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· 【药品名称】
通用名称：环孢素注射液
英文名称：Cyclosporin Injection

· 【成份】环孢素。

· 【性状】本品为淡黄色至棕黄色的澄明油状液体。

· 【适应症】器官移植 (预防肾、肝、心脏，心肺联合，肺和胰腺移植的排斥反应。 (治疗既往接受其它免疫抑制剂治疗但出现排斥反应的患者。 由于存在过敏的风险（见预防节），只有在不能口服（如刚刚术后）或是胃肠吸收受损的情况下才进行静脉输注山地明。此类病人应尽可能快地转向口服新山地明的治疗。 骨髓移植 (预防移植物排斥反应。 (移植物抗宿主病（GVHD）的初期预防和治疗。

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· 【用法用量】用法 浓缩液应用生理盐水或5％葡萄糖按1:20或1:100比例稀释，然后缓慢静脉输入，时间应大约为2－6小时。一经稀释，溶液必须于24小时内使用或遗弃。 操作建议 应使用玻璃输注瓶。塑料瓶必须符合欧洲药典关于血液制品用塑料容器规定，且不含PVC。输注用浓缩液中包含的聚氧乙烯化蓖麻油能导致PVC中的邻苯二甲酸酯剥离。瓶子和瓶塞应不含硅油和任何脂类物质。 至于儿童不可触及处。 剂量和用法 如下的建议剂量只作为指导原则。建议剂量为3-5mg/kg，约相当于口服剂量的1/3。对血中环孢素水平的日常监测至关重要，可应用单克隆抗体酶联免疫法进行监测。所得结果作为决定不同个体病人所需获得靶浓度的剂量的指导（查询有关血液水平监测信息见预防节）。 器官移植 当环孢素与其它免疫抑制剂（如皮质类固醇，或作为3－4种药物治疗方案中的一种药物）联合应用时，应给予较小剂量（如静脉输注1-2mg/kg/天,然后口服3-6mg/kg/天）。病人应尽早进行口服环孢素的治疗。 骨髓移植 第一次给药应在移植前一天进行，最好为静脉输注3-5mg/kg/天。在术后的最初阶段应每日注射该剂量，最多不超过2周。改为口服维持治疗后，剂量约为12.5mg/kg/天。 胃肠道失调吸收受损的病人可以继续静脉输注。 部分病人在停服环孢素后可出现GVHD。GVHD通常是由重建导致。

· 【不良反应】本品的不良反应通常是剂量依赖性的，剂量减少后可逆。不良反应的范围在不同的适应症中大体是相同的，除了在频率和严重程度方面有些不同。因为在移植的适应症中应用时由于起始剂量高并且维持治疗时间长，所以发生在移植受者上的不良反应较其它适应症患者的更常见和严重。 发生率的估计：非常常见：≥10%；常见：≥1%-<10%；不常见：≥0.1%-<1%；罕见：≥0.01%-<0.1%；非常罕见：<0.01% 肾脏 非常常见：肾脏功能受损（发生率10-50%，根据适应症的不同而不同） 心血管系统 非常常见：高血压（15-40%） 中枢神经系统 非常常见：震颤（10-20%），头痛（最高15%） 常见：感觉异常 不常见：脑部症状，例如痉挛，精神错乱，定向力障碍，反应力受损，激越，失眠，视觉障碍，皮质盲，昏迷，麻痹和小脑的共济失调 罕见：运动多神经病 非常罕见：视神经盘水肿，包括视神经乳头水肿，伴随有继发于良性颅内高压的可能视觉损害。 胃肠道和肝脏 常见：食欲减退，恶心，呕吐，腹痛，腹泻，牙龈增生和肝功能受损。 罕见：胰腺炎 代谢 非常常见：高血脂症。 常见：高尿酸血症，高钾血症，低镁血症 罕见：高血糖 肌肉骨骼系统： 常见：肌肉痉挛，肌痛 罕见：肌肉无力，肌病 血液 不常见：贫血，血小板减少症 罕见：血栓性血小板减少性紫癜，微血管病理性溶血性贫血，溶血性尿毒症综合征。 皮肤和附属物 常见：多毛症 不常见：皮肤过敏反应 全身 常见：疲劳 不常见：水肿，体重增加 内分泌系统 罕见：月经紊乱，男性乳房发育 肿瘤和淋巴组织增生紊乱 可以发生恶性肿瘤和淋巴组织增生紊乱，但在移植受体中的发生频率和分布同接受传统免疫抑制治疗的病人相似

· 【禁忌】对环孢素或聚氧乙烯化蓖麻油具高敏感性的人群。

· 【注意事项】
只有对免疫抑制治疗有经验的、能够进行必要监测（定期全面的体格检查，测量血压，化验）的医生才能处方本品。接受本品的移植病人应该在配备有必需的实验室和医疗设备的中心进行治疗。应给予负责维持治疗和随访的医生所有对恰当护理有用的资料。 静脉输注浓缩液中含有聚氧乙烯化蓖麻油，其已被报告会导致类过敏性反应，如面红、胸廓上移、合并呼吸困难和喘息的急性呼吸系统窘迫，血压改变和心动过速。 对于那些曾经接受含聚氧乙烯化蓖麻油药物（如Cremophor EL）静脉注射或输液的病人，或易发生高敏感性反应的病人应特别小心。所有接受静脉输注本品的病人均应在输注后持续观察至少30分钟，此后应进行定期观察。一旦出现过敏反应则应中断输注，床旁应准备肾上腺素（水性溶液1：1000）和氧气。 由于存在过敏反应的风险，只在不能口服的情况下才能静脉输注山地明浓缩液。在此情况下，病人应尽早转为口服新山地明治疗。 在输注本品前通过预防性地应用抗组胺药（H1和H2拮抗剂），有可能防止类过敏性反应的发生。 与其它免疫抑制剂相同，环孢素有增加发生淋巴瘤和其他恶性肿瘤的风险，尤其是皮肤的肿瘤。 此种发生恶性肿瘤风险的增加与免疫抑制的程度和持续时间更加相关，与应用的是哪一个免疫抑制剂相关性不大。 另外，对一个包含多种免疫抑制剂的治疗方案必须慎重，因为它可能导致致命的淋巴增生紊乱和实质器官肿瘤的发生。 像病人应用其他免疫抑制剂一样，使用环孢素的病人易于发生细菌、霉菌、寄生虫和病毒的感染，且经常为机会致病菌。因为感染可能会是致命的，所以应采取有效的预防与治疗措施，特别是接受长期多种免疫抑制剂治疗的病人。 应用本品治疗的最初几周内，一种常见的和潜在的严重并发症是血清肌酐和尿素氮水平的增高。这些功能性改变是剂量依赖性和可逆的，当减少剂量时通常会转为正常。部分长期治疗的病人可能导致肾脏的结构改变（如间质性纤维化），这些改变必须与肾脏移植病人的慢性排斥反应区分开来。 应用本品治疗还可见剂量依赖性和可逆性的血清胆红素增加，偶有肝脏酶水平的增加。 要求定期对肝脏和肾脏功能指标进行检查，必要时减少剂量。 当山地明用于移植患者时，对环孢素血药浓度进行常规监测是重要的安全措施。 血中环孢素水平最好应用特异的单克隆抗体检测（测定未改变的药物）。当然也可采用HPLC方法（也是测定未改变的药物）。对于血浆或血清中的测定，应该采用一个分别进行的（时间和温度）标准化的方法。在肝移植受者中，最初的血液水平监测可以选择单独的特异性单克隆抗体，或是特异性与非特异性单克隆抗体平行进行以确保免疫抑制在一适当的水平。 必须要记住的是，环孢素在血液、血浆或血清中的水平只是影响病人临床状态的诸多因素之一。其结果只能被视为基于全部范围的其它临床和生化参数的治疗指导。 使用山地明治疗期间要定期监测血压，如果出现高血压，必须进行适当的抗高血压治疗。应优先使用不干扰环孢素药代动力学的抗高血压药物，如依拉地平或硝苯地平（参见“药物相互作用”）。 有报道少数病例应用本品治疗后导致轻微、可逆的血脂增加，因此在开始治疗前和其后一个月应测定血脂水平。如有增加，应减少饮食中脂肪摄入，并可适当减少本品剂量。 环孢素增加发生高血钾的风险，特别是对于有肾功能不全的病人。在服用环孢素和同时服用保钾利尿剂、血管紧张素转换酶抑制剂、血管紧张素II受体拮抗剂、含有钾的药物及服用高钾的食物的病人中要慎重。在这种情况下，建议定期检查血钾水平。 环孢素增加镁的排出可导致症状性的低镁血症，特别是在移植期间。在移植期间建议监测血镁，特别是有神经症状时。如果确实需要，可以额外补充镁。 接受本品治疗的病人饮食中应避免高钾摄入，并且不能服用含钾药物或保钾利尿剂。 由于环孢素偶会导致或加重高血钾，应对严重肾功能不良的病人进行血清中钾的监测。 对于高尿酸血症的病人应特别注意。 在应用环孢素治疗期间，接种的疫苗效力有可能降低，并且应避免使用活疫苗。 将药物置于儿童不能接触的地方。

· 【孕妇及哺乳期妇女用药】妊娠期：动物试验已经证明了大鼠和家兔的生殖毒性（见临床前安全性资料） 在怀孕妇女中使用山地明的经验是有限的。在使用免疫抑制剂治疗的孕妇移植患者中增加了早产的风险。 观察了最长达7年（最大约7岁）曾于胎儿期在子宫内暴露于环孢素（母亲服用环孢素）的儿童，这些儿童的肾功能和血压均正常，但观察例数有限。 然而，尚未在孕妇中进行充分的对照试验，因此，在妊娠期间不应使用山地明，除非能证明对母亲的潜在利益大于对胎儿的潜在风险。
哺乳期：环孢素流经乳汁。因此正在接受本品治疗的母亲不要哺乳。

· 【儿童用药】见特殊临床情况下的药物动力学

· 【老年用药】特殊临床情况下的药物动力学

· 【药物相互作用】食物的相互作用 同柚子汁一起服用时发现环孢素的生物利用度增加。 药物的相互作用已报告同多种药物有药物间的相互作用。下述列出的是有良好的文件记录并且认为有临床相关性的。 已知许多药物通过竞争性地抑制或诱导肝酶-特别是细胞色素P-450NF（CyP3A家族，该酶系统参与代谢与消除环孢素）可以增加或降低血浆或全血的环孢素浓度。 降低环孢素血浓度的药物 巴比妥类药物，卡马西平，苯妥英，安乃近，萘夫西林，和静注（非口服）磺胺二甲嘧啶利福平，奥曲肽，丙丁酚，奥利司他，圣约翰草（金丝桃属顶体），曲格列酮，噻氯吡啶，磺吡酮，和特比萘芬。 增加血浆或全血中环孢素水平的药物 某些大环内酯类抗生素（包括红霉素和阿奇霉素）酮康唑，氟康唑，伊曲康唑，地尔硫卓，尼卡地平，维拉帕米，甲氧氯普胺，口服避孕药，达那唑，甲泼尼龙（高剂量），别嘌呤，胺碘酮，胆酸及其衍生物，蛋白酶抑制剂，伊马替尼。 其他相关的药物相互作用 在应用环孢素与其它已知有肾毒性协同作用的药物：氨基糖甙类（包括庆大霉素和妥布霉素）两性霉素B、环丙沙星、万古霉素，甲氧苄啶（+磺胺二甲嘧啶）非甾体抗炎药（包括双氯芬酸，吲哚美辛，奈普生和舒林酸）和美法仑，H2组胺受体阻断剂（如西咪替丁，雷尼替丁）。 由于可能增加肾毒性，应避免与他克罗姆合并用药。 在应用环孢素期间疫苗的作用可能降低，同时应避免使用活疫苗。 与单独服用环孢素相比，联合应用硝苯地平和环孢素可导致牙龈增生的发生率增加。 联合应用环孢素和双氯酚酸时发现双氯酚酸的生物利用度会显著增加，可能并发可逆性的肾功能衰竭。生物利用度的增加很可能是因为双氯酚酸高首过效应的降低。环孢素与低首过效应的NSAIDs（例如：乙酰水杨酸盐）合用时，该NSAIDs的生物利用度通常不会有增高。 环孢素可能会减少地高辛、秋水仙碱、泼尼松龙和HMG-CoA还原酶抑制剂（他汀类）的清除。几例使用地高辛的患者在开始使用环孢素治疗的几天内发生了严重的洋地黄叶毒性。也有报道称使用环孢素，特别是有肾功能障碍的患者使用环孢素可增加秋水仙碱的毒性作用（如肌病和肾病）。如果地高辛或秋水仙碱与环孢素同时使用，则要求进行密切的临床观察以便能够早期检测出地高辛或秋水仙碱的毒性表现，之后降低给药剂量或停药。 文献报道和上市后的使用情况表明，环孢素与洛伐他汀、昔伐司汀、阿伐他汀、普伐他汀合并用药可引起肌毒性（包括肌痛、虚弱、肌炎和横纹肌溶解），但罕见于与氟伐他汀合用时。当与环孢素同时给药时，应根据标签说明降低给药剂量。对具有肌病征兆和症状的患者、或具有发生严重肾损害风险因素的患者（包括肾衰、继而发生横纹肌溶解）需要暂时降低或终止他汀类药物的治疗。 在使用依维莫司或西罗莫司与全剂量环孢素微乳剂联合给药的试验中出现了血清肌酐水平升高。这种作用通常随着环孢素给药剂量的降低而恢复。依维莫司或西罗莫司对环孢素药代动力学只有较小的影响。与环孢素联合给药明显增加了依维莫司或西罗莫司的血药浓度。 建议： 当不可避免地联合使用与环孢素存在相互作用的药物时，应遵守下列建议。 已知有肾毒性协同作用的药物 应严密监测肾功能（特别是血清肌酐水平）。当发生明显的肾功能损伤时，应降低联合使用的其他药品的剂量或考虑替代治疗。 在移植患者中，已有报道在合并给予纤维酸衍生物（如苯扎贝特，非诺贝特）后发生了明显的、但可恢复的肾功能损害（伴随血清肌酐水平升高）。因此对这些患者必须密切监测其肾功能。如果发生明显的肾功能损害，应停止合并用药。 已知降低或升高环孢素生物利用度的药物： 接受移植的病人应经常进行血液中环孢素水平的检测，特别在开始和结束其他药物治疗时，如有需要，环孢素的剂量应进行调整或停止合并给药。在非移植患者中，环孢素血药浓度监测值是不可靠的，因为在这些患者中尚未充分建立血药浓度与临床作用之间的相关性。 当需要联合使用能提高血液中环孢素水平的药物时，应更加频繁的监测肾功能和严密监测那些比血液环孢素药物水平更易检测的不良反应。 使用环孢素治疗引起牙龈增生的病人应避免使用硝苯地平。 与未接受环孢素治疗的患者相比，在接受环孢素治疗的患者中应用已知有很强的首过效应的非甾体类抗炎药（如双氯酚酸）时，应采用较低的剂量。 如果和环孢素同时使用地高辛、秋水仙碱、洛伐他汀，普伐他汀和西伐他汀等药物，应小心进行临床监测，及早发现毒性反应，从而降低剂量或停药。

· 【药物过量】少有对付过剂量治疗的经验。一旦出现此种情况，则应对症治疗，并辅之全身性支持手段。任何肾毒性的症状在停药后都会逆转。 透析和活性炭血液吸附无法充分去除身体中的环孢素。

· 【药理毒理】药理 环孢素是一种含11个氨基酸的环形多肽。动物实验表明，环孢素能延长皮肤、心脏、肾脏、胰腺，骨髓，小肠和肺等同种异体移植器官和组织的存活，是一高效的免疫抑制剂。研究表明：环孢素既可抑制细胞介导反应的发展——包括同种移植免疫，迟发的皮肤高敏感性，实验性过敏脑骨髓炎，弗氏佐剂性关节炎，移植物抗宿主病（GVHD）；又可抑制T细胞依赖的抗体生成――以及包括白介素-2（T细胞生长因子，TCGF）在内淋巴因子的生成与释放。 有证据表明，环孢素能将静止的淋巴细胞阻滞于Go期和G1早期，并能够抑制通过抗原接触而被激活的T细胞释放淋巴因子。 现有的全部证据提示环孢素可以对淋巴细胞产生特异和可逆的作用。与细胞生长抑制剂不同，环孢素不损害血细胞生成或影响巨噬细胞的功能。与接受其它抑制细胞生长的免疫抑制剂的器官移植病人相比，接受环孢素治疗的病人较少发生感染。 本品在人类接受器官和骨髓移植后，预防和治疗移植排斥和GVHD方面已得到成功的应用。在一些被认为或推断为自身免疫的情况下，也有有益的作用。 临床前安全性资料 在标准的口服给药实验系统中（大鼠每天口服给药剂量达到17mg/kg，家兔达到30mg/kg），环孢素没有致突变作用或致畸作用。在毒性给药剂量时（大鼠每天口服给药剂量为30mg/kg，家兔为100mg/kg），环孢素具有胚胎和胎儿毒性，表现为产前和产后死亡率增加，以及胎儿体重降低和相应的骨骼发育迟缓。 在两篇发表的研究试验中，暴露于环孢素（皮下给药10mg/kg/day）的胎兔直至35周龄的家兔都出现了肾单位数减少、肾肥大、全身性高血压和进行性肾功能不全。 孕鼠静脉给药环孢素12mg/kg/day（是推荐的人静脉给药剂量的2倍）结果增加了胎鼠室间隔缺损的发生率。 这些结果尚未在其它动物中得到证明，其与人的相关性未知。 在雄性和雌性大鼠与小鼠中进行了致癌试验。在小鼠78周试验中，当每天给药剂量为1，4和16mg/kg时，雌性小鼠出现了具有统计学意义的发生淋巴细胞性淋巴瘤的迹象，而中间剂量组雄性动物肝细胞癌的发生率明显超过了对照组。在大鼠24个月试验中，当每天给药剂量为0.5，2和8mg/kg时，低剂量组发生胰岛细胞腺瘤明显超过了对照组。肝细胞癌和胰岛细胞腺瘤没有剂量相关性。 对雄性和雌性大鼠进行的试验未发现对生育的损害。 在Ames试验、V79-HGPRT试验、小鼠和中国仓鼠微核试验、中国仓鼠骨髓染色体畸变试验、小鼠显性致死试验和给药小鼠精子DNA修复试验中未发现环孢素具有致突变性/遗传毒性。分析由环孢素诱导的人体外淋巴细胞姐妹染色单体交换（SCE）试验在该系统的高浓度时得出了阳性结果（即诱导SCE）。 在器官移植患者中，恶性肿瘤发生率升高是公认的免疫抑制并发症。最常见的肿瘤形式为非霍奇金氏淋巴瘤和皮肤癌。使用环孢素治疗期间发生恶性肿瘤的风险高于正常、健康的人群，但与接受其它免疫抑制治疗的患者相似。业已报道，减少或终止免疫抑制治疗可使病灶消退。

· 【药代动力学】分布 环孢素主要分布于血液外，平均表观分布容积为3.5l/kg。血液中的分布取决于药物的浓度：血浆中分布的为33－47％，淋巴细胞4－9％，粒细胞5－12％，红血球41－58％。高浓度时，白细胞和红细胞的摄入被饱和。在血浆中，约90％的环孢素与蛋白质结合。（主要为脂蛋白）。 代谢 环孢素被广泛地生物转化，代谢的主要部位是细胞色素P450（CyP4503A4）依赖型一氧化物酶系统。目前发现了多于15种的代谢产物。主要代谢途径为不同分子部位的一羟基化合反应、二羟基化合反应和N－脱甲基化反应。已经发现影响细胞色素P450（CyP4503A4）依赖型酶系统的药物，它们能增加或降低血液中环孢素的水平（见相互作用节）。到目前为止，所有的代谢产物均被鉴定含有母药的完整的肽结构。一些代谢产物有轻微的免疫抑制作用（达到环孢素的10％）。 清除 由于测定方法和受试者的不同，环孢素最终清除的半衰期相差甚远。范围从健康志愿者的6.3小时到肾移植患者的7－16小时，对严重肝病患者甚至达到20.4小时。其主要经汁清除。口服剂量只有6％经尿液排泻，未变化的药物少于1％。 特殊临床情况下的药物动力学 高龄患者 环孢素在高龄患者和中年患者中的分布没有差别。 儿童 平均说来，儿童体内环孢素的排除稍快于成年人。因此有必要使用较大剂量（相对于体重）以达到同样的血液水平。 肾衰 由于环孢素的清除主要经胆汁，肾衰对于药物动力学并无相关的临床影响。在肾衰患者中，按3.5mg/kg给药剂量静脉滴注4小时后，平均血药峰浓度为1800ng/mL(范围1536–2331ng/mL)。 肝衰竭 肝衰竭减慢环孢素的清除。有必要对严重肝功能异常的病人进行血清肌酐和血环孢素水平的密切监测以进行相应的剂量调整。

· 【贮藏】30℃以下贮藏。 药物超过印于包装上的截止日期（＝EXP）不能再使用。 置于儿童不可触及处。

· 【有效期】48个月 稀释溶液的稳定性 如果可能，山地明浓缩液应在无菌地加入注射液后立即使用。应用注射液稀释后应在24小时内使用，在使用前已加入药液的注射液应于冰箱内保存（2-8℃）。 丢弃未用的药液。

Drug Description

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Sandimmune® Soft Gelatin Capsules 
(cyclosporine) Capsules, USP

Sandimmune® Oral Solution 
(cyclosporine) Oral Solution, USP

Sandimmune® Injection 
(cyclosporine) Injection, USP

 

WARNING

Only physicians experienced in immunosuppressive therapy and management of organ transplant patients should prescribe Sandimmune (cyclosporine). Patients receiving the drug should be managed in facilities equipped and staffed with adequate laboratory and supportive medical resources. The physician responsible for maintenance therapy should have complete information requisite for the follow-up of the patient.

Sandimmune (cyclosporine) should be administered with adrenal corticosteroids but not with other immunosuppressive agents. Increased susceptibility to infection and the possible development of lymphoma may result from immunosuppression.

Sandimmune Soft Gelatin Capsules (cyclosporine capsules, USP) and Sandimmune Oral Solution (cyclosporine oral solution, USP) have decreased bioavailability in comparison to Neoral Soft Gelatin Capsules (cyclosporine capsules, USP) MODIFIED and Neoral Oral Solution (cyclosporine oral solution, USP) MODIFIED.

Sandimmune and Neoral are not bioequivalent and cannot be used interchangeably without physician supervision.

The absorption of cyclosporine during chronic administration of Sandimmune Soft Gelatin Capsules and Oral Solution was found to be erratic. It is recommended that patients taking the soft gelatin capsules or oral solution over a period of time be monitored at repeated intervals for cyclosporine blood concentrations and subsequent dose adjustments be made in order to avoid toxicity due to high concentrations and possible organ rejection due to low absorption of cyclosporine. This is of special importance in liver transplants. Numerous assays are being developed to measure blood concentrations of cyclosporine. Comparison of concentrations in published literature to patient concentrations using current assays must be done with detailed knowledge of the assay methods employed. (See Blood Concentration Monitoring under DOSAGE AND ADMINISTRATION)

 

Drug Description

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Sandimmune® Soft Gelatin Capsules 
(cyclosporine) Capsules, USP

Sandimmune® Oral Solution 
(cyclosporine) Oral Solution, USP

Sandimmune® Injection 
(cyclosporine) Injection, USP

WARNING

Only physicians experienced in immunosuppressive therapy and management of organ transplant patients should prescribe Sandimmune (cyclosporine). Patients receiving the drug should be managed in facilities equipped and staffed with adequate laboratory and supportive medical resources. The physician responsible for maintenance therapy should have complete information requisite for the follow-up of the patient.

Sandimmune (cyclosporine) should be administered with adrenal corticosteroids but not with other immunosuppressive agents. Increased susceptibility to infection and the possible development of lymphoma may result from immunosuppression.

Sandimmune Soft Gelatin Capsules (cyclosporine capsules, USP) and Sandimmune Oral Solution (cyclosporine oral solution, USP) have decreased bioavailability in comparison to Neoral Soft Gelatin Capsules (cyclosporine capsules, USP) MODIFIED and Neoral Oral Solution (cyclosporine oral solution, USP) MODIFIED.

Sandimmune and Neoral are not bioequivalent and cannot be used interchangeably without physician supervision.

The absorption of cyclosporine during chronic administration of Sandimmune Soft Gelatin Capsules and Oral Solution was found to be erratic. It is recommended that patients taking the soft gelatin capsules or oral solution over a period of time be monitored at repeated intervals for cyclosporine blood concentrations and subsequent dose adjustments be made in order to avoid toxicity due to high concentrations and possible organ rejection due to low absorption of cyclosporine. This is of special importance in liver transplants. Numerous assays are being developed to measure blood concentrations of cyclosporine. Comparison of concentrations in published literature to patient concentrations using current assays must be done with detailed knowledge of the assay methods employed. (See Blood Concentration Monitoring under DOSAGE AND ADMINISTRATION)

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-leucylN-methyl-L-leucyl-N-methyl-L-valyl-3-hydroxy-N,4-dimethyl-L-2-amino-6-octenoyl-L-α-amino-butyrylN-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 intravenous (IV) 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

For Consumers

WHAT ARE THE POSSIBLE SIDE EFFECTS OF CYCLOSPORINE (GENGRAF, NEORAL, SANDIMMUNE)?

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficult breathing; swelling of your face, lips, tongue, or throat.

Call your doctor at once if you have a serious side effect such as:

· fever, sweating, chills, body aches, flu symptoms, sores in your mouth and throat, weight loss;

· change in your mental state, problems with speech or walking, decreased vision (may start gradually and get worse quickly);

· easy bruising or bleeding, pale skin, confusion or weakness;

· feeling light-headed...

Read All Potential Side Effects and See Pictures of Sandimmune »

Indications & Dosage

INDICATIONS

Sandimmune (cyclosporine) is indicated for the prophylaxis of organ rejection in kidney, liver, and heart allogeneic transplants. It is always to be used with adrenal corticosteroids. The drug may also be used in the treatment of chronic rejection in patients previously treated with other immunosuppressive agents.

Because of the risk of anaphylaxis, Sandimmune Injection (cyclosporine injection, USP) should be reserved for patients who are unable to take the soft gelatin capsules or oral solution.

DOSAGE AND ADMINISTRATION

Sandimmune Soft Gelatin Capsules (cyclosporine capsules, USP) and Sandimmune Oral Solution (cyclosporine oral solution, USP)

Sandimmune Soft Gelatin Capsules (cyclosporine capsules, USP) and Sandimmune Oral Solution (cyclosporine oral solution, USP) have decreased bioavailability in comparison to Neoral Soft Gelatin Capsules (cyclosporine capsules, USP) MODIFIED and Neoral Oral Solution (cyclosporine oral solution, USP) MODIFIED. Sandimmune and Neoral are not bioequivalent and cannot be used interchangeably without physician supervision.

The initial oral dose of Sandimmune (cyclosporine) should be given 4 to 12 hours prior to transplantation as a single dose of 15 mg/kg. Although a daily single dose of 14 to 18 mg/kg was used in most clinical trials, few centers continue to use the highest dose, most favoring the lower end of the scale. There is a trend towards use of even lower initial doses for renal transplantation in the ranges of 10 to 14 mg/kg/day. The initial single daily dose is continued postoperatively for 1 to 2 weeks and then tapered by 5% per week to a maintenance dose of 5 to 10 mg/kg/day. Some centers have successfully tapered the maintenance dose to as low as 3 mg/kg/day in selected renal transplant patients without an apparent rise in rejection rate.

(See Blood Concentration Monitoring, below)

Specific Populations

Renal Impairment

Cyclosporine undergoes minimal renal elimination and its pharmacokinetics do not appear to be significantly altered in patients with end-stage renal disease who receive routine hemodialysis treatments (See CLINICAL PHARMACOLOGY). However, due to its nephrotoxic potential (See WARNINGS), careful monitoring of renal function is recommended; cyclosporine dosage should be reduced if indicated. (See WARNINGS AND PRECAUTIONS)

Hepatic Impairment

The clearance of cyclosporine may be significantly reduced in severe liver disease patients (See CLINICAL PHARMACOLOGY). Dose reduction may be necessary in patients with severe liver impairment to maintain blood concentrations within the recommended target range. (See WARNINGS AND PRECAUTIONS)

Pediatrics

In pediatric usage, the same dose and dosing regimen may be used as in adults although in several studies, children have required and tolerated higher doses than those used in adults.

Adjunct therapy with adrenal corticosteroids is recommended. Different tapering dosage schedules of prednisone appear to achieve similar results. A dosage schedule based on the patient's weight started with 2.0 mg/kg/day for the first 4 days tapered to 1.0 mg/kg/day by 1 week, 0.6 mg/kg/day by 2 weeks, 0.3 mg/kg/day by 1 month, and 0.15 mg/kg/day by 2 months and thereafter as a maintenance dose. Another center started with an initial dose of 200 mg tapered by 40 mg/day until reaching 20 mg/day. After 2 months at this dose, a further reduction to 10 mg/day was made. Adjustments in dosage of prednisone must be made according to the clinical situation.

To make Sandimmune Oral Solution (cyclosporine oral solution, USP) more palatable, the oral solution may be diluted with milk, chocolate milk, or orange juice preferably at room temperature. Patients should avoid switching diluents frequently. Sandimmune Soft Gelatin Capsules and Oral Solution should be administered on a consistent schedule with regard to time of day and relation to meals.

Take the prescribed amount of Sandimmune (cyclosporine) from the container using the dosage syringe supplied after removal of the protective cover, and transfer the solution to a glass of milk, chocolate milk, or orange juice. Stir well and drink at once. Do not allow to stand before drinking. It is best to use a glass container and rinse it with more diluent to ensure that the total dose is taken. After use, replace the dosage syringe in the protective cover. Do not rinse the dosage syringe with water or other cleaning agents either before or after use. If the dosage syringe requires cleaning, it must be completely dry before resuming use. Introduction of water into the product by any means will cause variation in dose.

Sandimmune® Injection (cyclosporine injection, USP)

FOR INFUSION ONLY

Note: Anaphylactic reactions have occurred with Sandimmune Injection (cyclosporine injection, USP). (See WARNINGS)

Patients unable to take Sandimmune Soft Gelatin Capsules or Oral Solution pre-or postoperatively may be treated with the intravenous (IV) concentrate. Sandimmune Injection (cyclosporine injection, USP) is administered at 1/3 the oral dose. The initial dose of Sandimmune Injection (cyclosporine injection, USP) should be given 4 to 12 hours prior to transplantation as a single intravenous dose of 5 to 6 mg/kg/day. This daily single dose is continued postoperatively until the patient can tolerate the soft gelatin capsules or oral solution. Patients should be switched to Sandimmune Soft Gelatin Capsules or Oral Solution as soon as possible after surgery. In pediatric usage, the same dose and dosing regimen may be used, although higher doses may be required.

Adjunct steroid therapy is to be used. (See aforementioned.)

Immediately before use, the intravenous concentrate should be diluted 1 mL Sandimmune Injection (cyclosporine injection, USP) in 20 mL to 100 mL 0.9% Sodium Chloride Injection or 5% Dextrose Injection and given in a slow intravenous infusion over approximately 2 to 6 hours.

Diluted infusion solutions should be discarded after 24 hours.

The Cremophor® EL (polyoxyethylated castor oil) contained in the concentrate for intravenous infusion can cause phthalate stripping from PVC.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

Blood Concentration Monitoring

Several study centers have found blood concentration monitoring of cyclosporine useful in patient management. While no fixed relationships have yet been established, in one series of 375 consecutive cadaveric renal transplant recipients, dosage was adjusted to achieve specific whole blood 24-hour trough concentrations of 100 to 200 ng/mL as determined by high-pressure liquid chromatography (HPLC).

Of major importance to blood concentration analysis is the type of assay used. The above concentrations are specific to the parent cyclosporine molecule and correlate directly to the new monoclonal specific radioimmunoassays (mRIA-sp). Nonspecific assays are also available which detect the parent compound molecule and various of its metabolites. Older studies often cited concentrations using a nonspecific assay which were roughly twice those of specific assays. Assay results are not interchangeable and their use should be guided by their approved labeling. If plasma specimens are employed, concentrations will vary with the temperature at the time of separation from whole blood. Plasma concentrations may range from ½ to 1/5 of whole blood concentrations. Refer to individual assay labeling for complete instructions. In addition, Transplantation Proceedings (June 1990) contains position papers and a broad consensus generated at the Cyclosporine-Therapeutic Drug Monitoring conference that year. Blood concentration monitoring is not a replacement for renal function monitoring or tissue biopsies.

HOW SUPPLIED

Sandimmune® Soft Gelatin Capsules (cyclosporine capsules, USP)

25 mg: Oblong, pink, branded 78/240. Unit dose packages of 30 capsules, 3 blister cards of 10 capsules .................................... NDC 0078-0240-15

100 mg: Oblong, dusty rose, branded 78/241. Unit dose packages of 30 capsules, 3 blister cards of 10 capsules ................... NDC 0078-0241-15

Store and Dispense

Store at 25°C (77°F); excursions permitted to 15C to 30°C (59 to 86°F) [see USP Controlled Room Temperature].

An odor may be detected upon opening the unit dose container, which will dissipate shortly thereafter. This odor does not affect the quality of the product.

Sandimmune® Oral Solution (cyclosporine oral solution, USP)

Supplied in 50 mL bottles containing 100 mg of cyclosporine per mL .................... NDC 0078-0110-22

A dosage syringe is provided for dispensing.

Store and Dispense

In the original container at temperatures below 30°C (86°F). Do not store in the refrigerator. Protect from freezing. Once opened, the contents must be used within 2 months.

Sandimmune® Injection (cyclosporine injection, USP)

FOR INTRAVENOUS INFUSION

Supplied as a 5 mL sterile ampul containing 50 mg of cyclosporine per mL, in boxes of 10 ampuls .................................. NDC 0078-0109-01

Store and Dispense

At temperatures below 30°C (86°F). Protect from light.

FOR INFUSION ONLY

Distributed by: Novartis Pharmaceuticals Corporation East Hanover, New Jersey 07936.

Side Effects & Drug Interactions

SIDE EFFECTS

The principal adverse reactions of Sandimmune (cyclosporine) therapy are renal dysfunction, tremor, hirsutism, hypertension, and gum hyperplasia.

Hypertension

Hypertension, which is usually mild to moderate, may occur in approximately 50% of patients following renal transplantation and in most cardiac transplant patients.

Glomerular Capillary Thrombosis

Glomerular capillary thrombosis has been found in patients treated with cyclosporine and may progress to graft failure. The pathologic changes resemble those seen in the hemolytic-uremic syndrome and include thrombosis of the renal microvasculature, with platelet-fibrin thrombi occluding glomerular capillaries and afferent arterioles, microangiopathic hemolytic anemia, thrombocytopenia, and decreased renal function. Similar findings have been observed when other immunosuppressives have been employed post transplantation.

Hypomagnesemia

Hypomagnesemia has been reported in some, but not all, patients exhibiting convulsions while on cyclosporine therapy. Although magnesium-depletion studies in normal subjects suggest that hypomagnesemia is associated with neurologic disorders, multiple factors, including hypertension, high-dose methylprednisolone, hypocholesterolemia, and nephrotoxicity associated with high plasma concentrations of cyclosporine appear to be related to the neurological manifestations of cyclosporine toxicity.

Clinical Studies

The following reactions occurred in 3% or greater of 892 patients involved in clinical trials of kidney, heart, and liver transplants:

The following reactions occurred in 2% or less of patients: allergic reactions, anemia, anorexia, confusion, conjunctivitis, edema, fever, brittle fingernails, gastritis, hearing loss, hiccups, hyperglycemia, muscle pain, peptic ulcer, thrombocytopenia, tinnitus.

The following reactions occurred rarely: anxiety, chest pain, constipation, depression, hair breaking,hematuria, joint pain, lethargy, mouth sores, myocardial infarction, night sweats, pancreatitis, pruritus, swallowing difficulty, tingling, upper GI bleeding, visual disturbance, weakness, weight loss.

Renal Transplant Patients in Whom Therapy Was Discontinued

Sandimmune (cyclosporine) was discontinued on a temporary basis and then restarted in 18 additional patients.

Patients receiving immunosuppressive therapies, including cyclosporine and cyclosporine -containing regimens, are at increased risk of infections (viral, bacterial, fungal, parasitic). Both generalized and localized infections can occur. Pre-existing infections may also be aggravated. Fatal outcomes have been reported. (See WARNINGS)

Infectious Complications in the Randomized Renal Transplant Patients

Cremophor® EL (polyoxyethylated castor oil) is known to cause hyperlipemia and electrophoreticabnormalities of lipoproteins. These effects are reversible upon discontinuation of treatment but are usually not a reason to stop treatment.

Postmarketing Experience

Hepatotoxicity

Cases of hepatotoxicity and liver injury including cholestasis, jaundice, hepatitis and liver failure; serious and/or fatal outcomes have been reported. (See WARNINGS, Hepatotoxicity)

Increased Risk of Infections

Cases of JC virus-associated progressive multifocal leukoencephalopathy (PML), sometimes fatal; and polyoma virus-associated nephropathy (PVAN), especially BK virus resulting in graft loss have been reported. (See WARNINGS, Polyoma Virus Infection)

Headache, including Migraine

Cases of migraine have been reported. In some cases, patients have been unable to continue cyclosporine, however, the final decision on treatment discontinuation should be made by the treating physician following the careful assessment of benefits versus risks.

Pain of Lower Extremities

Isolated cases of pain of lower extremities have been reported in association with cyclosporine. Pain of lower extremities has also been noted as part of Calcineurin-Inhibitor Induced Pain Syndrome (CIPS) as described in the literature.

DRUG INTERACTIONS

Effect Of Drugs And Other Agents On Cyclosporine Pharmacokinetics And/Or Safety

All of the individual drugs cited below are well substantiated to interact with cyclosporine. In addition, concomitant use of nonsteroidal anti-inflammatory drugs (NSAIDs) with cyclosporine, particularly in the setting of dehydration, may potentiate renal dysfunction. Caution should be exercised when using other drugs which are known to impair renal function. (See WARNINGS, Nephrotoxicity)

Drugs That May Potentiate Renal Dysfunction

During the concomitant use of a drug that may exhibit additive or synergistic renal impairment potential with cyclosporine, close monitoring of renal function (in particular serum creatinine) should be performed. If a significant impairment of renal function occurs, reduction in the dosage of cyclosporine and/or coadministered drug or an alternative treatment should be considered.

Cyclosporine is extensively metabolized by CYP 3A isoenzymes, in particular CYP3A4, and is a substrate of the multidrug efflux transporter P-glycoprotein. Various agents are known to either increase or decrease plasma or whole blood concentrations of cyclosporine usually by inhibition or induction of CYP3A4 or P-glycoprotein transporter or both. Compounds that decrease cyclosporine absorption such as orlistat should be avoided. Appropriate Sandimmune (cyclosporine) dosage adjustment to achieve the desired cyclosporine concentrations is essential when drugs that significantly alter cyclosporine concentrations are used concomitantly. (See Blood Concentration Monitoring)

Drugs That Increase Cyclosporine Concentrations

HIV Protease inhibitors

The HIV protease inhibitors (e.g., indinavir, nelfinavir, ritonavir, and saquinavir) are known to inhibit cytochrome P-450 3A and thus could potentially increase the concentrations of cyclosporine, however no formal studies of the interaction are available. Care should be exercised when these drugs are administered concomitantly.

Grapefruit juice

Grapefruit and grapefruit juice affect metabolism, increasing blood concentrations of cyclosporine, thus should be avoided.

Drugs/Dietary Supplements That Decrease Cyclosporine Concentrations

Bosentan

Co-administration of bosentan (250 to 1000 mg every 12 hours based on tolerability) and cyclosporine (300 mg every 12 hours for 2 days then dosing to achieve a Cmin of 200 to 250 ng/mL) for 7 days in healthy subjects resulted in decreases in the cyclosporine mean dose-normalized AUC, Cmax, and trough concentration of approximately 50%, 30% and 60%, respectively, compared to when cyclosporine was given alone. (See also Effect of Cyclosporine on the Pharmacokinetics and/or Safety of Other Drugs or Agents) Coadministration of cyclosporine with bosentan should be avoided.

Boceprevir

Coadministration of boceprevir (800 mg three times daily for 7 days) and cyclosporine (100 mg single dose) in healthy subjects resulted in increases in the mean AUC and Cmax of cyclosporine approximately 2.7-fold and 2-fold, respectively, compared to when cyclosporine was given alone.

Telaprevir

Coadministration of telaprevir (750 mg every 8 hours for 11 days) with cyclosporine (10 mg on day 8) in healthy subjects resulted in increases in the mean dose-normalized AUC and Cmax of cyclosporine approximately 4.5-fold and 1.3-fold, respectively, compared to when cyclosporine (100 mg single dose) was given alone.

St. John's Wort

There have been reports of a serious drug interaction between cyclosporine and the herbal dietary supplement, St. John's Wort. This interaction has been reported to produce a marked reduction in the blood concentrations of cyclosporine, resulting in subtherapeutic levels, rejection of transplanted organs, and graft loss.

Rifabutin

Rifabutin is known to increase the metabolism of other drugs metabolized by the cytochrome P-450 system. The interaction between rifabutin and cyclosporine has not been studied. Care should be exercised when these two drugs are administered concomitantly.

Effect Of Cyclosporine On The Pharmacokinetics And/Or Safety Of Other Drugs Or Agents

Cyclosporine is an inhibitor of CYP3A4 and of multiple drug efflux transporters (e.g., P-glycoprotein) and may increase plasma concentrations of comedications that are substrates of CYP3A4, Pglycoprotein, or organic anion transporter proteins.

Cyclosporine may reduce the clearance of digoxin, colchicine, prednisolone, HMG-CoA reductase inhibitors (statins) and aliskiren, bosentan, dabigatran, repaglinide, NSAIDs, sirolimus, etoposide, and other drugs.

See the full prescribing information of the other drug for further information and specific recommendations. The decision on coadministration of cyclosporine with other drugs or agents should be made by the healthcare provider following the careful assessment of benefits and risks.

Digoxin

Severe digitalis toxicity has been seen within days of starting cyclosporine in several patients taking digoxin. If digoxin is used concurrently with cyclosporine, serum digoxin concentrations should be monitored.

Colchicine

There are reports on the potential of cyclosporine to enhance the toxic effects of colchicine such as myopathyand neuropathy, especially in patients with renal dysfunction. Concomitant administration of cyclosporine and colchicine results in significant increases in colchicine plasma concentrations. If colchicine is used concurrently with cyclosporine, a reduction in the dosage of colchicine is recommended.

HMG Co-A Reductase Inhibitors (statins)

Literature and postmarketing cases of myotoxicity, including muscle pain and weakness, myositis, and rhabdomyolysis, have been reported with concomitant administration of cyclosporine with lovastatin, simvastatin, atorvastatin, pravastatin, and rarely, fluvastatin. When concurrently administered with cyclosporine, the dosage of these statins should be reduced according to label recommendations. Statin therapy needs to be temporarily withheld or discontinued in patients with signs and symptoms of myopathy or those with risk factors predisposing to severe renal injury, including renal failure, secondary to rhabdomyolysis.

Repaglinide

Cyclosporine may increase the plasma concentrations of repaglinide and thereby increase the risk of hypoglycemia. In 12 healthy male subjects who received two doses of 100 mg cyclosporine capsule orally 12 hours apart with a single dose of 0.25 mg repaglinide tablet (one half of a 0.5 mg tablet) orally 13 hours after the cyclosporine initial dose, the repaglinide mean Cmax and AUC were increased 1.8 fold (range: 0.6 to 3.7 fold) and 2.4 fold (range 1.2 to 5.3 fold), respectively. Close monitoring of blood glucose level is advisable for a patient taking cyclosporine and repaglinide concomitantly.

Ambrisentan

Coadministration of ambrisentan (5 mg daily) and cyclosporine (100 to 150 mg twice daily initially, then dosing to achieve Cmin 150 to 200 ng/mL) for 8 days in healthy subjects resulted mean increases in ambrisentan AUC and Cmax of approximately 2-fold and 1.5-fold, respectively, compared to ambrisentan alone. When coadministering ambrisentan with cyclosporine, the ambrisentan dose should not be titrated to the recommended maximum daily dose.

Anthracycline Antibiotics

High doses of cyclosporine (e.g., at starting intravenous dose of 16 mg/kg/day) may increase the exposure to anthracycline antibiotics (e.g., doxorubicin, mitoxantrone, daunorubicin) in cancer patients.

Aliskiren

Cyclosporine alters the pharmacokinetics of aliskiren, a substrate of P-glycoprotein and CYP3A4. In 14 healthy subjects who received concomitantly single doses of cyclosporine (200 mg) and reduced dose aliskiren (75 mg), the mean Cmax of aliskiren was increased by approximately 2.5-fold (90% CI: 1.96 to 3.17) and the mean AUC by approximately 4.3 fold (90% CI: 3.52 to 5.21), compared to when these subjects received aliskiren alone. The concomitant administration of aliskiren with cyclosporine prolonged the median aliskiren elimination half-life (26 hours versus 43 to 45 hours) and the Tmax (0.5 hours versus 1.5 to 2.0 hours). The mean AUC and Cmax of cyclosporine were comparable to reported literature values. Coadministration of cyclosporine and aliskiren in these subjects also resulted in an increase in the number and/or intensity of adverse events, mainly headache, hot flush, nausea, vomiting, and somnolence. The coadministration of cyclosporine with aliskiren is not recommended.

Bosentan

In healthy subjects, coadministration of bosentan and cyclosporine resulted in time-dependent mean increases in dose-normalized bosentan trough concentrations (i.e., approximately 21-fold on day 1 and 2-fold on day 8 (steady state)) compared to when bosentan was given alone as a single dose on day 1. (See also Effect of Drugs and Other Agents on Cyclosporine Pharmacokinetics and/or Safety) Coadministration of cyclosporine with bosentan should be avoided.

Dabigatran

The effect of cyclosporine on dabigatran concentrations had not been formally studied. Concomitant administration of dabigatran and cyclosporine may result in increased plasma dabigatran concentrations due to the P-gp inhibitory activity of cyclosporine. Coadministration of cyclosporine with dabigatran should be avoided.

Potassium Sparing Diuretics

Cyclosporine should not be used with potassium-sparing diuretics because hyperkalemia can occur. Caution is also required when cyclosporine is coadministered with potassium-sparing drugs (e.g., angiotensin-converting enzyme inhibitors, angiotensin II receptor antagonists), potassium-containing drugs as well as in patients on a potassium-rich diet. Control of potassium levels in these situations is advisable.

Nonsteroidal Anti-inflammatory Drug (NSAID) Interactions

Clinical status and serum creatinine should be closely monitored when cyclosporine is used with NSAIDs in rheumatoid arthritis patients. (See WARNINGS)

Pharmacodynamic interactions have been reported to occur between cyclosporine and both naproxen and sulindac, in that concomitant use is associated with additive decreases in renal function, as determined by 99mTc-diethylenetriaminepentaacetic acid (DTPA) and (p-aminohippuric acid) PAH clearances. Although concomitant administration of diclofenac does not affect blood concentrations of cyclosporine, it has been associated with approximate doubling of diclofenac blood levels and occasional reports of reversible decreases in renal function. Consequently, the dose of diclofenac should be in the lower end of the therapeutic range.

Methotrexate Interaction

Preliminary data indicate that when methotrexate and cyclosporine were coadministered to rheumatoid arthritis patients (N=20), methotrexate concentrations (AUCs) were increased approximately 30% and the concentrations (AUCs) of its metabolite, 7-hydroxy methotrexate, were decreased by approximately 80%. The clinical significance of this interaction is not known. Cyclosporine concentrations do not appear to have been altered (N=6).

Sirolimus

Elevations in serum creatinine were observed in studies using sirolimus in combination with full-dose cyclosporine. This effect is often reversible with cyclosporine dose reduction. Simultaneous coadministration of cyclosporine significantly increases blood levels of sirolimus. To minimize increases in sirolimus blood concentrations, it is recommended that sirolimus be given 4 hours after cyclosporine administration.

Nifedipine

Frequent gingival hyperplasia when nifedipine is given concurrently with cyclosporine has been reported. The concomitant use of nifedipine should be avoided in patients in whom gingival hyperplasia develops as a side effect of cyclosporine.

Methylprednisolone

Convulsions when high dose methylprednisolone is given concomitantly with cyclosporine have been reported.

Other Immunosuppressive Drugs and Agents

Psoriasis patients receiving other immunosuppressive agents or radiation therapy (including PUVA and UVB) should not receive concurrent cyclosporine because of the possibility of excessive immunosuppression.

Effect Of Cyclosporine On The Efficacy Of Live Vaccines

During treatment with cyclosporine, vaccination may be less effective. The use of live vaccines should be avoided.

For additional information on Cyclosporine Drug Interactions please contact Novartis Medical Affairs Department at 1-888-NOW-NOVA (1-888-669-6682).

Warnings & Precautions

WARNINGS

Kidney, Liver, And Heart Transplant

(See BOXED WARNING): Sandimmune (cyclosporine), when used in high doses, can cause hepatotoxicity and nephrotoxicity.

Nephrotoxicity

It is not unusual for serum creatinine and BUN levels to be elevated during Sandimmune (cyclosporine) therapy. These elevations in renal transplant patients do not necessarily indicate rejection, and each patient must be fully evaluated before dosage adjustment is initiated.

Nephrotoxicity has been noted in 25% of cases of renal transplantation, 38% of cases of cardiac transplantation, and 37% of cases of liver transplantation. Mild nephrotoxicity was generally noted 2 to 3 months after transplant and consisted of an arrest in the fall of the preoperative elevations of BUN and creatinine at a range of 35 to 45 mg/dl and 2.0 to 2.5 mg/dl, respectively. These elevations were often responsive to dosage reduction.

More overt nephrotoxicity was seen early after transplantation and was characterized by a rapidly rising BUN and creatinine. Since these events are similar to rejection episodes, care must be taken to differentiate between them. This form of nephrotoxicity is usually responsive to Sandimmune (cyclosporine) dosage reduction.

Although specific diagnostic criteria which reliably differentiate renal graft rejection from drug toxicity have not been found, a number of parameters have been significantly associated to one or the other. It should be noted however, that up to 20% of patients may have simultaneous nephrotoxicity and rejection.

A form of chronic progressive cyclosporine-associated nephrotoxicity is characterized by serial deterioration in renal function and morphologic changes in the kidneys. From 5% to 15% of transplant recipients will fail to show a reduction in a rising serum creatinine despite a decrease or discontinuation of cyclosporine therapy. Renal biopsies from these patients will demonstrate an interstitial fibrosis with tubular atrophy. In addition, toxic tubulopathy, peritubular capillary congestion, arteriolopathy, and a striped form of interstitial fibrosis with tubular atrophy may be present. Though none of these morphologic changes is entirely specific, a histologic diagnosis of chronic progressive cyclosporine-associated nephrotoxicity requires evidence of these.

When considering the development of chronic nephrotoxicity it is noteworthy that several authors have reported an association between the appearance of interstitial fibrosis and higher cumulative doses or persistently high circulating trough concentrations of cyclosporine. This is particularly true during the first 6 posttransplant months when the dosage tends to be highest and when, in kidney recipients, the organ appears to be most vulnerable to the toxic effects of cyclosporine. Among other contributing factors to the development of interstitial fibrosis in these patients must be included, prolonged perfusion time, warm ischemia time, as well as episodes of acute toxicity, and acute and chronic rejection. The reversibility of interstitial fibrosis and its correlation to renal function have not yet been determined.

Impaired renal function at any time requires close monitoring, and frequent dosage adjustment may be indicated. In patients with persistent high elevations of BUN and creatinine who are unresponsive to dosage adjustments, consideration should be given to switching to other immunosuppressive therapy. In the event of severe and unremitting rejection, it is preferable to allow the kidney transplant to be rejected and removed rather than increase the Sandimmune (cyclosporine) dosage to a very high level in an attempt to reverse the rejection.

Due to the potential for additive or synergistic impairment of renal function, caution should be exercised when coadministering Sandimmune with other drugs that may impair renal function. (See PRECAUTIONS: DRUG INTERACTIONS)

Thrombotic Microangiopathy

Occasionally patients have developed a syndrome of thrombocytopenia and microangiopathic hemolytic anemia which may result in graft failure. The vasculopathy can occur in the absence of rejection and is accompanied by avid platelet consumption within the graft as demonstrated by Indium 111 labeled platelet studies. Neither the pathogenesis nor the management of this syndrome is clear. Though resolution has occurred after reduction or discontinuation of Sandimmune (cyclosporine) and 1) administration of streptokinase and heparin or 2) plasmapheresis, this appears to depend upon early detection with Indium 111 labeled platelet scans. (See ADVERSE REACTIONS)

Hyperkalemia

Significant hyperkalemia (sometimes associated with hyperchloremic metabolic acidosis) and hyperuricemiahave been seen occasionally in individual patients.

Hepatotoxicity

Cases of hepatotoxicity and liver injury including cholestasis, jaundice, hepatitis, and liver failure have been reported in patients treated with cyclosporine. Most reports included patients with significant comorbidities, underlying conditions and other confounding factors including infectious complications and comedications with hepatotoxic potential. In some cases, mainly in transplant patients, fatal outcomes have been reported (See ADVERSE REACTIONS, Postmarketing Experience)

Hepatotoxicity, usually manifested by elevations in hepatic enzymes and bilirubin, was reported in patients treated with cyclosporine in clinical trials: 4% in renal transplantation, 7% in cardiac transplantation, and 4% in liver transplantation. This was usually noted during the first month of therapy when high doses of Sandimmune (cyclosporine) were used. The chemistry elevations usually decreased with a reduction in dosage.

Malignancies

As in patients receiving other immunosuppressants, those patients receiving Sandimmune (cyclosporine) are at increased risk for development of lymphomas and other malignancies, particularly those of the skin. The increased risk appears related to the intensity and duration of immunosuppression rather than to the use of specific agents. Because of the danger of oversuppression of the immune system, which can also increase susceptibility to infection, Sandimmune (cyclosporine) should not be administered with other immunosuppressive agents except adrenal corticosteroids. The efficacy and safety of cyclosporine in combination with other immunosuppressive agents have not been determined. Some malignancies may be fatal. Transplant patients receiving cyclosporine are at increased risk for serious infection with fatal outcome.

Serious Infections

Patients receiving immunosuppressants, including Sandimmune, are at increased risk of developing bacterial, viral, fungal, and protozoal infections, including opportunistic infections. These infections may lead to serious, including fatal, outcomes (See BOXED WARNING, and ADVERSE REACTIONS).

Polyoma Virus Infections

Patients receiving immunosuppressants, including Sandimmune, are at increased risk for opportunistic infections, including polyoma virus infections. Polyoma virus infections in transplant patients may have serious, and sometimes, fatal outcomes. These include cases of JC virus-associated progressive multifocal leukoencephalopathy (PML), and polyoma virus-associated nephropathy (PVAN), especially due to BK virus infection, which have been observed in patients receiving cyclosporine.

PVAN is associated with serious outcomes, including deteriorating renal function and renal graft loss, (SeeADVERSE REACTIONS/Postmarketing Experience). Patient monitoring may help detect patients at risk for PVAN.

Cases of PML have been reported in patients treated with cyclosporine_ PML, which is sometimes fatal, commonly presents with hemiparesis, apathy, confusion, cognitive deficiencies and ataxia. Risk factors for PML include treatment with immunosuppressant therapies and impairment of immune function. In immunosuppressed patients, physicians should consider PML in the differential diagnosis in patients reporting neurological symptoms and consultation with a neurologist should be considered as clinically indicated.

Consideration should be given to reducing the total immunosuppression in transplant patients who develop PML or PVAN. However, reduced immunosuppression may place the graft at risk.

Neurotoxicity

There have been reports of convulsions in adult and pediatric patients receiving cyclosporine, particularly in combination with high-dose methylprednisolone.

Encephalopathy, including Posterior Reversible Encephalopathy Syndrome (PRES), has been described both in postmarketing reports and in the literature. Manifestations include impaired consciousness, convulsions, visual disturbances (including blindness), loss of motor function, movement disorders and psychiatric disturbances. In many cases, changes in the white matter have been detected using imaging techniques and pathologic specimens. Predisposing factors such as hypertension, hypomagnesemia, hypocholesterolemia, high-dose corticosteroids, high cyclosporine blood concentrations, and graft-versus-host disease have been noted in many but not all of the reported cases. The changes in most cases have been reversible upon discontinuation of cyclosporine, and in some cases, improvement was noted after reduction of dose. It appears that patients receiving liver transplant are more susceptible to encephalopathy than those receiving kidney transplant. Another rare manifestation of cyclosporine-induced neurotoxicity is optic disc edema including papilloedema, with possible visual impairment, secondary to benign intracranial hypertension.

Specific Excipients

Anaphylactic Reactions

Rarely (approximately 1 in 1000), patients receiving Sandimmune Injection (cyclosporine injection, USP) have experienced anaphylactic reactions. Although the exact cause of these reactions is unknown, it is believed to be due to the Cremophor EL (polyoxyethylated castor oil) used as the vehicle for the intravenous (IV) formulation. These reactions can consist of flushing of the face and upper thorax, and noncardiogenic pulmonary edema, with acute respiratory distress, dyspnea, wheezing, blood pressure changes, and tachycardia. One patient died after respiratory arrest and aspiration pneumonia. In some cases, the reaction subsided after the infusion was stopped.

Patients receiving Sandimmune Injection (cyclosporine injection, USP) should be under continuous observation for at least the first 30 minutes following the start of the infusion and at frequent intervals thereafter. If anaphylaxis occurs, the infusion should be stopped. An aqueous solution of epinephrine 1:1000 should be available at the bedside as well as a source of oxygen.

Anaphylactic reactions have not been reported with the soft gelatin capsules or oral solution which lack Cremophor EL (polyoxyethylated castor oil). In fact, patients experiencing anaphylactic reactions have been treated subsequently with the soft gelatin capsules or oral solution without incident.

Alcohol (ethanol)

The alcohol content (See DESCRIPTION) of Sandimmune should be taken into account when given to patients in whom alcohol intake should be avoided or minimized, e.g. pregnant or breastfeeding women, in patients presenting with liver disease or epilepsy, in alcoholic patients, or pediatric patients. For an adult weighing 70 kg, the maximum daily oral dose would deliver about 1 gram of alcohol which is approximately 6% of the amount of alcohol contained in a standard drink. The daily intravenous dose would deliver approximately 15% of the amount of alcohol contained in a standard drink.

Care should be taken in using Sandimmune (cyclosporine) with nephrotoxic drugs. (See PRECAUTIONS)

Conversion from Neoral to Sandimmune

Because Sandimmune (cyclosporine) is not bioequivalent to Neoral, conversion from Neoral to Sandimmune (cyclosporine) using a 1:1 ratio (mg/kg/day) may result in a lower cyclosporine blood concentration. Conversion from Neoral to Sandimmune (cyclosporine) should be made with increased blood concentration monitoring to avoid the potential of underdosing.

PRECAUTIONS

General

Patients with malabsorption may have difficulty in achieving therapeutic concentrations with Sandimmune Soft Gelatin Capsules or Oral Solution.

Hypertension

Hypertension is a common side effect of Sandimmune (cyclosporine) therapy. (See ADVERSE REACTIONS) Mild or moderate hypertension is more frequently encountered than severe hypertension and the incidence decreases over time. Antihypertensive therapy may be required. Control of blood pressure can be accomplished with any of the common antihypertensive agents. However, since cyclosporine may cause hyperkalemia, potassium-sparing diuretics should not be used. While calcium antagonists can be effective agents in treating cyclosporine-associated hypertension, care should be taken since interference with cyclosporine metabolism may require a dosage adjustment. (See DRUG INTERACTIONS)

Vaccination

During treatment with Sandimmune (cyclosporine), vaccination may be less effective and the use of live attenuated vaccines should be avoided.

Laboratory Tests

Renal and liver functions should be assessed repeatedly by measurement of BUN, serum creatinine, serum bilirubin, and liver enzymes.

Carcinogenesis, Mutagenesis, And Impairment Of Fertility

Cyclosporine gave no evidence of mutagenic or teratogenic effects in appropriate test systems. Only at dose levels toxic to dams, were adverse effects seen in reproduction studies in rats. (See Pregnancy)

Carcinogenicity studies were carried out in male and female rats and mice. In the 78-week mouse study, at doses of 1, 4, and 16 mg/kg/day, evidence of a statistically significant trend was found for lymphocyticlymphomas in females, and the incidence of hepatocellular carcinomas in mid-dose males significantly exceeded the control value. In the 24–month rat study, conducted at 0.5, 2, and 8 mg/kg/day, pancreatic islet cell adenomas significantly exceeded the control rate in the low-dose level. The hepatocellular carcinomas and pancreatic islet cell adenomas were not dose related.

No impairment in fertility was demonstrated in studies in male and female rats.

Cyclosporine has not been found mutagenic/genotoxic in the Ames Test, the V79-HGPRT Test, the micronucleus test in mice and Chinese hamsters, the chromosome-aberration tests in Chinese hamster bone marrow, the mouse dominant lethal assay, and the DNA-repair test in sperm from treated mice. A recent study analyzing sister chromatid exchange (SCE) induction by cyclosporine using human lymphocytes in vitro gave indication of a positive effect (i.e., induction of SCE), at high concentrations in this system. In two published research studies, rabbits exposed to cyclosporine in utero (10 mg/kg/day subcutaneously) demonstrated reduced numbers of nephrons, renal hypertrophy, systemic hypertension and progressive renal insufficiency up to 35 weeks of age. Pregnant rats which received 12 mg/kg/day of cyclosporine intravenously (twice the recommended human intravenous dose) had fetuses with an increased incidence of ventricular septal defect. These findings have not been demonstrated in other species and their relevance for humans is unknown.

An increased incidence of malignancy is a recognized complication of immunosuppression in recipients of organ transplants. The most common forms of neoplasms are non-Hodgkin's lymphoma and carcinomas of the skin. The risk of malignancies in cyclosporine recipients is higher than in the normal, healthy population, but similar to that in patients receiving other immunosuppressive therapies. It has been reported that reduction or discontinuance of immunosuppression may cause the lesions to regress.

Pregnancy

Pregnancy Category C

Animal studies have shown reproductive toxicity in rats and rabbits. Cyclosporine gave no evidence of mutagenic or teratogenic effects in the standard test systems with oral application (rats up to 17 mg/kg and rabbits up to 30 mg/kg per day orally). Sandimmune Oral Solution (cyclosporine oral solution, USP) has been shown to be embryo-and fetotoxic in rats and rabbits when given in doses 2-5 times the human dose. At toxic doses (rats at 30 mg/kg/day and rabbits at 100 mg/kg/day), Sandimmune Oral Solution (cyclosporine oral solution, USP) was embryo-and fetotoxic as indicated by increased pre-and postnatal mortality and reduced fetal weight together with related skeletal retardations. In the well-tolerated dose range (rats at up to 17 mg/kg/day and rabbits at up to 30 mg/kg/day), Sandimmune Oral Solution (cyclosporine oral solution, USP) proved to be without any embryolethal or teratogenic effects.

There are no adequate and well-controlled studies in pregnant women and therefore, Sandimmune (cyclosporine) should not be used during pregnancy unless the potential benefit to the mother justifies the potential risk to the fetus.

In pregnant transplant recipients who are being treated with immunosuppressants, the risk of premature birthis increased. The following data represent the reported outcomes of 116 pregnancies in women receiving Sandimmune (cyclosporine) during pregnancy, 90% of whom were transplant patients, and most of whom received Sandimmune (cyclosporine) throughout the entire gestational period. Since most of the patients were not prospectively identified, the results are likely to be biased toward negative outcomes. The only consistent patterns of abnormality were premature birth (gestational period of 28 to 36 weeks) and low birth weight for gestational age. It is not possible to separate the effects of Sandimmune (cyclosporine) on these pregnancies from the effects of the other immunosuppressants, the underlying maternal disorders, or other aspects of the transplantation milieu. Sixteen fetal losses occurred. Most of the pregnancies (85 of 100) were complicated by disorders; including, preeclampsia, eclampsia, premature labor, abruptio placentae, oligohydramnios, Rh incompatibility and fetoplacental dysfunction. Preterm delivery occurred in 47%. Seven malformations were reported in 5 viable infants and in 2 cases of fetal loss. Twenty-eight percent of the infants were small for gestational age. Neonatal complications occurred in 27%. In a report of 23 children followed up to 4 years, postnatal development was said to be normal. More information on cyclosporine use in pregnancy is available from Novartis Pharmaceuticals Corporation.

A limited number of observations in children exposed to cyclosporine in utero are available, up to an age of approximately 7 years. Renal function and blood pressure in these children were normal.

The alcohol content of the Sandimmune formulations should also be taken into account in pregnant women. (See WARNINGS, Special Excipients)

Nursing Mothers

Cyclosporine is present in breast milk. Because of the potential for serious adverse drug reactions in nursing infants from Sandimmune, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Sandimmune contains ethanol. Ethanol will be present in human milk at levels similar to that found in maternal serum and if present in breast milk will be orally absorbed by a nursing infant. (See WARNINGS)

Pediatric Use

Although no adequate and well-controlled studies have been conducted in children, patients as young as 6 months of age have received the drug with no unusual adverse effects.

Geriatric Use

Clinical studies of Sandimmune (cyclosporine) did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

Overdosage & Contraindications

OVERDOSE

There is a minimal experience with overdosage. Because of the slow absorption of Sandimmune Soft Gelatin Capsules or Oral Solution, forced emesis and gastric lavage would be of value up to 2 hours after administration. Transient hepatotoxicity and nephrotoxicity may occur which should resolve following drug withdrawal. Oral doses of cyclosporine up to 10 g (about 150 mg/kg) have been tolerated with relatively minor clinical consequences, such as vomiting, drowsiness, headache, tachycardia and, in a few patients, moderately severe, reversible impairment of renal function. However, serious symptoms of intoxication have been reported following accidental parenteral overdosage with cyclosporine in premature neonates. General supportive measures and symptomatic treatment should be followed in all cases of overdosage. Sandimmune (cyclosporine) is not dialyzable to any great extent, nor is it cleared well by charcoal hemoperfusion. The oral LD50 is 2329 mg/kg in mice, 1480 mg/kg in rats, and > 1000 mg/kg in rabbits. The intravenous (IV) LD50 is 148 mg/kg in mice, 104 mg/kg in rats, and 46 mg/kg in rabbits.

CONTRAINDICATIONS

Sandimmune Injection (cyclosporine injection, USP) is contraindicated in patients with a hypersensitivity to Sandimmune (cyclosporine) and/or Cremophor® EL (polyoxyethylated castor oil).

Clinical Pharmacology

CLINICAL PHARMACOLOGY

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. 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 adjuvantarthritis, 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 cyclosporine.

The exact mechanism of action of 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. 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. 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 to 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% to 47% is in plasma, 4% to 9% in lymphocytes, 5% to 12% in granulocytes, and 41% to 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 to 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 leucineresidues, 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.

Medication Guide

PATIENT INFORMATION

Patients should be advised that any change of cyclosporine formulation should be made cautiously and only under physician supervision because it may result in the need for a change in dosage.

Patients should be informed of the necessity of repeated laboratory tests while they are receiving the drug. They should be given careful dosage instructions, advised of the potential risks during pregnancy, and informed of the increased risk of neoplasia.

Patients using cyclosporine oral solution with its accompanying syringe for dosage measurement should be cautioned not to rinse the syringe either before or after use. Introduction of water into the product by any means will cause variation in dose.