阿斯利康正式进军生物类似药领域 与富士胶片等开发Avastin仿制药
来源：生物谷 发布时间： 富士-协和麒麟生物制剂公司（Fujifilm Kyowa Kirin Biologics，以下简称“富士-协和麒麟生物制剂”）近日宣布，与国际制药巨头英国阿斯利康公司（以下简称“阿斯利康公司”）达成协议，建立合资公司以共同开发和商业化用于治疗多种实体瘤的药物FKB238。
FKB238是Roche全球畅销药物之一-贝伐单抗（Avastin）的生物类似药，Avastin是抗VEGF1的人源化单克隆抗体，在一系列癌症，包括结肠直肠癌和II型非小细胞肺癌的治疗中有明显疗效。富士-协和麒麟生物制剂于2014年12月在欧洲开始了FKB238的一期临床试验。
根据协议，新的合资企业由两家公司共同出资，并将使用富士-协和麒麟生物制剂目前为止得到的所有关于FKB238非临床和临床数据。富士-协和麒麟生物制剂会将FKB238的权利转交至新合资企业，因此将一次性收到4500万美金的的回报。
“通过将富士多年来在照相胶片业务中积累起来的生产、质量控制、分析等先进技术，与协和发酵麒麟在生物制药研发及生产方面的专有技术及知识相结合，富士-协和麒麟希望打造一个知名的生物制药企业，同时降低生物类似药的生产成本，并在不断扩大的生物类似药市场中保持领先地位。”Fujifilm制药部门总经理Takatoshi Ishikawa说到， “我们相信与阿斯利康的合资企业，能加速FKB238药物的开发，尽快地帮助和惠及患者。”
阿斯利康方面则表示，进入生物类似药领域不会改变这家英国巨头制药公司开发创新药物的长期策略，只是为未来“affordable drug cocktails”治疗方案提供多一种选择。罗氏方面则回应，已经预料到生物类似药的竞争并做好了准备。Roche预计其Rituxan和Herceptin的第一批生物类似药会在2017年下半年上市，而Avastin的生物类似药由于拥有更长的专利保护期，会再延后一段时间上市。
富士-协和麒麟生物制剂公司是由日本相片及医疗设备巨头富士（Fujifilm）和日本制药商协和发酵麒麟（Kyowa Hakko Kirin）于2012年3月份以50/50投资成立的合资企业，目的是开发、生产及销售生物仿制药。目前，该公司在研多个单克隆抗体重磅炸弹的Biosimilar药物，其中，其开发的阿达木单抗（adalimumab）的生物仿制药(项目代号：FKB327)，这是一种完全人源化的TNF-α单克隆抗体，是全球最畅销药物Humira的生物仿制药。FKB327目前正在美国和其他国家进行三期临床。
贝伐单抗生物仿制药是富士-协和麒麟生物制剂公司研发管线中的第二种药物，据公开报道，该药物的细胞株由协和发酵麒麟完成构建。安维汀（Avastin）是瑞士制药巨头罗氏（Roche）第二畅销的抗癌药物，2014年全球销售额高达70.21亿美元，位列《2014年全球最畅销的25个药物》榜单第7名。在欧盟，Avastin已获批的适应症包括：乳腺癌、结直肠癌、非小细胞肺癌、卵巢癌。安维汀（Bevacizumab，Avastin）是重组的人源化单克隆抗体。日获得FDA的批准，是美国第一个获得批准上市的抑制肿瘤血管生成的药。
就在2015年4月，欧盟委员会（EC）基于关键性大型III期GOG-0240研究的显著生存数据，批准了Avastin联合标准化疗（紫杉醇+顺铂，或紫杉醇+拓扑替康）用于持续性、复发性或转移性宫颈癌的治疗。Avastin是继2006年拓扑替康和顺铂获批近10年来，批准用于治疗晚期宫颈癌的首个新药，标志着宫颈癌临床治疗的重大里程碑。目前，在欧盟地区，晚期宫颈癌的治疗选择仅限于化疗。在当前标准化疗方案基础上联用Avastin，将为晚期宫颈癌患者提供更显着的治疗益处。Avastin宫颈癌新适应症的获批，意味着该明星药物在全球范围内将继续造福更多患者。&
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治疗晚期结直肠癌新药___阿瓦斯丁(avastin)
治疗直肠癌的新药Avastin ：：
Avastin获准作为晚期二线治疗药 ()
生物制药公司Genentech在6月20日称，FDA已批准Avastin的扩大适应症，即作为晚期结肠癌的二线治疗药物。
此前，Avastin+化疗联用已获准作为晚期结肠癌的一线治疗药。
人类基因知识突飞猛进，令开发癌症药物的研究有大突破。三种由生物技术发展出来的抗癌新药，专门对付体内某种助长癌瘤生长扩散的物质，它们在消灭癌细胞的同时，并不损害健康细胞，因此比普通的化疗高出一筹。其中最瞩目的是治疗直肠癌的新药Avastin ，它能阻止癌瘤自制血管，使其无法吸收养分「饿死」。临床测试证明，它将可用来治疗晚期病人，令其生存率大增50 ％，平均寿命延长5 个月。研究结果本月初在美国临床肿瘤学会年会上公布时，与会者都振奋地交头接耳，因为他们知道这些研究成果的划时代意义。 　　明报报道，在1970 年代，哈佛大学研究员福尔曼首次指出，癌症肿瘤似乎能够在人体内自制新血管，供其吸取氧气和养分之用，毒瘤藉此不断扩散，由一个器官扩散至另一个器官，最终夺命。他因此推断，废去肿瘤制造血管的能力，使其「饿死」，便能减慢甚或停止肿瘤扩散。 　　平均延长寿命5 个月 　　一直以来，科学家的研究皆不甚成功，直至最近，科学家终於以其理论制成新药Avastin ，并首次以大规模临床测试证实福尔曼的假设。Avastin 是一种蛋白质，也是一种人造抗体，专门对付被某些癌瘤用来诱使血管形成的物质。 　　令化疗效果更快更持久 　　Avastin 的临? 测试有800 人参与，在标准化疗之外再服用Avastin 的结肠直肠癌（Colorectal cancer ）病人，证实比那些只接受化疗的病人，在研究期间的生存机会高出一半。 要指出某疗法是否有效的指标繁多而复杂，不过一项令人易於理解的计算方法是有否令病人寿命延长，而Avastin 被发现令平均寿命由15.6 个月延长到20.3 个月。《纽约时报》说，若一种新抗癌药能延长病人寿命两三个月便等於成功，Avastin 延命5 个月，已超出期望。 　　参与临床试验的加州大学三藩市分校胃肠肿瘤专家韦洛克说：你看到的是病人彷佛马上受惠，在感觉上以及肿瘤负荷上都减轻了。我想它真的使化疗效果加快，而且可能令效果更持久。 　　研究人员说，副作用基本上可以控制，只是会令许多病人血压上升，这可用普通方法治疗。Avastin 已显示对效果不佳，但该公司正研究它对胰脏癌、前列腺癌、卵巢癌和肾癌的效用。 可望明年推出市场 　　目前，多家生物技术公司共同研发出近10 种类似药理的药物，Avastin 被视为样板，备受业界关注。由於临? 测试结果理据充足，研发出Avastin 的美国著名基因工程公司Genentech 可能会在明年内向美国食品及药物管理局申请推出市场，而不像惯例那样再作第二次大型研究。 　　另外两种药物，包括纽约生物科技制药公司ImClone 研发的治疗结肠直肠癌药Erbitux ，以及AstraZeneca 公司的药Iressa ，都是用以阻挡一种体内分子，使其无法协助癌肿瘤发展起对化疗的抵抗能力。临? 实验都证实，它们能令濒死病人的癌瘤缩小，只是尚未能如Avastin 那样延长病人寿命。 癌症医生绝少说「治愈」，因为癌症随时都会复发，但现在很多医生都希望，若把这两三种目前世界上最先进的抗癌药物结合现有的化疗方法，或能长久抑制肿瘤。因此医学界都欢呼，他们即将踏入治癌新纪元。专家相信，以深厚基因知识为基础的疗法，已开始有效对付各大癌症杀手，例如肺癌、乳癌、直肠癌和前列腺癌等。 　　医学界：标志治癌新纪元　　对癌病的临床研究已有15 年的加州大学肿瘤专家韦洛克说：我向来对所谓研究进展有保留，但也不得不说这是划时代的。它令研究者、病人和生物医药公司而言都是一大鼓舞，真是令人兴奋得不得了。
AVASTIN(Bevacizumab)英文说明书
U.S. BLA Amendment: Bevacizumab&Genentech, Inc.1 of 27: GNE_clean_PI_Feb_131.14.1.3 Labeling Text 1AVASTIN& 2(Bevacizumab) 3For Intravenous Use 4WARNINGS 5Gastrointestinal Perforations/Wound Healing Complications 6AVASTIN administration can result in the development of gastrointestinal 7perforation and wound dehiscence, in some instances resulting in fatality. 8Gastrointestinal perforation, sometimes associated with intra-abdominal 9abscess, occurred throughout treatment with AVASTIN (i.e., was not 10correlated to duration of exposure). The incidence of gastrointestinal 11perforation in patients receiving bolus-IFL with AVASTIN was 2%. The 12typical presentation was reported as abdominal pain associated with 13symptoms such as constipation and vomiting. Gastrointestinal perforation 14should be included in the differential diagnosis of patients presenting with 15abdominal pain on AVASTIN. AVASTIN therapy should be permanently 16discontinued in patients with gastrointestinal perforation or wound 17dehiscence requiring medical intervention. The appropriate interval 18between termination of AVASTIN and subsequent elective surgery 19required to avoid the risks of impaired wound healing/wound dehiscence 20has not been determined. (See WARNINGS: Gastrointestinal 21Perforations/Wound Healing Complications and DOSAGE AND 22ADMINISTRATION: Dose Modifications.) 23Hemorrhage 24Serious, and in some cases fatal, hemoptysis has occurred in patients with 25non&small cell lung cancer treated with chemotherapy and AVASTIN. In 26a small study, the incidence of serious or fatal hemoptysis was 31% in 27patients with squamous histology and 4% in patients with adenocarcinoma 28receiving AVASTIN as compared to no cases in patients treated with 29chemotherapy alone. Patients with recent hemoptysis should not receive 30AVASTIN. (See WARNINGS: Hemorrhage and DOSAGE AND 31ADMINISTRATION: Dose Modifications .) 32U.S. BLA Amendment: Bevacizumab&Genentech, Inc.2 of 27: GNE_clean_PI_Feb_13DESCRIPTION 33AVASTIN& (Bevacizumab) is a recombinant humanized monoclonal 34IgG1 antibody that binds to and inhibits the biologic activity of human 35vascular endothelial growth factor (VEGF) in in vitro and in vivo assay 36systems. Bevacizumab contains human framework regions and the 37complementarity-determining regions of a murine antibody that binds to 38VEGF (1). Bevacizumab is produced in a Chinese Hamster Ovary 39mammalian cell expression system in a nutrient medium containing the 40antibiotic gentamicin and has a molecular weight of approximately 41149 kilodaltons. AVASTIN is a clear to slightly opalescent, colorless to 42pale brown, sterile, pH 6.2 solution for intravenous (IV) infusion. 43AVASTIN is supplied in 100 mg and 400 mg preservative- free, single- use 44vials to deliver 4 mL or 16 mL of AVASTIN (25 mg/mL). The 100 mg 45product is formulated in 240 mg a,a-trehalose dihydrate, 23.2 mg sodium 46phosphate (monobasic, monohydrate), 4.8 mg sodium phosphate (dibasic, 47anhydrous), 1.6 mg polysorbate 20, and Water for Injection, USP. The 48400 mg product is formulated in 960 mg a,a-trehalose dihydrate, 92.8 mg 49sodium phosphate (monobasic, monohydrate), 19.2 mg sodium phosphate 50(dibasic, anhydrous), 6.4 mg polysorbate 20, and Water for Injection, 51USP. 52CLINICAL PHARMACOLOGY 53Mechanism of Action 54Bevacizumab binds VEGF and prevents the interaction of VEGF to its 55receptors (Flt-1 and KDR) on the surface of endothelial cells. The 56interaction of VEGF with its receptors leads to endothelial cell 57proliferation and new blood vessel formation in in vitro models of 58angiogenesis. Administration of Bevacizumab to xenotransplant models 59of colon cancer in nude (athymic) mice caused reduction of microvascular 60growth and inhibition of metastatic disease progression. 61Pharmacokinetics 62The pharmacokinetic profile of Bevacizumab was assessed using an assay 63that measures total serum Bevacizumab concentrations (i.e., the assay did 64U.S. BLA Amendment: Bevacizumab&Genentech, Inc.3 of 27: GNE_clean_PI_Feb_13not distinguish between free Bevacizumab and Bevacizumab bound to 65VEGF ligand). Based on a population pharmacokinetic analysis of 66491 patients who received 1 to 20 mg/kg of AVASTIN weekly, every 672 weeks, or every 3 weeks, the estimated half-life of Bevacizumab was 68approximately 20 days (range 11-50 days). The predicted time to reach 69steady state was 100 days. The accumulation ratio following a dose of 7010 mg/kg of Bevacizumab every 2 weeks was 2.8. 71The clearance of Bevacizumab varied by body weight, by gender, and by 72tumor burden. After correcting for body weight, males had a higher 73Bevacizumab clearance (0.262 L/day vs. 0.207 L/day) and a larger Vc 74(3.25 L vs. 2.66 L) than females. Patients with higher tumor burden (at or 75above median value of tumor surface area) had a higher Bevacizumab 76clearance (0.249 L/day vs. 0.199 L/day) than patients with tumor burdens 77below the median. In a randomized study of 813 patients (Study 1), there 78was no evidence of lesser efficacy (hazard ratio for overall survival) in 79males or patients with higher tumor burden treated with AVASTIN as 80compared to females and patients with low tumor burden. The 81relationship between Bevacizumab exposure and clinical outcomes has not 82been explored. 83Special Populations 84Analyses of demographic data suggest that no dose adjustments are 85necessary for age or sex. 86Patients with renal impairment. No studies have been conducted to 87examine the pharmacokinetics of Bevacizumab in patients with renal 88impairment. 89Patients with hepatic dysfunction. No studies have been conducted to 90examine the pharmacokinetics of Bevacizumab in patients with hepatic 91impairment. 92U.S. BLA Amendment: Bevacizumab&Genentech, Inc.4 of 27: GNE_clean_PI_Feb_13CLINICAL STUDIES 93The safety and efficacy of AVASTIN in the initial treatment of patients 94with metastatic carcinoma of the colon and rectum were studied in two 95randomized, controlled clinical trials in combination with intravenous 965-fluorouracil&based chemotherapy. 97AVASTIN in Combination with Bolus-IFL 98Study 1 was a randomized, double-blind, active-controlled clinical trial 99evaluating AVASTIN as first- line treatment of metastatic carcinoma of the 100colon or rectum. Patients were randomized to bolus-IFL (irinotecan 101125 mg/m2 IV, 5-fluorouracil 500 mg/m2 IV, and leucovorin 20 mg/m2 IV 102given once weekly for 4 weeks every 6 weeks) plus placebo (Arm 1), 103bolus-IFL plus AVASTIN (5 mg/kg every 2 weeks) (Arm 2), or 5-FU/LV 104plus AVASTIN (5 mg/kg every 2 weeks) (Arm 3). Enrollment in Arm 3 105was discontinued, as pre-specified, when the toxicity of AVASTIN in 106combination with the bolus-IFL regimen was deemed acceptable. 107Of the 813 patients randomized to Arms 1 and 2, the median age was 60, 10840% were female, and 79% were Caucasian. Fifty-seven percent had an 109ECOG performance status of 0. Twenty-one percent had a rectal primary 110and 28% received prior adjuvant chemotherapy. In the majority of 111patients, 56%, the dominant site of disease was extra-abdominal, while the 112liver was the dominant site in 38% of patients. The patient characteristics 113were similar across the study arms. The primary endpoint of this trial was 114overall survival. Results are presented in Table 1 and Figure 1. 115U.S. BLA Amendment: Bevacizumab&Genentech, Inc.5 of 27: GNE_clean_PI_Feb_13Table 1Study 1 Efficacy ResultsIFL + PlaceboIFL + AVASTIN5 mg/kg q 2 wksNumber of Patients 411 402Overall SurvivalaMedian (months) 15.6 20.3Hazard ratio 0.66Progression-Free SurvivalaMedian (months) 6.4 10.6Hazard ratio 0.54Overall Response RatebRate (percent) 35% 45%Duration of ResponseMedian (months) 7.1 10.4a p < 0.001 by stratified logrank test.b p
150/100 mmHg)43% 60% 67%Severe Hypertensiona( > 200/110 mmHg)2% 7% 10%a This includes patients with either a systolic or diastolic reading greater than thecutoff value on one or more occasions.236Among patients with severe hypertension in the AVASTIN arms, slightly 237over half the patients (51%) had a diastolic reading greater than 110 238associated with a systolic reading less than 200. 239Medication classes used for management of patients with Grade 3 240hypertension receiving AVASTIN included angiotensin-converting 241enzyme inhibitors, beta blockers, diuretics, and calcium channel blockers. 242Four months after discontinuation of therapy, persistent hypertension was 243present in 18 of 26 patients that received bolus-IFL plus AVASTIN and 2448 of 10 patients that received bolus-IFL plus placebo. 245Across all clinical studies (n = 1032), development or worsening of 246hypertension resulted in hospitalization or discontinuation of AVASTIN in 24717 patients. Four of these 17 patients developed hypertensive 248encephalopathy. Severe hypertension was complicated by subarachnoid 249hemorrhage in one patient. 250U.S. BLA Amendment: Bevacizumab&Genentech, Inc.11 of 27: GNE_clean_PI_Feb_13AVASTIN should be permanently discontinued in patients with 251hypertensive crisis. Temporary suspension is recommended in patients 252with severe hypertension that is not controlled with medical management. 253Proteinuria (See DOSAGE AND ADMINISTRATION: Dose 254Modifications) 255In Study 1, both the incidence and severity of proteinuria (defined as a 256urine dipstick reading of 1+ or greater) was increased in patients receiving 257AVASTIN as compared to those receiving bolus-IFL plus placebo. 258Urinary dipstick readings of 2+ or greater occurred in 14% of patients 259receiving bolus-IFL plus placebo, 17% receiving bolus-IFL plus 260AVASTIN, and in 28% of patients receiving 5-FU/LV plus AVASTIN. 261Twenty- four&hour urine collections were obtained in patients with new 262onset or worsening proteinuria. None of the 118 patients receiving 263bolus-IFL plus placebo, three of 158 patients (2%) receiving 264bolus-IFL plus AVASTIN, and two of 50 (4%) patients receiving 2655-FU/LV plus AVASTIN who had a 24- hour collection experienced 266NCI-CTC Grade 3 proteinuria ( > 3.5 gm protein/24 hours). 267In a dose-ranging, placebo-controlled, randomized study of AVASTIN in 268patients with metastatic renal cell carcinoma, an indication for which 269AVASTIN is not approved, 24-hour urine collections were obtained in 270approximately half the patients enrolled. Among patients in whom 27124-hour urine collections were obtained, four of 19 (21%) patients 272receiving AVASTIN at 10 mg/kg every two weeks, two of 14 (14%) 273receiving AVASTIN at 3 mg/kg every two weeks, and none of the 27415 placebo patients experienced NCI-CTC Grade 3 proteinuria ( > 3.5 gm 275protein/24 hours). 276Nephrotic syndrome occurred in five of %) patients receiving 277AVASTIN in Genentech-sponsored studies. One patient died and one 278required dialysis. In three patients, proteinuria decreased in severity 279several months after discontinuation of AVASTIN. No patient had 280U.S. BLA Amendment: Bevacizumab&Genentech, Inc.12 of 27: GNE_clean_PI_Feb_13normalization of urinary protein levels (by 24-hour urine) following 281discontinuation of AVASTIN. 282AVASTIN should be discontinued in patients with nephrotic syndrome. 283The safety of continued AVASTIN treatment in patients with moderate to 284severe proteinuria has not been evaluated. In most clinical studies, 285AVASTIN was interrupted for &sup3; 2 grams of proteinuria/24 hours and 286resumed when proteinuria was < 2 gm/24 hours. Patients with moderate 287to severe proteinuria based on 24-hour collections should be monitored 288regularly until improvement and/or resolution is observed. 289Congestive Heart Failure 290Congestive heart failure (CHF), defined as NCI-CTC Grade 2-4 left 291ventricular dysfunction, was reported in 22 of 1032 (2%) patients 292receiving AVASTIN in Genentech-sponsored studies. Congestive heart 293failure occurred in six of 44 (14%) patients receiving AVASTIN and 294concurrent anthracyclines. Congestive heart failure occurred in 13 of 299 295(4%) patients who received prior anthracyclines and/or left chest wall 296irradiation. In a controlled study, the incidence was higher in patients 297receiving AVASTIN plus chemotherapy as compared to patients receiving 298chemotherapy alone. The safety of continuation or resumption of 299AVASTIN in patients with cardiac dysfunction has not been studied. 300PRECAUTIONS 301General 302AVASTIN should be used with caution in patients with known 303hypersensitivity to AVASTIN or any component of this drug product. 304Infusion Reactions 305Infusion reactions with the first dose of AVASTIN were uncommon 306(< 3%). Severe reactions during the infusion of AVASTIN occurred in 307two patients. One patient developed stridor and wheezing during their 308first dose. A second patient, receiving paclitaxel followed by AVASTIN, 309developed a Grade 3 hypersensitivity reaction requiring hospitalization 310U.S. BLA Amendment: Bevacizumab&Genentech, Inc.13 of 27: GNE_clean_PI_Feb_13during their third infusion of AVASTIN. Both patients responded to 311medical management. Information on rechallenge is not available. 312AVASTIN infusion should be interrupted in all patients with severe 313infusion reactions and appropriate medical therapy administered. 314There are no data regarding the most appropriate method of identification 315of patients who may safely be retreated with AVASTIN after experiencing 316a severe infusion reaction. 317Surgery 318AVASTIN therapy should not be initiated for at least 28 days following 319major surgery. The surgical incision should be fully healed prior to 320initiation of AVASTIN. Because of the potential for impaired wound 321healing, AVASTIN should be suspended prior to elective surgery. The 322appropriate interval between the last dose of AVASTIN and elective 323 however, the half- life of AVASTIN is estimated to be 32420 days (see CLINICAL PHARMACOLOGY: Pharmacokinetics) and 325the interval chosen should take into consideration the half- life of the drug. 326(See WARNINGS: Gastrointestinal Perforations/Wound Healing 327Complications.) 328Cardiovascular Disease 329Patients were excluded from participation in AVASTIN clinical trials if, in 330the previous year, they had experienced clinically significant 331cardiovascular disease. Thus, the safety of AVASTIN in patients with 332clinically significant cardiovascular disease has not been adequately 333evaluated. 334Immunogenicity 335As with all therapeutic proteins, there is a potential for immunogenicity. 336The incidence of antibody development in patients receiving AVASTIN 337has not been adequately determined because the assay sensitivity was 338inadequate to reliably detect lower titers. Enzyme-linked immunosorbant 339assays (ELISAs) were performed on sera from approximately 500 patients 340U.S. BLA Amendment: Bevacizumab&Genentech, Inc.14 of 27: GNE_clean_PI_Feb_13treated with AVASTIN, primarily in combination with chemotherapy. 341High titer human anti-AVASTIN antibodies were not detected. 342Immunogenicity data are highly dependent on the sensitivity and 343specificity of the assay. Additionally, the observed incidence of antibody 344positivity in an assay may be influenced by several factors, including 345sample handling, timing of sample collection, concomitant medications, 346and underlying disease. For these reasons, comparison of the incidence of 347antibodies to AVASTIN with the incidence of antibodies to other products 348may be misleading. 349Laboratory Tests 350Blood pressure monitoring should be conducted every two to three weeks 351during treatment with AVASTIN. Patients who develop hypertension on 352AVASTIN may require blood pressure monitoring at more frequent 353intervals. Patients with AVASTIN-induced or -exacerbated hypertension 354who discontinue AVASTIN should continue to have their blood pressure 355monitored at regular intervals. 356Patients receiving AVASTIN should be monitored for the development or 357worsening of proteinuria with serial urinalyses. Patients with a 2+ or 358greater urine dipstick reading should undergo further assessment, e.g., a 35924-hour urine collection. (See WARNINGS: Proteinuria and DOSAGE 360AND ADMINISTRATION: Dose Modifications.) 361Drug Interactions 362No formal drug interaction studies with anti-neoplastic agents have been 363conducted. In Study 1, patients with colorectal cancer were given 364irinotecan/5-FU/leucovorin (bolus-IFL) with or without AVASTIN. 365Irinotecan concentrations were similar in patients receiving bolus-IFL 366alone and in combination with AVAS TIN. The concentrations of SN38, 367the active metabolite of irinotecan, were on average 33% higher in patients 368receiving bolus-IFL in combination with AVASTIN when compared with 369bolus-IFL alone. In Study 1, patients receiving bolus-IFL plus AVASTIN 370U.S. BLA Amendment: Bevacizumab&Genentech, Inc.15 of 27: GNE_clean_PI_Feb_13had a higher incidence of Grade 3-4 diarrhea and neutropenia. Due to 371high inter-patient variability and limited sampling, the extent of the 372increase in SN38 levels in patients receiving concurrent irinotecan and 373AVASTIN is uncertain. 374Carcinogenesis, Mutagenesis, Impairment of Fertility 375No carcinogenicity data are available for AVASTIN in animals or 376humans. 377AVASTIN may impair fertility. Dose-related decreases in ovarian and 378uterine weights, endometrial proliferation, number of menstrual cycles, and 379arrested follicular development or absent corpora lutea were observed in 380female cynomolgus monkeys treated with 10 or 50 mg/kg of AVASTIN for 38113 or 26 weeks. Following a 4- or 12-week recovery period, which 382examined only the high&dose group, trends suggestive of reversibility were 383noted in the two females for each regimen that were assigned to recover. 384After the 12-week recovery period, follicular maturation arrest was no 385longer observed, but ovarian weights were still moderately decreased. 386Reduced endometrial proliferation was no longer observed at the 12-week 387recovery time point, but uterine weight decreases were still notable, 388corpora lutea were absent in 1 out of 2 animals, and the number of 389menstrual cycles remained reduced (67%). 390Pregnancy Category C 391AVASTIN has been shown to be teratogenic in rabbits when administered 392in doses that are two-fold greater than the recommended human dose on a 393mg/kg basis. Observed effects included decreases in maternal and fetal 394body weights, an increased number of fetal resorptions, and an increased 395incidence of specific gross and skeletal fetal alterations. Adverse fetal 396outcomes were observed at all doses tested. 397Angiogenesis is critical to fetal development and the inhibition of 398angiogenesis following administration of AVASTIN is likely to result in 399adverse effects on pregnancy. There are no adequate and well-controlled 400U.S. BLA Amendment: Bevacizumab&Genentech, Inc.16 of 27: GNE_clean_PI_Feb_13studies in pregnant women. AVASTIN should be used during pregnancy 401or in any woman not employing adequate contraception only if the 402potential benefit jus tifies the potential risk to the fetus. All patients should 403be counseled regarding the potential risk of AVASTIN to the developing 404fetus prior to initiation of therapy. If the patient becomes pregnant while 405receiving AVASTIN, she should be apprised of the potential hazard to the 406fetus and/or the potential risk of loss of pregnancy. Patients who 407discontinue AVASTIN should also be counseled concerning the prolonged 408exposure following discontinuation of therapy (half- life of approximately 40920 days) and the possible effects of AVASTIN on fetal development. 410Nursing Mothers 411It is not known whether AVASTIN is secreted in human milk. Because 412human IgG1 is secreted into human milk, the potential for absorption and 413harm to the infant after ingestion is unknown. Women should be advised 414to discontinue nursing during treatment with AVASTIN and for a 415prolonged period following the use of AVASTIN, taking into account the 416half- life of the product, approximately 20 days . (See 417CLINICAL PHARMACOLOGY: Pharmacokinetics.) 418Pediatric Use 419The safety and effectiveness of AVASTIN in pediatric patients has not 420been studied. However, physeal dysplasia was observed in juvenile 421cynomolgus monkeys with open growth plates treated for four weeks with 422doses that were less than the recommended human dose based on mg/kg 423and exposure. The incidence and severity of physeal dysplasia were 424dose-related and were at least partially reversible upon cessation of 425treatment. 426Geriatric Use 427In Study 1, NCI-CTC Grade 3-4 adverse eve nts were collected in all 428patients receiving study drug (396 bolus-IFL 392 bolus-IFL 429plus AVASTIN; 109 5-FU/LV plus AVASTIN), while NCI-CTC Grade 1 430and 2 adverse events were collected in a subset of 309 patients. There 431U.S. BLA Amendment: Bevacizumab&Genentech, Inc.17 of 27: GNE_clean_PI_Feb_13were insufficient numb ers of patients 65 years and older in the subset in 432which Grade 1-4 adverse events were collected to determine whether the 433overall adverse event profile was different in the elderly as compared to 434younger patients. Among the 392 patients receiving bolus-IFL plus 435AVASTIN, 126 were at least 65 years of age. Severe adverse events that 436occurred at a higher incidence ( &sup3; 2%) in the elderly when compared to 437those less than 65 years were asthenia, sepsis, deep thrombophlebitis, 438hypertension, hypotension, myocardial infarction, congestive heart failure, 439diarrhea, constipation, anorexia, leukopenia, anemia, dehydration, 440hypokalemia, and hyponatremia. The effect of AVASTIN on overall 441survival was similar in elderly patients as compared to younger patients. 442Of the 742 patients enrolled in Genentech-sponsored clinical studies in 443which all adverse events were captured, 212 (29%) were age 65 or older 444and 43 (6%) were age 75 or older. Adverse events of any severity that 445occurred at a higher incidence in the elderly as compared to younger 446patients, in addition to those described above, were dyspepsia, 447gastrointestinal hemorrhage, edema, epistaxis, increased cough, and voice 448alteration. 449ADVERSE EVENTS 450The most serious adverse events associated with AVASTIN were: 451& Gastrointestinal Perforations/Wound Healing Complications (see 452WARNINGS) 453& Hemorrhage (see WARNINGS) 454& Hypertensive Crises (see WARNINGS) 455& Nephrotic Syndrome (see WARNINGS) 456& Congestive Heart Failure (see WARNINGS) 457The most common severe (NCI-CTC Grade 3-4) adverse events among 4581032 patients receiving AVASTIN in Genentech-sponsored studies were 459asthenia, pain, hypertension, diarrhea, and leukopenia. 460U.S. BLA Amendment: Bevacizumab&Genentech, Inc.18 of 27: GNE_clean_PI_Feb_13The most common adverse events of any severity among the 742 patients 461receiving AVASTIN in Genentech-sponsored studies were asthenia, pain, 462abdominal pain, headache, hypertension, diarrhea, nausea, vomiting, 463anorexia, stomatitis, constipation, upper respiratory infection, epistaxis, 464dyspnea, exfoliative dermatitis, and proteinuria. 465Because clinical trials are conducted under widely varying conditions, 466adverse reaction rates observed in the clinical trials of a drug cannot be 467directly compared to rates in the clinical trials of another drug and may not 468reflect the rates observed in practice. The adverse reaction information 469from clinical trials does, however, provide a basis for identifying the 470adverse events that appear to be related to drug use and for approximating 471rates. 472A total of 1032 patients with metastatic colorectal cancer (n = 568) and 473with other cancers (n = 464) received AVASTIN either as a single agent 474(n = 157) or in combination with chemotherapy (n = 875) in 475Genentech-sponsored clinical trials. All adverse events were collected in 476742 of the 1032 for the remaining 290, all NCI-CTC Grade 3 477and 4 adverse events and only selected Grade 1 and 2 adverse events 478(hypertension, proteinuria, thromboembolic events) were collected. 479Adverse events across all Genentech-sponsored studies were used to 480further characterize specific adverse events. (See WARNINGS: 481Hemorrhage, Hypertension, Proteinuria, Congestive Heart Failure 482and PRECAUTIONS: Geriatric Use.) 483Comparative data on adverse experiences, except where indicated, are 484limited to Study 1, a randomized, active-controlled study in 897 patients 485receiving initial treatment for metastatic colorectal cancer. All NCI-CTC 486Grade 3 and 4 adverse events and selected Grade 1 and 2 adverse events 487(hypertension, proteinuria, thromboembolic events) were reported for the 488overall study population. In Study 1, the median age was 60, 60% were 489male, 78% had colon primary lesion, and 29% had prior adjuvant or 490neoadjuvant chemotherapy. The median duration of exposure to 491U.S. BLA Amendment: Bevacizumab&Genentech, Inc.19 of 27: GNE_clean_PI_Feb_13AVASTIN in Study 1 was 8 months in Arm 2 and 7 months in Arm 3. All 492adverse events, including all NCI-CTC Grade 1 and 2 events, were 493reported in a subset of 309 patients. The baseline entry characteristics in 494the 309 patient safety subset were similar to the overall study population 495and well-balanced across the three study arms. 496Severe and life-threatening (NCI-CTC Grade 3 and 4) adverse events, 497which occurred at a higher incidence ( &sup3; 2%) in patients receiving 498bolus-IFL plus AVASTIN as compared to bolus-IFL plus placebo, are 499presented in Table 4. 500Table 4NCI-CTC Grade 3 and 4 Adverse Events in Study 1(Occurring at Higher Incidence (&sup3; 2%) in AVASTIN vs. Control)Arm 1IFL + Placebo(n = 396)Arm 2IFL + AVASTIN(n = 392)Grade 3-4 Events 295 (74%) 340 (87%)Body as a WholeAsthenia 28 (7%) 38 (10%)Abdominal Pain 20 (5%) 32 (8%)Pain 21 (5%) 30 (8%)CardiovascularDeep Vein Thrombosis 19 (5%) 34 (9%)Hypertension 10 (2%) 46 (12%)Intra-Abdominal Thrombosis 5 (1%) 13 (3%)Syncope 4 (1%) 11 (3%)DigestiveDiarrhea 99 (25%) 133 (34%)Constipation 9 (2%) 14 (4%)Hemic/LymphaticLeukopenia 122 (31%) 145 (37%)Neutropeniaa 41 (14%) 58 (21%)a Central laboratories were collected on Days 1 and 21 of each cycle.Neutrophil counts are available in 303 patients in Arm 1 and 276 in Arm 2.501U.S. BLA Amendment: Bevacizumab&Genentech, Inc.20 of 27: GNE_clean_PI_Feb_13Adverse events of any severity, which occurred at a higher incidence 502( &sup3; 5%) in the initial phase of the study in patients receiving AVASTIN 503(bolus-IFL plus AVASTIN or 5-FU/LV plus AVASTIN) as compared to 504the bolus-IFL plus placebo arm, are presented in Table 5. 505U.S. BLA Amendment: Bevacizumab&Genentech, Inc.21 of 27: GNE_clean_PI_Feb_13Table 5NCI-CTC Grade 1-4 Adverse Events in Study 1 Subset(Occurring at Higher Incidence (&sup3; 5%) in AVASTIN vs. Control)Arm 1IFL + Placebo(n = 98)Arm 2IFL + AVASTIN(n = 102)Arm 35-FU/LV + AVASTIN(n = 109)Body as a WholeAsthenia 68 (70%) 75 (74%) 80 (73%)Pain 54 (55%) 62 (61%) 67 (62%)Abdominal Pain 54 (55%) 62 (61%) 55 (50%)Headache 19 (19%) 27 (26%) 30 (26%)CardiovascularHypertension 14 (14%) 23 (23%) 37 (34%)Hypotension 7 (7%) 15 (15%) 8 (7%)Deep Vein Thrombosis 3 (3%) 9 (9%) 6 (6%)DigestiveVomiting 46 (47%) 53 (52%) 51 (47%)Anorexia 29 (30%) 44 (43%) 38 (35%)Constipation 28 (29%) 41 (40%) 32 (29%)Stomatitis 18 (18%) 33 (32%) 33 (30%)Dyspepsia 15 (15%) 25 (24%) 19 (17%)Weight Loss 10 (10%) 15 (15%) 18 (16%)Flatulence 10 (10%) 11 (11%) 21 (19%)GI Hemorrhage 6 (6%) 25 (24%) 21 (19%)Dry Mouth 2 (2%) 7 (7%) 4 (4%)Colitis 1 (1%) 6 (6%) 1 (1%)Hemic/LymphaticThrombocytopenia 0 5 (5%) 5 (5%)Metabolic/NutritionHypokalemia 11 (11%) 12 (12%) 18 (16%)Bilirubinemia 0 1 (1%) 7 (6%)MusculoskeletalMyalgia 7 (7%) 8 (8%) 16 (15%)NervousDizziness 20 (20%) 27 (26%) 21 (19%)Confusion 1 (1%) 1 (1%) 6 (6%)Abnormal Gait 0 1 (1%) 5 (5%)506U.S. BLA Amendment: Bevacizumab&Genentech, Inc.22 of 27: GNE_clean_PI_Feb_13Table 5 (cont&d)NCI-CTC Grade 1-4 Adverse Events in Study 1 SubsetArm 1IFL + Placebo(n = 98)Arm 2IFL + AVASTIN(n = 102)Arm 35-FU/LV + AVASTIN(n = 109)RespiratoryUpper Respiratory Infection 38 (39%) 48 (47%) 44 (40%)Dyspnea 15 (15%) 26 (26%) 27 (25%)Epistaxis 10 (10%) 36 (35%) 35 (32%)Voice Alteration 2 (2%) 9 (9%) 6 (6%)Skin/AppendagesAlopecia 25 (26%) 33 (32%) 6 (6%)Dry Skin 7 (7%) 7 (7%) 22 (20%)Exfoliative Dermatitis 3 (3%) 3 (3%) 21 (19%)Nail Disorder 3 (3%) 2 (2%) 9 (8%)Skin Discoloration 3 (3%) 2 (2%) 17 (16%)Skin Ulcer 1 (1%) 6 (6%) 7 (6%)Special SensesTaste Disorder 9 (9%) 14 (14%) 23 (21%)Excess Lacrimation 2 (2%) 6 (6%) 20 (18%)UrogenitalProteinuria 24 (24%) 37 (36%) 39 (36%)Urinary Frequency/Urgency 1 (1%) 3 (3%) 6 (6%)507Mucocutaneous Hemorrhage 508In Study 1, both serious and non-serious hemorrhagic events occurred at a 509higher incidence in patients receiving AVASTIN. (See WARNINGS: 510Hemorrhage.) In the 309 patients in which Grade 1-4 events were 511collected, epistaxis was common and reported in 35% of patients receiving 512bolus-IFL plus AVASTIN compared with 10% of patients receiving 513bolus-IFL plus placebo. These events were generally mild in severity 514(NCI-CTC Grade 1) and resolved without medical intervention. Other 515mild to moderate hemorrhagic events reported more frequently in patients 516receiving bolus-IFL plus AVASTIN when compared to those receiving 517bolus-IFL plus placebo included gastrointestinal hemorrhage (24% vs. 518U.S. BLA Amendment: Bevacizumab&Genentech, Inc.23 of 27: GNE_clean_PI_Feb_136%), minor gum bleeding (2% vs. 0), and vaginal hemorrhage (4% vs. 5192%). 520Thromboembolism 521In Study 1, 18% of patients receiving bolus-IFL plus AVASTIN and 15% 522of patients receiving bolus-IFL plus placebo experienced a Grade 3-4 523thromboembolic event. The incidence of the following Grade 3 and 4 524thromboembolic events were higher in patients receiving bolus-IFL plus 525AVASTIN as compared to patients receiving bolus-IFL plus placebo: 526cerebrovascular events (4 vs. 0 patients), myocardial infarction (6 vs. 3), 527deep venous thrombosis (34 vs. 19), and intra-abdominal thrombosis (13 528vs. 5). In contrast, the incidence of pulmonary embolism was higher in 529patients receiving bolus-IFL plus placebo (16 vs. 20). 530In Study 1, 53 of 392 (14%) patients who received bolus-IFL plus 531AVASTIN and 30 of 396 (8%) patients who received bolus-IFL plus 532placebo had a thromboembolic event and received full-dose warfarin. 533Two patients in each treatment arm (four total) developed bleeding 534complications. In the two patients treated with full-dose warfarin and 535AVASTIN, these events were associated with marked elevations in their 536INR. Eleven of 53 (21%) patients receiving bolus-IFL plus AVASTIN 537and one of 30 (3%) patients receiving bolus-IFL developed an additional 538thromboembolic event. 539Other Serious Adverse Events 540The following other serious adverse events are considered unusual in 541cancer patients receiving cytotoxic chemotherapy and occurred in at least 542one subject treated with AVASTIN in clinical studies. 543Body as a Whole: polyserositis 544Digestive: intestinal obstruction, intestinal necrosis, mesenteric venous 545occlusion, anastomotic ulceration 546Hemic and lymphatic: pancytopenia 547Metabolic and nutritional disorders: hyponatremia. 548U.S. BLA Amendment: Bevacizumab&Genentech, Inc.24 of 27: GNE_clean_PI_Feb_13Urogenital: ureteral stricture 549OVERDOSAGE 550The maximum tolerated dose of AVASTIN has not been determined. The 551highest dose tested in humans (20 mg/kg IV) was associated with 552headache in nine of 16 patients and with severe headache in three of 55316 patients. 554DOSAGE AND ADMINISTRATION 555The recommended dose of AVASTIN is 5 mg/kg given once every 55614 days as an IV infusion until disease progression is detected. 557AVASTIN therapy should not be initiated for at least 28 days following 558major surgery. The surgical incision should be fully healed prior to 559initiation of AVASTIN. 560Dose Modifications 561There are no recommended dose reductions for the use of AVASTIN. If 562needed, AVASTIN should be either discontinued or temporarily 563suspended as described below. 564AVASTIN should be permanently discontinued in patients who develop 565gastrointestinal perforation, wound dehiscence requiring medical 566intervention, serious bleeding, nephrotic syndrome, or hypertensive crisis. 567Temporary suspension of AVASTIN is recommended in patients with 568evidence of moderate to severe proteinuria pending further evaluation and 569in patients with severe hypertension that is not controlled with medical 570management. The risk of continuation or temporary suspension of 571AVASTIN in patients with moderate to severe proteinuria is unknown. 572AVASTIN should be suspended at least several weeks prior to elective 573surgery. (See WARNINGS: Gastrointestinal Perforation/Wound 574Healing Complications and PRECAUTIONS: Surgery.) AVASTIN 575should not be resumed until the surgical incision is fully healed. 576U.S. BLA Amendment: Bevacizumab&Genentech, Inc.25 of 27: GNE_clean_PI_Feb_13Preparation for Administration 577AVASTIN should be diluted for infusion by a healthcare professional 578using aseptic technique. Withdraw the necessary amount of AVASTIN 579for a dose of 5 mg/kg and dilute in a total volume of 100 mL of 0.9% 580Sodium Chloride Injection, USP. Discard any unused portion left in a 581vial, as the product contains no preservatives. Parenteral drug products 582should be inspected visually for particulate matter and discoloration prior 583to administration. 584Diluted AVASTIN solutions for infusion may be stored at 2-8&C 585(36-46&F) for up to 8 hours. No incompatibilities between AVASTIN and 586polyvinylchloride or polyolefin bags have been observed. 587AVASTIN infusions should not be administered or mixed with 588dextrose solutions. 589Administration 590DO NOT ADMINISTER AS AN IV PUSH OR BOLUS. The initial 591AVASTIN dose should be delivered over 90 minutes as an IV infusion 592following chemotherapy. If the first infusion is well tolerated, the second 593infusion may be administered over 60 minutes. If the 60- minute infusion 594is well tolerated, all subsequent infusions may be administered over 59530 minutes. 596Stability and Storage 597AVASTIN vials must be refrigerated at 2-8&C (36-46&F). AVASTIN 598vials should be protected from light. Store in the original carton until time 599of use. DO NOT FREEZE. DO NOT SHAKE. 600HOW SUPPLIED 601AVASTIN is supplied as 4 mL and 16 mL of a sterile solution in single& 602use glass vials to deliver 100 and 400 mg of Bevacizumab per vial, 603respectively. 604U.S. BLA Amendment: Bevacizumab&Genentech, Inc.26 of 27: GNE_clean_PI_Feb_13Single unit 100 mg carton: Contains one 4 mL vial of AVASTIN 605(25 mg/mL). NDC
606Single unit 400 mg carton: Contains one 16 mL vial of AVASTIN 607(25 mg/mL). NDC
608U.S. BLA Amendment: Bevacizumab&Genentech, Inc.27 of 27: GNE_clean_PI_Feb_13REFERENCES 6091. Presta LG, Chen H, O&Connor SJ, Chisholm V, Meng YG, 610Krummen L, et al. Humanization of an anti- vascular endothelial 611growth factor monoclonal antibody for the therapy of solid tumors 612and other disorders. Cancer Res 3-9. 613614AVASTIN&(Bevacizumab)For Intravenous UseManufactured by:Genentech, Inc.1 DNA WaySouth San Francisco, CA G#####-R0February
Genentech, Inc.615
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