近日，FDA批准了其Zortress用于预防成年患者接受肝脏移植手术后可能的器官排斥反应。Zortress是FDA批准的首个雷帕霉素（mTOR）抑制剂用于成人的肝移植。这也是美国FDA十几年来批准的第一个免疫抑制剂用于肝移植。
批准日期：2013年2月17日 公司：诺华
ZORTRESS（依维莫司[everolimus]）片剂，用于口服
美国最初批准：2009年
警告：恶性肿瘤和严重感染，肾脏移植物血栓形成;肾毒性;心脏移植中的安全性，查看完整的盒装警告的完整处方信息。
只有经过免疫抑制治疗和移植患者管理经验的医生才能使用Zortress。
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。
肾移植血栓形成的发生率增加。
与Zortress组合使用需要减少剂量的环孢菌素以减少肾毒性。
心脏移植临床试验中死亡率增加。不建议在心脏移植中使用。
最近的重大变化
警告和注意事项，胚胎 - 胎儿毒性：1/2018
作用机制
依维莫司抑制抗原和白细胞介素（IL-2和IL-15）刺激的T和B淋巴细胞的激活和增殖。
在细胞中，依维莫司与细胞质蛋白FK506结合蛋白-12（FKBP-12）结合，形成免疫抑制复合物（依维莫司：FKBP-12），其结合并抑制哺乳动物雷帕霉素靶蛋白（mTOR），这是一个关键的调节因子。激酶。在依维莫司磷酸化存在p70 S6核糖体蛋白激酶的情况下
（p70S6K），mTOR的底物被抑制。因此，抑制了核糖体S6蛋白的磷酸化和随后的蛋白质合成和细胞增殖。 依维莫司：FKBP-12复合物对钙调神经活性没有影响。
在大鼠和非人类灵长类动物模型中，依维莫司有效地减少了肾同种异体移植排斥反应，从而延长了移植物的存活期。
适应症和用法
Zortress是一种mTOR抑制剂免疫抑制剂，用于预防成人患者的器官排斥反应：
肾移植：低中度免疫风险。与巴利昔单抗，环孢菌素（减少剂量）和皮质类固醇联合使用。
肝移植：移植后不超过30天。与他克莫司（减量剂量）和皮质类固醇联合使用。
使用限制。
安全性和有效性尚未确定如下：
肾移植患者具有高免疫风险。
除肾脏或肝脏外的移植器官的接受者。
小儿患者（不到18岁）。
剂量和给药
肾移植：移植后尽快开始每日两次口服0.75mg。
肝移植：从移植后30天开始每天两次口服1mg。
监测依维莫司浓度：使用LC/MS/MS分析方法调整维持剂量，以达到3-8ng/mL目标范围内的浓度。
在环孢菌素或他克莫司的同时持续服用或不服用食物。
轻度肝功能损害：将每日初始剂量减少三分之一。
中度或严重的肝脏损伤：将每日初始剂量减少一半。
剂量形式和强度
Zortress有0.25毫克，0.5毫克，0.75毫克和1毫克片剂。
禁忌症
对依维莫司，西罗莫司或药物成分的超敏反应。
警告和注意事项
血管性水肿[伴随血管紧张素转换酶（ACE抑制剂）的风险增加]：监测症状并及时治疗。
延迟伤口愈合/积液：监测症状;及时治疗，以尽量减少并发症。
间质性肺病（ILD）/非传染性肺炎：监测forsymptoms或放射学变化;通过剂量减少或停止直至症状消退来管理;考虑使用皮质类固醇。
高脂血症（血清胆固醇和甘油三酯升高）：
监测并考虑抗脂质治疗。
蛋白尿（谷物浓度较高时风险增加）：监测蛋白质。
多瘤病毒感染（潜伏病毒感染的激活; BK病毒相关肾病）：考虑减少免疫抑制。
TMA/TTP/HUS（与环孢菌素同时使用可能会增加风险）：
监测血液学变化或症状。
移植后新发糖尿病：监测血糖。
男性不育：可能发生精子症或少精子症。
免疫接种：避免接种活疫苗。
胚胎 - 胎儿毒性：建议雌性具有胎儿潜在风险的生殖潜力，并在Zortress治疗期间使用有效避孕药，并在最后一次给药后8周。
不良反应
最常见的不良反应如下：
肾移植（发生率大于或等于20％）：外周性水肿，便秘，高血压，恶心，贫血，尿路感染和高脂血症。
肝移植（发病率大于10％）：腹泻，头痛，外周性水肿，高血压，恶心，发热，腹痛，白细胞减少和高胆固醇血症。
要报告疑似不良反应，请致电1-888-669-6682联系NovartisPharmaceuticals Corporation或致电1-800-FDA-1088或www.fda.gov/medwatch联系FDA。
药物相互作用
强 - 中度CYP3A4抑制剂（例如，环孢菌素，酮康唑，红霉素，维拉帕米）和CYP3A4诱导剂（例如利福平）可以影响浓度。考虑Zortress剂量调整。
用于特定人群
怀孕：根据动物数据可能会对孕产妇和胎儿造成伤害。
哺乳期：不推荐母乳喂养。
女性和生殖潜力的雄性：可能会影响生育能力。
包装提供/存储和处理
Zortress（依维莫司）片剂包装在儿童防水泡中。
表11.Zortress（依维莫司）片剂的描述
0.25mg NDC：0078-0417-20
0.5mg  NDC：0078-0414-20。
0.75mg NDC：0078-0415-20
1mg    NDC：0078-0422-20
每种强度都有60片（6个泡罩条，每片10片）。
存储
储存在25°C（77°F）; 允许偏移15°C至30°C（59°F至86°F）[见USP受控室温]。
避免光照，避免潮湿
完整说明书附件：https://www.pharma.us.novartis.com/sites/www.pharma.us.novartis.com/files/zortress.pdf
ZORTRESS (everolimus) tablets, for oral use
ZORTRESS- everolimus tablet
Novartis Pharmaceuticals Corporation
WARNING : MALIGNANCIES AND SERIOUS INFECTIONS, KIDNEY GRAFT THROMBOSIS; NEPHROTOXICITY; AND MORTALITY IN HEART TRANSP L ANTATION
Malignancies and Serious Infections
Only physicians experienced in immunosuppressive therapy and management of transplant patients should prescribe Zortress. Patients receiving the drug should be managed in facilities equipped and staffed 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[see Warnings and Precautions] .
Increased susceptibility to infection and the possible development of malignancies such as lymphoma and skin cancer may result from immunosuppression[see Warnings and Precautions
Kidney Graft Thrombosis
An increased risk of kidney arterial and venous thrombosis, resulting in graft loss, was reported, mostly within the first 30 days posttransplantation[see Warnings and Precautions] .
Nephrotoxicity
Increased nephrotoxicity can occur with use of standard doses of cyclosporine in combination with Zortress. Therefore reduced doses of cyclosporine should be used in combination with Zortress in order to reduce renal dysfunction. It is important to monitor the cyclosporine and everolimus whole blood trough concentrations[see Dosage and Administration,Warnings and Precautions, Clinical Pharmacology] .
Mortality in Heart Transplantation
Increased mortality, often associated with serious infections, within the first three months posttransplantation was observed in a clinical trial of de novo heart transplant patients receiving immunosuppressive regimens with or without induction therapy. Use in heart transplantation is not recommended[see Warnings and Precautions] .
INDICATIONS AND USAGE
1.1 Prophylaxis of Organ Rejection in Kidney Transplantation
Zortress is indicated for the prophylaxis of organ rejection in adult patients at low-moderate immunologic risk receiving a kidney transplant[see Clinical Studies] . Zortress is to be administered in combination with basiliximab induction and concurrently with reduced doses of cyclosporine and with corticosteroids. Therapeutic drug monitoring (TDM) of everolimus and cyclosporine is recommended for all patients receiving these products[see Dosage and Administration] .
1.2 Prophylaxis of Organ Rejection in Liver Transplantation
Zortress is indicated for the prophylaxis of allograft rejection in adult patients receiving a liver transplant. Zortress is to be administered no earlier than 30 days posttransplant concurrently in combination with reduced doses of tacrolimus and with corticosteroids[s ee Warnings and Precautions, Clinical Studies].
Therapeutic drug monitoring (TDM) of everolimus and tacrolimus is recommended for all patients receiving these products[s ee Dosage and Administration] .
1.3 Limitations of Use
The safety and efficacy of Zortress has not been established in the following populations:
Kidney transplant patients at high immunologic risk
Recipients of transplanted organs other than kidney and liver[s ee Warnings and Precautions]
Pediatric patients (less than18 years)
2 DOSAGE AND ADMINISTRATION
Patients receiving Zortress may require dose adjustments based on everolimus blood concentrations achieved, tolerability, individual response, change in concomitant medications and the clinical situation. Optimally, dose adjustments of Zortress should be based on trough concentrations obtained 4 or 5 days after a previous dosing change. Dose adjustment is required if the trough concentration is below 3 ng/mL. The total daily dose of Zortress should be doubled using the available tablet strengths (0.25 mg, 0.5 mg or 0.75 mg). Dose adjustment is also required if the trough concentration is greater than 8 ng/mL on 2 consecutive measures; the dose of ZORTRESS® should be decreased by 0.25 mg twice daily[s ee Dosage and Administration, Clinical Pharmacology] .
2.1 Dosage in Adult Kidney Transplant Patients
An initial Zortress dose of 0.75 mg orally twice daily (1.5mg per day) is recommended for adult kidney transplant patients in combination with reduced dose cyclosporine, administered as soon as possible after transplantation [ s ee Dosage and Administration, Clinical Studies] .
Oral prednisone should be initiated once oral medication is tolerated. Steroid doses may be further tapered on an individualized basis depending on the clinical status of patient and function of graft.
2.2 Dosage in Adult Liver Transplant Patients
Start Zortress at least 30 days posttransplant. An initial dose of 1.0 mg orally twice daily (2.0mg per day) is recommended for adult liver transplant patients in combination with reduced dose tacrolimus[s eeDosage and Administration, Clinical Studies] .
Steroid doses may be further tapered on an individualized basis depending on the clinical status of patient and function of graft.