FDA批准TBO-filgrastim(TBO-粒细胞集落刺激因子,又名XM02-filgrastim)用于正在接受对骨髓有影响的化疗药物的某些癌症类型患者(non-myeloid malignancies,非骨髓恶性肿瘤),以减少严重中性粒细胞减少症(neutropenia)的持续时间。

TBO-filgrastim是一种短效重组G-CSF,该药为安进(Amgen)Neupogen的生物仿制药。这是在过去十多年中在美国获批的首个新的粒细胞集落刺激因子(G-CSF)产品。

(tbo-filgrastim)注射剂使用批准日期： 2012年8月29日；公司：Sicor Biotech

filgrastim的完整处方资料

tbo-filgrastim注射剂为皮下使用

美国初次批准：2012
 
适应证和用途

Tbo-filgrastim是一种白细胞生长因子适用于在非-骨髓恶性病患者接受骨髓抑制抗癌药伴有临床意义发热性中性粒细胞减少的发生率，减少严重中性粒细胞减少时间。

剂量和给药方法
（1）推荐剂量：5 μg/kg每天作为皮下注射给药。
（2）首次给药不早于骨髓抑制化疗后24小时。不要在化疗前24小时内给药。

剂型和规格
（1）300 μg/0.5 mL在单次使用预装注射器
（2）480 μg/0.8 mL在单次使用预装注射器

禁忌证
无。

警告和注意事项
（1）脾破裂：如怀疑终止tbo-filgrastim。
（2）急性呼吸窘迫综合征(ARDS)监视和立即处理。如怀疑终止tbo-filgrastim •
（3）过敏反应(血管神经性水肿，过敏性皮炎，药物超敏性，超敏性，皮疹，瘙痒皮疹和荨麻疹) •
（4）镰状细胞危象：可能发生严重和有时致命性危象。如怀疑终止tbo-filgrastim。

不良反应
（1）对tbo-filgrastim最常见不良反应是骨痛。
为报告怀疑不良反应，连续TEVA电话1-866-832-8537或FDA电话1-800-FDA-1088或www.fda.gov/medwatch.

特殊人群中使用
（1） 在妊娠期间只有如果潜在获益升高对胎儿潜在风险，才应使用Tbo-filgrastim•
（2）不知道tbo-filgrastim是否排泄在人乳汁中。
（3）尚未在18岁以下患者中确定tbo-filgrastim 的安全性和有效性。

如何供应/贮存和处置

注射用Tbo-filgrastim溶液以单次使用，无防腐剂，预装I 型玻璃注射器供应持久附着不锈钢针头。注射器可能有或无一种UltraSafe Passive® 针头防护供应。
活性物质是tbo-filgrastim。
Tbo-filgrastim 300 μg/0.5 mL：各个预装注射器含300 μg的tbo-filgrastim在0.5 mL溶液有蓝色活塞在：
（1）1包无安全针头防护：NDC 63459-910-17
（2）5包无安全针头防护：NDC 63459-910-36
（3）10包无安全针头防护：NDC 63459-910-46
（4）1包在托盘中有安全针头防护：NDC 63459-910-23
（5）5包在托盘中有安全针头防护：NDC 63459-910-25
（6）10包在托盘中有安全针头防护：NDC 63459-910-27
（7）1包在泡中有安全针头防护：NDC 63459-910-11
（8）5包在泡中有安全针头防护：NDC 63459-910-35
（9）10包在泡中有安全针头防护：NDC 63459-910-15
Tbo-filgrastim 480 μg/0.8 mL：各个预装注射器含480 μg的tbo-filgrastim在0.8 mL溶液有透明活塞在：
（1）1包无安全针头防护：NDC 63459-912-17 •
（2）5包无安全针头防护：NDC 63459-912-36 •
（3）10包无安全针头防护：NDC 63459-912-46
（4）1包在托盘中有安全针头防护：NDC 63459-912-23 •
（5）5包在托盘中有安全针头防护：NDC 63459-912-25 •
（6）10包在托盘中有安全针头防护：NDC 63459-912-27
（7）1包在泡中有安全针头防护：NDC 63459-912-11 •
（8）5包在泡中有安全针头防护：NDC 63459-912-35 •
（9）10包在泡中有安全针头防护：NDC 63459-912-15
Tbo-filgrastim注射器应贮存在冰箱在36°至46°F(2°至8°C)。避光保护。在保质期，产品可被取出从36°至46° F(2°至8°C)贮存73°至81°F(23°至27° C)间共单一时期至5天。如在5天内不使用，产品可回至36°至46°F(2°至8° C)直至失效期。
避免震荡。使用前应肉眼观察。只应使用澄明无颗粒溶液。暴露至23°至30° F(-1° 至-5 °C)直至72小时和温度低至5°至-13° F(-15至-25° C)共至24小时对tbo-filgrastim稳定性无不良影响。
单次使用注射器 – 遗弃未使用部分。任何未使用产品或废弃材料应按当地要求遗弃。

患者注意事项[资讯信息]

忠告患者以下风险和潜在风险用白细胞生长因子例如tbo-filgrastim：
（1）骨痛是常见。可能需要镇痛药例如对乙酰氨基酚或NSAIDS。
（2）可能发生脾破裂或增大，腹痛，左上腹疼痛，或左肩痛可能是其信号。劝告患者在这些区域疼痛发作时立即报告他们的医生。
（3）呼吸困难有或无发热，可能进展至急性呼吸窘迫综合征。劝告患者呼吸困难立即报告至他们的医生。
（4）严重过敏反应，包括过敏反应，皮疹，和荨麻疹：患者 应立即报告这类反应。
（5）有镰刀细胞病，镰状细胞危象患者和曾发生死亡。对有镰刀细胞病患者给予人粒细胞集落-刺激因子前讨论潜在风险和获益。
（6）感染风险增加在情况使用Tbo-filgrastim。应警惕患者感染征象例如发热，红或肿胀和应立即向其医生报告这些发现。
（7）当接受tbo-filgrastim时，告知患者不要成为妊娠。如发生妊娠，劝告患者胎儿危害的可能性。

(tbo-filgrastim)注射剂使用完整处方资料

1）http://www.oneyao.net/article/2012/0909/article_30908.html

Tbo-filgrastim Injection

1. DESCRIPTION 

Tbo-filgrastim is a nonglycosylated recombinant methionyl human granulocyte colony-stimulating growth factor (r-metHuG-CSF) manufactured by recombinant DNA technology using the bacterium strain E coli K802. It has a molecular weight of approximately 18.8 kDa and is composed of 175 amino acids. The endogenous human G-CSF is glycosylated and does not have the additional methionine amino acid residue in its NH2 terminal end.

The product is a sterile, clear, colorless, preservative-free solution containing tbo-filgrastim, glacial acetic acid, sorbitol, polysorbate 80, sodium hydroxide, and Water for Injection. The product is available in single-use prefilled syringes that contain either 300 mcg or 480 mcg of tbo-filgrastim at a fill volume of 0.5 mL or 0.8 mL, respectively. See table below for product composition of each single-use prefilled syringe.

2. INDICATIONS AND USAGE 

Tbo-filgrastim is indicated to reduce the duration of severe neutropenia in patients with non-myeloid malignancies receiving myelosuppressive anti-cancer drugs associated with a clinically significant incidence of febrile neutropenia.

3. DOSAGE AND ADMINISTRATION 

3.1 Dosage

The recommended dose of tbo-filgrastim is 5 mcg/kg per day administered as a subcutaneous injection. Administer the first dose of tbo-filgrastim no earlier than 24 hours following myelosuppressive chemotherapy. Do not administer tbo-filgrastim within 24 hours prior to chemotherapy [see Warnings and Precautions].

Daily dosing with tbo-filgrastim should continue until the expected neutrophil nadir is passed and the neutrophil count has recovered to the normal range. Monitor complete blood count (CBC) prior to chemotherapy and twice per week until recovery.

3.2 General Considerations for Administration

Tbo-filgrastim should be administered by a healthcare professional.

Visually inspect parenteral drug products for particulate matter and discoloration prior to administration. Do not administer tbo-filgrastim if discoloration or particulates are observed.

The prefilled syringe is for single use only. Discard unused portions.

Recommended sites for subcutaneous tbo-filgrastim injections include the abdomen (except for the two inch area around the navel), the front of the middle thighs, the upper outer areas of the buttocks, or the upper back portion of the upper arms. The injection site should be varied daily. Tbo-filgrastim should not be injected into an area that is tender, red, bruised, or hard or that has scars or stretch marks.

3.3 Instructions for Use of the Safety Needle Guard Device

Hold the syringe assembly by the open sides of the device and remove the needle shield.

Expel any extra volume depending on dose needed.

Inject tbo-filgrastim subcutaneously as recommended [see General Considerations for Administration].

Push the plunger as far as it will go to inject all the medication. Injection of the entire prefilled syringe contents is necessary to activate the needle guard.

With the plunger still pressed all the way down, remove the needle from the skin.

Slowly let go of the plunger and allow the empty syringe to move up inside the device until the entire needle is guarded.

Discard the syringe assembly in approved containers.

4. CONTRAINDICATIONS 

None.

5. MECHANISM OF ACTION 

Tbo-filgrastim is a human granulocyte colony-stimulating factor (G-CSF) produced by recombinant DNA technology. Tbo-filgrastim binds to G-CSF receptors and stimulates proliferation of neutrophils. G-CSF is known to stimulate differentiation commitment and some end-cell functional activation, which increases neutrophil counts and activity.

6. USE IN SPECIFIC POPULATIONS 

6.1 Usage in Pregnancy

Pregnancy Category C

There are no adequate and well-controlled studies of tbo-filgrastim in pregnant women. In an embryofetal developmental study, treatment of pregnant rabbits with tbo-filgrastim resulted in adverse embryofetal findings, including increased spontaneous abortion and fetal malformations at a maternally toxic dose. Tbo-filgrastim should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

In the embryofetal developmental study, pregnant rabbits were administered subcutaneous doses of tbo-filgrastim during the period of organogenesis at 1, 10 and 100 mcg/kg/day. Increased abortions were evident in rabbits treated with tbo-filgrastim at 100 mcg/kg/day. This dose was maternally toxic as demonstrated by reduced body weight. Other embryofetal findings at this dose level consisted of post-implantation loss‚ decreased in mean live litter size and fetal weight, and fetal malformations such as malformed hindlimbs and cleft palate. The dose of 100 mcg/kg/day corresponds to a systemic exposure (AUC0-24) of approximately 50-90 times the exposures observed in patients treated with the clinical tbo-filgrastim dose of 5 mcg/kg/day.

6.2 Nursing Mothers

It is not known whether tbo-filgrastim is secreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when tbo-filgrastim is administered to a nursing woman. Other recombinant G-CSF products are poorly secreted in breast milk and G-CSF is not orally absorbed by neonates.

6.3 Pediatric Use

The safety and effectiveness of tbo-filgrastim in pediatric patients have not been established.

6.4 Geriatric Use

Among 677 cancer patients enrolled in clinical trials of tbo-filgrastim, a total of 111 patients were 65 years of age and older. No overall differences in safety or effectiveness were observed between patients age 65 and older and younger patients.

6.5 Renal Impairment

The safety and efficacy of tbo-filgrastim have not been studied in patients with moderate or severe renal impairment. No dose adjustment is recommended for patients with mild renal impairment.

6.6 Hepatic Impairment

The safety and efficacy of tbo-filgrastim have not been studied in patients with hepatic impairment.

7. WARNINGS AND PRECAUTIONS 

7.1 Splenic Rupture

Splenic rupture, including fatal cases, can occur following administration of human granulocyte colony-stimulating factors. In patients who report upper abdominal or shoulder pain after receiving tbo-filgrastim, discontinue tbo-filgrastim and evaluate for an enlarged spleen or splenic rupture.

7.2 Acute Respiratory Distress Syndrome (ARDS)

Acute respiratory distress syndrome (ARDS) can occur in patients receiving human granulocyte colony-stimulating factors. Evaluate patients who develop fever and lung infiltrates or respiratory distress after receiving tbo-filgrastim, for ARDS. Discontinue tbo-filgrastim in patients with ARDS.

7.3 Allergic Reactions

Serious allergic reactions including anaphylaxis can occur in patients receiving human granulocyte colony-stimulating factors. Reactions can occur on initial exposure. The administration of antihistamines‚ steroids‚ bronchodilators‚ and/or epinephrine may reduce the severity of the reactions. Permanently discontinue tbo-filgrastim in patients with serious allergic reactions. Do not administer tbo-filgrastim to patients with a history of serious allergic reactions to filgrastim or pegfilgrastim.

7.4 Use in Patients with Sickle Cell Disease

Severe and sometimes fatal sickle cell crises can occur in patients with sickle cell disease receiving human granulocyte colony-stimulating factors. Consider the potential risks and benefits prior to the administration of human granulocyte colony-stimulating factors in patients with sickle cell disease. Discontinue tbo-filgrastim in patients undergoing a sickle cell crisis.

7.5 Potential for Tumor Growth Stimulatory Effects on Malignant Cells

The granulocyte colony stimulating factor (G-CSF) receptor through which tbo-filgrastim acts has been found on tumor cell lines. The possibility that tbo-filgrastim acts as a growth factor for any tumor type, including myeloid malignancies and myelodysplasia, diseases for which tbo-filgrastim is not approved, cannot be excluded.

8. ADVERSE REACTIONS 

The following potential serious adverse reactions are discussed in greater detail in other sections of the labeling:

• Splenic Rupture [see Warnings and Precautions]

• Acute Respiratory Distress Syndrome [see Warnings and Precautions]

• Serious Allergic Reactions [see Warnings and Precautions]

• Use in Patients with Sickle Cell Disorders [see Warnings and Precautions]

• Potential for Tumor Growth Stimulatory Effects on Malignant Cells [see Warnings and Precautions]

The most common treatment-emergent adverse reaction that occurred at an incidence of at least 1% or greater in patients treated with tbo-filgrastim at the recommended dose and was numerically two times more frequent than in the placebo group was bone pain.

8.1 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 to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

Tbo-filgrastim clinical trials safety data are based upon the results of three randomized clinical trials in patients receiving myeloablative chemotherapy for breast cancer (N=348), lung cancer (N=240) and Non-Hodgkin’s lymphoma (N=92). In the breast cancer study, 99% of patients were female, the median age was 50 years, and 86% of patients were Caucasian. In the lung cancer study, 80% of patients were male, the median age was 58 years, and 95% of patients were Caucasian. In the Non-Hodgkin’s lymphoma 52% of patients were male, the median age was 55 years, and 88% of patients were Caucasian. In all three studies a placebo (Cycle 1 of the breast cancer study only) or a non-US-approved filgrastim product were used as controls. Both tbo-filgrastim and the non-US-approved filgrastim product were administered at 5 mcg/kg subcutaneously once daily beginning one day after chemotherapy for at least five days and continued to a maximum of 14 days or until an ANC of ≥10,000 x106/L after nadir was reached.

Bone pain was the most frequent treatment-emergent adverse reaction that occurred in at least 1% or greater in patients treated with tbo-filgrastim at the recommended dose and was numerically two times more frequent than in the placebo group. The overall incidence of bone pain in Cycle 1 of treatment was 3.4% (3.4% tbo-filgrastim, 1.4% placebo, 7.5% non-US-approved filgrastim product ).

Leukocytosis

In clinical studies, leukocytosis (WBC counts > 100,000 x 106/L) was observed in less than 1% patients with non-myeloid malignancies receiving tbo-filgrastim. No complications attributable to leukocytosis were reported in clinical studies.

8.2 Immunogenicity

As with all therapeutic proteins, there is a potential for immunogenicity. The incidence of antibody development in patients receiving tbo-filgrastim has not been adequately determined.

9. OVERDOSAGE 

No case of overdose has been reported.

10. DRUG INTERACTIONS 

No formal drug interaction studies between tbo-filgrastim and other drugs have been performed.

Drugs which may potentiate the release of neutrophils‚ such as lithium‚ should be used with caution.

Increased hematopoietic activity of the bone marrow in response to growth factor therapy has been associated with transient positive bone imaging changes. This should be considered when interpreting bone imaging results.

11. PHARMACOKINETICS  

In healthy subjects, the absolute bioavailability of 5 mcg/kg subcutaneous tbo-filgrastim was 33%. Increasing the dose of tbo-filgrastim from 5 to 10 mcg/kg in these healthy subjects resulted in an approximately 200% increase in both the maximum concentration (Cmax) and the area under the curve (AUC0-48h) of the drug.

In the clinical trials of patients with cancer, the AUC and Cmax were greater and more variable compared to healthy volunteers receiving the same dose of tbo-filgrastim subcutaneously. The median time to maximum concentration was between 4 to 6 hours and the median elimination half-life was between 3.2 to 3.8 hours. Accumulation was not observed after repeated dosing.

Pharmacokinetics in Specific Populations

Age: Not evaluated.

Gender: No gender-related differences were observed.

Renal Impairment: Mild renal impairment (creatinine clearance 60 - 89 mL/min) had no effect on tbo-filgrastim pharmacokinetics (N=11). The pharmacokinetic profile in patients with moderate and severe renal impairment has not been assessed.

Hepatic Impairment: The pharmacokinetic profile in patients with hepatic impairment has not been assessed.

12. HOW SUPPLIED/STORAGE AND HANDLING 

1) How Available:

a) Brand name: NEUTROVAL, by GLA.

b) Generic drugs: None.

2) How Supplied:

Tbo-filgrastim solution for injection is supplied as a single-use, preservative-free, prefilled syringe of Type I glass which has a permanently attached stainless steel needle. Syringes may be supplied with or without an UltraSafe Passive® Needle Guard.

The active substance is tbo-filgrastim.

Tbo-filgrastim syringes should be stored in a refrigerator at 36° to 46° F (2° to 8° C). Protect from light. Within its shelf life, the product may be removed from 36° to 46° F (2° to 8° C) storage for a single period of up to 5 days between 73° to 81° F (23° to 27° C). If not used within 5 days, the product may be returned to 36° to 46° F (2° to 8° C) up to the expiration date.

Avoid shaking. The solution should be visually inspected prior to use. Only clear solutions without particles should be used. Exposure to 23° to 30° F (-1° to -5 °C) for up to 72 hours and temperatures as low as 5° to -13° F (-15 to -25° C) for up to 24 hours do not adversely affect the stability of tbo-filgrastim.