注射用盐酸伊达比星说明书

· 通用名称：注射用盐酸伊达比星
英文名称：Idarubicin Hydrochloride for Injection

· 【成份】本品主要成份为盐酸伊达比星，辅料名称：乳糖

· 【性状】本品为橙红色的疏松冻干块状物。

· 【适应症】本品为一抗有丝分裂和细胞毒制剂。用于成人急性非淋巴细胞性白血病(ANLL)的一线治疗，以及复发和难治患者的诱导缓解治疗。作为二线治疗药物用于成人和儿童的急性淋巴细胞性白血病(ALL)。

· 【规格】（1）5mg （2）10mg

· 【用法用量】急性非淋巴细胞性白血病(ANLL)：
在成人急性非淋巴细胞性白血病，与阿糖胞苷联合用药时的推荐剂量为按体表面积计算每天静脉注入 12mg/m2，连续使用三天。另一种单独和联合用药的用法，推荐剂量为按体表面积计算每天静脉注射 8mg/m2，连续使用五天。
急性淋巴细胞性白血病(ALL)：
作为单独用药，成人急性淋巴细胞性白血病的推荐剂量为按体表面积计算每天静脉注入 12mg/m2，连续使用三天；儿童 10mg/m2,连续使用三天。 然而，所有的给药方案均应考虑到病人的血象，以及在联合用药期间其他细胞毒药物的使用剂量而调整给药剂量。通常，按体表面积计算剂量。
本品仅用于静脉注射
建议在检查针头确实在静脉内后，溶解后的注射用盐酸伊达比星经过滴注生理盐水的通畅的输注管与生理盐水一起在 5-10 分钟内注入静脉内。这样可减少血栓形成的危险和药物外溢后引起的严重的蜂窝组织炎及坏死。小静脉注射或在同一静脉内反复注射可能造成静脉硬化。
使用介绍：
瓶内药物处于负压状态下，从而在溶液配制时可减少气雾形成。当针头插入后应特别小心。在配制药液时必须避免吸入任何气雾。
将注射用粉针溶于注射用水以制备注射剂，5ml 溶剂溶解 5mg 样品，10ml 溶剂溶解 10mg 样品

· 【不良反应】严惩骨髓抑制和心脏毒性，致死性的感染。可逆性脱发，胃肠道反应如恶心、呕吐、粘膜炎，尤其是口腔粘膜炎，出现于治疗后3-10日，食道炎、腹泻，发热，寒战，皮疹。有酶和胆红素增高。使用本药1-2天后尿液呈现红色。

· 【禁忌】·对伊达比星或其辅料、其他蒽环类或蒽二酮类药物过敏
·严重肝功能损害
·严重肾功能损害
·严重心肌功能不全
·近期发生过心肌梗塞
·严重心律失常
·持续的骨髓抑制
·曾以伊达比星和/或其他蒽环类和蒽二酮类药物最大累积剂量治疗
·治疗期间应停止哺乳

· 【注意事项】
·一般：
伊达比星必须在有使用细胞毒药物经验的医生指导下使用。
伊达比星治疗开始前，患者应已从之前的细胞毒药物治疗的急性毒性反应(如口腔炎、中性粒细胞
减少、血小板减少、全身性感染)中恢复。
·心功能
使用蒽环类药物有发生心脏毒性的风险，表现为早期（即急性）或晚期（即迟发）事件。
早期（即急性）事件：伊达比星的早期心脏毒性主要包括窦性心动过速和/或心电图(ECG)异常，如非特异性 ST-T 波改变；快速性心律失常，包括室性早博和室性心动过速、心动过缓、以及房室和束支传导阻滞都有报道。这些不良事件通常对后续的迟发性心脏毒性的发生并无预示作用，很少有临床意义，而且通常无需为此停止伊达比星的治疗。
晚期（即迟发）事件：迟发性心脏毒性通常在治疗后期或在治疗结束后 2 至 3 个月内发生，但也有报道在治疗结束后数月到数年出现的迟发性事件。迟发性心肌病可表现为左心室射血分数(LVEF)降低和/或充血性心力衰竭(CHF)的症状和体征，如呼吸困难、肺水肿、坠积性水肿、心脏肥大、肝脏肿大、少尿、腹水、胸腔积液和奔马律。也有亚急性症状，如心包炎/心肌炎的报道。蒽环类药物引起的最严重的心肌病为危及生命的充血性心力衰竭，表现为累积性的剂量限制性毒性。
尚未规定静脉注射或口服伊达比星的累积剂量上限。但据报道，接受静脉注射剂量累积达 150 -
290mg/m2的患者中有 5%发生与伊达比星相关的心肌病。现有的数据显示，口服伊达比星总累积剂量可
达 400mg/ m2，提示其导致心脏毒性的可能性较小。
在使用伊达比星治疗前，需要进行心脏功能的评估，而且在整个治疗期间需要监测心脏功能，以尽可能地减少发生严重心脏功能损害的风险。在治疗期间定期监测左室射血分数(LVEF)，一旦出现心脏功能损害的表现应立即停用伊达比星，可减小心脏毒性发生的风险。可以运用 MUGA 扫描（多门核素血管造影术）或者超声心动图（ECHO）对心脏功能进行反复的量化评估（对 LVEF 的评估）。推荐在基线的时候进行心电图、MUGA 扫描或者 ECHO 检查，这尤其适合于那些具有高危风险因素的患者。应反复进行 MUGA 扫描或 ECHO 检查以评估左室射血分数，尤其是在使用高累积剂量蒽环类药物时。整个随访
期间用于评估的技术要保持一致。
发生心脏毒性的危险因素包括活动性或非活动性的心血管疾病、目前或既往接受过纵膈/心脏周围区域的放射治疗，之前用过其他蒽环类药物或者蒽二酮药物、同时使用其他抑制心肌收缩功能的药物或者具有心脏毒性的药物（例如曲妥珠单抗）。除非患者的心功能得到严密的监测，否则蒽环类药物包括伊达比星不能与其他具有心脏毒性的药物同时使用。患者在停止使用其他具有心脏毒性的药物（特别是具有长半衰期的药物例如曲妥珠单抗）之后接受蒽环类药物，也可能会增加发生心脏毒性的风险。
曲妥珠单抗的半衰期约为 28.5 天并且在血循环中可以持续至 24 周。因此，如果可能，医师应该在停用曲妥珠单抗之后的 24 周内避免使用以蒽环类药物为基础的治疗。但是，如果要在这段时间内使用蒽环类药物，须密切监测心脏功能。对接受高累积剂量伊达比星及具有高危风险的患者应进行严格的心脏功能的监测。然而无论是否存在心脏毒性危险因素，在累积剂量较低时仍有可能发生心脏毒性。
婴儿和儿童似乎对伊达比星诱发的心脏毒性更加易感，必须长期进行定期的心脏功能评估。
伊达比星和其他蒽环类或蒽二酮类药物的毒性作用可能具有累积性。
·血液毒性
伊达比星是强烈的骨髓抑制剂。所有患者使用治疗剂量的本品都会出现严重的骨髓抑制。
使用伊达比星前及每个周期中都应进行血液学检查，包括白细胞（WBC）计数。剂量依赖性的、可逆的白细胞减少和/或粒细胞减少（中性粒细胞减少为主）是伊达比星主要的血液学毒性，并且是伊达比星最常见的急性剂量限制性毒性。白细胞减少或中性粒细胞减少通常很严重，血小板减少和贫血也有可能发生。中性粒细胞和血小板计数一般在用药后的 10 至 14 天达到最低点，但大部分患者的细胞计数会在第 3 周内恢复至正常范围。严重骨髓抑制的临床表现包括发热、感染、脓毒血症/败血症、感染性休克、出血、组织缺氧、甚至死亡。
·继发性白血病
有报道在使用蒽环类药物包括伊达比星的患者中出现了继发性白血病，可伴或不伴白血病前期症状。下列情况下出现继发性白血病更为常见：当与作用机制为破坏 DNA 结构的抗癌药物联合使用时，或患者既往多次使用细胞毒药物时，或者蒽环类药物治疗剂量加量时。此类白血病的潜伏期通常为 1～
3 年。
·胃肠道
伊达比星会引起呕吐反应。粘膜炎（主要是口腔炎，食管炎少见）通常会发生在给药后的早期，如果情况严重，数天后可能会进展为粘膜溃疡。绝大多数患者在给药后的第三周得以恢复。
有时，对于患急性白血病或其他疾病或接受已知会引起胃肠道并发症药物的患者口服伊达比星，偶尔会发生严重的胃肠道不良反应(如穿孔或出血)。对于有出血和/或穿孔高风险的活动性胃肠道疾病患者，医生必须权衡口服伊达比星的益处与风险。
·肝功能和/或肾功能
由于肝和/或肾功能损害会影响伊达比星的代谢，所以在临床治疗前及治疗过程中应常规进行肝肾功能的实验室检查（使用血清胆红素和血清肌酐作为指标）。在一些 III 期临床试验中规定如果血清胆红素和/或肌酐水平超过 2.0mg/100ml，则禁止使用伊达比星治疗。如果胆红素水平范围在 1.2 到2.0mg/100ml，其他蒽环类药物通常会减少 50%的剂量。
·注射部位的影响
小静脉注射或者反复注射同一静脉可能造成静脉硬化，按照推荐的给药流程操作可以尽可能的减少注射部位静脉炎/血栓性静脉炎的发生。
·药物外渗
伊达比星静脉注射时发生外渗会导致局部疼痛、严重组织损伤（发疱、严重的蜂窝组织炎）和坏死。注射时一旦发生药液外渗的症状和体征，应立即停止注射。
·肿瘤溶解综合征
使用伊达比星可能会导致高尿酸血症，其原因是伴随药物诱导的肿瘤细胞的迅速崩解而产生过度的嘌呤分解代谢 (肿瘤溶解综合征)。因此在初始治疗开始后需要监测血尿酸、钾、磷酸钙、肌酐等情况。水化、碱化尿液、预防性使用别嘌呤醇防止高尿酸血症的出现，从而尽可能的减少肿瘤溶解综合症的发生。
·免疫抑制效应/感染易感性增加
对于接受化疗药物包括伊达比星而导致免疫妥协的患者接种活疫苗或者减毒活疫苗可能会产生严重甚至致命的感染。正在接受伊达比星治疗的患者应当避免接种活疫苗。可以接种死疫苗或者灭活疫苗，但是对这些疫苗的免疫应答可能会降低。
·生殖系统
建议接受伊达比星治疗的男性患者在治疗期间及治疗结束后 6 个月内采取有效的避孕措施；如适当和可能，可咨询相关机构保存精子，因为治疗可能会导致不可逆的生育功能损伤。
·其他：
已有报道和其他细胞毒药物一样，使用伊达比星的患者有发生血栓性静脉炎、血栓栓塞，包括肺栓塞的情况。
·对驾驶和使用机器能力的影响：
未系统研究过伊达比星对驾车和操作机器能力的影响。
·我们推荐以下的安全措施用于所有细胞毒制剂：
- 操作人员必须受过药物配制及操作的良好技术训练。
- 怀孕的工作人员应避免接触本品。
- 操作者应穿戴防护服装，包括护目镜，工作袍及一次性手套和面罩。
- 药物配制应在指定区域进行(在垂直层流系统下更佳)，工作台表面应铺塑料涂层的吸水纸。
- 所有用于药物配制、注射或清洗的材料包括手套等，用后应置于标有“高度危险”废弃袋内高温焚烧。
- 如不慎与皮肤或眼睛接触，应立即用大量清水和肥皂，或含重碳酸钠的溶液冲洗，并向医生咨询。
- 药液渗出或漏出，应用 1%次氯酸钠溶液处理，然后用水冲洗，所有的清洗材料均应按上法处理。
·配伍禁忌：
注射用盐酸伊达比星不可与肝素混合，因会产生沉淀。本品亦不得与其他药物混合。
本品应避免与碱性溶液长期接触，以免引起药品降解。

· 【孕妇及哺乳期妇女用药】生育力损害：伊达比星可引起人类精子染色体的损伤。因此接受伊达比星治疗的男性应采取有效的避孕措施。
妊娠 ：体外和体内的研究已经证实伊达比星具有潜在的胚胎毒性。但是没有对孕妇进行过充分的、严格对照的研究。育龄妇女应被告知采取避孕措施。只有当权衡潜在益处大于对胎儿的潜在风险时，才能在怀孕期间采用伊达比星治疗。且须将药物对胎儿的潜在危害告知患者。
哺乳：尚不清楚伊达比星及其代谢物是否经乳汁分泌。建议用本品化疗的母亲避免哺乳。
如适当和可能，应建议在完成治疗后有生育意愿的患者首先进行遗传咨询。

· 【儿童用药】参 见 【 用 法 用 量 】 的 详 细 描 述 。

· 【老年用药】参 见 【 用 法 用 量 】 的 详 细 描 述 。

· 【药物相互作用】伊达比星是强烈的骨髓抑制剂，如与其他具有相似作用机制的药物组成联合化疗方案可导致骨髓抑制作用相加。与其他有潜在心脏毒性药物联合化疗时，或者是同时应用其他作用于心脏的药物（如钙离子通道拮抗剂）时，需要在整个治疗期间严密监测心脏功能。
合并用药所引起的肝肾功能的变化可能会影响伊达比星的代谢、药代动力学、疗效和/或毒性反应。
伊达比星治疗同时或之前的 2-3 周内进行放疗可导致累加的骨髓抑制。

· 【药物过量】过大剂量的注射用盐酸伊达比星可能在 24 小时内引起急性心肌毒性，一至二周内产生严重的骨髓抑制。在此期间应加强支持疗法和应用输血，无菌隔离护理等措施。也有报道蒽环类药物过量后引起的心力衰竭可于数月后出现。病人应密切观察，一旦出现心力衰竭的症状和体征时应予以相应治疗。

· 【药理毒理】 伊达比星是一种 DNA 嵌入剂，作用于拓扑异构酶 II，抑制核酸合成。
蒽环结构 4 位的改变使该化合物具有高亲脂性，与阿霉素和柔红霉素相比提高了细胞对药物的摄入。
与柔红霉素相比，伊达比星具有更高的活性，静脉或口服用药对鼠白血病和淋巴瘤均有效。
人和鼠的体外实验表明，与阿霉素和柔红霉素相比，蒽环类耐药细胞对伊达比星显示出较低程度的交叉耐药性。
动物心脏毒性研究提示伊达比星比阿霉素和柔红霉素具有更高的治疗指数,其主要代谢产物伊达比星醇在体内和体外实验中均显示出抗肿瘤活性。在大鼠实验中，伊达比星醇的心脏毒性明显低于相同剂量的伊达比星。
静脉注射给药后，小鼠的 LD50 为 4.4mg/kg,大鼠为 2.9mg/kg,狗为 1.0mg/kg。单剂静脉给药后，主要靶器官为血液淋巴系统，尤其在狗还表现为胃肠道。
伊达比星静脉重复给药后，主要的靶器官，在大鼠和狗为血液淋巴系统、胃肠道、肾脏、肝脏和生殖系统。急性和亚急性心脏毒性研究显示，伊达比星静脉给药后，只有在致死剂量下才产生中度的心脏毒性，而阿霉素和柔红霉素在非致死剂量下已产生心肌损害。
伊达比星在许多体内和体外试验中显示有生殖毒性。大鼠的实验中也发现有生殖毒性、胚胎毒性和致畸性。在出生前后伊达比星静脉给药剂量达 0.2mg/kg/天时，未发现对大鼠亲代或子代有明显响。
尚不明确伊达比星是否分泌入乳汁。像其它蒽环类和细胞毒性药一样，发现伊达比星对大鼠有致癌性。
狗的局部耐受性试验显示药物溢出可导致组织坏死。

· 【药代动力学】 肝肾功能正常的患者静脉给药后伊达比星从体循环中清除，其终末血浆半衰期在 11-25小时之间。大部分药物经代谢生成活性代谢产物伊达比星醇，而该代谢产物的清除更慢，血浆半衰期在 41-69 小时之间。绝大部分药物是以伊达比星醇的形式经胆汁和尿液排出体外。
在白血病人体内进行的细胞内药物浓度(有核血细胞和骨髓细胞)的研究表明，注射本品几分钟后，伊达比星即达到细胞浓度峰值。伊达比星和伊达比星醇在有核血细胞和骨髓细胞中的浓度比在血浆中的浓度高一百倍以上。
伊达比星和伊达比星醇在血浆和细胞中的消除速率相当，其终末半衰期约 15 小时。伊达比星醇的终末半衰期大约是 72 小时。

· 【贮藏】25℃以下 配制的药液于 2-8℃可至少保存 48 小时，室温可保存 24 小时。但根据药物良好操作规范，建议溶 液在 2-8℃时,保存一般不应超过 24 小时。多余量弃去。

 Idarubicin

Generic Name: Idarubicin hydrochloride
      Dosage Form: injection, solution

 Warnings

1. Idarubicin Hydrochloride Injection should be given slowly into a freely flowing intravenous infusion. It must never be given intramuscularly or subcutaneously. Severe local tissue necrosis can occur if there is extravasation during administration.
2. As is the case with other anthracyclines the use of Idarubicin Hydrochloride Injection can cause myocardial toxicity leading to congestive heart failure. Cardiac toxicity is more common in patients who have received prior anthracyclines or who have pre-existing cardiac disease.
3. As is usual with antileukemic agents, severe myelosuppression occurs when Idarubicin Hydrochloride Injection is used at effective therapeutic doses.
4. It is recommended that Idarubicin Hydrochloride Injection be administered only under the supervision of a physician who is experienced in leukemia chemotherapy and in facilities with laboratory and supportive resources adequate to monitor drug tolerance and protect and maintain a patient compromised by drug toxicity. The physician and institution must be capable of responding rapidly and completely to severe hemorrhagic conditions and/or overwhelming infection.
5. Dosage should be reduced in patients with impaired hepatic or renal function (see DOSAGE AND ADMINISTRATION).

 DESCRIPTION:

Idarubicin Hydrochloride Injection, USP contains Idarubicin hydrochloride and is a sterile, semi-synthetic, preservative-free solution (PFS) antineoplastic anthracycline for intravenous use. Chemically, Idarubicin hydrochloride is 5, 12- Naphthacenedione, 9-acetyl-7-[(3-amino-2,3,6-trideoxy-α-L-lyxo-hexopyranosyl)oxy]-7,8,9,10-tetrahydro-6,9,11-trihydroxyhydrochloride, (7S-cis). The structural formula is as follows:

Idarubicin Hydrochloride Injection, USP is a sterile, red-orange, isotonic parenteral preservative-free solution, available in 5 mL (5 mg), 10 mL (10 mg) and 20 mL (20 mg) single dose only vials.

Each mL contains Idarubicin HCl, USP 1 mg and the following inactive ingredients: Glycerin, USP 25 mg and Water for Injection, USP q.s. Hydrochloric Acid, NF is used to adjust the pH to a target of 3.5.

CLINICAL PHARMACOLOGY:

Mechanism of Action

Idarubicin hydrochloride is a DNA-intercalating analog of daunorubicin which has an inhibitory effect on nucleic acid synthesis and interacts with the enzyme topoisomerase II.  The absence of a methoxy group at position 4 of the anthracycline structure gives the compound a high lipophilicity which results in an increased rate of cellular uptake compared with other anthracyclines.

Pharmacokinetics

General Pharmacokinetics

Pharmacokinetic studies have been performed in adult leukemia patients with normal renal and hepatic function following intravenous administration of 10 to 12 mg/m2 of Idarubicin daily for 3 to 4 days as a single agent or combined with cytarabine.  The plasma concentrations of Idarubicin are best described by a two or three compartment open model.  The elimination rate of Idarubicin from plasma is slow with an estimated mean terminal half-life of 22 hours (range, 4 to 48 hours) when used as a single agent and 20 hours (range, 7 to 38 hours) when used in combination with cytarabine.  The elimination of the primary active metabolite, Idarubicinol, is considerably slower than that of the parent drug with an estimated mean terminal half-life that exceeds 45 hours; hence, its plasma levels are sustained for a period greater than 8 days.

Distribution

The disposition profile shows a rapid distributive phase with a very high volume of distribution presumably reflecting extensive tissue binding.  Studies of cellular (nucleated blood and bone marrow cells) drug concentrations in leukemia patients have shown that peak cellular Idarubicin concentrations are reached a few minutes after injection.  Concentrations of Idarubicin and Idarubicinol in nucleated blood and bone marrow cells are more than a hundred times the plasma concentrations.  Idarubicin disappearance rates in plasma and cells were comparable with a terminal half-life of about 15 hours.  The terminal half-life of Idarubicinol in cells was about 72 hours.  The extent of drug and metabolite accumulation predicted in leukemia patients for Days 2 and 3 of dosing, based on the mean plasma levels and half-life obtained after the first dose, is 1.7- and 2.3-fold, respectively, and suggests no change in kinetics following a daily x 3 regimen.  The percentages of Idarubicin and Idarubicinol bound to human plasma proteins averaged 97% and 94%, respectively, at concentrations similar to maximum plasma levels obtained in the pharmacokinetic studies.  The binding is concentration independent.  The plasma clearance is twice the expected hepatic plasma flow indicating extensive extrahepatic metabolism.

Metabolism

The primary active metabolite formed is Idarubicinol.  As Idarubicinol has cytotoxic activity, it presumably contributes to the effects of Idarubicin.

Elimination

The drug is eliminated predominately by biliary and to a lesser extent by renal excretion, mostly in the form of Idarubicinol.

Pharmacokinetics in Special Populations

Pediatric Patients

Idarubicin studies in pediatric leukemia patients, at doses of 4.2 to 13.3 mg/m2/day x 3, suggest dose independent kinetics.  There is no difference between the half-lives of the drug following daily x 3 or weekly x 3 administration.  Cerebrospinal fluid (CSF) levels of Idarubicin and Idarubicinol were measured in pediatric leukemia patients treated intravenously.  Idarubicin was detected in 2 of 21 CSF samples  (0.14 and 1.57 ng/mL), while Idarubicinol was detected in 20 of these 21 CSF samples obtained 18 to 30 hours after dosing (mean = 0.51 ng/mL; range, 0.22 to 1.05 ng/mL).  The clinical relevance of these findings is unknown.

Hepatic and Renal Impairment

The pharmacokinetics of Idarubicin have not been evaluated in leukemia patients with hepatic impairment.  It is expected that in patients with moderate or severe hepatic dysfunction, the metabolism of Idarubicin may be impaired and lead to higher systemic drug levels.  The disposition of Idarubicin may be also affected by renal impairment.  Therefore, a dose reduction should be considered in patients with hepatic and/or renal impairment (see DOSAGE AND ADMINISTRATION).

Drug-Drug Interactions

No formal drug interaction studies have been performed.

CLINICAL STUDIES:

Four prospective randomized studies, three U.S. and one Italian, have been conducted to compare the efficacy and safety of Idarubicin (IDR) to that of daunorubicin (DNR), each in combination with cytarabine as induction therapy in previously untreated adult patients with acute myeloid leukemia (AML).  These data are summarized in the following table and demonstrate significantly greater complete remission rates for the IDR regimen in two of the three U.S. studies and significantly longer overall survival for the IDR regimen in two of the three U.S. studies.

*      Memorial Sloan Kettering Cancer Center

**    Southeastern Cancer Study Group

***  Gruppo Italiano Malattie Ematologiche Maligne dell’ Adulto

+        Overall p < 0.05, unadjusted for prognostic factors or multiple endpoints

a        Patients who had persistent leukemia after the first induction course received a second course

b        Cytarabine 25 mg/m2 bolus IV followed by 200 mg/m2 daily x 5 days by continuous infusion

c        Cytarabine 100 mg/m2 daily x 7 days by continuous infusion

There is no consensus regarding optional regimens to be used for consolidation; however, the following consolidation regimens were used in U.S. controlled trials.  Patients received the same anthracycline for consolidation as was used for induction.

Studies 1 and 3 utilized 2 courses of consolidation therapy consisting of Idarubicin 12 or 13 mg/m2daily for 2 days, respectively (or DNR 50 or 45 mg/m2 daily for 2 days), and cytarabine, either 25 mg/m2by IV bolus followed by 200 mg/m2 daily by continuous infusion for 4 days (Study 1), or 100 mg/m2daily for 5 days by continuous infusion (Study 3).  A rest period of 4 to 6 weeks is recommended prior to initiation of consolidation and between the courses.  Hematologic recovery is mandatory prior to initiation of each consolidation course.

Study 2 utilized 3 consolidation courses, administered at intervals of 21 days or upon hematologic recovery.  Each course consisted of Idarubicin 15 mg/m2 IV for 1 dose (or DNR 50 mg/m2 IV for 1 dose), cytarabine 100 mg/m2 every 12 hours for 10 doses and 6‑thioguanine 100 mg/m2 orally for 10 doses.  If severe myelosuppression occurred, subsequent courses were given with 25% reduction in the doses of all drugs.  In addition, this study included 4 courses of maintenance therapy (2 days of the same anthracycline as was used in induction and 5 days of cytarabine).

Toxicities and duration of aplasia were similar during induction on the 2 arms in the U.S. studies except for an increase in mucositis on the IDR arm in one study.  During consolidation, duration of aplasia on the IDR arm was longer in all three studies and mucositis was more frequent in two studies.  During consolidation, transfusion requirements were higher on the IDR arm in the two studies in which they were tabulated, and patients on the IDR arm in Study 3 spent more days on IV antibiotics (Study 3 used a higher dose of Idarubicin).

The benefit of consolidation and maintenance therapy in prolonging the duration of remission and survival is not proven.

Intensive maintenance with Idarubicin is not recommended in view of the considerable toxicity (including deaths in remission) experienced by patients during the maintenance phase of Study 2.

A higher induction death rate was noted in patients on the IDR arm in the Italian trial.  Since this was not noted in patients of similar age in the U.S. trials, one may speculate that it was due to a difference in the level of supportive care.

INDICATIONS AND USAGE:

Idarubicin Hydrochloride Injection, USP in combination with other approved antileukemic drugs is indicated for the treatment of acute myeloid leukemia (AML) in adults. This includes French-American-British (FAB) classifications M1 through M7.

WARNINGS:

Idarubicin is intended for administration under the supervision of a physician who is experienced in leukemia chemotherapy.

Idarubicin is a potent bone marrow suppressant.  Idarubicin should not be given to patients with pre-existing bone marrow suppression induced by previous drug therapy or radiotherapy unless the benefit warrants the risk.

Severe myelosuppression will occur in all patients given a therapeutic dose of this agent for induction, consolidation or maintenance.  Careful hematologic monitoring is required.  Deaths due to infection and/or bleeding have been reported during the period of severe myelosuppression.  Facilities with laboratory and supportive resources adequate to monitor drug tolerability and protect and maintain a patient compromised by drug toxicity should be available.  It must be possible to treat rapidly and completely a severe hemorrhagic condition and/or a severe infection.

Pre-existing heart disease and previous therapy with anthracyclines at high cumulative doses or other potentially cardiotoxic agents are co-factors for increased risk of Idarubicin-induced cardiac toxicity and the benefit to risk ratio of Idarubicin therapy in such patients should be weighed before starting treatment with Idarubicin.  Myocardial toxicity as manifested by potentially fatal congestive heart failure, acute life-threatening arrhythmias or other cardiomyopathies may occur following therapy with Idarubicin.  Appropriate therapeutic measures for the management of congestive heart failure and/or arrhythmias are indicated.

Cardiac function should be carefully monitored during treatment in order to minimize the risk of cardiac toxicity of the type described for other anthracycline compounds.  The risk of such myocardial toxicity may be higher following concomitant or previous radiation to the mediastinal-pericardial area or in patients with anemia, bone marrow depression, infections, leukemic pericarditis and/or myocarditis, active or dormant cardiovascular disease, previous therapy with other anthracyclines or anthracenediones, and concomitant use of drugs with the ability to suppress cardiac contractility or cardiotoxic drugs (e.g., trastuzumab, cyclophosphamide and paclitaxel).  Do not administer Idarubicin with other cardiotoxic agents unless the patient’s cardiac function is monitored frequently.  Patients receiving anthracyclines after stopping treatment with other cardiotoxic agents, especially those with long half-lives, may also be at an increased risk of developing cardiotoxicity.  Avoid the use of anthracycline-based therapy for at least 5 half-lives after discontinuation of the cardiotoxic agent.  If anthracyclines are used before this time, carefully monitor the cardiac function.  While there are no reliable means for predicting congestive heart failure, cardiomyopathy induced by anthracyclines is usually associated with a decrease of the left ventricular ejection fraction (LVEF) from pretreatment baseline values.

Since hepatic and/or renal function impairment can affect the disposition of Idarubicin, liver and kidney function should be evaluated with conventional clinical laboratory tests (using serum bilirubin and serum creatinine as indicators) prior to and during treatment.  In a number of Phase III clinical trials, treatment was not given if bilirubin and/or creatinine serum levels exceeded 2 mg%.  However, in one Phase III trial, patients with bilirubin levels between 2.6 and 5 mg% received the anthracycline with a 50% reduction in dose.  Dose reduction of Idarubicin should be considered if the bilirubin and/or creatinine levels are above the normal range (see DOSAGE AND ADMINISTRATION).

Pregnancy Category D

Idarubicin was embryotoxic and teratogenic in the rat at a dose of 1.2 mg/m2/day or one tenth the human dose, which was nontoxic to dams.  Idarubicin was embryotoxic but not teratogenic in the rabbit even at a dose of 2.4 mg/m2/day or two tenths the human dose, which was toxic to dams.  There is no conclusive information about Idarubicin adversely affecting human fertility or causing teratogenesis.  There has been one report of a fetal fatality after maternal exposure to Idarubicin during the second trimester.

There are no adequate and well-controlled studies in pregnant women.  If Idarubicin is to be used during pregnancy, or if the patient becomes pregnant during therapy, the patient should be apprised of the potential hazard to the fetus.  Women of childbearing potential should be advised to avoid pregnancy.

PRECAUTIONS:

General

Therapy with Idarubicin requires close observation of the patient and careful laboratory monitoring.  Hyperuricemia secondary to rapid lysis of leukemic cells may be induced.  Appropriate measures must be taken to prevent hyperuricemia and to control any systemic infection before beginning therapy.  Extravasation of Idarubicin can cause severe local tissue necrosis.  Extravasation may occur with or without an accompanying stinging or burning sensation even if blood returns well on aspiration of the infusion needle.  If signs or symptoms of extravasation occur the injection or infusion should be terminated immediately and restarted in another vein (see DOSAGE AND ADMINISTRATION).

Laboratory Tests

Frequent complete blood counts and monitoring of hepatic and renal function tests are recommended.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Formal long-term carcinogenicity studies have not been conducted with Idarubicin.  Idarubicin and related compounds have been shown to have mutagenic and carcinogenic properties when tested in experimental models (including bacterial systems, mammalian cells in culture and female Sprague-Dawley rats).

In male dogs given 1.8 mg/m2/day 3 times/week (about one seventh the weekly human dose on a mg/m2 basis) for 13 weeks, or 3 times the human dose, testicular atrophy was observed with inhibition of spermatogenesis and sperm maturation with few or no mature sperm.  These effects were not readily reversed after a recovery of 8 weeks.

Pregnancy Category D

(See WARNINGS.)

Nursing Mothers

It is not known whether this drug is excreted in human milk.  Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Idarubicin, mothers should discontinue nursing prior to taking this drug.

Pediatric Use

Safety and effectiveness in children have not been established.

Geriatric Use

Patients over 60 years of age who were undergoing induction therapy experienced congestive heart failure, serious arrhythmias, chest pain, myocardial infarction, and asymptomatic declines in LVEF more frequently than younger patients (see ADVERSE REACTIONS).

ADVERSE REACTIONS:

Approximately 550 patients with AML have received Idarubicin in combination with cytarabine in controlled clinical trials worldwide.  In addition, over 550 patients with acute leukemia have been treated in uncontrolled trials utilizing Idarubicin as a single agent or in combination.  The table below lists the adverse experiences reported in U.S. Study 2 (see CLINICAL STUDIES) and is representative of the experiences in other studies.  These adverse experiences constitute all reported or observed experiences, including those not considered to be drug related.  Patients undergoing induction therapy for AML are seriously ill due to their disease, are receiving multiple transfusions, and concomitant medications including potentially toxic antibiotics and antifungal agents.  The contribution of the study drug to the adverse experience profile is difficult to establish.

The duration of aplasia and incidence of mucositis were greater on the IDR arm than the DNR arm, especially during consolidation in some U.S. controlled trials (see CLINICAL STUDIES).

The following information reflects experience based on U.S. controlled clinical trials.

Myelosuppression

Severe myelosuppression is the major toxicity associated with Idarubicin therapy, but this effect of the drug is required in order to eradicate the leukemic clone.  During the period of myelosuppression, patients are at risk of developing infection and bleeding which may be life-threatening or fatal.

Gastrointestinal

Nausea and/or vomiting, mucositis, abdominal pain and diarrhea were reported frequently, but were severe (equivalent to WHO Grade 4) in less than 5% of patients.  Severe enterocolitis with perforation has been reported rarely.  The risk of perforation may be increased by instrumental intervention.  The possibility of perforation should be considered in patients who develop severe abdominal pain and appropriate steps for diagnosis and management should be taken.

Dermatologic

Alopecia was reported frequently and dermatologic reactions including generalized rash, urticaria and a bullous erythrodermatous rash of the palms and soles have occurred.  The dermatologic reactions were usually attributed to concomitant antibiotic therapy.  Local reactions including hives at the injection site have been reported.  Recall of skin reaction due to prior radiotherapy has occurred with Idarubicin administration.

Hepatic and Renal

Changes in hepatic and renal function tests have been observed.  These changes were usually transient and occurred in the setting of sepsis and while patients were receiving potentially hepatotoxic and nephrotoxic antibiotics and antifungal agents.  Severe changes in renal function (equivalent to WHO Grade 4) occurred in no more than 1% of patients, while severe changes in hepatic function (equivalent to WHO Grade 4) occurred in less than 5% of patients.

Cardiac

Congestive heart failure (frequently attributed to fluid overload), serious arrhythmias including atrial fibrillation, chest pain, myocardial infarction and asymptomatic declines in LVEF have been reported in patients undergoing induction therapy for AML.  Myocardial insufficiency and arrhythmias were usually reversible and occurred in the setting of sepsis, anemia and aggressive intravenous fluid administration.  The events were reported more frequently in patients over age 60 years and in those with pre-existing cardiac disease.

OVERDOSAGE:

There is no known antidote to Idarubicin. Two cases of fatal overdosage in patients receiving therapy for AML have been reported. The doses were 135 mg/m2 over 3 days and 45 mg/m2 of Idarubicin and 90 mg/m2 of daunorubicin over a three day period.

It is anticipated that overdosage with Idarubicin will result in severe and prolonged myelosuppression and possibly in increased severity of gastrointestinal toxicity. Adequate supportive care including platelet transfusions, antibiotics and symptomatic treatment of mucositis is required. The effect of acute overdose on cardiac function is not fully known, but severe arrhythmia occurred in 1 of the 2 patients exposed. It is anticipated that very high doses of Idarubicin may cause acute cardiac toxicity and may be associated with a higher incidence of delayed cardiac failure.

Disposition studies with Idarubicin in patients undergoing dialysis have not been carried out. The profound multicompartment behavior, extensive extravascular distribution and tissue binding, coupled with the low unbound fraction available in the plasma pool make it unlikely that therapeutic efficacy or toxicity would be altered by conventional peritoneal or hemodialysis.

DOSAGE AND ADMINISTRATION:

(See WARNINGS.)

For induction therapy in adult patients with AML the following dose schedule is recommended:

Idarubicin hydrochloride injection 12 mg/m2 daily for 3 days by slow (10 to 15 min) intravenous injection in combination with cytarabine. The cytarabine may be given as 100 mg/m2 daily by continuous infusion for 7 days or as cytarabine 25 mg/m2 intravenous bolus followed by cytarabine 200 mg/m2 daily for 5 days continuous infusion.  In patients with unequivocal evidence of leukemia after the first induction course, a second course may be administered. Administration of the second course should be delayed in patients who experience severe mucositis, until recovery from this toxicity has occurred, and a dose reduction of 25% is recommended. In patients with hepatic and/or renal impairment, a dose reduction of Idarubicin hydrochloride injection should be considered. Idarubicin hydrochloride injection should not be administered if the bilirubin level exceeds 5 mg% (see WARNINGS).

The benefit of consolidation in prolonging the duration of remissions and survival is not proven. There is no consensus regarding optional regimens to be used for consolidation (see CLINICAL STUDIES for doses used in U.S. clinical studies).

Preparation and Administration Precautions

Caution in handling the solution must be exercised as skin reactions associated with Idarubicin Hydrochloride Injection may occur.  Skin accidentally exposed to Idarubicin Hydrochloride Injection should be washed thoroughly with soap and water and if the eyes are involved, standard irrigation techniques should be used immediately.  The use of goggles, gloves, and protective gowns is recommended during preparation and administration of the drug.

Care in the administration of Idarubicin Hydrochloride Injection will reduce the chance of perivenous infiltration.  It may also decrease the chance of local reactions such as urticaria and erythematous streaking.  During intravenous administration of Idarubicin Hydrochloride Injection extravasation may occur with or without an accompanying stinging or burning sensation even if blood returns well on aspiration of the infusion needle.  If any signs or symptoms of extravasation have occurred, the injection or infusion should be immediately terminated and restarted in another vein.  If it is known or suspected that subcutaneous extravasation has occurred, it is recommended that intermittent ice packs (1/2 hour immediately, then 1/2 hour 4 times per day for 3 days) be placed over the area of extravasation and that the affected extremity be elevated.  Because of the progressive nature of extravasation reactions, the area of injection should be frequently examined and plastic surgery consultation obtained early if there is any sign of a local reaction such as pain, erythema, edema or vesication.  If ulceration begins or there is severe persistent pain at the site of extravasation, early wide excision of the involved area should be considered.

Idarubicin Hydrochloride Injection should be administered slowly (over 10 to 15 minutes) into the tubing of a freely running intravenous infusion of Sodium Chloride Injection, USP (0.9%) or 5% Dextrose Injection, USP.  The tubing should be attached to a Butterfly needle or other suitable device and inserted preferably into a large vein.

Incompatibility

Unless specific compatibility data are available, Idarubicin Hydrochloride Injection should not be mixed with other drugs.  Precipitation occurs with heparin.  Prolonged contact with any solution of an alkaline pH will result in degradation of the drug.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and containers permit.

Handling and Disposal

Procedures for handling and disposal of anticancer drugs should be considered.  Several guidelines on this subject have been published.1-8  There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate.

 HOW SUPPLIED:

Idarubicin Hydrochloride Injection, USP contains no preservative and is for single dose only.

REFRIGERATE AT:  2° to 8°C (36° to 46°F).
Protect from light (keep in outer carton).

The container closure is not made with natural rubber latex.

REFERENCES:

1.    ONS Clinical Practice Committee. Cancer Chemotherapy Guidelines and Recommendations for Practice. Pittsburgh, PA: Oncology Nursing Society. 1999: 32-41.

2.    Recommendations for the Safe Handling of Parenteral Antineoplastic Drugs. Washington, DC; Division of Safety, Clinical Center Pharmacy Department and Cancer Nursing Services, National Institutes of Health; 1992. US Department of Health and Human Services, Public Health Service Publication NIH 92-2621.

3.    AMA Council on Scientific Affairs. Guidelines for Handling Parenteral Antineoplastics. JAMA. 1985; 253: 1590-1591.

4.    National Study Commission on Cytotoxic Exposure - Recommendations for Handling Cytotoxic Agents. 1987. Available from Louis P. Jeffrey, Sc.D., Chairman, National Study Commission on Cytotoxic Exposure, Massachusetts College of Pharmacy and Allied Health Sciences, 179 Longwood Avenue, Boston, MA 02115.

5.    Clinical Oncological Society of Australia: Guidelines and Recommendations for Safe Handling of Antineoplastic Agents. Med J Australia. 1983; 1:426-428.

6.    Jones RB, Frank R, Mass T. Safe Handling of Chemotherapeutic Agents: A Report from the Mount Sinai Medical Center. CA Cancer J Clin. 1983; 33: 258-263.

7.    American Society of Hospital Pharmacists. ASHP Technical Assistance Bulletin on Handling Cytotoxic and Hazardous Drugs. Am J Hosp Pharm. 1990; 47:1033-1049.

8.    Controlling Occupational Exposure to Hazardous Drugs (OSHA Work-Practice Guidelines). Am J Health-Syst Pharm. 1996; 53: 1669-1685.

Revised: 05/2017

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