白消安注射液(白舒非)说明书如下:

【药品名称】
通用名称：白消安注射液
其他名称名称：白舒非Busulfex
英文名称：Busulfan  Injection

【成份】
白舒非主要成份及其化学名称为：1，4—丁二醇二甲磺酸酯
其结构式为：
分子式：C6H14O6S2
分子量：246.29
辅料：二甲基乙酰胺、聚乙二醇400

【性状】
白舒非为无色或几乎无色的澄明液体。

【适应症】
白舒非适用于联合环磷酰胺，作为慢性髓性白血病同种异体的造血祖细胞移植前的预处理方案。

【规格】
10毫升：60毫克

【用法用量】
白舒非应通过中心静脉导管给药，每次给药需输注2小时，每6小时一次连续4天，共16次。所有患者均应预防性给予苯妥因，因为已知白消安可通过血脑屏障并诱发癫痫。苯妥因使白消安的血浆AUC下降15％；而其它抗惊厥药物则可能使白消安血浆AUC升高，从而增加肝静脉闭塞症或癫痫发生的风险。如必须使用其他抗惊厥药，则应监测血浆白消安的暴露程度（见“药物相互作用”）。止吐药应在次开始之前给予，并按一定计划在整个用药期间持续给药。
按校准的理想体重给药时，白舒非清除率的可预测性。若依据实际体重、理想体重或其他因子计算白舒非的剂量，则可能使消瘦、正常和肥胖患者之间的清除率产生显著不同。在组成骨髓或外周血祖细胞移植预处理方案时，白舒非的成人剂量通常为0.8mg/kg，取理想体重或实际体重的低值，每6小时给药一次连续4天（共16次）。对肥胖或特别肥胖的患者，白舒非应按校准的理想体重给药。理想体重（IBW）的计算公式如下（身高cm，体重kg）：
IBW(kg，男性)=50+0.91×(身高cm-152)
IBW(kg，女性)=45XxX0.91×(身高cm-152)。
校准的理想体重（AIBW）公式为：AIBW=IBWXxX0.25×(实际体重-IBW)。
在骨髓移植前3天，白舒非第16次给药之后6小时，给予环磷酰胺，剂量为60mg/kg，每次静注1小时，每天一次共2天。

【不良反应】
二甲乙酰胺（DMA），白舒非配方中的溶剂，曾在1962年，被作为潜在的癌症化疗药物研究。在I期试验中，耐受剂量（MTD）为14.8g/m2/d，连用四天。按mg/m2计算，推荐剂量的每日白舒非中含有42％MTD的DMA。I期试验中的剂量限制性毒性为肝脏毒性（表现为转氨酶SGOT升高）以及神经系统毒性（表现为幻觉）。幻觉多在DMA给药计划完成一天后发生，并伴有脑电图改变。白舒非推荐用于预处理方案的剂量为0.8mg/kg，每6小时一次共16次，而DMA发生幻觉的剂量为上述方案中含有的DMA量的1.9倍。其他神经毒性包括嗜睡、困倦和精神错乱。但对于在白舒非使用中观察到的肝毒性和神经毒性，已很难确定DMA和/或其它合并用药在其中相对的作用程度。
用推荐剂量方案的白舒非治疗，将在100％的患者中产生深度骨髓抑制，包括粒细胞缺乏、血小板减少、贫血或血液成分联合缺乏。
不良反应的主要信息来源为白舒非的临床试验（n=61），以及从文献中找到的高剂量口服白消安预处理随机对照试验资料。
白舒非的临床试验：在白舒非的同种异体干细胞移植临床试验中，所有患者均给予白舒非，每次0.8mg/kg，静脉滴注2小时，每6小时一次，四天内共给16次，联合给予环磷酰胺60mg/kg×2天。接受这一剂量的可评价患者中，93％在第9次给药时AUC维持在1500Mmin以下，通常认为在这一水平下可使肝静脉闭塞症的发生风险小。

以下部分描述了白舒非临床试验中有临床意义的不良事件，不论是否由该药物引起。
血液系统：在推荐剂量方案下，白舒非使100％的患者发生深度骨髓抑制。研究中对大多数患者进行了重组人粒细胞集落刺激因子（G-CSF）预防性给药；造血祖细胞输注后，中性粒细胞数恢复至≥500个/mm3的中位时间为13天，每个患者的血小板输注中位次数为6，红细胞输注中位次数为4。报告有1例（2％）凝血酶原时间延长。
胃肠道：胃肠道毒性很常见，通常被认为与药物有关。仅少数被归入严重毒性。同种异体移植临床试验至移植后28天时，92％的患者发生轻或中度恶心，95％患者出现轻或中度呕吐，7％发生严重恶心。同种异体移植临床试验中，白舒非给药期间（移植前7天至移植前4天）的呕吐发生率为43％。26％患者发生3-4级口腔炎，2％患者发生3级食管炎。同种异体试验中3-4级腹泻的发生率为5％，轻中度腹泻的发生率为75％。轻中度便秘发生于38％的患者，8％患者出现肠梗阻且其中2％为重度。44％患者报告了轻中度消化不良。2％患者出现呕血。2％患者发生胰腺炎。24％患者有轻中度直肠不适。重度厌食见于21％患者而轻中度见于64％患者。
肝脏：同种异体干细胞移植试验中，高胆红素血症发生于49％的患者。移植28天内有30％患者出现3/4级高胆红素血症，其中的5％为威胁生命的。6名患者的高胆红素血症与移植物抗宿主病有关，5名则与肝静脉闭塞症有关。SGPT升高的3/4级升高见于7％患者。15％患者有轻中度碱性磷酸酶升高。12％患者发生轻中度黄疸，6％患者出现肝脏肿大。
肝静脉闭塞症：已知肝静脉闭塞症（HVOD）是移植前预处理的一种潜在并发症。参加同种异体研究的61名患者有5名（8％）发生HVOD，其中2名为致死性。
移植物抗宿主病：同种异体研究中，移植物抗宿主病（GVHD）发生于18％的患者（11/16）；3％为重度，15％为轻中度。有3例（5％）因GVHD而死亡。
水肿：79％患者出现某种形式的水肿，高血容量或体重增加；所有事件均报告为轻中度。
感染/发热：51％的患者经历过1次或多次感染。1名患者患致死性肺炎，而3％患者的肺炎是威胁生命的。80％患者出现发热，78％为轻中度，3％为重度。46％患者曾有寒战。
心血管系统：44％患者报告了轻中度心动过速。7名患者（11％）首次报告于白舒非给药期间。其他的心律失常均为轻中度，包括心律不齐（5％）、房颤（2％）、室性早搏（2％）和III度传导阻滞（2％）。轻或中度血栓形成见于33％患者，所有病例均与中央静脉导管有关。36％患者报告了高血压，其中3/4级为7％。11％患者报告了低血压，3％患者为3/4级。25％患者报告有轻度的血管扩张（潮红或热性红斑）。其它心血管事件还包括心肌肥大（5％）、轻度的心电图异常（2％）、3/4级左心衰竭（1名患者，2％），中度的心包积液（2％）。这些事件大多是在用环磷酰胺后报告的。
肺：25％患者发生轻度或中度呼吸困难，2％发生重度呼吸困难。1名患者（2％）出现重度过度通气；另2名患者（3％）则为轻中度。分别有44％和28％的患者报告了轻度鼻炎和轻中度咳嗽。25％患者报告了轻度鼻出血。同种异体研究中，3名患者（5％）被证实发生肺泡出血，这3人均需机械通气支持，终均死亡；另1名患者，经电子胸腔镜楔形活检发现非特异性肺间质纤维化，并于移植后98天死于呼吸衰竭。其它肺不良事件均为轻或中度，包括咽炎（18％）、呃逆（18％）哮喘（8％）、肺不张（2％）、胸腔积液（3％）、低氧血症（2％）、咯血（3％）和鼻窦炎（3％）。
神经系统：报告多的中枢神经系统不良事件为：失眠（84％），焦虑（75％），眩晕（30％）和抑郁（23％）；除1名患者（1％）发生重度失眠之外，上述不良反应均为轻或中度。1名患者（1％）在HVOD继发的多器官功能衰竭终末期，出现威胁生命的大脑出血和昏迷。其他重度不良事件包括：谵妄（2％），骚动不安（2％）和脑病（2％）。精神错乱的总发生率为11％，5％患者报告发生幻觉。同种异体研究中出现谵妄和幻觉的患者，其精神错乱发生在白舒非给药完成时。在白舒非同种异体临床研究中，困倦总发生率为7％，嗜睡发生率为2％。自身移植研究中，尽管给予了苯妥因预防，仍有1名患者在环磷酰胺给药时出现癫痫发作。
肾：21％患者血清肌酐轻中度升高。3％患者BUN升高，而3/4级升高的患者达2％。7％患者有排尿困难，15％有少尿，8％出现血尿。在同种异体临床试验中，有4例（7％）3/4级的出血性膀胱炎。
皮肤：报告有皮疹（57％）和瘙痒（28％），两类事件绝大部分为轻度。15％的患者轻度脱发，2％为中度脱发。10％患者报告了轻度疱疹，8％有轻中度斑丘疹。10％患者出现大疱，5％出现剥脱性皮炎。红斑结节见于2％患者，痤疮见于7％患者，8％患者发生皮肤褪色。
代谢：67％患者出现高血糖，3/4级高血糖见于15％患者。77％患者有轻中度低镁血症；轻中度低钾血症有62％，而重度低钾有2％；轻中度低钙为46％，重度低钙有3％，轻中度低磷有17％，低钠血症有2％。
其他：报告的其它不良事件包括：头痛（轻中度46％，重度5％）、腹痛（轻中度69％，重度3％）、虚弱（轻中度49％，重度2％）、非特异性疼痛（轻中度43％，重度2％）、过敏反应（轻中度24％，重度2％）、注射部位炎症（轻中度25％）、注射部位疼痛（轻中度15％）、胸痛（轻中度26％）、背痛（轻中度23％）、肌肉痛（轻中度16％）、关节痛（轻中度13％）以及听力障碍（3％）。
死亡：同种异体移植研究中，至移植后28天内发生2例死亡；另有6例死亡在移植后29天至移植后100天期间发生。
口服白消安文献综述：通过查阅文献，找出四项相关随机对照研究，评价了同种异体骨髓移植治疗慢性髓性白血病时，含高剂量口服白消安的预处理方案（见“临床研究”）。下表4总结了这些试验中报道的安全性结果，试验人群患各种血液系统恶性疾病（急性髓性白血病（AML）、慢性髓性白血病（CML）和急性淋巴细胞白血病（ALL））。

【禁忌】
对白舒非的任何一种成份有过敏史的患者。

【注意事项】
1．一般注意事项：
血液系统：使用推荐量白舒非时，深度骨髓抑制非常普遍。可表现为粒细胞缺乏、血小板减少、贫血或者这些情况的任意组合形式。应密切观察患者，是否存在局部或系统性感染以及出血症状，应经常监测患者的血液系统状态。
告知患者：应向患者解释：发生继发性肿瘤的风险可能升高。
实验室检查：接受白舒非的患者需每天监测全血细胞计数，包括细胞分类计数和血小板计数，监测需持续到确认移植成功为止。为监测肝脏毒性（该毒性可能预示肝静脉闭塞症的发生），应每天查血清转氨酶、碱性磷酸酶和胆红素，一直持续到移植后28天。
肾功能不全：未研究过白舒非在肾功能紊乱患者中的应用。
肝功能不全：尚无白舒非在肝功能不全患者中的用药经验。
其他：白消安可在许多器官中导致细胞生长异常。有报道，在淋巴结、胰腺、甲状腺、肾上腺、肝、肺和骨髓中，发现以巨大、深染的核为特征的细胞学异常。这一细胞异常可以非常严重，以致于在解释肺、膀胱、乳房和宫颈脱落细胞学检查结果时，会发生困难。
2．重要注意事项
白舒非应由具有造血干细胞移植经验的合格医师监督给药。只有充分具备诊断和治疗设施时，才可能对药物引起的并发症进行恰当处理。
以下重要注意事项涉及同种异体移植时白舒非的不同生理影响。
血液系统：在推荐剂量方案下：白舒非治疗常见的严重后果是深度骨髓抑制，见于所有患者。可发生重度粒细胞缺乏、血小板减少、贫血或者这些情况以各种组合形式出现。血象监测应从治疗期间持续至血象完全恢复，应经常做全血细胞计数，包括白细胞分类和血小板计数。白舒非临床试验中，100％的治疗患者均发生中性粒细胞计数降至0.5×109/L以下，发生的中位时间为移植后4天。当大多数患者预防性应用G-CSF后，中性粒细胞计数恢复的中位时间为移植后13天。98％的患者中，发生血小板减少（血小板<25，000/mm3或需要输血小板）的中位时间为移植后5~6天。69％的患者发生贫血(血红蛋白低于8.0g/dL)。当有医疗指征时，应进行抗生素治疗以及输血小板和红细胞支持。
神经系统：在接受高剂量口服白消安的患者中有发生癫痫的报道。当时口服剂量所达到的血浆药物水平，与推荐剂量白舒非所能达到的相似。尽管预防性使用了苯妥英，在白舒非的自体移植临床试验中，仍发生一例癫痫（1/42）。这一事件发生于预处理时环磷酰胺给药期间，在后一次白消安注射液给药后36小时。在白舒非治疗开始前，应预防性给予抗惊厥药物。对于有癫痫史或脑外伤史的患者，或者同时应用其它可能致癫痫药物的患者，在给予推荐剂量的白舒非时，应予特别注意。
肝：现有文献提示，白消安的AUC值（血浆浓度-时间曲线下面积）过高时（>1，500Mmin），可能与肝静脉闭塞症（HVOD）发生风险的升高有关。在推荐剂量方案的白舒非治疗时，如患者曾经放疗或曾用过大于等于3周期的化疗或曾接受过造血祖细胞移植，则这些患者发生HVOD的风险也将升高。在同种异体移植研究中，HVOD发生于8.2％（5/61）接受白舒非治疗的患者，其中2例为致死性的（2/5，40％）。在此临床试验中，按Jone’s标准诊断HVOD（高胆红素血症，以及下述三项中的2项：疼痛性肝脏肿大，体重增加超过5％或腹水）。文献报道的随机对照试验中，HVOD的发生率为7.7~12％。
心脏：有报道，患地中海贫血的儿童患者，以高剂量口服白消安加环磷酰胺为造血祖细胞移植预处理方案时，曾有心包填塞填塞发生（8/400或一系列患者中的2％）。这8名儿童中6名死亡，另2名因迅速进行心包穿刺而获救。大多数患者发生心包填塞前，出现腹痛和呕吐。在白舒非的临床试验中，没有患者出现心包填塞。
肺：长期应用白消安治疗的一个罕见但严重的并发症是由肺纤维化引起的支气管肺发育不良。该症状的平均发生时间为治疗后4年（4个月~10年）。
致癌，致突变及对生育能力的影响：白消安是一种致突变原和诱裂原。在体外试验中，可导致鼠伤寒沙门氏菌和果蝇的突变。白消安引起的染色体异常，在体内试验（大鼠、小鼠、仓鼠和人类）以及体外试验（啮齿类和人类细胞）均有报道。白消安的静脉给药（48mg/kg，以12mg/kg每二周一次的方案用药，或按mg/m2计算给予白舒非总量的30％），可增加试验鼠胸腺和卵巢肿瘤的发生率。一项研究中，243名支气管肺癌患者在手术切除后，给予白消安作为辅助治疗的一部分；结果在19名发生全血细胞减少的患者中，有4名发生了急性白血病。在口服白消安治疗后5~8年，可在临床观察到白血病的发生。推测白消安是一种人类的致癌原。
因慢性髓性白血病而长期小剂量服用白消安的绝经前妇女，常常发生卵巢功能抑制和闭经。白消安使雌性大鼠卵母细胞缺失，并在雄性大鼠和仓鼠中诱发不育。在人类男性患者中，也有用药后不育、无精症和睾丸萎缩的报道。
白舒非的溶剂DMA也可能影响生育。给大鼠0.45g/kg/d的DMA（按mg/m2算，相当于白舒非每日推荐剂量中所含DMA的44％），连用9天，可使大鼠的精子生成显著减少。在人工授精后四天，给仓鼠一次性皮下注射DMA2.2g/kg（按mg/m2算，相当于白舒非中所含DMA的27％），结果导致100％试验仓鼠的妊娠中止。
3．应用时的注意事项
与其他细胞毒性化合物一样，在处理和制备白舒非溶液时应格外小心。建议使用手套，因意外接触可能引起皮肤反应。如白舒非原液或稀释的溶液接触到皮肤或粘膜，请以清水彻底冲洗皮肤或粘膜。
白舒非为无色透明溶液。只要溶液及容器条件许可，非胃肠道药品在给药前，应肉眼观察是否有颗粒和变色。如在白舒非的安瓿瓶中发现颗粒物质，则此药不能使用。
静脉注射液的制备：
白舒非在使用前必须稀释，稀释液选用0.9％氯化钠注射液USP（生理盐水）或5％葡萄糖注射液USP（D5W）。溶剂量应为白舒非原液体积的10倍，以保证白消安的终浓度约为0.5mg/mL。以下举例计算1名体重70kg患者的用药剂量：
（70kg患者）×（0.8mg/kg）÷（6mg/mL）=9.3mL白舒非（总剂量56mg）
为制备输注用溶液，将9.3mL白舒非加入93mL溶剂中（生理盐水或D5W），计算如下：
(9.3mL白舒非)×(10)=93mL溶剂
93mL溶剂中加入9.3mL白舒非，则白消安终浓度为0.54mg/mL：
(9.3mL×6mg/mL÷102.3mL=0.54mg/mL)
所有步骤均要求严格无菌操作，穿戴手套和防护服时使用直立式层流安全罩。
禁止将白舒非注入不含生理盐水或D5W的静脉输液袋或大容量注射器中。切记始终是将白舒非加入溶剂，而不是将溶剂加入白舒非。颠倒若干次以彻底混合均匀。不要使用聚碳酸酯注射器以及带有聚碳酸酯滤器的针头。
应使用输液泵输注白舒非稀释溶液。设定输液流速，在2小时中将规定量的白舒非输完。在每次输药前后，用大约5ml的0.9％氯化钠注射液USP或5％葡萄糖注射液USP冲洗输液管道。不要同时输注其他相容性未知的静脉注射溶液。警告：未试验过白舒非的输注，且不推荐输注。
稳定性：
包装所示有效期前，于2℃-8℃(36-46F)冷藏的未开启的白舒非均为稳定的。
以0.9％氯化钠注射液USP或5％葡萄糖注射液USP稀释的白舒非稀释液，可在室温下（25C）稳定保存8小时，但输注必须在这一时限内完成。以0.9％氯化钠注射液USP稀释的白舒非稀释液可在冷藏（2℃-8℃）条件下稳定保存12小时，但输注也必须在这一时限内完成。

【孕妇及哺乳期妇女用药】
孕妇：给予妊娠妇女白消安治疗，可能损害胎儿。若在妊娠期间用药，白消安可在家鼠、大鼠和兔子的后代中造成畸胎。畸形和异常包括体形、体重增长和肌肉骨骼系统的显著变化。在妊娠大鼠中，白消安可造成雌性和雄性后代的不育，因白消安使后代的睾丸和卵巢中生殖细胞缺失。溶剂DMA，给予妊娠妇女时也可损害胎儿。大鼠中，在胎儿器官形成阶段给予DMA400mg/kg/d（按mg/m2计算，大约为白舒非每日剂量中所含DMA的40％），引起显著的发育异常，突出的异常包括：全身性水肿，腭裂，脊柱发育异常，肋骨发育异常和心脏大血管的严重异常。关于白消安或DMA在妊娠妇女中的应用，尚无充分的严格对照研究资料，若在妊娠期间使用白舒非或患者在使用白舒非期间怀孕，应告知患者该药对胚胎的可能危害。应告诫可能怀孕的妇女，在使用该药期间避孕。
哺乳期妇女：尚不清楚该药在人乳汁中是否有分泌。因为许多药物可自人类乳汁中分泌，而且人类和动物研究显示白消安具有潜在致癌原性，因此应权衡该药对哺乳期妇女的重要性，以决定是终止哺乳抑或终止用药。

【儿童用药】
尚不明确白舒非对儿童的安全性和有效性。有依据显示白消安在儿童中清除率高于成人。因此，有必要针对儿童，开发不同的口服白消安剂量方案。白舒非在儿童中的药代动力学研究正在进行中。目前尚未确定白舒非对儿童的推荐剂量。

【老年用药】
白舒非临床试验的61名治疗患者中，5名年龄在55岁以上（57~64岁）。此5人均达到骨髓清除并植入成功。
药物相互作用：
伊曲康唑可使白消安的清除率降低25％或更多，并可使某些患者的AUC>1，500Mmin。氟康唑以及5-HT3止吐剂恩丹西酮（Zofran）和格拉司琼（Kytril）可以与白舒非合用。
苯妥因使白消安的清除率增加15％或更多，可能由于其诱导谷胱甘肽S转移酶。白舒非的药代动学力研究是在应用了苯妥因的患者中进行的。因此推荐剂量白舒非的（实际）清除率可能更低，因而不用苯妥因的患者可能暴露在更高的AUC之下。
白消安通过与谷胱甘肽的结合从体内清除。在白舒非用药前（＜72小时）或同时使用对乙酰氨基酚，可能导致白消安清除减少，因为已知对乙酰氨基酚可降低血液和组织中的谷胱甘肽水平。

【药物过量】
除造血祖细胞移植外，尚无任何已知的白消安解毒剂。若无造血祖细胞支持，推荐剂量的白舒非会造成白消安过量。主要的毒性为深度骨髓造血细胞减少/再生障碍和全血细胞减少，同时还可能影响中枢神经系统、肝、肺和胃肠道。应密切监察血液系统状态，一旦有医疗指征时，即应开始积极支持治疗。曾报道一名体重18kg的4岁儿童，在一次性服用140mg的Myleran片剂后存活下来；另有一名2岁儿童，在计划骨髓移植前无意中服用了超过正常量的白消安（2.1mg/kg；总剂量23.3mg/kg），但未发生不良后果；然而一次2.4g的急性剂量对另一名10岁男孩却是致死性的。有报道白消安可以通过透析去除，因此一旦过量可以考虑透析；而且，白消安通过与谷胱甘肽结合而代谢，过量时也可考虑给予谷胱甘肽。

【药理毒理】
白舒非为强效的细胞毒性药物，可引起深度骨髓抑制。由于白消安是双功能团烷化剂，其四碳烃链的相对末端连接有2个不稳定磺化甲烷基团。在水溶液中，白消安水化并释放出磺化甲烷基团，由此产生活化的碳离子使DNA烷基化。白消安大部分的细胞毒性作用是由DNA损伤引起的。

【药代动力学】
一项包括59名患者的前瞻性试验，以白舒非—环磷酰胺作为同种异体造血干细胞移植前的预处理方案，研究了白舒非的药代动力学。每6小时给药一次，剂量为0.8mg/kg，4天共给药16次。59名接受白舒非的患者中有55名（93％）的AUC值维持在目标值以下（<1500μM·min）。


白舒非具有稳定的药代动力学特点，这表现在第9和第13次给药药物稳态Cmax的可重复性及这一参数很低的变异系数。

分布、代谢和排泄
白舒非分布、代谢和清除的研究还未进行过，但有相关的口服白消安文献资料。此外，对药物动力学参数的调节作用参见“药物相互作用”。
分布：白消安在脑脊液中达到的浓度与血浆中大致相等，其与血浆成份，主要是白蛋白的不可逆性结合率，估计在32.4±2.2％，这与白消安活化的亲电子特性有关。
代谢：白消安的主要代谢方式是与谷胱甘肽结合，既有自发结合，也有谷胱甘肽-S转移酶（GST）催化下的结合，结合后在肝脏内进一步氧化代谢。
排泄：14C标记的白消安用于人体后，48小时中约有30％的放射活性从尿中排出，而粪便中仅发现极微量药物。这种不完全排泄可能是由于长效代谢物的形成，或由于体内大分子物的非特异性烷基化。

【贮藏】
2℃~8℃

【包装】
10ml/支/盒。

【有效期】
24个月

Busilvex 6mg/ml(60 mg in 10ml)concentrate for solution for infusion
1. Name of the medicinal product
Busilvex 6 mg/ml concentrate for solution for infusion 
2. Qualitative and quantitative composition
One ml of concentrate contains 6 mg of busulfan (60 mg in 10 ml). 
After dilution: 1 ml of solution contains 0.5 mg of busulfan 
For the full list of excipients see section 6.1
3. Pharmaceutical form
Concentrate for solution for infusion (sterile concentrate). 
Clear, colourless solution.
4. Clinical particulars
4.1 Therapeutic indications
Busilvex followed by cyclophosphamide (BuCy2) is indicated as conditioning treatment prior to conventional haematopoietic progenitor cell transplantation (HPCT) in adult patients when the combination is considered the best available option. 
Busilvex following fludarabine (FB) is indicated as conditioning treatment prior to haematopoietic progenitor cell transplantation (HPCT) in adult patients who are candidates for a reduced-intensity conditioning (RIC) regimen. 
Busilvex followed by cyclophosphamide (BuCy4) or melphalan (BuMel) is indicated as conditioning treatment prior to conventional haematopoietic progenitor cell transplantation in paediatric patients.
4.2 Posology and method of administration
Busilvex administration should be supervised by a physician experienced in conditioning treatment prior to haematopoietic progenitor cell transplantation. 
Busilvex is administered prior to the haematopoietic progenitor cell transplantation (HPCT).
Posology
Busilvex in combination with cyclophosphamide or melphalan
In adults
The recommended dose and schedule of administration is: 
- 0.8 mg/kg body weight (BW) of busulfan as a two-hour infusion every 6 hours over 4 consecutive days for a total of 16 doses,
- followed by cyclophosphamide at 60 mg/kg/day over 2 days initiated for at least 24 hours following the 16th dose of Busilvex (see section 4.5).
Paediatric population (0 to 17 years)
The recommended dose of Busilvex is as follows:

followed by:
- 4 cycles of 50 mg/kg body weight (BW) cyclophosphamide (BuCy4) or 
- one administration of 140 mg/m2 melphalan (BuMel) 
initiated for at least 24 hours following the 16th dose of Busilvex.(see section 4.5).
Busilvex is administered as a two-hour infusion every 6 hours over 4 consecutive days for a total of 16 doses prior to cyclophosphamide or melphalan and haematopoietic progenitor cell transplantation (HPCT). 
Elderly patients 
Patients older than 50 years of age (n=23) have been successfully treated with Busilvex without dose-adjustment. However, for the safe use of Busilvex in patients older than 60 years only limited information is available. Same dose (see section 5.2) for elderly patients as for adults (< 50 years old) should be used.
Busilvex in combination with fludarabine (FB)
In adults 
The recommended dose and schedule of administration is: 
- fludarabine administered as a single daily one-hour infusion at 30 mg/m2 for 5 consecutive days or 40 mg/m2 for 4 consecutive days. 
- Busilvex will be administered at 3.2 mg/kg as a single daily three-hour infusion immediately after fludarabine for 2 or 3 consecutive days. 
Paediatric population (0 to 17 years)
The safety and efficacy of FB in pediatric population has not been established.
Elderly patients 
The administration of FB regimen has not been specifically investigated in elderly patients. However, more than 500 patients aged ≥ 55 years were reported in publications with FB conditioning regimens, yielding efficacy outcomes similar to younger patients. No dose adjustment was deemed necessary. 
Obese patients
In adults
For obese patients, dosing based on adjusted ideal body weight (AIBW) should be considered. 
Ideal body weight (IBW) is calculated as follows:
IBW men (kg) = 50 + 0.91x (height in cm-152); 
IBW women (kg) = 45 + 0.91x (height in cm-152). 
Adjusted ideal body weight (AIBW) is calculated as follows: 
AIBW= IBW+0.25x (actual body weight - IBW).
In paediatric population
The medicinal product is not recommended in obese children and adolescents with body mass index Weight (kg)/(m2) > 30 kg/m2 until further data become available.
Patients with renal impairment
Studies in renally impaired patients have not been conducted, however, as busulfan is moderately excreted in the urine, dose modification is not recommended in these patients. 
However, caution is recommended (see sections 4.8 and 5.2).
Patients with hepatic impairment
Busilvex as well as busulfan has not been studied in patients with hepatic impairment.
Caution is recommended, particularly in those patients with severe hepatic impairment (see section 4.4).
Method of administration
Precautions to be taken before handling or administering the medicinal product
Busilvex must be diluted prior to administration. A final concentration of approximately 0.5 mg/ml busulfan should be achieved. Busilvex should be administered by intravenous infusion via central venous catheter. 
For instructions on dilution of the medicinal product before administration, see section 6.6. 
Busilvex should not be given by rapid intravenous, bolus or peripheral injection. 
All patients should be pre-medicated with anticonvulsant medicinal products to prevent seizures reported with the use of high dose busulfan. 
It is recommended to administer anticonvulsants 12 h prior to Busilvex to 24 h after the last dose of Busilvex. 
In adult and paediatric studies, patients received either phenytoin or benzodiazepines as seizure prophylaxis treatment. (see sections 4.4 and 4.5). 
Antiemetics should be administered prior to the first dose of Busilvex and continued on a fixed schedule according to local practice through its administration.
4.3 Contraindications
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
Pregnancy (see section 4.6). 
4.4 Special warnings and precautions for use
The consequence of treatment with Busilvex at the recommended dose and schedule is profound myelosuppression, occurring in all patients. Severe granulocytopenia, thrombocytopenia, anaemia, or any combination thereof may develop. Frequent complete blood counts, including differential white blood cell counts, and platelet counts should be monitored during the treatment and until recovery is achieved. 
Prophylactic or empiric use of anti-infectives (bacterial, fungal, viral) should be considered for the prevention and management of infections during the neutropenic period. Platelet and red blood cell support, as well as the use of growth factors such as granulocyte colony stimulating agent (G-CSF), should be employed as medically indicated. 
In adults, absolute neutrophil counts < 0.5x109/l at a median of 4 days post transplant occurred in 100% of patients and recovered at median day 10 and 13 days following autologous and allogeneic transplant respectively (median neutropenic period of 6 and 9 days respectively). Thrombocytopenia (< 25x109/l or requiring platelet transfusion) occurred at a median of 5-6 days in 98% of patients. Anaemia (haemoglobin< 8.0 g/dl) occurred in 69% of patients. 
In paediatric population, absolute neutrophil counts < 0.5x109/l at a median of 3 days post transplant occurred in 100% of patients and lasted 5 and 18.5 days in autologous and allogeneic transplant respectively. In children, thrombocytopenia (< 25x109/l or requiring platelet transfusion) occurred in 100% of patients. Anaemia (haemoglobin< 8.0 g/dl) occurred in 100% of patients. 
In children < 9 kg, a therapeutic drug monitoring may be justified on a case by case basis, in particular in extremely young children and neonates (see section 5.2). 
The Fanconi anaemia cells have hypersensitivity to cross-linking agents. There is limited clinical experience of the use of busulfan as a component of a conditioning regimen prior to HSCT in children with Fanconi's anaemia. Therefore Busilvex should be used with caution in this type of patients.
Hepatic impairment 
Busilvex as well as busulfan has not been studied in patients with hepatic impairment. Since busulfan is mainly metabolized through the liver, caution should be observed when Busilvex is used in patients with pre-existing impairment of liver function, especially in those with severe hepatic impairment. It is recommended when treating these patients that serum transaminase, alkaline phosphatase, and bilirubin should be monitored regularly 28 days following transplant for early detection of hepatotoxicity. 
Hepatic veno-occlusive disease is a major complication that can occur during treatment with Busilvex. Patients who have received prior radiation therapy, greater than or equal to three cycles of chemotherapy, or prior progenitor cell transplant may be at an increased risk (see section 4.8).
Caution should be exercised when using paracetamol prior to (less than 72 hours) or concurrently with Busilvex due to a possible decrease in the metabolism of busulfan (See section 4.5).
As documented in clinical studies, no treated patients experienced cardiac tamponade or other specific cardiac toxicities related to Busilvex. However cardiac function should be monitored regularly in patients receiving Busilvex (see section 4.8). 
Occurrence of acute respiratory distress syndrome with subsequent respiratory failure associated with interstitial pulmonary fibrosis was reported in Busilvex studies in one patient who died, although, no clear aetiology was identified. In addition, busulfan might induce pulmonary toxicity that may be additive to the effects produced by other cytotoxic agents. Therefore, attention should be paid to this pulmonary issue in patients with prior history of mediastinal or pulmonary radiation (see section 4.8). 
Periodic monitoring of renal function should be considered during therapy with Busilvex (see section 4.8). 
Seizures have been reported with high dose busulfan treatment. Special caution should be exercised when administering the recommended dose of Busilvex to patients with a history of seizures. Patients should receive adequate anticonvulsant prophylaxis. In adults and children studies, data with Busilvex were obtained when using concomitant administration of either phenytoin or benzodiazepines for seizure prophylaxis. The effect of those anticonvulsant agents on busulfan pharmacokinetics was investigated in a phase II study (see section 4.5). 
The increased risk of a second malignancy should be explained to the patient. On the basis of human data, busulfan has been classified by the International Agency for Research on Cancer (IARC) as a human carcinogen. The World Health Organisation has concluded that there is a causal relationship between busulfan exposure and cancer. Leukaemia patients treated with busulfan developed many different cytological abnormalities, and some developed carcinomas. Busulfan is thought to be leukemogenic.
Fertility
Busulfan can impair fertility. Therefore, men treated with Busilvex are advised not to father a child during and up to 6 months after treatment and to seek advice on cryo-conservation of sperm prior to treatment because of the possibility of irreversible infertility due to therapy with Busilvex. Ovarian suppression and amenorrhoea with menopausal symptoms commonly occur in pre-menopausal patients. Busulfan treatment in a pre-adolescent girl prevented the onset of puberty due to ovarian failure. Impotence, sterility, azoospermia, and testicular atrophy have been reported in male patients. The solvent dimethylacetamide (DMA) may also impair fertility. DMA decreases fertility in male and female rodents (see sections 4.6 and 5.3).
4.5 Interaction with other medicinal products and other forms of interaction
No specific clinical trial was carried out to assess drug-drug interaction between intravenous busulfan and itraconazole. From published studies in adults, administration of itraconazole to patients receiving high-dose busulfan may result in reduced busulfan clearance. Patients should be monitored for signs of busulfan toxicity when itraconazole is used as an antifungal prophylaxis with intravenous busulfan. 
Published studies in adults described that ketobemidone (analgesic) might be associated with high levels of plasma busulfan. Therefore special care is recommended when combining these two compounds. 
In adults, for the BuCy2 regimen it has been reported that the time interval between the last oral busulfan administration and the first cyclophosphamide administration may influence the development of toxicities. A reduced incidence of Hepatic Veno Occlusive Disease (HVOD) and other regimen-related toxicity have been observed in patients when the lag time between the last dose of oral busulfan and the first dose of cyclophosphamide is > 24hours. 
There is no common metabolism pathway between busulfan and fludarabine. 
In adults, for the FB regimen, published studies did not report any mutual drug-drug interaction between intravenous busulfan and fludarabine. 
In paediatric population, for the BuMel regimen it has been reported that the administration of melphalan less than 24 hours after the last oral busulfan administration may influence the development of toxicities. 
Paracetamol is described to decrease glutathione levels in blood and tissues, and may therefore decrease busulfan clearance when used in combination (see section 4.4). 
Either phenytoin or benzodiazepines were administered for seizure prophylaxis in patients participating to the clinical trials conducted with intravenous busulfan (see section 4.2 and 4.4). 
The concomitant systemic administration of phenytoin to patients receiving high-dose of oral busulfan has been reported to increase busulfan clearance, due to induction of glutathion-S-transferase whereas no interaction has been reported when benzodiazepines such as diazepam, clonazepam or lorazepam have been used to prevent seizures with high-dose busulfan. 
No evidence of an induction effect of phenytoin has been seen on Busilvex data. A phase II clinical trial was performed to evaluate the influence of seizure prophylaxis treatment on intravenous busulfan pharmacokinetics. In this study, 24 adult patients received clonazepam (0.025-0.03 mg/kg/day as IV continuous infusions) as anticonvulsant therapy and the PK data of these patients were compared to historical data collected in patients treated with phenytoin. The analysis of data through a population pharmacokinetic method indicated no difference on intravenous busulfan clearance between phenytoin and clonazepam based therapy and therefore similar busulfan plasma exposures were achieved whatever the type of seizure prophylaxis. 
No interaction was observed when busulfan was combined with fluconazole (antifungal agent) or 5 HT3 antiemetics such as ondansetron or granisetron.
4.6 Fertility, pregnancy and lactation
Pregnancy
HPCT is contraindicated in pregnant women; therefore, Busilvex is contraindicated during pregnancy. Studies in animals have shown reproductive toxicity (embryo-fetal lethality and malformations). (see section 5.3) 
There are no or limited amount of data from the use of busulfan or DMA in pregnant women. A few cases of congenital abnormalities have been reported with low-dose oral busulfan, not necessarily attributable to the active substance, and third trimester exposure may be associated with impaired intrauterine growth.
Women of childbearing potential 
Women of childbearing potential have to use effective contraception during and up to 6 months after treatment.
Breast-feeding
It is unknown whether busulfan and DMA are excreted in human milk. Because of the potential for tumorigenicity shown for busulfan in human and animal studies, breast-feeding should be discontinued during treatment with busulfan.
Fertility
Busulfan and DMA can impair fertility in man or woman. Therefore it is advised not to father child during the treatment and up to 6 months after treatment and to seek advice on cryo-conservation of sperm prior to treatment because of the possibility of irreversible infertility (see section 4.4).
4.7 Effects on ability to drive and use machines
Not relevant
4.8 Undesirable effects
Summary of the safety profile
Busilvex in combination with cyclophosphamide or melphalan 
In adults
Adverse events information is derived from two clinical trials (n=103) of Busilvex. 
Serious toxicities involving the haematologic, hepatic and respiratory systems were considered as expected consequences of the conditioning regimen and transplant process. These include infection and Graft-versus host disease (GVHD) which although not directly related, were the major causes of morbidity and mortality, especially in allogeneic HPCT.
Blood and lymphatic system disorders:
Myelo-suppression and immuno-suppression were the desired therapeutic effects of the conditioning regimen. Therefore all patients experienced profound cytopenia: leucopenia 96%, thrombocytopenia 94%, and anemia 88%. The median time to neutropenia was 4 days for both autologous and allogeneic patients. The median duration of neutropenia was 6 days and 9 days for autologous and allogeneic patients. 
Immune system disorders:
The incidence of acute graft versus host disease (a-GVHD) data was collected in OMC-BUS-4 study (allogeneic)(n=61). A total of 11 patients (18%) experienced a-GVHD. The incidence of a-GVHD grades I-II was 13% (8/61), while the incidence of grade III-IV was 5% (3/61). Acute GVHD was rated as serious in 3 patients. Chronic GVHD (c-GVHD) was reported if serious or the cause of death, and was reported as the cause of death in 3 patients.
Infections and infestations: 
39% of patients (40/103) experienced one or more episodes of infection, of which 83% (33/40) were rated as mild or moderate. Pneumonia was fatal in 1% (1/103) and life-threatening in 3% of patients. Other infections were considered severe in 3% of patients. Fever was reported in 87% of patients and graded as mild/moderate in 84% and severe in 3%. 47% of patients experienced chills which were mild/moderate in 46% and severe in 1%.
Hepato-biliary disorders:
15% of SAEs involved liver toxicity. HVOD is a recognized potential complication of conditioning therapy post-transplant. Six of 103 patients (6%) experienced HVOD. HVOD occurred in: 8.2% (5/61) allogeneic patients (fatal in 2 patients) and 2.5% (1/42) of autologous patients. Elevated bilirubin (n=3) and elevated AST (n=1) were also observed. Two of the above four patients with serious serum hepatotoxicity were among patients with diagnosed HVOD.
Respiratory, thoracic and mediastinal disorders:
One patient experienced a fatal case of acute respiratory distress syndrome with subsequent respiratory failure associated with interstitial pulmonary fibrosis in the Busilvex studies.
Paediatric population
Adverse events information are derived from the clinical study in paediatrics (n=55). Serious toxicities involving the hepatic and respiratory systems were considered as expected consequences of the conditioning regimen and transplant process.
Immune system disorders:
The incidence of acute graft versus host disease (a-GVHD) data was collected in allogeneic patients (n=28). A total of 14 patients (50%) experienced a-GVHD. The incidence of a-GVHD grades I-II was 46.4% (13/28), while the incidence of grade III-IV was 3.6% (1/28). Chronic GVHD was reported only if it is the cause of death: one patient died 13 months post-transplant.
Infections and infestations: 
Infections (documented and non documented febrile neutropenia) were experienced in 89% of patients (49/55). Mild/moderate fever was reported in 76% of patients.
Hepato-biliary disorders :
Grade 3 elevated transaminases were reported in 24% of patients. 
Veno occlusive disease (VOD) was reported in 15% (4/27) and 7% (2/28) of the autologous and allogenic transplant respectively. VOD observed were neither fatal nor severe and resolved in all cases.
Busilvex in combination with fludarabine (FB) 
In adults
The safety profile of Busilvex combined with fludarabine (FB) has been examined through a review of adverse events reported in published data from clinical trials in RIC regimen. In these studies, a total of 1574 patients received FB as a reduced intensity conditioning (RIC) regimen prior to haematopoietic progenitor cell transplantation. 
Myelo-suppression and immuno-suppression were the desired therapeutic effects of the conditioning regimen and consequently were not considered undesirable effects.
Infections and infestations: 
The occurrence of infectious episodes or reactivation of opportunistic infectious agents mainly reflects the immune status of the patient receiving a conditioning regimen. 
The most frequent infectious adverse reactions were Cytomegalovirus (CMV) reactivation [range: 30.7% - 80.0%], Epstein-Barr Virus (EBV) reactivation [range: 2.3% - 61%], bacterial infections [range: 32.0% - 38.9%] and viral infections [range: 1.3% - 17.2%].
Gastrointestinal disorders:
The highest frequency of nausea and vomiting was 59.1% and the highest frequency of stomatitis was 11%.
Renal and urinary disorders:
It has been suggested that conditioning regimens containing fludarabine were associated with higher incidence of opportunistic infections after transplantation because of the immunosuppressive effect of fludarabine. Late haemorrhagic cystitis occurring 2 weeks post-transplant are likely related to viral infection / reactivation. Haemorrhagic cystitis including haemorrhagic cystitis induced by viral infection was reported in a range between 16% and 18.1%. 
Hepato-biliary disorders:
VOD was reported with a range between 3.9% and 15.4%. 
The treatment-related mortality/non-relapse mortality (TRM/NRM) reported until day+100 post-transplant has also been examined through a review of published data from clinical trials. It was considered as deaths that could be attributable to secondary side effects after HPCT and not related to the relapse/progression of the underlying haematological malignancies. 
The most frequent causes of reported TRM/NRMs were infection/sepsis, GVHD, pulmonary disorders and organ failure.
Tabulated summaries of adverse reactions
Frequencies are defined as: very common (≥ 1/10), common (≥ 1/100, < 1/10), uncommon (≥ 1/1,000, < 1/100) or not known (cannot be estimated from the available data). Undesirable effects coming from post-marketing survey have been implemented in the tables with the incidence “not known”.
Busilvex in combination with cyclophosphamide or melphalan 
Adverse reactions reported both in adults and paediatric patients as more than an isolated case are listed below, by system organ class and by frequency. Within each frequency grouping, adverse events are presented in order of decreasing seriousness.

* veno occlusive liver disease is more frequent in paediatric population. 
** reported in post marketing with IV busulfan 
*** reported in post marketing with oral busulfan
Busilvex in combination with fludarabine (FB)
The incidence of each adverse reactions presented in the following table has been defined according to the highest incidence observed in published clinical trials in RIC regimen for which the population treated with FB was clearly identified, whatever the schedules of busulfan administrations and endpoints. Adverse reactions reported as more than an isolated case are listed below, by system organ class and by frequency.

* reported in post marketing experience
** include haemorrhagic cystitis induced by viral infection
Reporting of suspected adverse reactions 
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via 
United Kingdom
Yellow Card Scheme
Website: www.mhra.gov.uk/yellowcard
Ireland
HPRA Pharmacovigilance
Earlsfort Terrace 
IRL - Dublin 2
Tel: +353 1 6764971
Fax: +353 1 6762517
Website: www.hpra.ie
e-mail: medsafety@hpra.ie
4.9 Overdose
The principal toxic effect is profound myeloablation and pancytopenia but the central nervous system, liver, lungs, and gastrointestinal tract may also be affected. 
There is no known antidote to Busilvex other than haematopoietic progenitor cell transplantation. In the absence of haematopoietic progenitor cell transplantation, the recommended dose of Busilvex would constitute an overdose of busulfan. The haematologic status should be closely monitored and vigorous supportive measures instituted as medically indicated. 
There have been two reports that busulfan is dialyzable, thus dialysis should be considered in the case of an overdose. Since, busulfan is metabolized through conjugation with glutathione, administration of glutathione might be considered. 
It must be considered that overdose of Busilvex will also increase exposure to DMA. In human the principal toxic effects were hepatotoxicity and central nervous system (CNS) effects. CNS changes precede any of the more severe side effects. No specific antidote for DMA overdose is known. In case of overdose, management would include general supportive care.
5. Pharmacological properties
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Alkyl sulfonates, ATC code: L01AB01.
Mechanism of action
Busulfan is a potent cytotoxic agent and a bifunctional alkylating agent. In aqueous media, release of the methanesulphonate groups produces carbonium ions which can alkylate DNA, thought to be an important biological mechanism for its cytotoxic effect.
Clinical efficacy and safety
Busilvex in combination with cyclophosphamide
In adults
Documentation on the safety and efficacy of Busilvex in combination with cyclophosphamide in the BuCy2 regimen prior to conventional allogeneic and/or autologous HPCT derives from two clinical trials (OMC-BUS-4 and OMC-BUS-3).
Two prospective, single arm, open-label, uncontrolled phase II studies were conducted in patients with haematological disease, the majority of whom had advanced disease. 
Diseases included were acute leukaemia past first remission, in first or subsequent relapse, in first remission (high risk), or induction failures; chronic melogenous leukaemia in chronic or advanced phase; primary refractory or resistant relapsed Hodgkin's disease or non-Hodgkin's lymphoma, and myelodysplastic syndrome. 
Patients received doses of 0.8 mg/kg busulfan every 6 hours infusion for a total 16 doses followed by cyclophosphamide at 60 mg/kg once per day for two days (BuCy2 regimen). 
The primary efficacy parameters in these studies were myeloablation, engraftment, relapse, and survival. 
In both studies, all patients received a 16/16 dose regimen of Busilvex. No patients were discontinued from treatment due to adverse reactions related to Busilvex. 
All patients experienced a profound myelosuppression. The time to Absolute Neutrophil Count (ANC) greater than 0.5x109 /l was 13 days (range 9-29 days) in allogenic patients (OMC-BUS 4), and 10 days (range 8-19 days) in autologous patients (OMC-BUS 3). All evaluable patients engrafted. There is no primary or secondary graft rejection. Overall mortality and non- relapse mortality at more than 100 days post-transplant was (8/61) 13% and (6/61) 10% in allotransplanted patients, respectively. During the same period there was no death in autologous recipients.
Paediatric population
Documentation of the safety and efficacy of Busilvex in combination with cyclophosphamide in the BuCy4 or with melphalan in the BuMel regimen prior to conventional allogeneic and/or autologous HPCT derives from clinical trial F60002 IN 101 G0.
The patients received the dosing mentioned in section 4.2.
All patients experienced a profound myelosuppression. The time to Absolute Neutrophil Count (ANC) greater than 0.5x109/l was 21 days (range 12-47 days) in allogenic patients, and 11 days (range 10-15 days) in autologous patients. All children engrafted. There is no primary or secondary graft rejection. 93% of allogeneic patients showed complete chimerism. There was no regimen-related death through the first 100-day post-transplant and up to one year post-transplant.
Busilvex in combination with fludarabine (FB) 
In adults
Documentation on the safety and efficacy of Busilvex in combination with fludarabine (FB) prior to allogeneic HPCT derives from the literature review of 7 published studies involving 731 patients with myeloid and lymphoid malignancies reporting the use of intravenous busulfan infused once daily instead of four doses per day. 
Patients received a conditioning regimen based on the administration of fludarabine immediately followed by single daily dose of 3.2 mg/kg busulfan over 2 or 3 consecutive days. Total dose of busulfan per patient was between 6.4 mg/kg and 9.6 mg/kg. 
The FB combination allowed sufficient myeloablation modulated by the intensity of conditioning regimen through the variation of number of days of busulfan infusion. Fast and complete engraftment rates in 80-100% of patients were reported in the majority of studies. A majority of publications reported a complete donor chimerism at day+30 for 90-100% of patients. The long-term outcomes confirmed that the efficacy was maintained without unexpected effects. 
Data from a recently completed prospective multicentre phase 2 study including 80 patients, aged 18 to 65 years old, diagnosed with different hematologic malignancies who underwent allo-HCT with an FB (3 days of Busilvex) reduced intensity conditioning regimen became available. In this study, all, but one, patients engrafted, at a median of 15 (range, 10-23) days after allo-HCT. The cumulative incidence of neutrophil recovery at day 28 was 98.8% (95%CI, 85.7-99.9%). Platelet engraftment occurred at a median of 9 (range, 1-16) days after allo-HCT. 
The 2-year OS rate was 61.9% (95%CI, 51.1-72.7%)]. At 2 years, the cumulative incidence of NRM was 11.3% (95%CI, 5.5-19.3%), and that of relapse or progression from allo-HCT was 43.8% (95CI, 31.1-55.7%). The Kaplan-Meier estimate of DFS at 2 years was 49.9% (95%CI, 32.6-72.7).
5.2 Pharmacokinetic properties
The pharmacokinetics of Busilvex has been investigated. The information presented on biotransformation and elimination is based on oral busulfan.
Pharmacokinetics in adults
Absorption
The pharmacokinetics of intravenous busulfan was studied in 124 evaluable patients following a 2-hour intravenous infusion for a total of 16 doses over four days. Immediate and complete availability of the dose is obtained after intravenous infusion of busulfan. Similar blood exposure was observed when comparing plasma concentrations in adult patients receiving oral and intravenous busulfan at 1 mg/kg and 0.8 mg/kg respectively. Low inter (CV=21%) and intra (CV=12%) patient variability on busulfan exposure was demonstrated through a population pharmacokinetic analysis, performed on 102 patients. 
Distribution
Terminal volume of distribution Vz ranged between 0.62 and 0.85 l/kg.
Busulfan concentrations in the cerebrospinal fluid are comparable to those in plasma although these concentrations are probably insufficient for anti-neoplastic activity.
Reversible binding to plasma proteins was around 7% while irreversible binding, primarily to albumin, was about 32%.
Biotransformation
Busulfan is metabolised mainly through conjugation with glutathione (spontaneous and glutathione-S-transferase mediated). The glutathione conjugate is then further metabolised in the liver by oxidation. None of the metabolites is thought to contribute significantly to either efficacy or toxicity.
Elimination
Total clearance in plasma ranged 2.25 - 2.74 ml/minute/kg. The terminal half-life ranged from 2.8 to 3.9 hours.
Approximately 30% of the administered dose is excreted into the urine over 48 hours with 1% as unchanged busulfan. Elimination in faeces is negligible. Irreversible protein binding may explain the incomplete recovery. Contribution of long-lasting metabolites is not excluded.
Linearity 
The dose proportional increase of busulfan exposure was demonstrated following intravenous busulfan up to 1 mg/kg.
Compared to the four times a day regimen, the once-daily regimen is characterized by a higher peak concentration, no drug accumulation and a wash out period (without circulating busulfan concentration) between consecutive administrations. The review of the literature allows a comparison of PK series performed either within the same study or between studies and demonstrated unchanged dose-independent PK parameters regardless the dosage or the schedule of administration. It seems that the recommended intravenous busulfan dose administered either as an individual infusion (3.2 mg/kg) or into 4 divided infusions (0.8 mg/kg) provided equivalent daily plasma exposure with similar both inter-and intrapatient variability. As a result, the control of intravenous busulfan AUC within the therapeutic windows is not modified and a similar targeting performance between the two schedules was illustrated.
Pharmacokinetic/pharmacodynamic relationships
The literature on busulfan suggests a therapeutic AUC window between 900 and 1500 µmol/L.minute per administration (equivalent to a daily exposure between 3600 and 6000 µmol/L.minute). During clinical trials with intravenous busulfan administered as 0.80 mg/kg four-times daily, 90% of patients AUCs were below the upper AUC limit (1500 µmol/L.minute) and at least 80% were within the targeted therapeutic window (900-1500 µmol/L.minute). Similar targeting rate is achieved within the daily exposure of 3600 - 6000 µmol/L.minute following the administration of intravenous busulfan 3.2 mg/kg once daily.
Special populations
Hepatic or renal impairment
The effects of renal dysfunction on intravenous busulfan disposition have not been assessed. 
The effects of hepatic dysfunction on intravenous busulfan disposition have not been assessed. Nevertheless the risk of liver toxicity may be increased in this population. 
No age effect on busulfan clearance was evidenced from available intravenous busulfan data in patients over 60 years.
Paediatric population 
A continuous variation of clearance ranging from 2.49 to 3.92 ml/minute/kg has been established in children from < 6 months up to 17 years old. The terminal half life ranged from 2.26 to 2.52 h.
Inter and intra patient variabilities in plasma exposure were lower than 20% and 10%, respectively.
A population pharmacokinetic analysis has been performed in a cohort of 205 children adequately distributed with respect to bodyweight (3.5 to 62.5 kg), biological and diseases (malignant and non-malignant) characteristics, thus representative of the high heterogeneity of children undergoing HPCT. This study demonstrated that bodyweight was the predominant covariate to explain the busulfan pharmacokinetic variability in children over body surface area or age. 
The recommended posology for children as detailed in section 4.2 enabled over 70% up to 90% of children ≥ 9 kg in achieving the therapeutic window (900-1500 µmol/L.minute). However a higher variability was observed in children < 9 kg leading to 60% of children achieving the therapeutic window (900-1500 µmol/L.minute). For the 40% of children < 9 kg outside the target, the AUC was evenly distributed either below or above the targeted limits; i.e. 20% each < 900 and > 1500 µmol/L.min following 1 mg/kg. In this regard, for children < 9 kg, a monitoring of the plasma concentrations of busulfan (therapeutic drug monitoring) for dose-adjustment may improve the busulfan targeting performance, especially in extremely young children and neonates. 
Pharmacokinetic/pharmacodynamic relationships:
The successful engraftment achieved in all patients during phase II trials suggests the appropriateness of the targeted AUCs. Occurrence of VOD was not related to overexposure. PK/PD relationship was observed between stomatitis and AUCs in autologous patients and between bilirubin increase and AUCs in a combined autologous and allogeneic patient analysis.
5.3 Preclinical safety data
Busulfan is mutagenic and clastogenic. Busulfan was mutagenic in Salmonella typhimurium, Drosophila melanogaster and barley. Busulfan induced chromosomal aberrations in vitro (rodent and human cell) and in vivo (rodents and humans). Various chromosome aberrations have been observed in cells from patients receiving oral busulfan.
Busulfan belongs to a class of substances which are potentially carcinogenic based on their mechanism of action. On the basis of human data, busulfan has been classified by the IARC as a human carcinogen. WHO has concluded that there is a causal relationship between busulfan exposure and cancer. The available data in animals support the carcinogenic potential of busulfan. Intravenous administration of busulfan to mice significantly increased the incidences of thymic and ovarian tumours.
Busulfan is a teratogen in rats, mice and rabbits. Malformations and anomalies included significant alterations in the musculoskeletal system, body weight gain, and size. In pregnant rats, busulfan produced sterility in both male and female offspring due to the absence of germinal cells in testes and ovaries. Busulfan was shown to cause sterility in rodents. Busulfan depleted oocytes of female rats, and induced sterility in male rats and hamster.
Repeated doses of DMA produced signs of liver toxicity, the first being increases in serum clinical enzymes followed by histopatological changes in the hepatocytes. Higher doses can produce hepatic necrosis and liver damage can be seen following single high exposures.
DMA is teratogenic in rats. Doses of 400 mg/kg/day DMA administered during organogenesis caused significant developmental anomalies. The malformations included serious heart and/or major vessels anomalies: a common truncus arteriosis and no ductus arteriosis, coarctation of the pulmonary trunk and the pulmonary arteries, intraventricular defects of the heart. Other frequent anomalies included cleft palate, anasarca and skeletal anomalies of the vertebrae and ribs. DMA decreases fertility in male and female rodents. A single s.c. dose of 2.2 g/kg administered on gestation day 4 terminated pregnancy in 100% of tested hamster. In rats, a DMA daily dose of 450 mg/kg given to rats for nine days caused inactive spermatogenesis.
6. Pharmaceutical particulars
6.1 List of excipients
Dimethylacetamide
Macrogol 400.
6.2 Incompatibilities
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6. 
Do not use polycarbonate syringes with Busilvex.
6.3 Shelf life
Vials: 3 years
Diluted solution:
Chemical and physical in-use stability after dilution in glucose 5% or sodium chloride 9 mg/ml (0.9%) solution for injection has been demonstrated for:
- 8 hours (including infusion time) after dilution when stored at 20 °C ± 5 °C
- 12 hours after dilution when stored at 2 °C-8 °C followed by 3 hours stored at 20 °C ± 5 °C (including infusion time). 
From a microbiological point of view, the product should be used immediately after dilution. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than the above mentioned conditions when dilution has taken place in controlled and validated aseptic conditions.
6.4 Special precautions for storage
Store in a refrigerator (2°C – 8°C).
Do not freeze the diluted solution.
For storage conditions after dilution of the medicinal product see section 6.3.
6.5 Nature and contents of container
10 ml of concentrate for solution for infusion in clear glass vials (type I) with a butyl rubber stopper covered by a purple flip-off aluminium seal cap.
Multipack containing 8 (2 packs of 4) vials.
6.6 Special precautions for disposal and other handling
Preparation of Busilvex
Procedures for proper handling and disposal of anticancer medicinal products should be considered. 
All transfer procedures require strict adherence to aseptic techniques, preferably employing a vertical laminar flow safety hood 
As with other cytotoxic compounds, caution should be exercised in handling and preparing the Busilvex solution: 
- The use of gloves and protective clothing is recommended. 
- If Busilvex or diluted Busilvex solution contacts the skin or mucosa, wash them thoroughly with water immediately.
Calculation of the quantity of Busilvex to be diluted and of the diluent
Busilvex must be diluted prior to use with either sodium chloride 9 mg/ml (0.9%) solution for injection or glucose solution for injection 5%.
The quantity of the diluent must be 10 times the volume of Busilvex ensuring the final concentration of busulfan remains at approximately 0.5 mg/ml. By example: 
The amount of Busilvex and diluent to be administered would be calculated as follows:
for a patient with a Y kg body weight:
• Quantity of Busilvex:

Y: body weight of the patient in kg 
D: dose of Busilvex (see section 4.2) 
• Quantity of diluent:
(A ml Busilvex) x (10) = B ml of diluent
To prepare the final solution for infusion, add (A) ml of Busilvex to (B) ml of diluent (sodium chloride 9 mg/ml (0.9%) solution for injection or glucose solution for injection 5%)
Preparation of the solution for infusion
• Busilvex must be prepared by a healthcare professional using sterile transfer techniques. Using a non polycarbonate syringe fitted with a needle: 
- the calculated volume of Busilvex must be removed from the vial. 
- the contents of the syringe must be dispensed into an intravenous bag (or syringe) which already contains the calculated amount of the selected diluent. Busilvex must always be added to the diluent, not the diluent to Busilvex. Busilvex must not be put into an intravenous bag that does not contain sodium chloride 9 mg/ml (0.9%) solution for injection or glucose solution for injection 5%. 
• The diluted solution must be mixed thoroughly by inverting several times. 
After dilution, 1 ml of solution for infusion contains 0.5 mg of busulfan. 
Diluted Busilvex is a clear colourless solution.
Instructions for use
Prior to and following each infusion, flush the indwelling catheter line with approximately 5 ml of sodium chloride 9 mg/ml (0.9%) solution for injection or glucose (5%) solution for injection. 
The residual medicinal product must not be flushed in the administration tubing as rapid infusion of Busilvex has not been tested and is not recommended. 
The entire prescribed Busilvex dose should be delivered over two or three hours depending of the conditioning regimen. 
Small volumes may be administered over 2 hours using electric syringes. In this case infusion sets with minimal priming space should be used (i.e. 0.3-0.6 ml), primed with medicinal product solution prior to beginning the actual Busilvex infusion and then flushed with sodium chloride 9 mg/ml (0.9%) solution for injection or glucose (5%) solution for injection. 
Busilvex must not be infused concomitantly with another intravenous solution. 
Polycarbonate syringes must not be used with Busilvex.
For single use only. Only a clear solution without any particles should be used.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements for cytotoxic medicinal products.
7. Marketing authorisation holder
Pierre Fabre Médicament 
45, Place Abel Gance 
F-92654 Boulogne Billancourt Cedex
France
8. Marketing authorisation number(s)
EU/1/03/254/002
9. Date of first authorisation/renewal of the authorisation
Date of first authorisation: 09 July, 2003 
Date of latest renewal: 08 July, 2008
10. Date of revision of the text
08/2014