【药品名称】
通用名：氯法拉滨
其他名：克罗拉滨、氯法他滨
英文名：Clofarabine
汉语拼音：Lüfalabin
中文化学名：2-氯-9-(2-去氧-2-氟-β-D-阿拉伯呋喃)-9H-嘌呤-6-胺
英文化学名：2- chloro-9-(2-deoxy-2-fluoro-β-D-arabinofuranosyl)-9H-purin-6-amine
分子式：C10H11ClFN5O3       
分子量：303.68
氯法拉滨（clofarabine）属于核苷酸类似物，由美国Genzyme公司研发，2004年12月28日批准用于2至19岁的青少年顽固性或复发性急性淋巴细胞白血病的治疗，其商品名为CLOLAR，本品已被FDA授予罕见药物地位，用于治疗2至19岁的青少年急性淋巴细胞白血病（acute lymphocytic leukemia ，ALL）。本品在2005年1月份已在美国首次上市。氯法拉滨作为目前唯一可以特异性用于青少年白血病的化疗药，治疗白血病总体反应率高，并且很好耐受，没有不可预知的不良反应。既可以静脉给药，也可以口服，本品为十多年来首个获准专门用于青少年的白血病治疗新药。
本品2005年在美国上市.
【作用机制】氯法拉滨属于一种核苷酸类似物，其经脱氧胞苷激酶磷酸化为三磷酸盐后，首先能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a，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。氯法拉滨在人体细胞内经由脱氧胞苷激酶和单磷酸激酶及二磷酸激酶磷酸化后，续而产生三磷酸盐代谢产物。氯法拉滨对胞苷激酶及磷酸激酶具有高亲和力，其亲和力与正常酶作用底物相当或更高。氯法拉滨通过抑制核糖核酸还原酶，使细胞内三磷酸脱氧核糖核苷酸池数目减少，并通过竞争性抑制DNA聚合酶而结合入DNA链，最终导致DNA合成受到抑制，从而终止了DNA链的延长以及抑制了DNA的修复。氯法拉滨对这些酶的亲和力与脱氧胞苷相当或更高。在细胞分裂间期，氯法拉滨发挥了在DNA修复过程中结合入DNA链从而抑制DNA链修复的作用。氯法拉滨三磷酸盐还能破坏完整的线粒体膜，导致前细胞凋亡线粒体蛋白，细胞色素C和细胞凋亡诱导因子的释放，从而启动了细胞的程序化凋亡。
【人体药代动力学】药代动力学研究在40名2~19岁复发性或顽固性ALL或AML的小儿科病人(21男性/19女性)中进行。给予52mg/m2的剂量，在较广体表面积范围的前提下获得了相近浓度的药物摄入。氯法拉滨在体内47%结合于血浆蛋白，主要是结合于白蛋白。依据非区划分析，稳定态时全身清除率和分布容积分别为28.8L/h/m2和172L/m2,消除半衰期为5.2h。在ALL和AML或男性与女性中未发现明显的药代动力学差异。
未发现人群中有氯法拉滨或氯法拉滨三磷酸盐暴露-反应或中毒反应。
依据24小时的尿液收集分析，49~60%剂量的氯法拉滨以尿途径无变化排泄。以人体肝细胞进行的体外研究显示很有限的代谢(0.2%)，因此氯法拉滨非肾途径的代谢仍未知。
尽管未将药物之间相互作用的临床研究纳入日程，依据离体研究，细胞色素P450抑制剂和诱导剂不太可能影响氯法拉滨的代谢。氯法拉滨对细胞色素P450酶作用物代谢影响的研究尚未进行。氯法拉滨对肾脏或肝脏功能不良者的药代动力学未进行评估。
【治疗情况、耐受性，毒副作用】
氯法拉滨治疗白血病总体反应率高，并且很好耐受，没有不可预知的不良反应。它的疗效好，毒副作用不大，是FDA经快通道批准的，其依据是一项有49例复治的复发性或抵抗性ALL患儿参加的核心Ⅱ期临床试验的结果。该试验中，患儿连续5天每天静脉滴注1-2小时CLOLAR（52mg/m2 ）。依据缓解情况，接受2-6周期治疗，每周期28天。结果发现，总缓解率为30%，其中20%达到完全缓解或髓相完全缓解（除血小板未恢复），10%达部分缓解。14%的患儿在氯法拉滨治疗后，接受了骨髓或干细胞移植。氯法拉滨的副作用不大，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。因此氯法拉滨给儿童白血病患者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。

【适应症】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例的同时，它的潜在适应症包括很多实体瘤以及一些免疫性疾病。

【本品特点】
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。
-------------------------------------------------------------

Clolar for Intravenous Infusion (Genzyme)
CLOLAR™ For Intravenous Infusion (CLOLAR™; clofarabine) contains clofarabine, a purine nucleoside anti-metabolite. 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 clear and practically colorless, and free from foreign matter.
The chemical structure of clofarabine is 2-chloro-9-(2-deoxy-2-fluoro-(beta)-D-arabinofuranosyl)-9H-purin-6-amine. The molecular formula of clofarabine is C 10 H 11 ClFN 5 O 3 with a molecular weight of 303.68.
CLINICAL PHARMACOLOGY
Mechanism of Action
Clofarabine is sequentially metabolized intracellularly to the 5'-monophosphate metabolite by deoxycytidine kinase and mono- and di-phosphokinases 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 .

Human 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/m 2 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 estimated to be 28.8 L/h/m 2 and 172 L/m 2 , respectively. The terminal half-life was estimated to be 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%); therefore, the pathways of non-renal elimination remain unknown.

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. The pharmacokinetics of clofarabine have not been evaluated in patients with renal or hepatic dysfunction.

CLINICAL STUDIES
Sixty-six (66) pediatric ALL patients were exposed to CLOLAR™. Fifty-eight (58) of the patients received the recommended pediatric dose of CLOLAR™ 52 mg/m 2 daily × 5 as an intravenous infusion (IVI).

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/m 2 /day IVI daily × 5 and escalated to 70 mg/m 2 /day IVI 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/m 2 daily × 5. In the 17 ALL patients there were 2 complete remissions (12.5%) and 2 partial remissions (12.5%) at varying doses. Dose-limiting toxicities (DLTs) in this study were reversible hyperbilirubinemia and elevated transaminase levels and skin rash, experienced at 70 mg/m 2 . As a result of this study, the recommended dose for subsequent study in pediatric patients was determined to be 52 mg/m 2 /day for 5 days.

Single Arm Study in Pediatric ALL
A single arm study was conducted in relapsed/refractory pediatric patients with ALL at a single dose. All patients had disease that had relapsed after and/or was refractory to two or more prior therapies. Most patients, 46/49 (93.8%), had received 2 to 4 prior regimens and 15/49 (30.6%) of the patients had undergone at least 1 prior transplant. The median age of the treated patients was 12 years. There were more males, 29/49 (59.2%), than females, 20/49 (40.8%). Most of the patients were either Caucasian (n=20, 40.8%) or Hispanic (n=20, 40.8%), with 12.2% African-American (n=6), and 6.1% Other race (n=3). All patients received a dose of 52 mg/m 2 daily × 5 IVI. There was no dose modification during the remission induction phase of treatment (maximum of 2 cycles). Doses could be modified (reduced/delayed) during the post-induction phase. There was no dose escalation. The planned study endpoint was the rate of Complete Remission (CR), defined as no evidence of circulating blasts or extramedullary disease, an M1 bone marrow (<5% blasts), and recovery of peripheral counts [platelets > 100 × 10 9 /L and absolute neutrophil count (ANC) > 1.0 × 10 9 /L] and Complete Remission in the Absence of Total Platelet Recovery (CRp), defined as meeting all criteria for CR except for recovery of platelet counts to > 100 × 10 9 /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 bone marrow that did not qualify for CR or CRp. Transplantation rate was not a study endpoint.

Response rates for these studies were determined by an unblinded Independent Response Review Panel (IRRP).

Table 1 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 540 mg (range 29-1905 mg) in 1 (42.9%), 2 (38.8%) or 3 or more (18.4%) cycles.

Table 1: Results in Pediatric ALL Study

n=49
Responses	n	%	95% CI
CR	6	12.2	4.6 to 24.8
CRp	4	8.2	2.3 to 19.6
PR	5	10.2	3.4 to 22.2

Of the 15 responding pediatric ALL patients, 6 had post-clofarabine bone marrow transplantation, so that duration of response could not be determined. In the 9 responding patients who were not transplanted, the response durations for CR were 43, 50, 82, 93+, and 160+ days; for CRp the response duration was 32 days; and for PR the response durations were 7, 16, and 21 days.

INDICATIONS AND USAGE
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. This use is based on the induction of complete responses. Randomized trials demonstrating increased survival or other clinical benefit have not been conducted.

CONTRAINDICATIONS
None

WARNINGS
CLOLAR™ should be administered under the supervision of a qualified physician experienced in the use of antineoplastic therapy. Suppression of bone marrow function should be anticipated. This is usually reversible and appears to be dose dependent. The use of CLOLAR™ is likely to increase the risk of infection, including severe sepsis, as a result of bone marrow suppression. Administration of CLOLAR™ results in a rapid reduction in peripheral leukemia cells. For this reason, patients undergoing treatment with CLOLAR™ should be evaluated and monitored for signs and symptoms of tumor lysis syndrome, as well as 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. Physicians are encouraged to give continuous IV fluids throughout the five days of CLOLAR™ administration to reduce the effects of tumor lysis and other adverse events. Allopurinol should be administered if hyperuricemia is expected. CLOLAR™ should be discontinued immediately in the event of clinically significant signs or symptoms of SIRS or capillary leak syndrome, either of which can be fatal, and use of steroids, diuretics, and albumin considered. CLOLAR™ can be re-instituted when the patient is stable, generally at a lower dose.

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. Careful hematological monitoring during therapy is important, and hepatic and renal function should be assessed prior to and during treatment with CLOLAR™ because of CLOLAR™'s predominantly renal excretion and because the liver is a target organ for CLOLAR™ toxicity. The respiratory status and blood pressure should be closely monitored during infusion of CLOLAR™.

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.

Pregnancy - Teratogenic Effects: 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/m 2 /day (approximately equivalent to the recommended clinical dose on a mg/m 2 basis), and in rabbits receiving 12 mg/m 2 /day (approximately 23% of the recommended clinical dose on a mg/m 2 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.

PRECAUTIONS
Information for Patients and Caregivers
Physicians are advised to discuss the following with patients to whom CLOLAR™ will be administered and patient caregivers, as appropriate.

Dehydration/Hypotension
Patients receiving CLOLAR™ may experience vomiting and diarrhea; they should therefore be advised regarding appropriate measures to avoid dehydration. Patients should be instructed to seek medical advice if they experience symptoms of dizziness, lightheadedness, fainting spells, or decreased urine output. CLOLAR™ administration should be stopped if the patient develops hypotension for any reason during the 5 days of administration. If hypotension is transient and resolves without pharmacological intervention, CLOLAR™ treatment can be re-instituted, generally at a lower dose.

Concomitant Medications
Since CLOLAR™ is excreted primarily by the kidneys, drugs with known renal toxicity should be avoided during the 5 days of CLOLAR™ administration. In addition, since the liver is a known target organ for CLOLAR™ toxicity, concomitant use of medications known to induce hepatic toxicity should also be avoided. Patients taking medications known to affect blood pressure or cardiac function should be closely monitored during administration of CLOLAR™.

Pregnancy/Nursing
All patients should be advised to use effective contraceptive measures to prevent pregnancy. Female patients should be advised to avoid breast-feeding during treatment with CLOLAR™.

Laboratory Tests
Complete blood counts and platelet counts should be obtained at regular intervals during CLOLAR™ therapy, and more frequently in patients who develop cytopenias. In addition, liver and kidney function should be monitored frequently during the 5 days of CLOLAR™ administration.

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.

Drug/Laboratory Tests Interactions
There are no known clinically significant interactions of CLOLAR™ with other medications or laboratory tests. No formal drug/laboratory test interaction studies have been conducted with CLOLAR™.

Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis
Clofarabine has not been tested for carcinogenic potential.

Mutagenesis
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).

Impairment of Fertility
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/m 2 /day, approximately 17% of the recommended clinical dose on a mg/m 2 basis). The testes of rats receiving 25 mg/kg/day (150 mg/m 2 /day, approximately 3 times the recommended clinical dose on a mg/m 2 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/m 2 /day, approximately 14% of the recommended clinical dose on a mg/m 2 basis). Ovarian atrophy or degeneration and uterine mucosal apoptosis were observed in female mice at 75 mg/kg/day (225 mg/m 2 /day, approximately 4-fold of the recommended human dose on a mg/m 2 basis), the only dose administered to female mice. The effect on human fertility is unknown.
Pregnancy
Teratogenic Effects: Pregnancy Category D

See WARNINGS .
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.

Other Special Population: Adults
Safety and efficacy have not been established in adults. One study was performed in highly refractory and/or relapsed adult patients with hematologic malignancies. The Phase 2 dose of CLOLAR™ was determined to be 40 mg/m 2 /day administered as a 1- to 2-hour IVI daily × 5 every 28 days.

ADVERSE REACTIONS
One hundred thirteen (113) pediatric patients with ALL (67) or AML (46) were exposed to CLOLAR™.

Ninety-six (96) of the pediatric patients treated in clinical trials received the recommended dose of CLOLAR™ 52 mg/m 2 daily × 5.

The most common adverse effects after CLOLAR™ treatment, regardless of causality, were gastrointestinal tract symptoms, including vomiting, nausea, and diarrhea; hematologic effects, including anemia, leukopenia, thrombocytopenia, neutropenia, and febrile neutropenia; and infection.

Table 2 lists adverse events by System Organ Class regardless of causality, including severe or life-threatening events (NCI CTC grade 3 or grade 4), reported in >/=10% of the 96 patients in the 52 mg/m 2 /day dose group. More detailed information and follow-up of certain events is given below.

Table 2: Most Commonly Reported (>/=10% Overall)
Adverse Events by System Organ Class (N=96)

System Organ Class Adverse Event 1	52mg/m 2 (N=96)
	Total		Grade 3		Grade 4
	N	%	n	%	n	%
Blood and Lymphatic System Disorders
Febrile neutropenia	55	57	51	53	3	3
Neutropenia	10	10	3	3	7	7
Transfusion reaction	10	10	3	3	.	.
Cardiac Disorders
Tachycardia NOS	33	34	6	6	.	.
Gastrointestinal Disorders
Abdominal pain NOS	35	36	7	7	.	.
Constipation	20	21	.	.	.	.
Diarrhea NOS	51	53	10	10	.	.
Gingival bleeding	14	15	7	7	1	1
Nausea	72	75	14	15	1	1
Sore throat NOS	13	14	.	.	.	.
Vomiting NOS	80	83	8	8	1	1
General Disorders and Administration Site Conditions
Edema NOS	19	20	1	1	2	2
Fatigue	35	36	3	3	1	1
Injection site pain	13	14	1	1	.	.
Lethargy	11	11	.	.	.	.
Mucosal inflammation NOS	17	18	3	3	.	.
Pain NOS	18	19	6	6	1	1
Pyrexia	39	41	15	16	.	.
Rigors	36	38	3	3	.	.
Hepato-Biliary Disorders
Hepatomegaly	14	15	8	8	.	.
Jaundice NOS	14	15	2	2	.	.
Infections and Infestations
Bacteremia	10	10	10	10	.	.
Cellulitis	11	11	9	9	.	.
Herpes simplex	11	11	6	6	.	.
Oral candidiasis	12	13	2	2	.	.
Pneumonia NOS	10	10	5	5	2	2
Sepsis NOS	14	15	7	7	7	7
Staphylococcal infection NOS	12	13	10	10	.	.
Investigations
Weight decreased	10	10	1	1	.	.
Metabolism and Nutrition Disorders
Anorexia	30	31	5	5	7	7
Appetite decreased NOS	11	11	.	.	.	.
Musculoskeletal, Connective Tissue and Bone Disorders
Arthralgia	11	11	3	3	.	.
Back pain	12	13	3	3	.	.
Myalgia	13	14	.	.	.	.
Pain in limb	28	29	5	5	.	.
Nervous System Disorders
Dizziness (except vertigo)	15	16	.	.	.	.
Headache NOS	44	46	4	4	.	.
Somnolence	10	10	1	1	.	.
Tremor NEC	10	10	.	.	.	.
Psychiatric Disorders
Anxiety NEC	21	22	2	2	.	.
Depression NEC	11	11	1	1	.	.
Irritability	11	11	1	1	.	.
Renal and Urinary Disorders
Hematuria	16	17	2	2	.	.
Respiratory, Thoracic and Mediastinal Disorders
Cough	18	19	.	.	.	.
Dyspnea NOS	12	13	4	4	2	2
Epistaxis	30	31	14	15	.	.
Pleural effusion	10	10	3	3	2	2
Respiratory distress	13	14	6	6	5	5
Skin and Subcutaneous Tissue Disorders
Contusion	11	11	1	1	.	.
Dermatitis NOS	39	41	7	7	.	.
Dry skin	10	10	1	1	.	.
Erythema NEC	17	18	.	.	.	.
Palmar-plantar erythrodysesthesia syndrome	12	13	4	4	.	.
Petechiae	28	29	7	7	.	.
Pruritus NOS	45	47	1	1	.	.
Vascular Disorders
Flushing	17	18	.	.	.	.
Hypertension NOS	11	11	4	4	.	.
Hypotension NOS	28	29	12	13	7	7
1 Patients with more than one occurrence of the same preferred term are counted only once. Grade 4 includes deaths (Grade 5).

Cardiovascular
The most frequently reported cardiac disorder was tachycardia (34%), which was, however, already present in 27.4% of patients at study entry. Most of the cardiac adverse events were reported in the first 2 cycles. Pericardial effusion was a frequent finding in these patients on post-treatment studies, [19/55 (35%)]. The effusion was almost always minimal to small and in no cases had hemodynamic significance.

Left ventricular systolic dysfunction (LVSD) was also noted. Fifteen out of fifty-five patients [15/55 (27%)] had some evidence of LVSD after study entry. In most cases where subsequent follow-up data were available, the LVSD appeared to be transient. The exact etiology for the LVSD is unclear because of previous therapy or serious concurrent illness.

Hepatic
Hepato-biliary toxicities were frequently observed in pediatric patients during treatment with CLOLAR™. Grade 3 or 4 elevated aspartate aminotransferase (AST) occurred in 38% of patients and grade 3 or 4 elevated alanine aminotransferase (ALT) occurred in 44% of patients. Grade 3 or 4 elevated bilirubin occurred in 15% of patients, with 2 cases of grade 4 hyperbilirubinemia resulting in treatment discontinuation.

For patients with follow-up data, elevations in AST and ALT were transient and typically of <2 weeks duration. The majority of AST and ALT elevations occurred within 1 week of CLOLAR™ administration and returned to baseline or </= grade 2 within several days. Although less common, elevations in bilirubin appeared to be more persistent. Where follow-up data are available, the median time to recovery from grade 3 and grade 4 elevations in bilirubin to </= grade 2 was 6 days.

Infection
At baseline, 47% of the patients had 1 or more concurrent infections. A total of 85% of patients experienced at least 1 infection after CLOLAR™ treatment, including fungal, viral and bacterial infections.

Renal
The most prevalent renal toxicity was elevated creatinine. Grade 3 or 4 elevated creatinine occurred in 6% of patients. Nephrotoxic medications, tumor lysis, and tumor lysis with hyperuricemia may contribute to renal toxicity.

Systemic Inflammatory Response Syndrome (SIRS)/Capillary Leak Syndrome
Capillary leak syndrome or SIRS (signs and symptoms of cytokine release, e.g., tachypnea, tachycardia, hypotension, pulmonary edema) occurred in 4 pediatric patients overall (3 ALL, 1 AML). Several patients developed rapid onset of respiratory distress, hypotension, capillary leak (pleural and pericardial effusions), and multi-organ failure. Close monitoring for this syndrome and early intervention are recommended. The use of prophylactic steroids (e.g., 100 mg/m 2 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 at a lower dose.

Overdosage
There were no known overdoses of CLOLAR™. The highest daily dose administered to a human to date (on a mg/m 2 basis) has been 70 mg/m 2 /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.

DOSAGE AND ADMINISTRATION
Recommended Dose
CLOLAR™ should be diluted per instructions below with 5% Dextrose Injection, USP, or 0.9% Sodium Chloride Injection, USP, prior to intravenous infusion (IVI).

The recommended pediatric dose and schedule is 52 mg/m 2 administered by intravenous infusion (IVI) 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.

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.

Physicians are encouraged to give continuous IV fluids throughout the 5 days of CLOLAR™ administration to reduce the effects of tumor lysis and other adverse events. The use of prophylactic steroids (e.g., 100 mg/m 2 hydrocortisone on Days 1 through 3) may be of benefit in preventing signs or symptoms of SIRS or capillary leak (e.g., hypotension). If patients show early signs or symptoms of SIRS or capillary leak (e.g., hypotension), the physician should immediately discontinue CLOLAR™ administration and provide appropriate supportive measures. Close monitoring of renal and hepatic function during the 5 days of CLOLAR™ administration is advised. If substantial increases in creatinine or bilirubin are noted, physicians should immediately discontinue administration of CLOLAR™. CLOLAR™ should be re-instituted when the patient is stable and organ function has returned to baseline, possibly at a lower dose. If hyperuricemia is anticipated (tumor lysis), patients should prophylactically receive allopurinol.

STORAGE AND HANDLING
Vials containing undiluted CLOLAR™ should be stored at 25°C (77°F); excursions permitted to 15-30°C (59-86°F).

CLOLAR™ should be filtered through a sterile 0.2 µm syringe filter and then further diluted with 5% Dextrose Injection, USP, or 0.9% Sodium Chloride Injection, USP, prior to intravenous infusion (IVI). The resulting admixture may be stored at room temperature, but must be used within 24 hours of preparation.

HOW SUPPLIED
CLOLAR™ is formulated at a concentration of 1 mg/mL in sodium chloride (9 mg/mL), USP, and Water for Injection, USP, quantity sufficient (qs) to 1mL. CLOLAR™ is supplied in 20 mL flint vials in a box of 4 (NDC 58468-0100-2). The 20 mL flint vials contain 20 mL (20 mg) of solution. The pH range of the solution is 4.5 to 7.5. The solution is clear and practically colorless, is preservative-free, and is free from foreign matter.
附件：

201031800504423.pdf    

----------------------------------------------------------
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！
----------------------------------------------------------
产地国家: 美国
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 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
----------------------------------------------------------
产地国家: 美国
原产地英文商品名:
CLOLAR 1MG/ML 20MLS/VIAL
原产地英文药品名:
CLOFARABINE
原产地英文化合物名称:
2-chloro-9-(2-deoxy-2-fluoro-β-D-arabinofuranosyl)-9H-purin-6-amine
中文参考商品译名:
克罗拉 1毫克/毫升 20毫升/瓶
中文参考药品译名:
氯法拉滨
中文参考化合物名称:
2-氯-9-(2-去氧-2-氟-β-D-阿拉伯呋喃)-9H-嘌呤-6-胺
生产厂家中文参考译名:
健赞
生产厂家英文名:
GENZYME