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· 【产品名称】注射用阿糖胞苷

 

 

· 【规格】0.1g

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· 【性状】本品为白色至类白色冻干块状物。

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· 【适应症】

阿糖胞苷主要适用于成人和儿童急性非淋巴细胞性白血病的诱导缓解和维持治疗。它对其它类型的白血病也有治疗作用，如：急性淋巴细胞性白血病、慢性髓细胞性白血病（急变期）。本品可单独或与其它抗肿瘤药联合应用；联合用药疗效更好。如果无维持治疗，阿糖胞苷诱导的缓解很短暂。本品曾实验性地用于其它不同肿瘤的治疗。一般而言，仅对少数实体肿瘤患者有效。含阿糖胞苷的联合治疗方案对儿童非何杰金氏淋巴瘤有效。伴或不伴其它肿瘤化疗药，2-3g/m2高剂量的阿糖胞苷在1-3小时内静脉滴注，每12小时一次，共2-6天，对高危白血病、难治性和复发性急性白血病有效。本品单独或与其它药物联合（甲氨蝶呤，氢化可的松琥珀酸钠）鞘内应用可预防或治疗脑膜白血病。

 

· 【用法用量】本品口服无活性。根据所用治疗方案设定不同的给药方法和疗程。本品可供静脉滴注，注射，皮下注射或鞘内注射。与缓慢的静脉滴注相比﹐给予快速静脉注射时患者能耐受更高的剂量。这个现象可能与快速注射后﹐药物迅速失活及短时间内高浓度的药物作用于可疑正常细胞和肿瘤细胞有关。正常和肿瘤细胞对这些不同的给药方法的反应似是类似的﹐没有证据表明两种给药方式中的哪一种更具临床优势。目前积累的临床经验提示﹐与以往的基本治疗过程相比﹐成功的应用阿糖胞苷是在治疗开始时就调整药物每日的剂量﹐以求得到在毒性耐受范围内最大的白血病细胞杀伤作用﹐这是因为药物毒性迫使对剂量作出相应调整。在大多数治疗过程中﹐本品需要与其他具细胞毒性药物联合使用﹐合用其他药物后需要对本品做相应剂量变化﹐下面是文献报道的本品在联合应用中的剂量表。剂量表、1. 急性髓细胞性白血病、(1) 诱导缓解﹐成人。低剂量化疗: 阿糖胞苷-2ｏ0 mg/m2﹐每日持续输入共5 天(12ｏ 小时)﹐总剂量1000 mg/m2﹐每2周重复1次﹐需要根据血象反应作调整。高剂量化疗:在开始高剂量化疗前﹐医师必须熟悉所有涉及此化疗药物的文献报道，不良反应，注意事项，禁忌症和警告。阿糖胞苷:- 2 g/m2每12 小时1次(每次输入时间大于3 小时)从第1天到第6天给药(包括第6 天﹐即12 次) ;或者- 3 g/m2每12 小时1次(每次输入时间大于1 小时)﹐从第1天到第6天给药(包括第6 天﹐即12 次) ;或者-3 g/m2每12 小时1次(每次输入时间大于75 分钟)﹐从第1天到第6天给药 (包括第6 天﹐即12 次)。阿糖胞苷﹐多柔比星:阿糖胞苷、3 g/m2每12 小时1次(每次输入时间大于2 小时)﹐从第1天到第6天给药(包括第6天﹐即12次) 多柔比星、30 mg/m2静脉注射﹐第6﹐7天。阿糖胞苷﹐门冬酰胺酶:阿糖胞苷 、3 g/m2﹐分别于0，12，24，36小时给药﹐每次输入大于3 小时﹐在第42 小时﹐门冬酰胺酶60ｏ0 单位/m2肌注﹐第1天及第2天给药﹐第8﹐9天重复一次。联合化疗:在开始高剂量化疗前﹐医师必须熟悉所有涉及此化疗药物的文献报道，不良反应，注意事项，禁忌症和警告。阿糖胞苷﹐多柔比星:阿糖胞苷 、100 mg/m2/天﹐持续静注﹐从第1天到第10天给药(含第10 天), 多柔比星 、30 mg/m2/天﹐30 分钟内静脉注射﹐第1到第3天给药(含第3 天),如果病情未缓解﹐在2-4周间歇后﹐必要时增加疗程(完整的疗程或作调整)。阿糖胞苷﹐硫鸟嘌呤﹐柔红霉素:阿糖胞苷 、100 mg/m2/天﹐静注(大于30 分钟)﹐每12小时1次﹐第1-7天(含第7天), 硫鸟嘌呤 、100 mg/m2口服﹐每12小时1次﹐第1-7天(含第7 天), 柔红霉素 、60 mg/m2/天﹐静脉注射﹐第5到第7天给药(含第7 天),如果病情未缓解﹐在2-4 周间歇后﹐必要时增加疗程(完整的疗程或作调整)。阿糖胞苷﹐多柔比星﹐长春新碱﹐泼尼松龙:阿糖胞苷 、100 mg/m2/天﹐持续静注﹐第1-7天给药(含第7 天), 多柔比星 、30 mg/m2/天﹐静注﹐第1-3 天(含第3 天), 长春新碱 、1.5 mg/m2/天﹐静脉注射﹐第1和第5天给药, 泼尼松龙 、40 mg/m2/天﹐每12 小时静注1次﹐第1到第5天给药(含第5 天),如果病情未缓解﹐在2-4 周间歇后﹐必要时增加疗程(完整的疗程或作调整)。阿糖胞苷﹐柔红霉素﹐硫鸟嘌呤﹐泼尼松龙﹐长春新碱: 阿糖胞苷 、100 mg/m2﹐每12小时静注一次﹐第1-7天给药(含第7 天), 柔红霉素 、7ｏ mg/m2/天﹐静注﹐第1-3 天(含第3天), 硫鸟嘌呤 、100 mg/m2﹐每12 小时口服1次﹐第1-7天给药(含第7 天), 泼尼松龙 、40 mg/m2/天﹐口服﹐第1-7天给药(含第7 天), 长春新碱 、1 mg/m2/天﹐静脉注射﹐第1和第7天给药如果病情未缓解﹐在2-4周间歇后﹐必要时增加疗程(完整的疗程或作调整)。阿糖胞苷﹐柔红霉素:阿糖胞苷 、100 mg/m2天﹐持续静注﹐第1-7天给药(含第7 天), 柔红霉素 、45 mg/m2/天﹐静注﹐第1-3天(含第3 天)。(2) 成人巩固治疗、巩固治疗方案是对诱导方案作调整﹐总体来看﹐治疗方案与诱导阶段相似﹐但在缓解后巩固阶段﹐每个疗程之间都有较长的时间间歇。(3) 儿童诱导及巩固治疗、大量研究表明﹐在同一方案治疗下﹐儿童急性髓性白血病较成人效果要好﹐当成人药物剂量是根据体重或体表面积计算时﹐儿童的剂量也相应计算﹐但一些药物特定为成人剂量时﹐儿童剂量则应根据年龄，体重，体表面积等因素做一调整。2. 急性淋巴细胞白血病。 总体上剂量表与急性髓细胞性白血病相应﹐略作调整。3. 脑膜白血病的鞘内应用。 (1) 在急性白血病中﹐本品鞘内应用的剂量范围为5 mg/m2-75 mg/m2。给药的次数可从每天一次﹐共4天至4天1次。最常用的方法是3ｏ mg/m2﹐每四天一次﹐直至脑脊液检查正常﹐然后再给予1个疗程治疗。一般根据中枢神经系统表现类型和严重程度﹐以及对以前治疗的反应来决定给药方案。本品与甲氨蝶呤和氢化可的松琥珀酸钠一起鞘内给药﹐可用于新诊断的急性淋巴细胞性白血病儿童的脑膜白血病的预防和治疗。(2) Sullivan报道三药联用预防治疗能防止以后的中枢神经系统受累﹐并使痊愈和生存率与开始即给予预防性中枢神经系统放疗加甲氨蝶呤鞘内给药相似。预防性三联治疗即、 本品30 mg/m2﹐氢化可的松琥珀酸钠15 mg/m2和甲氨蝶呤15 mg/m2。在开始上述治疗前﹐医生必须熟悉此报道。在急性脑膜白血病成功治疗后﹐三联预防治疗急性脑膜白血病治疗似是有效的。医生在开始治疗前﹐必须熟悉目前的有关文献。(3) 剂量调整。当出现严重的血象降低时﹐本品的剂量必须作调整或暂时终止治疗。总体上﹐当外周血小板

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· 【不良反应】1. 可预见的不良反应。(1) 阿糖胞苷是一种骨髓抑制剂﹐应用后会出现贫血﹑白细胞减少症﹑血小板减少症﹑巨幼红细胞增多症和网状红细胞减少。这些反应的严重程度取决于剂量和疗程。骨髓和周围血涂片可见细胞形态学改变。5天连续静脉滴注或50mg/m2-600 mg/m2快速注射后﹐呈双相白细胞抑制。与用药前的细胞计数﹑剂量或疗程无关﹐白细胞计数在24 小时内开始下降﹐7-9天达低谷﹐然后在12天时有一个短暂的上升。第2次更严重的下降出现在15-24天﹐白细胞计数在随后的10天内迅速上升至用药前水平。可明显观察到在第5天出现血小板抑制﹐并在12-15天降至最低点﹐然后在以后的10天内迅速上升至用药前水平。(2) 阿糖胞苷综合征。本品综合征主要表现为 、发热﹑肌痛﹑骨痛﹑偶尔胸痛﹐斑丘疹﹑结膜炎和不适。通常发生于用药后6-12小时。皮质类固醇能预防和治疗此征。如认为需要治疗此征﹐皮质类固醇可与本品同时应用。2. 最常见的不良反应。厌食﹑肝功能不正常﹑恶心﹑发热﹑呕吐﹑皮疹﹑腹泻﹑血栓性静脉炎﹑口腔或肛门炎症或溃疡﹐恶心和呕吐在快速静脉注射后最常见。3. 较少见的不良反应。 脓毒血症﹑肺炎﹑注射部位蜂窝组织炎﹑腹痛﹑皮肤溃疡﹑雀斑﹑尿潴留﹑黄疸﹑肾功能不全﹑结膜炎﹑神经炎 (可能伴皮疹)﹑神经毒﹑眩晕﹑咽痛﹑脱发﹑食道溃疡﹑过敏(见警告)﹑食道炎﹑过敏性水肿﹑胸痛﹑瘙痒﹑头痛﹑呼吸困难﹑荨麻疹。4. 大剂量治疗。有报道﹐与本品的常规给药方案不同﹐大剂量(2-3 g/m2)应用阿糖胞苷后可出现严重的﹑甚至是致命的中枢神经系统﹑胃肠道和肺部毒性,这些反应包括、(1) 可逆性的角膜毒性和出血性结膜炎,预防性局部应用皮质类固醇滴眼液能预防或减轻症状 。(2) 大脑和小脑功能失调﹐包括性格改变﹑嗜睡和昏迷﹐通常可逆。(3) 严重的胃肠道溃疡﹐包括小肠积气囊肿导致的腹膜炎。(4) 脓毒血症和肝脓肿 。(5) 肺水肿 。(6) 肝脏损害伴高胆红素血症 。(7) 肠坏死 。(8) 坏死性结肠炎。5. 两个成人急性非淋巴细胞性白血病患者联合应用本品﹑柔红霉素和门冬酰胺酶作为巩固治疗后﹐出现周围运动和感觉神经病变。(1) 由于可以通过改变剂量和疗程以避免罕见的不可逆神经病变﹐大剂量使用阿糖胞苷的患者应观察神经病变。(2) 10个患者应用中等剂量阿糖胞苷(1 g/m2)﹐伴或不伴其他化疗药物(meat-AMSA 胺苯丫啶﹑柔红霉素﹑鬼臼乙叉甙)﹐可出现不明原因的弥散性间质肺炎﹐并被认为与本品有关。6. 罕见导致脱皮的严重的皮疹。也有报道﹐与本品常规治疗方案相比﹐大剂量治疗时完全脱发更多见。7. 如果需大剂量治疗﹐不得使用含苯甲醇的稀释剂。已有报道﹐实验性应用大剂量本品和环磷酰胺作为骨髓移植的预处理时﹐出现心肌病变增加﹐并致死,这可能与疗程有关。8. 有医院实验性应用大剂量阿糖胞苷治疗复发性白血病后﹐出现突发呼吸窘迫并迅速发展成肺水肿﹐经X线证实有心肌肥大。其中一例患者因此最终致死。

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· 【禁忌】对阿糖胞苷过敏者禁用。

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· 【注意事项】本品使用苯甲醇作为溶媒﹐禁止用于儿童肌肉注射。1. 特别注意。 (1) 只有对肿瘤化疗有经验的医生才可用阿糖胞苷。(2) 患者在诱导治疗时﹐应有足够的实验室和辅助设备以监测患者对药物的耐受性﹐确保患者免遭药物的毒性损害。(3) 在考虑应用本品治疗时﹐医生必须考虑药物可能的有效作用和其毒性反应。(4) 在考虑应用或开始使用时﹐医生必须熟悉下列内容:本品是一种强效的骨髓抑制剂。对既往药物已引起骨髓抑制的患者必须谨慎地开始用药。患者用药时必须接受密切的医疗监护﹐在诱导治疗时﹐每天须测定白细胞和血小板计数。在周围血象粒细胞消失后﹐需经常进行骨髓检查。必须具备可处理复杂、可能致死的骨髓抑制(粒细胞减少和其他机体防御功能受损所致的感染和血小板减少所致的出血)的条件。有关过敏所致心跳呼吸停止﹐并需心肺复苏有1例报道。该例于静脉给予阿糖胞苷后立即发生。如果用大剂量治疗﹐不要用含苯甲醇的稀释剂。有报道未成熟婴儿的致死性的“痉挛综合征”与苯甲醇有关。许多医生用不含防腐剂的0.9%氯化钠制备注射剂并立即应用。应用本品的患者必须被密切观察。血小板、白细胞计数和骨髓的经常检查应视为常规。当药物引起骨髓抑制使血小板计数低于500ｏ0/mm3﹐或多核粒细胞计数低于1000/mm3时﹐应考虑停药或改变治疗方案。外周血有形成分计数在停药后可能进一步降低﹐在停药后12-24天达最低谷。需要时﹐当有确切骨髓恢复的表现(连续的骨髓检查)时﹐可再次开始治疗。当患者周围血象达所谓的“正常”时停药﹐可能会使病情不能控制。(5) 一些患者药物注射或滴注部位可出现血栓性静脉炎﹐很少患者有皮下注射部位疼痛和炎症。在大多数情况下﹐药物能被很好地耐受。当快速给予大剂量静脉注射时﹐患者常常在注射后数小时有频繁地恶心和呕吐。当静脉滴注时则恶心和呕吐的程度较轻。人体的肝脏可对大部分的所给药物解毒。肝功能不良的患者用药时需小心并减少剂量。应用本品的患者应定期测定骨髓、肝和肾功能。与其他细胞毒药物相似﹐本品可引起继发于肿瘤细胞快速分解的高尿酸血症。临床医生应观察患者血尿酸水平并准备在需要时用支持和药物治疗来控制病情。(6) 有报告本品联合应用其他药物时发生急性胰腺炎。(7) 两个急性髓细胞白血病患儿给予常规剂量鞘内和静脉注射阿糖胞苷﹐加用其他联合治疗药物后﹐产生延迟的进行性上行性麻痹﹐并导致其中的一人致死。(8) 两个患者给予常规剂量阿糖胞苷和表柔比星治疗导致腹部触痛（腹膜炎）和愈创树酯阳性的结肠炎。两者均经非手术治疗缓解﹐并有嗜中性粒细胞缺乏和血小板缺乏﹐同时接受其他药物治疗。作者建议对接受本品治疗时﹐如患者出现外科腹部症状但无确切的外科诊断时﹐应进行审慎、保守地处理。2. 鞘内应用。(1) 如果鞘内应用﹐不要使用含苯甲醇的稀释液。许多医生用不含防腐剂的0.9%氯化钠制备注射剂并立即应用。(2) 本品鞘内应用可引起全身毒性﹐需仔细观察造血系统。(3) 可能需要调整抗白血病的治疗。(4) 大部分毒性作用罕见。鞘内注射后最常见的反应是恶心、呕吐和发热 ；这些反应是轻微和自限性的。曾报道有截瘫。在5个儿童中出现脑白质坏死 ；这些患儿也接受了甲氨蝶呤和氢化可的松的鞘内注射及中枢神经系统的放射治疗。(5) 单独神经毒性也有报道。因接受全身联合化疗﹐预防性中枢神经系统放疗和本品鞘内注射﹐有2个患者在缓解期出现失明。(6) 中枢神经系统白血病局灶病变对本品的鞘内注射可能无反应﹐放疗可能疗效更好。致癌、致突变、对生殖力的影响。(7) 有报道本品可引起广泛的染色体损伤﹐包括染色质断裂﹐和嗤齿类细胞培养中的恶性转化。3. 配伍禁忌。本品物理性质上与肝素、胰岛素、甲氨蝶呤、5-氟脲嘧啶、乙氧奈胺青霉素、苯甲异恶唑青霉素、青霉素G和甲基强的松龙琥珀酸钠有配伍禁忌。配制后的稳定性和相容性:低剂量治疗；高剂量治疗。

· 

· 【药物相互作用】1. 地高辛患者接受含环磷酰胺，长春新碱和强的松的化疗方案，无论是否包括阿糖胞苷或甲基苄肼，联合β～醋地高辛治疗，其地高辛稳态血浆浓度和肾葡萄糖分泌发生可逆性地下降。洋地黄毒苷的稳态浓度似不变。因此接受类似联合化疗方案治疗的患者需密切监测地高辛的浓度。此类患者可考虑用洋地黄毒苷替代地高辛的使用。2. 庆大霉素在体外阿糖胞苷和庆大霉索药物相互作用的研究中，发现K．肺炎菌株对庆大霉紊敏感性的拮抗作用与阿糖胞苷相关。此研究建议:在使用庆大霉素治疗K．肺炎菌感染时，应用阿糖胞苷的患者如不迅速出现治疗作用可能需重新调整抗菌治疗方案。3. 氟胞嘧啶一例患者的临床证据显示在阿糖胞苷治疗期间氟胞嘧啶的疗效似受到抑制。这可能由于氟胞嘧啶的吸收受到竞争性的抑制所致。

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· 【孕妇及哺乳期妇女用药】1. 妊娠期用药无阿糖胞苷用于怀孕妇女的研究。已知本品对一些动物种属有致畸作用。对已经或可能怀孕妇女使用本品前需考虑对孕妇和胎儿潜在的利弊。建议育龄期妇女避孕。2. 怀孕期间接受过阿糖胞苷(单独或与其他药物联合应用)治疗的孕妇﹐可以分娩正常的婴儿﹐但也有可能是早产儿或低体重儿。一些接触过阿糖胞苷的正常婴儿从出生后六周开始随访一直到七岁﹐并未发现异常。有一名似乎正常的婴儿在出生90天时死于胃肠炎。3. 有先天性畸形的报道﹐特别是当胎儿在妊娠前3个月内接触了全身应用的阿糖胞苷时。此类畸形包括上肢和下肢远端缺损以及手足和耳的畸形。4. 宫内接触阿糖胞苷的婴儿﹐在新生儿期有发生全血细胞减少﹐白细胞减少、贫血、血小板减少、电解质异常、短暂的嗜酸眭粒细胞增多、IgM水平增高和高热、脓毒血症及死亡的报道。这些婴儿中也有部分是早产儿。5. 对接受阿糖胞苷治疗的孕妇曾施行过治疗性流产。尽管有胎儿正常的报道﹐但其他报告均显示对胎儿有影响﹐这种影响包括脾肿大和绒毛膜组织中C组染色体三体异常。6. 因为细胞毒药物潜在的致畸作用﹐特剐在妊娠早期(最初的三个月)﹐应将对胎儿潜在的危险性和是否适宜继续怀孕告知已经或可能怀孕的应用本品的患者。如果治疗开始于怀孕中后期﹐仍存在致畸危险﹐但相对较小。虽然有在怀孕全程均接受治疗的患者仍分娩正常婴儿﹐但应建议对这些婴儿进行随访。7. 哺乳期用药目前尚不知道药物是否从人乳汁中分泌。由于许多药物可从人乳汁中分泌﹐而且阿糖胞苷对哺乳婴儿具有潜在的严重不良反应﹐必须根据药物对母亲的重要性来决定是否停止哺乳或停用药物。

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· 【药理毒理】本品为主要作用于细胞S增殖期的嘧啶类抗代谢药物，通过抑制细胞DNA 的合成，干扰细胞的增殖。阿糖胞苷进入人体后经激酶磷酸化后转为阿糖胞苷三磷酸及阿糖胞苷二磷酸，前者能强有力地抑制DNA聚合酶的合成，后者能抑制二磷酸胞苷转变为二磷酸脱氧胞苷，从而抑制细胞DNA聚合及合成。本品为细胞周期特异性药物，对处于S增殖期细胞的作用最为敏感，对抑制RNA及蛋白质合成的作用较弱。

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· 【药代动力学】可静脉、皮下、肌内或鞘内注射而吸收。静脉注射后能广泛分布于体液、组织及细胞内，静脉滴注后约有中等量的药物可透过血脑屏障，其浓度约为血浆中浓度的40％。本品在肝、肾等组织内代谢，在血及组织中很容易被胞嘧啶脱氨酶迅速脱氨而形成无活性的尿嘧啶阿拉伯糖苷。在脑脊液内，由于脱氨酶含量较低，故其脱氨作用较缓慢。静脉给药时，T1/2α为10～15分钟。T1/2β2～2.5小时；鞘内给药时，T1/2可延至11小时。在24小时内约10％以阿糖胞苷，70%～90％以尿嘧啶阿糖胞苷为主的无活性物质形式从肾脏排泄。

Cytarabine (Conventional)

Medically reviewed by Drugs.com. Last updated on Jul 27, 2019.

 

 

Pronunciation

 (sye TARE a been con VEN sha nal)

Index Terms

· Ara-C

· Arabinosylcytosine

· Conventional Cytarabine

· Cytarabine

· Cytarabine Hydrochloride

· Cytosar-U

· Cytosine Arabinosine Hydrochloride

 

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Solution, Injection:

Generic: 20 mg/mL (25 mL)

Solution, Injection [preservative free]:

Generic: 20 mg/mL (5 mL, 50 mL); 100 mg/mL (20 mL)

 

Pharmacologic Category

· Antineoplastic Agent, Antimetabolite

· Antineoplastic Agent, Antimetabolite (Pyrimidine Analog)

Pharmacology

Cytarabine inhibits DNA synthesis. Cytarabine gains entry into cells by a carrier process, and then must be converted to its active compound, aracytidine triphosphate. Cytarabine is a pyrimidine analog and is incorporated into DNA; however, the primary action is inhibition of DNA polymerase resulting in decreased DNA synthesis and repair. The degree of cytotoxicity correlates linearly with incorporation into DNA; therefore, incorporation into the DNA is responsible for drug activity and toxicity. Cytarabine is specific for the S phase of the cell cycle (blocks progression from the G1 to the S phase).

 

 

 

Absorption

Not effective when administered orally; less than 20% absorbed orally

Distribution

Vd: 3 ± 11.9 L/kg; total body water; widely and rapidly since it enters the cells readily; crosses blood-brain barrier with CSF levels of 40% to 50% of plasma level

Metabolism

Primarily hepatic; metabolized by deoxycytidine kinase and other nucleotide kinases to aracytidine triphosphate (active); about 86% to 96% of dose is metabolized to inactive uracil arabinoside (ARA-U); intrathecal administration results in little conversion to ARA-U due to the low levels of deaminase in the cerebral spinal fluid

Excretion

Urine (~80%; 90% as metabolite ARA-U) within 24 hours

Time to Peak

IM, SubQ: 20 to 60 minutes

Half-Life Elimination

IV: Initial: 7 to 20 minutes; Terminal: 1 to 3 hours; Intrathecal: 2 to 6 hours

Protein Binding

13%

 

 

Use: Labeled Indications

Acute myeloid leukemia: Remission induction (in combination with other chemotherapy medications) in acute myeloid leukemia (AML)

Acute lymphocytic leukemia: Treatment of acute lymphocytic leukemia (ALL)

Chronic myeloid leukemia: Treatment of chronic myeloid leukemia (CML; blast phase)

Meningeal leukemia: Prophylaxis and treatment of meningeal leukemia

Off Label UsesAcute myeloid leukemia (consolidation)

Data from several randomized clinical trials in patients with acute myeloid leukemia (AML) support the use of cytarabine (in combination with daunorubicin or idarubicin or mitoxantrone [5 + 2 regimens], in combination with daunorubicin and etoposide [5 + 2 + 5 regimen], or as a single agent) [Arlin 1990], [Bishop 1996], [Mayer 1994], [Wiernik 1992].

Acute myeloid leukemia (salvage)

Data from open-label studies in adult patients with relapsed or refractory acute myeloid leukemia (AML) support the use of cytarabine (in combination with cladribine and G-CSF [CLAG regimen] or with cladribine, mitoxantrone, and G-CSF [CLAG-M regimen] or in combination with fludarabine and G-CSF [FLAG regimen] or high dose cytarabine in combination with an anthracycline [HiDAC regimen] or in combination with mitoxantrone and etoposide [MEC regimen]) or in combination with clofarabine and filgrastim in the treatment of refractory or relapsed AML in adults [Amadori 1991], [Archimbaud 1991], [Archimbaud 1995], [Becker 2011], [Herzig 1985], [Montillo 1998], [Wierzbowska 2008], [Wrzesien-Kus 2003].

Acute promyelocytic leukemia (consolidation)

Data from two clinical trials in patients with high-risk acute promyelocytic leukemia (APL) support the use of cytarabine (in combination with idarubicin and tretinoin) [Lo Coco 2010], [Sanz 2010]. Data from two studies in patients with newly diagnosed APL also supports the use of cytarabine (in combination with daunorubicin) during the consolidation phase of treatment [Ades 2006], [Ades 2008].

Acute promyelocytic leukemia (induction)

Data from three clinical trials in patients with acute promyelocytic leukemia (APL) support the use of cytarabine (in combination with tretinoin and daunorubicin) for the treatment of APL [Ades 2006], [Ades 2008], [Powell 2010].

 

Chronic lymphocytic leukemia (refractory)

Data from a phase II study support the use of cytarabine (in combination with fludarabine, oxaliplatin, and rituximab) in the treatment of fludarabine-refractory chronic lymphocytic leukemia [Tsimberidou 2008].

Hodgkin lymphoma (relapsed or refractory)

Data from multiple trials support the use of cytarabine as a component of combination chemotherapy in the treatment of relapsed or refractory Hodgkin lymphoma (HL). A phase II trial using cytarabine in combination with cisplatin and dexamethasone (DHAP) illustrated the safety and toxicity of this regimen in patients with relapsed/refractory HL [Josting 2002]. A small phase II trial studied cytarabine in combination with etoposide, methylprednisolone, and cisplatin (ESHAP) and found it to be an active regimen in this patient population [Aparicio 1999]. Cytarabine in combination with carmustine, etoposide, and melphalan is an effective salvage regimen (Mini-BEAM) or transplant preparative regimen (BEAM) in patients with relapsed/refractory HL [Chopra 1993], [Colwill 1995], [Martin 2001].

Non-Hodgkin lymphoma

Data from multiple trials support the use of cytarabine as a component of combination chemotherapy in the treatment of non-Hodgkin lymphoma (NHL). The CALGB 9251 regimen utilizes cytarabine as a component of an multi-agent chemotherapy regimen in the treatment of aggressive Burkitt or Burkittlike NHL [Lee 2001], [Rizzieri 2004]. Cytarabine in combination with ifosfamide, mesna, and etoposide (IVAC, alternating with CODOX-M) also is effective in the management of highly aggressive NHL [Magrath 1996], [Mead 2008]. Data from 2 phase II trials support the use of cytarabine in combination with cisplatin and dexamethasone [DHAP regimen [Velasquez 1988]] or in combination with etoposide, methylprednisolone, and cisplatin [ESHAP regimen [Velasquez 1994]] in the treatment of relapsed or refractory NHL. Cytarabine may be used in combination with carmustine, etoposide, and melphalan (BEAM) as a transplant preparative regimen in the management of relapsed/refractory NHL [Linch 2010], [van Imhoff 2005].

Primary central nervous system lymphoma

Data from a multicenter open-label randomized phase II study support the use of cytarabine (in combination with methotrexate) in the treatment of primary central nervous system lymphoma [Ferreri 2009].

Contraindications

Hypersensitivity to cytarabine or any component of the formulation

Dosing: Adult

Note: Doses >1000 mg/m2 are associated with a moderate emetic potential in adults (Hesketh 2017; Roila 2016); antiemetics are recommended to prevent nausea and vomiting.

Acute myeloid leukemia (AML) remission induction: IV: Standard-dose (manufacturer's labeling; in combination with other chemotherapy agents): 100 mg/m2/day continuous infusion for 7 days or 200 mg/m2/day continuous infusion (as 100 mg/m2 over 12 hours every 12 hours) for 7 days

Indication-specific dosing:

AML induction: IV:

7 + 3 regimens (a second induction course may be administered if needed; refer to specific references): 100 mg/m2/day continuous infusion for 7 days (in combination with daunorubicin or idarubicin ormitoxantrone) (Arlin, 1990; Dillman, 1991; Fernandez, 2009; Vogler, 1992; Wiernik, 1992) or (Adults <60 years) 200 mg/m2/day continuous infusion for 7 days (in combination with daunorubicin) (Dillman, 1991)

Low intensity therapy (off-label dosing): Adults ≥65 years: SubQ: 20 mg/m2/day for 14 days out of every 28-day cycle for at least 4 cycles (Fenaux, 2010) or 10 mg/m2 every 12 hours for 21 days; if complete response not achieved, may repeat a second course after 15 days (Tilly, 1990)

AML consolidation (off-label use): IV:

5 + 2 regimens: 100 mg/m2/day continuous infusion for 5 days (in combination with daunorubicin oridarubicin or mitoxantrone) (Arlin, 1990; Wiernik, 1992)

5 + 2 + 5 regimen: 100 mg/m2/day continuous infusion for 5 days (in combination with daunorubicin and etoposide) (Bishop, 1996)

Single-agent: Adults ≤60 years: 3000 mg/m2 over 3 hours every 12 hours on days 1, 3, and 5 (total of 6 doses); repeat every 28 to 35 days for 4 courses (Mayer, 1994)

AML salvage treatment (off-label use): IV:

CLAG regimen: 2000 mg/m2/day over 4 hours for 5 days (in combination with cladribine and G-CSF); may repeat once if needed (Wrzesień-Kuś, 2003)

CLAG-M regimen: 2000 mg/m2/day over 4 hours for 5 days (in combination with cladribine, G-CSF, and mitoxantrone); may repeat once if needed (Wierzbowska, 2008)

FLAG regimen: 2000 mg/m2/day over 4 hours for 5 days (in combination with fludarabine and G-CSF); may repeat once if needed (Montillo, 1998)

GCLAC regimen: Adults 18 to 70 years (Becker, 2011):

Induction: 2,000 mg/m2 over 2 hours once daily for 5 days (in combination with clofarabine and filgrastim; administer 4 hours after initiation of clofarabine); may repeat induction once if needed.

Consolidation: 1,000 mg/m2 over 2 hours once daily for 5 days (in combination with clofarabine and filgrastim; administer 4 hours after initiation of clofarabine) for 1 or 2 cycles

HiDAC (high-dose cytarabine) ± an anthracycline: 3000 mg/m2 over 1 hour every 12 hours for 6 days (total of 12 doses) (Herzig, 1985)

MEC regimen: 1000 mg/m2/day over 6 hours for 6 days (in combination with mitoxantrone and etoposide) (Amadori, 1991) or

Adults <60 years: 500 mg/m2/day continuous infusion days 1, 2, and 3 and days 8, 9, and 10 (in combination with mitoxantrone and etoposide); may administer a second course if needed (Archimbaud, 1991; Archimbaud, 1995)

Acute promyelocytic leukemia (APL) induction (off-label dosing): IV: 200 mg/m2/day continuous infusion for 7 days beginning on day 3 of treatment (in combination with tretinoin and daunorubicin) (Ades, 2006; Ades, 2008; Powell, 2010)

APL consolidation (off-label use): IV:

In combination with idarubicin and tretinoin: High-risk patients (WBC ≥10,000/mm3) (Sanz, 2010): Adults ≤60 years:

First consolidation course: 1000 mg/m2/day for 4 days

Third consolidation course: 150 mg/m2 every 8 hours for 4 days

In combination with idarubicin, tretinoin, and thioguanine: High-risk patients (WBC >10,000/mm3) (Lo Coco, 2010): Adults ≤61 years:

First consolidation course: 1000 mg/m2/day for 4 days

Third consolidation course: 150 mg/m2 every 8 hours for 5 days

In combination with daunorubicin (Ades, 2006; Ades, 2008):

First consolidation course: 200 mg/m2/day for 7 days

Second consolidation course:

Age ≤60 years and low risk (WBC <10,000/mm3): 1000 mg/m2 every 12 hours for 4 days (8 doses)

Age <50 years and high risk (WBC ≥10,000/mm3): 2000 mg/m2 every 12 hours for 5 days (10 doses)

Age 50 to 60 years and high risk (WBC ≥10,000/mm3): 1500 mg/m2 every 12 hours for 5 days (10 doses) (Ades, 2008)

Age >60 years and high risk (WBC ≥10,000/mm3): 1000 mg/m2 every 12 hours for 4 days (8 doses)

Acute lymphocytic leukemia (ALL; off-label dosing):

Induction regimen, relapsed or refractory: IV: 3000 mg/m2 over 3 hours daily for 5 days (in combination with idarubicin [day 3]) (Weiss, 2002)

Dose-intensive regimen: IV: 3000 mg/m2 over 2 hours every 12 hours days 2 and 3 (4 doses/cycle) of even numbered cycles (in combination with methotrexate; alternates with Hyper-CVAD) (Kantarjian, 2000)

CALGB 8811 regimen (Larson, 1995): SubQ

Early intensification phase: 75 mg/m2/dose days 1 to 4 and 8 to 11 (4-week cycle; repeat once)

Late intensification phase: 75 mg/m2/dose days 29 to 32 and 36 to 39

Linker protocol: Adults <50 years: IV: 300 mg/m2/day days 1, 4, 8, and 11 of even numbered consolidation cycles (in combination with teniposide) (Linker, 1991)

Chronic lymphocytic leukemia (CLL; off-label use): OFAR regimen: IV: 1000 mg/m2/dose over 2 hours days 2 and 3 every 4 weeks for up to 6 cycles (in combination with oxaliplatin, fludarabine, and rituximab) (Tsimberidou, 2008)

Primary central nervous system (CNS) lymphoma (off-label use): IV: 2000 mg/m2 over 1 hour every 12 hours days 2 and 3 (total of 4 doses) every 3 weeks (in combination with methotrexate and followed by whole brain irradiation) for a total of 4 courses (Ferreri, 2009)

Hodgkin lymphoma, relapsed or refractory (off-label use): IV:

DHAP regimen: 2000 mg/m2 over 3 hours every 12 hours day 2 (total of 2 doses/cycle) for 2 cycles (in combination with dexamethasone and cisplatin) (Josting, 2002)

ESHAP regimen: 2000 mg/m2 day 5 (in combination with etoposide, methylprednisolone, and cisplatin) every 3 to 4 weeks for 3 or 6 cycles (Aparicio, 1999)

Mini-BEAM regimen: 100 mg/m2 every 12 hours days 2 to 5 (total of 8 doses) every 4 to 6 weeks (in combination with carmustine, etoposide, and melphalan) (Colwill, 1995; Martin, 2001)

BEAM regimen (transplant preparative regimen): 200 mg/m2 twice daily for 4 days beginning 5 days prior to transplant (in combination with carmustine, etoposide, and melphalan) (Chopra, 1993)

Non-Hodgkin lymphomas (off-label use): IV:

CALGB 9251 regimen: Cycles 2, 4, and 6: 150 mg/m2/day continuous infusion days 4 and 5 (Lee, 2001; Rizzieri, 2004)

CODOX-M/IVAC regimen:

Adults ≤60 years: Cycles 2 and 4 (IVAC): 2000 mg/m2 every 12 hours days 1 and 2 (total of 4 doses/cycle) (IVAC is combination with ifosfamide, mesna, and etoposide; IVAC alternates with CODOX-M) (Magrath, 1996)

Adults ≤65 years: Cycles 2 and 4 (IVAC): 2000 mg/m2 over 3 hours every 12 hours days 1 and 2 (total of 4 doses/cycle) (IVAC is combination with ifosfamide, mesna, and etoposide; IVAC alternates with CODOX-M) (Mead, 2008)

Adults >65 years: Cycles 2 and 4 (IVAC): 1000 mg/m2 over 3 hours every 12 hours days 1 and 2 (total of 4 doses/cycle) (IVAC is combination with ifosfamide, mesna, and etoposide; IVAC alternates with CODOX-M) (Mead, 2008)

DHAP regimen:

Adults ≤70 years: 2000 mg/m2 over 3 hours every 12 hours day 2 (total of 2 doses/cycle) every 3 to 4 weeks for 6 to 10 cycles (in combination with dexamethasone and cisplatin) (Velasquez, 1988)

Adults >70 years: 1000 mg/m2 over 3 hours every 12 hours day 2 (total of 2 doses/cycle) every 3 to 4 weeks for 6 to 10 cycles (in combination with dexamethasone and cisplatin) (Velasquez, 1988)

ESHAP regimen: 2000 mg/m2 over 2 hours day 5 every 3 to 4 weeks for 6 to 8 cycles (in combination with etoposide, methylprednisolone, and cisplatin) (Velasquez, 1994)

BEAM regimen (transplant preparative regimen): 200 mg/m2 twice daily for 3 days beginning 4 days prior to transplant (in combination with carmustine, etoposide, and melphalan) (Linch, 2010) or 100 mg/m2 over 1 hour every 12 hours for 4 days beginning 5 days prior to transplant (in combination with carmustine, etoposide, and melphalan) (van Imhoff, 2005)

Meningeal leukemia: Intrathecal: Note: Optimal intrathecal chemotherapy dosing should be based on age rather than on body surface area (BSA); CSF volume correlates with age and not to BSA (Bleyer, 1983; Kerr, 2001). Dosing provided in the manufacturer's labeling is BSA-based (usual dose 30 mg/m2every 4 days; range: 5 to 75 mg/m2 once daily for 4 days or once every 4 days until CNS findings normalize, followed by 1 additional treatment).

Off-label uses or doses for intrathecal therapy: Intrathecal:

CNS prophylaxis (ALL): 100 mg weekly for 8 doses, then every 2 weeks for 8 doses, then monthly for 6 doses (high-risk patients) or 100 mg on day 7 or 8 with each chemotherapy cycle for 4 doses (low risk patients) or 16 doses (high-risk patients) (Cortes, 1995)

or as part of intrathecal triple therapy (TIT): 40 mg days 0 and 14 during induction, days 1, 4, 8, and 11 during CNS therapy phase, every 18 weeks during intensification and maintenance phases (Storring, 2009)

CNS prophylaxis (APL, as part of TIT): 50 mg per dose; administer 1 dose prior to consolidation and 2 doses during each of 2 consolidation phases (total of 5 doses) (Ades, 2006; Ades, 2008)

CNS leukemia treatment (ALL, as part of TIT): 40 mg twice weekly until CSF cleared (Storring, 2009)

CNS lymphoma treatment: 50 mg twice a week for 4 weeks, then weekly for 4-8 weeks, then every other week for 4 weeks, then every 4 weeks for 4 doses (Glantz, 1999)

Leptomeningeal metastases treatment: 25 to 100 mg twice weekly for 4 weeks, then once weekly for 4 weeks, then a maintenance regimen of once a month (Chamberlain, 2010) or 40 to 60 mg per dose (DeAngelis, 2005)

 

 

Dosing: Geriatric

Refer to adult dosing.

Dosing: Pediatric

Note: Dosing and frequency may vary by protocol and/or treatment phase; refer to specific protocol. In pediatric patients, IV dosing may be based on either BSA (mg/m2) or weight (mg/kg); use extra precaution to verify dosing parameters during calculations. Intrathecal dosing is based on the age of the patient. Cytarabine is associated with a low to high emetic potential (depending on dose or regimen); antiemetics are recommended to prevent nausea and vomiting (Dupuis 2013; Paw Cho Sing 2019).

Acute lymphocytic leukemia, B-cell (B-ALL):

High risk B-ALL: Limited data available, multiple regimens reported:

Larsen 2016: Consolidation and delayed intensification I and II: Children and Adolescents: IV, SubQ: 75 mg/m2 over 1 to 30 minutes or subcutaneous once daily for 4 days every 7 days for 2 courses; specific days depends on protocol phase.

Steinherz 1993: NYII Protocol: Consolidation: Children and Adolescents: IV: 3,000 mg/m2 over 3 hours for 4 doses on Days 28, 29, 35, and 36; experts at some centers have suggested fewer doses (eg, 2 doses).

Isolated CNS; relapse: Limited data available; multiple regimens reported: Infants, Children, and Adolescents: IV: 300 mg/m2/dose; frequency dependent upon protocol.

Ribeiro 1995, Rivera 1996: Children and Adolescents ≤14 years: Induction: Administer on Days 8, 22, 36; for Maintenance administer every 5 weeks for 52 weeks in combination with teniposide.

Winick 1993: Continuation therapy: Infants, Children, and Adolescents: Administer on day 1 and 4 of week 7, 14, 21, 28, 35, 42, 49, and 56 in conjunction with teniposide.

Acute myeloid leukemia (AML):

Remission induction:

Manufacturer's labeling: Infants, Children, and Adolescents: IV: Standard dose: 100 mg/m2/day continuous infusion for 7 days or 200 mg/m2/day continuous infusion (as 100 mg/m2/dose over 12 hours every 12 hours) for 7 days.

Alternate dosing: Limited data available:

ADE regimen (Gamis 2014): Note: Some aspects of protocol dosing based on previous reports (Cooper 2012; Gibson 2011; Guest 2014; Woods 1990).

Induction 1 ADE (10 + 3 + 5) and Induction 2 ADE (8 + 3 + 5):

Infants and Children with BSA <0.6 m2: IV: 3.3 mg/kg over 1 to 30 minutes every 12 hours for 10 days (induction 1) or 8 days (induction 2) in combination with daunorubicin and etoposide.

Children and Adolescents with BSA ≥0.6 m2: IV: 100 mg/m2 over 1 to 30 minutes every 12 hours for 10 days (induction 1) or 8 days (induction 2) in combination with daunorubicin and etoposide.

7 + 3 regimen (Woods 1990):

Infants and Children <3 years: IV: 3.3 mg/kg/day continuous infusion for 7 days; minimum of 2 courses (in combination with daunorubicin).

Children ≥3 years and Adolescents: IV: 100 mg/m2/day continuous infusion for 7 days; minimum of 2 courses (in combination with daunorubicin).

Intensification: Limited data available (Gamis 2014): Note: Some aspects of protocol dosing based on previous reports (Cooper 2012; Gibson 2011; Guest 2014; Woods 1990).

Intensification 1: AE therapy.

Infants and Children with BSA <0.6 m2: IV: 33 mg/kg over 1 hour every 12 hours for 5 days (in combination with etoposide).

Children and Adolescents with BSA ≥0.6 m2: IV: 1,000 mg/m2 over 1 hour every 12 hours for 5 days (in combination with etoposide).

Intensification 2 (for patients not undergoing stem cell transplant): MA therapy:

Infants and Children with BSA <0.6 m2: IV: 33 mg/kg over 1 hour every 12 hours for 4 days (in combination with mitoxantrone).

Children and Adolescents with ≥0.6 m2: IV: 1,000 mg/m2 over 1 hour every 12 hours for 4 days (in combination with mitoxantrone).

Intensification 3 (for patients not undergoing stem cell transplant):

Infants and Children with BSA <0.6 m2: IV: 99 mg/kg every 12 hours on days 1, 2, 8 and 9 in combination with E. coli L-asparaginase; Note: Some centers have substituted Erwinia asparaginase due to E. coli L-Asparaginase no longer being available.

Children and Adolescents with BSA ≥0.6 m2: IV: 3,000 mg/m2 every 12 hours on Days 1, 2, 8, and 9 in combination with E. coli L-asparaginase; Note: Some centers have substituted Erwinia asparaginase due to E. coli L-Asparaginase no longer being available.

Consolidation or refractory disease: Capizzi II regimen (high-dose cytarabine [fixed]): Children ≥6 years and Adolescents: IV: 3,000 mg/m2 over 3 hours every 12 hours for 4 doses, followed by E. coli L-Asparaginase (some centers have substituted Erwinia asparaginase due to E. coli L-Asparaginase no longer being available) 6 hours after the last dose of cytarabine (Capizzi 1984).

Salvage treatment for refractory/recurrent disease: Limited data available:

Clofarabine/cytarabine regimen: Children and Adolescents: IV: 1,000 mg/m2 over 2 hours once daily for 5 days (in combination with clofarabine; administer cytarabine 4 hours after initiation of clofarabine) for up to 2 induction cycles (Cooper 2014).

FLAG regimen: Children ≥11 years and Adolescents: IV: 2,000 mg/m2 over 4 hours once daily for 5 days (in combination with fludarabine and G-CSF); may repeat once if needed (Montillo 1998).

MEC regimen:

Children ≥5 years and Adolescents: IV: 1,000 mg/m2 over 6 hours for 6 days (in combination with etoposide and mitoxantrone) (Amadori 1991).

Adolescents ≥15 years: IV: 500 mg/m2/day continuous infusion days 1, 2, and 3 and days 8, 9, and 10 (in combination with mitoxantrone and etoposide); may administer a second course if needed (Archimbaud 1991; Archimbaud 1995).

Non-Hodgkin lymphomas: Limited data available:

Intermediate-risk B-cell NHL (Group B): Consolidation: R-CYM 1 and 2 regimen (Goldman 2013; Patte 2007): Children and Adolescents: IV: 100 mg/m2/day as a continuous infusion over 24 hours on Days 2 through 6 (5 days; total dose: 500 mg/m2 as a 120-hour infusion) (in combination with rituximab and methotrexate).

High-risk B-cell NHL (Group C): Consolidation: R-CYVE 1 and 2 regimen (Cairo 2007; Patte 2001): Infants ≥6 months, Children, and Adolescents: IV: 50 mg/m2 infused over 12 hours (2000 to 0800) for 5 doses (Days 1 to 5); follow each 12-hour infusion dose with 3,000 mg/m2 infused over 3 hours which starts at the end of the 12-hour infusion (0800 - 1100) x 5 doses (days 2 to 6) in combination with etoposide.

B-lineage lymphoblastic lymphoma (B-LLy) (Termuhlen 2013):

Consolidation phase: Children and Adolescents: IV, SubQ: 75 mg/m2 once daily for 4 days every 7 days for 4 courses (Days 0 to 3, 7 to 10, 14 to 17, 21 to 24).

Delayed intensification: Children and Adolescents: IV, SubQ: 75 mg/m2 once daily for 4 days every 7 days for 2 courses (Days 35 to 38 and 42 to 45).

Meningeal leukemia: Infants, Children, and Adolescents: Note: Optimal intrathecal chemotherapy dosing should be based on age (see following information) rather than on body surface area (BSA); CSF volume correlates with age and not to BSA (Bleyer 1983; Kerr 2001).

Manufacturer's labeling (based on BSA): Intrathecal: 30 mg/m2 every 4 days; range: 5 to 75 mg/m2once daily for 4 days or once every 4 days until CNS findings normalize, followed by one additional treatment.

Alternate dosing: Age-based intrathecal dosing: Intrathecal:

CNS prophylaxis (AML) (Woods 1990):

<1 years: 20 mg per dose.

1 to <2 years: 30 mg per dose.

2 to <3 years: 50 mg per dose.

≥3 years: 70 mg per dose.

CNS prophylaxis (ALL): Dosing regimens variable, age-specific regimens reported from literature:

Gaynon 1993: Administer on day 0 of induction therapy: Children and Adolescents:

<2 years: 30 mg per dose.

2 to <3 years: 50 mg per dose.

≥3 years: 70 mg per dose.

Pieters 2007: Administer on day 15 of induction therapy, days 1 and 15 of reinduction phase; and day 1 of cycle 2 of maintenance 1A phase: Infants and young Children (≤12 months at enrollment):

<1 year: 15 mg per dose.

≥1 years: 20 mg per dose.

Lin 2008: Administer as part of triple intrathecal therapy (TIT) on days 1 and 15 of induction therapy; days 1, 15, 50, and 64 (standard risk patients) or days 1, 15, 29, and 43 (high-risk patients) during consolidation therapy; day 1 of reinduction therapy, and during maintenance therapy (very high-risk patients receive on days 1, 22, 45, and 59 of induction, days 8, 22, 36, and 50 of consolidation therapy, days 8 and 38 of reinduction therapy, and during maintenance): Infants, Children, and Adolescents:

<1 year: 18 mg per dose.

1 to <2 years: 24 mg per dose.

2 to <3 years: 30 mg per dose.

>3 years: 36 mg per dose.

Treatment, CNS leukemia (ALL), Very high-risk: Administer as part of triple intrathecal therapy (TIT) weekly until CSF remission, then every 4 weeks throughout continuation treatment (Lin 2008): Infants, Children, and Adolescents:

<1 year: 18 mg per dose.

1 to <2 years: 24 mg per dose.

2 to <3 years: 30 mg per dose.

≥3 years: 36 mg per dose.

Dosing: Obesity

American Society of Clinical Oncology (ASCO) Guidelines for appropriate chemotherapy dosing in obese adults with cancer (excludes leukemias):Utilize patient’s actual body weight (full weight) for calculation of body surface area- or weight-based dosing, particularly when the intent of therapy is curative; manage regimen-related toxicities in the same manner as for nonobese patients; if a dose reduction is utilized due to toxicity, consider resumption of full weight-based dosing with subsequent cycles, especially if cause of toxicity (eg, hepatic or renal impairment) is resolved (Griggs 2012).

American Society for Blood and Marrow Transplantation (ASBMT) practice guideline committee position statement on chemotherapy dosing in obesity: Utilize actual body weight (full weight) for calculation of body surface area in cytarabine dosing for hematopoietic stem cell transplant conditioning regimens (Bubalo 2014).

Reconstitution

Note: Solutions containing bacteriostatic agents may be used for SubQ and standard-dose (100 to 200 mg/m2) IV cytarabine preparations, but should not be used for the preparation of either intrathecal doses or high-dose IV therapies. Do not use the bulk package to prepare intrathecal doses.

IV:

Powder for reconstitution: Reconstitute with bacteriostatic water for injection (for standard-dose).

For IV infusion: Further dilute in 250 to 1,000 mL 0.9% NaCl or D5W.

Intrathecal: Powder for reconstitution: Reconstitute with preservative free sodium chloride 0.9%; may further dilute to preferred final volume (volume generally based on institution or practitioner preference; may be up to 12 mL) with Elliott's B solution, sodium chloride 0.9% or lactated Ringer’s. Intrathecal medications should not be prepared during the preparation of any other agents.

Triple intrathecal therapy (TIT): Cytarabine 30 to 50 mg with hydrocortisone sodium succinate 15 to 25 mg and methotrexate 12 mg are reported to be compatible together in a syringe (Cheung 1984) and cytarabine 18 to 36 mg with hydrocortisone 12 to 24 mg and methotrexate 6 to 12 mg, prepared to a final volume of 6 to 12 mL, is reported compatible as well (Lin 2008).

Intrathecal preparations should be administered as soon as possible after preparation because intrathecal preparations are preservative free.

Administration

IV: Infuse standard dose therapy for AML (100 to 200 mg/m2/day) as a continuous infusion. Infuse high-dose therapy (off-label) over 1 to 3 hours (usually). Other rates have been used, refer to specific reference.

In adults, doses >1,000 mg/m2 are associated with a moderate emetic potential (Hesketh 2017; Roila 2016).

Intrathecal: Intrathecal doses should be administered as soon as possible after preparation.

May also be administered SubQ.

Storage

Store intact vials of powder for reconstitution at 20°C to 25°C (68°F to 77°F); store intact vials of solution at 15°C to 30°C (59°F to 86°F). Protect from light. Pharmacy bulk vials should be used within 4 hours of initial entry.

IV:

Powder for reconstitution: Reconstituted solutions should be stored at room temperature and used within 48 hours.

For IV infusion: Solutions for IV infusion diluted in D5W or NS retained 94% to 100% of potency after 8 days when stored at room temperature, although the manufacturer recommends administration as soon as possible after preparation.

Intrathecal: Administer as soon as possible after preparation. After preparation, store intrathecal medications in an isolated location or container clearly marked with a label identifying as "intrathecal" use only.

Drug Interactions

Baricitinib: Immunosuppressants may enhance the immunosuppressive effect of Baricitinib. Management: Use of baricitinib in combination with potent immunosuppressants such as azathioprine or cyclosporine is not recommended. Concurrent use with antirheumatic doses of methotrexate or nonbiologic disease modifying antirheumatic drugs (DMARDs) is permitted. Consider therapy modification

BCG (Intravesical): Immunosuppressants may diminish the therapeutic effect of BCG (Intravesical).Avoid combination

BCG (Intravesical): Myelosuppressive Agents may diminish the therapeutic effect of BCG (Intravesical).Avoid combination

Chloramphenicol (Ophthalmic): May enhance the adverse/toxic effect of Myelosuppressive Agents.Monitor therapy

Cladribine: May enhance the immunosuppressive effect of Immunosuppressants. Avoid combination

Cladribine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Avoid combination

Cladribine: Agents that Undergo Intracellular Phosphorylation may diminish the therapeutic effect of Cladribine. Avoid combination

CloZAPine: Myelosuppressive Agents may enhance the adverse/toxic effect of CloZAPine. Specifically, the risk for neutropenia may be increased. Monitor therapy

Coccidioides immitis Skin Test: Immunosuppressants may diminish the diagnostic effect of Coccidioides immitis Skin Test. Monitor therapy

Deferiprone: Myelosuppressive Agents may enhance the neutropenic effect of Deferiprone. Avoid combination

Denosumab: May enhance the adverse/toxic effect of Immunosuppressants. Specifically, the risk for serious infections may be increased. Monitor therapy

Dipyrone: May enhance the adverse/toxic effect of Myelosuppressive Agents. Specifically, the risk for agranulocytosis and pancytopenia may be increased Avoid combination

Echinacea: May diminish the therapeutic effect of Immunosuppressants. Consider therapy modification

Fingolimod: Immunosuppressants may enhance the immunosuppressive effect of Fingolimod. Management: Avoid the concomitant use of fingolimod and other immunosuppressants when possible. If combined, monitor patients closely for additive immunosuppressant effects (eg, infections).Consider therapy modification

Flucytosine: Cytarabine (Conventional) may diminish the therapeutic effect of Flucytosine. Consider therapy modification

Leflunomide: Immunosuppressants may enhance the adverse/toxic effect of Leflunomide. Specifically, the risk for hematologic toxicity such as pancytopenia, agranulocytosis, and/or thrombocytopenia may be increased. Management: Consider not using a leflunomide loading dose in patients receiving other immunosuppressants. Patients receiving both leflunomide and another immunosuppressant should be monitored for bone marrow suppression at least monthly. Consider therapy modification

Lenograstim: Antineoplastic Agents may diminish the therapeutic effect of Lenograstim. Management: Avoid the use of lenograstim 24 hours before until 24 hours after the completion of myelosuppressive cytotoxic chemotherapy. Consider therapy modification

Lipegfilgrastim: Antineoplastic Agents may diminish the therapeutic effect of Lipegfilgrastim. Management: Avoid concomitant use of lipegfilgrastim and myelosuppressive cytotoxic chemotherapy. Lipegfilgrastim should be administered at least 24 hours after the completion of myelosuppressive cytotoxic chemotherapy. Consider therapy modification

Natalizumab: Immunosuppressants may enhance the adverse/toxic effect of Natalizumab. Specifically, the risk of concurrent infection may be increased. Avoid combination

Nivolumab: Immunosuppressants may diminish the therapeutic effect of Nivolumab. Consider therapy modification

Ocrelizumab: May enhance the immunosuppressive effect of Immunosuppressants. Monitor therapy

Palifermin: May enhance the adverse/toxic effect of Antineoplastic Agents. Specifically, the duration and severity of oral mucositis may be increased. Management: Do not administer palifermin within 24 hours before, during infusion of, or within 24 hours after administration of myelotoxic chemotherapy.Consider therapy modification

Pidotimod: Immunosuppressants may diminish the therapeutic effect of Pidotimod. Monitor therapy

Pimecrolimus: May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination

Promazine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Monitor therapy

Roflumilast: May enhance the immunosuppressive effect of Immunosuppressants. Consider therapy modification

Siponimod: Immunosuppressants may enhance the immunosuppressive effect of Siponimod. Monitor therapy

Sipuleucel-T: Immunosuppressants may diminish the therapeutic effect of Sipuleucel-T. Management: Evaluate patients to see if it is medically appropriate to reduce or discontinue therapy with immunosuppressants prior to initiating sipuleucel-T therapy. Consider therapy modification

Tacrolimus (Topical): May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination

Tertomotide: Immunosuppressants may diminish the therapeutic effect of Tertomotide. Monitor therapy

Tofacitinib: Immunosuppressants may enhance the immunosuppressive effect of Tofacitinib. Management: Concurrent use with antirheumatic doses of methotrexate or nonbiologic disease modifying antirheumatic drugs (DMARDs) is permitted, and this warning seems particularly focused on more potent immunosuppressants. Consider therapy modification

Trastuzumab: May enhance the neutropenic effect of Immunosuppressants. Monitor therapy

Vaccines (Inactivated): Immunosuppressants may diminish the therapeutic effect of Vaccines (Inactivated). Management: Vaccine efficacy may be reduced. Complete all age-appropriate vaccinations at least 2 weeks prior to starting an immunosuppressant. If vaccinated during immunosuppressant therapy, revaccinate at least 3 months after immunosuppressant discontinuation.Consider therapy modification

Vaccines (Live): Immunosuppressants may enhance the adverse/toxic effect of Vaccines (Live). Immunosuppressants may diminish the therapeutic effect of Vaccines (Live). Management: Avoid use of live organism vaccines with immunosuppressants; live-attenuated vaccines should not be given for at least 3 months after immunosuppressants. Avoid combination

 

 

Adverse Reactions

Frequency not always defined. CNS, gastrointestinal, ophthalmic, and pulmonary toxicities are more common with high-dose regimens.

Cardiovascular: Angina pectoris, chest pain, local thrombophlebitis, pericarditis

Central nervous system: Aseptic meningitis, cerebral dysfunction, dizziness, headache, neuritis, neurotoxicity, paralysis (intrathecal and IV combination therapy), reversible posterior leukoencephalopathy syndrome

Dermatologic: Acute generalized exanthematous pustulosis, alopecia, dermal ulcer, ephelis, pruritus, skin rash, urticaria

Endocrine & metabolic: Hyperuricemia

Gastrointestinal: Abdominal pain, anal fissure, anorexia, diarrhea, esophageal ulcer, esophagitis, increased serum amylase, increased serum lipase, intestinal necrosis, mucositis, nausea, pancreatitis, sore throat, toxic megacolon, vomiting

Genitourinary: Urinary retention

Hematologic & oncologic: Anemia, bone marrow depression, hemorrhage, leukopenia, megaloblastic anemia, neutropenia (onset: 1 to 7 days; nadir [biphasic]: 7 to 9 days and at 15 to 24 days; recovery [biphasic]: 9 to 12 days and at 24 to 34 days), reticulocytopenia, thrombocytopenia (onset: 5 days; nadir: 12 to 15 days; recovery 15 to 25 days)

Hepatic: Hepatic insufficiency, hepatic sinusoidal obstruction syndrome (formerly known as hepatic veno-occlusive disease), increased serum transaminases (acute), jaundice

Hypersensitivity: Allergic edema, anaphylaxis

Infection: Sepsis

Local: Cellulitis at injection site, inflammation at injection site (SC injection), local inflammation (anus), pain at injection site (SC injection)

Neuromuscular & skeletal: Rhabdomyolysis

Ophthalmic: Conjunctivitis

Renal: Renal insufficiency

Respiratory: Acute respiratory distress, dyspnea, interstitial pneumonitis

Miscellaneous: Drug toxicity (cytarabine syndrome; chest pain, conjunctivitis, fever, maculopapular rash, malaise, myalgia, ostealgia), fever

Adverse events associated with high-dose cytarabine

Cardiovascular: Cardiomegaly, cardiomyopathy (in combination with cyclophosphamide)

Central nervous system: Neurotoxicity (patients with renal impairment: ≤55%), coma, drowsiness, neurocerebellar toxicity, peripheral neuropathy (motor and sensory), personality changes

Dermatologic: Alopecia (complete), desquamation, skin rash (severe)

Gastrointestinal: Gastrointestinal ulcer, necrotizing enterocolitis, pancreatitis, peritonitis, pneumatosis cystoides intestinalis

Hepatic: Hepatic abscess, hepatic injury, hyperbilirubinemia

Infection: Sepsis

Ophthalmic: Corneal toxicity, hemorrhagic conjunctivitis

Respiratory: Acute respiratory distress, pulmonary edema

Adverse events associated with intrathecal cytarabine administration

Central nervous system: Aphonia, leukoencephalopathy (necrotizing; with concurrent cranial irradiation, intrathecal methotrexate, and intrathecal hydrocortisone), nerve palsy (accessory nerve), neurotoxicity, paraplegia

Gastrointestinal: Dysphagia, nausea, vomiting

Ophthalmic: Blindness (with concurrent systemic chemotherapy and cranial irradiation), diplopia

Respiratory: Cough, hoarseness

Miscellaneous: Fever

ALERT: U.S. Boxed Warning

Experienced physician:

Only physicians experienced in cancer chemotherapy should use cytarabine.

Drug toxicities:

For induction therapy, patients should be treated in a facility with laboratory and supportive resources sufficient to monitor drug tolerance and protect and maintain a patient compromised by drug toxicity. The main toxic effect of cytarabine is bone marrow suppression with leukopenia, thrombocytopenia, and anemia. Less serious toxicity includes nausea, vomiting, diarrhea and abdominal pain, oral ulceration, and hepatic dysfunction.

The physician must judge possible benefit to the patient against known toxic effects of this drug in considering the advisability of therapy with cytarabine. Before making this judgment or beginning treatment, the physician should be familiar with the following text.

Warnings/Precautions

Concerns related to adverse effects:

• Bone marrow suppression: [US Boxed Warning]: Myelosuppression (leukopenia, thrombocytopenia and anemia) is the major toxicity of cytarabine. Use with caution in patients with prior drug-induced bone marrow suppression. Monitor blood counts frequently; once blasts are no longer apparent in the peripheral blood, bone marrow should be monitored frequently. Monitor for signs of infection or neutropenic fever due to neutropenia or bleeding due to thrombocytopenia.

• Cytarabine syndrome: Cytarabine (ARA-C) syndrome is characterized by fever, myalgia, bone pain, chest pain (occasionally), maculopapular rash, conjunctivitis, and malaise; generally occurs 6 to 12 hours following administration. May be managed with corticosteroids.

• Gastrointestinal toxicities: [US Boxed Warning]: Toxicities (less serious) include nausea, vomiting, diarrhea, abdominal pain, oral ulcerations and hepatic dysfunction. In adults, doses >1000 mg/m2 are associated with a moderate emetic potential (Hesketh 2017; Roila 2016). In pediatrics, doses >200 mg/m2 are associated with a moderate emetic potential and 3000 mg/m2 is associated with a high emetic potential (Dupuis 2011); antiemetics are recommended to prevent nausea and vomiting.

• Hypersensitivity: Anaphylaxis resulting in acute cardiopulmonary arrest has been reported (rare).

• Pancreatitis: There have been reports of acute pancreatitis in patients receiving continuous infusion cytarabine and in patients receiving cytarabine who were previously treated with L-asparaginase.

• Sudden respiratory distress syndrome: Sudden respiratory distress, rapidly progressing to pulmonary edema and cardiomegaly, has been reported with high-dose cytarabine. May present as severe dyspnea with a rapid onset and refractory hypoxia with diffuse pulmonary infiltrates, leading to respiratory failure; may be fatal (Morgan 2011).

• Tumor lysis syndrome: Tumor lysis syndrome and subsequent hyperuricemia may occur; consider antihyperuricemic therapy and hydrate accordingly.

Disease-related concerns:

• Hepatic impairment: Use with caution in patients with hepatic impairment; may be at higher risk for CNS toxicities and dosage adjustments may be required.

• Renal impairment: Use with caution in patients with impaired renal function (high dose cytarabine); may be at higher risk for CNS toxicities and dosage adjustments may be required.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information. There have been case reports of fatal cardiomyopathy when high-dose cytarabine was used in combination with cyclophosphamide as a preparation regimen for transplantation.

Special populations:

• Pediatric: Delayed progressive ascending paralysis has been reported in two children who received combination chemotherapy with IV and intrathecal cytarabine at conventional doses for the treatment of acute myeloid leukemia (was fatal in one patient).

Dosage form specific issues:

• Benzyl alcohol: Some products may contain benzyl alcohol; do not use products containing benzyl alcohol or products reconstituted with bacteriostatic diluent intrathecally or for high-dose cytarabine regimens. Benzyl alcohol is associated with gasping syndrome in premature infants.

Other warnings/precautions:

• Experienced physician: [US Boxed Warning]: Should be administered under the supervision of an experienced cancer chemotherapy physician. Due to the potential toxicities, induction treatment with cytarabine should be in a facility with sufficient laboratory and supportive resources.

• High-dose treatment: High-dose regimens have been associated with GI, CNS, pulmonary, ocular (reversible corneal toxicity and hemorrhagic conjunctivitis; prophylaxis with ophthalmic corticosteroids is recommended) toxicities, and cardiomyopathy. Neurotoxicity associated with high-dose treatment may present as acute cerebellar toxicity (with or without cerebral impairment), personality changes, or may be severe with seizure and/or coma; may be delayed, occurring up to 3 to 8 days after treatment has begun; possibly irreversible. Risk factors for neurotoxicity include cumulative cytarabine dose, prior CNS disease and renal impairment (incidence may be up to 55% in patients with renal impairment); high-dose therapy (>18 g/m2 per cycle) and age >50 years also increase the risk for cerebellar toxicity (Herzig 1987).

• Intrathecal safety: When used for intrathecal administration, should not be prepared during the preparation of any other agents. After preparation, store intrathecal medications in an isolated location or container clearly marked with a label identifying as "intrathecal" use only. Delivery of intrathecal medications to the patient should only be with other medications also intended for administration into the central nervous system (Jacobson 2009).

Monitoring Parameters

Liver function tests, CBC with differential and platelet count, serum creatinine, BUN, serum uric acid. Monitor for signs/symptoms of bleeding, infection, neutropenic fever, and/or tumor lysis syndrome.

Pregnancy Considerations

Based on the mechanism of action and findings from animal reproduction studies, fetal harm may occur if cytarabine is administered during pregnancy. Limb and ear defects have been noted in case reports of cytarabine exposure during the first trimester of pregnancy. The following have also been noted in the neonate: Pancytopenia, WBC depression, electrolyte abnormalities, prematurity, low birth weight, decreased hematocrit or platelets. Risk to the fetus is decreased if treatment can be avoided during the first trimester; however, females of reproductive potential should avoid becoming pregnant during treatment and be advised of the potential risks.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience lack of appetite, hair loss, muscle pain, bone pain, mouth irritation, or mouth sores. Have patient report immediately to prescriber signs of bleeding (vomiting blood or vomit that looks like coffee grounds; coughing up blood; hematuria; black, red, or tarry stools; bleeding from the gums; abnormal vaginal bleeding; bruises without a reason or that get bigger; or any severe or persistent bleeding), signs of a severe pulmonary disorder (lung or breathing problems like difficulty breathing, shortness of breath, or a cough that is new or worse), signs of infection, mood changes, confusion, neck rigidity, sensitivity to light, severe muscle weakness, numbness or tingling feeling, severe fatigue, angina, vision changes, eye pain, severe eye irritation, application site pain or irritation, shortness of breath, excessive weight gain, swelling of arms or legs, severe abdominal pain, severe nausea, vomiting, severe diarrhea, severe loss of strength and energy, signs of liver problems (dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or jaundice), signs of bowel problems (black, tarry, or bloody stools; fever; mucus in stools; vomiting; vomiting blood; severe abdominal pain; constipation; or diarrhea), signs of kidney problems (urinary retention, hematuria, change in amount of urine passed, or weight gain), signs of pancreatitis (severe abdominal pain, severe back pain, severe nausea, or vomiting), or signs of tumor lysis syndrome (tachycardia or abnormal heartbeat; any passing out; urinary retention; muscle weakness or cramps; nausea, vomiting, diarrhea or lack of appetite; or feeling sluggish) (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.