regorafenib 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. Discontinue regorafenib in patients with wound dehiscence. 5.9 Embryo-Fetal Toxicity Based on animal studies and its mechanism of action, Stivarga can cause fetal harm when administered to a pregnant woman. There are no available data on Stivarga use 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. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with Stivarga and for 2 months after the final dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with Stivarga and for 2 months after the final dose [see Use in Specific Populations (8.1), (8.3)]. 6 ADVERSE REACTIONS The 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, decreased weight, gastrointestinal and abdominal pain, rash, fever, and nausea. The most serious adverse reactions in patients receiving Stivarga are hepatotoxicity, hemorrhage, and gastrointestinal perforation. 6.1 Clinical Trials Experience Colorectal Cancer The 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. Adverse reactions that resulted in treatment discontinuation occurred in 8.2% of Stivarga-treated patients compared to 1.2% of patients who received 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 reported in ≥10% of patients treated with Stivarga in Study 1 and reported more commonly than in patients receiving placebo Adverse Reactions Stivarga (N=500) Placebo (N=253) Grade Grade All % ≥ 3 % All % ≥ 3 % General disorders and administration site conditions Asthenia/fatigue Pain Fever 64 29 28 15 3 2 46 21 15 9 2 0 Metabolism and nutrition disorders Decreased appetite and food intake 47 5 28 4 Skin and subcutaneous tissue disorders HFSR/PPE Rash 45 26 17 6 7 4 0 <1 Gastrointestinal disorders Diarrhea Mucositis 43 33 8 4 17 5 2 0 Investigations Weight loss 32 <1 10 0 Infections and infestations Infection 31 9 17 6 Vascular disorders Hypertension Hemorrhage ‡ 30 21 8 2 8 8 <1 <1 Respiratory, thoracic and mediastinal disorders Dysphonia 30 0 6 0 Nervous system disorders Headache 10 <1 7 0 Adverse reactions graded according to National Cancer Institute Common Toxicity for Adverse Events version 3.0 (NCI CTCAE v3.0). The term rash represents reports of events of drug eruption, rash, erythematous rash, generalized rash, macular rash, maculo-papular rash, papular rash, and pruritic rash. Fatal outcomes observed. Laboratory abnormalities observed in Study 1 are shown in Table Table 2: Laboratory test abnormalities reported in Study 1 Parameter Stivarga (N=500 *) Placebo (N=253 *) Grade † Grade † All % 3 % 4 % All % 3 % 4 %   Blood and lymphatic system disorders Anemia 79 5 1 66 3 0 Thrombocytopenia 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 Hyponatremia 30 7 1 22 4 0 Hypophosphatemia 57 31 1 11 4 0 Hepatobiliary disorders Hyperbilirubinemia 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 disorders Proteinuria 60 <1 0 34 <1 0 Investigations Increased INR ‡ 24 4 N/A 17 2 N/A Increased Lipase 46 9 2 19 3 2 Increased Amylase 26 2 <1 17 2 <1 % based on number of patients with post-baseline samples which may be less than 500 (regorafenib) or 253 (placebo). Common Terminology Criteria for Adverse Events (CTCAE), v3.0. International normalized ratio: No Grade 4 denoted in CTCAE, v3.0. Gastrointestinal Stromal Tumors The 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. Adverse reactions that resulted in treatment discontinuation were reported in 2.3% of Stivarga-treated 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 reported in ≥10% patients treated with Stivarga in Study 2 and reported more commonly than in patients receiving placebo Adverse Reactions Stivarga (N=132) Placebo (N=66) Grade Grade All % ≥ 3 % All % ≥ 3 % Skin and subcutaneous tissue disorders HFSR/PPE Rash Alopecia 67 30 24 22 7 2 12 3 2 2 0 0 General disorders and administration site conditions Asthenia/Fatigue Fever 52 21 4 0 39 11 2 2 Vascular disorders Hypertension Hemorrhage 59 11 28 4 27 3 5 0 Gastrointestinal disorders Diarrhea Mucositis Nausea Vomiting 47 40 20 17 8 2 2 <1 9 8 12 8 0 2 2 0 Respiratory, thoracic and mediastinal disorders Dysphonia 39 0 9 0 Infections and infestations Infection 32 5 5 0 Metabolism and nutrition disorders Decreased appetite and food intake Hypothyroidism  31 18 <1 0 21 6 3 0 Nervous system disorders Headache 16 0 9 0 Investigations Weight loss 14 0 8 0 Musculoskeletal and connective tissue disorders Musculoskeletal stiffness 14 0 3 0 Adverse reactions graded according to NCI CTCAE v4.0. The term rash represents reports of events of rash, erythematous rash, macular rash, maculo-papular rash, papular rash and pruritic rash. Hypothyroidism incidence based on subset of patients with normal TSH and no thyroid supplementation at baseline. Table 4: Laboratory test abnormalities reported in Study 2 Laboratory Parameter Stivarga (N=132) Placebo (N=66 ) Grade Grade All % 3 % 4 % All % 3 % 4 %   Blood and lymphatic system disorders Thrombocytopenia Neutropenia Lymphopenia 13 16 30 1 2 8 0 0 0 2 12 24 0 3 3 2 0 0 Metabolism and nutrition disorders Hypocalcemia Hypokalemia Hypophosphatemia 17 21 55 2 3 20 0 0 2 5 3 3 0 0 2 0 0 0 Hepatobiliary disorders Hyperbilirubinemia Increased AST Increased ALT 33 58 39 3 3 4 1 1 1 12 47 39 2 3 2 0 0 0 Renal and urinary disorders Proteinuria 33 3 - 30 3 -  Investigations Increased lipase 14 0 1 5 0 0 Percent based on number of patients with post-baseline samples which may be less than 132 (regorafenib) or 66 (placebo). NCI CTCAE v4.0. No Grade 4 denoted in NCI CTCAE v4.0. 6.2 Postmarketing Experience The 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 reaction  7 DRUG INTERACTIONS 7.1 Effect of Strong CYP3A4 Inducers on Regorafenib Co-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 Regorafenib Co-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 CYP3A4 inhibitors (e.g. clarithromycin, grapefruit juice, itraconazole, ketoconazole, nefazodone, posaconazole, telithromycin, and voriconazole) [see Clinical Pharmacology (12.3)]. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Based on animal studies and its mechanism of action, Stivarga can cause fetal harm when administered to a pregnant woman. There are no available data on Stivarga use in pregnant women. Administration of 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 [see Data]. Advise pregnant women of the potential hazard to a fetus. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4 % and 15 to 20%, respectively. Data Animal Data In 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. Daily administration of regorafenib to pregnant rats during organogenesis resulted in fetal findings of delayed ossification at doses > 0.8 mg/kg (approximately 5% of the recommended human dose based on body surface area) and 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. 8.2 Lactation Risk Summary There are no data on the presence of regorafenib or its metabolites in human milk, the effects of regorafenib on the breastfed infant, or on milk production. In rats, regorafenib and its metabolites are excreted in milk. 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. 8.3 Females and Males of Reproductive Potential Contraception Females Use effective contraception during treatment and for 2 months after completion of therapy. Males Advise male patients with female partners of reproductive potential to use effective contraception during treatment and for 2 months following the final dose of Stivarga [see Nonclinical Toxicology (13.1)]. Infertility There 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)]. 8.4 Pediatric Use The safety and efficacy of Stivarga in pediatric patients less than 18 years of age have not been established. Animal Data In 28-day repeat-dose studies in rats there were dose-dependent findings of dentin alteration and angiectasis. These findings occurred 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 Use Of 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 Impairment 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), since it has not been studied in this population. 8.7 Renal Impairment No 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 Race Based on pooled data from three placebo-controlled trials (Studies 1 and 2, and a study conducted in East Asia), a higher incidence of HFSR and liver function test abnormalities occurred in Asian patients treated with Stivarga as compared with Whites [see Warnings and Precautions (5.1, 5.3)]. No starting dose adjustment is necessary based on race. 10 OVERDOSAGE The highest dose of Stivarga studied clinically is 220 mg per day. The most frequently observed adverse drug reactions at this dose were dermatological events, dysphonia, diarrhea, mucosal inflammation, dry mouth, decreased appetite, hypertension, and fatigue. There is no known antidote for Stivarga overdose. In the event of suspected overdose, interrupt Stivarga, institute supportive care, and observe until clinical stabilization. 11 DESCRIPTION Stivarga (regorafenib) has the chemical name 4-[4-({[4-chloro-3-(trifluoromethyl) phenyl] carbamoyl} amino)-3-fluorophenoxy]-N-methylpyridine-2-carboxamide monohydrate. Regorafenib has the following structural formula: Regorafenib is a monohydrate and it has a molecular formula C21H15ClF4N4O3 • H2O and a molecular weight of 500.83. Regorafenib is practically insoluble in water, slightly soluble in acetonitrile, methanol, ethanol, and ethyl acetate and sparingly soluble in acetone. Stivarga tablets for oral administration are formulated as light pink, oval-shaped tablets debossed with "BAYER" on one side and "40" on the other. Each tablet contains 40 mg of regorafenib in the anhydrous state, which corresponds to 41.49 mg of regorafenib monohydrate, and the following inactive ingredients: cellulose microcrystalline, croscarmellose sodium, magnesium stearate, povidone, and colloidal silicon dioxide. The film-coating contains the following inactive ingredients: ferric oxide red, ferric oxide yellow, lecithin (soy), polyethylene glycol 3350, polyvinyl alcohol, talc, and titanium dioxide. 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Regorafenib is a small molecule inhibitor of multiple membrane-bound and intracellular kinases involved in normal cellular functions and in pathologic processes such as oncogenesis, tumor angiogenesis, and maintenance of the tumor microenvironment. In in vitro biochemical or cellular assays, regorafenib or its major human active metabolites M-2 and M-5 inhibited the activity of RET, VEGFR1, VEGFR2, VEGFR3, KIT, PDGFR-alpha, PDGFR-beta, FGFR1, FGFR2, TIE2, DDR2, TrkA, Eph2A, RAF-1, BRAF, BRAF V600E, SAPK2, PTK5, and Abl at concentrations of regorafenib that have been achieved clinically. In in vivo models, regorafenib demonstrated anti-angiogenic activity in a rat tumor model, and inhibition of tumor growth as well as anti-metastatic activity in several mouse xenograft models including some for human colorectal carcinoma. 12.2 Pharmacodynamics Cardiac Electrophysiology The effect of multiple doses of Stivarga (160 mg once daily for 21 days) on the QTc interval was evaluated in an open-label, single-arm study in 25 patients with advanced solid tumors. No large changes in the mean QTc interval (i.e., > 20 msec) were detected in the study. 12.3 Pharmacokinetics Absorption Following a single 160 mg dose of Stivarga in patients with advanced solid tumors, regorafenib reaches a geometric mean peak plasma level (Cmax) of 2.5 µg/mL at a median time of 4 hours and a geometric mean area under the plasma concentration vs. time curve (AUC) of 70.4 µg*h/mL. The AUC of regorafenib at steady-state increases less than dose proportionally at doses greater than 60 mg. At steady-state, regorafenib reaches a geometric mean Cmax of 3.9 µg/mL and a geometric mean AUC of 58.3 µg*h/mL. The coefficient of variation of AUC and Cmax is between 35% and 44%. The mean relative bioavailability of tablets compared to an oral solution is 69% to 83%. In a food-effect study, 24 healthy men received a single 160 mg dose of Stivarga on three separate occasions: under a fasted state, with a high-fat meal and with a low-fat meal. A high-fat meal (945 calories and 54.6 g fat) increased the mean AUC of regorafenib by 48% and decreased the mean AUC of the M-2 and M-5 metabolites by 20% and 51%, respectively, as compared to the fasted state. A low-fat meal (319 calories and 8.2 g fat) increased the mean AUC of regorafenib, M-2 and M-5 by 36%, 40% and 23%, respectively as compared to fasted conditions. Stivarga was administered with a low-fat meal in Studies 1 and 2 [see Dosage and Administration (2.1), Clinical Studies (14)]. Distribution Regorafenib undergoes enterohepatic circulation with multiple plasma concentration peaks observed across the 24-hour dosing interval. Regorafenib is highly bound (99.5%) to human plasma proteins. Elimination Following a single 160 mg oral dose of Stivarga, the geometric mean (minimum to maximum) elimination half-lives for regorafenib and the M-2 metabolite in plasma are 28 hours (14 to 58 hours) and 25 hours (14 to 32 hours), respectively. M-5 has a longer mean (minimum to maximum) elimination half-life of 51 hours (32 to 70 hours). Metabolism Regorafenib is metabolized by CYP3A4 and UGT1A9. The main circulating metabolites of regorafenib measured at steady-state in human plasma are M-2 (N-oxide) and M-5 (N-oxide and N-desmethyl). Both metabolites have similar in vitro pharmacological activity and steady-state concentrations as regorafenib. M-2 and M-5 are highly protein bound (99.8% and 99.95%, respectively). Excretion Approximately 71% of a radiolabeled dose was excreted in feces (47% as parent compound, 24% as metabolites) and 19% of the dose was excreted in urine (17% as glucuronides) within 12 days after administration of a radiolabeled oral solution at a dose of 120 mg. Specific Populations Age, sex, race and weight had no clinically meaningful effect on the pharmacokinetics of regorafenib. Hepatic Impairment The pharmacokinetics of regorafenib, M-2, and M-5 was evaluated in 14 patients with hepatocellular carcinoma (HCC) and mild hepatic impairment (Child-Pugh A); 4 patients with HCC and moderate hepatic impairment (Child-Pugh B); and 10 patients with solid tumors and normal hepatic function after the administration of a single 100 mg dose of Stivarga. No clinically important differences in the mean exposure of regorafenib, M-2, or M-5 were observed in patients with mild or moderate hepatic impairment compared to the patients with normal hepatic function. The pharmacokinetics of regorafenib has not been studied in patients with severe hepatic impairment (Child-Pugh C). Renal Impairment The pharmacokinetics of regorafenib, M-2, and M-5 was evaluated in 10 patients with mild renal impairment (CLcr 60-89 mL/min) and 18 patients with normal renal function following the administration of Stivarga at a dose of 160 mg daily for 21 days. No differences in the mean steady-state exposure of regorafenib, M-2, or M-5 were observed in patients with mild renal impairment compared to patients with normal renal function. Limited pharmacokinetic data were available from patients with moderate renal impairment (CLcr 30-59 mL/min). The pharmacokinetics of regorafenib has not been studied in patients with severe renal impairment or end-stage renal disease. Drug Interaction Studies Effect of Regorafenib on Cytochrome P450 Substrates: In vitro studies suggested that regorafenib is an inhibitor of CYP2C8, CYP2C9, CYP2B6, CYP3A4 and CYP2C19; M-2 is an inhibitor of CYP2C9, CYP2C8, CYP3A4 and CYP2D6, and M-5 is an inhibitor of CYP2C8. In vitrostudies suggested that regorafenib is not an inducer of CYP1A2, CYP2B6, CYP2C19, and CYP3A4 enzyme activity. Patients with advanced solid tumors received single oral doses of CYP substrates, 2 mg of midazolam (CYP3A4), 40 mg of omeprazole (CYP2C19) and 10 mg of warfarin (CYP2C9) or 4 mg of rosiglitazone (CYP2C8) one week before and two weeks after Stivarga at a dose of 160 mg once daily. No clinically meaningful effect was observed in the mean AUC of rosiglitazone (N=12) or the mean omeprazole (N=11) plasma concentrations measured 6 hours after dosing or the mean AUC of midazolam (N=15). The mean AUC of warfarin (N=8) increased by 25% [see Warnings and Precautions (5.2)]. Effect of CYP3A4 Strong Inducers on Regorafenib: Twenty-two healthy men received a single 160 mg dose of Stivarga alone and then 7 days after starting rifampin. Rifampin, a strong CYP3A4 inducer, was administered at a dose of 600 mg daily for 9 days. The mean AUC of regorafenib decreased by 50% and mean AUC of M-5 increased by 264%. No change in the mean AUC of M-2 was observed [see Drug Interactions (7.1)]. Effect of CYP3A4 Strong Inhibitors on Regorafenib: Eighteen healthy men received a single 160 mg dose of Stivarga alone and then 5 days after starting ketoconazole. Ketoconazole, a strong CYP3A4 inhibitor, was administered at a dose of 400 mg daily for 18 days. The mean AUC of regorafenib increased by 33% and the mean AUC of M-2 and M-5 both decreased by 93% [see Drug Interactions (7.2)]. Effect of Neomycin on Regorafenib: Twenty-seven healthy men received a single 160 mg dose of Stivarga and then 5 days after starting neomycin. Neomycin, a non-absorbable antibiotic, was administered at a dose of 1 gram three times daily for 5 days. No clinically meaningful effect on the mean AUC of regorafenib was observed; however, the mean AUC of M-2 decreased by 76% and the mean AUC of M-5 decreased by 86%. The decreased exposure of M-2 and M-5 may result in a decreased efficacy of Stivarga. The effects of other antibiotics on the exposure of regorafenib and its active metabolites have not been studied. Effect of Regorafenib on UGT1A1 Substrates: In vitro studies showed that regorafenib, M-2, and M-5 competitively inhibit UGT1A9 and UGT1A1 at therapeutically relevant concentrations. Eleven patients received irinotecan-containing combination chemotherapy with Stivarga at a dose of 160 mg. The mean AUC of irinotecan increased by 28% and the mean AUC of SN-38 increased by 44% when irinotecan was administered 5 days after the last of 7 daily doses of Stivarga. In vitro screening of transporters: In vitro data suggested that regorafenib, M-2, and M-5 are inhibitors of breast cancer resistance protein (BCRP) and that regorafenib and M-2 are inhibitors of multidrug resistance protein 1 (MDR1). 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Studies examining the carcinogenic potential of regorafenib have not been conducted. Regorafenib itself did not demonstrate genotoxicity inin vitro or in vivo assays; however, a major human active metabolite of regorafenib, (M-2), was positive for clastogenicity, causing chromosome aberration in Chinese hamster V79 cells. Dedicated studies to examine the effects of regorafenib on fertility have not been conducted; however, there were histological findings of tubular atrophy and degeneration in the testes, atrophy in the seminal vesicle, and cellular debris and oligospermia in the epididymides in male rats at doses similar to those in human at the clinical recommended dose based on AUC. In female rats, there were increased findings of necrotic corpora lutea in the ovaries at the same exposures. There were similar findings in dogs of both sexes in repeat dose studies at exposures approximately 83% of the human exposure at the recommended human dose based on AUC. These findings suggest that regorafenib may adversely affect fertility in humans. 13.2 Animal Toxicology and/or Pharmacology In a chronic 26-week repeat dose study in rats there was a dose-dependent increase in the finding of thickening of the atrioventricular valve. At a dose that resulted in an exposure of approximately 12% of the human exposure at the recommended dose, this finding was present in half of the examined animals. 14 CLINICAL STUDIES 14.1 Colorectal Cancer The clinical efficacy and safety of Stivarga were evaluated in an international, multicenter, randomized (2:1), double-blind, placebo-controlled trial (Study 1) in 760 patients with previously-treated metastatic colorectal cancer. The major efficacy outcome measure was overall survival (OS); additional efficacy outcome measures included progression-free survival (PFS) and objective tumor response rate. Patients were randomized to receive 160 mg regorafenib orally once daily (N=505) plus best supportive care (BSC) or placebo (N=255) plus BSC for the first 21 days of each 28-day cycle. Stivarga was administered with a low-fat breakfast that contains less than 30% fat [see Dosage and Administration (2.1), Clinical Pharmacology (12.3)]. Treatment continued until disease progression or unacceptable toxicity. Baseline demongraphics were: median age 61 years, 61% men, 78% White, and all patients had an ECOG performance status of 0 or 1. The primary sites of disease were colon (65%), rectum (29%), or both (6%). History of KRAS evaluation was reported for 729 (96%) patients; 430 (59%) of these patients were reported to have KRAS mutation. The median number of prior lines of therapy for metastatic disease was 3. All patients received prior treatment with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, and with bevacizumab. All but one patient with KRAS mutation-negative tumors received panitumumab or cetuximab. The addition of Stivarga to BSC resulted in a statistically significant improvement in survival compared to placebo plus BSC (see Table 5 and Figure 1). Table 5 Efficacy Results from Study 1 Stivarga (N=505) Placebo (N=255) Overall Survival Number of Deaths (%) 275 (55%) 157 (62%) Median Overall Survival (months) 6.4 5.0 95% CI * (5.8, 7.3) (4.4, 5.8) HR (95% CI) 0.77 (0.64, 0.94) Stratified log-rank test p-value †, ‡ 0.0102 Progression-Free Survival Number of Deaths or Progressions (%) 417 (83%) 231 (91%) Median Progression-Free Survival (months) 2.0 1.7 95% CI (1.9, 2.3) (1.7, 1.8) HR (95% CI) 0.49 (0.42, 0.58) Stratified log-rank test p-value † <0.0001 Overall Response Rate Overall Response, N (%) 5 (1%) 1 (0.4%) 95% CI 0.3%, 2.3% 0%, 2.2% CI=confidence interval Stratified by geographic region and time from diagnosis of metastatic disease. Crossed the O’Brien-Fleming boundary (two-sided p-value < 0.018) at second interim analysis. Figure 1: Kaplan-Meier Curves of Overall Survival 14.2 Gastrointestinal Stromal Tumors The efficacy and safety of Stivarga were evaluated in an international, multicenter, randomized (2:1), double-blind, placebo-controlled trial (Study 2) in 199 patients with unresectable, locally advanced or metastatic gastrointestinal stromal tumor (GIST), who had been previously treated with imatinib mesylate and sunitinib malate. Randomization was stratified by line of therapy (third vs. four or more) and geographic region (Asia vs. rest of the world). The major efficacy outcome measure of Study 2 was progression-free survival (PFS) based on disease assessment by independent radiological review using modified RECIST 1.1 criteria, in which lymph nodes and bone lesions were not target lesions and progressively growing new tumor nodule within a pre-existing tumor mass was progression. The key secondary outcome measure was overall survival. Patients were randomized to receive 160 mg regorafenib orally once daily (N=133) plus best supportive care (BSC) or placebo (N=66) plus BSC for the first 21 days of each 28-day cycle. Treatment continued until disease progression or unacceptable toxicity. In Study 2, the median age of patients was 60 years, 64% were men, 68% were White, and all patients had baseline ECOG performance status of 0 (55%) or 1 (45%). At the time of disease progression as assessed by central review, the study blind was broken and all patients were offered the opportunity to take Stivarga at the investigator’s discretion. Fifty-six (85%) patients randomized to placebo and 41 (31%) patients randomized to Stivarga received open-label Stivarga. A statistically significant improvement in PFS was demonstrated among patients treated with Stivarga compared to placebo (see Table 6 and Figure 2). There was no statistically significant difference in overall survival at the time of the planned interim analysis based on 29% of the total events for the final analysis. Table 6 Efficacy Results for Study 2 Stivarga (N=133) Placebo (N=66) Progression-free Survival Number of deaths or progressions (%) 82 (62%) 63 (96%) Median Progression-Free Survival (months) 4.8 0.9 95% CI (3.9, 5.7) (0.9, 1.1) HR (95% CI) 0.27 (0.19, 0.39) Stratified log-rank test p-value* <0.0001 Overall Survival Number of Deaths (%) 29 (22%) 17 (26%) Median Overall Survival (months) NR† NR† HR (95% CI) 0.77 (0.42, 1.41) Stratified log-rank test p-value*,† 0.2 Stratified by line of treatment and geographical region. NR: Not reached Figure 2: Kaplan-Meier Curves of Progression-Free Survival for Study 2 16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied Tablets are supplied in packages containing three bottles, with each bottle containing 28 tablets, for a total of 84 tablets per package (NDC 50419-171-03). 16.2 Storage and Handling Store Stivarga at 25°C (77°F); excursions are permitted from 15 to 30°C (59 to 86°F) [see USP Controlled Room Temperature]. Store tablets in the original bottle and do not remove the desiccant. Keep the bottle tightly closed after first opening. Discard any unused tablets 7 weeks after opening the bottle.Dispose of unused tablets in accordance with local requirements. 17 PATIENT COUNSELING INFORMATION See FDA-Approved Patient Labeling (Patient Information). Hepatotoxicity Advise patients that they will need to undergo monitoring for liver damage and to report immediately any signs or symptoms of severe liver damage to their healthcare provider [see Warnings and Precautions (5.1), Use in Specific Populations (8.8)]. Hemorrhage Advise patients to contact their healthcare provider for unusual bleeding, bruising, or symptoms of bleeding, such as lightheadedness [see Warnings and Precautions (5.2)]. Dermatologic Toxicity Advise patients to contact their healthcare provider if they experience skin changes associated with redness, pain, blisters, bleeding, or swelling [see Warnings and Precautions (5.3)]. Hypertension Advise patients they will need to undergo blood pressure monitoring and to contact their healthcare provider if blood pressure is elevated or if symptoms from hypertension occur including severe headache, lightheadedness, or neurologic symptoms [see Warnings and Precautions (5.4)]. Myocardial Ischemia and Infarction Advise patients to seek immediate emergency help if they experience chest pain, shortness of breath, feel dizzy, or feel like passing out [see Warnings and Precautions (5.5)]. Reversible posterior leukoencephalopathy syndrome Advise patients to contact their healthcare provider if they experience signs and symptoms of RPLS [see Warnings and Precautions (5.6)]. Gastrointestinal Perforation or Fistula Advise patients to contact a healthcare provider immediately if they experience severe pains in their abdomen, persistent swelling of the abdomen, high fever, chills, nausea, vomiting , or dehydration [see Warnings and Precautions (5.7)]. Wound Healing Complications Advise patients to contact their healthcare provider if they plan to undergo a surgical procedure or had recent surgery [see Warnings and Precautions (5.8)]. Embryo-Fetal Toxicity Advise patients that regorafenib can cause fetal harm. Advise a pregnant woman of the potential risk to a fetus [see Warnings and Precautions (5.9), Use in Specific Populations (8.1, 8.3)]. Females and Males of Reproductive Potential • Advise women of reproductive potential of the need for effective contraception during Stivarga treatment and for 2 months after completion of treatment. Instruct women of reproductive potential to immediately contact her healthcare provider if pregnancy is suspected or confirmed during or within 2 months of completing treatment with Stivarga [see Warnings and Precautions (5.9) and Use in Specific Populations (8.1, 8.3)]. • Advise men of reproductive potential of the need for effective contraception during Stivarga treatment and for 2 months after completion of treatment [see Use in Specific Populations (8.3)]. Lactation Advise nursing mothers that it is not known whether regorafenib is present in breast milk and discuss whether to discontinue nursing or to discontinue regorafenib [see Use in Specific Populations (8.2)]. Administration • Advise patients to swallow the Stivarga tablet whole with water at the same time each day with a low-fat meal. Inform patients that the low-fat meal should contain less than 600 calories and less than 30% fat [see Dosage and Administration (2.1)]. • Advise patients to store medicine in the original container. Do not place medication in daily or weekly pill boxes. Discard any remaining tablets 7 weeks after opening the bottle. Tightly close bottle after each opening and keep the desiccant in the bottle [see How Supplied/Storage and Handling (16.2)]. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=824f19c9-0546-4a8a-8d8f-c4055c04f7c7 抗癌药Stivarga（regorafenib）获欧盟批准 2013年9月1日，多激酶抑制剂Stivarga（regorafenib）已获欧盟委员会（EC）批准，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（mCRC）成人患者的治疗。 Stivarga的获批，是基于关键性III期CORRECT临床试验的数据，结果表明，与安慰剂相比，regorafenib显着延长了总生存期（OS），并显着延缓了癌症的进展。该项研究的完整数据已提交至2012年6月的美国临床肿瘤学会第48届年会，并于2012年11月在线发表于《柳叶刀》（The Lancet）。 Stivarga是首个也是唯一一种在转移性结直肠癌（mCRC）中表现出总生存期益处的多激酶抑制剂，目前，该药已获美国、日本等国批准，用于转移性结直肠癌（mCRC）和胃肠道间质瘤（GIST）的治疗。 在全球范围内，结直肠癌（CRC）是第三种最常见的癌症，每年发生超过100万例，5年生存率平均为55%。 Stivarga是一种口服多激酶抑制剂，在临床前研究中，regorafenib能够抑制数个促血管生成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。该药还可以抑制癌和肿瘤微环境中的多种激酶，包括VEGFR 1-3, KIT, RET, PDGFR及FGFR。 Stivarga由拜耳开发，由拜耳和Onyx制药联合推广。 FDA扩大批准Stivarga治疗胃肠道间质瘤 美国食品和药物管理局（FDA）扩大了Stivarga（regorafenib）的适应症，批准其用于治疗不能手术切除和对其他两种FDA批准的药物：伊马替尼（格列卫）和舒尼替尼（索坦）耐药的进展期胃肠道间质瘤（GIST）。 GIST的癌细胞在胃肠道组织中形成。据美国国家癌症研究所统计数据显示，每年在美国有3,300至6,000个诊断为胃肠道间质瘤的新病例，最常见于老年人。 Stivarga是一种多激酶抑制剂，能够阻断促进肿瘤生长的多种酶。 “Stivarga是被FDA批准的用于治疗胃肠道间质瘤的第三个药物”，FDA的药品评价和研究中心的血液学和肿瘤学产品办公室主任，Richard Pazdur博士说“它为对现有药物不再有效的GIST患者，提供了一个重要的新的治疗选择。” FDA批准了该药的优先审查的资格，优先审查程序用于没有有效的替代治疗存在或能够比现有治疗方法带来显著治疗进展的药物。也被授予孤儿药的名称，因为它是用于治疗一种罕见的疾病。 Stivarga的安全性和有效性基于一项临床研究结果（Lancet 2013 Jan 26;381(9863):295-302），本研究对199例胃肠道间质瘤患者进行评估，这些患者都为经格列卫或舒尼替尼治疗后进展的不能手术切除的患者。被随机分配到接受Stivarga或安慰剂治疗。所有患者都接受了最佳的支持治疗，包括治疗不良反应和癌症相关症状。 研究中接受Stivarga或安慰剂的患者，接受治疗直到癌症进展或不良反应无法耐受。结果显示，Stivarga延迟了患者的肿瘤的生长（无进展生存期），比服用安慰剂的患者平均延长3.9个月（4.8vs 0.9个月，风险比0.27，P<0.0001）。接受安慰剂治疗的患者在癌症进展后，有机会切换到Stivarga的治疗。 Stivarga治疗的患者常见的不良反应是虚弱和疲劳，手足综合征，腹泻，食欲不振，高血压，口腔溃疡，感染，声音变化，疼痛，消瘦，肚子痛，皮疹，发热和恶心等症状。 严重的不良反应发生在不到1％的患者中，其中包括肝功能损害，严重出血，起泡和脱皮，需要紧急治疗的高血压，心脏攻击，肠道内穿孔。 Stivarga在2012年9月被批准用于治疗结直肠癌 拜耳Stivarga（regorafenib）新适应症获日本批准 2013年8月20日，口服多激酶抑制剂Stivarga （regorafenib）新适应症申请获日本卫生劳动福利部（MHLW）批准，用于既往经系统性癌症治疗（systemic cancer therapy）后病情恶化的肠胃道间质瘤（GIST）患者的治疗。这是Stivarga在日本获批的第二个适应症。 Stivarga新适应症的批准，是基于关键性III期GRID试验的结果。数据表明，在既往经甲磺酸伊马替尼（imatinib mesylate）和苹果酸舒尼替尼（sunitinib malate）治疗后病情恶化的GIST患者中，与安慰剂相比，Stivarga显着改善了疾病无进展生存期（PFS）。GRID研究的数据已提交至2012年6月举行的美国临床肿瘤学会（ASCO）会议，并在线发表于2012年11月22日的《柳叶刀》（The Lancet）。 目前，Stivarga已获美国、日本在内的数个国家批准，用于转移性结直肠癌（mCRC）患者的治疗。该药于2013年6月27日获欧洲药品管理局（EMA）人用医药产品委员会（CHMP）积极意见，建议批准用于mCRC成人患者的治疗，欧盟委员会（EC）预计将在2013年晚些时候做出审批决定。 2013年2月25日，FDA批准Stivarga新适用症，用于既往经其他激酶抑制剂（Gleevec、Sutent）治疗后病情恶化的或不能手术切除的GIST患者的治疗。 Stivarga是FDA批准的第三个治疗胃肠道间质瘤的药物，另2个药物为诺华的格列卫（Gleevec）、辉瑞的索坦（Sutent）。Stivarga由拜耳开发，由拜耳和Onyx制药共同推广，该药于2012年9月获批用于mCRC治疗。 胃肠道间质瘤（GIST）是癌细胞发生在胃肠道的一种肿瘤，患者多为老年人。 Stivarga是一种口服多激酶抑制剂，在临床前研究中，能够抑制数个促血管生成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。该药还可以抑制癌和肿瘤微环境中的多种激酶，包括VEGFR 1-3, KIT, RET, PDGFR及FGFR 【国外上市】2012年9月27日FDA批准，2013年8月20日，拜耳公司（Bayer）宣布，口服多激酶抑制剂Stivarga（regorafenib）新适应症申请获日本卫生劳动福利部（MHLW）批准，用于既往系统性癌症治疗（systemic  ancer therapy）后病情恶化的肠胃道间质瘤（GIST）患者。 -------------------------------------------------- 产地国家: 美国 原产地英文商品名: Stivarga 40mg/Tablet 84Tablets 原产地英文药品名: Regorafenib 中文参考商品译名: Stivarga 40毫克／片  84片/瓶（28片*3小瓶/盒） 中文参考药品译名: 瑞格菲尼 生产厂家中文参考译名: 拜尔制药 生产厂家英文名: Bayer -------------------------------------------------- 产地国家: 日本 原产地英文商品名: Stivarga 40mg/Tablet 28Tablets 原产地英文药品名: Regorafenib Hydrate 中文参考商品译名: Stivarga 40毫克/片  28片/盒（4*7） 中文参考药品译名: 瑞格菲尼 生产厂家中文参考译名: 拜尔制药 生产厂家英文名: Bayer -------------------------------------------------- 产地国家: 德国 原产地英文商品名: Stivarga Filmcoated 40mg/Tablet 84Tablets 原产地英文药品名: Regorafenib 中文参考商品译名: Stivarga薄膜包衣片 40毫克/片 84片/瓶（28片*3小瓶/盒） 中文参考药品译名: 瑞格菲尼 生产厂家中文参考译名: 拜尔制药 生产厂家英文名: Bayer Vital Germany -------------------------------------------------- 产地国家: 瑞士 原产地英文商品名: Stivarga  Filmtabl 40mg/Tablet  84Tablets 原产地英文药品名: Regorafenib 中文参考商品译名: Stivarga 40毫克／片 84片/瓶（28片*3小瓶/盒） 中文参考药品译名: 瑞格菲尼 生产厂家中文参考译名: 拜尔制药 生产厂家英文名: Bayer (Schweiz) AG