近日，FDA批准由诺华制药公司生产的依维莫司（everolimus）片（商品名Zortress）可与小剂量环孢素、巴利昔单抗以及皮质类固醇药物联合使用，用于预防伴有低度至中度免疫风险的成人肾移植患者的器官排异反应。该药通过与哺乳动物雷帕霉素靶点（mTOR）结合，抑制抗原激活T细胞增殖，从而达到免疫抑制效果。目前，依维莫司已在美国以外的70多个国家被批准用于肾和心脏移植的药物治疗。

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。

ZORTRESS

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.

Precaution(s):

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

制造商：
诺华制药公司

类药物：
免疫抑制剂（大环内酯类）

活性成分（补）：
everolimus的0.25mg，为0.5mg，0.75mg;标签。

适应症（补）：
在低，中度肾移植患者的免疫风险预防器官排斥反应，与巴利昔单抗诱导和环孢素和皮质类固醇剂量减少组合。

药理：
everolimus的细胞质结合蛋白，FK506结合蛋白- 12，形成一个复杂的结合，抑制了哺乳动物雷帕霉素靶（mTOR）的。这种相互作用抑制p70的蛋白激酶活性的核糖体中六，在核糖体S6蛋白磷酸化的抑制，随后的蛋白质合成和细胞增殖的影响。这一行动因而抑制抗原和白细胞介素（IL - 2和IL - 15的）刺激活化和T，B淋巴细胞增殖的影响。

临床试验：
24个月，跨国公司，开放标签，随机试验，涉及833例肾移植患者初发年龄18-70岁，评估everolimus的1.5mg/day或everolimus的3mg/day环孢素和皮质类固醇加上减少剂量1.44克/天霉酸环孢素和皮质类固醇加上标准剂量。在12个月，everolimus的1.5mg/day被证明是失败的方面疗效（25.3％和24.2％，分别相当于霉酸），作为治疗活检证实的急性排斥反应，移植失败，死亡或丧失定义为后续起来。此外，计算的平均肾小球滤过率everolimus的1.5mg/day和霉酸（GFR）的人在可比的12个月（54.6mL/min和52.3mL/min，分别）。

两个多中心，双盲的头12个月（），随机试验，纳入1171年总从头肾移植患者相比，固定剂量的everolimus的1.5mg/day和3mg/day环孢素和皮质类固醇与标准剂量霉酚酸酯2g/day结合和皮质类固醇。对GFR的12个月的分析表明这两个群体的everolimus的肾功能损害率增加相比，霉酚酸酯组在这两个试验。因此，应减少剂量环孢素使用时与everolimus的结合，everolimus的谷浓度应进行调整，维持在3至8ng/mL使用的治疗药物监测。

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（1.5mg/day）与降低剂量环孢素结合。 5月4-5日一次调整剂量，以达到everolimus的低谷浓度的目标范围：3-8ng/mL。中度肝功能不全：减少1 / 2，初期每日剂量每日剂量。启动口服强的松尽快口服药物是不能容忍的。

儿童：
<18yrs：不建议。

禁忌（补）：
西罗莫司过敏。

注意事项（补）：
风险增加感染，淋巴瘤及（如皮肤）其他恶性肿瘤。避免阳光，紫外线光。高风险或其他免疫器官预防：不成立。肝功能损害或严重遗传性疾病（如半乳糖不容忍，拉普乳糖酶缺乏，葡萄糖，半乳糖吸收不良）：不建议。糖尿病。获取everolimus的和环孢素（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周后治疗。哺乳母亲：不建议。

互动（补）：
避免使用活疫苗，标准剂量的环孢素。增加与ACE抑制剂的血管性水肿的危险。由CYP3A4和中强化/或P -糖蛋白抑制剂;避免（如酮康唑，伊曲康唑，伏立康唑强抑制剂，克拉霉素，泰利霉素，利托那韦，柚子汁，地高辛）;监测和调整（例如，红霉素，氟康唑，尼卡温和抑制剂剂量，硫氮酮，奈非那韦，茚地那韦，泼那韦），或CYP3A4和P -糖蛋白底物（如维拉帕米）。由CYP3A4的诱导剂（如卡马西平，苯巴比妥，苯妥英，依非韦伦，奈韦拉平拮抗，圣约翰草）;避免（如利福平，利福布丁）强烈诱导。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。与其他肾毒性药物，CYP3A4的底物或CYP2D6注意与治疗指数狭窄。

不良反应（补）：
周围水肿，肠胃不适，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，移植血栓形成，延缓伤口愈合/裂开，多瘤病毒感染（如，BK病毒相关性肾病），非感染性肺炎（剂量减少或中断和/或管理类固醇），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，男性不孕。

如何提供：
制表符- 60（10 × 6水泡条）

最后更新：
2010年7月22日

美国FDA于2009年3月30日批准Novartis（诺华）公司的依维莫司片（Everolimus Tablets，商品名：Afinitor。）用于已采用舒尼替尼或索拉非尼治疗无效的晚期肾细胞癌患者。该药于2003年首次在瑞典上市，2007年10月14日在欧洲被批准用于治疗胃肠胰腺神经分泌瘤。