BLINCYTO（blinatumomab）注射获美国FDA快速批准, 成为首个上市的双特异性抗体新药 2014年12月3日美国食品药品监督管理局（FDA）批准blinatumomab（一种具有独特作用机制的药物）（Blincyto，安进）用于治疗费城染色体阴性前B细胞急性淋巴细胞白血病（ALL）。这项批准适用于复发或以前疗法难治的患者。 Blinatumomab通过了药物快速批准程序，而且被指定为突破性治疗药物，优先审查并获得孤儿药称号。这个称号适用于重要的新药，明显缩短了批准决策时间。FDA预计2015年5月19日完成这项申请的复审。 Blinatumomab是第一类双特异性T细胞衔接器（BiTE）新药，细胞毒性T细胞直接靶向表达CD19的癌细胞。CD19是一种在B细胞衍生的ALLs或非霍奇金淋巴瘤表面表达的蛋白质。 FDA中心的RichardPazdur博士说：“免疫疗法，尤其是具有特殊作用机制的blinatumomab为白血病患者带来了很大希望 FDA的药品评价和研究中心血液学和肿瘤学产品室主任Richard Pazdur，医学博士说：“免疫治疗，尤其是Blincyto有其独特的作用机制，对有白血病患者尤其鼓舞人有前途。“认识到这个新治疗的潜能，FDA与承办单位在我们突破性治疗指定程序下主动共事便于批准这个新型药物。” BLINCYTO（blinatumomab）注射为静脉内使用 批准日期：2014年12月23日 公司：Amgen Inc 美国最初批准：2014年 适应症和用法 BLINCYTO是双特异性CD19定向CD3 T细胞扣合片表示为费城染色体阴性复发或难治的B细胞的前体急性淋巴细胞白血病（ALL）的治疗。这个指示下，加速审批核准。继续批准该适应症可能会在随后的试验验证的临床获益队伍。 用法用量 - 住院推荐的前9天的第一个周期的和的第2天的第二次循环的。 - 治疗的单个循环由4周的连续静脉输注之后是2周无治疗间隔期。  - 对于患者至少45公斤重，在周期1，管理BLINCYTO9微克/天的第1-7天，并在在8-28天28微克/天。对于后续周期，管理BLINCYTO在28微克/天的日子1-28。 •管理 -  Premedicate地塞米松20mg的静脉内前1小时，以每个周期BLINCYTO的首次剂量之前，步骤剂量（如第1个周期第8天），或4小时或更长时间中断后重新开始的输注时。 - 管理作为连续静脉内输注用输液泵以恒定流速。 - 该输液袋应注入超过24小时或48小时。 -  BLINCYTO应通过专用的腔注入。 •准备 - 四解稳定剂被提供并且被用于涂覆预充液IV袋之前加入复溶BLINCYTO的。 - 重新构建BLINCYTO用注射用无菌水，USP，只。 - 当准备输液的解决方案，因为BLINCYTO不含抗菌防腐剂无菌技术要严格遵守。 - 使用掺混说明中描述的特定卷。 FULL PRESCRIBING INFORMATION: CONTENTS* 1. INDICATIONS AND USAGE BLINCYTO is indicated for the treatment of Philadelphia chromosome-negative relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL). This indication is approved under accelerated approval. Continued approval for this indication may be contingent upon verification of clinical benefit in subsequent trials [see Clinical Studies (14.1)]. 2. DOSAGE AND ADMINISTRATION Hospitalization is recommended for the first 9 days of the first cycle and the first 2 days of the second cycle. For all subsequent cycle starts and reinitiation (eg, if treatment is interrupted for 4 or more hours), supervision by a healthcare professional or hospitalization is recommended. Do not flush the BLINCYTO infusion line especially when changing infusion bags. Flushing when changing bags or at completion of infusion can result in excess dosage and complications thereof.  Preparation and administration errors resulting in overdose have occurred [see Dosage and Administration (2.2 and 2.4) and Warnings and Precautions (5.9)]. 2.1 Dosage A single cycle of treatment of BLINCYTO consists of 4 weeks of continuous intravenous infusion followed by a 2-week treatment-free interval. For patients at least 45 kg in weight: -  In Cycle 1, administer BLINCYTO at 9 mcg/day on Days 1–7 and at 28 mcg/day on Days 8–28. -  For subsequent cycles, administer BLINCYTO at 28 mcg/day on Days 1–28. Allow for at least 2 weeks treatment-free between cycles of BLINCYTO. A treatment course consists of up to 2 cycles of BLINCYTO for induction followed by 3 additional cycles for consolidation treatment (up to a total of 5 cycles). 2.2 Administration Premedicate with dexamethasone 20 mg intravenously 1 hour prior to the first dose of BLINCYTO of each cycle, prior to a step dose (such as Cycle 1 day 8), or when restarting an infusion after an interruption of 4 or more hours. Administer BLINCYTO as a continuous intravenous infusion at a constant flow rate using an infusion pump. The pump should be programmable, lockable, non-elastomeric, and have an alarm. BLINCYTO infusion bags should be infused over 24 hours or 48 hours [see Dosage and Administration (2.4)]. Infuse the total 240 mL BLINCYTO solution according to the instructions on the pharmacy label on the bag at one of the following constant infusion rates: -  Infusion rate of 10 mL/h for a duration of 24 hours, OR -  Infusion rate of 5 mL/h for a duration of 48 hours The BLINCYTO solution for infusion must be administered using IV tubing that contains a sterile, non-pyrogenic, low protein-binding, 0.2 micron in-line filter. Important Note: Do not flush the infusion line, especially when changing infusion bags. Flushing when changing bags or at completion of infusion can result in excess dosage. BLINCYTO should be infused through a dedicated lumen. At the end of the infusion, any unused BLINCYTO solution in the IV bag and IV lines should be disposed of in accordance with local requirements. 2.3 Dosage Adjustments If the interruption after an adverse event is no longer than 7 days, continue the same cycle to a total of 28 days of infusion inclusive of days before and after the interruption in that cycle.  If an interruption due to an adverse event is longer than 7 days, start a new cycle. Based on the Common Terminology Criteria for Adverse Events (CTCAE). Grade 3 is severe, and Grade 4 is life-threatening. 2.4 Reconstitution and Preparation of Solution for Infusion It is very important that the instructions for preparation (including admixing) and administration provided in this section are strictly followed to minimize medication errors (including underdose and overdose) [see Warnings and Precautions (5.9)]. Call 1-800-77-AMGEN (1-800-772-6436) if you have questions about the reconstitution and preparation of BLINCYTO. 2.4.1  Gather Supplies NOTE: 1 package BLINCYTO includes 1 vial of BLINCYTO and 1 vial of IV Solution Stabilizer. Before preparation, ensure you have the following supplies ready: 1 package of BLINCYTO for preparation of 9 mcg/day dose infused over 24 hours at a rate of 10 mL/h, 9 mcg/day dose infused over 48 hours at a rate of 5 mL/h, and 28 mcg/day dose infused over 24 hours at a rate of 10 mL/h 2 packages of BLINCYTO for preparation of 28 mcg/day dose infused over 48 hours at a rate of 5 mL/h The following supplies are also required, but not included in the package: Sterile, single-use disposable syringes 21- to 23- gauge needle(s) (recommended) Preservative-free Sterile Water for Injection, USP 250 mL 0.9% Sodium Chloride IV bag To minimize the number of aseptic transfers, it is recommended to use a 250 mL-prefilled IV bag. 250 mL-prefilled IV bags typically contain overfill with a total volume of 265 to 275 mL. BLINCYTO dose calculations provided in section 2.4.4 are based on a starting volume of 265 mL to 275 mL 0.9% Sodium Chloride. Use only polyolefin, PVC non-di-ethylhexylphthalate (non-DEHP), or ethyl vinyl acetate (EVA) infusion bags/pump cassettes. Polyolefin, PVC non-DEHP, or EVA IV tubing with a sterile, non-pyrogenic, low protein-binding 0.2 micron in-line filter Ensure that the IV tubing is compatible with the infusion pump. 2.4.2 Aseptic Preparation Aseptic technique must be strictly observed when preparing the solution for infusion since BLINCYTO vials do not contain antimicrobial preservatives. To prevent accidental contamination, prepare BLINCYTO according to aseptic standards, including but not limited to: Preparation must be done in a USP <797> compliant facility. Preparation must be done in an ISO Class 5 laminar flow hood or better. The admixing area should have appropriate environmental specifications, confirmed by periodic monitoring. Personnel should be appropriately trained in aseptic manipulations and admixing of oncology drugs. Personnel should wear appropriate protective clothing and gloves. Gloves and surfaces should be disinfected. 2.4.3  SPECIAL CONSIDERATIONS TO SUPPORT ACCURATE PREPARATION A) IV Solution Stabilizer is provided with the BLINCYTO package and is used to coat the prefilled IV bag prior to addition of reconstituted BLINCYTO to prevent adhesion of BLINCYTO to IV bags and IV lines. Therefore, add IV Solution Stabilizer to the IV bag containing 0.9% Sodium Chloride. Do not use IV Solution Stabilizer for reconstitution of BLINCYTO. B) The entire volume of the admixed BLINCYTO will be more than the volume administered to the patient (240 mL) to account for the priming of the IV line and to ensure that the patient will receive the full dose of BLINCYTO. C) When preparing an IV bag, remove air from IV bag. This is particularly important for use with an ambulatory infusion pump. D) Use the specific volumes described in the admixing instructions [see Dosage and Administration (2.4.4)] to minimize errors in calculation. 2.4.4  Preparation of BLINCYTO Solution for Infusion Using a Prefilled 250 mL 0.9% Sodium Chloride IV Bag Sodium Chloride IV Bag Specific admixing instructions are provided for each dose and infusion time.  Verify the prescribed dose and infusion time of BLINCYTO and identify the appropriate dosing preparation section listed below.  Follow the steps for reconstituting BLINCYTO and preparing the IV bag. See section 2.4.4.1 for 9 mcg/day infused over 24 hours at a rate of 10 mL/h. See section 2.4.4.2 for 9 mcg/day infused over 48 hours at a rate of 5 mL/h. See section 2.4.4.3 for 28 mcg/day infused over 24 hours at a rate of 10 mL/h. See section 2.4.4.4 for 28 mcg/day infused over 48 hours at a rate of 5 mL/h. 2.4.4.1 Preparation of BLINCYTO 9 mcg/day infused over 24 hours at a rate of 10 mL/h Use a prefilled 250 mL 0.9% Sodium Chloride IV bag. 250 mL-prefilled bags typically contain overfill to a total volume of 265 to 275 mL. If necessary adjust the IV bag volume by adding or removing 0.9% Sodium Chloride to achieve a starting volume between 265 and 275 mL. Using a 10 mL syringe, aseptically transfer 5.5 mL of IV Solution Stabilizer to the IV bag with 0.9% Sodium Chloride. Gently mix the contents of the bag to avoid foaming. Discard remaining IV Solution Stabilizer vial. Using a 5 mL syringe, reconstitute one vial of BLINCYTO using 3 mL of preservative-free Sterile Water for Injection, USP. Direct preservative-free Sterile Water for Injection, USP, toward the side of the vial during reconstitution. Gently swirl contents to avoid excess foaming. Do not shake. Do not reconstitute BLINCYTO with IV Solution Stabilizer. The addition of preservative-free Sterile Water for Injection, USP, to the lyophilized powder results in a final BLINCYTO concentration of 12.5 mcg/mL. Visually inspect the reconstituted solution for particulate matter and discoloration during reconstitution and prior to infusion. The resulting solution should be clear to slightly opalescent, colorless to slightly yellow. Do not use if solution is cloudy or has precipitated. Using a 1 mL syringe, aseptically transfer 0.83 mL of reconstituted BLINCYTO into the IV bag. Gently mix the contents of the bag to avoid foaming. Under aseptic conditions, attach the IV tubing to the IV bag with the sterile 0.2 micron in-line filter. Remove air from the IV bag and prime the IV line only with the prepared solution for infusion. Do not prime with 0.9% Sodium Chloride. Store at 2°C to 8°C if not used immediately. 2.4.4.2 Preparation of BLINCYTO 9 mcg/day infused over 48 hours at a rate of 5 mL/h Use a prefilled 250 mL 0.9% Sodium Chloride IV bag. 250 mL-prefilled bags typically contain overfill to a total volume of 265 to 275 mL. If necessary adjust the IV bag volume by adding or removing 0.9% Sodium Chloride to achieve a starting volume between 265 and 275 mL. Using a 10 mL syringe, aseptically transfer 5.5 mL of IV Solution Stabilizer to the IV bag with 0.9% Sodium Chloride. Gently mix the contents of the bag to avoid foaming. Discard remaining IV Solution Stabilizer vial. Using a 5 mL syringe, reconstitute one vial of BLINCYTO using 3 mL of preservative-free Sterile Water for Injection, USP. Direct preservative-free Sterile Water for Injection, USP, toward the side of the vial during reconstitution. Gently swirl contents to avoid excess foaming. Do not shake. Do not reconstitute BLINCYTO with IV Solution Stabilizer. The addition of preservative-free Sterile Water for Injection, USP, to the lyophilized powder results in a final BLINCYTO concentration of 12.5 mcg/mL. Visually inspect the reconstituted solution for particulate matter and discoloration during reconstitution and prior to infusion. The resulting solution should be clear to slightly opalescent, colorless to slightly yellow. Do not use if solution is cloudy or has precipitated. Using a 3 mL syringe, aseptically transfer 1.7 mL of reconstituted BLINCYTO into the IV bag. Gently mix the contents of the bag to avoid foaming. Under aseptic conditions, attach the IV tubing to the IV bag with the sterile 0.2 micron in-line filter. Remove air from the IV bag and prime the IV line only with the prepared solution for infusion. Do not prime with 0.9% Sodium Chloride. Store at 2°C to 8°C if not used immediately. 2.4.4.3 Preparation of BLINCYTO 28 mcg/day infused over 24 hours at a rate of 10 mL/h Use a prefilled 250 mL 0.9% Sodium Chloride IV bag. 250 mL-prefilled bags typically contain overfill to a total volume of 265 to 275 mL. If necessary adjust the IV bag volume by adding or removing 0.9% Sodium Chloride to achieve a starting volume between 265 and 275 mL. Using a 10 mL syringe, aseptically transfer 5.6 mL of IV Solution Stabilizer to the IV bag with 0.9% Sodium Chloride. Gently mix the contents of the bag to avoid foaming. Discard remaining IV Solution Stabilizer vial. Using a 5 mL syringe, reconstitute one vial of BLINCYTO using 3 mL of preservative-free Sterile Water for Injection, USP. Direct preservative-free Sterile Water for Injection, USP, toward the side of the vial during reconstitution. Gently swirl contents to avoid excess foaming. Do not shake. Do not reconstitute BLINCYTO with IV Solution Stabilizer. The addition of preservative-free Sterile Water for Injection, USP, to the lyophilized powder results in a final BLINCYTO concentration of 12.5 mcg/mL. Visually inspect the reconstituted solution for particulate matter and discoloration during reconstitution and prior to infusion. The resulting solution should be clear to slightly opalescent, colorless to slightly yellow. Do not use if solution is cloudy or has precipitated. Using a 3 mL syringe, aseptically transfer 2.6 mL of reconstituted BLINCYTO into the IV bag. Gently mix the contents of the bag to avoid foaming. Under aseptic conditions, attach the IV tubing to the IV bag with the sterile 0.2 micron in-line filter. Remove air from the IV bag and prime the IV line only with the prepared solution for infusion. Do not prime with 0.9% Sodium Chloride. Store at 2°C to 8°C if not used immediately. 2.4.4.4 Preparation of BLINCYTO 28 mcg/day infused over 48 hours at a rate of 5 mL/h Use a prefilled 250 mL 0.9% Sodium Chloride IV bag. 250 mL-prefilled bags typically contain overfill to a total volume of 265 to 275 mL. If necessary adjust the IV bag volume by adding or removing 0.9% Sodium Chloride to achieve a starting volume between 265 and 275 mL. Using a 10 mL syringe, aseptically transfer 5.6 mL of IV Solution Stabilizer to the IV bag with 0.9% Sodium Chloride. Gently mix the contents of the bag to avoid foaming. Discard remaining IV Solution Stabilizer vials. Use two vials of BLINCYTO. Using a 5 mL syringe, reconstitute each vial of BLINCYTO using 3 mL of preservative-free Sterile Water for Injection, USP. Direct preservative-free Sterile Water for Injection, USP, toward the side of the vial during reconstitution. Gently swirl contents to avoid excess foaming. Do not shake. Do not reconstitute BLINCYTO with IV Solution Stabilizer. The addition of preservative-free Sterile Water for Injection, USP, to the lyophilized powder results in a final BLINCYTO concentration of 12.5 mcg/mL. Visually inspect the reconstituted solution for particulate matter and discoloration during reconstitution and prior to infusion. The resulting solution should be clear to slightly opalescent, colorless to slightly yellow. Do not use if solution is cloudy or has precipitated. Using a 3 mL syringe, aseptically transfer 5.2 mL of reconstituted BLINCYTO into the IV bag (2.7 mL from one vial and the remaining 2.5 mL from the second vial). Gently mix the contents of the bag to avoid foaming. Under aseptic conditions, attach the IV tubing to the IV bag with the sterile 0.2 micron in-line filter. Remove air from the IV bag and prime the IV line only with the prepared solution for infusion. Do not prime with 0.9% Sodium Chloride. Store at 2°C to 8°C if not used immediately. 2.5  Storage Requirements The information in Table 1 indicates the storage time for the reconstituted BLINCYTO vial and prepared IV bag containing BLINCYTO solution for infusion. Lyophilized BLINCYTO vial and IV Solution Stabilizer may be stored for a maximum of 8 hours at room temperature. Table 1. Storage Time for Reconstituted BLINCYTO and IV Solution Stabilizer   While stored, protect BLINCYTO and IV Solution Stabilizer vials from light. Storage time includes infusion time. If IV bag containing BLINCYTO solution for infusion is not administered within the time frames and temperatures indicated, it must be discarded; it should not be refrigerated again. 3. DOSAGE FORMS AND STRENGTHS For injection: 35 mcg of lyophilized powder in a single-use vial for reconstitution. 4. CONTRAINDICATIONS BLINCYTO is contraindicated in patients with known hypersensitivity to blinatumomab or to any component of the product formulation. 5. WARNINGS AND PRECAUTIONS 5.1   Cytokine Release Syndrome Cytokine Release Syndrome (CRS), which may be life-threatening or fatal, occurred in patients receiving BLINCYTO.  Infusion reactions have occurred with the BLINCYTO infusion and may be clinically indistinguishable from manifestations of CRS.  Serious adverse events that may be associated with CRS included pyrexia, headache, nausea, asthenia, hypotension, increased alanine aminotransferase, increased aspartate aminotransferase, and increased total bilirubin; these events infrequently led to BLINCYTO discontinuation. Life-threatening or fatal CRS was infrequently reported in patients receiving BLINCYTO. In some cases, disseminated intravascular coagulation (DIC), capillary leak syndrome (CLS), and hemophagocytic lymphohistiocytosis/macrophage activation syndrome (HLH/MAS) have been reported in the setting of CRS.  Patients should be closely monitored for signs or symptoms of these events. Management of these events may require either temporary interruption or discontinuation of BLINCYTO [see Dosage and Administration (2.3)]. 5.2 Neurological Toxicities In patients receiving BLINCYTO in clinical trials, neurological toxicities have occurred in approximately 50% of patients. The median time to onset of any neurological toxicity was 7 days. Grade 3 or higher (severe, life-threatening, or fatal) neurological toxicities following initiation of BLINCYTO administration occurred in approximately 15% of patients and included encephalopathy, convulsions, speech disorders, disturbances in consciousness, confusion and disorientation, and coordination and balance disorders. The majority of events resolved following interruption of BLINCYTO, but some resulted in treatment discontinuation.  Monitor patients receiving BLINCYTO for signs and symptoms of neurological toxicities, and interrupt or discontinue BLINCYTO as recommended [see Dosage and Administration (2.3)].   5.3  Infections In patients receiving BLINCYTO in clinical trials, serious infections such as sepsis, pneumonia, bacteremia, opportunistic infections, and catheter-site infections were observed in approximately 25% of patients, some of which were life-threatening or fatal. As appropriate, administer prophylactic antibiotics and employ surveillance testing during treatment with BLINCYTO.  Monitor patients for signs and symptoms of infection and treat appropriately. 5.4  Tumor Lysis Syndrome Tumor lysis syndrome (TLS), which may be life-threatening or fatal, has been observed in patients receiving BLINCYTO. Appropriate prophylactic measures, including pretreatment nontoxic cytoreduction and on-treatment hydration, should be used for the prevention of TLS during BLINCYTO treatment. Monitor for signs or symptoms of TLS. Management of these events may require either temporary interruption or discontinuation of BLINCYTO [see Dosage and Administration (2.3)]. 5.5  Neutropenia and Febrile Neutropenia Neutropenia and febrile neutropenia, including life-threatening cases, have been observed in patients receiving BLINCYTO. Monitor laboratory parameters (including, but not limited to, white blood cell count and absolute neutrophil count) during BLINCYTO infusion. Interrupt BLINCYTO if prolonged neutropenia occurs.  5.6  Effects on Ability to Drive and Use Machines Due to the potential for neurologic events, including seizures, patients receiving BLINCYTO are at risk for loss of consciousness [see Warnings and Precautions (5.2)]. Advise patients to refrain from driving and engaging in hazardous occupations or activities such as operating heavy or potentially dangerous machinery while BLINCYTO is being administered.  5.7  Elevated Liver Enzymes Treatment with BLINCYTO was associated with transient elevations in liver enzymes. Although the majority of these events were observed in the setting of CRS, some were observed outside of this setting. For these events, the median time to onset was 15 days.  In patients receiving BLINCYTO in clinical trials, Grade 3 or greater elevations in liver enzymes occurred in approximately 6% of patients outside the setting of CRS and resulted in treatment discontinuation in less than 1% of patients. Monitor alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transferase (GGT), and total blood bilirubin prior to the start of and during BLINCYTO treatment. Interrupt BLINCYTO if the transaminases rise to greater than 5 times the upper limit of normal or if bilirubin rises to more than 3 times the upper limit of normal. 5.8  Leukoencephalopathy Cranial magnetic resonance imaging (MRI) changes showing leukoencephalopathy have been observed in patients receiving BLINCYTO, especially in patients with prior treatment with cranial irradiation and antileukemic chemotherapy (including systemic high-dose methotrexate or intrathecal cytarabine). The clinical significance of these imaging changes is unknown.    5.9 Preparation and Administration Errors Preparation and administration errors have occurred with BLINCYTO treatment. Follow instructions for preparation (including admixing) and administration strictly to minimize medication errors (including underdose and overdose) [see Dosage and Administration (2.2) and (2.4)]. 6. ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the label: Cytokine Release Syndrome [see Warnings and Precautions (5.1)] Neurological Toxicities [see Warnings and Precautions (5.2)] Infections [see Warnings and Precautions (5.3)] Tumor Lysis Syndrome [see Warnings and Precautions (5.4)] Neutropenia and Febrile Neutropenia [see Warnings and Precautions (5.5)] Effects on Ability to Drive and Use Machines [see Warnings and Precautions (5.6)] Elevated Liver Enzymes [see Warnings and Precautions (5.7)] Leukoencephalopathy [see Warnings and Precautions (5.8)] Preparation and Administration Errors [see Warnings and Precautions (5.9)] 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 safety data described in this section reflect exposure to BLINCYTO in clinical trials in which 212 patients with relapsed or refractory ALL received up to 28 mcg/day. All patients received at least one dose of BLINCYTO. The median age of the study population was 37 years (range: 18 to 79 years), 63% were male, 79% were White, 3% were Asian, and 3% were Black or African American. The most common adverse reactions (≥ 20%) were pyrexia (62%), headache (36%), peripheral edema (25%), febrile neutropenia (25%), nausea (25%), hypokalemia (23%), and constipation (20%). Serious adverse reactions were reported in 65% of patients. The most common serious adverse reactions (≥ 2%) included febrile neutropenia, pyrexia, pneumonia, sepsis, neutropenia, device-related infection, tremor, encephalopathy, infection, overdose, confusion, Staphylococcal bacteremia, and headache. Adverse reactions of Grade 3 or higher were reported in 80% of patients. Discontinuation of therapy due to adverse reactions occurred in 18% of patients treated with BLINCYTO. The adverse reactions reported most frequently as the reason for discontinuation of treatment included encephalopathy and sepsis. Fatal adverse events occurred in 15% of patients. The majority of these events were infections. No fatal adverse events occurred on treatment among patients in remission. The adverse reactions with ≥ 10% incidence for any grade or ≥ 5% incidence for Grade 3 or higher are summarized in Table 2. Table 2. Adverse Reactions With ≥ 10% Incidence for Any Grade or ≥ 5% Incidence for Grade 3 or Higher (N = 212) Grading based on NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 Diarrhea includes the following terms: colitis, diarrhea, enteritis, and neutropenic colitis. Tremor includes the following terms: resting tremor and tremor. Dyspnea includes the following terms: acute respiratory failure, bronchial hyperactivity, bronchospasm, dyspnea, dyspnea exertional, respiratory distress, respiratory failure, and wheezing. Rash includes the following terms: erythema, rash, erythematous rash, generalized rash, macular rash, maculo-papular rash, papular rash, and vesicular rash. Additional important adverse reactions that did not meet the threshold criteria for inclusion in Table 2 were: Blood and lymphatic system disorders: leukocytosis (2%), lymphopenia (1%) Cardiac disorders: tachycardia (8%) General disorders and administration site conditions: edema (5%) Immune system disorders: cytokine storm (1%) Investigations: decreased immunoglobulins (9%), increased blood bilirubin (8%), increased gamma-glutamyl-transferase (6%), increased liver enzymes (1%) Metabolism and nutrition disorders: tumor lysis syndrome (4%), hypoalbuminemia (4%) Nervous system disorders: encephalopathy (5%), paresthesia (5%), aphasia (4%), convulsion (2%), memory impairment (2%), cognitive disorder (1%), speech disorder (< 1%) Psychiatric disorders: confusion (7%), disorientation (3%) Vascular disorders: capillary leak syndrome (< 1%). Hypersensitivity reactions related to BLINCYTO treatment were hypersensitivity (1%) and bronchospasm (< 1%). 6.2 Immunogenicity As with all therapeutic proteins, there is potential for immunogenicity. The immunogenicity of BLINCYTO has been evaluated using either an electrochemiluminescence detection technology (ECL) or an enzyme-linked immunosorbent assay (ELISA) screening immunoassay for the detection of binding anti-blinatumomab antibodies. For patients whose sera tested positive in the screening immunoassay, an in vitro biological assay was performed to detect neutralizing antibodies.   In clinical studies, less than 1% of patients treated with BLINCYTO tested positive for binding anti-blinatumomab antibodies. All patients who tested positive for binding antibodies also tested positive for neutralizing anti-blinatumomab antibodies. Anti-blinatumomab antibody formation may affect pharmacokinetics of BLINCYTO. No association was seen between antibody development and development of adverse events.  If formation of anti-blinatumomab antibodies with a clinically significant effect is suspected, contact Amgen at 1-800-77-AMGEN (1-800-772-6436) to discuss antibody testing. The detection of anti-blinatumomab 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 blinatumomab with the incidence of antibodies to other products may be misleading. 7. DRUG INTERACTIONS No formal drug interaction studies have been conducted with BLINCYTO. Initiation of BLINCYTO treatment causes transient release of cytokines that may suppress CYP450 enzymes. The highest drug- drug interaction risk is during the first 9 days of the first cycle and the first 2 days of the second cycle in patients who are receiving concomitant CYP450 substrates, particularly those with a narrow therapeutic index. In these patients, monitor for toxicity (eg, warfarin) or drug concentrations (eg, cyclosporine). Adjust the dose of the concomitant drug as needed [see Clinical Pharmacology (12.2 and 12.3)]. 8. USE IN SPECIFIC POPULATIONS 8.1  Pregnancy Pregnancy Category C  Risk Summary There are no adequate and well-controlled studies of BLINCYTO in pregnant women. Based on its mechanism of action, BLINCYTO may cause fetal toxicity including B-cell lymphocytopenia when administered to a pregnant woman. BLINCYTO should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Animal Data Animal reproduction studies have not been conducted with blinatumomab. In embryo-fetal developmental toxicity studies, a murine surrogate molecule was administered intravenously to pregnant mice during the period of organogenesis. The surrogate molecule crossed the placental barrier and did not cause embryo-fetal toxicity or teratogenicity. The expected depletions of B and T cells were observed in the pregnant mice, but hematological effects were not assessed in fetuses.  8.3 Lactation It is not known whether blinatumomab 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 blinatumomab, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. 8.4 Pediatric Use There is limited experience in pediatric patients. BLINCYTO was evaluated in a dose-escalation study of 41 pediatric patients with relapsed or refractory B-precursor ALL. The median age was 6 years (range: 2 to 17 years).  BLINCYTO was administered at doses of 5 to 30 mcg/m2/day. The recommended phase 2 regimen was 5 mcg/m2/day on Days 1-7 and 15 mcg/m2/day on Days 8-28 for cycle 1, and 15 mcg/m2/day on Days 1-28 for subsequent cycles. At a higher dose, a fatal cardiac failure event occurred in the setting of life-threatening cytokine release syndrome (CRS) [see Warnings and Precautions (5.1)]. The steady-state concentrations of blinatumomab were comparable in adult and pediatric patients at the equivalent dose levels based on body surface area (BSA)-based regimens. 8.5 Geriatric Use Of the total number of patients with relapsed or refractory ALL, approximately 13% were 65 years of age and over. Generally, safety and efficacy were similar between elderly patients (≥ 65 years of age) and patients less than 65 years of age treated with BLINCYTO. Elderly patients experienced a higher rate of neurological toxicities, including cognitive disorder, encephalopathy, confusion, and serious infections [see Warnings and Precautions (5.2) and (5.3)]. 8.6  Hepatic Impairment No formal pharmacokinetic studies using BLINCYTO have been conducted in patients with hepatic impairment. 8.7  Renal Impairment No formal pharmacokinetic studies using BLINCYTO have been conducted in patients with renal impairment. No dose adjustment is needed for patients with baseline creatinine clearance (CrCL) equal to or greater than 30 mL/min. There is no information available in patients with CrCL less than 30 mL/min or patients on hemodialysis [see Clinical Pharmacology (12.3)]. 10. OVERDOSAGE Overdoses have been observed, including one patient who received 133-fold the recommended therapeutic dose of BLINCYTO delivered over a short duration. Overdoses resulted in adverse reactions which were consistent with the reactions observed at the recommended therapeutic dose and included fever, tremors, and headache.  In the event of overdose, interrupt the infusion, monitor the patient for signs of toxicity, and provide supportive care [see Warnings and Precautions (5.9)]. Consider reinitiation of BLINCYTO at the correct therapeutic dose when all toxicities have resolved and no earlier than 12 hours after interruption of the infusion [see Dosage and Administration (2.1)].   11. DESCRIPTION BLINCYTO (blinatumomab) is a bispecific CD19-directed CD3 T-cell engager that binds to CD19 (expressed on cells of B-lineage origin) and CD3 (expressed on T cells). BLINCYTO is produced in Chinese hamster ovary cells.  It consists of 504 amino acids and has a molecular weight of approximately 54 kilodaltons. Each BLINCYTO package contains 1 vial BLINCYTO and 1 vial IV Solution Stabilizer. BLINCYTO is supplied in a single-use vial as a sterile, preservative-free, white to off-white lyophilized powder for intravenous administration.  Each single-use vial of BLINCYTO contains 35 mcg blinatumomab, citric acid monohydrate (3.35 mg), lysine hydrochloride (23.23 mg), polysorbate 80 (0.64 mg), trehalose dihydrate (95.5 mg), and sodium hydroxide to adjust pH to 7.0.  After reconstitution with 3 mL of preservative-free Sterile Water for Injection, USP, the resulting concentration is 12.5 mcg/mL blinatumomab.  IV Solution Stabilizer is supplied in a single-use vial as a sterile, preservative-free, colorless to slightly yellow, clear solution. Each single-use vial of IV Solution Stabilizer contains citric acid monohydrate (52.5 mg), lysine hydrochloride (2283.8 mg), polysorbate 80 (10 mg), sodium hydroxide to adjust pH to 7.0, and water for injection. 12. CLINICAL PHARMACOLOGY 12.1  Mechanism of Action Blinatumomab is a bispecific CD19-directed CD3 T-cell engager that binds to CD19 expressed on the surface of cells of B-lineage origin and CD3 expressed on the surface of T cells. It activates endogenous T cells by connecting CD3 in the T-cell receptor (TCR) complex with CD19 on benign and malignant B cells. Blinatumomab mediates the formation of a synapse between the T cell and the tumor cell, upregulation of cell adhesion molecules, production of cytolytic proteins, release of inflammatory cytokines, and proliferation of T cells, which result in redirected lysis of CD19+ cells. 12.2  Pharmacodynamics During the continuous intravenous infusion over 4 weeks, the pharmacodynamic response was characterized by T-cell activation and initial redistribution, reduction in peripheral B cells, and transient cytokine elevation. Peripheral T cell redistribution (ie, T cell adhesion to blood vessel endothelium and/or transmigration into tissue) occurred after start of BLINCYTO infusion or dose escalation. T cell counts initially declined within 1 to 2 days and then returned to baseline levels within 7 to 14 days in majority patients. Increase of T cell counts above baseline (T cell expansion) was observed in few patients. Peripheral B cell counts decreased to less than or equal to 10 cells/microliter during the first treatment cycle at doses ≥ 5 mcg/m2/day or ≥ 9 mcg/day in the majority of patients. No recovery of peripheral B-cell counts was observed during the 2-week BLINCYTO-free period between treatment cycles. Incomplete depletion of B cells occurred at doses of 0.5 mcg/m2/day and 1.5 mcg/m2/day and in a few patients at higher doses. Cytokines including IL-2, IL-4, IL-6, IL-8, IL-10, IL-12, TNF-α, and IFN-γ were measured, and IL-6, IL-10, and IFN-γ were elevated. The highest elevation of cytokines was observed in the first 2 days following start of BLINCYTO infusion. The elevated cytokine levels returned to baseline within 24 to 48 hours during the infusion. In subsequent treatment cycles, cytokine elevation occurred in fewer patients with lesser intensity compared to the initial 48 hours of the first treatment cycle. 12.3  Pharmacokinetics The pharmacokinetics of blinatumomab appear linear over a dose range from 5 to 90 mcg/m2/day (approximately equivalent to 9 to 162 mcg/day) in adult patients. Following continuous intravenous infusion, the steady-state serum concentration (Css) was achieved within a day and remained stable over time. The increase in mean Css values was approximately proportional to the dose in the range tested. At the clinical doses of 9 mcg/day and 28 mcg/day for the treatment of relapsed/refractory ALL, the mean (SD) Css was 211 (258) pg/mL and 621 (502) pg/mL, respectively.  Distribution The estimated mean (SD) volume of distribution based on terminal phase (Vz) was 4.52 (2.89) L with continuous intravenous infusion of blinatumomab. Metabolism The metabolic pathway of blinatumomab has not been characterized.  Like other protein therapeutics, BLINCYTO is expected to be degraded into small peptides and amino acids via catabolic pathways. Elimination The estimated mean (SD) systemic clearance with continuous intravenous infusion in patients receiving blinatumomab in clinical studies was 2.92 (2.83) L/hour. The mean (SD) half-life was 2.11 (1.42) hours.  Negligible amounts of blinatumomab were excreted in the urine at the tested clinical doses. Body Weight, Body Surface Area, Gender, and Age Results of population pharmacokinetic analyses indicate that age (18 to 80 years of age), gender, body weight (44 to 134 kg), and body surface area (1.39 to 2.57 m2) do not influence the pharmacokinetics of blinatumomab.  Renal Impairment No formal pharmacokinetic studies of blinatumomab have been conducted in patients with renal impairment.  Pharmacokinetic analyses showed an approximately 2-fold difference in mean blinatumomab clearance values between patients with moderate renal impairment (CrCL ranging from 30 to 59 mL/min, N = 21) and normal renal function (CrCL more than 90 mL/min, N = 215). However, high interpatient variability was discerned (CV% up to 95.6%), and clearance values in renal impaired patients were essentially within the range observed in patients with normal renal function. There is no information available in patients with severe renal impairment (CrCL less than 30 mL/min) or patients on hemodialysis. Drug Interactions Transient elevation of cytokines may suppress CYP450 enzyme activities [see Drug Interactions (7) and Clinical Pharmacology (12.2)]. 13. NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility No carcinogenicity or genotoxicity studies have been conducted with blinatumomab. No studies have been conducted to evaluate the effects of blinatumomab on fertility. A murine surrogate molecule had no adverse effects on male and female reproductive organs in a 13-week repeat-dose toxicity study in mice. 14. CLINICAL STUDIES 14.1  Acute Lymphoblastic Leukemia The safety and efficacy of BLINCYTO were evaluated in an open-label, multicenter, single-arm study. Eligible patients were ≥ 18 years of age with Philadelphia chromosome-negative relapsed or refractory B‑precursor ALL (relapsed with first remission duration of ≤ 12 months in first salvage or relapsed or refractory after first salvage therapy or relapsed within 12 months of allogeneic hematopoietic stem cell transplantation [HSCT], and had ≥ 10% blasts in bone marrow). BLINCYTO was administered as a continuous intravenous infusion. In the first cycle, the initial dose was 9 mcg/day for week 1, then 28 mcg/day for the remaining 3 weeks. The target dose of 28 mcg/day was administered in cycle 2 and subsequent cycles starting on day 1 of each cycle.  Dose adjustment was possible in case of adverse events. The treated population included 185 patients who received at least 1 infusion of BLINCYTO; the median number of treatment cycles was 2 (range: 1 to 5). Patients who responded to BLINCYTO but later relapsed had the option to be retreated with BLINCYTO. Among treated patients, the median age was 39 years (range: 18 to 79 years), 63 out of 185 (34.1%) had undergone HSCT prior to receiving BLINCYTO, and 32 out of 185 (17.3%) had received more than 2 prior salvage therapies.  The primary endpoint was the complete remission/complete remission with partial hematological recovery (CR/CRh*) rate within 2 cycles of treatment with BLINCYTO. Seventy-seven out of 185 (41.6%) evaluable patients achieved CR/CRh* within the first 2 treatment cycles, with the majority of responses (81%, 62 out of 77) occurring within cycle 1 of treatment. See Table 3 for efficacy results from this study.  The HSCT rate among those who achieved CR/CRh* was 39% (30 out of 77). Table 3. Efficacy Results in Patients ≥ 18 Years of Age With Philadelphia Chromosome-Negative Relapsed or Refractory B-cell precursor Acute Lymphoblastic Leukemia (ALL)  CR (complete remission) was defined as ≤ 5% of blasts in the bone marrow, no evidence of disease, and full recovery of peripheral blood counts (platelets > 100,000/microliter and absolute neutrophil counts [ANC] > 1,000/microliter). CRh* (complete remission with partial hematological recovery) was defined as ≤ 5% of blasts in the bone marrow, no evidence of disease, and partial recovery of peripheral blood counts (platelets > 50,000/microliter and ANC > 500/microliter). MRD (minimal residual disease) response was defined as MRD by PCR < 1 x 10‑4 n1: number of patients who achieved MRD response and the respective remission status; n2: number of patients who achieved the respective remission status. Six CR/CRh* responders with missing MRD data were considered as MRD-nonresponders. DOR (duration of response)/RFS (relapse-free survival) was defined as time since first response of CR or CRh* to relapse or death, whichever is earlier. 16. HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied Each BLINCYTO package (NDC 55513-160-01) contains: One BLINCYTO 35 mcg single-use vial containing a sterile, preservative-free, white to off-white lyophilized powder and One IV Solution Stabilizer 10 mL single-use glass vial containing a sterile, preservative-free, colorless to slightly yellow, clear solution. Do not use the IV Solution Stabilizer to reconstitute BLINCYTO. 16.2 Storage and Handling Store BLINCYTO and IV Solution Stabilizer vials in the original package refrigerated at 2°C to 8°C (36°F to 46°F) and protect from light until time of use. Do not freeze.  Store and transport the prepared IV bag containing BLINCYTO solution for infusion at 2°C to 8°C (36°F to 46°F) conditions. Ship in packaging that has been validated to maintain temperature of the contents at 2°C to 8°C (36°F to 46°F). Do not freeze. 17. PATIENT COUNSELING INFORMATION See FDA-approved Medication Guide. Advise patients to contact a healthcare professional for any of the following: Signs and symptoms that may be associated with cytokine release syndrome and infusion reactions including pyrexia, fatigue, nausea, vomiting, chills, hypotension, rash, and wheezing [see Warnings and Precautions (5.1) and Adverse Reactions (6.1)] Signs and symptoms of neurological toxicities including convulsions, speech disorders, and confusion [see Warnings and Precautions (5.2) and Adverse Reactions (6.1)] Signs and symptoms of infections including pneumonia [see Warnings and Precautions (5.3) and Adverse Reactions (6.1)] Advise patients to refrain from driving and engaging in hazardous occupations or activities such as operating heavy or potentially dangerous machinery while BLINCYTO is being administered. Patients should be advised that they may experience neurological events [see Warnings and Precautions (5.6)].  Inform patients that: It is very important to keep the area around the intravenous catheter clean to reduce the risk of infection. They should not adjust the setting on the infusion pump. Any changes to pump function may result in dosing errors. If there is a problem with the infusion pump or the pump alarms, patients should contact their doctor or nurse immediately. http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=38b482a8-960b-4591-9857-5031ecb830aa FDA批准BLINCYTOTM（BLINATUMOMAB）-免疫疗法用于治疗复发或难治性前B细胞急性淋巴细胞白血病 BLINCYTO是FDA批准的首个也是唯一的双特异性T细胞CD3结合CD19靶向（BiTE®）的免疫疗法。 BLINCYTO (Blinatumomab)注射液的规格为每支35μg，供单次使用 2014年12月3日美国食品和药品监督管理局（FDA）已批准BLINCYTOTM（Blinatumomab）用于费城染色体阴性（Ph-）的复发性或难治性前B细胞急性淋巴细胞白血病（ALL）的治疗。该适应症按照加速审批通道获得批准。在随后的临床试验中将验证临床获益，并据此对该适应症做进一步批准。 此次批准使BLINCYTO成为首个FDA批准的双特异性T细胞CD3结合CD19靶向 抗体（BiTE®）；同时BLINCYTO也是批准用于费城染色体阴性（Ph-）的复发性或难治性前B细胞急性淋巴细胞白血病（ALL）的首个单药免疫治疗药物。Ph-复发性或难治性B细胞前体细胞性ALL是一种罕见且进展快速的血液和骨髓肿瘤。 安进公司研发部执行副总裁Sean E. Harper医学博士指出，“FDA将BLINCYTO指定为突破性治疗并予以加速审评，这显然表明对于这种通常易发生于年轻成人患者的复发性或难治性前B细胞ALL疾病而言，目前迫切需要新的治疗选择”。Sean博士同时指出：“BiTE®是一种有助于机体自身免疫系统战胜肿瘤的创新治疗方法，BLINCYTO是BiTE®研究平台首次在临床和法规上的验证”。 BLINCYTO的批准基于安进公司的211临床试验的结果，该试验是一项多中心、单臂、开放标签的II期研究。合格的入选患者为：年龄≥18岁，费城染色体阴性的复发性或难治性前B细胞ALL的患者。复发性或难治性的定义为首次治疗后首次缓解时间小于12个月的复发者，或首次挽救治疗后复发或难治，或进行异体造血干细胞移植 (HSCT) 后12个月内复发，且骨髓中原始细胞≥10%。在临床试验评价的185例患者中，41.6% (77/185; 95% CI: 34.4-49.1) 的患者在2个BLINCYTO治疗周期内达到完全缓解或完全缓解伴部分血液学缓解 (CR/CRh*)，这也是该研究的首要终点。大多数缓解 (81% [62/77]) 发生于第1周期的治疗。达到CR/CRh*的患者中，39% (30/77) 进行了HSCT，75.3% (58/77; 95% CI: 64.2-84.4) 达到最小残留病灶 (MRD)的缓解，MRD是分子水平的残留病灶的根除指标。 希望之城（City of Hope）的血液学/肿瘤学临床教授Anthony S. Stein博士指出：“BLINCYTO获得批准代表免疫治疗研究取得了重要的里程碑式进步，BLINCYTO给临床医师提供了一种新的单药治疗的机会帮助患者战胜此类既往治疗选择有限且高度侵袭的肿瘤疾病”。 BLINCYTO的产品标签中包含一项有关细胞因子释放综合征 (CRS) 和神经毒性的黑框警告。 在接受BLINCYTO治疗的患者中已观察到可能危及生命或导致死亡的细胞因子释放综合征 (CRS)。对于此类情况，建议暂停或终止使用BLINCYTO。在接受BLINCYTO治疗的患者中已观察到可能严重、危及生命或导致死亡的神经毒性。对于此类情况，建议暂停或终止使用BLINCYTO。 BLINCYTO禁止用于已知对Blinatumomab或制剂中任何成分过敏的患者。应当对患者的感染症状与体征进行监测，并作适当处理。 BLINCYTO使用期间，建议患者避免驾驶和进行危险职业或活动，例如开车，操作重型或潜在危险的机器。 应当严格遵守药物配制（包括混合）和给药的指导说明，避免药物过量和剂量不足。 最常见的不良反应 (20%) 包括发热 (62%)、头痛 (36%)、外周水肿 (25%)、发热性中性粒细胞减少 (25%)、恶心 (25%)、低钾血症 (23%)、皮疹 (21%)、震颤 (20%) 和便秘 (20%)。65%的患者报告了严重不良反应。最常见的严重不良反应 (2%) 包括中性粒细胞减少性发热、发热、肺炎、败血症、中性粒细胞减少、医疗器械相关感染、震颤、脑病、感染、药物过量、意识模糊、葡萄球菌菌血症和头痛。 FDA已批准一份有关BLINCYTO的风险评估及管控策略 (REMS)。BLINCYTO REMS的目的是告知医疗专业人员有关CRS、神经毒性、药物配制和给药错误方面的严重风险。有关BLINCYTO REMS计划的更多信息请参见 关于BLINCYTOTM (blinatumomab) BLINCYTO是首个BiTE®抗体结构，是美国食品和药品管理局（FDA）批准的首个单药免疫疗法3。BLINCYTO被FDA授予突破性治疗并被指定进行优先审评，现已在美国获得批准用于费城染色体阴性（Ph-）的复发性或难治性前B细胞急性淋巴白血病（ALL）的治疗。