部份中文新山地明处方资料（仅供参考）
新山地明输液50毫克/毫升
Sandimmun Infusion 50mg/ml
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
SANDIMMUN Concentrate for Solution for Infusion 50mg/ml
1. Name of the medicinal product
SANDIMMUN® Concentrate for Solution for Infusion 50mg/ml.
2. Qualitative and quantitative composition
The concentrate for solution for infusion contains 50 mg/ml. Each ampoule of 1 ml contains 50 mg of ciclosporin. Each ampoule of 5 ml contains 250 mg of ciclosporin.
Excipients with known effect:
Ethanol: 278 mg/ml. Sandimmun 50 mg/ml concentrate for solution for infusion contains around 34% v/v ethanol (27.8% m/v ethanol).
Macrogolglycerol ricinoleate/ Polyoxyl 35 castor oil: 650 mg/ml
For the full list of excipients, see section 6.1.
3. Pharmaceutical form
Concentrate for solution for infusion
Clear, brown-yellow oleaginous concentrate.
4. Clinical particulars
4.1 Therapeutic indications
Transplantation indications
Solid organ transplantation
Prevention of graft rejection following solid organ transplantation.
Treatment of transplant cellular rejection in patients previously receiving other immunosuppressive agents.
Bone marrow transplantation
Prevention of graft rejection following allogeneic bone marrow and stem cell transplantation.
Prevention or treatment of graft-versus-host disease (GVHD).
4.2 Posology and method of administration
Posology
The dose ranges given for oral administration are intended to serve as guidelines only.
Sandimmun should only be prescribed by, or in close collaboration with, a physician with experience of immunosuppressive therapy and/or organ transplantation.
Transplantation
Solid organ transplantation
The recommended dose of Sandimmun concentrate for solution for infusion is approximately one-third of the corresponding oral dose, and it is recommend that patients be switched to oral therapy as soon as possible.
For reference the initial oral dose of Sandimmun or Sandimmun Neoral is 10 to 15 mg/kg given in 2 divided doses which should be initiated within 12 hours before surgery. This dose should be maintained as the daily dose for 1 to 2 weeks post-operatively, being gradually reduced in accordance with blood levels according to local immunosuppressive protocols until a recommended maintenance dose of about 2 to 6 mg/kg given in 2 divided doses is reached.
When oral Sandimmun or Sandimmun Neoral is given with other immunosuppressants (e.g. with corticosteroids or as part of a triple or quadruple medicinal product therapy), lower doses (e.g. 3 to 6 mg/kg given in 2 divided doses for the initial treatment) may be used.
Bone marrow transplantation
The initial dose should be given on the day before transplantation. In most cases, Sandimmun concentrate for solution for infusion is preferred for this purpose. The recommended intravenous dose is 3 to 5 mg/kg/day. Infusion is continued at this dose level during the immediate post-transplant period of up to 2 weeks, before a change is made to oral maintenance therapy with Sandimmun or Sandimmun Neoral at daily oral doses of about 12.5 mg/kg given in 2 divided doses.
Maintenance treatment should be continued for at least 3 months (and preferably for 6 months) before the dose is gradually decreased to zero by 1 year after transplantation.
If oral Sandimmun or Sandimmun Neoral is used to initiate therapy, the recommended daily dose is 12.5 to 15 mg/kg given in 2 divided doses, starting on the day before transplantation.
Higher doses of oral Sandimmun or Sandimmun Neoral, or the use of Sandimmun intravenous therapy, may be necessary in the presence of gastrointestinal disturbances which might decrease absorption.
In some patients, GVHD occurs after discontinuation of ciclosporin treatment, but usually responds favourably to re-introduction of therapy. In such cases an initial oral loading dose of 10 to 12.5 mg/kg should be given, followed by daily oral administration of the maintenance dose previously found to be satisfactory. Low doses of Sandimmun should be used to treat mild, chronic GVHD.
Special populations
Patients with renal impairment
All indications
Ciclosporin undergoes minimal renal elimination and its pharmacokinetics are not extensively affected by renal impairment (see section 5.2). However, due to its nephrotoxic potential (see section 4.8), careful monitoring of renal function is recommended (see section 4.4).
Patients with hepatic impairment
Ciclosporin is extensively metabolised by the liver. An approximate 2- to 3-fold increase in ciclosporin exposure may be observed in patients with hepatic impairment. Dose reduction may be necessary in patients with severe liver impairment to maintain blood levels within the recommended target range (see sections 4.4 and 5.2) and it is recommended that ciclosporin blood levels are monitored until stable levels are reached.
Paediatric population
Clinical studies have included children from 1 year of age. In several studies, paediatric patients required and tolerated higher doses of ciclosporin per kg body weight than those used in adults.
Use of Sandimmun in children for non-transplantation indications other than nephrotic syndrome cannot be recommended (see section 4.4).
Elderly population (age 65 years and above)
Experience with Sandimmun in the elderly is limited.
In rheumatoid arthritis clinical trials with ciclosporin, patients aged 65 or older were more likely to develop systolic hypertension on therapy, and more likely to show serum creatinine rises ≥50% above the baseline after 3 to 4 months of therapy.
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 medication and increased susceptibility for infections.
Method of administration
Intravenous administration.
Types of containers suitable for the infusion solution are mentioned in section 6.2.
Because of the risk of anaphylaxis (see section 4.4) the use of Sandimmun concentrate for solution for infusion should be reserved for organ transplant patients who are unable to take the medicinal product orally (e.g. shortly after surgery), or in whom absorption of the oral forms might be impaired during episodes of gastrointestinal disorders. In such cases, it is recommended to switch to oral administration as soon as feasible. Another well-established use of the concentrate for solution for infusion is the initial treatment of patients undergoing bone marrow transplantation.
The concentrate for solution for infusion should be diluted 1:20 to 1:100 with normal saline or 5% glucose and given as a slow intravenous infusion over 2 to 6 hours.
Once an ampoule is opened, the contents should be used immediately. Diluted infusion solutions must be discarded after 24 hours.
Precautions to be taken before handling or administering the medicinal product
For instructions on dilution of the medicinal product before administration, see section 6.6.
4.3 Contraindications
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
Combination with products containing Hypericum perforatum (St John´s Wort) (see section 4.5).
Combination with medicines that are substrates for the multidrug efflux transporter P-glycoprotein or the organic anion transporter proteins (OATP) and for which elevated plasma concentrations are associated with serious and/or life-threatening events, e.g. bosentan, dabigatran etexilate and aliskiren (see section 4.5).
4.4 Special warnings and precautions for use
Medical supervision
Sandimmun should be prescribed only by physicians who are experienced in immunosuppressive therapy and can provide adequate follow-up, including regular full physical examination, measurement of blood pressure and control of laboratory safety parameters. Transplantation patients receiving this medicinal product should be managed in facilities with adequate laboratory and supportive medical resources. The physician responsible for maintenance therapy should receive complete information for the follow-up of the patient.
Polyoxyl castor oil and anaphylactoid reactions
Sandimmun concentrate for solution for infusion contains polyoxyl castor oil, which has been reported to cause anaphylactoid reactions following intravenous administration. These reactions can consist of flushing of the face and upper thorax, and non-cardiogenic pulmonary oedema, with acute respiratory distress, dyspnoea, wheezing, blood pressure changes and tachycardia. Special caution is therefore necessary in patients who have previously received preparations containing polyoxyl castor oil (e.g. a preparation containing Cremophor® EL) by intravenous injection or infusion, and in patients with an allergic predisposition. Thus, patients receiving Sandimmun concentrate for solution for infusion should be under continuous observation for at least the first 30 minutes after the start of the infusion and at frequent intervals thereafter. If anaphylaxis occurs, the infusion should be discontinued. An aqueous solution of adrenaline 1:1000 and a source of oxygen should be available by the bedside. Prophylactic administration of an antihistamine (H1 + H2 blocker) prior to Sandimmun concentrate for solution for infusion has also been successfully employed to prevent the occurrence of anaphylactoid reactions.
Lymphomas and other malignancies
Like other immunosuppressants, ciclosporin increases the risk of developing lymphomas and other malignancies, particularly those of the skin. The increased risk appears to be related to the degree and duration of immunosuppression rather than to the use of specific agents.
A treatment regimen containing multiple immunosuppressants (including ciclosporin) should therefore be used with caution as this could lead to lymphoproliferative disorders and solid organ tumours, some with reported fatalities.
In view of the potential risk of skin malignancy, patients on Sandimmun, in particular those treated for psoriasis or atopic dermatitis, should be warned to avoid excess unprotected sun exposure and should not receive concomitant ultraviolet B irradiation or PUVA photochemotherapy.
Infections
Like other immunosuppressants, ciclosporin predisposes patients to the development of a variety of bacterial, fungal, parasitic and viral infections, often with opportunistic pathogens. Activation of latent polyomavirus infections that may lead to polyomavirus associated nephropathy (PVAN), especially to BK virus nephropathy (BKVN), or to JC virus associated progressive multifocal leukoencephalopathy (PML), have been observed in patients receiving ciclosporin. These conditions are often related to a high total immunosuppressive burden and should be considered in the differential diagnosis in immunosuppressed patients with deteriorating renal function or neurological symptoms. Serious and/or fatal outcomes have been reported. Effective pre-emptive and therapeutic strategies should be employed, particularly in patients on multiple long-term immunosuppressive therapy.
Renal toxicity
A frequent and potentially serious complication, an increase in serum creatinine and urea, may occur during Sandimmun therapy. These functional changes are dose-dependent and are initially reversible, usually responding to dose reduction. During long-term treatment, some patients may develop structural changes in the kidney (e.g. interstitial fibrosis) which, in renal transplant patients, must be differentiated from changes due to chronic rejection. Frequent monitoring of renal function is therefore required according to local guidelines for the indication in question (see sections 4.2 and 4.8).
Hepatotoxicity
Sandimmun may also cause dose-dependent, reversible increases in serum bilirubin and in liver enzymes (see section 4.8). There have been solicited and spontaneous reports of hepatotoxicity and liver injury including cholestasis, jaundice, hepatitis and liver failure in patients treated with ciclosporin. Most reports included patients with significant co-morbidities, underlying conditions and other confounding factors including infectious complications and co-medications with hepatotoxic potential. In some cases, mainly in transplant patients, fatal outcomes have been reported (see section 4.8). Close monitoring of parameters that assess hepatic function is required and abnormal values may necessitate dose reduction (see sections 4.2 and 5.2).
Elderly population (age 65 years and above)
In elderly patients, renal function should be monitored with particular care.
Monitoring ciclosporin levels (see section 4.2)
When Sandimmun is used in transplant patients, routine monitoring of ciclosporin blood levels is an important safety measure. For monitoring ciclosporin levels in whole blood, a specific monoclonal antibody (measurement of parent compound) is preferred; a high-performance liquid chromatography (HPLC) method, which also measures the parent compound, can be used as well. If plasma or serum is used, a standard separation protocol (time and temperature) should be followed. For the initial monitoring of liver transplant patients, either the specific monoclonal antibody should be used, or parallel measurements using both the specific monoclonal antibody and the non-specific monoclonal antibody should be performed, to ensure a dosage that provides adequate immunosuppression.
Hypertension
Regular monitoring of blood pressure is required during Sandimmun therapy. If hypertension develops, appropriate antihypertensive treatment must be instituted. Preference should be given to an antihypertensive agent that does not interfere with the pharmacokinetics of ciclosporin, e.g. isradipine (see section 4.5).
Blood lipids increased
Since Sandimmun has been reported to induce a reversible slight increase in blood lipids, it is advisable to perform lipid determinations before treatment and after the first month of therapy. In the event of increased lipids being found, restriction of dietary fat and, if appropriate, a dose reduction, should be considered.
Hyperkalaemia
Ciclosporin enhances the risk of hyperkalaemia, especially in patients with renal dysfunction. Caution is also required when ciclosporin is co-administered with potassium-sparing drugs (e.g. potassium-sparing diuretics, angiotensin converting enzyme (ACE) inhibitors, angiotensin II receptor antagonists) or potassium-containing medicinal products as well as in patients on a potassium rich diet. Control of potassium levels in these situations is advisable.
Hypomagnesaemia
Ciclosporin enhances the clearance of magnesium. This can lead to symptomatic hypomagnesaemia, especially in the peri-transplant period. Control of serum magnesium levels is therefore recommended in the peri-transplant period, particularly in the presence of neurological symptom/signs. If considered necessary, magnesium supplementation should be given.
Hyperuricaemia
Caution is required when treating patients with hyperuricaemia.
Live-attenuated vaccines
During treatment with ciclosporin, vaccination may be less effective. The use of live attenuated vaccines should be avoided (see section 4.5).
Interactions
Caution should be observed when co-administering ciclosporin with drugs that substantially increase or decrease ciclosporin plasma concentrations, through inhibition or induction of CYP3A4 and/or P-glycoprotein (see section 4.5).
Renal toxicity should be monitored when initiating ciclosporin use together with active substances that increase ciclosporin levels or with substances that exhibit nephrotoxic synergy (see section 4.5).
Concomitant use of ciclosporin and tacrolimus should be avoided (see section 4.5).
Ciclosporin is an inhibitor of CYP3A4, the multidrug efflux transporter P-glycoprotein and organic anion transporter proteins (OATP) and may increase plasma levels of co-medications that are substrates of this enzyme and/or transporter. Caution should be observed while co-administering ciclosporin with such drugs or concomitant use should be avoided (see section 4.5). Ciclosporin increases the exposure to HMG-CoA reductase inhibitors (statins). When concurrently administered with ciclosporin, the dosage of the statins should be reduced and concomitant use of certain statins should be avoided according to their 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 (see section 4.5).
Following concomitant administration of ciclosporin and lercanidipine, the AUC of lercanidipine was increased three-fold and the AUC of ciclosporin was increased 21%. Therefore the simultaneous combination of ciclosporin and lercanidipine should be avoided. Administration of ciclosporin 3 hours after lercanidipine yielded no change of the lercanidipine AUC, but the ciclosporin AUC was increased by 27%. This combination should therefore be given with caution with an interval of at least 3 hours.
Special excipients: Polyoxyl 35 castor oil
Sandimmun contains polyoxyl 35 castor oil, which may cause stomach upsets and diarrhoea.
Special excipients: Ethanol
Sandimmun contains around 34.4% vol. ethanol. A 100 mg dose of Sandimmun contains 556 mg ethanol, equivalent to nearly 15 ml beer or 5 ml wine. This may be harmful in alcoholic patients and should be taken into account in pregnant or breast-feeding women, in patients presenting with liver disease or epilepsy, or if the patients is a child.
Paediatric use in non-transplantation indications
Except for the treatment of nephrotic syndrome, there is no adequate experience available with Sandimmun. Its use in children under 16 years of age for non-transplantation indications other than nephrotic syndrome cannot be recommended.
4.5 Interaction with other medicinal products and other forms of interaction
Drug interactions
Of the many drugs reported to interact with ciclosporin, those for which the interactions are adequately substantiated and considered to have clinical implications are listed below.
Various agents are known to either increase or decrease plasma or whole blood ciclosporin levels usually by inhibition or induction of enzymes involved in the metabolism of ciclosporin, in particular CYP3A4.
Ciclosporin is also an inhibitor of CYP3A4, the multidrug efflux transporter P-glycoprotein and organic anion transporter proteins (OATP) and may increase plasma levels of co-medications that are substrates of this enzyme and/or transporters.
Medicinal products known to reduce or increase the bioavailability of ciclosporin: In transplant patients frequent measurement of ciclosporin levels and, if necessary, ciclosporin dosage adjustment is required, particularly during the introduction or withdrawal of the co-administered medication. In non-transplant patients the relationship between blood level and clinical effects is less well established. If medicinal products known to increase ciclosporin levels are given concomitantly, frequent assessment of renal function and careful monitoring for ciclosporin-related side effects may be more appropriate than blood level measurement.
Drugs that decrease ciclosporin levels
All inducers of CYP3A4 and/or P-glycoprotein are expected to decrease ciclosporin levels. Examples of drugs that decrease ciclosporin levels are:
Barbiturates, carbamazepine, oxcarbazepine, phenytoin; nafcillin, intravenous sulfadimidine, probucol, orlistat, hypericum perforatum (St. John's wort), ticlopidine, sulfinpyrazone, terbinafine, bosentan.
Products containing Hypericum perforatum (St John´s Wort) must not be used concomitantly with Sandimmun due to the risk of decreased blood levels of ciclosporin and thereby reduced effect (see section 4.3).
Rifampicin induces ciclosporin intestinal and liver metabolism. Ciclosporin doses may need to be increased 3- to 5-fold during co-administration.
Octreotide decreases oral absorption of ciclosporin and a 50% increase in the ciclosporin dose or a switch to intravenous administration could be necessary.
Drugs that increase ciclosporin levels
All inhibitors of CYP3A4 and/or P-glycoprotein may lead to increased levels of cyclosporine. Examples are:
Nicardipine, metoclopramide, oral contraceptives, methylprednisolone (high dose), allopurinol, cholic acid and derivatives, protease inhibitors, imatinib, colchicine, nefazodone.
Macrolide antibiotics: Erythromycin can increase ciclosporin exposure 4- to 7-fold, sometimes resulting in nephrotoxicity. Clarithromycin has been reported to double the exposure of ciclosporin. Azitromycin increases ciclosporin levels by around 20%.
Azole antibiotics: Ketoconazole, fluconazole, itraconazole and voriconazole could more than double ciclosporin exposure.
Verapamil increases ciclosporin blood concentrations 2- to 3-fold.
Co-administration with telaprevir resulted in approximately 4.64- fold increase in ciclosporin dose normalised exposure (AUC).
Amiodarone substantially increases the plasma ciclosporin concentration concurrently with an increase in serum creatinine. This interaction can occur for a long time after withdrawal of amiodarone, due to its very long half-life (about 50 days).
Danazol has been reported to increase ciclosporin blood concentrations by approximately 50%.
Diltiazem (at doses of 90 mg/day) can increase ciclosporin plasma concentrations by up to 50%.
Imatinib could increase ciclosporin exposure and Cmax by around 20%.
Food interactions
The concomitant intake of grapefruit and grapefruit juice has been reported to increase the bioavailability of ciclosporin.
Combinations with increased risk for nephrotoxicity
Care should be taken when using ciclosporin together with other active substances that exhibit nephrotoxic synergy such as: aminoglycosides (including gentamycin, tobramycin), amphotericin B, ciprofloxacin, vancomycin, trimethoprim (+ sulfamethoxazole); fibric acid derivatives (e.g. bezafibrate, fenofibrate); NSAIDs (including diclofenac, naproxen, sulindac); melphalan histamine H2-receptor antagonists (e.g. cimetidine, ranitidine); methotrexate (see section 4.4).
During the concomitant use of a drug that may exhibit nephrotoxic synergy, close monitoring of renal function should be performed. If a significant impairment of renal function occurs, the dosage of the co-administered medicinal product should be reduced or alternative treatment considered.
Concomitant use of ciclosporin and tacrolimus should be avoided due to the risk for nephrotoxicity and pharmacokinetic interaction via CYP3A4 and/or P-gp (see section 4.4).
Effects of ciclosporin on other drugs
Ciclosporin is an inhibitor of CYP3A4, the multidrug efflux transporter P-glycoprotein (P-gp) and organic anion transporter proteins (OATP). Co-administration of drugs that are substrates of CYP3A4, P-gp and OATP with ciclosporin may increase plasma levels of co-medications that are substrates of this enzyme and/or transporter.
Some examples are listed below:
Ciclosporin may reduce the clearance of digoxin, colchicine, HMG-CoA reductase inhibitors (statins) and etoposide. If any of these drugs are used concurrently with ciclosporin, close clinical observation is required in order to enable early detection of toxic manifestations of the medicinal products, followed by reduction of its dosage or its withdrawal. When concurrently administered with ciclosporin, the dosage of the statins should be reduced and concomitant use of certain statins should be avoided according to their label recommendations. Exposure changes of commonly used statins with ciclosporin are summarised in Table 1. 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.
Table 1 Summary of exposure changes of commonly used statins with ciclosporin

Statin	Doses available	Fold change in exposure with ciclosporin
Atorvastatin	10-80 mg	8-10
Simvastatin	10-80 mg	6-8
Fluvastatin	20-80 mg	2-4
Lovastatin	20-40 mg	5-8
Pravastatin	20-80 mg	5-10
Rosuvastatin	5-40 mg	5-10
Pitavastatin	1-4 mg	4-6

Caution is recommended when co-administering ciclosporin with lercanidipine (see section 4.4).
Following concomitant administration of ciclosporin and aliskiren, a P-gp substrate, the Cmax of aliskiren was increased approximately 2.5-fold and the AUC approximately 5-fold. However, the pharmacokinetic profile of ciclosporin was not significantly altered. Co-administration of ciclosporin and aliskiren is not recommended (see section 4.3).
Concomitant administration of dabigatran extexilate is not recommended due to the P-gp inhibitory activity of ciclosporin (see section 4.3).
The concurrent administration of nifedipine with ciclosporin may result in an increased rate of gingival hyperplasia compared with that observed when ciclosporin is given alone.
The concomitant use of diclofenac and ciclosporin has been found to result in a significant increase in the bioavailability of diclofenac, with the possible consequence of reversible renal function impairment. The increase in the bioavailability of diclofenac is most probably caused by a reduction of its high first-pass effect. If NSAIDs with a low first-pass effect (e.g. acetylsalicylic acid) are given together with ciclosporin, no increase in their bioavailability is to be expected.
Elevations in serum creatinine were observed in the studies using everolimus or sirolimus in combination with full-dose ciclosporin for microemulsion. This effect is often reversible with ciclosporin dose reduction. Everolimus and sirolimus had only a minor influence on ciclosporin pharmacokinetics. Co-administration of ciclosporin significantly increases blood levels of everolimus and sirolimus.
Caution is required with concomitant use of potassium-sparing medicinal products (e.g. potassium-sparing diuretics, ACE inhibitors, angiotensin II receptor antagonists) or potassium-containing medicinal products since they may lead to significant increases in serum potassium (see section 4.4).
Ciclosporin may increase the plasma concentrations of repaglinide and thereby increase the risk of hypoglycaemia.
Co-administration of bosentan and ciclosporin in healthy volunteers increases the bosentan exposure several-fold and there was a 35% decrease in ciclosporin exposure. Co-administration of ciclosporin with bosentan is not recommended (see above subsection “Drugs that decrease ciclosporin levels” and section 4.3).
Multiple dose administration of ambrisentan and ciclosporin in healthy volunteers resulted in an approximately 2-fold increase in ambrisentan exposure, while the ciclosporin exposure was marginally increased (approximately 10%).
A significantly increased exposure to anthracycline antibiotics (e.g. doxorubicine, mitoxanthrone, daunorubicine) was observed in oncology patients with the intravenous co-administration of anthracycline antibiotics and very high doses of ciclosporin.
During treatment with ciclosporin, vaccination may be less effective and the use of live attenuated vaccines should be avoided.
Paediatric population
Interaction studies have only been performed in adults.
4.6 Fertility, pregnancy and lactation
Pregnancy
Animal studies have shown reproductive toxicity in rats and rabbits.
Experience with Sandimmun in pregnant women is limited. Pregnant women receiving immunosuppressive therapies after transplantation, including ciclosporin and ciclosporin-containing regimens, are at risk of premature delivery (<37 weeks).
A limited number of observations in children exposed to ciclosporin in utero are available, up to an age of approximately 7 years. Renal function and blood pressure in these children were normal. However, there are no adequate and well-controlled studies in pregnant women and therefore Sandimmun should not be used during pregnancy unless the potential benefit to the mother justifies the potential risk to the foetus. The ethanol content of the Sandimmun formulations should also be taken into account in pregnant women (see section 4.4).
Breast-feeding
Ciclosporin passes into breast milk. The ethanol content of the Sandimmun formulations should also be taken into account in women who are breast-feeding (see section 4.4). Mothers receiving treatment with Sandimmun should not breast-feed because of the potential of Sandimmun to cause serious adverse drug reactions in breast-fed newborns/infants. A decision should be made whether to abstain from breast-feeding or to abstain from using the medicinal drug, taking into account the importance of the medicinal product to the mother.
Fertility
There is limited data on the effect of Sandimmun on human fertility (see section 5.3).
4.7 Effects on ability to drive and use machines
No data exist on the effects of Sandimmun on the ability to drive and use machines.
4.8 Undesirable effects
Summary of the safety profile
The principal adverse reactions observed in clinical trials and associated with the administration of ciclosporin include renal dysfunction, tremor, hirsutism, hypertension, diarrhoea, anorexia, nausea and vomiting.
Many side effects associated with ciclosporin therapy are dose-dependent and responsive to dose reduction. In the various indications the overall spectrum of side effects is essentially the same; there are, however, differences in incidence and severity. As a consequence of the higher initial doses and longer maintenance therapy required after transplantation, side effects are more frequent and usually more severe in transplant patients than in patients treated for other indications.
Anaphylactoid reactions have been observed following intravenous administration (see section 4.4).
Infections and infestations
Patients receiving immunosuppressive therapies, including ciclosporin and ciclosporin-containing regimens, are at increased risk of infections (viral, bacterial, fungal, parasitic) (see section 4.4). Both generalised and localised infections can occur. Pre-existing infections may also be aggravated and reactivation of polyomavirus infections may lead to polyomavirus-associated nephropathy (PVAN) or to JC virus associated progressive multifocal leukopathy (PML). Serious and/or fatal outcomes have been reported.
Neoplasms benign, malignant and unspecified (including cysts and polyps)
Patients receiving immunosuppressive therapies, including ciclosporin and ciclosporin containing regimens, are at increased risk of developing lymphomas or lymphoproliferative disorders and other malignancies, particularly of the skin. The frequency of malignancies increases with the intensity and duration of therapy (see section 4.4). Some malignancies may be fatal.
Tabulated summary of adverse drug reactions from clinical trials
Adverse drug reactions from clinical trials (Table 1) are listed by MedDRA system organ class. Within each system organ class, the adverse drug reactions are ranked by frequency, with the most frequent reactions first. Within each frequency grouping, adverse drug reactions are presented in order of decreasing seriousness. In addition the corresponding frequency category for each adverse drug reaction is based on the following convention (CIOMS III): very common (≥1/10); common (≥1/100, <1/10); uncommon (≥1/1,000, <1/100); rare (≥1/10,000, <1/1,000) very rare (<1/10,000), not known (cannot be estimated from the available data).
Table 1: Adverse drug reactions from clinical trials
Blood and lymphatic system disorders
Common  Leucopenia 
Uncommon  Thrombocytopenia, anaemia
Rare  Haemolytic uraemic syndrome, microangiopathic haemolytic anaemia
Not known*  Thrombotic microangiopathy, thrombotic thrombocytopenic purpura
Metabolism and nutrition disorders
Very common  Hyperlipidaemia
Common  Hyperglycaemia, anorexia, hyperuricaemia, hyperkalaemia, hypomagnesaemia
Nervous system disorders
Very common  Tremor, headache
Common  Convulsions, paraesthesia
Uncommon  Encephalopathy including Posterior Reversible Encephalopathy Syndrome (PRES), signs and symptoms such as convulsions, confusion, disorientation, decreased responsiveness, agitation, insomnia, visual disturbances, cortical blindness, coma, paresis and cerebellar ataxia
Rare  Motor polyneuropathy
Very rare  Optic disc oedema, including papilloedema, with possible visual impairment secondary to benign intracranial hypertension
Not known*  Migraine
Vascular disorders
Very common  Hypertension
Common  Flushing
Gastrointestinal disorders
Common  Nausea, vomiting, abdominal discomfort/pain, diarrhoea, gingival hyperplasia, peptic ulcer
Rare  Pancreatitis
Hepatobiliary disorders
Common  Hepatic function abnormal (see section 4.4)
Not known*  Hepatotoxicity and liver injury including cholestasis, jaundice, hepatitis and liver failure with some fatal outcome (see section 4.4)
Skin and subcutaneous tissue disorders
Very common  Hirsutism
Common  Acne, hypertrichosis
Uncommon  Allergic rashes
Musculoskeletal and connective tissue disorders
Common  Myalgia, muscle cramps
Rare  Muscle weakness, myopathy
Not known*  Pain of lower extremities
Renal and urinary disorders
Very common  Renal dysfunction (see section 4.4)
Reproductive system and breast disorders
Rare  Menstrual disturbances, gynaecomastia
General disorders and administration site conditions
Common  Pyrexia, fatigue
Uncommon  Oedema, weight increase
Adverse events reported from post marketing experience where the ADR frequency is not known due to the lack of a real denominator.
Other adverse drug reactions from post-marketing experience
There have been solicited and spontaneous reports of hepatotoxicity and liver injury including cholestasis, jaundice hepatitis and liver failure in patients treated with ciclosporin. Most reports included patients with significant co-morbidities, underlying conditions and other confounding factors including infectious complications and co-medications with hepatotoxic potential. In some cases, mainly in transplant patients, fatal outcomes have been reported (see section 4.4).
Acute and chronic nephrotoxicity
Patients receiving calcineurin inhibitor (CNI) therapies, including ciclosporin and ciclosporin-containing regimens, are at increased risk of acute or chronic nephrotoxicity. There have been reports from clinical trials and from the post-marketing setting associated with the use of Sandimmun. Cases of acute nephrotoxicity reported disorders of ion homeostasis, such as hyperkalaemia, hypomagnesaemia, and hyperuricaemia. Cases reporting chronic morphological changes included arteriolar hyalinosis, tubular atrophy and interstitial fibrosis (see section 4.4).
Pain of lower extremities
Isolated cases of pain of lower extremities have been reported in association with ciclosporin. Pain of lower extremities has also been noted as part of Calcineurin-Inhibitor Induced Pain Syndrome (CIPS).
Paediatric population
Clinical studies have included children from 1 year of age using standard ciclosporin dosage with a comparable safety profile to adults.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorization of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via Yellow Card Scheme (www.mhra.gov.uk/yellowcard).
4.9 Overdose
The oral LD50 of ciclosporin is 2,329 mg/kg in mice, 1,480 mg/kg in rats and > 1,000 mg/kg in rabbits. The intravenous LD50 is 148 mg/kg in mice, 104 mg/kg in rats, and 46 mg/kg in rabbits.
Symptoms
Experience with acute overdosage of ciclosporin is limited. Oral doses of ciclosporin of 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 ciclosporin in premature neonates.
Treatment
In all cases of overdosage, general supportive measures should be followed and symptomatic treatment applied. Forced emesis and gastric lavage may be of value within the first few hours after oral intake. Ciclosporin is not dialysable to any great extent, nor is it well cleared by charcoal haemoperfusion.
5. Pharmacological properties
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Immunosuppressive agents, calcineurin inhibitors, ATC code: L04AD01
Ciclosporin (also known as ciclosporin A) is a cyclic polypeptide consisting of 11 amino acids. It is a potent immunosuppressive agent, which in animals prolongs survival of allogeneic transplants of skin, heart, kidney, pancreas, bone marrow, small intestine or lung. Studies suggest that ciclosporin inhibits the development of cell-mediated reactions, including allograft immunity, delayed cutaneous hypersensitivity, experimental allergic encephalomyelitis, Freund's adjuvant arthritis, graft-versus-host disease (GVHD), and also T-cell dependent antibody production. At the cellular level it inhibits production and release of lymphokines including interleukin 2 (T-cell growth factor, TCGF). Ciclosporin appears to block the resting lymphocytes in the G0 or G1 phase of the cell cycle, and inhibits the antigen-triggered release of lymphokines by activated T-cells.
All available evidence suggests that ciclosporin acts specifically and reversibly on lymphocytes. Unlike cytostatic agents, it does not depress haemopoiesis and has no effect on the function of phagocytic cells.
Successful solid organ and bone marrow transplantations have been performed in man using ciclosporin to prevent and treat rejection and GVHD. Ciclosporin has been used successfully both in hepatitis C virus (HCV) positive and HCV negative liver transplants recipients. Beneficial effects of ciclosporin therapy have also been shown in a variety of conditions that are known, or may be considered to be of autoimmune origin.
Paediatric population: Ciclosporin has been shown to be efficacious in steroid-dependent nephrotic syndrome.
5.2 Pharmacokinetic properties
Distribution
Ciclosporin is distributed largely outside the blood volume, with an average apparent distribution volume of 3.5 l/kg. In the blood, 33 to 47% is present in plasma, 4 to 9% in lymphocytes, 5 to 12% in granulocytes, and 41 to 58% in erythrocytes. In plasma, approximately 90% is bound to proteins, mostly lipoproteins.
Biotransformation
Ciclosporin is extensively metabolised to approximately 15 metabolites. Metabolism mainly takes place in the liver via cytochrome P450 3A4 (CYP3A4), and the main pathways of metabolism consist of mono- and dihydroxylation and N-demethylation at various positions of the molecule. All metabolites identified so far contain the intact peptide structure of the parent compound; some possess weak immunosuppressive activity (up to one-tenth that of the unchanged drug).
Elimination
There is a high variability in the data reported on the terminal half-life of ciclosporin depending on the assay applied and on the target population. The terminal half-life ranged from 6.3 hours in healthy volunteers to 20.4 hours in patients with severe liver disease. Excretion is primarily biliary, with only 6% of an oral dose excreted in the urine, and with less than 1% in the unchanged form (see sections 4.2 and 4.4). The elimination half-life in kidney-transplanted patients was approximately 11 hours, with a range between 4 and 25 hours.
Special populations
Patients with renal impairment
In a study performed in patients with terminal renal failure, the systemic clearance was approximately two thirds of the mean systemic clearance in patients with normally functioning kidneys. Less than 1% of the administered dose is removed by dialysis.
Patients with hepatic impairment
An approximate 2- to 3-fold increase in ciclosporin exposure may be observed in patients with hepatic impairment. In a study performed in severe liver disease patients with biopsy-proven cirrhosis, the terminal half-life was 20.4 hours (range between 10.8 to 48.0 hours) compared to 7.4 to 11.0 hours in healthy subjects.
Paediatric population
Pharmacokinetic data from paediatric patients given Sandimmun Neoral or Sandimmun are very limited. In 15 renal transplant patients aged 3 -16 years, ciclosporin whole blood clearance after intravenous administration of Sandimmun was 10.6±3.7 ml/min/kg (assay: Cyclo-trac specific RIA). In a study of 7 renal transplant patients aged 2-16 years, the ciclosporin clearance ranged from 9.8 to15.5 ml/min/kg. In 9 liver transplant patients aged 0.65-6 years, clearance was 9.3±5.4 ml/min/kg (assay: HPLC). In comparison to adult transplant populations, the differences in bioavailability between Sandimmun Neoral and Sandimmun in paediatrics are comparable to those observed in adults.
5.3 Preclinical safety data
Ciclosporin gave no evidence of mutagenic or teratogenic effects in the standard test systems with oral application (rats up to 17 mg/kg/day and rabbits up to 30 mg/kg/day orally). At toxic doses (rats at 30 mg/kg/day and rabbits at 100 mg/kg/day orally), ciclosporin was embryo- and foetotoxic as indicated by increased prenatal and postnatal mortality, and reduced foetal weight together with related skeletal retardations.
In two published research studies, rabbits exposed to ciclosporin 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 ciclosporin intravenously (twice the recommended human intravenous dose) had foetuses with an increased incidence of ventricular septal defect. These findings have not been demonstrated in other species and their relevance for humans is unknown. No impairment in fertility was demonstrated in studies in male and female rats.
Ciclosporin was tested in a number of in vitro and in vivo tests for genotoxicity with no evidence for a clincally relevant mutagenic potential.
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 lymphocytic lymphomas 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 at the low dose level. The hepatocellular carcinomas and pancreatic islet cell adenomas were not dose related.
6. Pharmaceutical particulars
6.1 List of excipients
Ethanol anhydrous
Macrogolglycerol ricinoleate/ polyoxyl 35 castor oil
6.2 Incompatibilities
Sandimmun concentrate for solution for infusion contains macrogolglycerol ricinoleate/polyoxyl 35 castor oil, which can cause phathalate stripping from polyvinyl chloride. If available, glass containers should be used for infusion. Plastic bottles should be used only if they conform to the requirements for “Sterile plastic containers for human blood and blood components” or “Empty sterile containers of plasticised polyvinyl chloride for human blood and blood components” of the current European Pharmacopoeia. Containers and stoppers should be free of silicone oil and fatty substances.
6.3 Shelf life
4 years
6.4 Special precautions for storage
This medicinal product does not require any special temperature storage conditions. Store in the original package. Once an ampoule has been opened, the contents should be used immediately. Following dilution, the solution should be used immediately. If it is not used immediately, the conditions and duration of storage are the responsibility of the user and storage should not be longer than 24 hours at 2 to 8°C, unless dilution has been carried out under controlled and validated aseptic conditions.
6.5 Nature and contents of container
Sandimmun Concentrate for Solution for Infusion is available in 1ml and 5ml uncoloured glass (type I) ampoules.
6.6 Special precautions for disposal and other handling
The concentrate should be diluted 1:20 to 1:100 with normal saline or 5% glucose, and given as a slow intravenous infusion over approximately 2 to 6 hours. Diluted infusion solutions must be discarded after 24 hours.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
7. Marketing authorisation holder
Novartis Pharmaceuticals UK Limited
Trading as SANDOZ PHARMACEUTICALS
Frimley Business Park
Frimley
Camberley
Surrey
GU16 7SR
8. Marketing authorisation number(s)
00101/0153
9. Date of first authorisation/renewal of the authorisation
17 February 1983 / 17 February 1998.
10. Date of revision of the text
24 July 2015