免疫抑制剂Zortress获准用于肝移植受者

圣路易斯(MD Consult)——2013年2月15日， 诺华公司宣布，美国食品药品管理局(FDA)已批准Zortress (依维莫司)用于预防肝移植成人患者器官排斥反应。Zortress是一种免疫抑制剂，FDA此前已批准其用于肾移植患者。

这项批准令是基于一项为期12个月的多中心、开放、随机对照3期研究的结果。该研究共纳入719例肝移植患者，在术后头30天及随机分组前，患者接受他克莫司和皮质类固醇药物治疗，同时使用或不使用麦考酚吗乙酯，未接受抗体诱导治疗。术后30天，患者被随机分组，分别接受Zortress+减量他克莫司(245例)、Zortress+4个月时停用他克莫司(231例)和标准剂量他克莫司(对照组，243例)。此外，各组均包括使用皮质类固醇药物至少至术后6个月。他克莫司停药组的患者招募已提前终止，原因是急性排斥反应和不良反应发生率较高，集中出现在分组后4个月他克莫司停药前后。

12个月时移植失败终点指标包括治疗活检证实的急性排斥反应(tBPAR)、移植物失功、死亡或失访。失访患者并没有出现tBPAR、死亡或移植物失功，但在12个月访视之前失去联系。研究结果显示，在12个月时，Zortress+减量他克莫司组移植失败率与标准剂量他克莫司组相当，但低于他克莫司对照组。

肝移植患者最常见不良反应包括腹泻、头痛、外周性水肿、高血压、恶心、发热、腹痛以及白细胞减少症。与Zortress使用有关的潜在严重不良反应包括超敏反应、淋巴瘤及其他恶性肿瘤、严重感染、移植肾血栓形成、肝动脉血栓形成、Zortress和钙调磷酸酶抑制剂诱导的肾毒性、心脏移植患者死亡率增加、血管性水肿、创伤愈合/积液、间质性肺病/非感染性肺炎、高脂血症、蛋白尿、多瘤病毒感染、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、新发糖尿病以及男性不育症。

只有在移植患者免疫抑制治疗和诊治方面具有经验的医生才可开具Zortress。肝移植患者在移植手术30天后才能同时使用Zortress和减量的他克莫司及皮质类固醇药物。建议对治疗药物进行监测。需联合应用减量的环孢霉素，以减少Zortress肾毒性风险。不推荐Zortress+他克莫司停药治疗方案。使用Zortress的肝移植患者应避免接种活疫苗。

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ST LOUIS (MD Consult) - On February 15, 2013, Novartis announced that the US Food and Drug Administration (FDA) has approved Zortress (everolimus) for the prophylaxis of organ rejection in adult liver transplant recipients. Zortress is an immunosuppressant. The FDA has previously approved Zortress for use in kidney transplant recipients.

The US approval was granted on the basis of 12-month results from a phase 3, multicenter, open-label, randomized, controlled study conducted in 719 liver transplant recipients, with treatment beginning 30 days post-transplant. In the study, during the first 30 days after transplant and before randomization, patients received tacrolimus and corticosteroids, with or without mycophenolatemofetil. No induction antibody was administered. Thirty days after liver transplantation, patients were randomly assigned to receive either Zortress plus reduced-exposure tacrolimus (n = 245), Zortress followed by tacrolimus withdrawal at 4 months (n = 231) or standard-exposure tacrolimus only (control, n = 243). All study arms included twice-daily treatment. Additionally, all arms included corticosteroids for at least 6 months post-transplant. Enrollment into the tacrolimus withdrawal arm was prematurely halted as a result of higher incidence of acute rejection episodes and adverse reactions leading to treatment discontinuation, clustered around the time of tacrolimus elimination at 4 months post randomization.

The efficacy failure end point at 12 months included treated biopsy proven acute rejection (tBPAR), graft loss, death, or loss to follow-up by month 12. Loss to follow-up represented patients who did not experience tBPAR, death, or graft loss, and whose last contact date occurred before the 12-month visit. Study results showed that Zortress plus reduced-exposure tacrolimus was comparable with standard-exposure tacrolimus with respect to efficacy failure. The incidence of efficacy failure was lower in the Zortress plus reduced-exposure tacrolimus group compared with the tacrolimus control group at month 12.

The most common adverse reactions seen in liver transplant recipients included diarrhea, headache, peripheral edema, hypertension, nausea, pyrexia, abdominal pain, and leukopenia. Potential serious adverse reactions associated with Zortress use include hypersensitivity reactions, lymphomas and other malignancies, serious infections, kidney graft thrombosis, hepatic artery thrombosis, Zortress and calcineurin inhibitor-induced nephrotoxicity, increased mortality in heart transplantation, angioedema, wound healing/fluid accumulation, interstitial lung disease/noninfectious pneumonitis, hyperlipidemia, proteinuria, polyoma virus infections, thrombotic microangiopathy/thrombotic thrombocytopenic purpura/hemolytic uremic syndrome, new onset diabetes, and male infertility.

Only physicians experienced in immunosuppressive therapy and management of transplant patients should prescribe Zortress. In liver transplant recipients, Zortress is to be administered no earlier than 30 days post-transplant concurrently in combination with reduced doses of tacrolimus and with corticosteroids. Therapeutic drug monitoring is recommended. Reduced doses of cyclosporine are required for use in combination with Zortress to reduce the risk of nephrotoxicity. A treatment regimen of Zortress with tacrolimus elimination is not recommended. Live immunizations should be avoided in liver transplant recipients receiving Zortress.