Astagraf XL（他克莫司缓释胶囊）获FDA批准用于预防肾移植排斥
近日，安斯泰来（Astellas）开发的ASTAGRAF XL（他克莫司缓释胶囊，tacrolimus extended release capsules）获FDA批准，与霉酚酸酯（MMF）及皮质类醇联用、结合或无巴利昔单抗（basiliximab）诱导，用于预防成人肾移植受者中的器官排斥。安斯泰来于2012年9月提交了该药的新药申请（NDA）。
在美国，ASTAGRAF XL是首个每日一次的他克莫司制剂，该药作为免疫抑制组合方案中的核心组成部分，为肾移植受者预防器官排斥反应提供了一个很有潜力的疗法。
该药的获批，是基于2项主要的、随机、比较III期临床研究，涉及美国、欧洲、加拿大、南美、澳大利亚、南非等国的1093例患者（545例他克莫司缓释胶囊治疗）。
在2007年，他克莫司缓释胶囊在欧洲获批以商品名Advagraf销售；2008年，该药在日本获批以商品名Graceptor销售。总体而言，他克莫司缓释胶囊已获得了全球73个国家的监管批准，每年经该药治疗的患者数超过14万人。
批准日期：2013年7月20日  公司：安斯泰来（Astellas）
ASTAGRAF XL（他克莫司[tacrolimus extended-release ]）缓释胶囊，用于口服使用
美国初步批准：1994年
警告：
恶性肿瘤和严重感染移植患者;和女性肝移植患者中的增加的死亡率完整的处方信息见完整的盒装警告。
•ASTAGRAF XL或其他免疫抑制剂导致严重感染和恶性肿瘤的风险增加，可能导致住院或死亡。
•ASTAGRAF XL女性肝移植患者的死亡率增加。未批准用于肝移植。
作用机制
他克莫司与细胞内蛋白FKBP-12结合。然后形成他克莫司-FKBP-12，钙，钙调蛋白和钙调神经磷酸酶（无处不在的哺乳动物细胞内酶）的复合物，并且钙调神经磷酸酶的磷酸酶活性被抑制。这种抑制防止了各种因子如活化的T细胞（NF-AT）的核因子和活化的B细胞（NF-κB）的核因子κ-轻链增强子的去磷酸化和易位。
他克莫司抑制几种细胞因子的表达和/或产生，所述细胞因子包括白介素（IL）-1β，IL-2，IL-3，IL-4，IL-5，IL-6，IL-8，IL-干扰素，肿瘤坏死因子-α和粒细胞巨噬细胞集落刺激因子。他克莫司还抑制IL-2受体表达和一氧化氮释放，诱导凋亡和产生可导致免疫抑制活性的转化生长因子-β。最终结果是T淋巴细胞活化和增殖以及T辅助细胞依赖性B细胞应答（即免疫抑制）的抑制。
适应症和用法
ASTAGRAF XL是一种钙调神经磷酸酶抑制剂免疫抑制剂，用于预防肾移植患者的器官排斥，联合其他免疫抑制剂
使用限制：
•不可与其他他克莫司产品互换或替代
剂量和给药
•每天早晨在餐前至少1小时或在用餐后至少2小时，在空腹的情况下每天早晨服用。
•避免吃葡萄柚或喝葡萄柚汁或酒精
MMF =霉酚酸吗啉
推荐的ASTAGRAF XL起始剂量（严重肝损伤的患者可能需要较低的起始剂量）
与MMF，类固醇和basiliximab诱导
0.15至0.2mg/kg，在再灌注前或移植程序完成后48小时内（可延迟时间，直到肾功能恢复）
与MMF和类固醇;无巴利昔单抗诱导
 第一剂量（手术前）：在再灌注前12小时内作为单剂量0.1mg/kg
第二剂量（手术后）：在术前剂量后至少4小时和再灌注后12小时内为0.2mg / kg。
ASTAGRAF XL目标全血槽集中
时间段
他克莫司靶标全血槽集中
第1个月
7至15ng/mL，与巴利昔单抗诱导
10至15ng/mL，没有巴利昔单抗诱导
第2至6月
5〜15ng/mL
> 6个月
5〜10ng/mL
•非裔美国人可能需要滴定到更高的剂量才能达到目标他克莫司浓度
●在开始给药后第一周内和剂量变化后，在CYP3A4诱导物和/或抑制剂的共同给药的变化，或肾脏或肝脏功能的变化的不同天数内，评估他克莫司全血谷浓度至少两次
剂量形式和强度
胶囊：0.5mg，1mg，5mg
禁忌症
已知对他克莫司的超敏反应
警告和注意事项
•移植排斥和其他由于用药错误导致的严重不良反应：指导患者或护理人员识别ASTAGRAF XL胶囊的外观
•移植后新发糖尿病：监测血糖
•ASTAGRAF XL和伴随肾毒性药物引起的肾毒性（急性和/或慢性）：监测肾功能;考虑减少剂量
•神经毒性[包括后可逆性脑病综合征（PRES）的风险]：监测神经系统异常;减少剂量或停用ASTAGRAF XL
•高钾血症：与高钾血症相关的其他药物可能增加风险;监测血清钾水平
•高血压：可能需要抗高血压治疗
•QT延长：考虑在高风险患者中获得心电图和监测电解质
•纯红细胞发育不全：考虑停用
不良反应
最常见的不良反应（≥30％）是：腹泻，便秘，恶心，外周水肿，震颤和贫血
药物相互作用
•具有强CYP3A诱导剂的排斥风险以及与强CYP3A抑制剂的严重不良反应的风险：调整剂量并监测他克莫司浓度
•查看完全处方信息，用于临床显着的药物相互作用
https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=550a5cd4-fbf2-4c09-b577-6bde8fcbdf6e
ASTAGRAF XL™ (tacrolimus extended-release capsules), Prophylaxis of Organ Rejection in Adult Kidney Transplant Recipients, Now Available from Astellas
ASTAGRAF XLTM (tacrolimus extended-release capsules) for the prophylaxis of organ rejection in patients receiving a kidney transplant used with mycophenolate mofetil (MMF) and corticosteroids, with or without basiliximab induction, is now available in U.S. pharmacies.
"The availability of ASTAGRAF XL marks a significant moment for the transplantation community, giving new adult kidney transplant recipients an additional option in their immunosuppressant care," said James Robinson, President, Astellas Pharma US, Inc. "Astellas has long been a leader in the field of transplant immunology, and we are proud to continue to advance care for transplant recipients."
ASTAGRAF XL is the first once-daily oral tacrolimus formulation available in the U.S. for the prophylaxis of organ rejection in adult kidney transplant patients. ASTAGRAF XL was approved by the U.S. Food and Drug Administration (FDA) on July 19, 2013. In total, tacrolimus extended-release capsules have been approved for use in 73 countries.
The recommended starting dose of ASTAGRAF XL with basiliximab induction is 0.15 mg/kg once-daily. The recommended starting dose of ASTAGRAF XL without basiliximab induction is 0.1 mg/kg once-daily (pre-operative) and 0.2 mg/kg once-daily (post-operative). It is available in 0.5 mg, 1 mg and 5 mg capsules.
About ASTAGRAF XL (tacrolimus extended-release capsules)
ASTAGRAF XL capsules is a prescription medicine used with other medicines to help prevent organ rejection in people who have had a kidney transplant. ASTAGRAF XL is an extended-release capsule and is not the same as tacrolimus immediate-release capsules. Your doctor should decide what medicine is right for you.
ASTAGRAF XL is not for use with medicines called cyclosporine (Neoral®, Sandimmune®, Gengraf®). It is not known if ASTAGRAF XL is safe and effective when used with sirolimus (Rapamune®) in people who have had kidney transplants. It is not known if ASTAGRAF XL is safe and effective in children under 16 years of age who have had kidney transplants.
IMPORTANT SAFETY INFORMATION
What is the most important information I should know about ASTAGRAF XL?
ASTAGRAF XL can cause serious side effects, including:
1. Increased risk of cancer. People who take ASTAGRAF XL have an increased risk of getting some kinds of cancer, including skin and lymph gland cancer (lymphoma).
2. Increased risk of infection. ASTAGRAF XL is a medicine that affects your immune system and can lower the ability of your immune system to fight infections. Serious infections can happen in people receiving ASTAGRAF XL that can cause death. Call your doctor right away if you have symptoms of an infection such as fever, sweats or chills, cough or flu-like symptoms, muscle aches, warm, red or painful areas on your skin.
3. Increased risk of death in females who have had a liver transplant. You should not take ASTAGRAF XL without talking to your doctor if you have had a liver transplant.
What should I tell my doctor before taking ASTAGRAF XL?
Before you take ASTAGRAF XL tell your doctor if you: plan to receive any live vaccines, have or have had liver, kidney or heart problems, or have any other medical conditions. Talk to your doctor if you are pregnant or plan to become pregnant. Tell your doctor if you are breastfeeding or plan to breastfeed. ASTAGRAF XL can pass into your breast milk. You and your doctor should decide if you will take ASTAGRAF XL or breastfeed. You should not do both.
Tell your doctor about all the medicines you take, including prescription and over-the-counter medicines, vitamins and herbal supplements. ASTAGRAF XL may affect the way other medicines work and other medicines may affect how ASTAGRAF XL works.
Know the medicines you take. Keep a list of them and show it to your doctor and pharmacist when you get a new medicine. Tell your doctor or pharmacist if there are any changes to the list of medicines you take.
How should I take ASTAGRAF XL?
•Take ASTAGRAF XL exactly as your doctor tells you to take it.
•Your doctor will tell you how much ASTAGRAF XL to take and when to take it
•Your doctor may change your dose of ASTAGRAF XL if needed. Do not stop taking or change your dose of ASTAGRAF XL without talking to your doctor.
•Take ASTAGRAF XL capsules whole. Do not break, crush, chew or dissolve before swallowing. If you cannot swallow ASTAGRAF XL capsules whole, tell your doctor.
•Take ASTAGRAF XL at the same time each morning, preferably on an empty stomach at least one hour before, or at least two hours after, you have eaten a meal.
•If you miss your dose of ASTAGRAF XL, it should be taken as soon as possible, but no longer than 14 hours after your regularly scheduled ti