Neupogen是一种蛋白质，它通过与造血细胞表面的受体结合，刺激造血细胞增生分化为中性粒细胞，并使细胞功能活化。
Neulasta是免疫刺激Neupogen（filgrastim，非格司亭）的长效制剂。 Neulasta是非格司亭的第二代聚乙二醇化制剂，在每个化疗同期以固定剂量用药一次（6mg），以降低用骨髓抑制性抗癌药治疗的非髓性恶性肿瘤患者感染的出现，感染是发热中性白细胞减少的症状。
Amgen新制剂的出现使从对中性白细胞减少症的治疗转为对其预防性治疗。目前，不到10%的化疗病人接受Neupogen来预防中性粒细胞减少症的发生，中性粒细胞数严重降低是癌症治疗的常见并发征。使用Neupogen主要的不便之处是必须每天注射，连续2周（或到白细胞计数恢复到正常水平）。Neulasta每一疗程注射一次，使用方便。公司认为其方便的用药方法更适宜于老年患者和免疫妥协患者。

药品名称  非格司亭 
英文药名  Filgrastim 
药品别名
优保津、非格司亭、重组人体白细胞生成素、非雷司替、惠尔血、特尔津、瑞白、格拉诺赛特、吉粒芬、吉赛欣、津恤力、粒细胞集落刺激因子、rhG-CSF  Neupogen
药理作用
本药是由175个氨基酸组成的蛋白质通过重组DNA技术制成，与天然G-CSF的氨基酸序列和糖链完全相同，不同的是rhG-CSF链的N端含有蛋氨酸。分子量为1.8×104～2.4×104，编码基因位于17号染色体长臂的q21～q22之间。本药通过与粒系祖细胞及成熟中性粒细胞表面的特异性受体结合，促进前者的增殖分化并增强后者的功能(包括趋化性、吞噬和杀伤功能等)。本药还可促进髓系造血祖细胞的增殖、分化和成熟，调节中性粒细胞系的增殖与分化成熟；也可驱使中性粒细胞释放至血流，使外周中性粒细胞数量增多。
药动学
药代动力学研究发现，非格司亭的半衰期(t1/2)与用药剂量有关。对健康男子进行的静脉点滴和皮下注射给药的研究表明，用量为1μg/kg时，t1/2为1.4h；用量小于1.5μg/kg时，t1/2为1.4±0.3h，并有随剂量的增加而延长的现象，AUC为每小时21.6ng/ml；皮下注射，血药峰浓度(Cmax)出现在给药后3.5～4.5h，t1/2为2.15h，AUC为每小时21.6ng/ml，生物利用率为0.54。
用量在5μg/kg或以上时，机体清除力达到饱和，t1/2稳定在3.7±0.3h。相同剂量皮下注射给药4h后血药浓度比静脉点滴同一时间的为高。连续给药6天以上血药浓度与单次给药时无明显差异。本药皮下注射吸收良好，在血清中5min内即可测得。达峰时间为2～8h；静脉滴注后30min达血药峰浓度。半衰期约1～5h，静脉与皮下注射的消除半衰期相似，均约3～5h。本药起效迅速，静脉注射后5min先出现周围血中性粒细胞减少，4h后开始上升并逐渐超过原有水平，24h内达高峰。
连续静脉或皮下给药其血药浓度变化与单次给药相似，表明本药无蓄积作用。
适应证
1.用于治疗各种原因引起的中性粒细胞减少症(如恶性肿瘤放疗与化疗引起的粒细胞减少)，造血干细胞移植后促进髓系造血功能的恢复，周围血造血干细胞移植前的干细胞动员等。
2.其较大剂量亦可用于骨髓增生异常综合征(MDS)与再生障碍性贫血伴发的中性粒细胞减少症，以及先天性、周期性中性粒细胞减少症，但远期疗效不肯定。
3.用于获得性免疫缺陷综合征(艾滋病)本身及其感染或抗逆转录病毒制剂所引起的中性粒细胞减少。
4.预防用药：用于大剂量化疗后、既往有化疗后严重骨髓抑制史以及大范围放射治疗后再化疗的患者。
5.用于骨髓移植：主要用于造血干细胞的动员及移植后骨髓造血功能的重建。
禁忌证
对本品或其他粒细胞刺激因子制剂过敏者禁用。自身免疫性血小板紫癜者禁用。在化疗前或癌症化疗同时禁用本品。骨髓幼稚细胞未充分降低或外周血存在未成熟细胞的骨髓性白血病症者禁用。
注意事项
1.慎用：
(1)有药物过敏史者。
(2)过敏体质者。
(3)肝、肾、心、肺功能重度障碍者。
(4)急、慢性髓性白血病化疗后的患者(本药对髓性白血病细胞有刺激增殖作用)。
(5)MDS难治性贫血伴原始细胞增多型患者(本药对某些肿瘤细胞有刺激增殖作用)。
2.交叉过敏：对大肠杆菌蛋白过敏者，使用大肠杆菌重组的rhG-CSF后可能出现交叉过敏反应。
3.药物对儿童的影响：本药对早产儿、婴儿的安全性尚未确认。
4.药物对妊娠的影响：本药在人类孕期的安全性尚不清楚，故孕妇不宜使用。
5.药物对哺乳的影响：本药是否由乳汁分泌尚不清楚，故哺乳期妇女不宜使用。
6.用药中应定期监测血象，以避免造成中性粒细胞过多。
7.本药的使用对象仅限于中性粒细胞减少的患者。
8.用药过程中若出现过敏反应，应立即停药并给予适当处理。
9.由于迅速增殖分化的造血祖细胞对放(化)疗敏感，本药不应和放(化)疗同时使用。
10.周围血白细胞升至(2～5)×109/L时可停药；若其大于10×109/L或周围血液出现幼稚细胞时，应立即停药。
11.本药使用前应避免振荡，因振荡后起泡可减少实际吸入注射器的剂量。若发现溶液已起泡，可静置数min后再抽取。本药供静脉注射须用5%葡萄糖注射剂稀释，浓度不低于15μg/ml，若rhG-CSF的终浓度在2～15μg/ml之间，须在加本药之前于5%葡萄糖注射剂中先加入终浓度为0.2%的人血白蛋白，以避免输液系统对本药的吸附。
本药滴注速度不宜过快(快速静脉用药可使其作用减低)，每次至少持续1h以上，其稀释后应在6h内输完。
12.本药不能与其他注射剂混合使用。
13.皮下注射的血药浓度维持时间较长且用药更方便。
14.用药时间太短基本无效。非格司亭至少用5～7天，才能发挥刺激骨髓造血的作用，太短仅能刺激骨髓中的成熟粒细胞的释放，停药后则又降至低点。这种用法貌似经济，实则为浪费。
15.一般情况下化疗前或化疗中不要使用。因为此时应用非格司亭，促进骨髓中的造血细胞加速增殖，这些细胞对细胞毒化疗药物更为敏感。虽外周血白细胞数可达化疗所需指标，但是一旦很快给予化疗则发生严重骨髓抑制且不易恢复。
16.预防用药首次应在末次化疗给药后24～72h。根据所用化疗药物的代谢情况而定，尽量减少细胞毒化疗药物对骨髓造血细胞的毒害。
17.化疗引起的骨髓抑制有时单用集落刺激因子效果不显，往往见于化疗反应重，致患者营养状况差。此时不要过于依赖集落刺激因子，如同时加强营养支持治疗可能更为有效。
18.有研究表明，相同剂量分一天两次用药比一次给药效果好。
19.尽可能不静脉用药。原因之一是集落刺激因子的作用与血中峰浓度无关，而与达到有效血浓度的持续时间有关。皮下注射或肌内注射药物代谢缓慢，有利于其发挥作用。另外，集落刺激因子静脉用药可能引起严重的变态反应。
20.在保证有效的前提下尽量用小剂量。因为用量加大不良反应的概率及程度也会加大。
21.考虑集落刺激因子在临床有滥用的情况，预防用药的指征应严格掌握。
22.如果除提高粒细胞外同时又需提高免疫功能，则选择GM-CSF为好。23.长期应用集落刺激因子可导致骨髓增生不良和肝肾功能受损。
24.对预防性用药，用药早疗效好。有研究比较化疗后不同时间开始预防性用药的效果，发现化疗结束后24～48h用药者，中性粒细胞减少的天数最短。化疗后72h之内用药者，中性粒细胞减少的天数最少。
25.放化疗同步应用时使用非格司亭或GM-CSF可导致严重的血小板减少，应予注意。
不良反应
1.较常见的不良反应为骨痛及关节肌肉酸痛，多出现于大剂量静脉用药或用药后白细胞升至接近正常水平的患者，其程度为轻至中度，无需临床处理。
2.有时会有消化道反应(食欲缺乏、恶心、呕吐等)、肝功能损害(轻度可逆性ALT、AST、碱性磷酸酶升高)、一过性低血压及室上性心动过速等，还可引起发热、头痛、倦怠、心悸、尿酸和肌酐升高等。
3.偶有皮肤发红、皮疹、急性发热白细胞增多性皮肤病(表现为发热伴皮损与疼痛)。
4.长期用药者有时可见脾大，但多为亚临床型。
5.较严重的不良反应如水钠潴留、血栓形成、低血压或过敏性休克等罕见。
用法用量
1.成人：
(1)静脉注射：
①造血干细胞移植：在移植后的次日或第5天起，每天1次，给药5μg/kg。
②肿瘤化疗引起的中性粒细胞减少症(白细胞数减至2.0×109/L以下时)：每天5μg/kg。
(2)皮下注射：
①白血病及造血干细胞移植：每天2.5～5μg/kg，待白细胞升至大于2×109/L即停药。
②实体瘤日剂量可适当减少，一般为2～3μg/kg，每天1次。
③再生障碍性贫血、MDS或其他骨髓衰竭性疾病：每天剂量一般应超过肿瘤性疾病，且疗程宜长。
④用于外周血造血干细胞移植前的干细胞动员：于化疗后白细胞降至最低点(一般为停化疗后约2周)时开始用药，剂量为每天5～10μg/kg，至白细胞升至大于等于5.0×109/L时开始采集周围血干细胞，采集期间继续用药。
⑤肿瘤化疗引起的中性粒细胞减少症：每次2μg/kg，每天1次。
2.儿童：
(1)静脉注射：
①造血干细胞移植：用法用量同成人。
②肿瘤化疗引起的中性粒细胞减少症(白细胞数减至1.0×109/L以下时)：每天2μg/kg。
(2)皮下注射：用法用量同成人。
3.非格司亭的治疗用药：在发生粒细胞减少症时非格司亭的最小有效剂量尚未准确地确定。对化疗所致的粒细胞减少症，临床通常的用法是根据粒细胞减少的程度给予相适应的剂量。
(1)白细胞总数在2.0×109/L以下或中性粒细胞在1.0×109/L以下时，非格司亭的用量为每天2.0～5.0μg/kg，皮下注射，持续10～14天。用药过程中需监测外周血白细胞的变化，如连测两天白细胞总数≥10×109/L或中性粒细胞≥6.0×109/L时停用。如果已连续使用14天无明显效果，再用也无益。
(2)白细胞总数在2.0×109～3.0×109/L时，非格司亭的用量为每天1.0～2.0μg/kg，皮下注射，持续7～10天。用药过程中需监测外周血白细胞的变化，白细胞总数≥8.0×109/L减至同一用量隔日1次。如连测两天白细胞总数≥5.0×10＾9/L时停用。如果已连续使用14天无明显效果，再用也无益。4.非格司亭的预防用药：用药的剂量根据化疗所致的骨髓抑制的程度确定。用药一般采用低剂量即可，非格司亭的用量为每天1.0～2.0μg/kg，皮下注射，持续5～7天。白细胞总数≥10×109/L时停药。如果白细胞总数未达此指标，则可用7～10天或再用数日，达到上述指标再停药。
5.骨髓或外周血干细胞移植时造血干细胞的动员：单用时每天5～16μg/kg，皮下注射，每天分2次用，持续5～6天；与化疗联合动员时每天5～10μg/kg。常用量每天300μg。与GM-CSF联合应用于造血干细胞动员，可使CD＋34细胞及原始的CD＋34细胞增多。超过每天16μg/kg不良反应增加。
药物相应作用
本药与化疗药同时应用，会因迅速分化的定向造血干细胞对化疗药敏感而影响非格司亭的效果。对乙酰氨基酚或非甾体抗炎药治疗本品所致的胃痛是有效的，用解热镇痛的药治疗引起的发热、头痛、肌痛也有效。

专家点评
本品是应用基因重组工程技术制成的一种蛋白质。作用机制为粒系祖细胞及成熟中性粒细胞表面的特异性受体结合，促进前者的增殖分化并增强后者的功能。本品为Ⅱ类造血刺激因子，有细胞系特异性，仅作用于中性粒细胞及其祖细胞。适用于治疗各种原因引起的中性粒细胞减少症，较大剂量也可用于骨髓增生异常综合征，与再生障碍性贫血伴发的中性粒细胞减少症。骨髓抑制是大多数化疗药物的剂量限制毒性。对治疗策略中需要化疗的大多数恶性肿瘤来说，用足剂量以及按化疗周期安排按时开始下一周期化疗对保证应有的疗效都至关重要。另有一些恶性肿瘤的化疗疗效更与化疗药物的剂量强度(DoseIntensity，DI)有关，如恶性淋巴瘤、小细胞肺癌、生殖细胞肿瘤等对化疗敏感并可获根治的恶性肿瘤。集落刺激因子的临床应用，使得上述要求变得可能。非格司亭预防用药可加大主要为骨髓限制毒性的化疗药物类的用量，提高化疗疗效。另外，非格司亭的预防用药可促进化疗后骨髓造血功能的恢复，缩短中性粒细胞在正常值以下持续的时间，使化疗可按计划进行。
目前由于考虑价效比，主要用于化疗敏感且可获根治的恶性肿瘤。在下述情况下预防性作用：
1.第一周期化疗，常规不需要，仅在发生发热性中性粒细胞减少症的可能性大时(大于40%)使用。如果患者有发生化疗导致的感染性并发症的危险因素，如已存在中性粒细胞减少症或合并感染，或已接受盆腔野或包含大量骨髓组织的放射治疗，可考虑使用。
2.第一周期之后的化疗：如果所用化疗在前一周期化疗后发生发热性中性粒细胞减少症(如果前一周期的中性粒细胞减少症时间很短且无发热则不必使用)；但在下述情况下发生感染相关并发症的可能性加大，应预防用药：粒细胞减少症(中性粒细胞＜0.5×109/L)、原发疾病未控制、合并肺炎、高血压、败血症、深部真菌感染以及老年患者。
3.如果中性粒细胞减少症持续时间长延误化疗，且所治疗的恶性肿瘤为化疗敏感且可获根治的恶性肿瘤则予以使用。
4.同步放化疗或放射治疗引起的粒细胞减少，尤其在放射野包括纵隔时。
5.在化疗间歇期如果放疗包括大的射野，中性粒细胞减少可能会导致治疗耽搁，即考虑使用。对于化疗引起的严重的中性粒细胞减少，常可发生感染、发热。
大量临床研究表明，应用非格司亭或GM-CSF可缩短中性粒细胞恢复期，使发热的危险性减少约34%。

Neulasta(PEGFILGRASTIM) 完整处方说明书
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NeulastaPronunciation.
Generic Name: pegfilgrastim
Dosage Form: injection
Indications and Usage for Neulasta
Neulasta is indicated to decrease the incidence of infection, as manifested by febrile neutropenia, in patients with non-myeloid malignancies receiving myelosuppressive anti-cancer drugs associated with a clinically significant incidence of febrile neutropenia [see Clinical Studies (14)].
Neulasta is not indicated for the mobilization of peripheral blood progenitor cells for hematopoietic stem cell transplantation.
Neulasta Dosage and Administration
The recommended dosage of Neulasta is a single subcutaneous injection of 6 mg administered once per chemotherapy cycle in adults. Do not administer Neulasta between 14 days before and 24 hours after administration of cytotoxic chemotherapy.
Visually inspect parenteral drug products for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not administer Neulasta if discoloration or particulates are observed.
NOTE: The needle cover on the single-use prefilled syringe contains dry natural rubber (latex); persons with latex allergies should not administer this product.
Dosage Forms and Strengths
6mg per 0.6mL in single use prefilled syringe
Contraindications
Do not administer Neulasta to patients with a history of serious allergic reactions to pegfilgrastim or filgrastim.
Warnings and Precautions
Splenic Rupture
Splenic rupture, including fatal cases, can occur following the administration of Neulasta. Evaluate for an enlarged spleen or splenic rupture in patients who report left upper abdominal or shoulder pain after receiving Neulasta.
Acute Respiratory Distress Syndrome
Acute respiratory distress syndrome (ARDS) can occur in patients receiving Neulasta. Evaluate patients who develop fever and lung infiltrates or respiratory distress after receiving Neulasta, for ARDS. Discontinue Neulasta in patients with ARDS.
Serious Allergic Reactions
Serious allergic reactions, including anaphylaxis, can occur in patients receiving Neulasta. The majority of reported events occurred upon initial exposure. Allergic reactions, including anaphylaxis, can recur within days after the discontinuation of initial anti-allergic treatment. Permanently discontinue Neulasta in patients with serious allergic reactions. Do not administer Neulasta to patients with a history of serious allergic reactions to pegfilgrastim or filgrastim.
Use in Patients With Sickle Cell Disorders
Severe sickle cell crises can occur in patients with sickle cell disorders receiving Neulasta. Severe and sometimes fatal sickle cell crises can occur in patients with sickle cell disorders receiving filgrastim, the parent compound of pegfilgrastim.
Potential for Tumor Growth Stimulatory Effects on Malignant Cells
The granulocyte-colony stimulating factor (G-CSF) receptor through which pegfilgrastim and filgrastim act has been found on tumor cell lines. The possibility that pegfilgrastim acts as a growth factor for any tumor type, including myeloid malignancies and myelodysplasia, diseases for which pegfilgrastim is not approved, cannot be excluded.
Adverse Reactions
The following serious adverse reactions are discussed in greater detail in other sections of the labeling:
•Splenic Rupture [See Warnings and Precautions (5.1)]
•Acute Respiratory Distress Syndrome [See Warnings and Precautions (5.2)]
•Serious Allergic Reactions [See Warnings and Precautions (5.3)]
•Use in Patients with Sickle Cell Disorders [See Warnings and Precautions (5.4)]
•Potential for Tumor Growth Stimulatory Effects on Malignant Cells [See Warnings and Precautions (5.5)]
The most common adverse reactions occurring in ≥ 5% of patients and with a between-group difference of ≥ 5% higher in the pegfilgrastim arm in placebo controlled clinical trials are bone pain and pain in extremity.
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.
Neulasta clinical trials safety data are based upon 932 patients receiving Neulasta in seven randomized clinical trials. The population was 21 to 88 years of age and 92% female. The ethnicity was 75% Caucasian, 18% Hispanic, 5% Black, and 1% Asian. Patients with breast (n = 823), lung and thoracic tumors (n = 53) and lymphoma (n = 56) received Neulasta after nonmyeloablative cytotoxic chemotherapy. Most patients received a single 100 mcg/kg (n = 259) or a single 6 mg (n = 546) dose per chemotherapy cycle over 4 cycles.
The following adverse reaction data in Table 1 are from a randomized, double-blind, placebo-controlled study in patients with metastatic or non-metastatic breast cancer receiving docetaxel 100 mg/m2 every 21 days (Study 3). A total of 928 patients were randomized to receive either 6 mg Neulasta (n = 467) or placebo (n = 461). The patients were 21 to 88 years of age and 99% female. The ethnicity was 66% Caucasian, 31% Hispanic, 2% Black, and <1% Asian, Native American or other.
Bone pain and pain in extremity occurred at a higher incidence in Neulasta-treated patients as compared with placebo-treated patients.

Table 1. Adverse Reactions With ≥ 5% Higher Incidence in Neulasta Patients Compared to Placebo in Study 3

System Organ Class Preferred Term	Placebo (N= 461)	Neulasta 6 mg SC on Day 2 (N= 467)
Musculoskeletal and connective tissue disorders
Bone pain	26%	31%
Pain in extremity	4%	9%

Leukocytosis
In clinical studies, leukocytosis (WBC counts > 100 x 109/L) was observed in less than 1% of 932 patients with non-myeloid malignancies receiving Neulasta. No complications attributable to leukocytosis were reported in clinical studies.
Immunogenicity
As with all therapeutic proteins, there is a potential for immunogenicity. Binding antibodies to pegfilgrastim were detected using a BIAcore assay. The approximate limit of detection for this assay is 500 ng/mL. Pre-existing binding antibodies were detected in approximately 6% (51/849) of patients with metastatic breast cancer. Four of 521 pegfilgrastim-treated subjects who were negative at baseline developed binding antibodies to pegfilgrastim following treatment. None of these 4 patients had evidence of neutralizing antibodies detected using a cell-based bioassay.
The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay, and the observed incidence of antibody positivity in an assay may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to Neulasta with the incidence of antibodies to other products may be misleading.
Postmarketing Experience
The following adverse reactions have been identified during post approval use of Neulasta. 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. Decisions to include these reactions in labeling are typically based on one or more of the following factors: (1) seriousness of the reaction, (2) reported frequency of the reaction, or (3) strength of causal relationship to Neulasta.
Gastro-intestinal disorders: Splenic rupture [see Warnings and Precautions (5.1)]
Blood and lymphatic system disorder: Sickle cell crisis [see Warnings and Precautions (5.4)]
Hypersensitivity reactions: Allergic reactions/hypersensitivity, including anaphylaxis, skin rash, and urticaria, generalized erythema and flushing [see Warnings and Precautions (5.3)]
Respiratory, thoracic, and mediastinal disorder: ARDS [see Warnings and Precautions (5.2)]
General disorders and administration site conditions: Injection site reactions
Skin and subcutaneous tissue disorders: Sweet’s syndrome, Cutaneous vasculitis
Drug Interactions
No formal drug interaction studies between Neulasta and other drugs have been performed. Increased hematopoietic activity of the bone marrow in response to growth factor therapy may result in transiently positive bone-imaging changes. Consider these findings when interpreting bone-imaging results.
USE IN SPECIFIC POPULATIONS
Pregnancy
Pregnancy Category C
There are no adequate and well-controlled studies in pregnant women. Pegfilgrastim was embryotoxic and increased pregnancy loss in pregnant rabbits that received cumulative doses approximately 4 times the recommended human dose (based on body surface area). Signs of maternal toxicity occurred at these doses. Neulasta should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus.
In animal reproduction studies, when pregnant rabbits received pegfilgrastim at cumulative doses approximately 4 times the recommended human dose (based on body surface area), increased embryolethality and spontaneous abortions occurred. Signs of maternal toxicity (reductions in body weight gain/food consumption) and decreased fetal weights occurred at maternal doses approximately equivalent to the recommended human dose (based on body surface area). There were no structural anomalies observed in rabbit offspring at any dose tested. No evidence of reproductive/developmental toxicity occurred in the offspring of pregnant rats that received cumulative doses of pegfilgrastim approximately 10 times the recommended human dose (based on body surface area) [see Nonclinical Toxicology (13.3)].
Women who become pregnant during Neulasta treatment are encouraged to enroll in Amgen’s Pregnancy Surveillance Program. Patients or their physicians should call 1-800-77-AMGEN (1-800-772-6436) to enroll.
Nursing Mothers
It is not known whether pegfilgrastim is secreted in human milk. Other recombinant G-CSF products are poorly secreted in breast milk and G-CSF is not orally absorbed by neonates. Caution should be exercised when administered to a nursing woman.
Pediatric Use
Safety and effectiveness of Neulasta in pediatric patients have not been established. The adverse reaction profile and pharmacokinetics of pegfilgrastim were studied in 37 pediatric patients with sarcoma. The mean (± standard deviation [SD]) systemic exposure (AUC0-inf) of pegfilgrastim after subcutaneous administration at 100 mcg/kg was 22.0 (± 13.1) mcg·hr/mL in the 6 to 11 years age group (n = 10), 29.3 (± 23.2) mcg·hr/mL in the 12 to 21 years age group (n = 13), and 47.9 (± 22.5) mcg·hr/mL in the youngest age group (0 to 5 years, n = 11). The terminal elimination half-lives of the corresponding age groups were 20.2 (± 11.3) hours, 21.2 (± 16.0) hours, and 30.1 (± 38.2) hours, respectively. The most common adverse reaction was bone pain.
Geriatric Use
Of the 932 patients with cancer who received Neulasta in clinical studies, 139 (15%) were age 65 and over, and 18 (2%) were age 75 and over. No overall differences in safety or effectiveness were observed between patients age 65 and older and younger patients.
Renal Impairment
In a study of 30 subjects with varying degrees of renal dysfunction, including end stage renal disease, renal dysfunction had no effect on the pharmacokinetics of pegfilgrastim. Therefore, pegfilgrastim dose adjustment in patients with renal dysfunction is not necessary [Clinical Pharmacology (12.3)].
Overdosage
The maximum amount of Neulasta that can be safely administered in single or multiple doses has not been determined. Single subcutaneous doses of 300 mcg/kg have been administered to 8 healthy volunteers and 3 patients with non-small cell lung cancer without serious adverse effects. These patients experienced a mean maximum absolute neutrophil count (ANC) of 55 x 109/L, with a corresponding mean maximum WBC of 67 x 109/L. The absolute maximum ANC observed was 96 x 109/L with a corresponding absolute maximum WBC observed of 120 x 109/L. The duration of leukocytosis ranged from 6 to 13 days. The effectiveness of leukapheresis in the management of symptomatic individuals with Neulasta-induced leukocytosis has not been studied.
Neulasta Description
Neulasta (pegfilgrastim) is a covalent conjugate of recombinant methionyl human G-CSF (filgrastim) and monomethoxypolyethylene glycol. Filgrastim is a water-soluble 175 amino acid protein with a molecular weight of approximately 19 kilodaltons (kD). Filgrastim is obtained from the bacterial fermentation of a strain of E coli transformed with a genetically engineered plasmid containing the human G-CSF gene. To produce pegfilgrastim, a 20 kD monomethoxypolyethylene glycol molecule is covalently bound to the N-terminal methionyl residue of filgrastim. The average molecular weight of pegfilgrastim is approximately 39 kD.
Neulasta is supplied in 0.6 mL prefilled syringes for subcutaneous injection. Each syringe contains 6 mg pegfilgrastim (based on protein weight) in a sterile, clear, colorless, preservative-free solution (pH 4.0) containing acetate (0.35 mg), polysorbate 20 (0.02 mg), sodium (0.02 mg), and sorbitol (30 mg) in Water for Injection, USP.
Neulasta - Clinical Pharmacology
Mechanism of Action
Pegfilgrastim is a colony-stimulating factor that acts on hematopoietic cells by binding to specific cell surface receptors, thereby stimulating proliferation, differentiation, commitment, and end cell functional activation.
Pharmacokinetics
The pharmacokinetics of pegfilgrastim were studied in 379 patients with cancer. The pharmacokinetics of pegfilgrastim were nonlinear and clearance decreased with increases in dose. Neutrophil receptor binding is an important component of the clearance of pegfilgrastim, and serum clearance is directly related to the number of neutrophils. In addition to numbers of neutrophils, body weight appeared to be a factor. Patients with higher body weights experienced higher systemic exposure to pegfilgrastim after receiving a dose normalized for body weight. A large variability in the pharmacokinetics of pegfilgrastim was observed. The half-life of Neulasta ranged from 15 to 80 hours after subcutaneous injection.
No gender-related differences were observed in the pharmacokinetics of pegfilgrastim, and no differences were observed in the pharmacokinetics of geriatric patients (≥ 65 years of age) compared with younger patients (< 65 years of age) [see Use in Specific Populations (8.5)]. The pharmacokinetics of pegfilgrastim were studied in pediatric patients with sarcoma [see Use in Specific Populations (8.4)]. Renal dysfunction had no effect on the pharmacokinetics of pegfilgrastim. [see Use in Specific Populations (8.6)]. The pharmacokinetic profile in patients with hepatic insufficiency has not been assessed.
Nonclinical Toxicology
Carcinogenesis, Mutagenesis, Impairment of Fertility
No carcinogenicity or mutagenesis studies have been performed with pegfilgrastim.
Pegfilgrastim did not affect reproductive performance or fertility in male or female rats at cumulative weekly doses approximately 6 to 9 times higher than the recommended human dose (based on body surface area).
Reproductive and Developmental Toxicology
Pregnant rabbits were dosed with pegfilgrastim subcutaneously every other day during the period of organogenesis. At cumulative doses ranging from the approximate human dose to approximately 4 times the recommended human dose (based on body surface area), treated rabbits exhibited decreased maternal food consumption, maternal weight loss, as well as reduced fetal body weights and delayed ossification of the fetal skull; however, no structural anomalies were observed in the offspring from either study. Increased incidences of post-implantation losses and spontaneous abortions (more than half the pregnancies) were observed at cumulative doses approximately 4 times the recommended human dose, which were not seen when pregnant rabbits were exposed to the recommended human dose.
Three studies were conducted in pregnant rats dosed with pegfilgrastim at cumulative doses up to approximately 10 times the recommended human dose at the following stages of gestation: during the period of organogenesis, from mating through the first half of pregnancy, and from the first trimester through delivery and lactation. No evidence of fetal loss or structural malformations was observed in any study. Cumulative doses equivalent to approximately 3 and 10 times the recommended human dose resulted in transient evidence of wavy ribs in fetuses of treated mothers (detected at the end of gestation but no longer present in pups evaluated at the end of lactation).
Clinical Studies
Neulasta was evaluated in three randomized, double blind, controlled studies. Studies 1 and 2 were active-controlled studies that employed doxorubicin 60 mg/m2 and docetaxel 75 mg/m2 administered every 21 days for up to 4 cycles for the treatment of metastatic breast cancer. Study 1 investigated the utility of a fixed dose of Neulasta. Study 2 employed a weight-adjusted dose. In the absence of growth factor support, similar chemotherapy regimens have been reported to result in a 100% incidence of severe neutropenia (ANC < 0.5 x 109/L) with a mean duration of 5 to 7 days and a 30% to 40% incidence of febrile neutropenia. Based on the correlation between the duration of severe neutropenia and the incidence of febrile neutropenia found in studies with filgrastim, duration of severe neutropenia was chosen as the primary endpoint in both studies, and the efficacy of Neulasta was demonstrated by establishing comparability to filgrastim-treated patients in the mean days of severe neutropenia.
In Study 1, 157 patients were randomized to receive a single subcutaneous injection of Neulasta (6 mg) on day 2 of each chemotherapy cycle or daily subcutaneous filgrastim (5 mcg/kg/day) beginning on day 2 of each chemotherapy cycle. In Study 2, 310 patients were randomized to receive a single subcutaneous injection of Neulasta (100 mcg/kg) on day 2 or daily subcutaneous filgrastim (5 mcg/kg/day) beginning on day 2 of each chemotherapy cycle.
Both studies met the major efficacy outcome measure of demonstrating that the mean days of severe neutropenia of Neulasta-treated patients did not exceed that of filgrastim-treated patients by more than 1 day in cycle 1 of chemotherapy. The mean days of cycle 1 severe neutropenia in Study 1 were 1.8 days in the Neulasta arm compared to 1.6 days in the filgrastim arm [difference in means 0.2 (95% CI -0.2, 0.6)] and in Study 2 were 1.7 days in the Neulasta arm compared to 1.6 days in the Filgrastim arm [difference in means 0.1 (95% CI -0.2, 0.4)].
A secondary endpoint in both studies was days of severe neutropenia in cycles 2 through 4 with results similar to those for cycle 1.
Study 3 was a randomized, double-blind, placebo-controlled study that employed docetaxel 100 mg/m2 administered every 21 days for up to 4 cycles for the treatment of metastatic or non-metastatic breast cancer. In this study, 928 patients were randomized to receive a single subcutaneous injection of Neulasta (6 mg) or placebo on day 2 of each chemotherapy cycle. Study 3 met the major trial outcome measure of demonstrating that the incidence of febrile neutropenia (defined as temperature ≥ 38.2°C and ANC ≤ 0.5 x109/L) was lower for Neulasta-treated patients as compared to placebo-treated patients (1% versus 17%, respectively, p < 0.001). The incidence of hospitalizations (1% versus 14%) and IV anti-infective use (2% versus 10%) for the treatment of febrile neutropenia was also lower in the Neulasta-treated patients compared to the placebo-treated patients.
How Supplied/Storage and Handling
Neulasta is supplied in a prefilled single use syringe containing 6 mg pegfilgrastim, supplied with a 27-gauge, 1/2-inch needle with an UltraSafe® Needle Guard.
The needle cover of the prefilled syringe contains dry natural rubber (a derivative of latex).
Neulasta is provided in a dispensing pack containing one syringe
(NDC 55513-190-01).
Store refrigerated between 2° to 8°C (36° to 46°F) in the carton to protect from light. Do not shake. Discard syringes stored at room temperature for more than 48 hours. Avoid freezing; if frozen, thaw in the refrigerator before administration. Discard syringe if frozen more than once.

附件：
201072300045011.pdf
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注：以下产品有三个地域上市，价格方面以咨询为准！
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产地国家:美国
原产地英文商品名:
NEULASTA 6MG/0.6ML/SYRINGE
原产地英文药品名:
PEGFILGRASTIM
中文参考商品译名:
纽拉思塔 6毫克/0.6毫升/注射器
中文参考药品译名:
培非格司亭
生产厂家中文参考译名:
安进
生产厂家英文名:
Amgen
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产地国家: 西班牙
原产地英文商品名:
NEULASTA 6MG/0.6ML/SYRINGE
原产地英文药品名:
PEGFILGRASTIM
中文参考商品译名:
纽拉思塔 6毫克/0.6毫升/注射器
中文参考药品译名:
培非格司亭
生产厂家中文参考译名:
安进
生产厂家英文名:
Amgen
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产地国家: 意大利
原产地英文商品名:
NEULASTA 6MG/0.6ML/SYRINGE
原产地英文药品名:
PEGFILGRASTIM
中文参考商品译名:
纽拉思塔 6毫克/0.6毫升/注射器
中文参考药品译名:
培非格司亭
生产厂家中文参考译名:
安进
生产厂家英文名:
Amgen