克罗拉滨（氯法拉滨） 药品名称：克罗拉滨Clofarabine 剂型、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： 1、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；                 　　 2、是目前唯一适合用于治疗儿童白血病的药物；　　 3、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%。　　 4、病人耐受性好，无不可预知的不良反应； 　 5、具有潜在广谱抗肿瘤特性。　　 前景：目前全球儿童白血病的治愈率很高，但适合用于儿童的抗白血病药物仍然是空白。儿童使用成人药物往往产生很多严重的不良反应、严重影响儿童患者的生活质量。 克罗拉滨作为第一个特别适合用于儿童白血病的治疗药物，具有重大的意义。并且已经在美国获准快速审批。   治疗儿童白血病特效药—克罗拉滨针剂 克罗拉滨作为世界上目前唯一可以用于儿童白血病的化疗药，其疗效显著，总体反应率高，并且很好耐受，没有不可预知的不良反应。是近10年来第一个经国FDA批准用于治疗儿童顽固性或复发性急性淋巴细胞性白血病的新药，目前国内尚无厂家生产此药，该药投入生产后，将填补我国治疗儿童白血病3.1类新药空白。 【原产地英文商品名】CLOLAR 1MG/ML 20MLS/VIAL 4VIALS/BOX 【原产地英文药品名】CLOFARABINE 【中文参考商品译名】克罗拉滨 1毫克/毫升 20毫升/瓶 4瓶/盒 【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 ------------------------------------------------------------- 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. ----------------------------------------------------------------------- 药品名称：氯法拉滨 英文名称: Clofarabine；　　 又名：Clofarabine，Clolar，卢伐拉滨，克罗拉滨 化学名称: 2-氯-9-(2-去氧-2-氟-β-D-阿拉伯呋喃)-9H-嘌呤-6-胺,2-chloro-9-(2-deoxy-2-fluoro-β-D-arabinofuranosyl)-9H-purin-6-amine; CAS No： 123318-82-1； 　　 分 子 式： C10H11ClFN5O3； 　　 分 子 量： 303.68； 　　 性 状： 白色结晶性粉末 剂型、规格：静脉输注用，20ml：20mg 　  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。 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。 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。 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。 Clolar Generic Name: clofarabine Dosage Form: injection FULL PRESCRIBING INFORMATION Clolar® (clofarabine) Injection 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. This use is based on the induction of complete responses. Randomized trials demonstrating increased survival or other clinical benefit have not been conducted. Clolar Dosage and Administration Recommended Dosage Administer the recommended pediatric dose of 52 mg/m2 as an intravenous infusion over 2 hours daily for 5 consecutive days. Treatment cycles are repeated following recovery or return to baseline organ function, approximately every 2 to 6 weeks. The dosage is based on the patient’s body surface area (BSA), calculated using the actual height and weight before the start of each cycle. To prevent drug incompatibilities, no other medications should be administered through the same intravenous line. Provide supportive care, such as intravenous fluids, allopurinol, and alkalinize urine throughout the 5 days of Clolar administration to reduce the effects of tumor lysis and other adverse events. Discontinue Clolar if hypotension develops during the 5 days of administration. Monitor renal and hepatic function during the 5 days of Clolar administration [see WARNINGS AND PRECAUTIONS (5.6)]. Monitor patients taking medications known to affect blood pressure. Monitor cardiac function during administration of Clolar. Recommended Concomitant Medications and Medications to Avoid Consider prophylactic anti-emetic medications as Clolar is moderately emetogenic. Consider the use of prophylactic steroids to prevent signs or symptoms of Systemic Inflammatory Response Syndrome (SIRS) or capillary leak (e.g., hypotension, tachycardia, tachypnea, and pulmonary edema). Consider avoiding drugs with known renal toxicity during the 5 days of Clolar administration. Consider avoiding concomitant use of medications known to induce hepatic toxicity. Dose Modifications and Reinitiation of Therapy Hematologic Toxicity Administer subsequent cycles no sooner than 14 days from the starting day of the previous cycle provided the patient’s ANC is ≥0.75 x 109/L. If a patient experiences a Grade 4 neutropenia (ANC <0.5 x 109/L) lasting ≥4 weeks, reduce dose by 25% for the next cycle. Non-hematologic Toxicity Withhold Clolar if a patient develops a clinically significant infection, until the infection is clinically controlled and then restart at the full dose. Withhold Clolar if a Grade 3 non-infectious non-hematologic toxicity (excluding transient elevations in serum transaminases and/or serum bilirubin and/or nausea/vomiting that was controlled by antiemetic therapy) occurs.  Re-institute Clolar administration at a 25% dose reduction when resolution or return to baseline. Discontinue Clolar administration if a Grade 4 non-infectious non-hematologic toxicity occurs. Discontinue Clolar administration if a patient shows early signs or symptoms of SIRS or capillary leak (e.g., hypotension, tachycardia, tachypnea, and pulmonary edema) occur and provide appropriate supportive measures. Discontinue Clolar administration if Grade 3 or higher increases in creatinine or bilirubin are noted. Re-institute Clolar when the patient is stable and organ function has returned to baseline, generally with a 25% dose reduction. If hyperuricemia is anticipated (tumor lysis), prophylactically administer allopurinol. Reconstitution/Preparation Clolar should be filtered through a sterile 0.2 micron syringe filter and then diluted with 5% Dextrose Injection, USP, or 0.9% Sodium Chloride Injection, USP, prior to intravenous (IV) infusion to a final concentration between 0.15 mg/mL and 0.4 mg/mL. Use within 24 hours of preparation. Store diluted Clolar at room temperature (15-30ºC). Incompatibilities Do not administer any other medications through the same intravenous line. Dosage Forms and Strengths 20 mg/20 mL (1 mg/mL) single use vial Contraindications None Warnings and Precautions 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) and 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 [see ADVERSE REACTIONS (6.1)]. 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 [see DOSAGE AND ADMINISTRATION (2.2)]. 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 [see USE IN SPECIFIC POPULATIONS (8.1)]. Adverse Reactions The following adverse reactions are discussed in greater detail in other sections of the label: Severe Bone Marrow Suppression [see WARNINGS AND PRECAUTIONS (5.1)] Serious Infections [see WARNINGS AND PRECAUTIONS (5.2)] Hyperuricemia (Tumor Lysis) [see WARNINGS AND PRECAUTIONS (5.3)] Systemic Inflammatory Response Syndrome (SIRS) and Capillary Leak Syndrome [see WARNINGS AND PRECAUTIONS (5.4)] Hepatic and Renal Impairment [see WARNINGS AND PRECAUTIONS (5.6)] Use in Pregnancy [see WARNINGS AND PRECAUTIONS (5.7)] 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 practice. The data described below reflect exposure to Clolar in 115 pediatric patients with relapsed or refractory Acute Lymphoblastic Leukemia (ALL) (70 patients) or Acute Myelogenous Leukemia (AML) (45 patients). One hundred and fifteen (115) of the pediatric patients treated in clinical trials received the recommended dose of Clolar 52 mg/m2 daily x 5.  The median number of cycles was 2.  The median cumulative amount of Clolar® received by pediatric patients during all cycles was 540 mg. The most common adverse reactions with Clolar are: nausea, vomiting, diarrhea, febrile neutropenia, headache, rash, pruritus, pyrexia, fatigue, palmar-plantar erythrodysesthesia syndrome, anxiety, flushing, and mucosal inflammation. Table 1 lists adverse events regardless of causality by System Organ Class, including severe or life-threatening (NCI CTC grade 3 or grade 4), reported in ≥ 5% of the 115 patients in the 52 mg/m2/day dose group (pooled analysis of pediatric patients with ALL and AML).  More detailed information and follow-up of certain events is given below.             Table 1: Most Commonly Reported (≥ 5% Overall) Adverse Events Regardless of Causality by System Organ Class (N=115 pooled analysis) System Organ Class¹ Preferred Term¹ ALL/AML (N=115) Worst NCI Common Terminology Criteria Grade¹ 3 4 5 N % N % N % N % Blood and Lymphatic System Disorders Febrile neutropenia 63 54.8 59 51.3 3 2.6 . . Neutropenia 11 9.6 3 2.6 8 7.0 . . Cardiac Disorders Pericardial effusion 9 7.8 . . 1 0.9 . . Tachycardia 40 34.8 6 5.2 . . . . Gastrointestinal Disorders Abdominal pain 40 34.8 8 7.0 . . . . Abdominal pain upper 9 7.8 1 0.9 . . . . Diarrhea 64 55.7 14 12.2 . . . . Gingival bleeding 16 13.9 7 6.1 1 0.9 . . Mouth hemorrhage 6 5.2 2 1.7 . . . . Nausea 84 73.0 16 13.9 1 0.9 . . Oral mucosal petechiae 6 5.2 4 3.5 . . . . Proctalgia 9 7.8 2 1.7 . . . . Stomatitis 8 7.0 1 0.9 . . . . Vomiting 90 78.3 9 7.8 1 0.9 . . General Disorders and Administration Site Conditions Asthenia 12 10.4 1 0.9 1 0.9 . . Chills 39 33.9 3 2.6 . . . . Fatigue 39 33.9 3 2.6 2 1.7 . . Irritability 11 9.6 1 0.9 . . . . Mucosal inflammation 18 15.7 2 1.7 . . . . Edema 14 12.2 2 1.7 . . . . Pain 17 14.8 7 6.1 1 0.9 . . Pyrexia 45 39.1 16 13.9 . . . . Hepatobiliary Disorder Jaundice 9 7.8 2 1.7 . . . . Infections and Infestations Bacteremia 10 8.7 10 8.7 . . . . Candidiasis 8 7.0 1 0.9 . . . . Catheter related infection 14 12.2 13 11.3 . . . . Cellulitis 9 7.8 7 6.1 . . . . Clostridium colitis 8 7.0 6 5.2 . . . . Herpes simplex 11 9.6 6 5.2 . . . . Herpes zoster 8 7.0 6 5.2 . . . . Oral candidiasis 13 11.3 2 1.7 . . . . Pneumonia 11 9.6 6 5.2 1 0.9 1 0.9 Sepsis 11 9.6 5 4.4 2 1.7 4 3.5 Septic shock 8 7.0 1 0.9 2 1.7 5 4.4 Staphylococcal bacteremia 7 6.1 5 4.4 1 0.9 . . Staphylococcal sepsis 6 5.2 5 4.4 1 0.9 . . Upper respiratory tract infection 6 5.2 1 0.9 . . . . Metabolism and Nutrition Disorders Anorexia 34 29.6 6 5.2 8 7.0 . . Musculoskeletal and Connective Tissue Disorders Arthralgia 10 8.7 3 2.6 . . . . Back pain 12 10.4 3 2.6 . . . . Bone pain 11 9.6 3 2.6 . . . . Myalgia 16 13.9 . . . . . . Pain in extremity 34 29.6 6 5.2 . . . . Neoplasms Benign, Malignant and Unspecified (incl cysts and polyps) Tumor lysis syndrome 7 6.1 7 6.1 . . . . Nervous System Disorders Headache 49 42.6 6 5.2 . . . . Lethargy 12 10.4 1 0.9 . . . . Somnolence 11 9.6 1 0.9 . . . . Psychiatric Disorders Agitation 6 5.2 1 0.9 . . . . Anxiety 24 20.9 2 1.7 . . . . Renal and Urinary Disorders Hematuria 15 13.0 2 1.7 . . . . Respiratory, Thoracic and Mediastinal Disorders Dyspnea 15 13.0 6 5.2 2 1.7 . . Epistaxis 31 27.0 15 13.0 . . . . Pleural effusion 14 12.2 4 3.5 2 1.7 . . Respiratory distress 12 10.4 5 4.4 4 3.5 1 0.9 Tachypnea 10 8.7 4 3.5 1 0.9 . . Skin and Subcutaneous Tissue Disorders Erythema 13 11.3 . . . . . . Palmar-plantar erythrodysesthesia syndrome 18 15.7 8 7.0 . . . . Petechiae 30 26.1 7 6.1 . . . . Pruritus 49 42.6 1 0.9 . . . . Rash 44 38.3 8 7.0 . . . . Rash pruritic 9 7.8 . . . . . . Vascular Disorders Flushing 22 19.1 . . . . . . Hypertension 15 13.0 6 5.2 . . . . Hypotension 33 28.7 13 11.3 9 7.8 . . ¹Patients with more than one preferred term within a SOC are counted only once in the SOC totals. Patients with more than one occurrence of the same preferred term are counted only once within that term and at the highest severity grade. The following less common adverse reactions have been reported in 1-4% of the 115 pediatric patients with ALL or AML: Gastrointestinal Disorders: cecitis, pancreatitis Hepatobiliary Disorders: hyperbilirubinemia Immune System Disorders: hypersensitivity Infections and Infestations: bacterial infection, Enterococcal bacteremia, Escherichia bacteremia, Escherichia sepsis, fungal infection, fungal sepsis, gastroenteritis adenovirus, infection, influenza, Parainfluenzae virus infection, pneumonia fungal, pneumonia primary atypical, Respiratory syncytial virus infection, sinusitis, staphylococcal infection Investigations: blood creatinine increased Psychiatric Disorders: mental status change Respiratory, Thoracic and Mediastinal Disorder: pulmonary edema Table 2 lists the incidence of treatment emergent laboratory abnormalities after Clolar administration at 52 mg/m2 among pediatric patients with ALL and AML (n=115).    Table 2: Incidence of Treatment Emergent Laboratory Abnormalities After Clolar® Administration Parameter Any Grade Grade 3 or higher Anemia (N=114) 95 (83.3%) 86 (75.4%) Leukopenia (N=114) 100 (87.7%) 100 (87.7%) Lymphopenia (N=113) 93 (82.3%) 93 (82.3%) Neutropenia (N=113) 72 (63.7%) 72 (63.7%) Thrombocytopenia (N=114) 92 (80.7%) 91 (79.8%) Elevated Creatinine (N=115) 57 (49.5%) 9 (7.8%) Elevated SGOT (N=100) 74 (74.0%) 36 (36.0%) Elevated SGPT (N=113) 91 (80.5%) 49 (43.4%) Elevated Total Bilirubin (N=114) 51 (44.7%) 15 (13.2%) Hematologic Toxicity The most frequently reported hematologic adverse reactions in pediatric patients included febrile neutropenia (55%) and non-febrile neutropenia (10%). Infection At baseline, 48% of the pediatric patients had 1 or more concurrent infections. A total of 83% of patients experienced at least 1 infection after Clolar treatment, including fungal, viral and bacterial infections. Hepatic Hepato-biliary toxicities were frequently observed in pediatric patients during treatment with Clolar. Grade 3 or 4 elevated aspartate aminotransferase (AST) occurred in 36% of patients and grade 3 or 4 elevated alanine aminotransferase (ALT) occurred in 44% of patients. Grade 3 or 4 elevated bilirubin occurred in 13% of patients, with 2 events reported as grade 4 hyperbilirubinemia (2%), one of which resulted in treatment discontinuation, one patient had multi-organ failure and died.  Two reports (2%) of veno-occlusive disease (VOD) were considered related to study drug. For patients with follow-up data, elevations in AST and ALT were transient and typically ≤ 15 days duration. The majority of AST and ALT elevations occurred within 10 days of Clolar administration and returned to ≤ grade 2 within 15 days.  Where follow-up data are available, the majority of bilirubin elevations returned to ≤ grade 2 within 10 days.  Eight patients had grade 3 or 4 elevations in serum bilirubin at the last time point measured; these patients died due to sepsis and/or multi-organ failure. Renal The most prevalent renal toxicity in pediatric patients was elevated creatinine. Grade 3 or 4 elevated creatinine occurred in 8% of patients. Acute renal failure was reported in 3 patients (3%) at grade 3 and 2 patients (2%) with grade 4. Nephrotoxic medications, tumor lysis, and tumor lysis with hyperuricemia may contribute to renal toxicity.  Hematuria was observed in 13% of patients overall. Systemic Inflammatory Response Syndrome (SIRS) Adverse reactions of SIRS were reported in 2 patients (2%) [see WARNINGS AND PRECAUTIONS (5.4)]. Capillary Leak Syndrome Adverse reactions of capillary leak syndrome were reported in 4 patients (4%). Symptoms included rapid onset of respiratory distress, hypotension, pleural and pericardial effusion, and multi-organ failure. Close monitoring for this syndrome and early intervention are recommended. The use of prophylactic steroids (e.g., 100 mg/m2 hydrocortisone on Days 1 through 3) may be of benefit in preventing signs or symptoms of SIRS or capillary leak. Physicians should be alert to early indications of this syndrome and should immediately discontinue Clolar administration if they occur and provide appropriate supportive measures. After the patient is stabilized and organ function has returned to baseline, re-treatment with Clolar can be considered with a 25% dose reduction. Post-marketing Experience The following adverse reactions have been identified during post approval use of Clolar.  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 connection to Clolar. Blood and lymphatic system disorders:  bone marrow failure Hepatobiliary disorders:  Serious hepatotoxic adverse reactions of veno-occlusive disease have been reported in adult patients following HSCT.  These patients received conditioning regimens that included busulfan, melphalan, and/or the combination of cyclophosphamide and total body irradiation. Skin and subcutaneous tissue disorders: Occurrences of Stevens-Johnson Syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported in patients who were receiving or had recently been treated with Clolar and other medications (e.g. allopurinol or antibiotics) known to cause these syndromes. Drug Interactions Although no clinical drug-drug interaction studies have been conducted to date, on the basis of the in vitro studies, cytochrome p450 inhibitors and inducers are unlikely to affect the metabolism of clofarabine.  The effect of clofarabine on the metabolism of cytochrome p450 substrates has not been studied. USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category D Clolar (clofarabine) may cause fetal harm when administered to a pregnant woman. Clofarabine was teratogenic in rats and rabbits.  Developmental toxicity (reduced fetal body weight and increased post-implantation loss) and increased incidences of malformations and variations (gross external, soft tissue, skeletal and retarded ossification) were observed in rats receiving 54 mg/m2/day (approximately equivalent to the recommended clinical dose on a mg/m2 basis), and in rabbits receiving 12 mg/m2/day (approximately 23% of the recommended clinical dose on a mg/m2 basis). There are no adequate and well-controlled studies in pregnant women using clofarabine. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant while receiving treatment with clofarabine.  All patients should be advised to use effective contraceptive measures to prevent pregnancy. Nursing Mothers It is not known whether clofarabine or its metabolites are excreted in human milk. Because of the potential for tumorigenicity shown for clofarabine in animal studies and the potential for serious adverse reactions, women treated with clofarabine should not nurse.  Female patients should be advised to avoid breast-feeding during treatment with Clolar. Pediatric Use Safety and effectiveness have been established in pediatric patients 1 to 21 years old with relapsed or refractory acute lymphoblastic leukemia. Geriatric Use Safety and effectiveness of Clolar has not been established in geriatric patients aged 65 and older. Adults with Hematologic Malignancies Safety and effectiveness have not been established in adults. Overdosage There were no known overdoses of Clolar. The highest daily dose administered to a human to date (on a mg/m2 basis) has been 70 mg/m2/day × 5 days (2 pediatric ALL patients). The toxicities included in these 2 patients included grade 4 hyperbilirubinemia, grade 2 and 3 vomiting, and grade 3 maculopapular rash. In a Phase I study of adults with refractory and/or relapsed hematologic malignancies, the recommended pediatric dose of 52 mg/m2/day was not tolerated. Clolar Description Clolar (clofarabine) injection contains clofarabine, a purine nucleoside metabolic inhibitor. Clolar (1 mg/mL) is supplied in a 20 mL, single-use vial.  The 20 mL vial contains 20 mg clofarabine formulated in 20 mL unbuffered normal saline (comprised of Water for Injection, USP, and Sodium Chloride USP). The pH range of the solution is 4.5 to 7.5. The solution is sterile, clear and practically colorless, and is preservative free. Clolar-Clinical Pharmacology Mechanism of Action Clofarabine is sequentially metabolized intracellularly to the 5’-monophosphate metabolite by deoxycytidine kinase and mono- and di-phospho-kinases to the active 5’‑triphosphate metabolite. Clofarabine has high affinity for the activating phosphorylating enzyme, deoxycytidine kinase, equal to or greater than that of the natural substrate, deoxycytidine. Clofarabine inhibits DNA synthesis by decreasing cellular deoxynucleotide triphosphate pools through an inhibitory action on ribonucleotide reductase, and by terminating DNA chain elongation and inhibiting repair through incorporation into the DNA chain by competitive inhibition of DNA polymerases. The affinity of clofarabine triphosphate for these enzymes is similar to or greater than that of deoxyadenosine triphosphate. In preclinical models, clofarabine has demonstrated the ability to inhibit DNA repair by incorporation into the DNA chain during the repair process. Clofarabine 5’-triphosphate also disrupts the integrity of mitochondrial membrane, leading to the release of the pro-apoptotic mitochondrial proteins, cytochrome C and apoptosis‑inducing factor, leading to programmed cell death.  Clofarabine is cytotoxic to rapidly proliferating and quiescent cancer cell types in vitro. Pharmacokinetics The population pharmacokinetics of Clolar were studied in 40 pediatric patients aged 2 to 19 years (21 males/19 females) with relapsed or refractory acute lymphoblastic leukemia (ALL) or acute myelogenous leukemia (AML).  At the given 52 mg/m2 dose, similar concentrations were obtained over a wide range of body surface areas (BSAs). Clofarabine was 47% bound to plasma proteins, predominantly to albumin. Based on non-compartmental analysis, systemic clearance and volume of distribution at steady-state were 28.8 L/h/m2 and 172 L/m2, respectively. The terminal half-life was 5.2 hours. No apparent difference in pharmacokinetics was observed between patients with ALL and AML or between males and females. No relationship between clofarabine or clofarabine triphosphate exposure and toxicity or response was found in this population. Based on 24-hour urine collections in the pediatric studies, 49 - 60% of the dose is excreted in the urine unchanged. In vitro studies using isolated human hepatocytes indicate very limited metabolism (0.2%).  The pathways of non-hepatic elimination remain unknown. The pharmacokinetics of clofarabine have not been evaluated in patients with renal or hepatic dysfunction. Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment of Fertility Clofarabine has not been tested for carcinogenic potential. Clofarabine showed clastogenic activity in the in vitro mammalian cell chromosome aberration assay (CHO cells) and in the in vivo rat micronucleus assay. It did not show evidence of mutagenic activity in the bacterial mutation assay (Ames test). Studies in mice, rats, and dogs have demonstrated dose-related adverse effects on male reproductive organs. Seminiferous tubule and testicular degeneration and atrophy were reported in male mice receiving intraperitoneal (IP) doses of 3 mg/kg/day (9 mg/m2/day, approximately 17% of clinical recommended dose on a mg/m2 basis). The testes of rats receiving 25 mg/kg/day (150 mg/m2/day, approximately 3 times the recommended clinical dose on a mg/m2 basis) in a 6-month IV study had bilateral degeneration of the seminiferous epithelium with retained spermatids and atrophy of interstitial cells. In a 6-month IV dog study, cell degeneration of the epididymis and degeneration of the seminiferous epithelium in the testes were observed in dogs receiving 0.375 mg/kg/day (7.5 mg/m2/day, approximately 14% of the clinical recommended dose on a mg/m2 basis). Ovarian atrophy or degeneration and uterine mucosal apoptosis were observed in female mice at 75 mg/kg/day (225 mg/m2/day, approximately 4-fold of recommended human dose on a mg/m2 basis), the only dose administered to female mice. The effect on human fertility is unknown. Clinical Studies Seventy-eight (78) pediatric patients with ALL were exposed to Clolar.  Seventy (70) of the patients received the recommended pediatric dose of Clolar 52 mg/m2 daily x 5 as an intravenous (IV) infusion. Dose Escalation Study in Pediatric Patients with Hematologic Malignancies The safety and efficacy of Clolar were evaluated in pediatric patients with refractory or relapsed hematologic malignancies in an open-label, dose-escalation, noncomparative study.  The starting dose of Clolar was 11.25 mg/m2/day IV infusion daily × 5 and escalated to 70 mg/m2/day IV infusion daily × 5. This dosing schedule was repeated every 2 to 6 weeks depending on toxicity and response. Nine of 17 ALL patients were treated with Clolar 52 mg/m2 daily × 5. In the 17 ALL patients there were 2 complete remissions (12%) and 2 partial remissions (12%) at varying doses. Dose-limiting toxicities (DLTs) in this study were reversible hyperbilirubinemia and elevated transaminase levels and skin rash, experienced at 70 mg/m2. As a result of this study, the recommended dose for subsequent study in pediatric patients was determined to be 52 mg/m2/day for 5 days. Single Arm Study in Pediatric ALL Clolar was evaluated in an open-label, single arm study of 61 pediatric patients with relapsed/refractory ALL.  Patients received a dose of 52 mg/m2 over 2 hours for 5 consecutive days repeated every 2 to 6 weeks for up to 12 cycles.  There was no dose escalation in this study.  All patients had disease that had relapsed after and/or was refractory to two or more prior therapies. Most patients, 38/61 (62%), had received > 2 prior regimens and 18/61 (30%) of the patients had undergone at least 1 prior transplant. The median age of the treated patients was 12 years, 61% were male, 39% were female, 44% were Caucasian, 38% were Hispanic, 12% were African-American, 2% were Asian and 5% were Other race.  The overall remission (OR) rate (Complete Remission [CR] + CR in the absence of total platelet recovery [CRp]) was evaluated.  CR was defined as no evidence of circulating blasts or extramedullary disease, an M1 bone marrow (≤ 5% blasts), and recovery of peripheral counts [platelets ≥ 100 × 109/L and absolute neutrophil count (ANC) ≥ 1.0 × 109/L]. CRp was defined as meeting all criteria for CR except for recovery of platelet counts to ≥ 100 × 109/L. Partial Response (PR) was also determined, defined as complete disappearance of circulating blasts, an M2 bone marrow (≥ 5% and ≤ 25% blasts), and appearance of normal progenitor cells or an M1 marrow that did not qualify for CR or CRp.  Duration of remission was also evaluated.  Transplantation rate was not a study endpoint. Response rates for these studies were determined by an unblinded Independent Response Review Panel (IRRP). Table 3 summarizes results for the pediatric ALL study.  Responses were seen in both pre-B and T-cell immunophenotypes of ALL.  The median cumulative dose was 530 mg (range 29-2815 mg) in 1 (41%), 2 (44%) or 3 or more (15%) cycles.  The median number of cycles was 2 (range 1-12).  The median time between cycles was 28 days with a range of 12 to 55 days. Table 3: Results in Single-Arm Pediatric ALL Study N = 61 CR % (n) [95% CI] 11.5 (4.7, 22.2) CRp % (n) [95% CI] 8.2 (2.7, 18.1) Median Duration of CR plus CRp (range in weeks)1 10.7 (4.3 to 58.6) CR = Complete response CRp = Complete response without platelet recovery 1       Does not include 4 patients who were transplanted (duration of response, including response after transplant, in these 4 patients was 28.6 to 107.7 weeks). Six (9.8%) patients achieved a PR; the clinical relevance of a PR in this setting is unknown. Of 35 patients who were refractory to their immediately preceding induction regimen, 6 (17%) achieved a CR or CRp.  Of 18 patients who had at least 1 prior hematopoietic stem cell transplant (HSCT), 5 (28%) achieved a CR or CRp. Among the 12 patients who achieved at least a CRp, 6 patients achieved the best response after 1 cycle of clofarabine, 5 patients required 2 courses and 1 patient achieved a CR after 3 cycles of therapy. REFERENCES NIOSH Alert: Preventing occupational exposures to antineoplastic and other hazardous drugs in healthcare settings. 2004. U.S. Department of Health and Human Services, Public Health Service, Centers for Disease Control and Prevention, National Institute for Occupational Safety and Health, DHHS (NIOSH) Publication No. 2004-165. OSHA Technical Manual, TED 1-0.15A, Section VI: Chapter 2. Controlling Occupational Exposure to Hazardous Drugs. OSHA, 1999. http://www.osha.gov/dts/osta/otm/otm_vi/otm_vi_2.html American Society of Health-System Pharmacists. ASHP guidelines on handling hazardous drugs. Am J Health-Syst Pharm. 2006; 63:1172-1193. Polovich, M., White, J. M., & Kelleher, L.O. (eds.) 2005. Chemotherapy and biotherapy guidelines and recommendations for practice (2nd. ed.) Pittsburgh, PA: Oncology Nursing Society. How Supplied/Storage and Handling Clolar (clofarabine) injection is supplied in single-use flint vials containing 20 mg of clofarabine in 20 mL of solution. Each box contains one Clolar vial (NDC 58468-0100-1) or four Clolar vials (NDC 58468-0100-2). The 20mL flint vials contain 20 mL (20 mg) of solution. The pH range of the solution is 4.5 to 7.5. Vials containing undiluted Clolar should be stored at 25°C (77°F); excursions permitted to 15 - 30°C (59 - 86°F). Diluted admixtures may be stored at room temperature, but must be used within 24 hours of preparation. Procedures for proper handling and disposal should be utilized. Handling and disposal of Clolar should conform to guidelines issued for cytotoxic drugs. Several guidelines on this subject have been published.1-4 Patient Counseling Information Hematologic Toxicity: Advise patients to return for regular blood counts and to report any symptoms associated with hematologic toxicity (such as weakness, fatigue, pallor, shortness of breath, easy bruising, petechiae, purpura, fever) to their physician [see WARNINGS AND PRECAUTIONS (5.1) and ADVERSE REACTIONS (6.1)]. Infection: Advise patients of the signs or symptoms of infection (eg. fever) and report to the physician immediately if any occur [see WARNINGS AND PRECAUTIONS (5.2) and ADVERSE REACTIONS (6.1)]. Hepatic and Renal Impairment: Advise patients to avoid medications including over the counter and herbal medications, which may be hepatotoxic or nephrotoxic, during the 5 days of Clolar administration [see WARNINGS AND PRECAUTIONS (5.6)]. Systemic Inflammatory Response Syndrome (SIRS)/Capillary Leak Syndrome: Advise patients of the signs or symptoms of SIRS, such as fever, tachycardia, tachypnea, dyspnea and symptoms suggestive of hypotension [see WARNINGS AND PRECAUTIONS (5.4) and ADVERSE REACTIONS (6.1)]. Advise male and female patients with reproductive potential to use effective contraceptive measures to prevent pregnancy [see WARNINGS AND PRECAUTIONS (5.7), USE IN SPECIFIC POPULATIONS (8.1)].  Advise female patients to avoid breast feeding during Clolar treatment [see USE IN SPECIFIC POPULATIONS (8.3)]. Rx Only Manufactured by: AAIPharma Services Charleston, SC 29405 Manufactured for: Genzyme Corporation 500 Kendall Street Cambridge, MA 02142 Distributed by: Genzyme Corporation 500 Kendall Street Cambridge, MA 02142 © 2010 Genzyme Corporation. All rights reserved. Clolar is a registered trademark of Genzyme Corporation. 8036 (12/10) Label - Principal Display Panel – 1 (20 mL) Single-Use Vial NDC 58468-0100-1 Clolar® clofarabine injection  MUST BE DILUTED PRIOR TO IV USE Contains 1 (20 mL) Single-Use Vial Each single-use 20 mL vial contains 20 mg clofarabine dissolved in 20 mL of sodium chloride injection, USP 0.9%, pH 4.5-7.5. Contains no preservatives. Sterile. Rx only Genzyme Oncology