Zortress (everolimus，依维莫司)用于预防有轻中度免疫风险的成人肾移植患者产生排异现象。Zortress与低剂量的钙调素抑制剂联合使用，如环孢菌素、巴利昔单抗或皮质激素类药物。依维莫司已以商品名Certican在在美国之外的70多个国家获得批准。
支持此项批准的3期试验显示，Zortress预防器官排异与保护肾功能，同时与使用麦考酚酸相比降低了60%的环孢菌素使用量，显示使用Zortress可在保持同样效果下降低使用钙调素抑制剂产生的副作用。
制造商：
诺华制药公司
药理分类：
免疫抑制剂（大环内酯类）
活性成分（补）：
依维莫司0.25mg，0.5mg，0.75mg;标签。
指示（补）：
在低风险的中度肾移植患者免疫与巴利昔单抗诱导和低剂量环孢素和皮质类固醇结合，预防器官排斥。
药理作用：
依维莫结合的胞浆蛋白，FK506结合蛋白- 12，形成一个复杂的结合和抑制哺乳动物雷帕霉素靶（mTOR）。这种相互作用抑制核糖体蛋白S6核糖体蛋白激酶活性，在核糖体S6蛋白磷酸化，随后的蛋白质合成和细胞增殖抑制造成。这一行动因此抑制抗原和白细胞介素（IL - 2和IL - 15的）刺激活化和T，B淋巴细胞增殖。
临床试验：
24个月，跨国公司，开放式，随机试验，涉及833例肾移植病人从头18-70岁，评估everolimus的1.5mg/day或everolimus的3mg/day加环孢素和皮质类固醇剂量减少到一点四四克/天霉酸加环孢素和皮质类固醇的标准剂量。在12个月内，依维莫司1.5mg/day被证明是媲美关于失败的原因（25.3％和24.2％，分别），作为治疗活检证实的急性排斥反应，移植失败，死亡或失访定义霉酸注册。此外，计算出的平均肾小球滤过率的everolimus 1.5mg/day和霉酸（GFR）的人在12个月（54.6mL/min和52.3mL/min，分别）相媲美。
两个多中心，双盲（首12个月），共招收1171从头肾移植患者随机试验比较了everolimus的1.5mg/day固定剂量和3mg/day环孢素和皮质类固醇与标准剂量的霉酚酸酯2g/day结合和皮质类固醇。对肾小球滤过率12个月的分析显示相比，增加了霉酚酸酯组在这两个试验组均everolimus的肾功能损害率。因此，应减少剂量环孢素A时，与everolimus的组合使用，依维莫司谷浓度应调整与维护，以8ng/mL 3使用治疗药物监测。
法律分类：
接收
成人：
尽快给移植后。燕子的整体。 ≥18yrs：最初0.75mg每12小时在降低剂量环孢素组合（1.5mg/day）。可在4-5天的时间间隔调整剂量，以达到everolimus的谷浓度的目标范围：3-8ng/mL。中度肝功能不全：减少1 / 2的初期每日剂量的剂量。启动口服泼尼松口服药物只要是不能容忍的。
儿童：
“18yrs：不推荐。
禁忌（补）：
雷帕霉素过敏。
警告/注意事项：
增加感染，淋巴瘤及（如皮肤）其他恶性肿瘤的危险。避免阳光，紫外线光。高风险或其他免疫器官的预防：不成立的。严重肝功能不全或遗传性疾病（如半乳糖不耐受，拉普乳糖酶缺乏，葡萄糖，半乳糖吸收不良）：不推荐。糖尿病。依维莫司和环孢素获取（见文献）全血浓度，定期和谷浓度在剂量调整。监视器CBCs，肾功能，尿蛋白，血脂，血糖，以及肺炎和感染。妊娠（Cat.C）;使用有效的避孕方法，并在长达8个星期治疗后。哺乳母亲：不推荐。
互动（补）：
避免使用活疫苗，标准剂量的环孢素。增加与ACE抑制剂血管性水肿的危险。由CYP3A4和/或P -糖蛋白抑制剂Potentiated;避免（如酮康唑，伊曲康唑，伏立康唑，克拉霉素，泰利霉素，利托那韦，柚子汁，地高辛）强抑制剂，监测和调整剂量中度抑制剂（如红霉素，氟康唑，尼卡地平，地尔硫，奈非那韦，茚地那韦，amprenavir）或CYP3A4和P -糖蛋白底物（如维拉帕米）。由CYP3A4诱导剂（如卡马西平，苯巴比妥，苯妥英，依非韦伦，奈韦拉平，圣约翰草）拮抗，避免强烈的诱导剂（如利福平，利福布丁）。避免辛伐他汀，洛伐他汀，监测与阿托伐他汀或普伐他汀如果使用。注意与其他肾毒性药物，或CYP2D6的底物与CYP3A4的一个狭窄的治疗指数。
不良反应（补）：
周边水肿，胃肠不适，便秘，高血压，贫血，感染（如泌尿道感染），高脂血症，血管性水肿，恶性肿瘤（如淋巴瘤，皮肤），蛋白尿，肾移植物血栓形成，延迟伤口愈合/裂开，多瘤病毒感染（如，BK病毒相关性肾病），非感染性肺炎（减少或中断剂量和/或皮质类固醇管理），血栓性微血管病，血栓性血小板减少性紫癜，溶血尿毒综合症，新发糖尿病患者移植后，男性不育症。
如何提供：
制表- 60（10 × 6水泡条）
Manufacturer:
Novartis Pharmaceuticals Corp
Pharmacological Class:
Immunosuppressant (macrolide)
Active Ingredient(s):
Everolimus 0.25mg, 0.5mg, 0.75mg; tabs.
Indication(s):
Organ rejection prophylaxis in renal transplant patients with low-moderate immunologic risk, in combination with basiliximab induction and reduced doses of cyclosporine and corticosteroids.
Pharmacology:
Everolimus binds to the cytoplasmic protein, FK506 Binding Protein-12, forming a complex that binds to and inhibits the mammalian target of rapamycin (mTOR). This interaction inhibits p70 S6 ribosomal protein kinase activity, resulting in inhibition of ribosomal S6 protein phosphorylation, subsequent protein synthesis and cell proliferation. This action consequently inhibits antigenic and interleukin (IL-2 and IL-15) stimulated activation and proliferation of T and B lymphocytes.
Clinical Trials:
A 24-month, multinational, open-label, randomized trial, involving 833 de novo renal transplant patients 18–70 years of age, evaluated everolimus 1.5mg/day or everolimus 3mg/day plus reduced doses of cyclosporine and corticosteroids to 1.44g/day mycophenolic acid plus standard doses of cyclosporine and corticosteroids. At 12 months, everolimus 1.5mg/day was shown to be comparable to mycophenolic acid with respect to efficacy failure (25.3% and 24.2%, respectively), defined as treated biopsy-proven acute rejection, graft loss, death or loss to follow-up. Additionally, the calculated mean glomerular filtration rate (GFR) for everolimus 1.5mg/day and mycophenolic acid were comparable at month 12 (54.6mL/min and 52.3mL/min, respectively).
Two multicenter, double-blind (for first 12 months), randomized trials enrolling 1171 total de novo renal transplant patients compared fixed doses of everolimus 1.5mg/day and 3mg/day combined with standard doses of cyclosporine and corticosteroids to mycophenolate mofetil 2g/day and corticosteroids. The 12-month analysis of GFR demonstrated increased rates of renal impairment in both everolimus groups compared to the mycophenolate mofetil group in both trials. Therefore, cyclosporine doses should be reduced when used in combination with everolimus, and everolimus trough concentrations should be adjusted and maintained between 3 to 8ng/mL using therapeutic drug monitoring.
Legal Classification:
Rx
Adults:
Give as soon as possible after transplantation. Swallow whole. ≥18yrs: Initially 0.75mg every 12 hours (1.5mg/day) in combination with reduced dose cyclosporine. May adjust dose at 4–5 day intervals to achieve everolimus trough concentration target range: 3–8ng/mL. Moderate hepatic dysfunction: reduce daily dose by 1/2 the initial daily dose. Initiate oral prednisone as soon as oral medication is tolerated.
Children:
<18yrs: not recommended.
Contraindication(s):
Sirolimus allergy.
Warnings/Precautions:
Increased risk of infections, lymphomas and other malignancies (eg, skin). Avoid sun, UV light. High immunologic risk or prophylaxis in other organs: not established. Severe hepatic impairment or hereditary disorders (eg, galactose intolerance, Lapp lactase deficiency, glucose-galactose malabsorption): not recommended. Diabetes. Obtain everolimus and cyclosporine (see literature) whole blood concentrations periodically; and trough concentrations during dose adjustments. Monitor CBCs, renal function, urine protein, lipids, blood glucose, and for pneumonitis and infections. Pregnancy (Cat.C); use effective method of contraception during and up to 8 weeks after therapy. Nursing mothers: not recommended.
Interaction(s):
Avoid live vaccines, standard doses of cyclosporine. Increased risk of angioedema with ACE-inhibitors. Potentiated by CYP3A4 and/or P-glycoprotein inhibitors; avoid strong inhibitors (eg, ketoconazole, itraconazole, voriconazole, clarithromycin, telithromycin, ritonavir, grapefruit juice, digoxin); monitor and adjust dose with moderate inhibitors (eg, erythromycin, fluconazole, nicardipine, diltiazem, nelfinavir, indinavir, amprenavir), or CYP3A4 and P-glycoprotein substrate (eg, verapamil). Antagonized by CYP3A4 inducers (eg, carbamazepine, phenobarbital, phenytoin, efavirenz, nevirapine, St. John’s Wort); avoid strong inducers (eg, rifampin, rifabutin). Avoid simvastatin, lovastatin; monitor if used with atorvastatin or pravastatin. Caution with other nephrotoxic drugs, CYP3A4 or CYP2D6 substrates with a narrow therapeutic index.
Adverse Reaction(s):
Peripheral edema, GI upset, constipation, hypertension, anemia, infections (eg, UTI), hyperlipidemia, angioedema, malignancies (eg, lymphomas, skin), proteinuria, nephrotoxicity, graft thrombosis, delayed wound healing/dehiscence, polyoma virus infections (eg, BK virus-associated nephropathy), non-infectious pneumonitis (reduce or interrupt dose and/or manage with corticosteroids), thrombotic microangiopathy, thrombotic thrombocytopenic purpura, hemolytic uremic syndrome, new-onset diabetes post-transplant, male infertility.
How Supplied:
Tabs—60 (10 x 6 blister strips)
Last Updated:
7/22/2010
2010-4-26-美国食物与药品管理局已经批准依维莫司(Zortress;诺华制药公司)，联合小剂量环孢素、巴利昔单抗以及皮质醇激素，用于预防成人肾移植患者器官排异反应，减低免疫危险因素。依维莫司通过连结哺乳动物雷帕霉素靶点（mTOR），抑制抗原激活T细胞增殖，从而达到免疫抑制效果。
诺华药业分部经理David Epstein 说：“对于需要肾移植的患者，器官有限使得必须强调有效药物的使用，从而保护器官移植患者的生存率。”在一遍公司新闻稿中，他这样写到：该新药是为肾移植患者提供更多治疗选择，越来越多的五种药物组合中的一个。
FDA的批准，是基于一项涉及肾移植患者的大的单相III期临床实验研究的数据。该研究显示：与对照组相比（麦考酚酸，环孢素A，皮质醇激素），依维莫司联合60%低剂量环孢素可以预防急性排异反应。