依维莫司（everolimus，Zortress）口服片剂是一种口服的哺乳动物雷帕霉素靶蛋白(mTOR)抑制剂,临床上常用于预防肾移植和心脏移植手术后的排异反应.近年来发现它对晚期肾细胞癌具有较好疗效,可用于舒尼替尼或者索拉非尼治疗失败的肾癌患者。

制造商：
诺华制药公司

类药物：
免疫抑制剂（大环内酯类抗生素）

活性成分（S）：
0.25mg的依维莫司，0.5毫克，0.75毫克;标签。

指示（S）：
结合basiliximab诱导和低剂量的环孢素和皮质类固醇，在低中度免疫风险的肾移植患者的器官排斥反应的预防。

药理作用：
依维莫司结合的细胞质蛋白，FK506结合蛋白-12，形成一个复杂的结合并抑制哺乳动物雷帕霉素（mTOR）的目标。这种相互作用抑制P70 S6核糖体蛋白激酶的活性，导致核糖体S6蛋白磷酸化，随后的蛋白质合成和细胞增殖的抑制。这个动作，因此抑制抗原和白细胞介素（IL-2和IL-15）刺激T和B淋巴细胞的活化和增殖。

临床试验：
24个月，跨国公司，开放标签，随机试验，涉及到1.44克/ 833从头肾移植患者18-70岁，评估依维莫司1.5mg/day或3mg/day依维莫司，加上低剂量环孢素和皮质类固醇一天酚酸加标准剂量环孢素和皮质类固醇。在12个月，依维莫司1.5mg/day被证明是疗效失败（分别是25.3％和24.2％），定义为治疗活检证实的急性排斥反应，移植物丢失，死亡或损失媲美酚酸起来。此外，计算的平均肾小球滤过率（GFR）的依维莫司1.5mg/day和麦考酚酸在12个月（54.6mL/min和52.3mL/min，分别）相媲美。

两个多中心，双盲（前12个月），随机试验招收1171总从头肾移植患者相比everolimus的1.5mg/day和3mg/day的固定剂量与标准剂量环孢素和皮质类固醇联合霉酚酸酯2g/day和皮质类固醇。 12个月的GFR分析表明，增加肾功能不全的发生率都依维莫司组相比，霉酚酸酯在这两个试验组。因此，环孢素剂量应减少everolimus的组合使用时，和依维莫司谷浓度应调整，并保持在3，8ng/mL使用治疗药物监测。

法律分类：
RX

成人：
移植后尽快给。吞下。 ≥0-18岁：最初0.75毫克每12小时（1.5mg/day）减少剂量环孢素结合。可能在4-5天的时间间隔调整剂量，以达到依维莫司谷浓度的目标范围：3-8ng/mL。中度肝功能不全：每日剂量减少1/2的初始剂量为每日。开始口服强的松只要口服药物的耐受性。

儿童：
<18yrs：不推荐。

禁忌症（S）：
雷帕霉素过敏。

警告/注意事项：
感染，淋巴瘤和其他恶性肿瘤（如皮肤）的风险增加。避免阳光，紫外线光。高免疫风险或其他机关的预防：不成立的。严重肝损伤或遗传性疾病（如半乳糖的不容忍现象，拉普乳糖酶缺乏，葡萄糖，半乳糖吸收不良）：不建议。糖尿病。获得依维莫司和环孢素A全血浓度（见文献）定期和槽浓度在调整剂量。监视器CBCS，肾功能，尿蛋白，血脂，血糖，肺炎和感染。使用期间和治疗长达8星期后怀孕（Cat.C）;有效的避孕方法。哺乳母亲：不推荐。

互动（补）：
避免活疫苗，标准剂量的环孢素。 ACE抑制剂与血管性水肿的危险性增加。 Potentiated CYP3A4和/或P-糖蛋白抑制剂;避免强抑制剂（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）;监测和调整剂量中度抑制剂（如红霉素，氟康唑，尼卡，地尔硫（艹卓），奈非那韦，茚地那韦，安普那韦），或CYP3A4和P-糖蛋白底物（如维拉帕米）。 CYP3A4诱导剂（如卡马西平，苯巴比妥，苯妥英钠，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）。如果使用与阿托伐他汀或普伐他汀避免辛伐他汀，洛伐他汀;显示器。注意与其他肾毒性药物，CYP3A4或CYP2D6底物与一个狭窄的治疗指数。

不良反应（S）：
周围水肿，胃肠不适，便秘，高血压，贫血，感染（如尿路感染），高脂血症，血管神经性水肿，恶性肿瘤（如淋巴瘤，皮肤），蛋白尿，肾，移植物抗血栓形成，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（减少或中断与皮质类固醇剂量和/或管理），血栓性微血管病，血栓性血小板减少性紫癜，溶血性尿毒综合征，新发糖尿病患者移植后，男性不育症。

如何提供：
标签-60（10×6泡罩条）

最后更新：
2010/7/22

Everolimus(也称为RAD001，SDZ-RAD，Afinitor，Certican，Zortress)，是ripamycin（sirolimus）的40-O-(2-羟乙基)衍生物，作用机制类似ripamycin靶向抑制mTOR活性,表现出免疫抑制剂和抗血管生成特性[1]。Everolimus竞争性结合FKBP12（IC50=1.8-2.6 nM）从而抑制p70 S6激酶活化，进而阻断生长因子介导的T细胞，B细胞和VSMC细胞增殖，促使细胞周期停滞在G1期。Everolimus抑制多种体外培养人肿瘤细胞系和体内动物移植瘤的增殖[2]。Everolimus已处于多种人体肿瘤如乳腺癌，胃癌，肝细胞癌和淋巴瘤的III期临床实验阶段。Everolimus以药物名Afinitor，Certican或Zortress上市用于诊治其他药物治疗无效的晚期肾细胞癌（RCC）。

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