Manufacturer：

Bristol-Myers Squibb
Legal Classification：

Rx
Pharmacological Class：

Epothilone microtubule inhibitor.
Generic Name：Ixabepilone 15mg/vial, 45mg/vial; pwd; for IV infusion after constitution and dilution; diluent contains alcohol, polyoxyethylated castor oil.
Indications：Metastatic or locally advanced breast cancer: In combination with capecitabine after failure of an anthracycline and a taxane; and as monotherapy after failure of an anthracycline, a taxane, and capecitabine.
Children
Not recommended.
Adults
Pretreat with both H1 and H2 blockers 1 hr before infusion; and with steroid if previous hypersensitivity reaction occurred. 40mg/m2 by IV infusion over 3 hrs, once every 3 weeks. Use max body surface area (BSA) of 2.2m2 to calculate dose if BSA >2.2m2. Moderate hepatic impairment (as monotherapy): initially 20mg/m2 per dose; max 30mg/m2 per dose (see literature). Neuropathy, myelosuppression, concomitant CYP3A4 inhibitors: reduce dose (see literature).

Contraindications

Baseline neutrophils <1500cells/mm3 or platelets <100,000/mm3. AST or ALT >2.5xULN or bilirubin >1xULN (in combination with capecitabine).
Precautions
Monitor liver function at baseline and periodically. Hepatic impairment (ALT or AST >10xULN or bilirubin >3xULN: not recommended; ALT or AST >5xULN: limited data, use caution). Diabetes. Neuropathy. Cardiac disease (discontinue if cardiac ischemia or cardiac dysfunction occurs). Monitor for neuropathy, neutropenia. Pregnancy (Cat.D), nursing mothers: not recommended.
Interactions
Potentiated by strong CYP3A4 inhibitors; avoid (eg, azole antifungals, protease inhibitors, certain macrolides, nefazodone, grapefruit juice). Antagonized by strong CYP3A4 inducers (eg, phenytoin, carbamazepine, rifampin, phenobarbital). Avoid St. John's wort.
Adverse Reactions
Peripheral sensory neuropathy, fatigue, asthenia, myalgia, arthralgia, alopecia, GI upset, stomatitis, mucositis, musculoskeletalpain,palmarplantarerythrodysesthesia syndrome, anorexia, abdominal pain, nail disorder; myelosuppression (neutropenia, leukopenia, anemia, thrombocytopenia); hypersensitivity reactions; others.
How Supplied
Kit—1 vial (w. diluent)

在31届欧洲医学肿瘤学协会年会（2006年9-10月在土耳其伊斯坦布尔召开）上公布的II期临床研究数据显示，Ixabepilone，一种半合成的epothilone B内酰胺类似物，在患者身上显示了良好的抗肿瘤作用，尤其是难治性乳腺癌的病人。第一个临床试验中包括了恶性乳腺癌的病例，尽管这些病人同时接受着阿霉素、紫杉醇、卡倍他滨治疗，但是病情未有效控制仍然有所进展。 对于这些高度难治性人群，Ixabepilone单独用药，客观反应率能够达到18%。 第二个临床试验评价了Ixabepilone和卡倍他滨联合应用，用于以前接受过阿霉素和紫杉醇治疗的恶性乳腺癌的病人。对于雌激素受体、孕激素受体和HER2三项全部阴性的病人亚群，部分反应率达到23%。
　　
Ixabepilone（BMS-247550; epothilone）是由百时美施贵宝公司开发的新一代抗有丝分裂药物。其作用机制与紫杉醇类似，最早是一种具有细胞毒作用并可抗微生物的细菌Sorangium cellulosum所自然产生的大环内酯（macrolides）类物质，半合成制成Ixabepilone。
　　
百时美施贵宝公司进行了一项临床II期试验，目的在于评价Ixabepilone单独给药对于对阿霉素、紫杉醇、卡陪他滨耐药的恶性乳腺癌患者的治疗效果，这项研究的结果公布在欧洲肿瘤医学肿瘤学协会2006年的年会上。
　　
临床试验入选的病例为恶性乳腺癌患者，这些病人以前虽然接受了8周以内的阿霉素、紫杉醇和卡陪他滨的化疗，但是仍然病情恶化。无论病人是否接受过辅助治疗，只要在接受阿霉素、紫杉醇、卡陪他滨进行药物化疗的6个月内病情复发，都可以作为入选的病例。 另外，一些同时对紫杉醇和卡陪他滨耐药的患者也在入选之列。
　　
总共有126名病例，接受了Ixabepilone每三周 40mg/m2, 静脉注射给药，最多18个周期的治疗。药物反应率由一家独立放射学评价委员会（IRRC）和本项试验研究人员依照RECIST标准进行评价。
入选病例基本情况：平均年龄51岁，karnofsky 行为能力70-100%，70%的病人有肝脏转移，88%的病例之前接受过两个疗程以上的恶性肿瘤药物治疗。病人治疗周期的中位数为4（1-16个周期），25%的病人接受8个或以上周期的给药。
　　
耐药肿瘤的治疗效果
　　
对接受治疗的126名病例进行了评价，独立放射评价委员会（IRRC）统计的客观反应率为11.1%, 研究人员评估的客观反应率为18.3%, 在反应可评价人群中（113人），客观反应率相似，相应的由独立放射评价委员会（IRRC）和研究人员统计的客观反应率分别为11.5%和 18.6%。
　　
在所有的治疗组别，反应出现的中位时间为6.1周，反应持续的中位时间为5.3个月。 病情无进展生存时间和总生存时间的中位数分别为3.1个月和 8.6个月；6个月生存率为68.2%。（见表-1）
　　
表-1 耐药性患者的疗效结果
　　
药物 Ixabepilone n=126 95% 置信区间
客观反应率（%）
独立放射评价委员会IRRC 11.1 6.2，17.9
研究人员 18.3 11.9，26.1
反应持续时间
中值（月） 5.3
反应开始时间
中值（周） 6.1
无病情进展生存时间
中值（月） 3.1 2.7，3.9
总生存时间
中值（月） 8.6 7.1，11.1
生存率
6个月生存率（%病人） 68.2 59.9，76.4
　　
不良反应可以控制
　　
54%的患者发生了3-4级的中性粒细胞减少症，一例与治疗相关的病人死亡是由于发生了脓毒血症和中性粒细胞减少。之前的报道显示90%的治疗病人发生了包括不同程度的骨髓抑制，包括白细胞减少等，严重的骨髓抑制可通过延迟给药时间和或减少给药剂量来控制。最常见的与治疗相关的3-4级的不良反应是外周感觉神经元病变（sensory peripheral neuropathy）、疲乏、肌痛、口腔炎。(见表-2)
　　
表-2 耐药性患者耐受性结果
　　
3/4级不良反应(%) Ixabepilone
外周感觉神经元病变Sensory peripheral neuropathy 14
疲乏 10
肌痛 7
口腔炎 6
　　
意大利Prato医院的Angelo di Leo博士 表示“这些资料不能支持Ixabepilone用作二线治疗药物”，并且补充说Ixabepilone可能更适合作为一线治疗药物，用于以往进行了阿霉素和紫杉醇或者新近辅助治疗的病人。
　　
研究负责人指出，尽管有6名病人由于外周感觉神经元病变（sensory peripheralneuropathy） 中断了实验，但是这种不良反应是累积性和可逆性的。对于3级神经病的中位解决时间是5.4周。研究者总结说，ixabepilone 对于这些难治性的病例显示出令人鼓舞的抗癌作用，和可控制的不良反应。
　　
Ixabepilone联合用药对于三阴的病人作用良好
雌激素受体阴性、孕激素受体阴性和HER-2阴性的患者是乳腺癌一种独特的亚型， 由于缺少相应有效的治疗选择，这类的乳腺癌病例尤其难治。根据Script的报道，这种三阴的乳腺癌预后差，相比其他类型的乳腺癌75%的总体生存率，这种三阴类型的乳腺癌只有67%的总体生存率。
　　
为了进一步确定Ixabepilone与卡倍他滨联合治疗II、III临床试验的剂量，首先进行了I/II临床试验。那些接受过三个方案以上化疗的病例被排除在入选病例之外。
　　
总共106名病人进行了该项试验，病人接受了于第一天三个小时滴注的Ixabepilone 40mg/m2或者是3天每次一个小时的Ixabepilone 40mg/m2的滴注，病人同时在21天的治疗周期的1-14天口服2000mg/m2的卡倍他滨。接受第一天3个小时Ixabepilone治疗病人的实验结果在ESMO会议上公布。
　　
分析的62名病例中，15名病人（24%）获得了客观反应，包括一名完全反应病例和14名部分反应病例。在22名三阴的病人中，5名（23%）达到部分反应。
　　
对这些接受Ixabepilone和卡倍他滨联合治疗的62名病人进行了药物的耐受性评价，外周神经病的问题尤为突出。二级的外周神经病发生率为31%的病人，3级外周神经病发生在21%的病人身上，但是94%病例的神经病变得到缓解，中位缓解时间为2.6周。总共有63%报告有手足症状综合症，主要是二级和三级。有27%的病人由于不良反应停止了治疗。主要的血液学异常为1-3级的白细胞减少和中性粒细胞减少，4级的白细胞减少症和中性粒细胞减少在病人中的发生率分别为12%和26%。
　　
Ixabepilone( BMS 施贵宝)在美国进行乳腺癌的III期临床试验，并在美国进行前列腺癌、胰腺癌和肾癌为适应症的II期临床试验。

IXEMPRA INJ 15毫克 KIT ( ixabepilone)
IXEMPRA INJ 45毫克 KIT ( ixabepilone)
Important Safety Information

Toxicity in hepatic impairment

IXEMPRA (ixabepilone) in combination with capecitabine is contraindicated in patients with AST or ALT >2.5 x ULN or bilirubin >1 x ULN due to increased risk of toxicity and neutropenia-related death.
 
In combination with capecitabine, the overall frequency of Grade 3/4 adverse reactions, febrile neutropenia, serious adverse reactions, and toxicity related deaths was greater in patients with hepatic impairment.
Caution should be used when using IXEMPRA as monotherapy in patients with AST or ALT >5 x ULN. Use of IXEMPRA in patients with AST or ALT >10 x ULN or bilirubin >3 x ULN is not recommended.
With monotherapy, Grade 4 neutropenia, febrile neutropenia, and serious adverse reactions were more frequent in patients with hepatic impairment.
Contraindications

IXEMPRA is contraindicated in patients:

with a known history of a severe (CTC Grade 3/4) hypersensitivity reaction to agents containing Cremophor® EL or its derivatives such as polyoxyethylated castor oil.
who have a baseline neutrophil count <1500 cells/mm3 or a platelet count <100,000 cells/mm3.

Peripheral neuropathy

Patients treated with IXEMPRA should be monitored for symptoms of neuropathy, such as burning sensation, hyperesthesia, hypoesthesia, paresthesia, discomfort, or neuropathic pain. Patients experiencing new or worseningperipheralneuropathy may require changes in the dose or discontinuation of IXEMPRA. Neuropathy was the most frequent cause of treatment discontinuation due to drug toxicity. Caution should be used when treating patients with diabetes mellitus or existing moderate to severe neuropathy.

Myelosuppression

Patients should be monitored for myelosuppression; frequent peripheral blood cell counts are recommended for all patients receiving IXEMPRA.
Patients who experience severe neutropenia or thrombocytopenia should have their dose reduced. Neutropenia related deaths occurred in patients administered IXEMPRA and capecitabine (1.9% of 414 patients) and IXEMPRA alone (0.4% in 240 patients).

Hypersensitivity reaction

Premedicate with an H1 and an H2 antagonist approximately 1 hour before IXEMPRA infusion and observe for hypersensitivity reactions (e.g., flushing, rash, dyspnea, and bronchospasm).
In case of severe hypersensitivity reactions, infusion of IXEMPRA should be stopped and aggressive supportive treatment (e.g., epinephrine, corticosteroids) started.
Patients who experience a hypersensitivity reaction in one cycle of IXEMPRA must be premedicated in subsequent cycles with a corticosteroid in addition to the H1 and H2 antagonists, and extension of the infusion time should be considered.
Pregnancy

Women should be advised not to become pregnant when taking IXEMPRA. If this drug is used during pregnancy or the patient becomes pregnant, the patient should be apprised of the potential hazard to the fetus.

Cardiac adverse reactions

Caution should be exercised in patients with a history of cardiac disease. Discontinuation of IXEMPRA should be considered in patients who develop cardiac ischemia or impaired cardiac function due to reports of cardiovascular adverse reactions (e.g., myocardial ischemia, superventricular arrhythmia, and ventricular dysfunction). The frequency of cardiac adverse reactions (myocardial ischemia and ventricular dysfunction) was higher in the IXEMPRA in combinationwithcapecitabine (1.9%) than in the capecitabine alone (0.3%) treatment group.

Potential for cognitive impairment from excipients

IXEMPRA contains dehydrated alcohol USP. Consideration should be given to the possibility of central nervous system and other effects of alcohol.

Adverse reactions

The most common adverse reactions (greater than or equal to 20%) reported by patients receiving IXEMPRA were peripheral sensory neuropathy, fatigue/asthenia, myalgia/arthralgia, alopecia, nausea, vomiting, stomatitis/mucositis, diarrhea, and musculoskeletal pain.  The following additional events occurred in greater than or equal to 20% in combination treatment: palmar-plantar erythrodysesthesia (hand-foot) syndrome, anorexia, abdominal pain, nail disorder, and constipation. Drug-associated hematologic abnormalities (>40%) include neutropenia, leukopenia, anemia, and thrombocytopenia.

价格：
IXEMPRA INJ 15毫克 KIT ( ixabepilone)
IXEMPRA INJ 45毫克 KIT ( ixabepilone)