· 【产品名称】注射用盐酸伊达比星

· 【商品名/商标】

善唯达

· 【规格】10mg

· 【性状】橙红色疏松冻干块状物。

· 【适应症】

成人急性非淋巴细胞性白血病(ANLL)。伊达比星作为一线用药用于复发和难治病人的诱导缓解。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)。

· 【用法用量】急性非淋巴细胞性白血病(ANLL)：在成人急性髓性白血病，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/m[sup]2[/sup]，连续使用三天，另一种用法为单独和联合用药，推荐剂量为每天静脉注射8mg/m[sup]2[/sup]，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按体表面积计算每天静脉注入12mg/m[sup]2[/sup]，连续使用三天；儿童10mg/m[sup]2[/sup]，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。

· 【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】严惩肝肾功能不全感染未得到控制曾接受药物或放射治疗引起骨髓抑制心脏病患者。

· 【注意事项】严惩肝肾功能不全，感染未得到控制，曾接受药物或放射治疗引起骨髓抑制，心脏病患者。妊娠及哺乳妇女。 老年人、高尿酸摁症患者及全身性感染病人慎用。治疗过程中或药几周内，可能发生心毒性反应，即潜在性、致肌病，表现为持续性的QRS低电压，收新时期延长(PEP/LVET)，左心室射血分数减低。出现这些反应时可用洋地黄、利尿剂、制钠盐及臣床休息等措施。治疗过程中应注意监测心脏功能。纵隔心包区有过治疗，用过潜在性心脏毒性药物。伴有其它疾病（如贫血、骨髓抑制、感染、心肌炎）者。心脏毒性反应则更大。本药是骨髓抑制剂，除非 大于弊的情况下，否则由于先前药物治疗或放疗引起骨髓抑制的病人不可使用本药。治疗剂量道德对白细胞有抑制作用，治疗时应注意监测粒性白细胞，红细胞和血站板。在治疗前和治疗中应监测肝和肾功能（血清胆红素、肌酐），如果胆红素或血清肌酐水平的1.2-2MG%，剂量应该减半，胆红或血清肌酐超过2MG%出不予给药。注意血中尿酸的浓度。静脉注射外渗会引起严惩的局部组织坏死，注射部位如果有蛰伤或灼热感，应马上停止，选用另一个静脉注射。对妊娠和哺乳的影响没有方献报道本药会影响人的生育能力或引起畸胎， 但对大鼠能致畸，具有胚胎毒性。生育期的妇女应该避，如用于孕妇或病人在治疗过程中怀孕，应告诉病人本药对胎儿有潜在的危害，用本药治疗的妇女不能哺乳。

· 【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。

· 【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。

· 【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。此外，发现对大鼠有生殖毒性、胚胎毒性和致畸性。在出生前后伊达比星静脉给药剂量高至0.2mg/kg/天时，未发现对大鼠亲代、子代有明显的影响。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。狗的局部耐受性实验显示药物益处可导致组织坏死。

· 【药物过量】过大剂量的伊达比星可能在24小时内引起急性心肌中毒，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，一旦出现心力衰竭征象时应予以常规治疗。

· 【药代动力学】肝肾功能正常的病人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肾脏排出体外。在白血病人体内进行的细胞药物浓度(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浓度高一千倍以上。伊达比星和伊达比星醇在血浆和细胞中的消除速率与其终末半衰期相当，约15小时。伊达比星醇在细胞内的终末半衰期大约是72小时。

 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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