部份中文新山地明处方资料（仅供参考）
SANDIMMUNE I.V 250MG(5ml)/ampuls 10ampuls/box
药品英文名
Ciclosporin
药品别名
环孢多肽A、环孢菌素A、环孢灵、赛斯平、山地明、环孢菌素、Cyclosporine、Cyclosporin A、Sandimmun、Sandimmune
药物剂型
1.滴眼剂：1%～4%；
2.胶囊：25mg，100mg；
3.口服液：100mg(50ml)；
4.静脉滴注浓缩液：50mg(5ml)。
药理作用
本品为一种亲脂性含11个氨基酸的环状多肽，是目前最有效的免疫抑制剂，其抗排异机理可能是对T辅助淋巴细胞有选择性抑制作用，主要通过干扰T辅助细胞而抑制依赖T细胞的免疫反应诱导早期阶段，选择性地抑制白细胞介素2的产生与释放，并减少对激活T辅助细胞必不可少的白细胞介素，进而阻止辅助细胞激活，白细胞介素1的缺乏并非本品直接作用于巨噬细胞而是通过对T诱导细胞的抑制作用。T诱导细胞被抑制能减少巨噬细胞产生白细胞介素。
最终抑制T细胞增殖与分化成杀伤细胞，阻止淋巴细胞合成淋巴因子、γ干扰素，抑制B细胞产生抗体。因而本品能抑制器官移植的排异反应以及骨髓移植后移植物对宿主的反应。本品可延长多种动物皮肤、心脏、肾脏、胰脏、骨髓、肺和小肠等组织器官同种移植的生存。还可抑制同种异体移植免疫、迟发性皮肤过敏、实验性变应性脑脊髓炎、弗氏佐剂性关节炎、移植物抗宿主反应及依赖T细胞的抗体生成等多种细胞介导的免疫反应。本品无细胞毒作用，不抑制血细胞生成，对天然T细胞及吞噬细胞功能影响较弱，与其他免疫抑制剂相比，使用本品的患者，不易发生感染。
药动学
在上消化道的吸收依赖于胆汁的分泌，口服吸收缓慢不完全且不规则，一次吸收剂量4%～60%，平均30%，血浆药物浓度达峰时间为2～8h。口服每天12.5mg/kg后，稳态血药浓度最低为100～200ng/ml，最高为500～100ng/ml。在稳态时口服液绝对生物利用度为20%～50%(平均34%)。个体差异性较大，而且不同器官移植患者生物利用度也不同，如成人肾移植患者为5%～89%；肝移植患者为8%～60%。剂量小于0.14g时，血浆浓度与剂量成正比。食物对其吸收的影响不一致，一般来说，口服同时进食可增加药物的吸收，本品分布大大超出血容量，表观分布容积为4～13l/kg。在全血中与红细胞和血浆蛋白的结合率大于90%，约66%与血红蛋白结合，35%与脂蛋白和白蛋白结合。血液中的药物33%～47%存在于血浆中，4%～9%存在于淋巴细胞中，5%～12%存在于粒细胞中，41%～58%在红细胞中，在较高浓度时在白细胞和红细胞中即达到饱和。肝脏是该药的主要贮存库，其次为胰腺、血液、心、肺、肾、神经和肌肉组织，也可以进入胎盘，在乳汁中有分泌。口服后的消除呈双相，血浆分布半衰期约2h，消除半衰期约19h，半衰期与剂量无关。主要在肝脏内代谢，生成约15个代谢物。肝微粒体细胞色素P450酶参与这些代谢过程。至今鉴定的所有代谢物均具有与母体相同的环状多肽结构。主要为在不同部位单羟基化或二羟基化以及N-脱甲基。90%的代谢产物及原药通过胆汁排泄，约6%随尿液排出，仅0.1%以原形药物由尿液中排出。儿童比成人有更大的血浆清除率，用药剂量宜加大；肝功能损害者和老年人清除较慢，亦应适当调整剂量。移植肾清除率为每分钟(7.2±4.2)ml/kg；移植肝清除率为每分钟(5.8±1.5)ml/kg。为了减少毒性反应及排异现象的发生，用药期间可采用放免法或HPLC法监测血药浓度，以确定适宜的最低浓度。一般24h内血药最低浓度，全血法为250～800ng/ml，血浆法为50～300ng/ml。
适应证
用于疱疹病毒性角膜炎、春季结膜炎(春季卡他性结膜炎)、角结膜干燥症、角膜移植排斥反应、蚕食性角膜溃疡、坏死性巩膜炎、激素控制不满意或不能耐受的葡萄膜炎，特别是后葡萄膜炎、全葡萄膜炎。在皮肤科CsA主要用于严重银屑病、坏疽性脓皮症、白塞病、后天性大疱性表皮松解(获得性大疱性表皮松解症)、扁平苔藓、遗传过敏性皮炎(异位性皮炎)、天疱疮、系统性红斑狼疮(SLE)、皮肌炎与多发性肌炎(皮肌炎)等。
禁忌证
1.对本品或聚氧乙基化蓖麻油过敏的患者(输注用浓缩液含后者)禁用。
2.1岁以下婴儿禁用。
3.肾功能不全、未控制的高血压、未控制的感染、肿瘤患者、病毒感染者禁用。
注意事项
1.慎用：
1岁以下儿童、孕妇及哺乳妇女不宜应用。严重肝肾功不全者慎用或酌减剂量。
2.本品应在经验丰富的医师或血液病专家指导下使用，定期检测肝肾功能和血药浓度，如出现毒性反应，及时调整剂量，个体化用量要求非常准确。
3.凡打开的口服液，应保存在30℃以下，2个月内服完。
4.除皮质激素外，本品避免与其他免疫抑制剂合用。免疫抑制过度有增加感染的可能性。口服液在服用前一定要用所附的吸管，以牛奶、巧克力或橘子汁稀释，温度最好在25℃。打开保护盖后，用吸管从容器内吸出所需要的药物量(一定要准确)，然后放入盛有牛奶、巧克力或橘子汁的玻璃杯中(不可用吸附性的塑料杯)，药液稀释搅拌后，立即饮用，并再用牛奶等清洗玻璃杯后饮用，确保剂量准确。用过的吸管放回原处前，一定要用清洁干毛巾擦干，不可用水或其他溶液清洗，以免造成药液混浊。经稀释后的输注液在48h后必须弃去。应使用玻璃容器贮放。因输液中的聚氧乙基化蓖麻油会使PVC中酞酸酯释放出。儿童对本品的吸收、消除速度较成人为快，其剂量可略高于成人。避免高钾饮食，不宜与含钾药物和保钾利尿剂联合应用。
不良反应
1.肾毒性：
可有肾小球血栓形成、肾小管受阻、线粒体肿胀、蛋白尿、管型尿等，偶见有高尿酸血症、高血钾症、血清肌酐值升高、氮质潴留、少尿或无尿。
2.肝脏毒性：
临床表现为低蛋白血症、高胆红素血症，血清转氨酶升高，有时伴有碱性磷酸酯酶和乳酸脱氢酶升高。其肝脏毒性与用药剂量及给药方法有密切关系，当血药浓度大于200ng/ml时易发生肝毒性，尤其是HBsAg阳性患者及术前肝功能损害者使用本品时更应注意。
3.神经系统反应：
常表现为运动性脊髓综合征、小脑样综合征及精神错乱、震颤、感觉异常(如头痛、听觉缺失、耳鸣等)。
4.胃肠道反应：
为厌食、恶心、呕吐等。也见有腹泻、胃肠炎和消化性溃疡。
5.皮肤反应：
多毛症(34.4%)、痤疮、瘙痒、皮疹、色素沉着和烧灼感。
6.心血管反应：
高血压(一般用药数周内发生)、痛性痉挛、水肿。
7.血液系统反应：
贫血、白细胞减少、血小板减少、淋巴瘤和淋巴增生性障碍。
8.呼吸系统反应：
鼻窦炎。
9.内分泌系统反应：
高血糖、男子妇型乳房。
10.其他：体重减轻。静脉给药可出现罕见但又严重的过敏反应如胸部和脸部发红、呼吸困难、喘息、血压变化和心动过速。输注的最初30min内应连续观察，并在以后定时继续观察。一旦发生应立即停药，严重者静脉注射肾上腺素和给氧抢救。
用法用量
一般为每天5～12mg/kg，个别可低至3mg/kg，高至每天25mg/kg。开始量常为每天3～4mg/kg，每天1次或分2次用，如在2～4周内未见改善，剂量可每天增加0.5～1mg/kg，随皮损的改善，逐渐减少到最小有效量维持，当病情完全控制后也可停药。现在提倡CsA间歇疗法及用其他药物作辅助治疗。静脉滴注：每次3～5mg/kg，以5%葡萄糖注射剂或生理盐水稀释成1：20～100的浓度4h内滴完。滴眼：将注射剂稀释为1%～4%溶液使用，每次1或2滴，每天1～5次。
药物相应作用
1.本品主要在肝内代谢灭活，因此凡能影响肝药酶活性的药物都可影响本品的代谢。
2.红霉素、交沙霉素、多西环素(强力霉素)、酮康唑、H2受体拮抗剂(如雷尼替丁等)、钙拮抗剂(硝苯地平)、雄激素、口服避孕药等均能影响肝细胞内细胞色素P450的活性，使本品的代谢速率降低，血药浓度增加，有增加毒性的危险。
3.卡马西平、苯妥英钠、苯巴比妥、异烟肼、利福平、新青霉素Ⅲ、磺胺等均能加速本品代谢，使其血药浓度降低，免疫抑制作用减弱。
4.氨基糖苷类抗生素、复方磺胺甲噁唑、两性霉素B、头孢菌素(头孢氨噻肟、头孢呋肟)、氮芥、非甾体抗炎药、甘露醇、呋塞米等都有可能加重肾毒性。
5.钙离子与钙调节蛋白结合，导致蛋白质构象改变，影响本品的分布，用本品时应禁与钙剂、潴钙利尿剂等合用，也应避免进食含钙量高的食物。
6.接种疫苗可减弱本品的免疫抑制活性，也应避免使用。
7.此外，在用本品之前，一般用过免疫抑制剂如环磷酰胺、硫唑嘌呤等可导致患者整体免疫力下降而易发生感染。长期合用泼尼松等激素也可诱发糖尿病、高血压、溃疡及骨质疏松等不良反应，且可使本品毒性增加。
8.与洛伐他汀、秋水仙碱合用，可加强肌肉的潜在毒性。
9.本品可降低泼尼松龙的清除率；高剂量的甲泼尼龙可提高本品的血浓度。
临床研究
CsA对各型严重的银屑病疗效确实，起效快，但停药后可复发。对坏疽性脓皮病、白塞病、获得性大疱性表皮松解症、扁平苔藓亦有较好效果。CsA口腔含漱治疗口腔扁平苔藓有效。CsA对SLE、皮肌炎、硬皮病的疗效尚难以评价。CsA对异位性皮炎、结节性痒疹有效。一般认为CsA辅助糖皮质激素治疗天疱疮有效，但有人认为CsA与糖皮质激素合用并不能提高疗效，只会增加不良反应。本品为一种选择性免疫抑制药，选择作用于T细胞系统，抑制白细胞介素-2的生成，从而抑制辅助性T细胞和细胞毒性T细胞。本品点眼眼内通透性较小，2%滴眼液滴眼后药物主要浓集于角膜，其次为巩膜，房水浓度较低。结膜下注射可在房水获得高度浓度。
制造商
诺华
包装规格[本品美国上高包装，采购以咨询为准]
SANDIMMUNE O/S 100MG 50ML  CYCLOSPORINE     00078-0110-22          
SANDIMMUNE AMP 250MG 5ML 10  CYCLOSPORINE     00078-0109-01       
SANDIMMUNE GEL CAP 25MG UD 30  CYCLOSPORINE     00078-0240-15 
SANDIMMUNE GEL CAP 100MG UD 30  CYCLOSPORINE     00078-0241-15 
SANDIMMUNE 50MG/ML 5ML AMP 10/PAC  CYCLOSPORINE     00078-0109-01
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Sandimmune®(cyclosporine capsules, USP)
Sandimmune®(cyclosporine oral solution, USP)
Sandimmune®(cyclosporine injection, USP)
Sandimmune(cyclosporine)
Description and Clinical Pharmacology
DESCRIPTION
Cyclosporine, the active principle in Sandimmune® (cyclosporine) is a cyclic polypeptide immunosuppressant agent consisting of 11 amino acids. It is produced as a metabolite by the fungus species Beauveria nivea.
Chemically, cyclosporine is designated as [R-[R*,R*-(E)]]-cyclic(L-alanyl-D-alanyl-N-methyl-L-leucyl-N-methyl-L-leucyl-N-methyl-L-valyl-3-hydroxy-N,4-dimethyl-L-2-amino-6-octenoyl-L-α-amino-butyryl-N-methylglycyl-N-methyl-L-leucyl-L-valyl-N-methyl-L-leucyl).
Sandimmune® Soft Gelatin Capsules (cyclosporine capsules, USP) are available in 25 mg and 100 mg strengths.
Each 25 mg capsule contains:
cyclosporine, USP………………………………………………………25 mg
alcohol, USP dehydrated………………………………max 12.7% by volume
Each 100 mg capsule contains:
cyclosporine, USP……………………………………………………….100 mg
alcohol, USP dehydrated………………………………max 12.7% by volume
Inactive Ingredients: corn oil, gelatin, iron oxide red, linoleoyl macrogolglycerides, sorbitol, and titanium dioxide. May also contain glycerol. 100 mg capsules may contain iron oxide yellow.
Sandimmune® Oral Solution (cyclosporine oral solution, USP) is available in 50 mL bottles.
Each mL contains:
cyclosporine, USP………………………………………………….100 mg
alcohol, Ph. Helv. …………………………………………12.5% by volume
dissolved in an olive oil, Ph. Helv./Labrafil M 1944 CS (polyoxyethylated oleic glycerides) vehicle which must be further diluted with milk, chocolate milk, or orange juice before oral administration.
Sandimmune® Injection (cyclosporine injection, USP) is available in a 5 mL sterile ampul for I.V. administration.
Each mL contains:
cyclosporine, USP………………………………………………………50 mg
*Cremophor® EL (polyoxyethylated castor oil)……………………..650 mg
alcohol, Ph. Helv. ……………………………………………………32.9% by volume
nitrogen…………………………………………………………….qs
which must be diluted further with 0.9% Sodium Chloride Injection or 5% Dextrose Injection before use.
The chemical structure of cyclosporine (also known as cyclosporin A) is
CLINICAL PHARMACOLOGY
Sandimmune® (cyclosporine) is a potent immunosuppressive agent which in animals prolongs survival of allogeneic transplants involving skin, heart, kidney, pancreas, bone marrow, small intestine, and lung. Sandimmune® (cyclosporine) has been demonstrated to suppress some humoral immunity and to a greater extent, cell-mediated reactions such as allograft rejection, delayed hypersensitivity, experimental allergic encephalomyelitis, Freund’s adjuvant arthritis, and graft vs. host disease in many animal species for a variety of organs.
Successful kidney, liver, and heart allogeneic transplants have been performed in man using Sandimmune® (cyclosporine).
The exact mechanism of action of Sandimmune® (cyclosporine) is not known. Experimental evidence suggests that the effectiveness of cyclosporine is due to specific and reversible inhibition of immunocompetent lymphocytes in the G0- or G1-phase of the cell cycle. T-lymphocytes are preferentially inhibited. The T-helper cell is the main target, although the T-suppressor cell may also be suppressed. Sandimmune® (cyclosporine) also inhibits lymphokine production and release including interleukin-2 or T-cell growth factor (TCGF).
No functional effects on phagocytic (changes in enzyme secretions not altered, chemotactic migration of granulocytes, macrophage migration, carbon clearance in vivo) or tumor cells (growth rate, metastasis) can be detected in animals. Sandimmune® (cyclosporine) does not cause bone marrow suppression in animal models or man.
The absorption of cyclosporine from the gastrointestinal tract is incomplete and variable. Peak concentrations (Cmax) in blood and plasma are achieved at about 3.5 hours. Cmax and area under the plasma or blood concentration/time curve (AUC) increase with the administered dose; for blood, the relationship is curvilinear (parabolic) between 0 and 1400 mg. As determined by a specific assay, Cmax is approximately 1.0 ng/mL/mg of dose for plasma and 2.7-1.4 ng/mL/mg of dose for blood (for low to high doses). Compared to an intravenous infusion, the absolute bioavailability of the oral solution is approximately 30% based upon the results in 2 patients. The bioavailability of Sandimmune® Soft Gelatin Capsules (cyclosporine capsules, USP) is equivalent to Sandimmune® Oral Solution, (cyclosporine oral solution, USP).
Cyclosporine is distributed largely outside the blood volume. In blood, the distribution is concentration dependent. Approximately 33%-47% is in plasma, 4%-9% in lymphocytes, 5%-12% in granulocytes, and 41%-58% in erythrocytes. At high concentrations, the uptake by leukocytes and erythrocytes becomes saturated. In plasma, approximately 90% is bound to proteins, primarily lipoproteins.
The disposition of cyclosporine from blood is biphasic with a terminal half-life of approximately 19 hours (range: 10-27 hours). Elimination is primarily biliary with only 6% of the dose excreted in the urine.
Cyclosporine is extensively metabolized but there is no major metabolic pathway. Only 0.1% of the dose is excreted in the urine as unchanged drug. Of 15 metabolites characterized in human urine, 9 have been assigned structures. The major pathways consist of hydroxylation of the Cγ-carbon of 2 of the leucine residues, Cη-carbon hydroxylation, and cyclic ether formation (with oxidation of the double bond) in the side chain of the amino acid 3-hydroxyl-N,4-dimethyl-L-2-amino-6-octenoic acid and N-demethylation of N-methyl leucine residues. Hydrolysis of the cyclic peptide chain or conjugation of the aforementioned metabolites do not appear to be important biotransformation pathways.
Specific Populations
Renal Impairment
In a study performed in 4 subjects with end-stage renal disease (creatinine clearance <5mL/min), an intravenous infusion of 3.5 mg/kg of cyclosporine over 4 hours administered at the end of a hemodialysis session resulted in a mean volume of distribution (Vdss) of 3.49 L/kg and systemic clearance (CL) of 0.369 L/hr/kg. This systemic CL (0.369 L/hr/kg) was approximately two thirds of the mean systemic CL (0.56 L/hr/kg) of cyclosporine in historical control subjects with normal renal function. In 5 liver transplant patients, the mean clearance of cyclosporine on and off hemodialysis was 463 mL/min and 398 mL/min, respectively. Less than 1% of the dose of cyclosporine was recovered in the dialysate.
Hepatic Impairment
Cyclosporine is extensively metabolized by the liver. Since severe hepatic impairment may result in significantly increased cyclosporine exposures, the dosage of cyclosporine may need to be reduced in these patients.
STORAGE
Cap: 25°C (77°F); excursions permitted to 15-30°C (59-86°F). Sol: <30°C (86°F). Do not refrigerate. Protect from freezing. Inj: <30°C (86°F). Protect from light.