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简介：
Neumega 重组人白介素11（rhIL-11）
化疗引起的骨髓抑制及与之相关的贫血、白细胞减少症和血小板减少症是很多化疗药物的剂量限制性毒性。尽管几种生长因子的应用，如促红细胞生长素、集落刺激因子的出现大大减轻了贫血及粒细胞减少症对患者的危害。但血小板减少却是一个一直都未解决的问题。虽然输注血小板可暂时缓解血小板减少，但这种作用仅是暂时的，同时还可能出现其它问题：如感染、输血反应、抗体产生。因此临床上对促进血小板生长因子的需要十分迫切。
在寻找血小板生长因子的过程中，人们陆续发现了TPO（促血小板生长素）、干细胞因子（c-kit片段）、白细胞介素1、3、6、11和GM-CSF，其中白细胞介素11（IL-11）显示了较好的作用。
重组人的IL-11（rhIL-11）由美国Genetics Institute （GI）公司研制成功，1997年11月经FDA批准上市，商品名为Neumega，它是目前治疗化疗导致的血小板减少症的的唯一有效的药物。
生物学特性和药理作用
人体内的IL-11是由原始骨髓基质细胞系产生的，它能刺激原始造血干细胞的生长，并能促进巨噬细胞前体细胞的分化和成熟。动物实验表明，IL-11能促进血小板计数的恢复，并能缓解骨髓抑制动物的血小板减少症。
Neumega是重组人的IL-11，是通过基因工程技术，在大肠杆菌中通过DNA重组方法生产。它由177个氨基酸组成的多肽，分子量为1900D，无糖基化。rhIL-11与天然的178个氨基酸的IL-11比较，末端仅少一个脯氨酸，但两者在体内和体外的活性没有差别。临床前研究表明在rhIL-11作用下，体内发育成熟的巨核细胞在超微结构上是正常的，形成的血小板在形态、功能和寿命方面也与正常的血小板相同。
rhIL-11无论是静脉应用还是皮下注射，其药代动力学均显示线性特点。静脉注射不同剂量的rhIL-11时，其血浆半衰期均为1.8-2.3小时，血浆清除率为2.2-2.7ml/min/kg。皮下注射不同剂量的rhIL-11时，血浆半衰期为6.9-8.1小时，生物利用度为69%。反复多次皮下注射其代谢特点无变化。
临床研究
最早开展的一项多中心、随机、安慰剂对照的临床研究明确了rhIL-11的作用。93例已接受过1周期化疗的患者入组，这些患者在第1周期的化疗中，均因为严重的血小板减少接受过血小板输注。入组患者随机分为3组：第2周期化疗后分别接受rhIL-11 50μg/kg、25μg/kg和安慰剂治疗共14-21天。
结果接受50μg/kg rhIL-11治疗的17例患者中8例没有因为血小板减少再一次接受血小板输注，而安慰剂组的28例患者中仅有1例没有接受血小板输注，其余的27例患者均因为血小板计数≤20000/mm3而接受血小板输注（P<0.05）。提示rhIL-11 50μg/kg能显著减少由于血小板降低而输注血小板事件的发生。
另一组77例乳腺癌患者中，所有患者均接受同样的化疗方案：CTX 3200mg/m2 + ADM 75mg/m2，所有患者在治疗中均使用G-CSF，按患者是否接受化疗随机分为注射rhIL-11 50μg/kg或安慰剂组。结果需rhIL-11治疗组的40例患者中仅有13例（32.5%）由于血小板减少接受血小板输注，而对照组的37例患者中有22例（59%）接受血小板输注（P=0.03）。既往未作过化疗的患者，由于血小板减少接受血小板输注在治疗组和对照组分别为27%和41%；既往作过化疗的患者则分别为36%和87.5%，表明rhIL-11在经过多次化疗后出现血小板减少症的患者中仍能获得更好的疗效。
同时，它还能缩短血小板计数恢复到50000/mm3以上的时间（9.3天和13.0天，P=0.01）。
基于以上研究，rhIL-11已于1997年被美国FDA批准上市，用于化疗所致严重血小板减少症的治疗。但在自体骨髓移植中，rhIL-11不能降低血小板输注事件的发生率，同时还会出现水肿和较高的心血管系统的不良反应。
不良反应
主要的不良反应为水钠潴留，患者可出现周围性水肿、呼吸困难、疲乏，严重者出现胸水、腹水、心包积液。水钠潴留可导致血红蛋白、红细胞计数下降，有时患者还需输注红细胞。注射局部可出现疼痛、红肿，还有少数患者出现皮疹、厌食、暂时性视力模糊（由视神经乳头水肿所致）、抗体形成、过敏等。部分患者出现心血管方面的不良反应，如心率不齐、晕厥、心动过速、房颤等。
用法用量
rhIL-11一般在化疗完成后6~24小时开始皮下注射，剂量为50μg/kg，每日一次，连用14天，或直到血小板最低点过后计数≥100，000/mm3方可停药。往往注射5~9天左右血小板数量开始上升，停止给药后连续7天血小板仍继续上升并于14天内恢复至基数水平。
虽然，rhIL-11是目前唯一批准用于血小板减少症治疗的药物，但由于它对血小板生长的刺激程度仅为中等，同时应用中又有一系列不良反应，因此人们还在不断研究以期开发出疗效更好、毒性更低的药物。目前正在进行研究的药物有融合蛋白PIXY321、C-mpl片段模拟肽、高度亲和的白介素3受体片段IL3-synthokine等。也有学者试图联合应用几种有效药物综合治疗血小板减少症。
美国FDA批准修改Neumega的安全标示
FDA批准在惠氏公司重组人白介素11（rhIL-11，oprelvekin，Neumega）的标签中加入一项安全性警告，即在骨髓清除性化疗后不能用本品治疗，因为会引起毒副作用。
一项随机安慰剂对照临床研究结果表明，本品在骨髓清除性化疗后无效，而且其使用与水肿、结膜出血、低血压以及心动过速等不良反应发生率显著上升有关。
目前已知本品会导致严重的体液潴留，从而引起外周性水肿、用力时呼吸困难，肺水肿、毛细血管漏综合征、房性心律失常、胸腔积液加剧等。
FDA已经收到了本品致严重体液潴留的上市后研究报告。有一些患者在骨髓移植后使用本品，结果导致死亡。
本品用于预防严重血小板减少症，减少非髓样恶性肿瘤患者在骨髓抑制性化疗后血小板输血。
NEUMEGA(oprelvekin)
Indications and Usage
NEUMEGA is indicated for the prevention of severe thrombocytopenia and the reduction of the need for platelet transfusions following myelosuppressive chemotherapy in adult patients with nonmyeloid malignancies who are at high risk of severe thrombocytopenia.
Efficacy was demonstrated in patients who had experienced severe thrombocytopenia following the previous chemotherapy cycle.
NEUMEGA is not indicated following myeloablative chemotherapy.
The safety and effectiveness of NEUMEGA have not been established in pediatric patients.
Important Safety Information
Allergic Reactions Including Anaphylaxis
NEUMEGA has caused allergic or hypersensitivity reactions, including anaphylaxis. Administration of NEUMEGA should be permanently discontinued in any patient who develops an allergic or hypersensitivity reaction (see WARNINGS, CONTRAINDICATIONS, ADVERSE REACTIONS and ADVERSE REACTIONS, Immunogenicity).
Serious adverse reactions have been associated with NEUMEGA administration, including allergic or hypersensitivity reactions and anaphylaxis. NEUMEGA is known to cause serious fluid retention that can result in peripheral edema, dyspnea, pulmonary edema, capillary leak syndrome, atrial arrhythmias (some with strokes),
dilutional anemia, and exacerbation of pre-existing pericardial or pleural effusions.
Neumega should be used with caution in patients with congestive heart failure (CHF), at risk of developing CHF, or with a history of heart failure. Other more common adverse events include mild to moderate fluid retention, tachycardia, conjunctival redness, and papilledema. Changes in visual acuity and/or visual field defects ranging from blurred vision to blindness can occur in patients with papilledema taking NEUMEGA.
In post-marketing surveillance, ventricular arrhythmias have been reported.
Dose adjustments are recommended for patients with severe renal impairment.
In randomized studies, most adverse events were reversible within several days following discontinuation of NEUMEGA.
INDICATIONS
Neumega is indicated for the prevention of severe thrombocytopenia and the reduction of the need for platelet transfusions following myelosuppressive chemotherapy in adult patients with nonmyeloid malignancies who are at high risk of severe thrombocytopenia.
Efficacy was demonstrated in patients who had experienced severe thrombocytopenia following the previous chemotherapy cycle.
Neumega is not indicated following myeloablative chemotherapy (see WARNINGS, Increased Toxicity Following Myeloablative Therapy). The safety and effectiveness of Neumega have not been established in pediatric patients.
DOSAGE AND ADMINISTRATION
The recommended dose of Neumega in adults without severe renal impairment is 50 mg/kg given once daily.
Neumega should be administered subcutaneously as a single injection in either the abdomen, thigh, or hip (or upper arm if not self-injecting).
A safe and effective dose has not been established in children (see PRECAUTIONS, Pediatric Use).
The recommended dose of Neumega in adults with severe renal impairment (creatinine clearance <30 mL/min) is 25 mg/kg.
An estimate of the patient's creatinine clearance (CLcr) in mL/min is required. CLcr in mL/min may be estimated from a spot serum creatinine (mg/dL) determination using the following formula:CLcr »[140 - age (years)] x weight (kg)
72 x serum creatinine (mg/dL) {x 0.85 for female patients}Dosing should be initiated six to 24 hours after the completion of chemotherapy. Platelet counts should be monitored periodically to assess the optimal duration of therapy. Dosing should be continued until the post-nadir platelet count is ≥50,000/mL.
In controlled clinical trials, doses were administered in courses of 10 to 21 days. Dosing beyond 21 days per treatment course is not recommended.
Treatment with Neumega should be discontinued at least two days before starting the next planned cycle of chemotherapy.
Preparation of Neumega
1. Neumega is a sterile, white, preservative-free, lyophilized powder for subcutaneous injection upon reconstitution.
Reconstitute the Neumega 5 mg vial using the 1.0 mL of Sterile Water for Injection, USP (without preservative) contained in the pre-filled syringe included in the kit The reconstituted Neumega solution is clear, colorless, isotonic, with a pH of 7.0, and contains 5 mg/mL of Neumega. Any unused portion of the reconstituted Neumega solution should be discarded.
2. During reconstitution, the Sterile Water for Injection, USP should be directed at the side of the vial and the contents gently swirled. Excessive or vigorous agitation should be avoided.
3. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. If particulate matter is present or the solution is discolored, the vial should not be
used.
4. Administer Neumega within 3 hours following reconstitution.
Reconstituted Neumega may be refrigerated [2°C to 8°C (36°F to 46°F)] or maintained at room temperature [up to 25°C (77°F)]. Do not freeze or shake the reconstituted solution.
HOW SUPPLIED
Neumega is supplied as a sterile, white, preservative-free, lyophilized powder （无菌、白色、无防腐剂、冻干粉）in vials containing 5 mg oprelvekin.
Neumega is available in boxes containing one single-dose Neumega vial and one pre-filled syringe containing 1 mL Sterile Water for Injection, USP.
- NDC 58394-004-08
Storage
The kit containing the vial of lyophilized Neumega and pre-filled diluent syringe should be stored in a refrigerator at 2°C to 8°C (36°F to 46°F). Protect Neumega powder from light. Do not freeze.
United States Patent Numbers: 5,215,895; 5,270,181; 5,371,193; 6,066,317; 6,143,524; 6,270,757.
This product's label may have been updated. For current package insert and further product information, please visit www.wyeth.com or call our medical communications department toll-free at 1-800-934-5556.
WyethÃ?
Wyeth Pharmaceuticals Inc.
Philadelphia, PA 19101
US Govt. License No. 3
FDA rev date: 08/10/06
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