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简介：   部份中文克拉屈滨处方资料（仅供参考） 通用名：克拉屈滨注射液 适应症 本品可试用于经干扰素治疗失败后活动性的伴有临床意义的贫血、中性粒细胞减少、血少板减少以及疾病相关症状的毛细胞白血病（HCL）治疗。 用法用量 静脉滴注。治疗多毛细胞白血病时的建议剂量为克拉屈滨0.09mg/kg/d，作24小时的连续滴注，连用7天。不推荐其它的用药方案。根据已有经验，如患者对初始疗程无效，增加疗程不会获得更大利益。临用前按计算量从安瓿中抽取克拉屈滨注射液，加入到贮有500ml 0.9%氯化钠注射液的瓶中（或袋内），混匀后作静脉滴注。全部程序须严格按无菌操作常规进行，每天配药一次，供当天静脉滴注之用。因为缺乏足够的配伍试验，不推荐与其它稀释液配伍使用。 不良反应 尚缺乏在中国人使用的安全性数据。 安全性数据来源于国外196位毛细胞白血病患者：起初的124位患者，加最初入选截止后在相同两中心入选的其他72位患者。毛细胞白血病患者的第1个月临床研究提示，严重中性白细胞减少率为70％，发热率为69％，感染率为28％。 开始治疗的第一个14天内经常报道的其他不良反应包括：疲劳（45％）、恶心（28％）、皮疹（27）、头痛（22％）和注射部位反应（19％）。大多数非血液学不良反应为轻至中度。 开始治疗的第一个月经常观察到骨髓抑制。70％的患者出现中性粒细胞减少（ANC＜500×106/L），而最初的发生率为26％。37％的患者出现严重贫血（血红蛋白＜8.5g/dl），而最初的发生率为10％。12％的患者出现血小板减少（血小板＜20×109/L），而最初的发生率为4％。 治疗第一个月54/196（28%）的患者出现感染。6％的患者出现严重感染（例如败血症、肺炎）；余下的为轻或中度。几位患者的死亡应归因于感染和/或与疾病有关的并发症。治疗第二个月感染的全部发生率为6％；这些感染为轻至中度感染，未出现严重的系统感染。三个月后每月感染发生率均小于或等于治疗前的发生率。 治疗第一个月11％的病人出现严重发热（例≥104℉）。不到1/3的发热患者出现感染。参与试验的196位患者中有19位于治疗前一个月出现感染。治疗第一个月54位患者出现感染：23位（42％）为细菌性感染，11位（20％）为病毒性感染，11位（20％）为真菌性感染。7/8的带状疱疹患者发病于治疗第一个月。14/16的真菌感染患者发病于治疗开始的2个月。实际上所有感染病人都据经验进行抗生素治疗。 淋巴细胞分析显示，克拉屈滨的治疗与CD4计数的长时间减少有关。治疗前平均CD4计数为766/μl。平均CD4计数的最低值为272/μl，发生于治疗的第4－6个月。治疗后15个月，平均CD4计数(500/μl。虽然9个月后才观察到CD8计数增加，但总的来说CD8与CD4的变化趋势相似。目前尚不清楚CD4淋巴细胞长时间减少的临床意义。 另一未知临床意义的不良反应为骨髓细胞长时间过少。两项关键的临床试验表明，4个月后42/124（34％）患者的骨髓细胞构成(35％。细胞过少最近发生于第1010天。目前尚不清楚细胞过少是骨髓纤维化引起还是克拉屈滨毒性引起。对外周血细胞计数无明显临床影响。 大多数皮疹均较轻微，且发生于正接受或最近已接受可引起皮疹药物治疗（例如别嘌醇或抗生素）的患者。 大多数患者的恶心也较轻微，不伴随呕吐，不需用止吐剂治疗。应及早控制需用止吐剂治疗患者的恶心，最常用药物为氯丙嗪。 治疗开始2周内出现的发生率＞5％的不良反应（不论是否与药物有关）包括： 全身系统：发热（69％）、疲劳（45％）、寒战（9％）、虚弱（9％）、发汗（9％）、不适（7％）、躯干痛（6％） 胃肠道系统：恶心（28％）、食欲减退（17％）、呕吐（13％）、腹泻（10％）、便秘（9％）、腹痛（6％） 血/淋巴系统：紫癜（10％）、淤点（8％）、鼻衄（5％） 神经系统：头痛（22％）、头昏（9％）、失眠（7％） 心血管系统：水肿（6％）、心动过速（6％） 呼吸系统：异常呼吸音（11％）、咳嗽（10％）、异常胸音（9％）、呼吸短促（7％） 皮肤/皮下组织：皮疹（27％）、注射部位反应（19％）、瘙痒（6％）、疼痛（6％）、红斑（6％） 肌肉骨骼系统：肌痛（7％）、关节痛（5％） 与静脉注射有关的不良反应包括：注射部位反应（9％）（例变红、肿胀、疼痛），血栓形成（2％）、静脉炎（2％）、导管破裂（1％）。这些不良反应由输入过程和/或内在导管（而不是药物或溶媒）引起。 从第15天到最后的随访，发生率大于5％的不良反应包括：疲劳（11％）、皮疹（10％）、头痛（7%）、咳嗽（7％）、不适（5％）。 下面对药物大批供应后出现的不良反应进行描述。这些不良反应主要的都已在接受多疗程克拉屈滨注射液治疗的不良反应中报道过： 血液学：伴有长时间各类血细胞减少的骨髓抑制，包括再生障碍性贫血；发生于治疗后几周的溶血性贫血（在淋巴样恶性肿瘤患者体内报道过）。 肝：胆红素和转氨酶出现可逆的轻微增加。 神经系统：神经病学毒性；然而，按克拉屈滨注射液的标准给药方案治疗很少有严重神经毒性的报道。 呼吸系统：肺间质浸润；为大多数病人感染的病因。 皮肤/皮下组织：荨麻疹，嗜曙红细胞过多。正接受或最近已接受可引起这些综合症的其他药物（例别嘌醇或抗生素）治疗的患者出现过Stevens-Johnson和毒性表皮坏死松解。 由于克拉屈滨注射液可传递免疫抑制，所以治疗急性期可出现机会感染。 禁忌 对本品过敏的患者禁用。 注意事项 本品为有效抗肿瘤药，同时也具有严重的潜在毒副作用。因此，本品应在三级甲等医院使用，应在有抗肿瘤治疗经验的临床医生指导下使用。 在用本品治疗的患者（特别是高剂量时）通常可观察到严重骨髓抑制，包括中性白细胞减少、贫血和血小板减少。参与临床研究的大多数患者在治疗开始时都具有血液学损害（为毛细胞白血病活动期的临床表现），用本品治疗后，外周血计数恢复前血液学呈现进一步损伤。治疗开始的第一个2周内，平均血小板计数、ANC和血红蛋白浓度下降，然后分别于第12天、第5周和第8周增至正常值。治疗的第一个月应着重注意本品的骨髓抑制作用。治疗的第1个月有44％的患者需补充RBCs，14％的患者需补充血小板。因此，本品从给药开始最初4至8周内，除了连续注意患者的体征变化外，须定期作血液学检查，以便及时发现患者是否出现贫血、中性白细胞减少、血小板减少以及潜在继发的感染或出血。与使用其他有效化疗药一样，应监测患者（特别是肝、肾功能失调患者）的肝、肾功能。 治疗中和治疗后，应定期监测患者的血液学以检测骨髓造血功能抑制程度。临床研究中所有细胞计数出现可逆性减少后，于第12天平均血小板计数达100×109/L，第5周平均绝对中性白细胞计数达1500×106/L，第8周平均血红蛋白达12g/dL。外周血计数恢复正常后，应进行骨髓吸引术和活检以确定本品的疗效。应进行适当的实验室和放射学研究以调查发热不良反应。应定期对肾和肝功能进行检测。 本品对于骨髓造血功能的抑制基本上是剂量依赖性和可逆性的，可在1～2个月内逐渐恢复。如遇严重情况，应按有关治疗原则（如输注血液成分、给予抗生素等）妥善处理。 治疗的第一个月，大约2/3的患者（131/196）因使用本品而出现发热（T≥100℉）。总的来说，47％（93/196）的患者同时出现中性白细胞减少（ANC≤1000）和发热，其中62位（32%）为严重中性白细胞减少患者（例ANC≤500）。由于发热大多发生于中性白细胞减少患者，治疗的第一个月应密切监测这类患者并根据经验进行抗生素治疗。虽然69％的患者出现发热，但不到1/3的发热副作用由感染引起。已知本品具有骨髓抑制作用，医生应权衡感染期患者使用本品的风险和利益。 目前尚无足够数据显示肝或肾功能不全患者的用药剂量。大剂量使用本品的患者有急性肾功能损伤的报道。本品应慎用于骨髓、免疫及肝、肾功能不良的患者。怀疑有肾或肝功能不全的患者也应慎用本品。 其他血液恶性肿瘤患者经本品治疗后很少有肿瘤溶解综合症的报道。 在剂量爬坡研究中最高剂量组（大约为推荐用量的4倍）观察到外周轴索多发性神经病，患者并未接受环孢菌素或全身放疗治疗。但一般按推荐的标准剂量方案给药，很少出现严重的神经毒性。 本品不得以含有葡萄糖的注射液作为稀释剂，因葡萄糖可以促进克拉屈滨的分解。本品的输液中不得随意加入其他药物。 由于本品为潜在的细胞毒药物，因此处理、配置和使用本品时都应加以注意 药物相互作用 尚不明确克拉屈滨与其它药物的相互作用。给予本品期间如同时使用对骨髓造血功能、免疫功能和肾功能有损害作用的药物，可能加重本品在这些方面的毒性。 http://www.info.pmda.go.jp/go/pack/4291408A1021_1_10/4291408A1021_1_10?view=body A package insert Name of drug classification Antineoplastic agent Sales name Leustatin 8 mg Property White to slightly yellowish white powder Solubility It is slightly soluble in propylene glycol or Macrogol 400, hardly soluble in water, methanol, ethanol (95), 2-propanol, glycerin or acetone, is very insoluble in 1-octanol, and hardly soluble in dichloromethane or n-heptane. composition Component·Content In 1 vial (8 mL) cladribine 8 mg Additive Sodium chloride 72mg PH adjusting agent 2 component Contraindications Patients with a history of hypersensitivity to the ingredients of this drug Pregnant women or women who may be pregnant [see "Administration to pregnant women, maternity women, lactating women, etc."] Indication or effect Hairy cell leukemia Normally, for adults, as a cladribine, a continuous intravenous drip infusion of 0.09 mg/kg per day for 7ays is one course. The following diseases of relapse / relapse or treatment resistance Low-grade or follicular B-cell non-Hodgkin's lymphoma, mantle cell lymphoma 7 days continuous infusion IV Usually, for adults, as a cladribine, intravenous drip infusion of 0.09 mg / kg daily for 7 days intravenously and withdraw for 3 to 5 weeks. Take this as one course and repeat administration. Two-hour intravenous infusion - Daily administration for 5 days Usually, adults receive intravenous drip infusion over 0. 2 mg / kg daily for 2 hours once a day as cladribine. This is done for 5 consecutive days, with at least 23 days off. Take this as one course and repeat administration. Hairy cell leukemia If response can not be obtained by administration of the first course, do not perform administration of the second course (there is no possibility that effects can be seen even if the number of courses is repeated). The administration of the second course should be performed at intervals of at least 1 month or longer only when a recurrence or relapse is observed in the case where the response obtained by administration of the first course is observed. Method of administration Regarding low malignancy or refractory low-malignancy or refractory B-cell non-Hodgkin's lymphoma and mantle cell lymphoma, two dosage regimens/doses with different amounts of this drug per day, administration time, and administration days are set Be careful not to cause errors when administering. For continuous intravenous drip infusion for 7 days, continuous intravenous drip infusion over 24 hours a day, this should be done continuously for 7 days. As this drug has not undergone a compounding change test, it should be avoided to blend with other intravenous drugs etc. or to inject at the same intravenous line at the same time. How to prepare daily dose 7 days continuous infusion IV Prepare by adding the converted amount of this drug (0.09 mg/kg or 0.09 mL/kg) to 500 to 1000 mL of physiological saline infusion bag. Two-hour intravenous infusion - Daily administration for 5 days Prepare by adding the converted amount of this drug (0.12mg/kg or 0.12 mL/kg) to an IV bag containing 100 to 500 mL of physiological saline. When diluting this drug, use physiological saline and do not use other diluent. Careful Administration Patients with renal impairment [Side effects may develop strongly.] Patients with hepatic disorders [May cause liver injury.] Patients with complications of infection [Myelosuppression sometimes causes infection to exacerbate (see "Warning", "Important basic attention", "Serious side effects")] Serious side effects Myelosuppression Pancytopenia (frequency unknown Note)), lymphopenia (87.0%), neutropenia (79.8%), leukopenia (77.9%), thrombocytopenia (53.8%), anemia [red blood cell depletion (48.1% Decrease in hematocrit (45.7%), decrease in hemoglobin (45.2%)] may develop or exacerbate and prolonged. The myelosuppressive effect of this drug is most prominent in the first month after administration. Especially observe the patient's condition such as blood test at least once a week for 8 weeks after the start of administration, and take appropriate measures if abnormality is found. Severe opportunistic infection (Frequency unknown Note)) Severe opportunistic infections such as sepsis and pneumonia may occur, so observe thoroughly, if abnormalities are found, discontinue administration immediately and administer antibiotics, antifungal agents, antiviral agents, etc. Take action. Gastrointestinal bleeding (1.0%) Gastrointestinal bleeding may occur, so observe the condition of the patient adequately, if abnormalities are found, discontinue administration immediately and take appropriate measures. Serious neurotoxicity (Frequency unknown Note)) Severe neurotoxicity (irreversible insomnia paraparesis / limb paralysis) has been reported in patients receiving high dose of this drug (4 to 9 times the usual dose of intravenous drip infusion). Although the appearance of neurotoxicity seems to be dose-correlated, severe neurotoxicity may occur rarely in usual dosage regimen. If neurotoxicity appears, take the drugs off or discontinue administration. Contents of neurotoxicity High dose 0.3 to 0.5mg/kg/day×7 to 14 days paraparesis, quadriplegia paralysis 0.15 to 0.2mg/kg / day×7 days Guillain-Barré syndrome, Brown · Secare syndrome Normal dose 0.09mg/kg/day×7days confusion, anxiety / depression, constipation Cheson, B. D., et al .: J. Clin. Oncol., 12: 2216-2228, 1994 Tumor collapse syndrome (Frequency unknown Note)) Tumor collapse syndrome may occur in patients with large tumor volumes. For patients with high leukocyte count at the start of administration, consideration should be given to administration of hyperuricemia treatment and appropriate hydration, etc., in order to suppress the onset of oncolytic syndrome. Interstitial pneumonia (1.0%) As interstitial pneumonia may appear, if observation is adequate and symptoms such as dyspnea, cough, fever etc. are observed, X-ray examination is promptly performed, administration of this drug is stopped, and adrenal cortex Appropriate treatment such as administration of hormonal agents should be performed. Serious skin disorder (Frequency unknown Note)) Skin mucosa ocular syndrome (Stevens-Johnson syndrome), toxic epidermal necrolysis (Lyell syndrome), etc. may occur, so observe thoroughly, if fever, rash of the oral mucosa, stomatitis, etc. are observed Discontinue administration and take appropriate measures. Acute renal failure (frequency unknown Note) Severe renal disorder such as acute renal failure may occur, so observe thoroughly by conducting a renal function test etc. If abnormalities are observed, administration should be discontinued and appropriate measures should be taken. Medicinal pharmacology Mechanism of action Cladribine is phosphorylated by deoxycytidine kinase and becomes 2-chloro-2'-deoxy-β-D-adenosine monophosphate (2-CdAMP). Cladribine is resistant to deamination by adenosine deaminase and because there are almost no 5'-nucleotidase in lymphocytes and monocytes, 2-CdAMP accumulates intracellularly and further active deoxynucleoside It is converted to 2-chloro-2'-deoxy-β-D-adenosine triphosphate (2-CdATP) which is triphosphate to express cytotoxicity. Therefore, it is considered that this agent has a selective cell killing effect on cells with high deoxycytidine kinase activity and low 5'-nucleotidase activity (lymphocytes, monocytes). Antitumor effect Cladribine showed cytotoxic effect on cell lines derived from lymphocyte and monocyte stem cells at a concentration of 100 nM or less. In addition, it showed concentration-dependent cytotoxic effects (IC50 for monocytes: 27 nM) on lymphocytes and monocytes isolated from normal fresh human peripheral blood, but effects were observed in fibroblast GM01380 (confluent) There was not.

cladribine

Generic Name: cladribine (KLAD ri been)
      Brand Name: Cladribine Novaplus, Leustatin

 

WARNING:

Cladribine injection 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.  Serious neurological toxicity (including irreversible paraparesis and quadraparesis) has been reported in patients who received Cladribine injection by continuous infusion at high doses (four to nine times the recommended dose for Hairy Cell Leukemia).  Neurologic toxicity appears to demonstrate a dose relationship; however, severe neurological toxicity has been reported rarely following treatment with standard Cladribine dosing regimens.

Acute nephrotoxicity has been observed with high doses of Cladribine injection (four to nine times the recommended dose for Hairy Cell Leukemia), especially when given concomitantly with other nephrotoxic agents/therapies.

 

 DESCRIPTION:

Cladribine Injection, USP (also commonly known as 2-chloro-2’-deoxy-ß-D-adenosine) is a synthetic antineoplastic agent for continuous intravenous infusion.  It is a clear, colorless, sterile, preservative-free, isotonic solution.  Cladribine injection, USP is available in single-dose vials containing 10 mg (1 mg/mL) of Cladribine, a chlorinated purine nucleoside analog.  Each milliliter of Cladribine injection, USP contains 1 mg of the active ingredient and 9 mg (0.15 mEq) of sodium chloride as an inactive ingredient.  The solution has a pH range of 5.5 to 8.0.  Phosphoric acid and/or dibasic sodium phosphate may have been added to adjust the pH to 6.3 ± 0.3.

The chemical name for Cladribine is 2-chloro-6-amino-9-(2-deoxy-ß-D-erythropento-furanosyl) purine and the structure is represented below:

CLINICAL PHARMACOLOGY:

 

Cellular Resistance and Sensitivity

The selective toxicity of 2-chloro-2’-deoxy-ß-D-adenosine towards certain normal and malignant lymphocyte and monocyte populations is based on the relative activities of deoxycytidine kinase and deoxynucleotidase.  Cladribine passively crosses the cell membrane.  In cells with a high ratio of deoxycytidine kinase to deoxynucleotidase, it is phosphorylated by deoxycytidine kinase to 2-chloro-2’-deoxy-ß-D-adenosine monophosphate (2-CdAMP).  Since 2-chloro-2’-deoxy-ß-D-adenosine is resistant to deamination by adenosine deaminase and there is little deoxynucleotide deaminase in lymphocytes and monocytes, 2-CdAMP accumulates intracellularly and is subsequently converted into the active triphosphate deoxynucleotide,2-chloro-2’-deoxy-ß-D-adenosine triphosphate (2-CdATP).  It is postulated that cells with high deoxycytidine kinase and low deoxynucleotidase activities will be selectively killed by 2-chloro-2’-deoxy-ß-D-adenosine as toxic deoxynucleotides accumulate intracellularly.

Cells containing high concentrations of deoxynucleotides are unable to properly repair single-strand DNA breaks.  The broken ends of DNA activate the enzyme poly (ADP-ribose) polymerase resulting in NAD and ATP depletion and disruption of cellular metabolism.  There is evidence, also, that 2-CdATP is incorporated into the DNA of dividing cells, resulting in impairment of DNA synthesis.  Thus, 2-chloro-2’-deoxy-ß-D-adenosine can be distinguished from other chemotherapeutic agents affecting purine metabolism in that it is cytotoxic to both actively dividing and quiescent lymphocytes and monocytes, inhibiting both DNA synthesis and repair.

Pharmacokinetics

In a clinical investigation, 17 patients with Hairy Cell Leukemia (HCL) and normal renal function were treated for seven days with the recommended treatment regimen of Cladribine injection (0.09 mg/kg/day) by continuous intravenous infusion.  The mean steady-state serum concentration was estimated to be 5.7 ng/mL with an estimated systemic clearance of 663.5 mL/h/kg when Cladribine injection was given by continuous infusion over seven days.  In Hairy Cell Leukemia patients, there does not appear to be a relationship between serum concentrations and ultimate clinical outcome.

In another study, eight patients with hematologic malignancies received a two (2) hour infusion of Cladribine injection (0.12 mg/kg).  The mean end-of-infusion plasma Cladribine injection concentration was 48 ± 19 ng/mL.  For five of these patients, the disappearance of Cladribine injection could be described by either a biphasic or triphasic decline.  For these patients with normal renal function, the mean terminal half-life was 5.4 hours.  Mean values for clearance and steady-state volume of distribution were 978 ± 422 mL/h/kg and 4.5 ± 2.8 L/kg, respectively.

Cladribine plasma concentration after intravenous administration declines multi-exponentially with an average half-life of 6.7 +/- 2.5 hours.  In general, the apparent volume of distribution of Cladribine is approximately 9 L/kg, indicating an extensive distribution in body tissues.

Cladribine penetrates into cerebrospinal fluid.  One report indicates that concentrations are approximately 25% of those in plasma.

Cladribine injection is bound approximately 20% to plasma proteins.

Except for some understanding of the mechanism of cellular toxicity, no other information is available on the metabolism of Cladribine injection in humans.  An average of 18% of the administered dose has been reported to be excreted in urine of patients with solid tumors during a five-day continuous intravenous infusion of 3.5 to 8.1 mg/m2/day of Cladribine injection.  The effect of renal and hepatic impairment on the elimination of Cladribine has not been investigated in humans.

CLINICAL STUDIES:

Two single-center open label studies of Cladribine injection have been conducted in patients with Hairy Cell Leukemia with evidence of active disease requiring therapy.  In the study conducted at the Scripps Clinic and Research Foundation (Study A), 89 patients were treated with a single course of Cladribine injection given by continuous intravenous infusion for seven days at a dose of 0.09 mg/kg/day.  In the study conducted at the M.D. Anderson Cancer Center (Study B), 35 patients were treated with a seven-day continuous intravenous infusion of Cladribine injection at a comparable dose of 3.6 mg/m2/day.  A complete response (CR) required clearing of the peripheral blood and bone marrow of hairy cells and recovery of the hemoglobin to 12 g/dL, platelet count to 100 x 109/L, and absolute neutrophil count to 1,500 x 106/L.  A good partial response (GPR) required the same hematologic parameters as a complete response, and that fewer than 5% hairy cells remain in the bone marrow.  A partial response (PR) required that hairy cells in the bone marrow be decreased by at least 50% from baseline and the same response for hematologic parameters as for complete response.  A pathologic relapse was defined as an increase in bone marrow hairy cells to 25% of pretreatment levels.  A clinical relapse was defined as the recurrence of cytopenias, specifically, decreases in hemoglobin ≥ 2 g/dL, ANC ≥ 25% or platelet counts ≥ 50,000.  Patients who met the criteria for a complete response but subsequently were found to have evidence of bone marrow hairy cells (< 25% of pretreatment levels) were reclassified as partial responses and were not considered to be complete responses with relapse.

Among patients evaluable for efficacy (N=106), using the hematologic and bone marrow response criteria described above, the complete response rates in patients treated with Cladribine injection were 65% and 68% for Study A and Study B, respectively, yielding a combined complete response rate of 66%.  Overall response rates (i.e., Complete plus Good Partial plus Partial Responses) were 89% and 86% in Study A and Study B, respectively, for a combined overall response rate of 88% in evaluable patients treated with Cladribine injection.

Using an intent-to-treat analysis (N=123) and further requiring no evidence of splenomegaly as a criterion for CR (i.e., no palpable spleen on physical examination and ≤ 13 cm on CT scan), the complete response rates for Study A and Study B were 54% and 53%, respectively, giving a combined CR rate of 54%.  The overall response rates (CR + GPR + PR) were 90% and 85%, for Studies A and B, respectively, yielding a combined overall response rate of 89%.

                                  RESPONSE RATES TO Cladribine INJECTION TREATMENT IN PATIENTS WITH HAIRY CELL LEUKEMIA

	CR	Overall
Evaluable Patients N=106	66%	88%
Intent-to-treat Population N=123	54%	89%

In these studies, 60% of the patients had not received prior chemotherapy for Hairy Cell Leukemia or had undergone splenectomy as the only prior treatment and were receiving Cladribine injection as a first-line treatment.  The remaining 40% of the patients received Cladribine injection as a second-line treatment, having been treated previously with other agents, including α-interferon and/or deoxycoformycin.  The overall response rate for patients without prior chemotherapy was 92%, compared with 84% for previously treated patients.  Cladribine injection is active in previously treated patients; however, retrospective analysis suggests that the overall response rate is decreased in patients previously treated with splenectomy or deoxycoformycin and in patients refractory to α-interferon.

                   OVERALL RESPONSE RATES (CR + GPR + PR) TO Cladribine INJECTION TREATMENT IN PATIENTS WITH HAIRY CELL LEUKEMIA

	OVERALL   RESPONSE (N=123)	NR + RELAPSE
No Prior Chemotherapy	68/74   92%	6 + 4   14%
Any Prior Chemotherapy	41/49   84%	8 +3   22%
Previous Splenectomy	32/41*   78%	9 + 1   24%
Previous Interferon	40/48   83%	8 + 3   23%
Interferon Refractory	6/11*   55%	5 + 2   64%
Previous Deoxycoformycin	3/6*   50%	3 + 1   66%

NR = No Response

* P < 0.05

After a reversible decline, normalization of peripheral blood counts (Hemoglobin >12 g/dL, Platelets >100 x 109/L, Absolute Neutrophil Count (ANC) >1,500 x 106/L) was achieved by 92% of evaluable patients.  The median time to normalization of peripheral counts was nine weeks from the start of treatment (Range: 2 to 72).  The median time to normalization of Platelet Count was two weeks, the median time to normalization of ANC was five weeks and the median time to normalization of Hemoglobin was eight weeks.  With normalization of Platelet Count and Hemoglobin, requirements for platelet and RBC transfusions were abolished after Months 1 and 2, respectively, in those patients with complete response.  Platelet recovery may be delayed in a minority of patients with severe baseline thrombocytopenia.  Corresponding to normalization of ANC, a trend toward a reduced incidence of infection was seen after the third month, when compared to the months immediately preceding Cladribine injection therapy (see also WARNINGS, PRECAUTIONS and ADVERSE REACTIONS).
 

   Cladribine INJECTION TREATMENT IN PATIENTS WITH HAIRY CELL LEUKEMIA TIME TO NORMALIZATION OF PERIPHERAL BLOOD COUNTS

Parameter	Median Time to   Normalization of Count*
Platelet Count	2 weeks
Absolute Neutrophil Count	5 weeks
Hemoglobin	8 weeks
ANC, Hemoglobin and Platelet Count	9 weeks

*Day 1 = First day of infusion

For patients achieving a complete response, the median time to response (i.e., absence of hairy cells in bone marrow and peripheral blood together with normalization of peripheral blood parameters), measured from treatment start, was approximately four months.  Since bone marrow aspiration and biopsy were frequently not performed at the time of peripheral blood normalization, the median time to complete response may actually be shorter than that which was recorded.  At the time of data cut-off, the median duration of complete response was greater than eight months and ranged to 25+ months.  Among 93 responding patients, seven had shown evidence of disease progression at the time of the data cut-off.  In four of these patients, disease was limited to the bone marrow without peripheral blood abnormalities (pathologic progression), while in three patients there were also peripheral blood abnormalities (clinical progression).  Seven patients who did not respond to a first course of Cladribine injection received a second course of therapy.  In the five patients who had adequate follow-up, additional courses did not appear to improve their overall response.

INDICATIONS AND USAGE:

Cladribine Injection, USP is indicated for the treatment of active Hairy Cell Leukemia as defined by clinically significant anemia, neutropenia, thrombocytopenia or disease-related symptoms.

CONTRAINDICATIONS:

Cladribine Injection is contraindicated in those patients who are hypersensitive to this drug or any of its components.

WARNINGS:

Due to increased risk of infection in the setting of immunosuppression with chemotherapy including Cladribine, it is recommended not to administer live attenuated vaccines to patients receiving Cladribine injection.

Severe bone marrow suppression, including neutropenia, anemia and thrombocytopenia, has been commonly observed in patients treated with Cladribine injection, especially at high doses.  At initiation of treatment, most patients in the clinical studies had hematologic impairment as a manifestation of active Hairy Cell Leukemia.  Following treatment with Cladribine injection, further hematologic impairment occurred before recovery of peripheral blood counts began.  During the first two weeks after treatment initiation, mean Platelet Count, ANC, and Hemoglobin concentration declined and subsequently increased with normalization of mean counts by Day 12, Week 5 and Week 8, respectively.  The myelosuppressive effects of Cladribine injection were most notable during the first month following treatment.  Forty-four percent (44%) of patients received transfusions with RBCs and 14% received transfusions with platelets during Month 1.  Careful hematologic monitoring, especially during the first four to eight weeks after treatment with Cladribine injection, is  recommended (see PRECAUTIONS).

Fever (T ≥ 100°F) was associated with the use of Cladribine injection in approximately two-thirds of patients (131/196) in the first month of therapy.  Virtually all of these patients were treated empirically with parenteral antibiotics.  Overall, 47% (93/196) of all patients had fever in the setting of neutropenia (ANC ≤ 1,000), including 62 patients (32%) with severe neutropenia (i.e., ANC ≤  500).

In a Phase I investigational study using Cladribine injection in high doses (four to nine times the recommended dose for Hairy Cell Leukemia) as part of a bone marrow transplant conditioning regimen, which also included high dose cyclophosphamide and total body irradiation, acute nephrotoxicity and delayed onset neurotoxicity were observed.  Thirty-one (31) poor-risk patients with drug-resistant acute leukemia in relapse (29 cases) or non-Hodgkins Lymphoma (two cases) received Cladribine for 7 to 14 days prior to bone marrow transplantation.  During infusion, eight patients experienced gastrointestinal symptoms.  While the bone marrow was initially cleared of all hematopoietic elements, including tumor cells, leukemia eventually recurred in all treated patients.  Within 7 to 13 days after starting treatment with Cladribine, six patients (19%) developed manifestations of renal dysfunction (e.g., acidosis, anuria, elevated serum creatinine, etc.) and five required dialysis.  Several of these patients were also being treated with other medications having known nephrotoxic potential.  Renal dysfunction was reversible in two of these patients.  In the four patients whose renal function had not recovered at the time of death, autopsies were performed; in two of these, evidence of tubular damage was noted.  Eleven (11) patients (35%) experienced delayed onset neurologic toxicity.  In the majority, this was characterized by progressive irreversible motor weakness (paraparesis/quadriparesis), of the upper and/or lower extremities, first noted 35 to 84 days after starting high dose therapy with Cladribine.  Non-invasive testing (electromyography and nerve conduction studies) was consistent with demyelinating disease.  Severe neurologic toxicity has also been noted with high doses of another drug in this class.

Axonal peripheral polyneuropathy was observed in a dose escalation study at the highest dose levels (approximately four times the recommended dose for Hairy Cell Leukemia) in patients not receiving cyclophosphamide or total body irradiation.  Severe neurological toxicity has been reported rarely following treatment with standard Cladribine dosing regimens.

In patients with Hairy Cell Leukemia treated with the recommended treatment regimen (0.09 mg/kg/day for seven consecutive days), there have been no reports of nephrologic toxicities.

Serious (e.g. respiratory infection, pneumonia and viral skin infections), including fatal infections (e.g., sepsis) were reported (see ADVERSE REACTIONS).

Of the 196 Hairy Cell Leukemia patients entered in the two trials, there were eight deaths following treatment.  Of these, six were of infectious etiology, including three pneumonias, and two occurred in the first month following Cladribine therapy.  Of the eight deaths, six occurred in previously treated patients who were refractory to α-interferon.

Benzyl alcohol is a constituent of the recommended diluent for the seven-day infusion solution.  Benzyl alcohol has been reported to be associated with a fatal “Gasping Syndrome” in premature infants (see DOSAGE AND ADMINISTRATION).

Pregnancy Category D

Cladribine can cause fetal harm when administered to a pregnant woman.  Although there is no evidence of teratogenicity in humans due to Cladribine, other drugs which inhibit DNA synthesis have been reported to be teratogenic in humans.  Cladribine is teratogenic in animals.  Advise females of reproductive potential to use highly effective contraception during treatment with Cladribine.  If Cladribine 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.

Cladribine is teratogenic in mice and rabbits and consequently has the potential to cause fetal harm when administered to a pregnant woman.  A significant increase in fetal variations was observed in mice receiving 1.5 mg/kg/day (4.5 mg/m2) and increased resorptions, reduced litter size and increased fetal malformations were observed when mice received 3 mg/kg/day (9 mg/m2).  Fetal death and malformations were observed in rabbits that received 3 mg/kg/day (33 mg/m2).  No fetal effects were seen in mice at 0.5 mg/kg/day (1.5 mg/m2) or in rabbits at 1 mg/kg/day (11 mg/m2).

PRECAUTIONS:

 

General

Cladribine injection is a potent antineoplastic agent with potentially significant toxic side effects.  It should be administered only under the supervision of a physician experienced with the use of cancer chemotherapeutic agents.  Patients undergoing therapy should be closely observed for signs of hematologic and non-hematologic toxicity.  Periodic assessment of peripheral blood counts, particularly during the first four to eight weeks posttreatment, is recommended to detect the development of anemia, neutropenia and thrombocytopenia and for early detection of any potential sequelae (e.g., infection or bleeding).  As with other potent chemotherapeutic agents, monitoring of renal and hepatic function is also recommended, especially in patients with underlying kidney or liver dysfunction (see WARNINGS and ADVERSE REACTIONS).

Fever was a frequently observed side effect during the first month on study.  Since the majority of fevers occurred in neutropenic patients, patients should be closely monitored during the first month of treatment and empiric antibiotics should be initiated as clinically indicated.  Although 69% of patients developed fevers, less than 1/3 of febrile events were associated with documented infection.  Given the known myelosuppressive effects of Cladribine, practitioners should carefully evaluate the risks and benefits of administering this drug to patients with active infections (see WARNINGS and ADVERSE REACTIONS).

There are inadequate data on dosing of patients with renal or hepatic insufficiency.  Development of acute renal insufficiency in some patients receiving high doses of Cladribine has been described.  Until more information is available, caution is advised when administering the drug to patients with known or suspected renal or hepatic insufficiency (see WARNINGS).

Rare cases of tumor lysis syndrome have been reported in patients treated with Cladribine with other hematologic malignancies having a high tumor burden.

Cladribine injection must be diluted in designated intravenous solutions prior to administration (see DOSAGE AND ADMINISTRATION).

Laboratory Tests

During and following treatment, the patient’s hematologic profile should be monitored regularly to determine the degree of hematopoietic suppression.  In the clinical studies, following reversible declines in all cell counts, the mean Platelet Count reached 100 x 109/L by Day 12, the mean Absolute Neutrophil Count reached 1,500 x 106/L by Week 5 and the mean Hemoglobin reached 12 g/dL by Week 8.  After peripheral counts have normalized, bone marrow aspiration and biopsy should be performed to confirm response to treatment with Cladribine.  Febrile events should be investigated with appropriate laboratory and radiologic studies.  Periodic assessment of renal function and hepatic function should be performed as clinically indicated.

Drug Interactions

There are no known drug interactions with Cladribine injection.  Caution should be exercised if Cladribine injection is administered before, after, or in conjunction with other drugs known to cause immunosuppression or myelosuppression (see WARNINGS).

Carcinogenesis

No animal carcinogenicity studies have been conducted with Cladribine.  However, its carcinogenic potential cannot be excluded based on demonstrated genotoxicity of Cladribine.

Mutagenesis

As expected for compounds in this class, the actions of Cladribine yield DNA damage.  In mammalian cells in culture, Cladribine caused the accumulation of DNA strand breaks.  Cladribine was also incorporated into DNA of human lymphoblastic leukemia cells.  Cladribine was not mutagenic in vitro(Ames and Chinese hamster ovary cell gene mutation tests) and did not induce unscheduled DNA synthesis in primary rat hepatocyte cultures.  However, Cladribine was clastogenic both in vitro(chromosome aberrations in Chinese hamster ovary cells) and in vivo (mouse bone marrow micronucleus test).

Impairment of Fertility

The effect on human fertility is unknown. When administered intravenously to Cynomolgus monkeys, Cladribine has been shown to cause suppression of rapidly generating cells, including testicular cells.

Pregnancy

Pregnancy Category D (see WARNINGS).

Nursing Mothers

It is not known whether this drug is excreted in human milk.  Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Cladribine, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug for the mother.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.  In a Phase I study involving patients 1 to 21 years old with relapsed acute leukemia, Cladribine injection was given by continuous intravenous infusion in doses ranging from 3 to 10.7 mg/m2/day for five days (one-half to twice the dose recommended in Hairy Cell Leukemia).  In this study, the dose-limiting toxicity was severe myelosuppression with profound neutropenia and thrombocytopenia.  At the highest dose (10.7 mg/m2/day), three of seven patients developed irreversible myelosuppression and fatal systemic bacterial or fungal infections.  No unique toxicities were noted in this study(1) (see WARNINGS and ADVERSE REACTIONS).

Geriatric Use

Clinical studies of Cladribine did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.  Other reported clinical experience has not identified differences in responses between the elderly and younger patients.  In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy in elderly patients.

ADVERSE REACTIONS:

 

Clinical Trials Experience

Adverse drug reactions reported by ≥ 1% of Cladribine-treated patients with HCL noted in the HCL clinical dataset (studies K90-091 and L91-048, n=576) are shown in the table below.

Adverse Drug Reactions in ≥ 1% of Patients Treated with Cladribine in HCL Clinical Trials

System Organ Class             Preferred Term	Cladribine (n=576) %
Blood and Lymphatic System Disorder (see also sections WARNINGS and PRECAUTIONS)
Anemia	1
Febrile neutropenia	8
Psychiatric Disorders
Anxiety	1
Insomnia	3
Nervous System Disorders
Dizziness	6
Headache	14
Cardiac Disorders
Tachycardia	2
Respiratory, Thoracic and Mediastinal Disorders
Breath sounds abnormal	4
Cough	7
Dyspnea*	5
Rales	1
Gastrointestinal Disorders
Abdominal pain**	4
Constipation	4
Diarrhea	7
Flatulence	1
Nausea	22
Vomiting	9
Skin and Subcutaneous Tissue Disorders
Ecchymosis	2
Hyperhidrosis	3
Petechiae	2
Pruritus	2
Rash***	16
Musculoskeletal, Connective Tissue, and Bone Disorders
Arthralgia	3
Myalgia	6
Pain****	6
General Disorders and Administration Site Conditions (see also sections WARNINGS and PRECAUTIONS)
Administration site reaction*****	11
Asthenia	6
Chills	2
Decreased appetite	8
Fatigue	31
Malaise	5
Muscular weakness	1
Edema peripheral	2
Pyrexia	33
Injury, Poisoning and Procedural Complications
Contusion	1

*       Dyspnea includes dyspnea, dyspnea exertional, and wheezing

**     Abdominal pain includes abdominal discomfort, abdominal pain, and abdominal pain (lower and upper)

***    Rash includes erythema, rash, and rash (macular, macula-papular, papular, pruritic, pustular and erythematous)

****  Pain includes pain, back pain, chest pain, arthritis pain, bone pain, and pain in extremity

*****Administration site reaction includes administration site reaction, catheter site (cellulitis, erythema, hemorrhage, and pain), and infusion site reaction (erythema, edema, and pain)

The following safety data are based on 196 patients with Hairy Cell Leukemia: the original cohort of 124 patients plus an additional 72 patients enrolled at the same two centers after the original enrollment cutoff.  In Month 1 of the Hairy Cell Leukemia clinical trials, severe neutropenia was noted in 70% of patients, fever in 69%, and infection was documented in 28%.  Most non-hematologic adverse experiences were mild to moderate in severity.

Myelosuppression was frequently observed during the first month after starting treatment.  Neutropenia (ANC < 500 x 106/L) was noted in 70% of patients, compared with 26% in whom it was present initially.  Severe anemia (Hemoglobin < 8.5 g/dL) developed in 37% of patients, compared with 10% initially and thrombocytopenia (Platelets < 20 x 109/L) developed in 12% of patients, compared to 4% in whom it was noted initially.

During the first month, 54 of 196 patients (28%) exhibited documented evidence of infection.  Serious infections (e.g., septicemia, pneumonia) were reported in 6% of all patients; the remainder were mild or moderate.  Several deaths were attributable to infection and/or complications related to the underlying disease.  During the second month, the overall rate of documented infection was 6%; these infections were mild to moderate and no severe systemic infections were seen.  After the third month, the monthly incidence of infection was either less than or equal to that of the months immediately preceding Cladribine therapy.

During the first month, 11% of patients experienced severe fever (i.e., ≥ 104°F).  Documented infections were noted in fewer than one-third of febrile episodes.  Of the 196 patients studied, 19 were noted to have a documented infection in the month prior to treatment.  In the month following treatment, there were 54 episodes of documented infection: 23 (42%) were bacterial, 11 (20%) were viral and 11 (20%) were fungal.  Seven (7) of 8 documented episodes of herpes zoster occurred during the month following treatment.  Fourteen (14) of 16 episodes of documented fungal infections occurred in the first two months following treatment.  Virtually all of these patients were treated empirically with antibiotics (see WARNINGS and PRECAUTIONS).

Analysis of lymphocyte subsets indicates that treatment with Cladribine is associated with prolonged depression of the CD4 counts.  Prior to treatment, the mean CD4 count was 766/μL.  The mean CD4 count nadir, which occurred four to six months following treatment, was 272/μL.  Fifteen (15) months after treatment, mean CD4 counts remained below 500/μL.  CD8 counts behaved similarly, though increasing counts were observed after nine months.  The clinical significance of the prolonged CD4 lymphopenia is unclear.

Another event of unknown clinical significance includes the observation of prolonged bone marrow hypocellularity.  Bone marrow cellularity of < 35% was noted after four months in 42 of 124 patients (34%) treated in the two pivotal trials.  This hypocellularity was noted as late as Day 1,010.  It is not known whether the hypocellularity is the result of disease related marrow fibrosis or if it is the result of Cladribine toxicity.  There was no apparent clinical effect on the peripheral blood counts.

The vast majority of rashes were mild.  Most episodes of nausea were mild, not accompanied by vomiting, and did not require treatment with antiemetics.  In patients requiring antiemetics, nausea was easily controlled, most frequently with chlorpromazine.

When used in other clinical settings the following ADRs were reported: bacteremia, cellulitis, localized infection, pneumonia, anemia, thrombocytopenia (with bleeding or petechiae), phlebitis, purpura, crepitations, localized edema and edema. 

For a description of adverse reactions associated with use of high doses in non-Hairy Cell Leukemia patients, see WARNINGS.

Postmarketing Experience

The following additional adverse reactions have been reported since the drug became commercially available.  These adverse reactions have been reported primarily in patients who received multiple courses of Cladribine injection:

Infections and infestations: Septic shock.  Opportunistic infections have occurred in the acute phase of treatment.

Blood and lymphatic system disorders: Bone marrow suppression with prolonged pancytopenia, including some reports of aplastic anemia; hemolytic anemia (including autoimmune hemolytic anemia), which was reported in patients with lymphoid malignancies, occurring within the first few weeks following treatment.  Rare cases of myelodysplastic syndrome have been reported.

Immune system disorders: Hypersensitivity.

Metabolism and nutrition disorders: Tumor lysis syndrome.

Psychiatric disorders: Confusion (including disorientation).

Hepatobiliary disorders: Reversible, generally mild increases in bilirubin (uncommon) and transaminases.

Nervous System disorders: Depressed level of consciousness, neurological toxicity (including peripheral sensory neuropathy, motor neuropathy (paralysis), polyneuropathy, paraparesis); however, severe neurotoxicity has been reported rarely following treatment with standard Cladribine dosing regimens.

Eye disorders: Conjunctivitis.

Respiratory, thoracic and mediastinal disorders: Pulmonary interstitial infiltrates (including lung infiltration, interstitial lung disease, pneumonitis and pulmonary fibrosis); in most cases, an infectious etiology was identified.

Skin and tissue disorders: Urticaria, hypereosinophilia; Stevens-Johnson.  In isolated cases toxic epidermal necrolysis has been reported in patients who were receiving or had recently been treated with other medications (e.g., allopurinol or antibiotics) known to cause these syndromes.

Renal and urinary disorders: Renal failure (including renal failure acute, renal impairment).

OVERDOSAGE:

High doses of Cladribine have been associated with: irreversible neurologic toxicity (paraparesis/quadriparesis), acute nephrotoxicity, and severe bone marrow suppression resulting in neutropenia, anemia and thrombocytopenia (see WARNINGS).  There is no known specific antidote to overdosage.  Treatment of overdosage consists of discontinuation of Cladribine, careful observation, and appropriate supportive measures.  It is not known whether the drug can be removed from the circulation by dialysis or hemofiltration.

DOSAGE AND ADMINISTRATION:

 

Usual Dosage

The recommended dose and schedule of Cladribine injection for active Hairy Cell Leukemia is as a single course given by continuous infusion for seven consecutive days at a dose of 0.09 mg/kg/day.  Deviations from this dosage regimen are not advised.  If the patient does not respond to the initial course of Cladribine injection for Hairy Cell Leukemia, it is unlikely that they will benefit from additional courses.  Physicians should consider delaying or discontinuing the drug if neurotoxicity or renal toxicity occurs (see WARNINGS).

Specific risk factors predisposing to increased toxicity from Cladribine injection have not been defined.  In view of the known toxicities of agents of this class, it would be prudent to proceed carefully in patients with known or suspected renal insufficiency or severe bone marrow impairment of any etiology.  Patients should be monitored closely for hematologic and non-hematologic toxicity (see WARNINGS and PRECAUTIONS).

Preparation and Administration of Intravenous Solutions

Cladribine injection must be diluted with the designated diluent prior to administration.  Since the drug product does not contain any antimicrobial preservative or bacteriostatic agent, aseptic technique and proper environmental precautions must be observed in preparation of Cladribine injection solutions.

To prepare a single daily dose

Cladribine injection should be passed through a sterile 0.22  μm disposable hydrophilic syringe filter prior to introduction into the infusion bag, prior to each daily infusion.  Add the calculated dose (0.09 mg/kg or 0.09 mL/kg) of Cladribine injection through the sterile filter to an infusion bag containing 500 mL of 0.9% Sodium Chloride Injection, USP.  Infuse continuously over 24 hours.  Repeat daily for a total of seven consecutive days.The use of 5% dextrose as a diluent is not recommended because of increased degradation of Cladribine.  Admixtures of Cladribine injection are chemically and physically stable for at least 24 hours at room temperature under normal room fluorescent light in Baxter Viaflex®PVC infusion containers.  Since limited compatibility data are available, adherence to the recommended diluents and infusion systems is advised.

	Dose of   Cladribine Injection	Recommended   Diluent	Quantity of   Diluent
24-hour infusion method	1 (day) x 0.09 mg/kg	0.9% Sodium   Chloride Injection, USP	500 mL

To prepare a 7-day infusion

The seven-day infusion solution should only be prepared with Bacteriostatic 0.9% Sodium Chloride Injection, USP (0.9% benzyl alcohol preserved).  In order to minimize the risk of microbial contamination, both Cladribine injection and the diluent should be passed through a sterile 0.22 μm disposable hydrophilic syringe filter as each solution is being introduced into the infusion reservoir.  First add the calculated dose of Cladribine injection (7 days x 0.09 mg/kg or mL/kg) to the infusion reservoir through the sterile filter. 

Then add a calculated amount of Bacteriostatic 0.9% Sodium Chloride Injection, USP (0.9% benzyl alcohol preserved) also through the filter to bring the total volume of the solution to 100 mL.  After completing solution preparation, clamp off the line, disconnect and discard the filter.  Aseptically aspirate air bubbles from the reservoir as necessary using the syringe and a dry second sterile filter or a sterile vent filter assembly.  Reclamp the line and discard the syringe and filter assembly.  Infuse continuously over seven days.  Solutions prepared with Bacteriostatic Sodium Chloride Injection for individuals weighing more than 85 kg may have reduced preservative effectiveness due to greater dilution of the benzyl alcohol preservative.  Admixtures for the seven-day infusion have demonstrated acceptable chemical and physical stability for at least seven days in the SIMS Deltec MEDICATION CASSETTE™ Reservoir.

	Dose of Cladribine  Injection	Recommended Diluent	Quantity of Diluent
7-day infusion method (use sterile 0.22 μm filter when preparing infusion solution	7 (days) x 0.09 mg/kg	Bacteriostatic 0.9% Sodium Chloride Injection, USP (0.9% benzyl alcohol)	q.s. to 100 mL

Since limited compatibility data are available, adherence to the recommended diluents and infusion systems is advised.  Solutions containing Cladribine injection should not be mixed with other intravenous drugs or additives or infused simultaneously via a common intravenous line, since compatibility testing has not been performed.  Preparations containing benzyl alcohol should not be used in neonates (see WARNINGS).

Care must be taken to assure the sterility of prepared solutions.  Once diluted, solutions of Cladribine injection should be administered promptly or stored in the refrigerator (2° to 8°C) for no more than eight hours prior to start of administration.  Vials of Cladribine injection are for single-use only.  Any unused portion should be discarded in an appropriate manner (see Handling and Disposal).

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.  A precipitate may occur during the exposure of Cladribine injection to low temperatures; it may be resolubilized by allowing the solution to warm naturally to room temperature and by shaking vigorously.  DO NOT HEAT OR MICROWAVE.

Chemical Stability of Vials

When stored in refrigerated conditions between 2° to 8°C (36° to 46°F) and protected from light, unopened vials of Cladribine injection are stable until the expiration date indicated on the package.  Freezing does not adversely affect the solution.  If freezing occurs, thaw naturally to room temperature.  DO NOT heat or microwave.  Once thawed, the vial of Cladribine injection is stable until expiry if refrigerated.  DO NOT refreeze.  Once diluted, solutions containing Cladribine injection should be administered promptly or stored in the refrigerator (2° to 8°C) for no more than 8 hours prior to administration.

Handling and Disposal

The potential hazards associated with cytotoxic agents are well established and proper precautions should be taken when handling, preparing, and administering Cladribine injection.  The use of disposable gloves and protective garments is recommended.  If Cladribine injection contacts the skin or mucous membranes, wash the involved surface immediately with copious amounts of water.  Several guidelines on this subject have been published.(2-8)  There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate.  Refer to your Institution’s guidelines and all applicable state/local regulations for disposal of cytotoxic waste.

HOW SUPPLIED:

Product No.	NDC No.
104010	63323-140-10	Cladribine Injection, USP is available as 10 mg per 10 mL (1 mg per mL), single-dose vial, packaged individually.

Store refrigerated 2° to 8°C (36° to 46°F).  Protect from light (keep in outer carton until time of use).

The container closure is not made with natural rubber latex.

REFERENCES:

1.    Santana VM, Mirro J, Harwood FC, et al: A phase I clinical trial of 2-Chloro-deoxyadenosine in pediatric patients with acute leukemia. J. Clin. Onc., 9: 416(1991).

2.    Recommendations for the Safe Handling of Parenteral Antineoplastic Drugs. NIH Publication No. 83-2621.  For sale by the Superintendent of Documents, U.S. Government Printing Office, Washington D.C. 20402.

3.    AMA Council Report. Guidelines for Handling Parenteral Antineoplastics, JAMA, March 15 (1985).

4.    National Study Commission on Cytotoxic Exposure-Recommendations for Handling Cytotoxic Agents.  Available from Louis P. Jeffrey, Sc.D., Chairman, National Study Commission on Cytotoxic Exposure, Massachusetts College of Pharmacy and Allied Health Sciences, 179 Longwood Avenue, Boston, Massachusetts 02115.

5.    Clinical Oncological Society of Australia: Guidelines and Recommendations for Safe Handling of Antineoplastic Agents, Med. J. Australia 1:425 (1983).

6.    Jones RB, et al. Safe Handling of Chemotherapeutic Agents: A Report from the Mount Sinai Medical Center. Ca—A Cancer Journal for Clinicians, Sept/Oct. 258-263 (1983).

7.    American Society of Hospital Pharmacists Technical Assistance Bulletin on Handling Cytotoxic Drugs in Hospitals. Am. J. Hosp. Pharm., 42:131 (1985).

8.    OSHA Work-Practice Guidelines for Personnel Dealing with Cytotoxic (antineoplastic) Drugs. Am. J. Hosp. Pharm., 43:1193 (1986).

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45989E

Revised:August 2016

PACKAGE LABEL - PRINCIPAL DISPLAY - Cladribine 10 mL Single Dose Vial Label

Cladribine Injection, USP

10 mg per 10 mL (1 mg per mL)

For intravenous infusion.

10 mL Single Dose Vial

Rx only

PACKAGE LABEL - PRINCIPAL DISPLAY - Cladribine 10 mL Single Dose Vial Carton Panel

Cladribine Injection, USP

10 mg per 10 mL (1 mg per mL)

For intravenous infusion.

Cladribine Cladribine injection
Product Information Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC:63323-140 Route of Administration INTRAVENOUS DEA Schedule
Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength Cladribine (Cladribine) Cladribine 1 mg  in 1 mL
Inactive Ingredients Ingredient Name Strength SODIUM CHLORIDE 9 mg  in 1 mL PHOSPHORIC ACID   SODIUM PHOSPHATE, DIBASIC
Packaging # Item Code Package Description 1 NDC:63323-140-10 1 VIAL, SINGLE-DOSE in 1 CARTON 1 10 mL in 1 VIAL, SINGLE-DOSE
Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA076571 12/01/2004
Labeler - Fresenius Kabi USA, LLC (608775388)

Establishment
Name	Address	ID/FEI	Operations
Fresenius Kabi USA, LLC		023648251	MANUFACTURE(63323-140)

Revised: 11/2016

Fresenius Kabi USA, LLC