柔红霉素/阿糖胞苷复方冻干粉注射剂(Vyxeos)

通用名：Daunorubicin and cytarabine

商品名：Vyxeos

全部名称：柔红霉素/阿糖胞苷复方冻干粉注射剂，Vyxeos，Daunorubicin and cytarabine

适应症

治疗相关性急性髓系白血病（t-AML）和伴骨髓增生异常相关改变的急性髓细胞白血病（AML-MRC）

用法用量

1、诱导治疗：VYXEOS 每单位剂量/㎡(即Daunorubicin 44 mg/㎡ 及Cytarabine 100 mg/㎡)，静脉输注超过90分钟，第一周期在第1,3,5天使用，间隔2~5周后进行第二周期用药（若无不可接受的毒性反应），第二周期在第1,3天使用。

2、巩固治疗：在诱导治疗后5~8周开始，VYXEOS 2/3单位剂量/㎡(即Daunorubicin 29 mg/㎡ 及Cytarabine 65 mg/㎡)，静脉输注超过90分钟，第1,3天使用；间隔周期为5~8周，至少使用2个巩固治疗周期。

不良反应

1、最常见的不良反应（发生率≥25％）：

1）出血事件，发热性中性粒细胞减少，皮疹

2）水肿，恶心，黏膜炎，腹泻，便秘，肌肉骨骼疼痛

3）乏力，腹痛，呼吸困难，头痛，咳嗽，食欲减退

4）心律失常，肺炎，菌血症，寒战，睡眠障碍和呕吐

禁忌

禁止使用其他含有柔红霉素和阿糖胞苷的产品替换本品。

对柔红霉素，阿糖胞苷或制剂中任何成分过敏。

注意事项

（1）严重或致命出血伴持续性血小板减少：在恢复正常前需监测血细胞计数。

（2）心脏毒性：不建议心脏功能差的患者使用VYXEOS。心脏功能受损的患者应终止使用VYXEOS，除非使用VYXEOS利大于弊。

（3）若发生重度或危及生命的过敏反应，停止使用VYXEOS，使用标准处理方法给予治疗，监测直到症状体征缓解。

（4）柔红霉素可能导致药物溢出部位的局部组织坏死，输注时需要注意监测。

（5）胚胎毒性：可能致胎儿危害。告知患者对胎儿的潜在风险和使用有效避孕。

贮藏

将未重构的VYXEOS样品瓶存放在冰箱中，温度为2°C至8°C（36°F至46°F），直立。

小瓶应存放在其原始纸箱中以防光。

作用机制

用于注射的VYXEOS（柔红霉素和阿糖胞苷）脂质体是柔红霉素和阿糖胞苷的脂质体制剂，其固定的摩尔比为1：5。已显示柔红霉素：阿糖胞苷的1：5摩尔比在体外和鼠模型中杀死白血病细胞具有协同作用。

柔红霉素具有抗有丝分裂和细胞毒活性，其特征在于DNA形成，抑制拓扑异构酶II活性，抑制DNA聚合酶活性，影响基因表达的调节和DNA损伤自由基。阿糖胞苷是细胞周期阶段特异性抗肿瘤剂，仅在细胞分裂的S期期间影响细胞。阿糖胞苷通过抑制DNA聚合酶起作用。

基于动物数据，脂质体进入并持续存在于骨髓中，在那里它们被骨髓细胞完整地取出。在携带白血病的小鼠中，脂质体被白血病细胞摄取的程度大于正常骨髓细胞。细胞内化后，脂质体经历降解，在细胞内环境中释放出阿糖胞苷和柔红霉素。

安全与疗效

Vyxeos，原名为CPX-351，是阿糖胞苷和柔红霉素按照 5：1的比例组合的脂质体，可增加协同作用，减少拮抗作用。

在一项重要的3期临床试验中，研究人员比较了Vyxeos和单用“7+3”方案（柔红霉素及阿糖胞苷）对309 名新诊断的t-AML 或 AML-MRC患者的安全性和有效性。

主要终点是总生存期（OS）。结果显示，Vyxeos表现出显著的优势：中位OS为9.6个月，而对照组为5.9个月（p = 0.005；HR=0.69；95%CI，0.52 - 0.90）；完全缓解率为38% vs 26%，有统计学意义的改善（P =0. 036）；整体上，30天的死亡率为6% vs 11%。

Vyxeos(cytarabine/ daunorubicin liposomal)

Indication

VYXEOS (daunorubicin and cytarabine) liposome for injection 44 mg/100 mg is indicated for the treatment of adults with newly-diagnosed therapy-related acute myeloid leukemia (t-AML) or AML with myelodysplasia-related changes (AML-MRC).

Important Safety Information

WARNING:

DO NOT INTERCHANGE WITH OTHER DAUNORUBICIN AND/OR CYTARABINE-CONTAINING PRODUCTS

VYXEOS has different dosage recommendations than daunorubicin hydrochloride injection, cytarabine injection, daunorubicin citrate liposome injection, and cytarabine liposome injection. Verify drug name and dose prior to preparation and administration to avoid dosing errors.

Contraindications

VYXEOS is contraindicated in patients with a history of serious hypersensitivity reactions to cytarabine, daunorubicin, or any component of the formulation.

Warnings and Precautions

Hemorrhage

Serious or fatal hemorrhage events, including fatal CNS hemorrhages, associated with prolonged thrombocytopenia, have occurred with VYXEOS. The overall incidence (grade 1-5) of hemorrhagic events was 74% in the VYXEOS arm and 56% in the control arm. The most frequently reported hemorrhagic event was epistaxis (36% in VYXEOS arm and 18% in control arm). Grade 3 or greater events occurred in 12% of VYXEOS-treated patients and in 8% of patients in the control arm. Fatal treatment-emergent CNS hemorrhage not in the setting of progressive disease occurred in 2% of patients in the VYXEOS arm and in 0.7% of patients in the control arm. Monitor blood counts regularly and administer platelet transfusion support as required.

Cardiotoxicity

VYXEOS contains daunorubicin, which has a known risk of cardiotoxicity. This risk may be increased in patients with prior anthracycline therapy, preexisting cardiac disease, previous radiotherapy to the mediastinum, or concomitant use of cardiotoxic drugs. Assess cardiac function prior to VYXEOS treatment and repeat prior to consolidation and as clinically required. Discontinue VYXEOS in patients with impaired cardiac function unless the benefit of initiating or continuing treatment outweighs the risk. VYXEOS is not recommended in patients with cardiac function that is less than normal.

Total cumulative doses of non-liposomal daunorubicin greater than 550 mg/m2 have been associated with an increased incidence of drug-induced congestive heart failure. The tolerable limit appears lower (400 mg/m2) in patients who received radiation therapy to the mediastinum. Calculate the lifetime cumulative anthracycline exposure prior to each cycle of VYXEOS. VYXEOS is not recommended in patients whose lifetime anthracycline exposure has reached the maximum cumulative limit.

Hypersensitivity Reactions

Serious or fatal hypersensitivity reactions, including anaphylactic reactions, have been reported with daunorubicin and cytarabine. Monitor patients for hypersensitivity reactions. If a mild or moderate hypersensitivity reaction occurs, interrupt or slow the rate of infusion with VYXEOS and manage symptoms. If a severe or life-threatening hypersensitivity reaction occurs, discontinue VYXEOS permanently, treat the symptoms, and monitor until symptoms resolve.

Copper Overload

VYXEOS contains copper. Consult with a hepatologist and nephrologist with expertise in managing acute copper toxicity in patients with Wilson’s disease treated with VYXEOS. Monitor total serum copper, serum non-ceruloplasmin-bound copper, 24-hour urine copper levels, and serial neuropsychological examinations during VYXEOS treatment in patients with Wilson’s disease or other copper-related metabolic disorders. Use only if the benefits outweigh the risks. Discontinue in patients with signs or symptoms of acute copper toxicity.

Tissue Necrosis

Daunorubicin has been associated with severe local tissue necrosis at the site of drug extravasation. Administer VYXEOS by the intravenous route only. Do not administer by intramuscular or subcutaneous route.

Embryo-Fetal Toxicity

VYXEOS can cause embryo-fetal harm when administered to a pregnant woman. Patients should avoid becoming pregnant while taking VYXEOS. If VYXEOS is used during pregnancy or if the patient becomes pregnant while taking VYXEOS, apprise the patient of the potential risk to a fetus. Advise females and males of reproductive potential to use effective contraception during treatment and for 6 months following the last dose of VYXEOS.

Most Common Adverse Reactions

The most common adverse reactions (incidence ≥25%) were hemorrhagic events (74%), febrile neutropenia (70%), rash (56%), edema (55%), nausea (49%), mucositis (48%), diarrhea (48%), constipation (42%), musculoskeletal pain (43%), fatigue (39%), abdominal pain (36%), dyspnea (36%), headache (35%), cough (35%), decreased appetite (33%), arrhythmia (31%), pneumonia (31%), bacteremia (29%), chills (27%), sleep disorders (26%), and vomiting (25%).

完整说明书详见：https://nctr-crs.fda.gov/fdalabel/services/spl/set-ids/7ea701ce-e7d3-4349-a9c2-642a501d45c8/spl-doc?hl=Vyxeos