英文药名：BESPONSA（inotuzumab ozogamicin for Injection）

中文药名：奥英妥珠单抗冻干注射剂

生产厂家：辉瑞制药
药品简介
BESPONSA（inotuzumab ozogamicin）冻干注射剂获FDA批准上市，BESPONSA是首个也是唯一一种CD22靶向抗体药物偶联物, 用于治疗成人复发或难治性前体B细胞急性淋巴细胞白血病.
批准日期：2017年8月17日 公司：辉瑞公司
BESPONSA(inotuzumab ozogamicin)冻干注射剂，为静脉使用
美国初始批注：2017
作用机制
Inotuzumab ozogamicin是一个指向CD22抗体-药物结合物(ADC)。Inotuzumab识别人CD22。小分子，N-乙酰l-ɣ-calicheamicin，是一种细胞毒药物被共价地附着至抗体通过一个连接物。非临床数据提示inotuzumab ozogamicin的抗癌活性是由于ADC结合至CD22-表达肿瘤细胞，接着通过ADC-CD22复合物的内化作用，和通过连接物的水解裂解在细胞内释放N-乙酰基-γ-卡奇霉素丁酰肼[dimethylhydrazide]。N-乙酰基-γ-卡奇霉素丁酰肼的活化丁酰肼诱导双链DNA断裂，随后诱导细胞周期停止和凋亡细胞死亡。
适应证和用途
BESPONSA是一种指向CD22抗体-药物结合物(ADC)适用为有复发或难治性B-细胞前体急性淋巴原始细胞性白血病(ALL)成年的治疗。
剂量和给药方法
●在所有输注前用一种皮质激素，解热药，和抗组织胺预先给药。
● 对疗程1和随后疗程给药方案，依赖于对治疗反应被显示如下。对给药细节见完整处方资料。

●对冻干粉的重建和制备和重建药物的给药指导见完整处方资料。
剂型和规格
注射用：0.9 mg冻干粉在单次-剂量小瓶为重建和进一步稀释。
禁忌证
无。
警告和注意事项
●骨髓抑制：监视完全血细胞计数；对感染的体征和症状；出血；或治疗期间骨髓抑制其他效应；适当地处理。
●输注相关反应：输注结束期间和后至少监视输注相关反应。
●QT间期延长：在基线和监视治疗期间得到心电图(ECGs)和电解质。当用同时药物已知延长QT间期监视更频。
●胚胎-胎儿毒性：可能致胎儿危害。忠告有生殖潜能女性对胎儿潜在风险和使用有效避孕。
不良反应
最常见(≥ 20%)不良反应是血小板减少，中性细胞减少，感染，贫血，白细胞减少，疲乏，出血，发热，恶心，头痛，发热性中性细胞减少，转氨酶增加，腹痛，-谷氨酸转氨酶增加，和高胆固醇血症。
在特殊人群中使用
哺乳：建议不哺乳喂养。
包装规格/贮存和处置
供应
注射用BESPONSA(inotuzumab ozogamicin)是被供应如一个白色至灰白色冻干粉在一个单次-剂量小瓶为重建和进一步稀释。每小瓶输送0.9 mg inotuzumab ozogamicin。每纸盒(NDC 0008-0100-01)含一个单次-剂量小瓶。
贮存和处置
冰箱(2-8°C；36-46°F) BESPONSA小瓶和贮存在原始纸盒避光保护。不要冻结。
BESPONSA是一种细胞毒药物。遵循可行的特异性处置和遗弃方法步骤。

BESPONSA® (inotuzumab ozogamicin) Approved for Treatment of Adult Relapsed or Refractory B-cell Precursor Acute Lymphoblastic Leukemia, Available for Order at Biologics, Inc
General Information
Besponsa (inotuzumab ozogamicin) is a CD22-directed antibody-drug conjugate (ADC).
Besponsa is specifically indicated for the treatment of adults with relapsed or refractory B-cell precursor acute lymphoblastic leukemia.
Besponsa is supplied as a solution for intravenous injection. The recommended dose schedule is as follows:
For the first cycle: the recommended total dose of Besponsa for all patients is 1.8 mg/m2 per cycle, administered as 3 divided doses on Day 1 (0.8 mg/m2), Day 8 (0.5 mg/m2), and Day 15 (0.5 mg/m2). Cycle 1 is 3 weeks in duration, but may be extended to 4 weeks if the patient achieves a complete remission (CR) or complete remission with incomplete hematologic recovery (CRi), and/or to allow recovery from toxicity. 
For subsequent cycles: In patients who achieve a CR or CRi, the recommended total dose of Besponsa is 1.5 mg/m2per cycle, administered as 3 divided doses on Day 1 (0.5 mg/m2), Day 8 (0.5 mg/m2), and Day 15 (0.5 mg/m2). Subsequent cycles are 4 weeks in duration. OR  In patients who do not achieve a CR or CRi, the recommended total dose of Besponsa is 1.8 mg/m2 per cycle given as 3 divided doses on Day 1 (0.8 mg/m2), Day 8 (0.5 mg/m2), and Day 15 (0.5 mg/m2). Subsequent cycles are 4 weeks in duration. Patients who do not achieve a CR or CRi within 3 cycles should discontinue treatment.
For patients proceeding to hematopoietic stem cell transplant (HSCT), the recommended duration of treatment with Besponsa is 2 cycles. A third cycle may be considered for those patients who do not achieve CR or CRi and minimal residual disease (MRD) negativity after 2 cycles.
For patients not proceeding to HSCT, additional cycles of treatment, up to a maximum of 6 cycles, may be administered.
Please see drug label for specific dose modifications based on toxicities.
Clinical Results
FDA Approvals
The FDA approval of Besponsa was based on a randomized trial of 326 patients with relapsed or refractory B-cell ALL who had received one or two prior treatments. Patients were randomized to receive treatment with Besponsa or an alternative chemotherapy regimen. The trial measured the percentage of patients with no evidence of disease and full recovery of blood counts after treatment (complete remission or CR). Of the 218 evaluated patients, 35.8 percent who received Besponsa experienced CR for a median 8.0 months; of the patients who received alternative chemotherapy, 17.4 percent experienced CR for a median 4.9 months.
Side Effects
Adverse effects associated with the use of Besponsa may include, but are not limited to, the following:
•thrombocytopenia
•neutropenia
•infection
•anemia
•leukopenia
•fatigue
•hemorrhage
•pyrexia
•nausea
•headache
•febrile neutropenia
•transaminases increased
•abdominal pain
•gamma-glutamyltransferase increased
•hyperbilirubinemia
The Besponsa drug label includes a boxed warning that severe liver damage (hepatotoxicity), including blockage of veins in the liver (veno-occlusive disease [VOD] or sinusoidal obstruction syndrome), occurred in some patients who took Besponsa.
Mechanism of Action
Besponsa (inotuzumab ozogamicin) is a CD22-directed antibody-drug conjugate (ADC). Inotuzumab recognizes human CD22.  The small molecule, N-acetyl-gamma-calicheamicin, is a cytotoxic agent that is covalently attached to the antibody via a linker. Nonclinical data suggest that the anticancer activity of inotuzumab ozogamicin is due to the binding of the ADC to CD22-expressing tumor cells, followed by internalization of the ADC-CD22 complex, and the intracellular release of N-acetyl-gamma-calicheamicin dimethylhydrazide via hydrolytic cleavage of the linker. Activation of N-acetyl-gamma-calicheamicin dimethylhydrazide induces double-strand DNA breaks, subsequently inducing cell cycle arrest and apoptotic cell death.
IMPORTANT BESPONSA® (inotuzumab ozogamicin) SAFETY INFORMATION FROM THE U.S. PRESCRIBING INFORMATION
WARNING: HEPATOTOXICITY, INCLUDING HEPATIC VENO-OCCLUSIVE DISEASE (VOD) (ALSO KNOWN AS SINUSOIDAL OBSTRUCTION SYNDROME) and INCREASED RISK OF POST–HEMATOPOIETIC STEM CELL TRANSPLANT (HSCT) NON-RELAPSE MORTALITY (NRM):
•Hepatotoxicity, including fatal and life-threatening VOD, occurred in patients who received BESPONSA. The risk of VOD was greater in patients who underwent HSCT after BESPONSA treatment. Consider identified risk factors. Monitor closely for signs and symptoms of VOD
•There was a higher post-HSCT non-relapse mortality rate in patients receiving BESPONSA, resulting in a higher Day 100 post-HSCT mortality rate
Hepatotoxicity, Including VOD: Hepatotoxicity, including fatal and life-threatening VOD, occurred in patients who received BESPONSA. The risk of VOD was greater in patients who underwent HSCT after BESPONSA treatment. The use of HSCT conditioning regimens containing 2 alkylating agents and last total bilirubin ≥ the upper limit of normal (ULN) before HSCT were significantly associated with an increased risk of VOD. Other risk factors for VOD in patients treated with BESPONSA included ongoing or prior liver disease, prior HSCT, increased age, later salvage lines, and a greater number of BESPONSA treatment cycles. Grade 3/4 increases in aspartate aminotransferase (AST), alanine aminotransferase (ALT), and total bilirubin have occurred.
Monitor closely for signs and symptoms of VOD; these may include elevations in total bilirubin, hepatomegaly (which may be painful), rapid weight gain, and ascites. Elevation of liver tests may require dosing interruption, dose reduction, or permanent discontinuation of BESPONSA. Permanently discontinue treatment if VOD occurs. If severe VOD occurs, treat according to standard medical practice.
Increased Risk of Post-HSCT Non-Relapse Mortality: There was a higher post-HSCT non-relapse mortality rate in patients receiving BESPONSA, resulting in a higher Day 100 post-HSCT mortality rate. In the BESPONSA arm, the most common causes of post-HSCT non-relapse mortality included VOD and infections. Monitor closely for toxicities post HSCT, including signs and symptoms of infection and VOD.
Myelosuppression: Myelosuppression, and severe, life-threatening and fatal complications of myelosuppression, including hemorrhagic events and infections, have occurred with BESPONSA. Thrombocytopenia, neutropenia, and febrile neutropenia were reported.
Monitor complete blood counts prior to each dose of BESPONSA and monitor for signs and symptoms of infection, bleeding/hemorrhage, or other effects of myelosuppression during treatment and provide appropriate management. As appropriate, administer prophylactic anti-infectives during and after treatment with BESPONSA. Dose interruption, dose reduction, or permanent discontinuation may be required.
Infusion-Related Reactions: Infusion-related reactions have occurred in patients who received BESPONSA. Premedicate with a corticosteroid, antipyretic, and antihistamine prior to dosing. Monitor patients closely during and for at least 1 hour after the end of the infusion for the potential onset of infusion-related reactions. Interrupt the infusion and institute appropriate medical management if an infusion-related reaction occurs. For severe or life-threatening infusion reactions, permanently discontinue BESPONSA.
QT Interval Prolongation: Increases in QT interval have occurred. Administer BESPONSA with caution in patients who have a history of or predisposition to QTc prolongation, who are taking medicinal products that are known to prolong QT interval, and in patients with electrolyte disturbances. Obtain electrocardiograms and electrolytes prior to treatment and after initiation of any drug known to prolong QTc, and periodically monitor as clinically indicated during treatment.
Embryo-Fetal Toxicity and Nursing Mothers: BESPONSA can cause embryo-fetal harm. Advise males and females of reproductive potential to use effective contraception during BESPONSA treatment and for at least 5 and 8 months after the last dose, respectively. Advise women against breastfeeding while receiving BESPONSA and for 2 months after the last dose.
Adverse Reactions: The most common (≥20%) adverse reactions observed with BESPONSA were thrombocytopenia, neutropenia, infection, anemia, leukopenia, fatigue, hemorrhage, pyrexia, nausea, headache, febrile neutropenia, transaminases increased, abdominal pain, gamma-glutamyltransferase increased, and hyperbilirubinemia.
The most common (≥2%) serious adverse reactions were infection, febrile neutropenia, hemorrhage, abdominal pain, pyrexia, VOD, and fatigue.