近日，美国食品和药物管理局（FDA）批准Zirabev（bevacizumab-bvzr，贝伐单抗），该药是罗氏品牌药安维汀（Avastin，通用名：bevacizumab，贝伐单抗）的生物仿制药，用于治疗5种类型的癌症：转移性结直肠癌，不可切除性、局部晚期、复发或转移性非鳞状非小细胞肺癌（NSCLC），复发性胶质母细胞瘤，转移性肾细胞癌（RCC），持续性复发性或转移性宫颈癌。
Zirabev是FDA获批的第21个生物仿制药，也是第2个贝伐单抗生物仿制药。2017年9月，安进和艾尔建Mvasi(bevacizumab-awwb)获得FDA批准，成为美国市场批准的首个贝伐单抗生物仿制药。
批准日期：2019年06月29日  公司：辉瑞公司
ZIRABEVTM（贝伐单抗[bevacizumab-bvzr]）注射液，用于静脉注射
美国最初批准：2019年
ZIRABEV（bevacizumab-bvzr）与安维汀（bevacizumab）生物相似*。
作用机制
贝伐单抗产品结合VEGF并阻止VEGF与其内皮细胞表面上的受体（Flt-1和KDR）的相互作用。VEGF与其受体的相互作用导致血管生成的体外模型中的内皮细胞增殖和新血管形成。给予贝伐单抗产品裸鼠（无胸腺）小鼠的结肠癌异种移植模型导致微血管生长减少和转移性疾病进展的抑制。
适应症和用法
ZIRABEV是一种血管内皮生长因子抑制剂，适用于治疗：
转移性结直肠癌，与基于静脉氟尿嘧啶的化疗联合用于一线或二线治疗。
转移性结肠直肠癌，与基于氟嘧啶核苷或氟嘧啶-奥沙利铂的化学疗法的二线治疗相结合，用于在含有一线贝伐单抗产品的方案上取得进展的患者。
使用限制：ZIRABEV不适用于结肠癌的辅助治疗。
无法切除，局部晚期，复发或转移性非鳞状非小细胞肺癌，与卡铂和紫杉醇联合用于一线治疗。
成人复发性胶质母细胞瘤。
转移性肾细胞癌与干扰素α联合应用。
持续性，复发性或转移性宫颈癌，与紫杉醇和顺铂或紫杉醇和托泊替康组合。
剂量和给药
大手术后不要给ZIRABEV治疗28天，直到手术伤完全愈合。
转移性结直肠癌
用推注-IFL每2周5mg/kg
用FOLFOX4每2周10mg/kg
每2周5mg/kg或每3周7.5mg/kg
氟嘧啶-伊立替康-或氟嘧啶-奥沙利铂为基础的化疗在一线贝伐单抗产品包括方案进展后一线非鳞状非小细胞肺癌。
卡铂和紫杉醇复发性胶质母细胞瘤每3周15mg/kg。
每2周10mg/kg
转移性肾细胞癌
干扰素α持续，复发或转移性宫颈癌，每2周10mg/kg。
紫杉醇和顺铂或紫杉醇和托泊替康每3周15mg/kg给药作为静脉输注。
剂量形式和强度
注射：单剂量小瓶中100mg/4mL（25mg/mL）或400mg/16mL（25mg/mL）。
禁忌症
没有
警告和注意事项
胃肠穿孔和瘘管：停止胃肠穿孔，气管食管瘘，4级瘘或涉及任何器官的瘘管形成。
手术和伤口愈合并发症：在需要医学干预或坏死性筋膜炎的伤口愈合并发症的患者中停止。选择性手术前至少保留28天。手术后至少28天内不要给予ZIRABEV，直到伤口完全愈合。
出血：发生严重或致命的出血。不要对最近的咯血进行治疗。停止3-4级出血。
动脉血栓栓塞事件（ATE）：严重ATE停止。
静脉血栓栓塞事件（VTE）：4级VTE停用。
高血压：监测血压和治疗高血压。如果不进行医学控制，则不予处理;恢复一旦控制。停止高血压危象或高血压脑病。
后部可逆性脑病综合征（PRES）：停止。
肾损伤和蛋白尿：监测尿蛋白。停止
肾病综合征。扣留至小于2克的尿液中的蛋白质。
输注相关反应：降低输液相关反应的速度。
停止严重的输液相关反应并进行医学治疗。
胚胎 - 胎儿毒性：可能导致胎儿伤害。建议女性对胎儿有潜在的风险并需要使用有效的避孕措施。
卵巢功能衰竭：告知女性潜在的风险。
充血性心力衰竭（CHF）：在患有CHF的患者中停用ZIRABEV。
不良反应
最常见的不良反应发生率（发生率> 10％）是鼻ep，头痛，高血压，鼻炎，蛋白尿，味觉改变，皮肤干燥，直肠出血，流泪病，背痛和剥脱性皮炎。
要报告疑似不良反应，请致电1-800-438-1985联系辉瑞公司，并通过www.Pfizer.com或FDA联系1-800-FDA-1088或www.fda.gov/medwatch。
用于特定人群
哺乳期：建议不要母乳喂养。
生物仿制药意味着生物产品基于数据证明其与FDA批准的生物产品（称为参考产品）非常相似，并且生物仿制药产品和参考产品之间没有临床上有意义的差异。已经证明ZIRABEV的生物相似性用于使用条件（例如，适应症，给药方案），强度，剂型和给药途径。
包装提供/存储和处理
ZIRABEV（bevacizumab-bvzr）注射液是一种透明至微乳白色无色至浅棕色无菌溶液，用于静脉输液，装在一个装有一个单剂量小瓶的纸盒中，具有以下优点：
100mg/4 mL（25mg/mL）（NDC 0069-0315-01）
400mg/16mL（25mg/mL）（NDC 0069-0342-01）
在原装纸箱中冷藏至2°C至8°C（36°F至46°F），直至使用时避免光照。 不要冷冻或摇动小瓶或纸盒。
完整说明资料附件：http://labeling.pfizer.com/ShowLabeling.aspx?id=11860
U.S. FDA Approval for Its Oncology Biosimilar, ZIRABEV™ (bevacizumab-bvzr)
About ZIRABEV (bevacizumab-bvzr)
ZIRABEV is a mAb biosimilar of the reference product, Avastin, which works by inhibiting the formation of new blood cells (angiogenesis) by specifically recognizing and binding to vascular endothelial growth factor (VEGF) protein. As part of the REFLECTIONS clinical trial program, ZIRABEV has been studied in nearly 400 patients to date.
ZIRABEV IMPORTANT SAFETY INFORMATION
Warnings and Precautions
Gastrointestinal Perforations and Fistulae. Serious and sometimes fatal gastrointestinal perforation occurred at a higher incidence in patients receiving bevacizumab products compared to patients receiving chemotherapy. Non-GI fistulae (<1% to 1.8%, highest in patients with cervical cancer). Discontinue for gastrointestinal perforations, tracheoesophageal fistula, grade 4 fistula, or fistula formation involving any internal organ
Surgery and Wound Healing Complications. The incidence of wound healing and surgical complications, including serious and fatal complications, is increased in bevacizumab-treated patients. Withhold for at least 28 days prior to elective surgery. Do not administer for at least 28 days following surgery and until the wound is fully healed. Discontinue in patients who develop wound healing complications that require medical intervention or necrotizing fasciitis
Hemorrhage. Severe or fatal hemorrhage, including hemoptysis, GI bleeding, hematemesis, central nervous system hemorrhage, epistaxis, and vaginal bleeding occurred up to 5-fold more frequently in patients receiving bevacizumab. In clinical studies, the incidence of grade≥3 hemorrhagic events among patients receiving bevacizumab ranged from 0.4% to 7%. Do not administer ZIRABEV to patients with serious hemorrhage or a recent history of hemoptysis(≥1/2 tsp of red blood). Discontinue ZIRABEV in patients who develop grade 3–4 hemorrhage
Additional serious and sometimes fatal adverse events with increased incidence in the bevacizumab-treated arm vs chemotherapy arm included:
Arterial thromboembolic events (grade ≥3, 5%, highest in patients with GBM). Discontinue in patients who develop a severe ATE.
Renal injury and proteinuria. Monitor proteinuria during ZIRABEV therapy. Patients with a 2+ or greater urine dipstick reading should undergo 24-hour urine collection. Withhold for proteinuria >2 grams per 24 hours and resume when less than 2 grams per 24 hours. Discontinue in patients who develop nephrotic syndrome
Grade 3–4 proteinuria ranged from 0.7% to 7% in clinical studies
Nephrotic syndrome(<1%)
Additional serious adverse events with increased incidence in the bevacizumab-treated arm vs chemotherapy arm included:
Venous thromboembolism (grade≥3, 11% seen in Study GOG-0240). Discontinue ZIRABEV in patients with a Grade 4 VTE, including pulmonary embolism
Hypertension (grade 3–4, 5%–18%). Monitor blood pressure during treatment and, for ZIRABEV associated hypertension, continue monitoring after discontinuation. Withhold for severe hypertension. Discontinue for hypertensive crisis or hypertensive encephalopathy
Posterior reversible encephalopathy syndrome (PRES) (<0.5%). Discontinue ZIRABEV in patients who develop PRES. Symptoms usually resolve or improve within days after discontinuing bevacizumab products, although some patients have experienced ongoing neurologic sequelae.
Congestive heart failure (CHF) (1%). Discontinue ZIRABEV in patients who develop CHF
Infusion-related reactions with the first dose of bevacizumab occurred in <3% of patients, and severe reactions occurred in 0.2% of patients. Decrease the rate of infusion for mild infusion-related reactions. Interrupt the infusion in patients with clinically significant infusion-related reactions and consider resuming at a slower rate following resolution. Discontinue in patients who develop a severe infusion-related reaction and administer appropriate medical therapy
Inform females of reproductive potential of the risk of ovarian failure prior to initiating treatment with ZIRABEV
Pregnancy Warning
Based on the mechanism of action and animal studies, bevacizumab products may cause fetal harm
Advise female patients that bevacizumab products may cause fetal harm and to inform their healthcare provider of a known or suspected pregnancy
Advise females of reproductive potential to use effective contraception during treatment with ZIRABEV and for 6 months after the last dose of ZIRABEV
Advise nursing women that breastfeeding is not recommended during treatment with ZIRABEV and for 6 months following their last dose of treatment
Bevacizumab products may impair fertility
Most Common Adverse Events
Across studies, the most common adverse reactions observed in bevacizumab patients at a rate >10% were:
Epistaxis, headache, hypertension, rhinitis, proteinuria, taste alteration, dry skin, rectal hemorrhage, lacrimation disorder, back pain, exfoliative dermatitis
Across all studies, bevacizumab was discontinued in 8% to 22% of patients because of adverse reactions
Indication-Specific Adverse Events
In first-line metastatic colorectal cancer (MCRC), the most common grade 3–4 events in Study 2107, which occurred at a (≥2%) higher incidence in the bevacizumab plus IFL vs IFL groups, were asthenia (10% vs 7%), abdominal pain (8% vs 5%), pain (8% vs 5%), hypertension (12% vs 2%), deep vein thrombosis (9% vs 5%), intra-abdominal thrombosis (3% vs 1%), syncope (3% vs 1%), diarrhea (34% vs 25%), constipation (4% vs 2%), leukopenia (37% vs 31%), and neutropenia (21% vs 14%)
In second-line MCRC, the most common grade 3–5 (nonhematologic) and 4–5 (hematologic) events in Study E3200, which occurred at a higher incidence (≥2%) in the bevacizumab plus FOLFOX4 vs FOLFOX4 groups, were fatigue (19% vs 13%), diarrhea (18% vs 13%), sensory neuropathy (17% vs 9%), nausea (12% vs 5%), vomiting (11% vs 4%), dehydration (10% vs 5%), hypertension (9% vs 2%), abdominal pain (8% vs 5%), hemorrhage (5% vs 1%), other neurological (5% vs 3%), ileus (4% vs 1%), and headache (3% vs 0%). These data are likely to underestimate the true adverse event rates due to the reporting mechanisms used in this study
In non–small cell lung cancer (NSCLC), grade 3–5 (nonhematologic) and grade 4–5 (hematologic) adverse events in Study E4599 occurring at a (≥2%) higher incidence in bevacizumab-treated patients vs controls were neutropenia (27% vs 17%), fatigue (16% vs 13%), hypertension (8% vs 0.7%), infection without neutropenia (7% vs 3%), venous thromboembolism (5% vs 3%), febrile neutropenia (5% vs 2%), pneumonitis/pulmonary infiltrates (5% vs 3%), infection with grade 3 or 4 neutropenia (4% vs 2%), hyponatremia (4% vs 1%), headache (3% vs 1%), and proteinuria (3% vs 0%)
In recurrent glioblastoma (rGBM) Study EORTC 26101, 22% of patients discontinued treatment in the bevacizumab with lomustine arm due to adverse reactions compared with 10% of patients in the lomustine arm. In patients receiving bevacizumab with lomustine, the adverse reaction profile was similar to that observed in other approved indications
In metastatic renal cell carcinoma (mRCC), the most common grade 3–5 adverse events in Study BO17705, occurring at a (≥2%) higher incidence in bevacizumab-treated patients vs controls, were fatigue (13% vs 8%), asthenia (10% vs 7%), proteinuria (7% vs 0%), hypertension (6% vs 1%, including hypertension and hypertensive crisis), and hemorrhage (3% vs 0.3%, including epistaxis, small intestinal hemorrhage, aneurysm ruptured, gastric ulcer hemorrhage, gingival bleeding, hemoptysis, hemorrhage intracranial, large intestinal hemorrhage, respiratory tract hemorrhage, and traumatic hematoma)
In persistent, recurrent, or metastatic cervical cancer, grade 3 or 4 adverse reactions in Study GOG-0240, occurring at a higher incidence (≥2%) in 218 patients receiving bevacizumab plus chemotherapy compared to 222 patients receiving chemotherapy alone, were abdominal pain (12% vs 10%), diarrhea (6% vs 3%), anal fistula (4% vs 0%), proctalgia (3% vs 0%), urinary tract infection (8% vs 6%), cellulitis (3% vs 0.5%), fatigue (14% vs 10%), hypertension (11% vs 0.5%), thrombosis (8% vs 3%), hypokalemia (7% vs 4%), hyponatremia (4% vs 1%), dehydration (4% vs 0.5%), neutropenia (8% vs 4%), lymphopenia (6% vs 3%), back pain (6% vs 3%), and pelvic pain (6% vs 1%)
INDICATIONS
Metastatic Colorectal Cancer
ZIRABEV, in combination with intravenous fluorouracil-based chemotherapy, is indicated for the first- or second-line treatment of patients with metastatic colorectal cancer(mCRC).
ZIRABEV, in combination with fluoropyrimidine-irinotecan- or fluoropyrimidine-oxaliplatin-based chemotherapy, is indicated for the second-line treatment of patients with mCRC who have progressed on a first-line bevacizumab product-containing regimen.
Limitation of Use: ZIRABEV is not indicated for adjuvant treatment of colon cancer.
First-Line Non-Squamous Non-Small Cell Lung Cancer
ZIRABEV, in combination with carboplatin and paclitaxel, is indicated for the first line treatment of patients with unresectable, locally advanced, recurrent or metastatic non–squamous non–small cell lung cancer (NSCLC).
Recurrent Glioblastoma
ZIRABEV is indicated for the treatment of recurrent glioblastoma (GBM) in adults.
Metastatic Renal Cell Carcinoma
ZIRABEV, in combination with interferon alfa, is indicated for the treatment of metastatic renal cell carcinoma (mRCC).
Persistent, Recurrent, or Metastatic Cervical Cancer
ZIRABEV, in combination with paclitaxel and cisplatin or paclitaxel and topotecan, is indicated for the treatment of patients with persistent, recurrent, or metastatic cervical cancer.