美国FDA批准Genzyme公司的clolar(clofarabine)用于治疗儿童顽固性及复发性急性淋巴细胞白血病(ALL)。clolar是10年来首次获FDA批准通过用于治疗儿童ALL的新药。 药品名称：氯法拉滨Clofarabine 规格：静脉注射剂，20ml：20mg。 适应症：急性淋巴细胞白血病和急性髓性白血病 临床特点及优势 结合了氟达拉滨(Fludarabine)和克拉屈滨(Cladribine) 的优点，既抑制DNA聚合酶，又抑制核糖核酸还原酶;是目前唯一适合用于治疗儿童白血病的药物;治疗有效率非常高，两次常规化疗无应答的患者, 对该药的总反应率为31%。　　 病人耐受性好，无不可预知的不良反应; 具有潜在广谱抗肿瘤特性。 美国Bioenvision公司开发, Genzyme公司生产，04.12.28FDA快速审评通道批准本品上市。现本品未申请进口，原料制剂均为3.1类。Bioenvision公司于2006年5月宣布，欧盟委员会已经批准其clofarabine（Evoltra）上市。用于治疗急性淋巴细胞性白血病。本品适用范围为复发的或对至少2种疗法无应答且没有其它疗法可选用的儿科急性淋巴细胞性白血病患者。此外，本品还可用于初次诊断为白血病的21岁及以下患者。 药理类型及作用机制 氯法拉滨是嘌呤核苷类衍生物，氯法拉滨通过抑制核苷酸还原酶作用，降低细胞内脱氧三磷酸核苷储量，抑制DNA的合成；通过与DNA链结合，竞争性抑制DNA聚合酶，使DNA链的延长和修复中止。氯法拉滨三磷酸物对这些酶的亲和力与脱氧胞苷相似或大于。临床前研究表明，在修复阶段，氯法拉滨通过与DNA链的结合，具有抑制DNA修复作用。氯法拉滨-5’-三磷酸化物也能破化线粒体膜的完整性，导致凋亡线粒体蛋白、细胞色素C、凋亡诱导因子的释放，最终导致程序性细胞死亡。 适应症及用法用量 适应症：用于1～21岁复发或顽固性急性淋巴细胞白血病病人，在至少使用两种以上治疗方式无效后使用。 用法用量：用5%葡萄糖或0.9%氯化钠注射液稀释成最终浓度为0.15mg/ml和0.4mg/m后方可供静脉滴注使用。配制后的药液可在室温保存，但必须在配制后24小时内使用。 小儿用法用量：剂量为50mg/m2/d，静脉滴注2小时，连续给药5天。约为2～6周，当器官功能恢复到基线水平时，再重复给药。剂量是根据体表面积计算，在每个给药周期开始前根据当时的身高和体重。为防止发生配伍禁忌，不要使用同一输液装置给予其它药物。 临床应用 氯法拉滨（Clofarbine）属于核苷酸类似物，2004年12月29日，美国FDA批准其可用于治疗儿童难治性或复发性急性淋巴细胞性白血病(ALL)氯法拉滨是近10年来第1个批准用于治疗儿童ALL的新药。FDA是经快通道批准该药的，其依据是一项有49例复治的复发性或难治性ALL患儿参加的核心II期临床试验的结果。14%的患儿在氯法拉滨治疗后，接受了骨髓或干细胞移植。氯法拉滨最常见的副作用有恶心、呕吐和腹泻等胃肠道症状，贫血、白细胞减少、血小板减少、中性粒细胞减少和发热伴中性粒细胞减少等血液学反应以及感染。氯法拉滨为这些患儿带来了希望，给部分患儿带来了持续的缓解并为部分患儿接受骨髓移植创造了条件，是高抵抗性白血病患儿一种新的有效且耐受良好的治疗选择。氯法拉滨在复发或难治性急性髓细胞性白血病患儿中也显示出希望。 　　 氯法拉滨潜在广谱抗肿瘤特性，在美国，用于乳腺癌、肺癌、结直肠癌、前列腺癌、肾癌、宫颈癌、胰腺癌、皮肤癌、膀胱癌、非小细胞肺癌、口腔癌、鼻咽癌、喉癌、上颌窦癌、食管癌、子宫瘤、黑色素瘤、平滑肌肉瘤的I期临床研究大部分已经完成。急性骨髓性白血病、慢性淋巴瘤、非霍奇金淋巴瘤处于II期临床研究阶段，抑制移植排斥研究处于I期临床研究阶段。所以在用于治疗急性白血病的同时，它的潜在适应症包括很多实体瘤以及一些免疫性疾病。 药理药效及副作用 氯法拉滨的作用机制与克拉曲滨（cladribine）和氟达拉滨(fludarabine)相似，克拉曲滨通过抑制核苷酸还原酶起作用，氟达拉滨抑制DNA聚合酶α；对人类和鼠类的白细胞进行实验表明，氯法拉滨将克拉曲滨和氟达拉滨的作用集于一体，其经脱氧胞苷激酶磷酸化，首先有效抑制核苷酸还原酶，使DNA合成终止，而且也能抑制DNA聚合酶α，使DNA链不再延长。氯法拉滨能更有效地被脱氧胞苷激酶磷酸化，而且在人类白血病细胞中的消除更慢，因此具有更好的细胞毒性。氯法拉滨对不同的细胞株和肿瘤模型都表现出了很强的抗癌活性。 　　 体外对哺乳动物细胞（CHO）细胞染色体变异试验及体内大鼠微核试验表明，氯法拉滨有诱裂活性。细菌变异试验（Ames试验）结果显示本品没有明显的致突变活性。对小鼠、大鼠和狗研究表明，本品对雄性动物的生殖器官能产生剂量依赖性严重不良影响。大鼠和兔研究表明，氯法拉滨具有致畸作用。113例儿科病人暴露于氯法拉滨（ALL 67，AML 46）。 临床试验中96例儿科病人接受本品的推荐剂量52 mg/m2/d×5天。不考虑因果关系，本品治疗后最常见的不良反应为消化道症状包括呕吐、恶心和腹泻；血液系统影响包括贫血、白细胞减少、血小板减少、中性白细胞减少、发热性中性白细胞减少以及感染。 Indication: Clolar is indicated for the treatment of pediatric patients 1 to 21 years old with relapsed or refractory acute lymphoblastic leukemia after at least two prior regimens. Randomized trials demonstrating increased survival or other clinical benefit have not been conducted. Key Efficacy Results: Clolar achieves a 30% rate of CR, CRp, or PR*  Responses were seen in both pre-B and T-cell ALL   *The clinical relevance of a PR in this setting is unknown. 50% of patients with a CR or CRp achieved best response after cycles 2 and 3  6 patients – 1 cycle    5 patients – 2 cycles    1 patients – 3 cycles Important Safety Information: Adverse Reactions Most common adverse reactions with Clolar® were nausea (73%), vomiting (78%), diarrhea (56%), febrile neutropenia (55%), headache (43%), rash (38%), pruritus (43%), pyrexia (39%), fatigue (34%), palmar-plantar erythrodysesthesia syndrome (16%), anxiety (21%), flushing (19%), and mucosal inflammation (16%). Precautions and Warnings Clolar should be administered under the supervision of a qualified physician experienced in the use of antineoplastic therapy. Hematologic Toxicity Monitor complete blood counts and platelet counts during Clolar therapy.   Suppression of bone marrow function should be anticipated. This is usually reversible and appears to be dose dependent. Severe bone marrow suppression, including neutropenia, anemia, and thrombocytopenia, has been observed in patients treated with Clolar. At initiation of treatment, most patients in the clinical studies had hematological impairment as a manifestation of leukemia.    Because of the pre-existing immunocompromised condition of these patients and prolonged neutropenia that can result from treatment with Clolar, patients are at increased risk for severe opportunistic infections. Infections The use of Clolar is likely to increase the risk of infection, including severe sepsis, as a result of bone marrow suppression. Monitor patients for signs and symptoms of infection and treat promptly. Hyperuricemia (Tumor Lysis) Administration of Clolar may result in a rapid reduction in peripheral leukemia cells. Evaluate and monitor patients undergoing treatment for signs and symptoms of tumor lysis syndrome. Provide intravenous infusion fluids throughout the five days of Clolar administration to reduce the effects of tumor lysis and other adverse events. Administer Allopurinol if hyperuricemia (tumor lysis) is expected. Systemic Inflammatory Response Syndrome (SIRS) or Capillary Leak Syndrome  Evaluate and monitor patients undergoing treatment with Clolar for signs and symptoms of cytokine release (e.g., tachypnea, tachycardia, hypotension, pulmonary edema) that could develop into systemic inflammatory response syndrome (SIRS), capillary leak syndrome and organ dysfunction.    Discontinue Clolar immediately in the event of clinically significant signs or symptoms of SIRS or capillary leak syndrome, either of which can be fatal, and consider use of steroids, diuretics, and albumin. Re-institute Clolar when the patient is stable, generally with a 25% dose reduction. The use of prophylactic steroids may be of benefit in preventing signs and symptoms of cytokine release. Hepatic Enzymes Hepato-biliary enzyme elevations were frequently observed in pediatric patients during treatment with Clolar. Some patients discontinued treatment due to hepatic enzyme abnormalities. For patients with follow-up data, elevations in AST and ALT were transient and typically < 15 days duration. Hepatic and Renal Impairment  Clolar has not been studied in patients with hepatic or renal dysfunction. Its use in such patients should be undertaken only with the greatest caution.    Patients who have previously received a hematopoietic stem cell transplant (HSCT) may be at higher risk for    hepatotoxicity suggestive of veno-occlusive disease (VOD) following treatment with clofarabine (40 mg/m2) when used in combination with etoposide (100 mg/m2) and cyclophosphamide (440 mg/m2). Severe hepatotoxic events have been reported in an ongoing Phase 1/2 combination study of clofarabine in pediatric patients with relapsed or refractory acute leukemia. Use in Pregnancy Clolar can cause fetal harm when administered to a pregnant woman. Intravenous doses of clofarabine in rats and rabbits administered during organogenesis caused an increase in resorptions, malformations, and variations. Women of childbearing potential should be advised to avoid becoming pregnant while receiving Clolar. Nursing Mothers Female patients should be advised to avoid breast-feeding during treatment with Clolar. Incidence of Treatment Emergent Laboratory Abnormalities  Grade 3 or higher myelosuppression: anemia (75%), leukopenia (88%), lymphopenia (82%), neutropenia (64%), and thrombocytopenia (80%).    Grade 3 or higher renal and liver abnormalities: elevated creatinine (8%), elevated SGOT (36%), elevated SGPT (43%), and elevated total bilirubin (13%). ------------------------------------------------------------- The diagnosis of acute lymphoblastic leukemia (ALL) can be a frightening thing to hear from your doctor. And if your child has not responded to therapy, you may have many questions about what to do next. By now you may know a lot about childhood leukemia and what to expect from therapy. This website is designed to help answer many of the questions you may have about Clolar, but is not medical advice and does not replace discussions you should have with your healthcare team. Healthcare professionals are an excellent resource for information about ALL and treatment options. How Clolar is Used  怎样使用Clolar Clolar is a type of medication to treat children, ages 1 to 21 with a type of leukemia called relapsed or refractory acute lymphoblastic leukemia (ALL), after at least 2 other treatment attempts have failed. Clolar can reduce the number of leukemia cells in the blood. At this time we do not know if Clolar will help a child with ALL live longer or cure him or her of the cancer. Important Safety Information for Patients Serious side effects 主要副作用 Clolar can cause serious side effects that include: Systemic inflammatory response syndrome (SIRS)/capillary leak syndrome (CLS). Signs include fast breathing, fast heartbeat, low blood pressure, and difficulty breathing. These signs should be reported to the physician right away, as SIRS and CLS can be life-threatening if not treated right way. If your child experiences clinically significant signs of SIRS or CLS, your physician should stop Clolar immediately and consider giving your child steroids, diuretics, and albumin. When your child has stabilized, Clolar can be continued, usually at a lower dose. Bone marrow suppression and infection. Clolar can stop your child’s bone marrow from making enough red blood cells, white blood cells, and platelets. Serious side effects can result from this, and include severe infection (sepsis), bleeding, and anemia. Effects on pregnancy and breastfeeding. Females should not become pregnant or breastfeed during treatment with Clolar because Clolar may harm the baby. Other side effects 其他副作用 The most common side effects with Clolar are stomach problems (including vomiting, diarrhea, and nausea), and effects on blood cells (including low red and white blood cells count, low platelet count, fever, and infection). A fast heartbeat has been noted in some patients taking Clolar. Clolar can also affect the liver and kidneys. For these reasons, your child’s healthcare professional will do blood tests to monitor his or her blood cells, kidney function, and liver function. Treatment with Clolar quickly reduces the number of leukemia cells in your child’s blood. For this reason, your doctor should monitor your child for signs and symptoms of tumor lysis syndrome (TLS), as well as signs and symptoms of cytokine release, which can develop into SIRS, CLS, and organ problems. Your doctor is encouraged to give continuous IV fluids throughout the five days of Clolar treatment to reduce certain side effects. Your doctor may also prescribe allopurinol to reduce the build-up of uric acid that occurs with TLS. Your doctor should stop the Clolar treatment if your child develops low blood pressure for any reason during the five days of treatment. －－－－－－－－－－－－－－－－－－－－－－－－－－－－ 【原产地英文商品名】CLOLAR 1MG/ML 20MLS/VIAL 【原产地英文药品名】CLOFARABINE 【中文参考商品译名】 注：以下产品不同规格和不同价格，购买时请以电话咨询为准！ ·Clolar克罗拉 1毫克/毫升 20毫升/瓶 4瓶/盒 ·Clolar克罗拉 1毫克/毫升 20毫升/瓶 【中文参考药品译名】氯法拉滨 【生产厂家中文参考译名】健赞 【生产厂家英文名】GENZYME