药品名称 

通用名：他克莫司胶囊 
商品名：普乐可复
英文名：Tacrolimus Capsules
别名: 他克莫司,大环哌南,普乐可复,Tacrolimus, Prograf, FK506 
性状:内容物为白色粉末。

药理毒理

作用机制 在分子水平，本品的作用似乎是由细胞质内与之结合的蛋白FKBP12介导的。FKBP12使得本品进入细胞内，并形成复合物，该复合物竞争性地与钙调素特异性地结合并抑制钙调素，后者介导T细胞内-钙依赖性抑制性信号传递系统，从而阻止一系列淋巴因子基因转录。

适应症

预防肝脏或肾脏移植术后的移植物排斥反应。 治疗肝脏或肾脏移植术后应用其他免疫抑制药物无法控制的移植物排斥反应。

用法用量 

推荐的剂量仅供参考，治疗过程中应根据患者个体需求进行本品的剂量调整。
如患者情况允许口服，应尽早开始口服本品。在一些肝移植患者，本品可以通过鼻饲来口服给药。
本品通常与其他免疫抑制药物一起使用，亦出现有单独使用本品的个例报道。本品不能与环孢素并用。
如出现排斥反应或不良事件发生，需考虑更改免疫抑制治疗方案。
在维持治疗阶段，建议持续使用本品来维持移植物的存活。如患者病情恶化（如出现急性排斥反应的征兆），应考虑改变免疫抑制剂用药方案。多种方案均可用于控制排斥反应，如增加类固醇激素用量、加用短期的单克隆或多克隆抗体、增加本品的用量。
如出现中毒征兆（如明显的不良事件），应减少本品的用量。并应告诉患者，在未经主管医师同意的情况下，不应擅自减量。
在移植术后患者的情况改善期内，本品的药代动力学可能会发生改变，需要调整本品的剂量。
每日服药两次（早晨和晚上），最好用水送服。建议空腹，或者至少在餐前1小时或餐后2-3小时服用。如必要可将胶囊内容物悬浮于水，经鼻饲管给药。若患者临床状况不能口服，首剂须静脉给药。
任何疑问，请遵医嘱！

不良反应

由于患者疾病非常严重，且经常是多药合用，与免疫抑制剂相关的不良反应通常难以确定。
有证据表明下述的多种不良反应均为可逆性，减量可使其减轻或消失。与静脉给药相比，口服给药的不良反应发生率较低。
多数患者似乎在术后最初几周出现较多的不良反应，可能与高剂量静脉用药有关。

禁忌症

妊娠、对他克莫司或其他大环内酯类药物过敏者、对胶囊中其他成份过敏者。

注意事项

本品治疗应在医学人员及严密的实验设备监测下进行。本品仅是处方药，免疫治疗方案的任何调整均应由有免疫治疗经验及对器官移植患者有管理经验的医师进行。主管维持治疗的医师应有足够的药物信息。
剂量和血药浓度的调节必须是在负责管理患者的移植中心。
应严密监测和管理患者，尤其是在移植术后的最初几个月内。
对下列参数应作常规监测：
血压、心电图、视力、血糖浓度、血钾及其他电解质浓度、血肌酐、尿素氮、血液学参数、凝血值及肝功能。若上述参数发生了有临床意义的变化，应重新审核本品的用量。
应经常进行肾功能检测。在移植术后的头几天内，应特别监测尿量。如有必要，须调整剂量。
曾报道过几例与本品治疗相关的神经性及中枢神经系统紊乱。因此，对有上述不良事件的患者应严密监控。如出现中枢神经症状，须立即重新考虑剂量。曾有报道几例患者发生严重震颤和运动性（表达性）失语症，这些可能是严重中枢神经系统疾病的征兆。
如同其他免疫抑制剂一样，也有报告使用本品的患者出现EB病毒相关性的淋巴细胞增生症。对于新采用本品治疗的患者，EB病毒相关性淋巴细胞增生症可能是由于以前的免疫抑制治疗过度引起。对于使用本品进行抢救治疗的患者，不应合并使用抗淋巴细胞治疗。2岁以下，EB病毒抗体阴性的儿童患者发生淋巴细胞增生症的危险性高。因此，对于该年龄组患者，之前应进行EB病毒血清学检查，在用本品时，应仔细监测。
本品不能与环孢素合用。
本品与视觉及神经系统紊乱有关。因此服用本品并已出现上述不良作用的患者，不应驾车或操作危险机械。此种影响可能会因喝酒而加重。

孕妇及哺乳期妇女用药

妊娠时禁用本品，动物实验（小鼠及兔子）表明，本品具有致畸作用，并且某些剂量还显示出对母体具有毒性。临床前及临床资料表明，该药能透过胎盘。因此在应用本品前应排除妊娠的可能性。
本品能干扰口服避孕药的代谢，应改用其他方式避孕。
临床前兔身上的试验表明，本品分泌进乳汁。哺乳期使用本品的经验有限。因不能排除对新生儿的有害影响，妇女患者在使用本品时不应哺乳。

儿童用药

对儿童患者，通常需用成人推荐剂量的1.5-2倍才能达到与成人相同的血药浓度（肝功能、肾功能受损者情况除外）。儿童患者的起始口服疗法的经验较少。对于肝肾移植的儿童服用剂量为按体重计算一日0.3mg/kg，如不能口服给药，则应给予连续24小时的静脉滴注。
肝肾移植的维持治疗阶段，必须持续使用本品来维持移植物功能。推荐需根据患者个体差异来定。在维持治疗期间有本品用量逐渐减少的趋势。剂量调整主要根据对排斥反应的临床治疗效果和患者的耐受性判断。

老年患者用药

对老年患者用药的临床资料较少，但均提示应与其他成人剂量相同。

药物相互作用 

体内观察：
药物相互作用的临床资料有限。然而本品在临床试验中与大量的药物联合应用。 据报道并用的甲强龙可以降低或升高本品的血浆浓度。
有报道达那唑和克霉唑增加本品血药浓度。
在大鼠本品降低戊巴比妥和安替比林的清除率和增加半衰期。
与环孢素A合用：
当与环孢素A同时给药时，本品增加环孢素A的半衰期。另外，出现协同/累加的肾毒性。因为这些原因，不推荐本品和环孢素联合应用，且患者由原来环孢素转换为本品时应特别注意。
体外资料：
像环孢素A一样，本品主要由肝细胞色素P450系统代谢。尤其，本品对细胞色素P450 3A4抑制作用广而强。
其它药物对经细胞色素P450 3A4代谢的他克莫司影响：
体外试验表明，下列药物可能是本品代谢的潜在抑制剂：溴麦角环肽、可的松、麦角胺、红霉素、孕二烯酮、炔雌醇、醋竹桃霉素、交沙霉素、氟康唑、酮康唑、咪康唑、咪达唑仑、尼伐地平、奥美拉唑、他莫昔芬和异搏定。
在体外模型中，没有观察到下列药物对本品代谢有抑制作用：阿司匹林、开博通、西咪替丁、环丙沙星、二氯芬酸、doxicycline、呋噻咪、格列苯脲、米帕明、利多卡因、扑热息痛、孕酮、雷尼替丁、磺胺甲基异恶唑、甲氧苄啶、万古霉素。
发现下列药物有矛盾的结果，抑制或不影响本品的代谢：二性霉素B、环孢素A、地尔硫卓、地塞米松和强的松龙。
从理论上说，并用下列药物能诱导细胞色素P450 3A系统更新从而降低本品的血液浓度：
这些药物包括巴比妥类（如苯巴比妥），苯妥因、利福平、卡马西平、安乃近、异烟肼等。
本品对经细胞色素P450 3A4代谢的其它药物的影响：
在人体肝细胞中发现，本品可能是细胞色素P450 3A4的诱导剂，但比利福平作用弱。
相反地，本品抑制可的松和睾丸酮的代谢。由于本品可能干扰类固醇性激素的代谢，所以口服避孕药的效果可能被降低。

规格

1mg/粒50粒/盒
5mg/粒30粒/盒
0.5mg/粒50粒/盒

有效期

有效期为3年, 打开铝箔包装后，应在12个月内用完.

贮藏

打开铝箔包装后，室温下（15-30℃）保存，放在原包装内

Advagraf

Active Substance: tacrolimus 
Common Name: tacrolimus 
ATC Code: L04AD02
Marketing Authorisation Holder: Astellas Pharma Europe B.V.
Active Substance: tacrolimus 
Status: Authorised
Authorisation Date: 2007-04-23
Therapeutic Area: Graft Rejection
Pharmacotherapeutic Group: Immunosuppressants

Therapeutic Indication

Prophylaxis of transplant rejection in adult kidney or liver allograft recipients.

Treatment of allograft rejection resistant to treatment with other immunosuppressive medicinal products in adult patients.

What is Advagraf?

Advagraf is a medicine containing the active substance tacrolimus. It is available as prolonged-released capsules containing tacrolimus (0.5 mg: yellow and orange; 1 mg: white and orange; 5 mg: greyish-red and orange). ‘Prolonged-release’ means that tacrolimus is released slowly from the capsule over a few hours.

What is Advagraf used for?

Advagraf is used in adult patients who have had a kidney or liver transplant, to prevent rejection (when the immune system attacks the transplanted organ). Advagraf can also be used to treat organ rejection in adult patients when other immunosuppressive medicines are not effective.

The medicine can only be obtained with a prescription.

How is Advagraf used?

Treatment with Advagraf should only be prescribed by doctors who have experience in the management of transplant patients.

Advagraf is for long-term use. Doses are calculated based on the patient’s weight. Doctors should monitor the levels of tacrolimus in the blood to check that they stay within predefined ranges.

In the prevention of rejection, the dose of Advagraf to use depends on the type of transplant the patient has received. In kidney transplant, the starting dose is 0.20 to 0.30 mg per kilogram body weight. In liver transplant, the starting dose is 0.10 to 0.20 mg/kg.

When treating rejection, these same doses may be used in kidney and liver transplants. Starting doses are 0.10 to 0.30 mg/kg in other types of transplant (heart, lung, pancreas or intestine).

Advagraf is given once a day, in the morning, at least one hour before or two to three hours after food.

How does Advagraf work?

Tacrolimus, the active substance in Advagraf, is an immunosuppressive agent. This means that it reduces the activity of the immune system (the body’s natural defences). Tacrolimus acts on some special cells in the immune system called T-cells that are primarily responsible for attacking the transplanted organ (organ rejection).

Tacrolimus has been used since the mid-1990s. In the European Union (EU), it has been available as capsules under the name Prograf or Prograft (depending on the country). Advagraf is very similar to Prograf / Prograft, but the way the medicine is made has been changed so that the active substance is released more slowly from the capsule than it is in Prograf / Prograft. This allows Advagraf to be given once a day, whereas Prograf / Prograft is given twice a day. This can help the patients stick to their treatment.

How has Advagraf been studied?

Because tacrolimus and Prograf / Prograft have already been used in the EU, the company presented the results of studies that had been carried out with Prograf / Prograft previously, as well as data from the published literature. It also presented the results of a clinical study in 668 kidney transplant patients comparing the use of Advagraf with that of Prograf / Prograft or ciclosporin (another immunosuppressive medicine used in the prevention of rejection). Patients also received mycophenolate mofetil (another medicine used in the prevention of rejection). The main measure of effectiveness was the number of patients in whom the transplant failed (as measured by looking at, for example, the need for a repeat transplant or a return to dialysis) after one year’s treatment. Further shorter studies were also carried out in 119 kidney transplant patients and 129 liver transplant patients, looking at how Advagraf is absorbed by the body in comparison to Prograf / Prograft.

What benefit has Advagraf shown during the studies?

Advagraf was as effective as both comparator medicines. After one year, 14% of the patients receiving Advagraf had experienced organ failure. The percentages were 15% in the patients treated with Prograf / Prograft, and 17% in those treated with ciclosporin. The shorter studies in kidney and liver transplant patients showed that Advagraf and Prograf / Prograft have comparable absorption in the body.

What is the risk associated with Advagraf?

The most common side effects with Advagraf (seen in more than 1 patient in 10) are tremor (shaking), headache, nausea (feeling sick), diarrhoea, kidney problems, hyperglycaemia (raised blood glucose levels), diabetes, hyperkalaemia (raised blood potassium levels), hypertension (high blood pressure) and insomnia (difficulty sleeping). For the full list of all side effects reported with Advagraf, see the package leaflet.

Advagraf should not be used in people who may be hypersensitive (allergic) to tacrolimus, to macrolide antibiotics (such as erythromycin) or to any of the other ingredients.

Patients and doctors must be careful when other medicines (including some herbal remedies) are taken at the same time as Advagraf, as there may be a need to adjust the dose of Advagraf or the dose of the medicine it is taken with. See the package leaflet for details.

Why has Advagraf been approved?

The Committee for Medicinal Products for Human Use (CHMP) decided that Advagraf’s benefits are greater than its risks for the prophylaxis of transplant rejection in adult kidney and liver allograft recipients, and in the treatment of allograft rejection resistant to treatment with other immunosuppressive medicinal products in adult patients. The Committee recommended that Advagraf be given marketing authorisation.

Other information about Advagraf

The European Commission granted a marketing authorisation valid throughout the EU for Advagraf on 23 April 2007. The marketing authorisation holder is Astellas Pharma Europe B.V.