近日，Zarxio(Filgrastim-sndz Injection)注射液已成为美国第一个获批的生物仿制药，用于与非格司亭相同的适应症
FDA局长说：“生物相似性将对需要它们的患者提供得到重要的治疗，”“患者和卫生保健社区可以相信被FDA批准的生物相似性产品复合监管局的严格的安全性，疗效和质量标准。”
注：请注意本品是非线性药代动力学，没有用等效性方法评价生物相似性。
批准日期：3月6, 2015；公司：Sandoz
ZARXIO(非格司亭 filgrastim-sndz)注射液，供皮下或静脉使用
美国初次批准：2015
作用机制
集落刺激因子是糖蛋白其作用于造血细胞hematopoietic cells 通过与特异性细胞表面受体结合和刺激增殖，承担的分化，和有些细胞终端功能活化。
内源性G-CSF是由单核细胞，纤维母细胞，和内皮细胞生成的一种谱系特异性细胞集落刺激因子。G-CSF调节骨髓内嗜中性的产生和影响嗜中性祖细胞增殖，分化，和被选定的终端细胞功能(包括增强吞噬能力，启动与呼吸爆发，抗体-依赖杀死，和增加某些细胞表面抗原表达关联的细胞代谢)。G-CSF没有物种特异性和曾显示对除嗜中性谱系外造血细胞类型有最小在体内或体外生成或活性影响。
适应证和用途
ZARXIO是一种白细胞生长因子适用为:
⑴减低感染的发生率，如表现为发热性中性粒细胞减少，非骨髓恶性病患者接受骨髓抑制性抗癌药伴随有发热严重中性粒细胞减少的显著发生率。
⑵ 减少至嗜中性恢复时间和发热的时间，急性髓性白血病患者(AML)诱导或巩固化疗治疗时间。
⑶ 减少中性粒细胞减少的时间和中性粒细胞减少-相关临床后遗症，如，在有非骨髓恶性病正在进行清髓化疗接着用骨髓移植(BMT)患者中，发热性中性粒细胞减少。
⑷ 动员自体造血干细胞至外周血为通过白细胞分离收集
⑸ 减少严重中性粒细胞减少后遗症的发生率和时间(如，发热，感染，口咽溃疡)在有先天性中性粒细胞减少，周期性中性粒细胞减少，或特发性中性粒细胞减少症状性患者中
剂量和给药方法
⑴癌症患者接受骨髓抑制性化疗或对AML诱导和/或巩固化疗 
推荐的起始剂量是5µg/kg/day皮下注射，短静脉输注(15至30分钟)，或连续静脉输注。见完整处方资料对推荐剂量调整和给药时机
⑵癌症患者进行骨髓移植
10µg/kg/day给予作为一个静脉输注不长于24小时。对推荐剂量调整和给药时机见完整处方资料。
⑶正在进行自体外周血造血祖细胞收集和治疗患者。
10µg/kg/day皮下注射
首次白细胞分离步骤前至少给予4天和继续直至末次白细胞分离
⑷患者有先天性中性粒细胞减少
推荐的起始剂量是6µg/kg皮下注射每天2次
⑸患者有周期性或特发性中性粒细胞减少
推荐的起始剂量是5 µg/kg皮下注射每天
⑹由于潜在在给药误差不建议直接给予低于0.3mL
剂型和规格
⑴ 注射液：300µg/0.5mL在一单次使用预装注射器有BD UltraSafe PassiveTM护针
⑵ 注射液：480µg/0.8mL在一单次使用预装注射器有BD UltraSafe PassiveTM护针
禁忌证
对人粒细胞集落刺激因子例如非格司亭或聚乙二醇非格司亭产品严重过敏性反应史患者
警告和注意事项
⑴ 致命性脾破裂：为一个脾增大或脾破裂评价报告左上腹或肩部疼痛患者。
⑵ 急性呼吸窘迫综合征(ARDS)：为ARDS评价发生发热和肺侵润或呼吸窘迫患者。有ARDS患者终止ZARXIO。
⑶ 严重过敏性反应，包括过敏反应：有严重过敏性反应患者永久终止ZARXIO。
⑷ 致命性镰状细胞危象：曾发生。
不良反应
患者中最常见不良反应：
⑴ 有非骨髓恶性病接受骨髓抑制性抗癌药(与安慰剂比较发生率差别≥ 5%)是发热, 疼痛，皮疹，咳嗽，和呼吸困难
⑵有AML(发生率差别≥ 2%)是疼痛，鼻衄和皮疹
⑶有非骨髓恶性病正在进行清髓化疗接着BMT(发生率差别≥ 5%)是皮疹
⑷正在进行外周血干细胞动员和采集(≥ 5%发生率)是骨痛，发热和头痛。
⑸(症状性)有严重慢性中性粒细胞减少(SCN)( 发生率差别≥ 5%)是疼痛，贫血，鼻衄，腹泻，感觉迟钝和脱发
特殊人群中使用
⑴妊娠期间只有潜在获益胜过对胎儿潜在风险才应使用ZARXIO。
⑵不知道非格司亭产品是否排泄在人乳汁中。
非格司亭 filgrastim]-sndz 商品名Zarxio FDA批准第一个生物相似性产品 粒细胞集落刺激因子
包装规格/储存与处理
注射单剂，防腐剂，无预充式注射器用超安全被动护针™，含有300微克/0.5mL的非格司亭，sndz的。
•1预充式注射器（NDC 61314-304-01）
•10预充式注射器包装（NDC 61314-304-10）
注射单剂，防腐剂，无预充式注射器用超安全被动护针™，含有480微克/0.8mL的非格司亭，sndz的。
•1预充式注射器（NDC 61314-312-01）
•10预充式注射器包装（NDC 61314-312-10）
乳胶敏感的人：对ZARXIO预充式注射器的可拆卸的针帽含有天然橡胶乳胶可能会导致过敏反应。安全使用ZARXIO乳胶敏感的个人还没有研究。

存储：
储存在原来的包装冰箱在2°C至8°C（36°F至46°F），以防止光线。不要摇晃。不要冷冻。在注射之前，ZARXIO可允许达到室温最多为24小时。离开高于25°C（77°F）的任何预充式注射器超过24小时应丢弃。
避免冻结;如果冻结，解冻在给药前的冰箱。如果丢弃冷冻黑莓比盎司ZARXIO

Zarxio (Filgrastim-sndz Injection)
Important Safety Information
CONTRAINDICATIONS
ZARXIO is contraindicated in patients with a history of serious allergic reactions to human granulocyte colony-stimulating factors such as filgrastim or pegfilgrastim products.
WARNINGS AND PRECAUTIONS
Splenic rupture, including fatal cases, has been reported following the administration of filgrastim products. Patients who report left upper abdominal or shoulder pain should be evaluated.
Acute respiratory distress syndrome (ARDS) has been reported in patients receiving filgrastim products. Patients who develop fever and lung infiltrates or respiratory distress should be evaluated. Discontinue ZARXIO in patients with ARDS.
Serious allergic reactions, including anaphylaxis, have been reported in patients receiving filgrastim products. The majority of reported events occurred upon initial exposure. Provide symptomatic treatment for allergic reactions. Allergic reactions, including anaphylaxis, in patients receiving filgrastim products can recur within days after the discontinuation of initial anti-allergic treatment. Permanently discontinue ZARXIO in patients with serious allergic reactions.
Sickle cell crisis, in some cases fatal, has been reported with the use of filgrastim products in patients with sickle cell trait or sickle cell disease.
Glomerulonephritis has occurred in patients receiving filgrastim products. The diagnoses were based upon azotemia, hematuria (microscopic and macroscopic), proteinuria, and renal biopsy. Generally, events of glomerulonephritis resolved after dose reduction or discontinuation of filgrastim. If glomerulonephritis is suspected, evaluate for cause. If causality is likely, consider dose-reduction or interruption of ZARXIO.
Alveolar hemorrhage manifesting as pulmonary infiltrates and hemoptysis requiring hospitalization have been reported in healthy donors treated with filgrastim products undergoing peripheral blood progenitor cell (PBPC) collection mobilization. Hemoptysis resolved with discontinuation of filgrastim. The use of ZARXIO for PBPC mobilization in healthy donors is not an approved indication.
Capillary leak syndrome (CLS) has been reported after G-CSF administration, including filgrastim products, and is characterized by hypotension, hypoalbuminemia, edema and hemoconcentration. Episodes vary in frequency, severity and may be life-threatening if treatment is delayed. Patients who develop symptoms of capillary leak syndrome should be closely monitored and receive appropriate treatment.
Confirm the diagnosis of severe chronic neutropenia (SCN) before initiating ZARXIO therapy. Myelodysplastic syndrome (MDS) and acute myelogenous leukemia (AML) have been reported to occur in the natural history of congenital neutropenia without cytokine therapy. Cytogenetic abnormalities, transformation to MDS, and AML have also been observed in patients treated with filgrastim products for SCN. Abnormal cytogenetics and MDS have been associated with the eventual development of myeloid leukemia. The effect of filgrastim products on the development of abnormal cytogenetics and the effect of continued filgrastim administration in patients with abnormal cytogenetics or MDS are unknown. If a patient with SCN develops abnormal cytogenetics or myelodysplasia‚ the risks and benefits of continuing ZARXIO should be carefully considered.
Thrombocytopenia has been reported in patients receiving filgrastim products. Monitor platelet counts.
Leukocytosis:
Patients with Cancer Receiving Myelosuppressive Chemotherapy: White blood cell counts of 100‚000/mm3 or greater were observed in approximately 2% of patients receiving filgrastim at dosages above 5 mcg/kg/day. In patients with cancer receiving ZARXIO as an adjunct to myelosuppressive chemotherapy‚ to avoid the potential risks of excessive leukocytosis‚ it is recommended that ZARXIO therapy be discontinued if the ANC surpasses 10‚000/mm3 after the chemotherapy-induced ANC nadir has occurred. Monitor CBCs at least twice weekly during therapy.
Peripheral Blood Progenitor Cell (PBPC) Collection and Therapy: During the period of administration of ZARXIO for PBPC mobilization in patients with cancer, discontinue ZARXIO if the leukocyte count rises to >100,000/mm3.
Cutaneous vasculitis has been reported in patients treated with filgrastim products. In most cases‚ the severity of cutaneous vasculitis was moderate or severe. Most of the reports involved patients with SCN receiving long-term filgrastim therapy. Hold ZARXIO therapy in patients with cutaneous vasculitis. ZARXIO may be started at a reduced dose when the symptoms resolve and the ANC has decreased.
The possibility that filgrastim acts as a growth factor for any tumor type, including myeloid malignancies and myelodysplasia, diseases for which filgrastim is not approved, cannot be excluded. The safety of filgrastim products in chronic myeloid leukemia (CML) and myelodysplasia has not been established. When ZARXIO is used to mobilize PBPC‚ tumor cells may be released from the marrow and subsequently collected in the leukapheresis product. Available data is limited and inconclusive.
The safety and efficacy of ZARXIO given simultaneously with cytotoxic chemotherapy have not been established. Do not use ZARXIO in the period 24 hours before through 24 hours after the administration of cytotoxic chemotherapy. The safety and efficacy of ZARXIO have not been evaluated in patients receiving concurrent radiation therapy. Avoid the simultaneous use of ZARXIO with chemotherapy and radiation therapy.
Increased hematopoietic activity of the bone marrow in response to growth factor therapy has been associated with transient positive bone-imaging changes on nuclear imaging.
ADVERSE REACTIONS
Most common adverse reactions in patients:
With nonmyeloid malignancies receiving myelosuppressive anti-cancer drugs (≥5% difference in incidence compared to placebo) are thrombocytopenia, nausea, pyrexia, chest pain, pain, fatigue, back pain, arthralgia, bone pain, pain in extremity, dizziness, cough, dyspnea, rash, blood lactate dehydrogenase increased and blood alkaline phosphatase increased
With AML (≥2% difference in incidence) are epistaxis, back pain, pain in extremity, erythema, and rash maculo-papular
With nonmyeloid malignancies undergoing myeloablative chemotherapy followed by BMT (≥5% difference in incidence) are rash and hypersensitivity
Undergoing peripheral blood progenitor cell mobilization and collection (≥5% incidence) are bone pain, pyrexia, blood alkaline phosphatase increased and headache
With severe chronic neutropenia (SCN) (≥5% difference in incidence) are arthralgia, bone pain, back pain, muscle spasms, musculoskeletal pain, pain in extremity, splenomegaly, anemia, upper respiratory tract infection, urinary tract infection, epistaxis, chest pain, diarrhea, hypoesthesia, and alopecia
Please see full Prescribing Information.
To report SUSPECTED ADVERSE REACTIONS, contact Sandoz Inc. at 1-800-525-8747 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
INDICATIONS
Patients with Cancer Receiving Myelosuppressive Chemotherapy: ZARXIO is indicated to decrease the incidence of infection, as manifested by febrile neutropenia, in patients with nonmyeloid malignancies receiving myelosuppressive anti-cancer drugs associated with a significant incidence of severe neutropenia with fever.
Patients with Acute Myeloid Leukemia Receiving Induction or Consolidation Chemotherapy: ZARXIO is indicated to reduce the time to neutrophil recovery and the duration of fever, following induction or consolidation chemotherapy treatment of patients with acute myeloid leukemia (AML).
Patients with Cancer Undergoing Bone Marrow Transplantation: ZARXIO is indicated to reduce the duration of neutropenia and neutropenia-related clinical sequelae, e.g., febrile neutropenia, in patients with nonmyeloid malignancies undergoing myeloablative chemotherapy followed by bone marrow transplantation.
Patients Undergoing Autologous Peripheral Blood Progenitor Cell Collection and Therapy: ZARXIO is indicated for the mobilization of autologous hematopoietic progenitor cells into the peripheral blood for collection by leukapheresis.
Patients with Severe Chronic Neutropenia: ZARXIO is indicated for chronic administration to reduce the incidence and duration of sequelae of neutropenia (e.g, fever, infections, oropharyngeal ulcers) in symptomatic patients with congenital neutropenia, cyclic neutropenia, or idiopathic neutropenia.
ZARXIO is a trademark of Novartis AG.
http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=fe707775-a0ae-41b5-a744-28c41889fce8