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奥英妥珠单抗冻干注射剂|BESPONSA(inotuzumab ozogamicin for Injection)

2017-10-30 04:51:48  作者:新特药房  来源:互联网  浏览次数:0  文字大小:【】【】【
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 ...

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) for injection, for intravenous use
Initial U.S. Approval: 2017
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
HEPATOTOXICITY, INCLUDING VOD
• Hepatotoxicity, including fatal and life-threatening VOD occurred in patients with relapsed or refractory acute lymphoblastic leukemia (ALL) who received inotuzumab ozogamicin. The risk of VOD was greater in patients who underwent HSCT after inotuzumab ozogamicin treatment; use of HSCT conditioning regimens containing 2 alkylating agents and last total bilirubin level ≥ 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 inotuzumab ozogamicin included ongoing or prior liver disease, prior HSCT, increased age, later salvage lines, and a greater number of inotuzumab ozogamicin treatment cycles.
• Elevation of liver tests may require dosing interruption, dose reduction, or permanent discontinuation of inotuzumab ozogamicin. Permanently discontinue treatment if VOD occurs. If severe VOD occurs, treat according to standard medical practice [see Dosage and Administration (3.3) and Warnings and Precautions (5.1)].
INCREASED RISK OF POST-HSCT NON-RELAPSE MORTALITY
• There was higher post-HSCT non-relapse mortality rate in patients receiving inotuzumab ozogamicin, resulting in a higher Day 100 post-HSCT mortality rate [see Warnings and Precautions (5.2)].
1. DESCRIPTION 
Inotuzumab ozogamicin is a CD22-directed antibody-drug conjugate (ADC) consisting of 3 components: 1) the recombinant humanized immunoglobulin class G subtype 4 (IgG4) kappa antibody inotuzumab, specific for human CD22, 2) N-acetyl-gamma-calicheamicin that causes double-stranded DNA breaks, and 3) an acid-cleavable linker composed of the condensation product of 4-(4’-acetylphenoxy)-butanoic acid (AcBut) and 3-methyl-3-mercaptobutane hydrazide (known as dimethylhydrazide) that covalently attaches N-acetyl-gamma-calicheamicin to inotuzumab.


Inotuzumab ozogamicin has an approximate molecular weight of 160 kDa. The average number of calicheamicin derivative molecules conjugated to each inotuzumab molecule is approximately 6 with a distribution from 2-8. Inotuzumab ozogamicin is produced by chemical conjugation of the antibody and small molecule components. The antibody is produced by mammalian (Chinese hamster ovary) cells, and the semisynthetic calicheamicin derivative is produced by microbial fermentation followed by synthetic modification.
Inotuzumab ozogamicin for injection is supplied as a sterile, white to off-white, preservative-free, lyophilized powder for intravenous administration. Each single-dose vial delivers 0.9 mg inotuzumab ozogamicin. Inactive ingredients are polysorbate 80 (0.36 mg), sodium chloride (2.16 mg), sucrose (180 mg), and tromethamine (8.64 mg). After reconstitution with 4 mL of Sterile Water for Injection, USP, the final concentration is 0.25 mg/mL of inotuzumab ozogamicin with a deliverable volume of 3.6 mL (0.9 mg) and a pH of approximately 8.0.
2. INDICATIONS AND USAGE 
Inotuzumab ozogamicin is indicated for the treatment of adults with relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL).
3. DOSAGE AND ADMINISTRATION 
3.1 Recommended Dosage
• Pre-medicate before each dose [see Dosage and Administration (3.2)].
• For the first cycle, the recommended total dose of inotuzumab ozogamicin 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 inotuzumab ozogamicin is 1.5 mg/m2 per 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 inotuzumab ozogamicin 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 inotuzumab ozogamicin 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 [see Warnings and Precautions (5.1)].
• For patients not proceeding to HSCT, additional cycles of treatment, up to a maximum of 6 cycles, may be administered.
Table 1 shows the recommended dosing regimens.
Table 1. Dosing Regimen for Cycle 1 and Subsequent Cycles Depending on Response to Treatment


Abbreviations: CR=complete remission; CRi=complete remission with incomplete hematologic recovery.
a +/-2 days (maintain minimum of 6 days between doses).
b Dose is based on the patient’s body surface area (m2).
c For patients who achieve a CR or a CRi, and/or to allow for recovery from toxicity, the cycle length may be extended up to 28 days (i.e., 7-day treatment-free interval starting on Day 21).
d CR is defined as < 5% blasts in the bone marrow and the absence of peripheral blood leukemic blasts, full recovery of peripheral blood counts (platelets ≥ 100 × 109/L and absolute neutrophil counts [ANC] ≥ 1 × 109/L) and resolution of any extramedullary disease.
e CRi is defined as < 5% blasts in the bone marrow and the absence of peripheral blood leukemic blasts, incomplete recovery of peripheral blood counts (platelets < 100 × 109/L and/or ANC < 1 × 109/L) and resolution of any extramedullary disease.
f 7-day treatment-free interval starting on Day 21.
3.2 Recommended Pre-medications and Cytoreduction
• Premedication with a corticosteroid, antipyretic, and antihistamine is recommended prior to dosing. Patients should be observed during and for at least 1 hour after the end of infusion for symptoms of infusion related reactions [see Warnings and Precautions (5.4)].
• For patients with circulating lymphoblasts, cytoreduction with a combination of hydroxyurea, steroids, and/or vincristine to a peripheral blast count of less than or equal to 10,000/mm3 is recommended prior to the first dose.
3.3 Dose Modification
Modify the dose of inotuzumab ozogamicin for toxicities (see Tables 2-4). Inotuzumab ozogamicin doses within a treatment cycle (i.e., Days 8 and/or 15) do not need to be interrupted due to neutropenia or thrombocytopenia, but dosing interruptions within a cycle are recommended for non-hematologic toxicities. If the dose is reduced due to inotuzumab ozogamicin-related toxicity, the dose must not be re-escalated.
Table 2. Inotuzumab Ozogamicin Dose Modifications for Hematologic Toxicities


Abbreviation: ANC=absolute neutrophil count.
a Platelet count used for dosing should be independent of blood transfusion.
Table 3. Inotuzumab Ozogamicin Dose Modifications for Non-hematologic Toxicities


Abbreviations: ALT=alanine aminotransferase; AST=aspartate aminotransferase; ULN=upper limit of normal; VOD=venoocclusive disease.
a Severity grade according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 3.0.
Table 4. Inotuzumab Ozogamicin Dose Modifications Depending on Duration of Dosing Interruption Due to Non-Hematologic Toxicity Toxicities


3.4 Instructions for Reconstitution, Dilution, and Administration
Protect the reconstituted and diluted inotuzumab ozogamicin solutions from light. Do not freeze the reconstituted or diluted solution.
The maximum time from reconstitution through the end of administration should be less than or equal to 8 hours, with less than or equal to 4 hours between reconstitution and dilution.
Reconstitution:
• Inotuzumab ozogamicin is a cytotoxic drug. Follow applicable special handling and disposal procedures.
• Calculate the dose (mg) and number of vials of inotuzumab ozogamicin required.
• Reconstitute each vial with 4 mL of Sterile Water for Injection, USP, to obtain a concentration of 0.25 mg/mL of inotuzumab ozogamicin that delivers 3.6 mL (0.9 mg).
• Gently swirl the vial to aid dissolution. DO NOT SHAKE.
• Inspect the reconstituted solution for particulates and discoloration. The reconstituted solution should be clear to opalescent, colorless to slightly yellow, and essentially free of visible foreign matter.
• See Table 5 for storage times and conditions for the reconstituted solution.
Dilution:
• Calculate the required volume of the reconstituted solution needed to obtain the appropriate dose according to the patient’s body surface area. Withdraw this amount from the vial(s) using a syringe. Discard any unused reconstituted inotuzumab ozogamicin solution left in the vial.
• Add reconstituted solution to an infusion container with 0.9% Sodium Chloride Injection, USP, to a make a total volume of 50 mL. An infusion container made of polyvinyl chloride (PVC) (di(2-ethylhexyl)phthalate [DEHP]-or non-DEHP-containing), polyolefin (polypropylene and/or polyethylene), or ethylene vinyl acetate (EVA) is recommended.
• Gently invert the infusion container to mix the diluted solution. DO NOT SHAKE.
• See Table 5 for storage times and conditions for the diluted solution.
Administration:
• See Table 5 for storage times and conditions for prior to and during administration of the diluted solution.
• Filtration of the diluted solution is not required. However, if the diluted solution is filtered, polyethersulfone (PES)-, polyvinylidene fluoride (PVDF)-,or hydrophilic polysulfone (HPS)-based filters are recommended. Do not use filters made of nylon or mixed cellulose ester (MCE).
• Infuse the diluted solution for 1 hour at a rate of 50 mL/h at room temperature (20-25°C; 68-77°F). Infusion lines made of PVC (DEHP-or non-DEHP-containing), polyolefin (polypropylene and/or polyethylene), or polybutadiene are recommended.
Do not mix inotuzumab ozogamicin or administer as an infusion with other medicinal products.
Table 5 shows the storage times and conditions for reconstitution, dilution, and administration of inotuzumab ozogamicin.
Table 5. Storage Times and Conditions for Reconstituted and Diluted Inotuzumab Ozogamicin Solution


a With less than or equal to 4 hours between reconstitution and dilution.
4. CONTRAINDICATIONS 
None.
5. WARNINGS AND PRECAUTIONS 
5.1 Hepatotoxicity, Including Hepatic Veno-occlusive Disease (VOD) (also known as Sinusoidal Obstruction Syndrome)
In the INO-VATE ALL trial, hepatotoxicity, including severe, life-threatening, and sometimes fatal hepatic VOD was observed in 23/164 patients (14%) in the inotuzumab ozogamicin arm during or following treatment or following a HSCT after completion of treatment. VOD was reported up to 56 days after the last dose during treatment or during follow-up without an intervening HSCT. The median time from subsequent HSCT to onset of VOD was 15 days (range: 3-57 days). In the inotuzumab ozogamicin arm, among the 79 patients who proceeded to a subsequent HSCT, VOD was reported in 18/79 patients (23%), and among all 164 patients treated, VOD was reported in 5/164 patients (3%) during study therapy or in follow-up without an intervening HSCT.
The risk of VOD was greater in patients who underwent HSCT after inotuzumab ozogamicin treatment; use of HSCT conditioning regimens containing 2 alkylating agents (e.g., busulfan in combination with other alkylating agents) and last total bilirubin level greater than or equal to the ULN before HSCT are significantly associated with an increased risk of VOD. Other risk factors for VOD in patients treated with inotuzumab ozogamicin included ongoing or prior liver disease, prior HSCT, increased age, later salvage lines, and a greater number of inotuzumab ozogamicin treatment cycles. Patients who have experienced prior VOD or have serious ongoing hepatic liver disease (e.g., cirrhosis, nodular regenerative hyperplasia, active hepatitis) are at an increased risk for worsening of liver disease, including developing VOD, following treatment with inotuzumab ozogamicin.
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. Due to the risk of VOD, for patients proceeding to HSCT, the recommended duration of treatment with inotuzumab ozogamicin is 2 cycles; a third cycle may be considered for those patients who do not achieve a CR or CRi and MRD negativity after 2 cycles [see Dosage and Administration (3.1)]. For patients who proceed to HSCT, monitor liver tests closely during the first month post-HSCT, then less frequently thereafter, according to standard medical practice.
In the INO-VATE ALL trial, increases in liver tests were reported. Grade 3/4 AST, ALT, and total bilirubin abnormal liver tests occurred in 7/160 (4%), 7/161 (4%), and 8/161 patients (5%), respectively.
In all patients, monitor liver tests, including ALT, AST, total bilirubin, and alkaline phosphatase, prior to and following each dose of inotuzumab ozogamicin. Elevations of liver tests may require dosing interruption, dose reduction, or permanent discontinuation of inotuzumab ozogamicin [see Dosage and Administration (3.3)].
5.2 Increased Risk of Post-Transplant Non-Relapse Mortality
In the INO-VATE ALL trial, a higher post-HSCT non-relapse mortality rate was observed in patients receiving inotuzumab ozogamicin compared to the Investigator’s choice of chemotherapy arm, resulting in a higher Day 100 post-HSCT mortality rate.
Overall, 79/164 patients (48%) in the inotuzumab ozogamicin arm and 35/162 patients (22%) in the Investigator’s choice of chemotherapy arm had a follow-up HSCT. The post-HSCT non-relapse mortality rate was 31/79 (39%) and 8/35 (23%) in the inotuzumab ozogamicin arm compared to the Investigator’s choice of chemotherapy arm, respectively.
In the inotuzumab ozogamicin arm, the most common causes of post-HSCT non-relapse mortality included VOD and infections. Five of the 18 VOD events that occurred post-HSCT were fatal. In the inotuzumab ozogamicin arm, among patients with ongoing VOD at time of death, 6 patients died due to multiorgan failure (MOF) or infection (3 patients died due to MOF, 2 patients died due to infection, and 1 patient died due to MOF and infection).
Monitor closely for toxicities post-HSCT, including signs and symptoms of infection and VOD [see Warnings and Precautions (5.1, 5.3)].
5.3 Myelosuppression
In the INO-VATE ALL trial, myelosuppression was observed in patients receiving inotuzumab ozogamicin [see Adverse Reactions (6.1)].
Thrombocytopenia and neutropenia were reported in 83/164 patients (51%) and 81/164 patients (49%), respectively. Grade 3 thrombocytopenia and neutropenia were reported in 23/164 patients (14%) and 33/164 patients (20%), respectively. Grade 4 thrombocytopenia and neutropenia were reported in 46/164 patients (28%) and 45/164 patients (27%), respectively. Febrile neutropenia, which may be life-threatening, was reported in 43/164 patients (26%). For patients who were in CR or CRi at the end of treatment, the recovery of platelet counts to > 50,000/mm3 was later than 45 days after the last dose in 15/164 patients (9%) who received inotuzumab ozogamicin and 3/162 patients (2%) who received Investigator’s choice of chemotherapy.
Complications associated with myelosuppression (including infections and bleeding/hemorrhagic events) were observed in patients receiving inotuzumab ozogamicin [see Adverse Reactions (6.1)]. Infections, including serious infections, some of which were life-threatening or fatal, were reported in 79/164 patients (48%). Fatal infections, including pneumonia, neutropenic sepsis, sepsis, septic shock, and pseudomonal sepsis, were reported in 8/164 patients (5%). Bacterial, viral, and fungal infections were reported.
Hemorrhagic events were reported in 54/164 patients (33%). Grade 3 or 4 hemorrhagic events were reported in 8/164 patients (5%). One Grade 5 (fatal) hemorrhagic event (intra-abdominal hemorrhage) was reported in 1/164 patients (1%). The most common hemorrhagic event was epistaxis which was reported in 24/164 patients (15%).
Monitor complete blood counts prior to each dose of inotuzumab ozogamicin and monitor for signs and symptoms of infection, bleeding/hemorrhage, or other effects of myelosuppression during treatment with inotuzumab ozogamicin. As appropriate, administer prophylactic anti-infectives and employ surveillance testing during and after treatment with inotuzumab ozogamicin. Management of severe infection, bleeding/hemorrhage, or other effects of myelosuppression, including severe neutropenia or thrombocytopenia, may require dosing interruption, dose reduction, or permanent discontinuation of inotuzumab ozogamicin [see Dosage and Administration (3.3)].
5.4 Infusion Related Reactions
In the INO-VATE ALL trial, infusion related reactions were observed in patients who received inotuzumab ozogamicin. Infusion related reactions (all Grade 2) were reported in 4/164 patients (2%). Infusion related reactions generally occurred in Cycle 1 shortly after the end of the inotuzumab ozogamicin infusion and resolved spontaneously or with medical management.
Premedicate with a corticosteroid, antipyretic, and antihistamine prior to dosing [see Dosage and Administration (3.2)].
Monitor patients closely during and for at least 1 hour after the end of infusion for the potential onset of infusion related reactions, including symptoms such as fever, chills, rash, or breathing problems. Interrupt infusion and institute appropriate medical management if an infusion related reaction occurs. Depending on the severity of the infusion related reaction, consider discontinuation of the infusion or administration of steroids and antihistamines. For severe or life-threatening infusion reactions, permanently discontinue inotuzumab ozogamicin [see Dosage and Administration (3.3)].
5.5 QT Interval Prolongation
In the INO-VATE ALL trial, increases in QT interval corrected for heart rate using Fridericia’s formula (QTcF) of ≥ to 60 msec from baseline were measured in 4/162 patients (3%). No patients had QTcF values greater than 500 msec [see Clinical Pharmacology]. Grade 2 QT prolongation was reported in 2/164 patients (1%). No ≥ Grade 3 QT prolongation or events of Torsade de Pointes were reported [see Adverse Reactions (6.1)].
Administer inotuzumab ozogamicin with caution in patients who have a history of or predisposition for QTc prolongation, who are taking medicinal products that are known to prolong QT interval [see Drug Interactions (7)], and in patients with electrolyte disturbances [see Drug Interactions (7)]. Obtain electrocardiograms (ECGs) and electrolytes prior to the start of treatment, after initiation of any drug known to prolong QTc, and periodically monitor as clinically indicated during treatment [see Drug Interactions (7), Clinical Pharmacology].
5.6 Embryo-Fetal Toxicity
Based on its mechanism of action and findings from animal studies, inotuzumab ozogamicin can cause embryo-fetal harm when administered to a pregnant woman. In animal studies, inotuzumab ozogamicin caused embryo-fetal toxicities, starting at a dose that was approximately 0.4 times the exposure in patients at the maximum recommended dose, based on the area under the concentration-time curve (AUC). Advise females of reproductive potential to use effective contraception during treatment with inotuzumab ozogamicin and for at least 8 months after the final dose of inotuzumab ozogamicin. Advise males with female partners of reproductive potential to use effective contraception during treatment with inotuzumab ozogamicin and for at least 5 months after the last dose of inotuzumab ozogamicin. Apprise pregnant women of the potential risk to the fetus. Advise women to contact their healthcare provider if they become pregnant or if pregnancy is suspected during treatment with inotuzumab ozogamicin [see Use in Specific Populations (8.1, 8.3), Clinical Pharmacology, Nonclinical Toxicology].
6. ADVERSE REACTIONS 
The following adverse reactions are discussed in greater detail in other sections of the label:
• Hepatotoxicity, including hepatic VOD (also known as SOS) [see Warnings and Precautions (5.1)]
• Increased risk of post-transplant non-relapse mortality [see Warnings and Precautions (5.2)]
• Myelosuppression [see Warnings and Precautions (5.3)]
• Infusion related reactions [see Warnings and Precautions (5.4)]
• QT interval prolongation [see Warnings and Precautions (5.5)]
6.1 Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
The adverse reactions described in this section reflect exposure to inotuzumab ozogamicin in 164 patients with relapsed or refractory ALL who participated in a randomized clinical study of inotuzumab ozogamicin versus Investigator’s choice of chemotherapy (fludarabine + cytarabine + granulocyte colony-stimulating factor [FLAG], mitoxantrone + cytarabine [MXN/Ara-C], or high dose cytarabine [HIDAC]) (INO-VATE ALL Trial [NCT01564784]) [see Clinical Studies].
Of the 164 patients who received inotuzumab ozogamicin, the median age was 47 years (range: 18-78 years), 56% were male, 68% had received 1 prior treatment regimen for ALL, 31% had received 2 prior treatment regimens for ALL, 68% were White, 19% were Asian, and 2% were Black.
In patients who received inotuzumab ozogamicin, the median duration of treatment was 8.9 weeks (range: 0.1-26.4 weeks), with a median of 3 treatment cycles started in each patient. In patients who received Investigator’s choice of chemotherapy, the median duration of treatment was 0.9 weeks (range: 0.1-15.6 weeks), with a median of 1 treatment cycle started in each patient. In patients who received inotuzumab ozogamicin, the most common (≥ 20%) adverse reactions were thrombocytopenia, neutropenia, infection, anemia, leukopenia, fatigue, hemorrhage, pyrexia, nausea, headache, febrile neutropenia, transaminases increased, abdominal pain, gamma-glutamyltransferase increased, and hyperbilirubinemia.
In patients who received inotuzumab ozogamicin, the most common (≥ 2%) serious adverse reactions were infection, febrile neutropenia, hemorrhage, abdominal pain, pyrexia, VOD, and fatigue.
In patients who received inotuzumab ozogamicin, the most common (≥ 2%) adverse reactions reported as the reason for permanent discontinuation were infection (6%), thrombocytopenia (2%), hyperbilirubinemia (2%), transaminases increased (2%), and hemorrhage (2%); the most common (≥ 5%) adverse reactions reported as the reason for dosing interruption were neutropenia (17%), infection (10%), thrombocytopenia (10%), transaminases increased (6%), and febrile neutropenia (5%); and the most common (≥ 1%) adverse reactions reported as the reason for dose reduction were neutropenia (1%), thrombocytopenia (1%), and transaminases increased (1%).
VOD was reported in 23/164 patients (14%) who received inotuzumab ozogamicin during or following treatment or following a HSCT after completion of treatment [see Warnings and Precautions (5.1)].
Table 6 shows the adverse reactions with ≥ 10% incidence reported in patients with relapsed or refractory ALL who received inotuzumab ozogamicin or Investigator’s choice of chemotherapy.
Table 6. Adverse Reactions With ≥ 10% Incidencea in Patients With Relapsed or Refractory B-Cell Precursor ALL Who Received Inotuzumab Ozogamicin or Investigator’s Choice of Chemotherapy (FLAG, MXN/Ara-C, or HIDAC)


Adverse reactions included treatment-emergent all-causality events that commenced on or after Cycle 1 Day 1 within 42 days after the last dose of inotuzumab ozogamicin, but prior to the start of a new anticancer treatment (including HSCT).
Preferred terms were retrieved by applying the Medical Dictionary for Regulatory Activities (MedDRA) version 18.1.
Severity grade of adverse reactions were according to NCI CTCAE version 3.0.
Abbreviations: ALL=acute lymphoblastic leukemia; FLAG=fludarabine + cytarabine + granulocyte colony-stimulating factor; HIDAC=high dose cytarabine; HSCT=hematopoietic stem cell transplant; MXN/Ara-C=mitoxantrone + cytarabine; N=number of patients; NCI CTCAE=National Cancer Institute Common Toxicity Criteria for Adverse Events.
a Only adverse reactions with ≥ 10% incidence in the inotuzumab ozogamicin arm are included.
b 19 patients randomized to FLAG, MXN/Ara-C, or HIDAC did not receive treatment.
c Infection includes any reported preferred terms for inotuzumab ozogamicin retrieved in the System Organ Class Infections and infestations.
d Thrombocytopenia includes the following reported preferred terms: Platelet count decreased and Thrombocytopenia.
e Neutropenia includes the following reported preferred terms: Neutropenia and Neutrophil count decreased.
f Anemia includes the following reported preferred terms: Anemia and Hemoglobin decreased.
g Leukopenia includes the following reported preferred terms: Leukopenia, Monocytopenia, and White blood cell count decreased.
h Lymphopenia includes the following reported preferred terms: B-lymphocyte count decreased, Lymphocyte count decreased, and Lymphopenia.
i Headache includes the following reported preferred terms: Headache, Migraine, and Sinus headache.
j Hemorrhage includes reported preferred terms for inotuzumab ozogamicin retrieved in the Standard MedDRA Query (narrow) for Hemorrhage terms (excluding laboratory terms), resulting in the following preferred terms: Conjunctival hemorrhage, Contusion, Ecchymosis, Epistaxis, Eyelid bleeding, Gastrointestinal hemorrhage, Gastritis hemorrhagic, Gingival bleeding, Hematemesis, Hematochezia, Hematotympanum, Hematuria, Hemorrhage intracranial, Hemorrhage subcutaneous, Hemorrhoidal hemorrhage, Intra-abdominal hemorrhage, Lip hemorrhage, Lower gastrointestinal hemorrhage, Mesenteric hemorrhage, Metrorrhagia, Mouth hemorrhage, Muscle hemorrhage, Oral mucosa hematoma, Petechiae, Post-procedural hematoma, Rectal hemorrhage, Shock hemorrhagic, Subcutaneous hematoma, Subdural hematoma, Upper gastrointestinal hemorrhage, and Vaginal hemorrhage.
k Abdominal pain includes the following reported preferred terms: Abdominal pain, Abdominal pain lower, Abdominal pain upper, Abdominal tenderness, Esophageal pain, and Hepatic pain.
l Stomatitis includes the following reported preferred terms: Aphthous ulcer, Mucosal inflammation, Mouth ulceration, Oral pain, Oropharyngeal pain, and Stomatitis.
m Fatigue includes the following reported preferred terms: Asthenia and Fatigue.
n Transaminases increased includes the following reported preferred terms: Aspartate aminotransferase increased, Alanine aminotransferase increased, Hepatocellular injury, and Hypertransaminasemia.
Additional adverse reactions (all grades) that were reported in less than 10% of patients treated with inotuzumab ozogamicin included: lipase increased (9%), abdominal distension (6%), amylase increased (5%), hyperuricemia (4%), ascites (4%), infusion related reaction (2%; includes the following: hypersensitivity and infusion related reaction), pancytopenia (2%; includes the following: bone marrow failure, febrile bone marrow aplasia, and pancytopenia), tumor lysis syndrome (2%), and electrocardiogram QT prolonged (1%).
Table 7 shows the clinically important laboratory abnormalities reported in patients with relapsed or refractory ALL who received inotuzumab ozogamicin or Investigator’s choice of chemotherapy.
Table 7. Laboratory Abnormalities in Patients With Relapsed or Refractory B-Cell Precursor ALL Who Received Inotuzumab Ozogamicin or Investigator’s Choice of Chemotherapy (FLAG, MXN/Ara-C, or HIDAC)


Severity grade of laboratory abnormalities according to NCI CTCAE version 3.0.
Abbreviations: ALL=acute lymphoblastic leukemia; ALP=alkaline phosphatase; ALT=alanine aminotransferase; AST=aspartate aminotransferase; FLAG=fludarabine + cytarabine + granulocyte colony-stimulating factor; GGT=gamma-glutamyltransferase; HIDAC=high dose cytarabine; MXN/Ara-C=mitoxantrone + cytarabine; N=number of patients; NCI CTCAE=National Cancer Institute Common Toxicity Criteria for Adverse Events.
a Laboratory abnormalities were summarized up to the end of treatment + 42 days but prior to the start of a new anti-cancer therapy.
6.2 Immunogenicity
As with all therapeutic proteins, there is potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to inotuzumab ozogamicin in the studies described below with the incidence of antibodies in other studies or to other products may be misleading.
In clinical studies of inotuzumab ozogamicin in patients with relapsed or refractory ALL, the immunogenicity of inotuzumab ozogamicin was evaluated using an electrochemiluminescence (ECL)-based immunoassay to test for anti-inotuzumab ozogamicin antibodies. For patients whose sera tested positive for anti-inotuzumab ozogamicin antibodies, a cell-based luminescence assay was performed to detect neutralizing antibodies.
In clinical studies of inotuzumab ozogamicin in patients with relapsed or refractory ALL, 7/236 patients (3%) tested positive for anti-inotuzumab ozogamicin antibodies. No patients tested positive for neutralizing anti-inotuzumab ozogamicin antibodies. In patients who tested positive for anti-inotuzumab ozogamicin antibodies, the presence of anti-inotuzumab ozogamicin antibodies did not affect clearance following inotuzumab ozogamicin treatment.
7. DRUG INTERACTIONS 
Drugs That Prolong the QT Interval
Concomitant use of inotuzumab ozogamicin with drugs known to prolong the QT interval or induce Torsades de Pointes may increase the risk of a clinically significant QTc interval prolongation [see Clinical Pharmacology]. Discontinue or use alternative concomitant drugs that do not prolong QT/QTc interval while the patient is using inotuzumab ozogamicin. When it is not feasible to avoid concomitant use of drugs known to prolong QT/QTc, obtain ECGs and electrolytes prior to the start of treatment, after initiation of any drug known to prolong QTc, and periodically monitor as clinically indicated during treatment [see Warnings and Precautions (5.5)].
8. USE IN SPECIFIC POPULATIONS 
8.1 Pregnancy
Risk Summary
Based on its mechanism of action and findings from animal studies [see Clinical Pharmacology, Nonclinical Toxicology], inotuzumab ozogamicin can cause embryo-fetal harm when administered to a pregnant woman. There are no available data on inotuzumab ozogamicin use in pregnant women to inform a drug-associated risk of major birth defects and miscarriage. In rat embryo-fetal development studies, inotuzumab ozogamicin caused embryo-fetal toxicity at maternal systemic exposures that were ≥ 0.4 times the exposure in patients at the maximum recommended dose, based on AUC [see Data]. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, advise the patient of the potential risk to a fetus.
Adverse outcomes in pregnancy occur regardless of the health of the mother or the use of medications. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies are 2-4% and 15-20%, respectively.
Data
Animal Data
In embryo-fetal development studies in rats, pregnant animals received daily intravenous doses of inotuzumab ozogamicin up to 0.36 mg/m2 during the period of organogenesis. Embryo-fetal toxicities including increased resorptions and fetal growth retardation as evidenced by decreased live fetal weights and delayed skeletal ossification were observed at ≥ 0.11 mg/m2 (approximately 2 times the exposure in patients at the maximum recommended dose, based on AUC). Fetal growth retardation also occurred at 0.04 mg/m2 (approximately 0.4 times the exposure in patients at the maximum recommended dose, based on AUC).
In an embryo-fetal development study in rabbits, pregnant animals received daily intravenous doses up to 0.15 mg/m2 (approximately 3 times the exposure in patients at the maximum recommended dose, based on AUC) during the period of organogenesis. At a dose of 0.15 mg/m2, slight maternal toxicity was observed in the absence of any effects on embryo-fetal development.
8.2 Lactation
Risk Summary
There are no data on the presence of inotuzumab ozogamicin or its metabolites in human milk, the effects on the breastfed infant, or the effects on milk production. Because of the potential for adverse reactions in breastfed infants, advise women not to breastfeed during treatment with inotuzumab ozogamicin and for at least 2 months after the last dose.
8.3 Females and Males of Reproductive Potential
Pregnancy Testing
Based on its mechanism of action and findings from animal studies, inotuzumab ozogamicin can cause embryo-fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1), Nonclinical Toxicology]. Verify the pregnancy status of females of reproductive potential prior to initiating inotuzumab ozogamicin.
Contraception
Females
Advise females of reproductive potential to avoid becoming pregnant while receiving inotuzumab ozogamicin. Advise females of reproductive potential to use effective contraception during treatment with inotuzumab ozogamicin and for at least 8 months after the last dose [see Nonclinical Toxicology].
Males
Advise males with female partners of reproductive potential to use effective contraception during treatment with inotuzumab ozogamicin and for at least 5 months after the last dose [see Nonclinical Toxicology].
Infertility
Females
Based on findings in animals, inotuzumab ozogamicin may impair fertility in females of reproductive potential [see Nonclinical Toxicology].
Males
Based on findings in animals, inotuzumab ozogamicin may impair fertility in males of reproductive potential [see Nonclinical Toxicology].
8.4 Pediatric Use
Safety and effectiveness have not been established in pediatric patients.
8.5 Geriatric Use
In the INO-VATE ALL trial, 30/164 patients (18%) treated with inotuzumab ozogamicin were ≥ 65 years of age. No differences in responses were identified between older and younger patients.
Based on a population pharmacokinetic analysis in 765 patients, no adjustment to the starting dose is required based on age [see Clinical Pharmacology].
8.6 Hepatic Impairment
Based on a population pharmacokinetic analysis, the clearance of inotuzumab ozogamicin in patients with mild hepatic impairment (total bilirubin less than or equal to ULN and AST greater than ULN, or total bilirubin greater than 1.0-1.5 × ULN and AST any level; n=150) was similar to patients with normal hepatic function (total bilirubin/AST less than or equal to ULN; n=611). In patients with moderate (total bilirubin greater than 1.5-3 × ULN and AST any level; n=3) and severe hepatic impairment (total bilirubin greater than 3 × ULN and AST any level; n=1), inotuzumab ozogamicin clearance did not appear to be reduced [see Clinical Pharmacology].
No adjustment to the starting dose is required when administering inotuzumab ozogamicin to patients with total bilirubin less than or equal to 1.5 × ULN and AST/ALT less than or equal to 2.5 × ULN [see Dosage and Administration (3.3)]. There is limited safety information available in patients with total bilirubin greater than 1.5 × ULN and/or AST/ALT greater than 2.5 × ULN prior to dosing. Interrupt dosing until recovery of total bilirubin to less than or equal to 1.5 × ULN and AST/ALT to less than or equal to 2.5 × ULN prior to each dose unless due to Gilbert’s syndrome or hemolysis. Permanently discontinue treatment if total bilirubin does not recover to less than or equal to 1.5 × ULN or AST/ALT does not recover to less than or equal to 2.5 × ULN [see Dosage and Administration (3.3), Warnings and Precautions (5.1)].
10. MECHANISM OF ACTION 
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.
11. PHARMACODYNAMICS  
During the treatment period, the pharmacodynamic response to inotuzumab ozogamicin was characterized by the depletion of CD22-positive leukemic blasts.
Cardiac Electrophysiology
In a randomized clinical study in patients with relapsed or refractory ALL, increases in QTcF of ≥ 60 msec from baseline were measured in 4/162 patients (3%) in the inotuzumab ozogamicin arm and 3/124 patients (2%) in the Investigator’s choice of chemotherapy arm. Increases in QTcF of > 500 msec were observed in none of the patients in the inotuzumab ozogamicin arm and 1/124 patients (1%) in the Investigator’s choice of chemotherapy arm. Central tendency analysis of the QTcF interval changes from baseline showed that the highest mean (upper bound of the 2-sided 90% CI) for QTcF was 15.3 (21.1) msec, which was observed at Cycle 4/Day 1/1 hour in the inotuzumab ozogamicin arm [see Warnings and Precautions (5.5)].
12. PHARMACOKINETICS  
The mean Cmax of inotuzumab ozogamicin was 308 ng/mL. The mean simulated total AUC per cycle was 100,000 ng•h/mL. In patients with relapsed or refractory ALL, steady-state drug concentration was achieved by Cycle 4. Following administration of multiple doses, a 5.3 times accumulation of inotuzumab ozogamicin was predicted by Cycle 4.
Distribution
N-acetyl-gamma-calicheamicin dimethylhydrazide is approximately 97% bound to human plasma proteins in vitro. In humans, the total volume of distribution of inotuzumab ozogamicin was approximately 12 L.
Elimination
The pharmacokinetics of inotuzumab ozogamicin was well characterized by a 2-compartment model with linear and time-dependent clearance components. In 234 patients with relapsed or refractory ALL, the clearance of inotuzumab ozogamicin at steady state was 0.0333 L/h and the terminal half-life (t½) was 12.3 days. Following administration of multiple doses, a 5.3 times accumulation of inotuzumab ozogamicin was predicted by Cycle 4.
Metabolism
In vitro, N-acetyl-gamma-calicheamicin dimethylhydrazide was primarily metabolized via nonenzymatic reduction. In humans, N-acetyl-gamma-calicheamicin dimethylhydrazide serum levels were typically below the limit of quantitation.
Specific Populations
The effect of intrinsic factors on inotuzumab ozogamicin pharmacokinetics was assessed using a population pharmacokinetic analysis unless otherwise specified. Age (18 to 92 years of age), sex, and race (Asian versus non-Asian [Caucasian, Black, and Unspecified]) had no clinically significant effect on the pharmacokinetics of inotuzumab ozogamicin. Body surface area was found to significantly affect inotuzumab ozogamicin disposition. Inotuzumab ozogamicin is dosed based on body surface area [see Dosage and Administration (3.1)].
Patients with Renal Impairment
The clearance of inotuzumab ozogamicin in patients with mild renal impairment (creatinine clearance [CLcr; based on the Cockcroft-Gault formula] 60-89 mL/min; n=237), moderate renal impairment (CLcr 30-59 mL/min; n=122), or severe renal impairment (CLcr 15-29 mL/min; n=4) was similar to patients with normal renal function (CLcr ≥90 mL/min; n=402). The safety and efficacy of inotuzumab ozogamicin in patients with end stage renal disease with or without hemodialysis is unknown.
Patients with Hepatic Impairment
The clearance of inotuzumab ozogamicin in patients with mild hepatic impairment (total bilirubin ≤ULN and AST > ULN, or total bilirubin >1.0-1.5 × ULN and AST any level; n=150) was similar to patients with normal hepatic function (total bilirubin/AST ≤ULN; n=611). There is insufficient data in patients with moderate and severe hepatic impairment (total bilirubin >1.5 ULN).
Drug Interactions
In vitro
Effect of Metabolic Pathways and Transporter Systems on Inotuzumab Ozogamicin
N-acetyl-gamma-calicheamicin dimethylhydrazide is a substrate of P-glycoprotein (P-gp).
Effect of Inotuzumab Ozogamicin on Metabolic Pathways and Transporter Systems
At clinically relevant concentrations, N-acetyl-gamma-calicheamicin dimethylhydrazide had a low potential to:
• Inhibit cytochrome P450 (CYP 450) Enzymes: CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4/5.
• Induce CYP450 Enzymes: CYP1A2, CYP2B6, and CYP3A4.
• Inhibit UGT Enzymes: UGT1A1, UGT1A4, UGT1A6, UGT1A9, and UGT2B7.
• Inhibit Drug Transporters: P-gp, breast cancer resistance protein (BCRP), organic anion transporter (OAT)1 and OAT3, organic cation transporter (OCT)2, and organic anion transporting polypeptide (OATP)1B1 and OATP1B3.
At clinically relevant concentrations, inotuzumab ozogamicin had a low potential to:
• Inhibit CYP450 Enzymes: CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4/5.
• Induce CYP450 Enzymes: CYP1A2, CYP2B6, and CYP3A4.
13. HOW SUPPLIED/STORAGE AND HANDLING 
How Supplied:
BESPONSA (inotuzumab ozogamicin) for Injection is supplied as a white to off-white lyophilized powder in a single-dose vial for reconstitution and further dilution. Each vial delivers 0.9 mg inotuzumab ozogamicin. Each carton (NDC 0008-0100-01) contains one single-dose vial.
Storage and Handling:
Refrigerate (2-8°C; 36-46°F) BESPONSA vials and store in the original carton to protect from light. Do not freeze.
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.
2017年8月17日,美国食品药品监督管理局(FDA)批准将BESPONSA®(奥英妥珠单抗)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(ALL)。BESPONSA此前获得美国食品药品监督管理局(FDA)的突破性疗法认证和优先审批资格。
BESPONSA的获批对于罹患复发或难治性急性B细胞淋巴细胞白血病的成人患者而言是重要的进步,该病是一种罕见疾病,如不加以治疗可以在短短几个月内致患者死亡。”辉瑞肿瘤事业部全球总裁Liz Barrett说,“就急性B细胞淋巴细胞白血病,BESPONSA有助于满足新治疗选择的重大需求,可以帮助更多的患者坚持到干细胞移植,从而实现病情的长期缓解。能够践行对恶性血液癌症患者的承诺,我们感到非常自豪,未来我们将继续努力,寻找治疗急性淋巴细胞白血病和其他血液癌症的新方法。”
该批准基于了3期INO-VATE ALL试验的结果,这是一项随机、开放标签、国际、多中心研究,纳入326例成人复发或难治性B细胞ALL患者,比较了BESPONSA与标准化疗的疗效与安全性。
“基于INO-VATE ALL试验的结果,BESPONSA 提高了多项疗效指标,,包括血液学缓解率、MRD阴性率和干细胞移植率,” INO-VATE ALL首席研究员兼美国德克萨斯大学MD安德森癌症中心教授,医学博士Hagop M. Kantarjian表示,“我期待着见证这种重要的新疗法对我的病人可能产生的影响。”
对于采用BESPONSA 治疗的患者,其完全缓解/不完全血象恢复下的完全缓解率(CR/CRI)*为81%[ 95% CI: 72%-88%],而采用化疗的患者完全缓解率只有29%[95% CI: 21%-39%]。在取得CR/CRi的所有患者中,相比接受化疗的患者(28%[95% CI:14%-47%]),接受BESPONSA治疗的患者的微小残留病变(MRD)阴性率也更高(78% [95% CI: 68%-87%])。接受BESPONSA 治疗的患者中有48%进行了造血干细胞移植(HSCT),而接受化疗的患者这一比例只有22%。接受BESPONSA 治疗的患者其总生存期(OS) 中位数为7.7个月[95% CI: 6.0, 9.2] ,而接受化疗的患者的这一数字为6.2 个月[95% CI: 4.7, 8.3] 。相比化疗,采用BESPONSA 治疗的患者的总生存期(OS)分析没有达到统计学意义上预先设定的边界条件。
关于急性淋巴细胞白血病
急性淋巴性白血病(ALL)是一种侵袭性极高的白血病,在成人患者中的预后极差。当前的基础治疗手段是长期的高强度化疗。据估计,2017年全美大约会有5970个新诊断的病例。其中大约40%为成人患者。在初始治疗后,有80%-90%的成人患者病情会得到完全缓解,剩余的患者(大约10%-20%)病情无法得到有效缓解,这意味着他们对治疗不再产生反应。此外,在那些病情缓解的患者中,又将有一半左右病情会出现复发。疾病复发后的中位生存期仅为4.5个月到6个月。
关于BESPONSA®(奥英妥珠单抗)
BESPONSA是一种抗体-药物偶联物(ADC),由靶向CD22的单克隆抗体(mAb)与细胞毒制剂偶联。CD22是一种在几乎所有B-ALL患者的癌细胞上表达的细胞表面抗原。当BESPONSA与恶性B细胞的CD22抗原结合时,BESPONSA 内化进入细胞,在此释放细胞毒制剂刺胞霉素杀死癌细胞。BESPONSA 以一小时静脉输注的方式给药,可以在门诊完成对适合患者的给药。

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