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培非格司亭注射器NEULASTA(PEGFILGRASTIM)

 

Neulasta（Pegfilgrastim）注射是一种人造蛋白质，刺激称为中性粒细胞的白细胞在身体里生长。白血细胞帮助人体抵抗感染的危害。 
Neulasta®（Pegfilgrastim）注射用于治疗白细胞减少，治疗某些接受癌症化疗引起的白血球缺乏。也用在除了骨髓癌的其他癌症。

 

 

美国首次批准：2002  公司：Amgen 
目前的主要变化
剂量和给药方法  12/2014 
警告和注意事项  12/2014 
适应症和用法
Neulasta是表示降低感染的发病率，其表现发热性中性粒细胞减少，患者接收与发热性中性粒细胞减少的临床显著发病率骨髓抑制抗癌药物的非髓系恶性血液病白细胞生长因子。 
Neulasta未指示对外周血祖细胞的动员造血干细胞移植。
用法用量
6毫克每化疗周期皮下注射一次。 
难道前14天，细胞毒性化疗的给药后24小时无法管理。 
剂型和规格
注射：6毫克/在单次使用预充液注射器为仅手动使用0.6mL的溶液。 
注射：6毫克/在一个单一的预充式注射器共同封装与在体喷油器Neulasta 0.6mL的溶液。
禁忌
不要给予Neulasta给患者带来严重的过敏反应培非司亭或格司亭的历史。 
警告和注意事项
严重可发生脾破裂。评估脾肿大或脾破裂患者左上腹或肩部疼痛。 
急性呼吸窘迫综合征（ARDS），可能会发生。评估在谁出现发热，肺浸润，或呼吸窘迫的病人急性呼吸窘迫综合征。在ARDS患者停止Neulasta。 
严重的过敏反应，包括过敏性休克，可以发生。永久停止Neulasta的患者有严重的过敏反应。 
在体喷油器Neulasta使用丙烯酸类粘合剂。对于谁拥有反应丙烯酸粘合剂的患者，使用本产品可能导致显著反应
严重的有时甚至是致命的镰状细胞危机可能发生。
不良反应
最常见的不良反应（发生率≥5％的差异）的安慰剂对照临床试验是骨骼疼痛和痛苦，肢体。 
特殊人群中使用
妊娠：根据动物实验数据，可能会对胎儿造成伤害。鼓励医生致电1-800-772-6436（1-800-77-AMGEN）招收妊娠患者在Amgen公司的妊娠监察计划。
哺乳母亲：当给予哺乳妇女应谨慎。 
儿童用药：Neulasta的安全性和有效性尚未确定。 
老年用药：在安全性或有效性总体差别患者65岁及以上的变化。 
肾损害：无需调整剂量。

 

 

 

聚乙二醇化非格司亭（Neulasta）。Neulasta学名pegfilgrastim，中文名聚乙二醇化非格司亭，由美国Amgen公司研发。Neulasta于2002年1月22日获美国食物与药品管理局（FDA）批准，4月9日，Neulasta在美国首次上市，当年就获4.635亿美元销售额佳绩，创2002年入市美国新药销售额/年的最高记录。同年8月，该产品在欧洲和澳大利亚以相似的适应症获准上市。
新药Neulasta(TM) (pegfilgrastim)通过美国食品与药品管理局（FDA）的审批。Neulasta在每个化疗疗程中只需要使用一次，主要适应征是用于减低化疗过程中感染的发生率,这种感染常常表现为中性粒细胞减少症相关的发热(即发热与抗感染的白细胞数量的严重下降有关)。中性粒细胞是白细胞的一种，在人体抵抗病原微生物感染中发挥着重要的作用。在非骨髓来源的恶心肿瘤肿瘤患者的化疗过程中，化疗药物也会引起髓系粒细胞的抑制作用，因而会出现中性粒细胞减少症，常常会增加临床中性粒细胞减少症相关的发热的发病率。中性粒细胞减少症是大多数肿瘤化疗中最常见也是最严重的一种并发症。有超过一半的肿瘤患者会在化疗中出现严重的中性粒细胞减少症，这使得他们极易发生严重的危及生命的感染。平均只有不到10%的患者在化疗前接受过预防中性粒细胞减少症的治疗，研究表明30%-40%未接受此方面预防治疗的化疗患者将会出现带有发热症状的中性粒细胞减少症。
每年都有数千患者因为中性粒细胞减少症及其并发症而就医,并且会因此而需要重新住院治疗。 Neulasta每个化疗疗程只用一次，减少了频繁注射给患者带来的痛苦以及医生与患者相聚带来感染的几率，也不用在化疗期间由于严重的感染疾病而频繁中断治疗。现在通过审批表明成千上万的化疗患者可以在每一轮化疗出现感染并发症之前使用Neulasta进行保护，从而减少了化疗风险。''Neulasta Neulasta(TM)是一种蛋白质，它可以刺激抗感染的白细胞(中性粒细胞)的产生。而中性粒细胞正是化疗的细胞毒性作用的对象。
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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 
---------------------------------------------------------
产地国家: 德国 
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 
---------------------------------------------------------
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 
---------------------------------------------------------
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

 

 

 

 

 

 

 

 

 

 

 

 

Neulasta® (pegfilgrastim) 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 clinically significant incidence of febrile neutropenia. 
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
6 mg per 0.6 mL 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.

 Generic Name: filgrastim (fil GRAS tim)

Brand Name: Neupogen, Neupogen SingleJect, Zarxio

 Pronunciation

(fil GRA stim)

Index TermsFilgrastim-sndzG-CSFGranulocyte Colony Stimulating FactorTbo-FilgrastimTevagrastimDosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Solution, Injection:

Neupogen: filgrastim 300 mcg/mL (1 mL); filgrastim 480 mcg/1.6 mL (1.6 mL) [contains polysorbate 80]

Solution Prefilled Syringe, Injection [preservative free]:

Neupogen: filgrastim 300 mcg/0.5 mL (0.5 mL); filgrastim 480 mcg/0.8 mL (0.8 mL) [contains polysorbate 80]

Zarxio: filgrastim-sndz 300 mcg/0.5 mL (0.5 mL); filgrastim-sndz 480 mcg/0.8 mL (0.8 mL) [contains polysorbate 80]

Solution Prefilled Syringe, Subcutaneous [preservative free]:

Granix: tbo-filgrastim 300 mcg/0.5 mL (0.5 mL); tbo-filgrastim 480 mcg/0.8 mL (0.8 mL) [contains polysorbate 80]

Brand Names: U.S.GranixNeupogenZarxioPharmacologic CategoryColony Stimulating FactorHematopoietic AgentPharmacology

Filgrastim, filgrastim-sndz, and tbo-filgrastim are granulocyte colony stimulating factors (G-CSF) produced by recombinant DNA technology. G-CSFs stimulate the production, maturation, and activation of neutrophils to increase both their migration and cytotoxicity.

Distribution

Vd: 150 mL/kg; Continuous infusion: No evidence of drug accumulation over a 11- to 20-day period

Metabolism

Systemically degraded

Onset of Action

Filgrastim: 1 to 2 days

Tbo-filgrastim: Time to maximum ANC: 3 to 5 days

Time to Peak

Serum: Filgrastim: SubQ: 2 to 8 hours; Tbo-filgrastim: 4 to 6 hours

Duration of Action

Filgrastim: Neutrophil counts generally return to baseline within 4 days

Tbo-filgrastim: ANC returned to baseline by 21 days after completion of chemotherapy

Half-Life Elimination

Neonates: 4.4 ± 0.4 hours (Gillan 1994)

Adults: Filgrastim: ~3.5 hours; Tbo-filgrastim: 3 to 4 hours

Special Populations: Renal Function Impairment

In a study with healthy volunteers, subjects with moderate renal impairment, and subjects with end-stage renal disease (ESRD) (n = 4 per group), higher serum concentrations were observed in subjects with ESRD.

Use: Labeled Indications

Myelosuppressive chemotherapy recipients with nonmyeloid malignancies:

Neupogen (filgrastim), Zarxio (filgrastim-sndz [biosimilar]), Grastofil [Canadian product]: To decrease the incidence of infection (neutropenic fever) in patients with nonmyeloid malignancies receiving myelosuppressive chemotherapy associated with a significant incidence of severe neutropenia with fever.

Granix (tbo-filgrastim): To decrease the duration of severe neutropenia in patients with nonmyeloid malignancies receiving myelosuppressive chemotherapy associated with a clinically significant incidence of neutropenic fever.

Acute myeloid leukemia (AML) following induction or consolidation chemotherapy (Neupogen, Zarxio, Grastofil [Canadian product]): To reduce the time to neutrophil recovery and the duration of fever following induction or consolidation chemotherapy in adults with AML.

Bone marrow transplantation (Neupogen, Zarxio, Grastofil [Canadian product]): To reduce the duration of neutropenia and neutropenia-related events (eg, neutropenic fever) in patients with nonmyeloid malignancies receiving myeloablative chemotherapy followed by marrow transplantation.

Hematopoietic radiation injury syndrome, acute (Neupogen): To increase survival in patients acutely exposed to myelosuppressive doses of radiation.

Peripheral blood progenitor cell collection and therapy (Neupogen, Zarxio, Grastofil [Canadian product]): Mobilization of autologous hematopoietic progenitor cells into the peripheral blood for apheresis collection.

Severe chronic neutropenia (Neupogen, Zarxio, Grastofil [Canadian product]): Long-term administration to reduce the incidence and duration of neutropenic complications (eg, fever, infections, oropharyngeal ulcers) in symptomatic patients with congenital, cyclic, or idiopathic neutropenia.

Off Label UsesAnemia in myelodysplastic syndrome

Based on the European LeukemiaNet guidelines for the management of primary myelodysplastic syndromes in adults, filgrastim (in combination with epoetin) is effective and recommended for the management of this condition [Malcovati 2013].

Hematopoietic stem cell mobilization for collection and subsequent autologous transplantation in patients with non-Hodgkin lymphoma or multiple myeloma

Data from two phase III prospective, randomized, double-blind, placebo-controlled trials supports the use of filgrastim (in combination with plerixafor) in the mobilization of hematopoietic stem cells for collection and subsequent autologous transplantation in patients with non-Hodgkin lymphoma or multiple myeloma [DiPersio 2009a], [DiPersio 2009b].

Neutropenia in HIV-infected patients receiving zidovudine (pediatrics)

Based on the Department of Health and Human Services (HHS) Pediatric HIV guidelines, filgrastim is effective and recommended for the treatment of neutropenia in pediatric patients with HIV infection receiving zidovudine.

Neutropenia in advanced HIV infection (adolescents and adults)

Data from a randomized, controlled, open-label, multicenter study supports the use of filgrastim in prevention and treatment of neutropenia in patients >13 years of age with advanced HIV infection [Kuritzkes 1998].

Neutropenia (hepatitis C treatment-associated)

Based on the American Association for the Study of Liver Diseases (AASLD) guidelines for the diagnosis, management, and treatment of hepatitis C, filgrastim is effective and recommended in the management of hepatitis C treatment-associated neutropenia [AASLD [Ghany 2009]].

Contraindications

History of serious allergic reactions to human granulocyte colony-stimulating factors, such as filgrastim or pegfilgrastim, or any component of the formulation

Canadian labeling: Additional contraindications (not in the US labeling): Neupogen, Grastofil: Known hypersensitivity to E. coli-derived products

Dosing: Adult

Note: Do not administer in the period 24 hours before to 24 hours after cytotoxic chemotherapy. May round the dose to the nearest vial size for convenience and cost minimization (Ozer 2000).International considerations: Dosages below expressed as micrograms; 1 mcg = 100,000 units (Hoglund 1998).

Myelosuppressive chemotherapy recipients with nonmyeloid malignancies (Neupogen [filgrastim], Zarxio [filgrastim-sndz; biosimilar], Grastofil [Canadian product]): SubQ, IV: 5 mcg/kg/day; doses may be increased by 5 mcg/kg (for each chemotherapy cycle) according to the duration and severity of the neutropenia; continue for up to 14 days until the absolute neutrophil count (ANC) reaches 10,000/mm3. Discontinue if the ANC surpasses 10,000/mm3 after the expected chemotherapy-induced neutrophil nadir.

Myelosuppressive chemotherapy recipients with nonmyeloid malignancies (Granix [tbo-filgrastim]):SubQ: 5 mcg/kg/day; continue until anticipated nadir has passed and neutrophil count has recovered to normal range.

Acute myeloid leukemia (AML) following induction or consolidation chemotherapy (Neupogen, Zarxio, Grastofil [Canadian product]): SubQ, IV: 5 mcg/kg/day; doses may be increased by 5 mcg/kg (for each chemotherapy cycle) according to the duration and severity of the neutropenia; continue for up to 14 days until the ANC reaches 10,000/mm3. Discontinue if the ANC surpasses 10,000/mm3 after the expected chemotherapy-induced neutrophil nadir.

Bone marrow transplantation (Neupogen, Zarxio, Grastofil [Canadian product]): IV infusion: 10 mcg/kg/day (administer ≥24 hours after chemotherapy and ≥24 hours after bone marrow infusion); adjust the dose according to the duration and severity of neutropenia; recommended steps based on neutrophil response:

When ANC >1,000/mm3 for 3 consecutive days: Reduce dose to 5 mcg/kg/day

If ANC remains >1,000/mm3 for 3 more consecutive days: Discontinue

If ANC decreases to <1,000/mm3: Resume at 5 mcg/kg/day.

If ANC decreases to <1,000/mm3 during the 5 mcg/kg/day dose: Increase dose to 10 mcg/kg/day and follow the above steps.

Hematopoietic radiation injury syndrome, acute (Neupogen): SubQ: 10 mcg/kg once daily; begin as soon as possible after suspected or confirmed radiation doses >2 gray (Gy) and continue filgrastim until ANC remains >1,000/mm3 for 3 consecutive CBCs or ANC exceeds 10,000/mm3 after the radiation-induced nadir. ASCO guidelines recommend initiating within 24 hours of exposure of a dose ≥2 Gy and/or significant decrease in absolute lymphocyte count, or for anticipated neutropenia <500/mm3 for ≥7 days (Smith 2015).

Peripheral blood progenitor (PBPC) cell collection and therapy (Neupogen, Zarxio, Grastofil[Canadian product]): SubQ: 10 mcg/kg daily, usually for 6 to 7 days (with apheresis occurring on days 5, 6, and 7). Begin at least 4 days before the first apheresis and continue until the last apheresis; discontinue for WBC >100,000/mm3

Severe chronic neutropenia (Neupogen, Zarxio, Grastofil [Canadian product]): SubQ:

Congenital: Initial: 6 mcg/kg/day in 2 divided doses; adjust the dose based on ANC and clinical response; mean dose: 6 mcg/kg/day.

Idiopathic: Initial: 5 mcg/kg once daily; adjust the dose based on ANC and clinical response; total daily dose may be administered in 1 or 2 divided doses; mean dose: 1.2 mcg/kg/day

Cyclic: Initial: 5 mcg/kg once daily; adjust the dose based on ANC and clinical response; total daily dose may be administered in 1 or 2 divided doses; mean dose: 2.1 mcg/kg/day

Anemia in myelodysplastic syndrome (off-label use; in combination with epoetin): SubQ: 300 mcg weekly in 2 to 3 divided doses (Malcovati 2013) or 1 mcg/kg once daily (Greenberg 2009) or 75 mcg, 150 mcg, or 300 mcg per dose 3 times weekly (Hellstrom-Lindberg 2003)

Hematopoietic stem cell mobilization in autologous transplantation in patients with non-Hodgkin lymphoma or multiple myeloma (in combination with plerixafor; off-label combination): SubQ: 10 mcg/kg once daily; begin 4 days before initiation of plerixafor; continue G-CSF on each day prior to apheresis for up to 8 days (DiPersio 2009a; DiPersio 2009b)

Hepatitis C treatment-associated neutropenia (off-label use): SubQ: 150 mcg once weekly to 300 mcg 3 times weekly; titrate to maintain ANC between 750 and 10,000/mm3 (Younossi 2008)

Neutropenia in advanced HIV infection (off-label use): SubQ: Initial: 1 mcg/kg once daily or 300 mcg one to three times per week; titrate to maintain ANC 2,000 to 10,000/mm3; doses up to 10 mcg/kg/day or 600 mcg daily were studied (Kuritzkes 1998).

Dosing: Geriatric

Refer to adult dosing.

Dosing: Pediatric

Note: Do not administer in the period 24 hours before to 24 hours after cytotoxic chemotherapy.International considerations: Dosages below expressed as micrograms; 1 mcg = 100,000 units (Hoglund 1998).

Myelosuppressive chemotherapy recipients with nonmyeloid malignancies (Neupogen [filgrastim], Zarxio [filgrastim-sndz; biosimilar], Gastrofil [Canadian product]): SubQ, IV: 5 mcg/kg/day; doses may be increased by 5 mcg/kg (for each chemotherapy cycle) according to the duration and severity of the neutropenia; continue for up to 14 days until the absolute neutrophil count (ANC) reaches 10,000/mm3. Discontinue if the ANC surpasses 10,000/mm3 after the expected chemotherapy-induced neutrophil nadir.

Bone marrow transplantation (Neupogen, Zarxio): IV infusion: 10 mcg/kg/day (administer ≥24 hours after chemotherapy and ≥24 hours after bone marrow infusion); adjust the dose according to the duration and severity of neutropenia; recommended steps based on neutrophil response:

When ANC >1,000/mm3 for 3 consecutive days: Reduce dose to 5 mcg/kg/day

If ANC remains >1,000/mm3 for 3 more consecutive days: Discontinue

If ANC decreases to <1,000/mm3: Resume at 5 mcg/kg/day

If ANC decreases to <1,000/mm3 during the 5 mcg/kg/day dose, increase dose to 10 mcg/kg/day and follow the above steps

Hematopoietic radiation injury syndrome, acute (Neupogen): SubQ: 10 mcg/kg once daily; begin as soon as possible after suspected or confirmed radiation doses >2 gray (Gy) and continue filgrastim until ANC remains >1,000/mm3 for 3 consecutive CBCs or ANC exceeds 10,000/mm3 after the radiation-induced nadir. ASCO guidelines recommend initiating within 24 hours of exposure of a dose ≥2 Gy and/or significant decrease in absolute lymphocyte count, or for anticipated neutropenia <500/mm3 for ≥7 days (Smith 2015).

Peripheral blood progenitor cell collection and therapy (Neupogen, Zarxio): SubQ: 10 mcg/kg daily, usually for 6 to 7 days (with apheresis occurring on days 5, 6, and 7). Begin at least 4 days before the first apheresis and continue until the last apheresis; discontinue for WBC >100,000/mm3

Severe chronic neutropenia (Neupogen, Zarxio, Grastofil [Canadian product]): Infants ≥1 month, Children, and Adolescents: SubQ:

Congenital: Initial: 6 mcg/kg/day in 2 divided doses; adjust the dose based on ANC and clinical response; mean dose: 6 mcg/kg/day.

Idiopathic: Initial: 5 mcg/kg once daily; adjust the dose based on ANC and clinical response; total daily dose may be administered in 1 or 2 divided doses; mean dose: 1.2 mcg/kg/day

Cyclic: Initial: 5 mcg/kg once daily; adjust the dose based on ANC and clinical response; total daily dose may be administered in 1 or 2 divided doses; mean dose: 2.1 mcg/kg/day

Neutropenia in advanced HIV infection (off-label use): Adolescents >13 years: SubQ: Refer to adult dosing.

Dosing: Renal Impairment

Renal impairment at treatment initiation:

Neupogen, Zarxio: No dosage adjustment necessary.

Granix:

Mild impairment: No dosage adjustment necessary.

Moderate to severe impairment: There are no dosage adjustments provided in the manufacturer′s labeling (has not been studied).

Renal toxicity during treatment: Glomerulonephritis due to filgrastim: Consider dose reduction or treatment interruption.

Dosing: Hepatic Impairment

Neupogen, Zarxio: No dosage adjustment necessary.

Granix: There are no dosage adjustments provided in the manufacturer′s labeling (has not been studied).

Reconstitution

Visually inspect prior to use; discard if discolored or if particulates are present.

Neupogen: Do not dilute with saline at any time; product may precipitate. Filgrastim (vial only; do not use prefilled syringe for IV preparation) may be diluted with D5W to a concentration of 5 to 15 mcg/mL for IV infusion administration (minimum concentration: 5 mcg/mL). Concentrations of 5 to 15 mcg/mL require addition of albumin (final albumin concentration of 2 mg/mL) to prevent adsorption to plastics. Dilution to <5 mcg/mL is not recommended. Do not shake. May be prepared in glass bottles, polyvinyl chloride (PVC) or polyolefin bags, and polypropylene syringes. Discard unused portion of vial.

Granix: Remove needle shield and expel extra volume if needed (depending on dose). Prefilled syringe is for single use only; discard unused portion.

Grastofil [Canadian product]: Do not dilute with saline at any time; product may precipitate. May be diluted with D5W to a concentration of 5 to 15 mcg/mL for IV infusion administration. Concentrations of 5 to 15 mcg/mL require addition of albumin (final albumin concentration of 2 mg/mL) to prevent adsorption to plastics. Dilution to <5 mcg/mL is not recommended. Do not shake. May be prepared in glass if diluted with D5W or in PVC or polyolefin IV bags if diluted in D5W plus albumin. Discard unused portion of syringe.

Zarxio: Do not dilute with saline at any time; product may precipitate. Filgrastim-sndz may be diluted with D5W to a concentration of 5 to 15 mcg/mL for IV infusion administration. Concentrations of 5 to 15 mcg/mL require addition of albumin (final albumin concentration of 2 mg/mL) to prevent adsorption to plastics. Do not shake. May be prepared in glass, PVC, polyolefin, and polypropylene. Discard unused portion of syringe.

Administration

Do not administer earlier than 24 hours after or in the 24 hours prior to cytotoxic chemotherapy.

IV (Neupogen, Zarxio, Grastofil [Canadian product]): May be administered IV as a short infusion over 15 to 30 minutes (chemotherapy-induced neutropenia) or by continuous infusion (chemotherapy-induced neutropenia) or as an infusion of no longer than 24 hours (bone marrow transplantation).

SubQ: May be administered SubQ (chemotherapy-induced neutropenia, peripheral blood progenitor cell collection, severe chronic neutropenia, hematopoietic radiation injury syndrome). Administer into the outer upper arm, abdomen (except within 2 inches of navel), front middle thigh, or the upper outer buttocks area. Rotate injection site; do not inject into areas that are tender, red, bruised, hardened, or scarred, or sites with stretch marks.

Some patients (or caregivers) may be appropriate candidates for subQ self-administration with proper training; patients/caregivers should follow the manufacturer instructions for preparation and administration. Do not skip doses, change schedule, or discontinue without consulting with health care provider. Granix is available in prefilled syringes with and without a needle guard; the prefilled syringe without a safety needle guard is intended for patient/caregiver self-administration. If filgrastim comes in contact with the skin, wash area thoroughly with soap and water; if eye contact occurs, flush exposed eye(s) with water.

Dietary Considerations

Some products may contain sodium.

Storage

Neupogen: Store at 2°C to 8°C (36°F to 46°F). Store in the original carton. Protect from light. Protect from direct sunlight. Avoid freezing; if frozen, thaw in the refrigerator before administration. Discard if frozen more than once. Do not shake. Transport via a pneumatic tube has not been studied. Prior to injection, allow to reach room temperature for up to 30 minutes and a maximum of 24 hours. Discard any vial or prefilled syringe left at room temperature for more than 24 hours. Solutions diluted for infusion in D5W may be stored at room temperature for up to 24 hours (infusion must be completed within 24 hours of preparation).

Extended storage information may be available for undiluted filgrastim; contact product manufacturer to obtain current recommendations. Sterility has been assessed and maintained for up to 7 days when prepared under strict aseptic conditions (Jacobson 1996; Singh 1994). The manufacturer recommends using within 24 hours due to the potential for bacterial contamination.

Granix: Store prefilled syringes at 2°C to 8°C (36°F to 46°F). Protect from light. Do not shake. May be removed from 2°C to 8°C (36°F to 46°F) storage for a single period of up to 5 days between 23°C to 27°C (73°F to 81°F). If not used within 5 days, the product may be returned to 2°C to 8°C (36°F to 46°F) up to the expiration date. Dispose of syringes if stored at room temperature for more than 5 days. Exposure to -1°C to -5°C (23°F to 30°F) for up to 72 hours and temperatures as low as -15°C to -25°C (5°F to -13°F) for up to 24 hours do not adversely affect stability. Discard unused product.

Zarxio: Store at 2°C to 8°C (36°F to 46°F). Store in the original carton. Protect from light. Avoid freezing; if frozen, thaw in the refrigerator before administration. Discard if frozen more than once. Do not shake. Transport via a pneumatic tube has not been studied. Prior to injection, allow to reach room temperature for up to 30 minutes and a maximum of 24 hours. Discard any prefilled syringe left at room temperature for more than 24 hours. Solutions diluted for infusion may be stored at room temperature for up to 24 hours (infusion must be completed within 24 hours of preparation).

Grastofil [Canadian product]: Store at 2ºC to 8ºC (36°F to 46°F). Protect from light. Do not shake. Accidental one-time exposure to temperatures up to 30ºC (86°F) or exposure to freezing temperatures <0ºC (32°F) does not adversely affect stability. If exposure at >30ºC or <0ºC has been greater than 24 hours or frozen more than once, do not use. May be removed from the refrigerator and stored at room temperature (≤25°C) for a single period of up to 7 days. Do not return to refrigerator.

Drug Interactions

Belotecan: Granulocyte Colony-Stimulating Factors may enhance the neutropenic effect of Belotecan.Consider therapy modification

Bleomycin: Filgrastim may enhance the adverse/toxic effect of Bleomycin. Specifically, the risk for pulmonary toxicity may be increased. Monitor therapy

Cyclophosphamide: Filgrastim may enhance the adverse/toxic effect of Cyclophosphamide. Specifically, the risk of pulmonary toxicity may be enhanced. Monitor therapy

Tisagenlecleucel: Granulocyte Colony-Stimulating Factors may enhance the adverse/toxic effect of Tisagenlecleucel. Avoid combination

Topotecan: Granulocyte Colony-Stimulating Factors may enhance the myelosuppressive effect of Topotecan. Consider therapy modification

Test Interactions

May interfere with bone imaging studies; increased hematopoietic activity of the bone marrow may appear as transient positive bone imaging changes

Adverse Reactions

>10%:

Cardiovascular: Chest pain (5% to 13%)

Central nervous system: Fatigue (20%), dizziness (14%), pain (12%)

Dermatologic: Skin rash (2% to 14%)

Gastrointestinal: Nausea (10% to 43%)

Hematologic & oncologic: Thrombocytopenia (5% to 38%), splenomegaly (≥5%; severe chronic neutropenia: 30%), petechia (17%)

Hepatic: Increased serum alkaline phosphatase (6% to 11%)

Neuromuscular & skeletal: Ostealgia (5% to 33%; dose and cycle related), back pain (2% to 15%)

Respiratory: Epistaxis (2% to 15%), cough (14%), dyspnea (13%)

Miscellaneous: Fever (12% to 48%; dose and cycle related)

1% to 10%:

Cardiovascular: Peripheral edema (≥5%), hypertension (≥4% ), cardiac arrhythmia (≤3%), myocardial infarction (≤3%)

Central nervous system: Headache (7% to 10%), hypoesthesia (≥5%), insomnia (≥5%), malaise (≥5%), mouth pain (≥5%)

Dermatologic: Alopecia (≥5%), erythema (≥2%), maculopapular rash (≥2%)

Endocrine & metabolic: Increased lactate dehydrogenase (6%)

Gastrointestinal: Vomiting (5% to 7%), decreased appetite (≥5%), constipation (≥2%), diarrhea (≥2% )

Genitourinary: Urinary tract infection (≥5%)

Hematologic & oncologic: Anemia (≥5%), leukocytosis (≤2%)

Hypersensitivity: Transfusion reaction (2% to 10%), hypersensitivity reaction (≥5%)

Immunologic: Antibody development (2% to 3%; no evidence of neutralizing response)

Infection: Sepsis (≥5%)

Neuromuscular & skeletal: Arthralgia (5% to 9%), limb pain (2% to 7%), muscle spasm (≥5%), musculoskeletal pain (≥5%) weakness (≥5%)

Respiratory: Bronchitis (≥5%), upper respiratory tract infection (≥5%)

<1% (Limited to important or life-threatening): Anaphylaxis, capillary leak syndrome, cerebral hemorrhage, decreased bone mineral density, decreased hemoglobin, euthymia nodosum, exacerbation of psoriasis, facial edema, glomerulonephritis, hematuria, hemoptysis, hepatomegaly, hypersensitivity angiitis, hypotension, injection site reaction, osteoporosis, proteinuria, pulmonary alveolar hemorrhage, pulmonary infiltrates, renal insufficiency, respiratory distress syndrome, severe sickle cell crisis, splenic rupture, Sweet syndrome, tachycardia, urticaria, wheezing

Warnings/Precautions

Concerns related to adverse reactions:

• Allergic reactions: Serious allergic reactions (including anaphylaxis) have been reported, usually with the initial exposure; may be managed symptomatically with administration of antihistamines, steroids, bronchodilators, and/or epinephrine. Allergic reactions may recur within days after the initial allergy management has been stopped. Do not administer filgrastim products to patients who have experienced serious allergic reaction to filgrastim or pegfilgrastim. Permanently discontinue filgrastim products in patients with serious allergic reactions.

• Alveolar hemorrhage: Reports of alveolar hemorrhage, manifested as pulmonary infiltrates and hemoptysis (requiring hospitalization), have occurred in healthy donors undergoing PBPC mobilization (off-label for use in healthy donors); hemoptysis resolved upon discontinuation.

• Capillary leak syndrome: Capillary leak syndrome (CLS), characterized by hypotension, hypoalbuminemia, edema, and hemoconcentration, may occur in patients receiving human granulocyte colony-stimulating factors (G-CSF). CLS episodes may vary in frequency and severity. If CLS develops, monitor closely and manage symptomatically (may require intensive care). CLS may be life-threatening if treatment is delayed.

• Cutaneous vasculitis: Moderate or severe cutaneous vasculitis has been reported, generally occurring in patients with severe chronic neutropenia on chronic therapy. Withhold treatment if cutaneous vasculitis occurs; may be restarted with a dose reduction once symptoms resolve and the ANC has decreased.

• Hematologic effects: White blood cell counts of ≥100,000/mm3 have been reported with filgrastim doses >5 mcg/kg/day. When filgrastim products are used as an adjunct to myelosuppressive chemotherapy, discontinue when absolute neutrophil count (ANC) exceeds 10,000/mm3 after the ANC nadir has occurred (to avoid potential excessive leukocytosis). Doses that increase the ANC beyond 10,000/mm3 may not result in additional clinical benefit. Monitor complete blood cell count (CBC) twice weekly during therapy. In patients receiving myelosuppressive chemotherapy, filgrastim discontinuation generally resulted in a 50% decrease in circulating neutrophils within 1 to 2 days, and a return to pretreatment levels in 1 to 7 days. When used for peripheral blood progenitor cell collection, discontinue filgrastim products if leukocytes >100,000/mm3. Thrombocytopenia has also been reported with filgrastim products; monitor platelet counts.

• Nephrotoxicity: Based on findings of azotemia, hematuria (micro- and macroscopic), proteinuria, and renal biopsy, glomerulonephritis has occurred in patients receiving filgrastim. Glomerulonephritis usually resolved after filgrastim dose reduction or discontinuation. If glomerulonephritis is suspected, evaluate for cause; if likely due to filgrastim, consider dose reduction or treatment interruption.

• Respiratory distress syndrome: Acute respiratory distress syndrome (ARDS) has been reported. Evaluate patients who develop fever and lung infiltrates or respiratory distress for ARDS; discontinue in patients with ARDS.

• Splenic rupture: Rare cases of splenic rupture have been reported (may be fatal); in patients with upper abdominal pain, left upper quadrant pain, or shoulder tip pain, withhold treatment and evaluate for enlarged spleen or splenic rupture.

Disease-related concerns:

• Severe chronic neutropenia: Establish diagnosis of severe chronic neutropenia (SCN) prior to initiation; use prior to appropriate diagnosis of SCN may impair or delay proper evaluation and treatment for neutropenia due to conditions other than SCN. Myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) have been reported to occur in the natural history of congenital neutropenia (without cytokine therapy). Cytogenetic abnormalities and transformation to MDS and AML have been observed with filgrastim when used to manage SCN, although the risk for MDS and AML appears to be in patients with congenital neutropenia. Abnormal cytogenetics and MDS are associated with the development of AML. The effects of continuing filgrastim products in patients who have developed abnormal cytogenetics or MDS are unknown; consider risk versus benefits of continuing treatment.

• Sickle cell disorders: May precipitate severe sickle cell crises, sometimes resulting in fatalities, in patients with sickle cell disorders (sickle cell trait or sickle cell disease); carefully evaluate potential risks and benefits. Discontinue in patients undergoing sickle cell crisis.

Concurrent drug therapy issues:

• Cytotoxic chemotherapy: Do not use filgrastim products in the period 24 hours before to 24 hours after administration of cytotoxic chemotherapy because of the potential sensitivity of rapidly dividing myeloid cells to cytotoxic chemotherapy. Transient increase in neutrophil count is seen 1 to 2 days after filgrastim initiation; however, for sustained neutrophil response, continue until post-nadir ANC reaches 10,000/mm3.

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Special populations:

• Elderly patients: The American Society of Clinical Oncology (ASCO) Recommendations for the Use of WBC Growth Factors Clinical Practice Guideline Update recommend that prophylactic colony-stimulating factors be used in patients ≥65 years with diffuse aggressive lymphoma treated with curative chemotherapy (eg, rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone), especially if patients have comorbid conditions (Smith 2015).

• Pediatric patients: Colony-stimulating factor (CSF) use in pediatric patients is typically directed by clinical pediatric protocols. The American Society of Clinical Oncology (ASCO) Recommendations for the Use of WBC Growth Factors Clinical Practice Guideline Update states that CSFs may be reasonable as primary prophylaxis in pediatric patients when chemotherapy regimens with a high likelihood of febrile neutropenia are employed. Likewise, secondary CSF prophylaxis should be limited to high-risk patients. In pediatric cancers in which dose-intense chemotherapy (with a survival benefit) is used, CSFs should be given to facilitate chemotherapy administration. CSFs should not be used in the pediatric population for non-relapsed acute lymphoblastic or myeloid leukemia when no infection is present (Smith 2015).

• Radiation therapy recipients: Avoid concurrent radiation therapy with filgrastim products; safety and efficacy have not been established with patients receiving radiation therapy.

Dosage form specific issues:

• Latex: The packaging of some dosage forms may contain latex. Granix (tbo-filgrastim), including all components, is not made with natural rubber latex.

• Polysorbate 80: Some dosage forms may contain polysorbate 80 (also known as Tweens). Hypersensitivity reactions, usually a delayed reaction, have been reported following exposure to pharmaceutical products containing polysorbate 80 in certain individuals (Isaksson 2002; Lucente 2000; Shelley 1995). Thrombocytopenia, ascites, pulmonary deterioration, and renal and hepatic failure have been reported in premature neonates after receiving parenteral products containing polysorbate 80 (Alade 1986; CDC 1984). See manufacturer's labeling.

Other warnings/precautions:

• Appropriate use: Filgrastim products should not be routinely used in the treatment of established neutropenic fever. CSFs may be considered in cancer patients with febrile neutropenia who are at high risk for infection-associated complications or who have prognostic factors indicative of a poor clinical outcome (eg, prolonged and severe neutropenia, age >65 years, hypotension, pneumonia, sepsis syndrome, presence of invasive fungal infection, uncontrolled primary disease, hospitalization at the time of fever development) (Freifeld 2011; Smith 2006). CSFs should not be routinely used for patients with neutropenia who are afebrile. Dose-dense regimens that require CSFs should only be used within the context of a clinical trial or if supported by convincing evidence (Smith 2015).

• International issues: Some products available internationally may have vial strength and dosing expressed as units (instead of as micrograms). Refer to prescribing information for specific strength and dosing information.

• Nuclear imaging: Increased bone marrow hematopoietic activity due to colony-stimulating factor use has been associated with transient bone-imaging changes; interpret results accordingly.

• Tumor growth effects: The G-CSF receptor through which filgrastim products act has been found on tumor cell lines. May potentially act as a growth factor for any tumor type (including myeloid malignancies and myelodysplasia). When used for stem cell mobilization, may release tumor cells from marrow, which could be collected in leukapheresis product; potential effect of tumor cell reinfusion is unknown.

Monitoring Parameters

Chemotherapy-induced neutropenia: Complete blood cell count (CBC) with differential and platelets prior to chemotherapy and twice weekly during growth factor treatment.

Bone marrow transplantation: CBC with differential and platelets frequently.

Hematopoietic radiation injury syndrome (acute): CBC at baseline (do not delay filgrastim for baseline CBC) and approximately every 3 days until ANC remains >1,000/mm3 for 3 consecutive CBCs. Estimate absorbed radiation dose (radiation exposure) based on information from public health authorities, biodosimetry (if available), or clinical findings (eg, onset of vomiting or lymphocyte depletion kinetics).

Peripheral progenitor cell collection: Neutrophil counts after 4 days of filgrastim treatment.

Severe chronic neutropenia: CBC with differential and platelets twice weekly during the first month of therapy and for 2 weeks following dose adjustments; once clinically stable, monthly for 1 year and quarterly thereafter. Monitor bone marrow and karyotype prior to treatment; and monitor marrow and cytogenetics annually throughout treatment.

Neutropenia in advanced HIV infection (off-label use): ANC 3 times weekly for 1st week then weekly thereafter (Kuritzkes 1999).

Pregnancy Risk Factor

C

Pregnancy Considerations

Adverse events were observed in animal reproduction studies. Filgrastim has been shown to cross the placenta in humans. Information related to the use of granulocyte-colony stimulating factor (G-CSF) in pregnant patients with congenital, cyclic, or idiopathic neutropenia (Boxer 2015; Zeidler 2014) and G-CSF-induced allogeneic peripheral blood stem cells donation is limited (Leitner 2001; Shibata 2003). One review suggests avoiding use during the first trimester until additional outcome information is available (Pessach 2013). Data collected from the Severe Chronic Neutropenia International Registry (SCNIR) note dosing for chronic conditions may need adjusted in pregnant women; the lowest effective dose to maintain the absolute neutrophil count is recommended (Zeidler 2014).

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience back pain, bone pain, joint pain, cough, or nausea. Have patient report immediately to prescriber signs of capillary leak syndrome (abnormal heartbeat; angina; shortness of breath; weight gain; vomiting blood or vomit that looks like coffee grounds; black, tarry, or bloody stools; urinary retention or change in amount of urine passed; or hematuria), signs of kidney problems (urinary retention, hematuria, change in amount of urine passed, or weight gain), dark urine, tachycardia, dizziness, passing out, sweating a lot, shortness of breath, fast breathing, coughing up blood, severe loss of strength and energy, bruising, bleeding, purple spots or redness of skin, severe headache, edema, left upper abdominal pain, or left shoulder pain (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.