近日，美国FDA批准Nulojix（belatacept）用于预防成人肾移植受者发生急性排斥反应。Nulojix是一种选择性T细胞辅刺激阻断剂，FDA已批准其与其他免疫抑制剂联用，其中包括巴利昔单抗、吗替麦考酚酯以及皮质类固醇。
批准日期：2011年6月15日 公司：百时美施贵宝
NULOJIX（贝拉西普[belatacept]）注射，用于静脉注射
美国最初批准：2011年
警告：移植后淋巴液过敏性疾病，其他恶性肿瘤和严重感染请参见完整的BOXED警告的完整预定信息。
•发生移植后淋巴增生性疾病（PTLD）的风险增加，主要涉及中枢神经系统（CNS）。对Epstein-Barr病毒（EBV）无免疫力的受者风险特别高;因此，仅用于EBV血清阳性患者。不要将NULOJIX用于EBV血清阴性或血清状况不明的移植受者。
•只有经过免疫抑制治疗和肾移植患者管理经验的医生才能开NULOJIX。
•免疫抑制可能导致对感染的易感性增加和恶性肿瘤的可能发展。
•不推荐在肝移植患者中使用，因为移植物丢失和死亡的风险增加。
最近的重大变化
警告和注意事项：5/2017
作用机制
Belatacept是一种选择性T细胞（淋巴细胞）共刺激阻断剂，与抗原呈递细胞上的CD80和CD86结合，从而阻断CD28介导的T淋巴细胞共刺激。 在体外，belatacept抑制T淋巴细胞增殖和细胞因子白细胞介素-2，干扰素-γ，白细胞介素-4和TNF-α的产生。 活化的T淋巴细胞是免疫排斥的主要介质。
在肾移植的非人灵长类动物模型中，与载体相比，belatacept单一疗法延长了移植物存活并减少了抗供体抗体的产生。
适应症和用法
•NULOJIX是一种选择性T细胞共刺激阻断剂，用于预防接受肾移植的成年患者的器官排斥反应。
•与巴利昔单抗诱导，霉酚酸酯和皮质类固醇联合使用。
使用限制：
•仅用于EBV血清反应阳性的患者。
•尚未建立用于预防肾脏以外移植器官中器官排斥的用途。
剂量和给药
•由于严重感染和恶性肿瘤的风险增加，不建议使用高于推荐或更频繁的剂量。
•有关完整的剂量说明，请参阅完整的处方信息。
NULOJIX用于肾移植受者的剂量。
初始阶段的剂量                                             剂量
第1天（移植当天，植入前）和第5天（第1天给药后约96小时） 每公斤10毫克
移植后第2周末和第4周结束                                每公斤10毫克
移植后第8周末和第12周结束                               每公斤10毫克
维护阶段的剂量                                              剂量
移植后第16周结束，此后每4周（正负3天）                  每公斤5毫克
仅用于静脉输注;管理超过30分钟。
•只能使用附带的无硅一次性注射器进行给药准备。
剂量形式和强度
注射用冻干粉：每瓶250毫克
禁忌症
EBV血清阴性或未知EBV血清状况的患者。
警告和注意事项
•移植后淋巴组织增生性疾病（PTLD）：风险增加，主要累及CNS;监测新的或恶化的神经，认知或行为体征和症状。 （BOXED警告）
•其他恶性肿瘤：所有免疫抑制剂的风险增加;似乎与强度和使用持续时间有关。避免长时间暴露在紫外线和阳光下。
•进行性多灶性白质脑病（PML）：风险增加;考虑报告新的或恶化的神经，认知或行为体征和症状的患者的诊断。不应超过推荐剂量的免疫抑制剂。
•其他严重感染：细菌，病毒，真菌和原虫感染的风险增加，包括机会性感染和肺结核。有些感染是致命的。多瘤病毒相关性肾病可导致肾移植物丢失;考虑减少免疫抑制。在使用NULOJIX之前评估结核病并开始潜伏感染的治疗。移植后建议进行巨细胞病毒和肺囊虫预防。
•肝移植：不建议使用。
•皮质类固醇最小化时的急性排斥和移植物丢失：皮质类固醇的使用应与NULOJIX临床试验经验一致。
•免疫接种：避免在治疗期间使用活疫苗。
•与抗胸腺细胞球蛋白共同给药：在新发肾移植受者中，尤其是肾移植物静脉血栓形成的其他易感因素的患者，与抗胸腺细胞球蛋白共同给药（在相同或几乎相同的时间）可能会带来风险用于肾同种异体移植物的静脉血栓形成。
不良反应
最常见的不良反应（NULOJIX治疗≥20％）是贫血，腹泻，尿路感染，外周性水肿，便秘，高血压，发热，移植物功能障碍，咳嗽，恶心，呕吐，头痛，低钾血症，高钾血症和白细胞减少。
要报告疑似不良反应，请致电1-800-721-5072联系Bristol-Myers Squibb或1-800-FDA-1088或www.fda.gov/medwatch联系FDA。
用于特定人群
•怀孕：根据动物数据，可能导致胎儿伤害;怀孕登记处可用。
•哺乳期：考虑到药物对母亲的重要性，停止使用药物或护理。
包装提供/存储和处理
用于静脉输注的NULOJIX®（belatacept）冻干粉末作为一次性小瓶提供，带有无硅胶的一次性注射器，包装如下：
NULOJIX 250MG VL 1 BELATACEPT BMS NULOJIX NDC：3037113
NULOJIX KIT FOR INJ 250MG SDV 1/EA BELATACEPT BRISTOL-MYERS SQUIBB COMPANY NDC：00003-0371-13
存储
NULOJIX冻干粉末在2°C至8°C（36°F至46°F）冷藏保存。 通过存放在原始包装中直到使用时保护NULOJIX免受光照。
应将重构的溶液立即从小瓶转移到输液袋或瓶中。 NULOJIX输液必须在NULOJIX冻干粉末构成后24小时内完成。 如果不立即使用，输液可以在冷藏条件下储存：2°C至8°C（36°F至46°F），避光最长24小时（最多4小时，共24小时） 小时可以在室温下：20°C至25°C [68°F至77°F]和室内照明）[见剂量和用量]。
完整说明资料附件：
https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=c16ac648-d5d2-9f7d-8637-e2328572754e
Nulojix powder injection 250mg（Belatacept）
IMPORTANT SAFETY INFORMATION
Post-Transplant Lymphoproliferative Disorder (PTLD)
NULOJIX patients are at increased risk for developing PTLD, predominantly involving the central nervous system (CNS)
Recipients without immunity to EBV (ie, seronegative) are at particularly increased risk; therefore, NULOJIX is contraindicated in transplant recipients who are EBV seronegative or with unknown serostatus
Monitor for new or worsening neurological, cognitive, or behavioral signs and symptoms
As the total burden of immunosuppression is a risk factor for PTLD, higher than recommended doses or more frequent dosing of NULOJIX or concomitant immunosuppressive agents are not recommended
Other known risk factors for PTLD include cytomegalovirus (CMV) infection and T-cell-depleting therapy
CMV prophylaxis is recommended for at least 3 months after transplantation
Use T-cell-depleting therapy to treat acute rejection cautiously
Patients who are EBV seropositive and CMV seronegative may be at increased risk of PTLD
Since CMV seronegative patients are at increased risk for CMV disease (a known risk factor for PTLD), the clinical significance of CMV serology for PTLD remains to be determined; however, these findings should be considered when prescribing NULOJIX
Management of Immunosuppression
Only physicians experienced in immunosuppressive therapy and management of kidney transplant patients should prescribe NULOJIX
Patients should be managed in facilities with adequate laboratory and supportive medical resources
The physician responsible for maintenance therapy should have complete information requisite for the follow-up of the patient
Progressive Multifocal Leukoencephalopathy (PML)
NULOJIX patients are at increased risk for PML, often a rapidly progressive and fatal opportunistic infection
In clinical trials, two cases were reported in patients receiving NULOJIX at higher cumulative doses and more frequently than the recommended regimen, along with MMF and corticosteroids; one occurred in a kidney transplant recipient and one occurred in a liver transplant recipient
As PML has been associated with high levels of immunosuppression, higher than recommended doses or more frequent dosing of NULOJIX and concomitant immunosuppressive agents, including MMF, are not recommended
Monitor for new or worsening neurological, cognitive, or behavioral signs and symptoms
PML is usually diagnosed by brain imaging, cerebrospinal fluid testing for JC viral DNA by polymerase chain reaction, and/or brain biopsy
Consultation with a specialist should be considered
If PML is diagnosed, consider reduction or withdrawal of immunosuppression, weighing risk to the allograft
Other Malignancies and Serious Infections
Increased susceptibility to infection and possible development of malignancies may result from immunosuppression
Patients should avoid prolonged exposure to ultraviolet light and sunlight
Patients receiving immunosuppressants, including NULOJIX, are at increased risk for bacterial, viral, fungal, and protozoal infections, including opportunistic infections and tuberculosis. Some infections were fatal
Polyoma virus-associated nephropathy can lead to deteriorating renal function and graft loss; consider reduction in immunosuppression, weighing risk to the graft
Tuberculosis was more frequently observed in patients receiving NULOJIX. eva luate for tuberculosis and initiate treatment for latent infection prior to NULOJIX use
CMV and Pneumocystis jiroveci prophylaxis is recommended after transplantation
Liver Transplant: use in liver transplant patients is not recommended due to increased risk of graft loss and death in a clinical trial with more frequent administration of NULOJIX than studied in kidney transplant, along with MMF and corticosteroids
Acute Rejection and Graft Loss with Corticosteroid Minimization
In NULOJIX postmarketing experience, corticosteroid minimization to 5 mg/day between Day 3 and Week 6 post-transplant was associated with an increased rate and grade of acute rejection, particularly Grade III
These Grade III rejections occurred in patients with 4-6 human leukocyte antigen (HLA) mismatches
Graft loss was a consequence of Grade III rejection in some patients
Corticosteroid utilization should be consistent with the NULOJIX clinical trial experience
Median (25th-75th percentile) corticosteroid doses were tapered to about 15 mg (10-20 mg)/day by the first 6 weeks and remained at about 10 mg (5-10 mg)/day for the first 6 months post-transplant
Immunizations: avoid use of live vaccines during NULOJIX treatment
Coadministration with Anti-Thymocyte Globulin: in de novo kidney transplant recipients, especially those with other predisposing risk factors for venous thrombosis of the renal allograft, coadministration (at the same or nearly the same time) with anti-thymocyte globulin may pose a risk for venous thrombosis of the renal allograft. If anti-thymocyte globulin (or any other cell-depleting induction treatment) and NULOJIX will be administered concomitantly, a 12-hour interval between the two administrations is suggested
Pregnancy: the data with NULOJIX use in pregnant women are insufficient to inform on drug-associated risk. NULOJIX is known to cross the placenta of animals. To monitor maternal-fetal outcomes of pregnant women who have received NULOJIX, or whose partners have received NULOJIX, healthcare providers are strongly encouraged to register pregnant patients in the Transplant Pregnancy Registry International (TPR) by calling 1-877-955-6877
Lactation: there are no data on the presence of NULOJIX in human milk or the effects on breastfed infants or human milk production to inform risk of NULOJIX to an infant during lactation. NULOJIX is excreted in rat milk and it is possible that the drug will be present in human milk. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for NULOJIX, and any potential adverse effects on the breastfed child from NULOJIX or from the underlying maternal conditions
Most Common Adverse Reactions (≥20%) through 3 years: anemia (45%), diarrhea (39%), urinary tract infection (37%), peripheral edema (34%), constipation (33%), hypertension (32%), pyrexia (28%), graft dysfunction (25%), cough (24%), nausea (24%), vomiting (22%), headache (21%), hypokalemia (21%), hyperkalemia (20%), and leukopenia (20%). No new adverse reactions were observed in the long-term extension (years 4-7) studies