2012年8月30日，梯瓦制药和美国食品药品管理局(FDA)宣布，已批准tbo-filgrastim(XM02 filgrastim)用于因接受化疗而导致中性粒细胞减少症的非骨髓恶性肿瘤患者，以减少严重中性粒细胞减少症的持续时间。Tbo-filgrastim是一种短效重组粒细胞集落刺激因子(G-CSF)。

一项纳入348例正在接受阿霉素和多西他赛治疗的晚期乳腺癌患者的临床研究对tbo-filgrastim的有效性进行了评价。患者被随机分组，接受tbo-filgrastim、美国未批准的filgrastim制剂或安慰剂治疗，tbo-filgrastim治疗组严重中性粒细胞减少症恢复时间为1.1天，而安慰剂组为3.8天。

共纳入680例接受大剂量骨髓抑制性化疗的乳腺癌、肺癌或非霍奇金淋巴瘤患者的三项临床研究评价了Tbo-filgrastim的安全性。接受tbo-filgrastim治疗者的最常见不良反应为骨痛。

接受tbo-filgrastim治疗可能出现的严重不良事件包括脾破裂、急性呼吸窘迫综合征、过敏反应以及镰状红细胞病患者镰状红细胞危象。

Tbo-filgrastim在化疗24 h后开始应用。该产品为皮下注射剂，其上市规格为300 μg/0.5 ml和480 μg/0.8 ml的单剂、不含防腐剂的预填充注射剂。梯瓦公司计划最早将从2013年11月开始销售tbo-filgrastim。

以下英文处方

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 300 mcg/0.5 mL: Each prefilled syringe contains 300 mcg of tbo-filgrastim in 0.5 mL solution with a blue plunger in:

• Packs of 1 without a safety needle guard: NDC 63459-910-17

• Packs of 5 without a safety needle guard: NDC 63459-910-36

• Packs of 10 without a safety needle guard: NDC 63459-910-46

• Packs of 1 with a safety needle guard in trays: NDC 63459-910-23

• Packs of 5 with a safety needle guard in trays: NDC 63459-910-25

• Packs of 10 with a safety needle guard in trays: NDC 63459-910-27

• Packs of 1 with a safety needle guard in blisters: NDC 63459-910-11

• Packs of 5 with a safety needle guard in blisters: NDC 63459-910-35

• Packs of 10 with a safety needle guard in blisters: NDC 63459-910-15

Tbo-filgrastim 480 mcg/0.8 mL: Each prefilled syringe contains 480 mcg of tbo-filgrastim in 0.8 mL solution with a clear plunger in:

• Packs of 1 without a safety needle guard: NDC 63459-912-17

• Packs of 5 without a safety needle guard: NDC 63459-912-36

• Packs of 10 without a safety needle guard: NDC 63459-912-46

• Packs of 1 with a safety needle guard in trays: NDC 63459-912-23

• Packs of 5 with a safety needle guard in trays: NDC 63459-912-25

• Packs of 10 with a safety needle guard in trays: NDC 63459-912-27

• Packs of 1 with a safety needle guard in blisters: NDC 63459-912-11

• Packs of 5 with a safety needle guard in blisters: NDC 63459-912-35

• Packs of 10 with a safety needle guard in blisters: NDC 63459-912-15

3) Storage and Handling:

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.

Single use syringe – discard unused portion. Any unused product or waste material should be disposed of in accordance with local requirements.